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1.  Both the Caspase CSP-1 and a Caspase-Independent Pathway Promote Programmed Cell Death in Parallel to the Canonical Pathway for Apoptosis in Caenorhabditis elegans 
PLoS Genetics  2013;9(3):e1003341.
Caspases are cysteine proteases that can drive apoptosis in metazoans and have critical functions in the elimination of cells during development, the maintenance of tissue homeostasis, and responses to cellular damage. Although a growing body of research suggests that programmed cell death can occur in the absence of caspases, mammalian studies of caspase-independent apoptosis are confounded by the existence of at least seven caspase homologs that can function redundantly to promote cell death. Caspase-independent programmed cell death is also thought to occur in the invertebrate nematode Caenorhabditis elegans. The C. elegans genome contains four caspase genes (ced-3, csp-1, csp-2, and csp-3), of which only ced-3 has been demonstrated to promote apoptosis. Here, we show that CSP-1 is a pro-apoptotic caspase that promotes programmed cell death in a subset of cells fated to die during C. elegans embryogenesis. csp-1 is expressed robustly in late pachytene nuclei of the germline and is required maternally for its role in embryonic programmed cell deaths. Unlike CED-3, CSP-1 is not regulated by the APAF-1 homolog CED-4 or the BCL-2 homolog CED-9, revealing that csp-1 functions independently of the canonical genetic pathway for apoptosis. Previously we demonstrated that embryos lacking all four caspases can eliminate cells through an extrusion mechanism and that these cells are apoptotic. Extruded cells differ from cells that normally undergo programmed cell death not only by being extruded but also by not being engulfed by neighboring cells. In this study, we identify in csp-3; csp-1; csp-2 ced-3 quadruple mutants apoptotic cell corpses that fully resemble wild-type cell corpses: these caspase-deficient cell corpses are morphologically apoptotic, are not extruded, and are internalized by engulfing cells. We conclude that both caspase-dependent and caspase-independent pathways promote apoptotic programmed cell death and the phagocytosis of cell corpses in parallel to the canonical apoptosis pathway involving CED-3 activation.
Author Summary
Caspases are cysteine proteases that in many cases drive apoptosis, an evolutionarily conserved and highly stereotyped form of cellular suicide with functions in animal development and tissue maintenance. The dysregulation of apoptosis can contribute to diseases as diverse as cancer, autoimmunity, and neurodegeneration. Caspases are often thought to be required for, or even to define, apoptosis. Although there is evidence that apoptosis can occur in the absence of caspase activity, caspase-independence can be difficult to prove, as most animals have multiple caspases. The nematode Caenorhabditis elegans has four caspases, CED-3, CSP-1, CSP-2, and CSP-3. CED-3 has a well-established role in apoptosis, but less is known about the functions of the CSP caspases. In this study, we show that CSP-1 promotes apoptosis in the developing C. elegans embryo and that CSP-1 is regulated differently than its homolog CED-3. Furthermore, we show that apoptosis and the engulfment of dying cells can occur in mutants lacking all four caspases, proving that neither apoptosis nor cell-corpse engulfment require caspase function and that caspase-independent activities can contribute to apoptosis of some cells during animal development.
doi:10.1371/journal.pgen.1003341
PMCID: PMC3591282  PMID: 23505386
2.  Caspase-2 Maintains Bone Homeostasis by Inducing Apoptosis of Oxidatively-Damaged Osteoclasts 
PLoS ONE  2014;9(4):e93696.
Osteoporosis is a silent disease, characterized by a porous bone micro-structure that enhances risk for fractures and associated disabilities. Senile, or age-related osteoporosis (SO), affects both men and women, resulting in increased morbidity and mortality. However, cellular and molecular mechanisms underlying senile osteoporosis are not fully known. Recent studies implicate the accumulation of reactive oxygen species (ROS) and increased oxidative stress as key factors in SO. Herein, we show that loss of caspase-2, a cysteine aspartate protease involved in oxidative stress-induced apoptosis, results in total body and femoral bone loss in aged mice (20% decrease in bone mineral density), and an increase in bone fragility (30% decrease in fracture strength). Importantly, we demonstrate that genetic ablation or selective inhibition of caspase-2 using zVDVAD-fmk results in increased numbers of bone-resorbing osteoclasts and enhanced tartrate-resistant acid phosphatase (TRAP) activity. Conversely, transfection of osteoclast precursors with wild type caspase-2 but not an enzymatic mutant, results in a decrease in TRAP activity. We demonstrate that caspase-2 expression is induced in osteoclasts treated with oxidants such as hydrogen peroxide and that loss of caspase-2 enhances resistance to oxidants, as measured by TRAP activity, and decreases oxidative stress-induced apoptosis of osteoclasts. Moreover, oxidative stress, quantified by assessment of the lipid peroxidation marker, 4-HNE, is increased in Casp2-/- bone, perhaps due to a decrease in antioxidant enzymes such as SOD2. Taken together, our data point to a critical and novel role for caspase-2 in maintaining bone homeostasis by modulating ROS levels and osteoclast apoptosis during conditions of enhanced oxidative stress that occur during aging.
doi:10.1371/journal.pone.0093696
PMCID: PMC3972236  PMID: 24691516
3.  Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015) 
Shay, Jerry W. | Homma, Noriko | Zhou, Ruyun | Naseer, Muhammad Imran | Chaudhary, Adeel G. | Al-Qahtani, Mohammed | Hirokawa, Nobutaka | Goudarzi, Maryam | Fornace, Albert J. | Baeesa, Saleh | Hussain, Deema | Bangash, Mohammed | Alghamdi, Fahad | Schulten, Hans-Juergen | Carracedo, Angel | Khan, Ishaq | Qashqari, Hanadi | Madkhali, Nawal | Saka, Mohamad | Saini, Kulvinder S. | Jamal, Awatif | Al-Maghrabi, Jaudah | Abuzenadah, Adel | Chaudhary, Adeel | Al Qahtani, Mohammed | Damanhouri, Ghazi | Alkhatabi, Heba | Goodeve, Anne | Crookes, Laura | Niksic, Nikolas | Beauchamp, Nicholas | Abuzenadah, Adel M. | Vaught, Jim | Budowle, Bruce | Assidi, Mourad | Buhmeida, Abdelbaset | Al-Maghrabi, Jaudah | Buhmeida, Abdelbaset | Assidi, Mourad | Merdad, Leena | Kumar, Sudhir | Miura, Sayaka | Gomez, Karen | Carracedo, Angel | Rasool, Mahmood | Rebai, Ahmed | Karim, Sajjad | Eldin, Hend F. Nour | Abusamra, Heba | Alhathli, Elham M. | Salem, Nada | Al-Qahtani, Mohammed H. | Kumar, Sudhir | Faheem, Hossam | Agarwa, Ashok | Nieschlag, Eberhard | Wistuba, Joachim | Damm, Oliver S. | Beg, Mohd A. | Abdel-Meguid, Taha A. | Mosli, Hisham A. | Bajouh, Osama S. | Abuzenadah, Adel M. | Al-Qahtani, Mohammed H. | Coskun, Serdar | Abu-Elmagd, Muhammad | Buhmeida, Abdelbaset | Dallol, Ashraf | Al-Maghrabi, Jaudah | Hakamy, Sahar | Al-Qahtani, Wejdan | Al-Harbi, Asia | Hussain, Shireen | Assidi, Mourad | Al-Qahtani, Mohammed | Abuzenadah, Adel | Ozkosem, Burak | DuBois, Rick | Messaoudi, Safia S. | Dandana, Maryam T. | Mahjoub, Touhami | Almawi, Wassim Y. | Abdalla, S. | Al-Aama, M. Nabil | Elzawahry, Asmaa | Takahashi, Tsuyoshi | Mimaki, Sachiyo | Furukawa, Eisaku | Nakatsuka, Rie | Kurosaka, Isao | Nishigaki, Takahiko | Nakamura, Hiromi | Serada, Satoshi | Naka, Tetsuji | Hirota, Seiichi | Shibata, Tatsuhiro | Tsuchihara, Katsuya | Nishida, Toshirou | Kato, Mamoru | Mehmood, Sajid | Ashraf, Naeem Mahmood | Asif, Awais | Bilal, Muhammad | Mehmood, Malik Siddique | Hussain, Aadil | Jamal, Qazi Mohammad Sajid | Siddiqui, Mughees Uddin | Alzohairy, Mohammad A. | Al Karaawi, Mohammad A. | Nedjadi, Taoufik | Al-Maghrabi, Jaudah | Assidi, Mourad | Al-Khattabi, Heba | Al-Ammari, Adel | Al-Sayyad, Ahmed | Buhmeida, Abdelbaset | Al-Qahtani, Mohammed | Zitouni, Hédia | Raguema, Nozha | Ali, Marwa Ben | Malah, Wided | Lfalah, Raja | Almawi, Wassim | Mahjoub, Touhami | Elanbari, Mohammed | Ptitsyn, Andrey | Mahjoub, Sana | El Ghali, Rabeb | Achour, Bechir | Amor, Nidhal Ben | Assidi, Mourad | N’siri, Brahim | Morjani, Hamid | Nedjadi, Taoufik | Al-Ammari, Adel | Al-Sayyad, Ahmed | Salem, Nada | Azhar, Esam | Al-Maghrabi, Jaudah | Chayeb, Vera | Dendena, Maryam | Zitouni, Hedia | Zouari-Limayem, Khedija | Mahjoub, Touhami | Refaat, Bassem | Ashshi, Ahmed M. | Batwa, Sarah A. | Ramadan, Hazem | Awad, Amal | Ateya, Ahmed | El-Shemi, Adel Galal Ahmed | Ashshi, Ahmad | Basalamah, Mohammed | Na, Youjin | Yun, Chae-Ok | El-Shemi, Adel Galal Ahmed | Ashshi, Ahmad | Basalamah, Mohammed | Na, Youjin | Yun, Chae-Ok | El-Shemi, Adel Galal | Refaat, Bassem | Kensara, Osama | Abdelfattah, Amr | Dheeb, Batol Imran | Al-Halbosiy, Mohammed M. F. | Al lihabi, Rghad Kadhim | Khashman, Basim Mohammed | Laiche, Djouhri | Adeel, Chaudhary | Taoufik, Nedjadi | Al-Afghani, Hani | Łastowska, Maria | Al-Balool, Haya H. | Sheth, Harsh | Mercer, Emma | Coxhead, Jonathan M. | Redfern, Chris P. F. | Peters, Heiko | Burt, Alastair D. | Santibanez-Koref, Mauro | Bacon, Chris M. | Chesler, Louis | Rust, Alistair G. | Adams, David J. | Williamson, Daniel | Clifford, Steven C. | Jackson, Michael S. | Singh, Mala | Mansuri, Mohmmad Shoab | Jadeja, Shahnawaz D. | Patel, Hima | Marfatia, Yogesh S. | Begum, Rasheedunnisa | Mohamed, Amal M. | Kamel, Alaa K. | Helmy, Nivin A. | Hammad, Sayda A. | Kayed, Hesham F. | Shehab, Marwa I. | El Gerzawy, Assad | Ead, Maha M. | Ead, Ola M. | Mekkawy, Mona | Mazen, Innas | El-Ruby, Mona | Shahid, S. M. A. | Jamal, Qazi Mohammad Sajid | Arif, J. M. | Lohani, Mohtashim | Imen, Moumni | Leila, Chaouch | Houyem, Ouragini | Kais, Douzi | Fethi, Chaouachi Dorra Mellouli | Mohamed, Bejaoui | Salem, Abbes | Faggad, Areeg | Gebreslasie, Amanuel T. | Zaki, Hani Y. | Abdalla, Badreldin E. | AlShammari, Maha S. | Al-Ali, Rhaya | Al-Balawi, Nader | Al-Enazi, Mansour | Al-Muraikhi, Ali | Busaleh, Fadi | Al-Sahwan, Ali | Borgio, Francis | Sayyed, Abdulazeez | Al-Ali, Amein | Acharya, Sadananda | Zaki, Maha S. | El-Bassyouni, Hala T. | Shehab, Marwa I. | Elshal, Mohammed F. | M., Kaleemuddin | Aldahlawi, Alia M. | Saadah, Omar | McCoy, J. Philip | El-Tarras, Adel E. | Awad, Nabil S. | Alharthi, Abdulla A. | Ibrahim, Mohamed M. M. | Alsehli, Haneen S. | Dallol, Ashraf | Gari, Abdullah M. | Abbas, Mohammed M. | Kadam, Roaa A. | Gari, Mazen M. | Alkaff, Mohmmed H. | Abuzenadah, Adel M. | Gari, Mamdooh A. | Abusamra, Heba | Karim, Sajjad | eldin, Hend F. Nour | Alhathli, Elham M. | Salem, Nada | Kumar, Sudhir | Al-Qahtani, Mohammed H. | Moradi, Fatima A. | Rashidi, Omran M. | Awan, Zuhier A. | Kaya, Ibrahim Hamza | Al-Harazi, Olfat | Colak, Dilek | Alkousi, Nabila A. | Athanasopoulos, Takis | Bahmaid, Afnan O. | Alhwait, Etimad A. | Gari, Mamdooh A. | Alsehli, Haneen S. | Abbas, Mohammed M. | Alkaf, Mohammed H. | Kadam, Roaa | Dallol, Ashraf | Kalamegam, Gauthaman | Eldin, Hend F. Nour | Karim, Sajjad | Abusamra, Heba | Alhathli, Elham | Salem, Nada | Al-Qahtani, Mohammed H. | Kumar, Sudhir | Alsayed, Salma N. | Aljohani, Fawziah H. | Habeeb, Samaher M. | Almashali, Rawan A. | Basit, Sulman | Ahmed, Samia M. | Sharma, Rakesh | Agarwal, Ashok | Durairajanayagam, Damayanthi | Samanta, Luna | Abu-Elmagd, Muhammad | Abuzenadah, Adel M. | Sabanegh, Edmund S. | Assidi, Mourad | Al-Qahtani, Mohammed | Agarwal, Ashok | Sharma, Rakesh | Samanta, Luna | Durairajanayagam, Damayanthi | Assidi, Mourad | Abu-Elmagd, Muhammad | Al-Qahtani, Mohammed | Abuzenadah, Adel M. | Sabanegh, Edmund S. | Samanta, Luna | Agarwal, Ashok | Sharma, Rakesh | Cui, Zhihong | Assidi, Mourad | Abuzenadah, Adel M. | Abu-Elmagd, Muhammad | Al-Qahtani, Mohammed | Alboogmi, Alaa A. | Alansari, Nuha A. | Al-Quaiti, Maha M. | Ashgan, Fai T. | Bandah, Afnan | Jamal, Hasan S. | Rozi, Abdullraheem | Mirza, Zeenat | Abuzenadah, Adel M. | Karim, Sajjad | Al-Qahtani, Mohammed H. | Karim, Sajjad | Schulten, Hans-Juergen | Al Sayyad, Ahmad J. | Farsi, Hasan M. A. | Al-Maghrabi, Jaudah A. | Mirza, Zeenat | Alotibi, Reem | Al-Ahmadi, Alaa | Alansari, Nuha A. | Albogmi, Alaa A. | Al-Quaiti, Maha M. | Ashgan, Fai T. | Bandah, Afnan | Al-Qahtani, Mohammed H. | Ebiya, Rasha A. | Darwish, Samia M. | Montaser, Metwally M. | Abusamra, Heba | Bajic, Vladimir B. | Al-Maghrabi, Jaudah | Gomaa, Wafaey | Hanbazazh, Mehenaz | Al-Ahwal, Mahmoud | Al-Harbi, Asia | Al-Qahtani, Wejdan | Hakamy, Saher | Baba, Ghali | Buhmeida, Abdelbaset | Al-Qahtani, Mohammed | Al-Maghrabi, Jaudah | Al-Harbi, Abdullah | Al-Ahwal, Mahmoud | Al-Harbi, Asia | Al-Qahtani, Wejdan | Hakamy, Sahar | Baba, Ghalia | Buhmeida, Abdelbaset | Al-Qahtani, Mohammed | Alhathli, Elham M. | Karim, Sajjad | Salem, Nada | Eldin, Hend Nour | Abusamra, Heba | Kumar, Sudhir | Al-Qahtani, Mohammed H. | Alyamani, Aisha A. | Kalamegam, Gauthaman | Alhwait, Etimad A. | Gari, Mamdooh A. | Abbas, Mohammed M. | Alkaf, Mohammed H. | Alsehli, Haneen S. | Kadam, Roaa A. | Al-Qahtani, Mohammed | Gadi, Rawan | Buhmeida, Abdelbaset | Assidi, Mourad | Chaudhary, Adeel | Merdad, Leena | Alfakeeh, Saadiah M. | Alhwait, Etimad A. | Gari, Mamdooh A. | Abbas, Mohammed M. | Alkaf, Mohammed H. | Alsehli, Haneen S. | Kadam, Roaa | Kalamegam, Gauthaman | Ghazala, Rubi | Mathew, Shilu | Hamed, M. Haroon | Assidi, Mourad | Al-Qahtani, Mohammed | Qadri, Ishtiaq | Mathew, Shilu | Mira, Lobna | Shaabad, Manal | Hussain, Shireen | Assidi, Mourad | Abu-Elmagd, Muhammad | Al-Qahtani, Mohammed | Mathew, Shilu | Shaabad, Manal | Mira, Lobna | Hussain, Shireen | Assidi, Mourad | Abu-Elmagd, Muhammad | Al-Qahtani, Mohammed | Rebai, Ahmed | Assidi, Mourad | Buhmeida, Abdelbaset | Abu-Elmagd, Muhammad | Dallol, Ashraf | Shay, Jerry W. | Almutairi, Mikhlid H. | Ambers, Angie | Churchill, Jennifer | King, Jonathan | Stoljarova, Monika | Gill-King, Harrell | Assidi, Mourad | Abu-Elmagd, Muhammad | Buhmeida, Abdelbaset | Al-Qatani, Muhammad | Budowle, Bruce | Abu-Elmagd, Muhammad | Ahmed, Farid | Dallol, Ashraf | Assidi, Mourad | Almagd, Taha Abo | Hakamy, Sahar | Agarwal, Ashok | Al-Qahtani, Muhammad | Abuzenadah, Adel | Karim, Sajjad | Schulten, Hans-Juergen | Al Sayyad, Ahmad J. | Farsi, Hasan M. A. | Al-Maghrabi, Jaudah A. | Buhmaida, Abdelbaset | Mirza, Zeenat | Alotibi, Reem | Al-Ahmadi, Alaa | Alansari, Nuha A. | Albogmi, Alaa A. | Al-Quaiti, Maha M. | Ashgan, Fai T. | Bandah, Afnan | Al-Qahtani, Mohammed H. | Satar, Rukhsana | Rasool, Mahmood | Ahmad, Waseem | Nazam, Nazia | Lone, Mohamad I. | Naseer, Muhammad I. | Jamal, Mohammad S. | Zaidi, Syed K. | Pushparaj, Peter N. | Jafri, Mohammad A. | Ansari, Shakeel A. | Alqahtani, Mohammed H. | Bashier, Hanan | Al Qahtani, Abrar | Mathew, Shilu | Nour, Amal M. | Alkhatabi, Heba | Zenadah, Adel M. Abu | Buhmeida, Abdelbaset | Assidi, Mourad | Al Qahtani, Muhammed | Faheem, Muhammad | Mathew, Shilu | Mathew, Shiny | Pushparaj, Peter Natesan | Al-Qahtani, Mohammad H. | Alhadrami, Hani A. | Dallol, Ashraf | Abuzenadah, Adel | Hussein, Ibtessam R. | Chaudhary, Adeel G. | Bader, Rima S. | Bassiouni, Randa | Alquaiti, Maha | Ashgan, Fai | Schulten, Hans | Alama, Mohamed Nabil | Al Qahtani, Mohammad H. | Lone, Mohammad I. | Nizam, Nazia | Ahmad, Waseem | Jafri, Mohammad A. | Rasool, Mahmood | Ansari, Shakeel A. | Al-Qahtani, Muhammed H. | Alshihri, Eradah | Abu-Elmagd, Muhammad | Alharbi, Lina | Assidi, Mourad | Al-Qahtani, Mohammed | Mathew, Shilu | Natesan, Peter Pushparaj | Al Qahtani, Muhammed | Kalamegam, Gauthaman | Pushparaj, Peter Natesan | Khan, Fazal | Kadam, Roaa | Ahmed, Farid | Assidi, Mourad | Sait, Khalid Hussain Wali | Anfinan, Nisreen | Al Qahtani, Mohammed | Naseer, Muhammad I. | Chaudhary, Adeel G. | Jamal, Mohammad S. | Mathew, Shilu | Mira, Lobna S. | Pushparaj, Peter N. | Ansari, Shakeel A. | Rasool, Mahmood | AlQahtani, Mohammed H. | Naseer, Muhammad I. | Chaudhary, Adeel G. | Mathew, Shilu | Mira, Lobna S. | Jamal, Mohammad S. | Sogaty, Sameera | Bassiouni, Randa I. | Rasool, Mahmood | AlQahtani, Mohammed H. | Rasool, Mahmood | Ansari, Shakeel A. | Jamal, Mohammad S. | Pushparaj, Peter N. | Sibiani, Abdulrahman M. S. | Ahmad, Waseem | Buhmeida, Abdelbaset | Jafri, Mohammad A. | Warsi, Mohiuddin K. | Naseer, Muhammad I. | Al-Qahtani, Mohammed H. | Rubi | Kumar, Kundan | Naqvi, Ahmad A. T. | Ahmad, Faizan | Hassan, Md I. | Jamal, Mohammad S. | Rasool, Mahmood | AlQahtani, Mohammed H. | Ali, Ashraf | Jarullah, Jummanah | Rasool, Mahmood | Buhmeida, Abdelbasit | Khan, Shahida | Abdussami, Ghufrana | Mahfooz, Maryam | Kamal, Mohammad A. | Damanhouri, Ghazi A. | Jamal, Mohammad S. | Jarullah, Bushra | Jarullah, Jummanah | Jarullah, Mohammad S. S. | Ali, Ashraf | Rasool, Mahmood | Jamal, Mohammad S. | Assidi, Mourad | Abu-Elmagd, Muhammad | Bajouh, Osama | Pushparaj, Peter Natesan | Al-Qahtani, Mohammed | Abuzenadah, Adel | Jamal, Mohammad S. | Jarullah, Jummanah | Mathkoor, Abdulah E. A. | Alsalmi, Hashim M. A. | Oun, Anas M. M. | Damanhauri, Ghazi A. | Rasool, Mahmood | AlQahtani, Mohammed H. | Naseer, Muhammad I. | Rasool, Mahmood | Sogaty, Sameera | Chudhary, Adeel G. | Abutalib, Yousif A. | Merico, Daniele | Walker, Susan | Marshall, Christian R. | Zarrei, Mehdi | Scherer, Stephen W. | Al-Qahtani, Mohammad H. | Naseer, Muhammad I. | Faheem, Muhammad | Chaudhary, Adeel G. | Rasool, Mahmood | Kalamegam, Gauthaman | Ashgan, Fai Talal | Assidi, Mourad | Ahmed, Farid | Zaidi, Syed Kashif | Jan, Mohammed M. | Al-Qahtani, Mohammad H. | Al-Zahrani, Maryam | Lary, Sahira | Hakamy, Sahar | Dallol, Ashraf | Al-Ahwal, Mahmoud | Al-Maghrabi, Jaudah | Dermitzakis, Emmanuel | Abuzenadah, Adel | Buhmeida, Abdelbaset | Al-Qahtani, Mohammed | Al-refai, Abeer A. | Saleh, Mona | Yassien, Rehab I. | Kamel, Mahmmoud | Habeb, Rabab M. | Filimban, Najlaa | Dallol, Ashraf | Ghannam, Nadia | Al-Qahtani, Mohammed | Abuzenadah, Adel Mohammed | Bibi, Fehmida | Akhtar, Sana | Azhar, Esam I. | Yasir, Muhammad | Nasser, Muhammad I. | Jiman-Fatani, Asif A. | Sawan, Ali | Lahzah, Ruaa A. | Ali, Asho | Hassan, Syed A. | Hasnain, Seyed E. | Tayubi, Iftikhar A. | Abujabal, Hamza A. | Magrabi, Alaa O. | Khan, Fazal | Kalamegam, Gauthaman | Pushparaj, Peter Natesan | Abuzenada, Adel | Kumosani, Taha Abduallah | Barbour, Elie | Al-Qahtani, Mohammed | Shabaad, Manal | Mathew, Shilu | Dallol, Ashraf | Merdad, Adnan | Buhmeida, Abdelbaset | Al-Qahtani, Mohammed | Assidi, Mourad | Abu-Elmagd, Muhammad | Gauthaman, Kalamegam | Gari, Mamdooh | Chaudhary, Adeel | Abuzenadah, Adel | Pushparaj, Peter Natesan | Al-Qahtani, Mohammed | Hassan, Syed A. | Tayubi, Iftikhar A. | Aljahdali, Hani M. A. | Al Nono, Reham | Gari, Mamdooh | Alsehli, Haneen | Ahmed, Farid | Abbas, Mohammed | Kalamegam, Gauthaman | Al-Qahtani, Mohammed | Mathew, Shilu | Khan, Fazal | Rasool, Mahmood | Jamal, Mohammed Sarwar | Naseer, Muhammad Imran | Mirza, Zeenat | Karim, Sajjad | Ansari, Shakeel | Assidi, Mourad | Kalamegam, Gauthaman | Gari, Mamdooh | Chaudhary, Adeel | Abuzenadah, Adel | Pushparaj, Peter Natesan | Al-Qahtani, Mohammed | Abu-Elmagd, Muhammad | Kalamegam, Gauthaman | Kadam, Roaa | Alghamdi, Mansour A. | Shamy, Magdy | Costa, Max | Khoder, Mamdouh I. | Assidi, Mourad | Pushparaj, Peter Natesan | Gari, Mamdooh | Al-Qahtani, Mohammed | Kharrat, Najla | Belmabrouk, Sabrine | Abdelhedi, Rania | Benmarzoug, Riadh | Assidi, Mourad | Al Qahtani, Mohammed H. | Rebai, Ahmed | Dhamanhouri, Ghazi | Pushparaj, Peter Natesan | Noorwali, Abdelwahab | Alwasiyah, Mohammad Khalid | Bahamaid, Afnan | Alfakeeh, Saadiah | Alyamani, Aisha | Alsehli, Haneen | Abbas, Mohammed | Gari, Mamdooh | Mobasheri, Ali | Kalamegam, Gauthaman | Al-Qahtani, Mohammed | Faheem, Muhammad | Mathew, Shilu | Pushparaj, Peter Natesan | Al-Qahtani, Mohammad H. | Mathew, Shilu | Faheem, Muhammad | Mathew, Shiny | Pushparaj, Peter Natesan | Al-Qahtani, Mohammad H. | Jamal, Mohammad Sarwar | Zaidi, Syed Kashif | Khan, Raziuddin | Bhatia, Kanchan | Al-Qahtani, Mohammed H. | Ahmad, Saif | AslamTayubi, Iftikhar | Tripathi, Manish | Hassan, Syed Asif | Shrivastava, Rahul | Tayubi, Iftikhar A. | Hassan, Syed | Abujabal, Hamza A. S. | Shah, Ishani | Jarullah, Bushra | Jamal, Mohammad S. | Jarullah, Jummanah | Sheikh, Ishfaq A. | Ahmad, Ejaz | Jamal, Mohammad S. | Rehan, Mohd | Abu-Elmagd, Muhammad | Tayubi, Iftikhar A. | AlBasri, Samera F. | Bajouh, Osama S. | Turki, Rola F. | Abuzenadah, Adel M. | Damanhouri, Ghazi A. | Beg, Mohd A. | Al-Qahtani, Mohammed | Hammoudah, Sahar A. F. | AlHarbi, Khalid M. | El-Attar, Lama M. | Darwish, Ahmed M. Z. | Ibrahim, Sara M. | Dallol, Ashraf | Choudhry, Hani | Abuzenadah, Adel | Awlia, Jalaludden | Chaudhary, Adeel | Ahmed, Farid | Al-Qahtani, Mohammed | Jafri, Mohammad A. | Abu-Elmagd, Muhammad | Assidi, Mourad | Al-Qahtani, Mohammed | khan, Imran | Yasir, Muhammad | Azhar, Esam I. | Al-basri, Sameera | Barbour, Elie | Kumosani, Taha | Khan, Fazal | Kalamegam, Gauthaman | Pushparaj, Peter Natesan | Abuzenada, Adel | Kumosani, Taha Abduallah | Barbour, Elie | EL Sayed, Heba M. | Hafez, Eman A. | Schulten, Hans-Juergen | Elaimi, Aisha Hassan | Hussein, Ibtessam R. | Bassiouni, Randa Ibrahim | Alwasiyah, Mohammad Khalid | Wintle, Richard F. | Chaudhary, Adeel | Scherer, Stephen W. | Al-Qahtani, Mohammed | Mirza, Zeenat | Pillai, Vikram Gopalakrishna | Karim, Sajjad | Sharma, Sujata | Kaur, Punit | Srinivasan, Alagiri | Singh, Tej P. | Al-Qahtani, Mohammed | Alotibi, Reem | Al-Ahmadi, Alaa | Al-Adwani, Fatima | Hussein, Deema | Karim, Sajjad | Al-Sharif, Mona | Jamal, Awatif | Al-Ghamdi, Fahad | Al-Maghrabi, Jaudah | Baeesa, Saleh S. | Bangash, Mohammed | Chaudhary, Adeel | Schulten, Hans-Juergen | Al-Qahtani, Mohammed | Faheem, Muhammad | Pushparaj, Peter Natesan | Mathew, Shilu | Kumosani, Taha Abdullah | Kalamegam, Gauthaman | Al-Qahtani, Mohammed | Al-Allaf, Faisal A. | Abduljaleel, Zainularifeen | Alashwal, Abdullah | Taher, Mohiuddin M. | Bouazzaoui, Abdellatif | Abalkhail, Halah | Ba-Hammam, Faisal A. | Athar, Mohammad | Kalamegam, Gauthaman | Pushparaj, Peter Natesan | Abu-Elmagd, Muhammad | Ahmed, Farid | Sait, Khalid HussainWali | Anfinan, Nisreen | Gari, Mamdooh | Chaudhary, Adeel | Abuzenadah, Adel | Assidi, Mourad | Al-Qahtani, Mohammed | Mami, Naira Ben | Haffani, Yosr Z. | Medhioub, Mouna | Hamzaoui, Lamine | Cherif, Ameur | Azouz, Msadok | Kalamegam, Gauthaman | Khan, Fazal | Mathew, Shilu | Nasser, Mohammed Imran | Rasool, Mahmood | Ahmed, Farid | Pushparaj, Peter Natesan | Al-Qahtani, Mohammed | Turkistany, Shereen A. | Al-harbi, Lina M. | Dallol, Ashraf | Sabir, Jamal | Chaudhary, Adeel | Abuzenadah, Adel | Al-Madoudi, Basmah | Al-Aslani, Bayan | Al-Harbi, Khulud | Al-Jahdali, Rwan | Qudaih, Hanadi | Al Hamzy, Emad | Assidi, Mourad | Al Qahtani, Mohammed | Ilyas, Asad M. | Ahmed, Youssri | Gari, Mamdooh | Ahmed, Farid | Alqahtani, Mohammed | Salem, Nada | Karim, Sajjad | Alhathli, Elham M. | Abusamra, Heba | Eldin, Hend F. Nour | Al-Qahtani, Mohammed H. | Kumar, Sudhir | Al-Adwani, Fatima | Hussein, Deema | Al-Sharif, Mona | Jamal, Awatif | Al-Ghamdi, Fahad | Al-Maghrabi, Jaudah | Baeesa, Saleh S. | Bangash, Mohammed | Chaudhary, Adeel | Al-Qahtani, Mohammed | Schulten, Hans-Juergen | Alamandi, Alaa | Alotibi, Reem | Hussein, Deema | Karim, Sajjad | Al-Maghrabi, Jaudah | Al-Ghamdi, Fahad | Jamal, Awatif | Baeesa, Saleh S. | Bangash, Mohammed | Chaudhary, Adeel | Schulten, Hans-Juergen | Al-Qahtani, Mohammed | Subhi, Ohoud | Bagatian, Nadia | Karim, Sajjad | Al-Johari, Adel | Al-Hamour, Osman Abdel | Al-Aradati, Hosam | Al-Mutawa, Abdulmonem | Al-Mashat, Faisal | Al-Maghrabi, Jaudah | Schulten, Hans-Juergen | Al-Qahtani, Mohammad | Bagatian, Nadia | Subhi, Ohoud | Karim, Sajjad | Al-Johari, Adel | Al-Hamour, Osman Abdel | Al-Mutawa, Abdulmonem | Al-Aradati, Hosam | Al-Mashat, Faisal | Al-Qahtani, Mohammad | Schulten, Hans-Juergen | Al-Maghrabi, Jaudah | shah, Muhammad W. | Yasir, Muhammad | Azhar, Esam I | Al-Masoodi, Saad | Haffani, Yosr Z. | Azouz, Msadok | Khamla, Emna | Jlassi, Chaima | Masmoudi, Ahmed S. | Cherif, Ameur | Belbahri, Lassaad | Al-Khayyat, Shadi | Attas, Roba | Abu-Sanad, Atlal | Abuzinadah, Mohammed | Merdad, Adnan | Dallol, Ashraf | Chaudhary, Adeel | Al-Qahtani, Mohammed | Abuzenadah, Adel | Bouazzi, Habib | Trujillo, Carlos | Alwasiyah, Mohammad Khalid | Al-Qahtani, Mohammed | Alotaibi, Maha | Nassir, Rami | Sheikh, Ishfaq A. | Kamal, Mohammad A. | Jiffri, Essam H. | Ashraf, Ghulam M. | Beg, Mohd A. | Aziz, Mohammad A. | Ali, Rizwan | Rasool, Mahmood | Jamal, Mohammad S. | Samman, Nusaibah | Abdussami, Ghufrana | Periyasamy, Sathish | Warsi, Mohiuddin K. | Aldress, Mohammed | Al Otaibi, Majed | Al Yousef, Zeyad | Boudjelal, Mohamed | Buhmeida, Abdelbasit | Al-Qahtani, Mohammed H. | AlAbdulkarim, Ibrahim | Ghazala, Rubi | Mathew, Shilu | Hamed, M. Haroon | Assidi, Mourad | Al-Qahtani, Mohammed | Qadri, Ishtiaq | Sheikh, Ishfaq A. | Abu-Elmagd, Muhammad | Turki, Rola F. | Damanhouri, Ghazi A. | Beg, Mohd A. | Suhail, Mohd | Qureshi, Abid | Jamal, Adil | Pushparaj, Peter Natesan | Al-Qahtani, Mohammad | Qadri, Ishtiaq | El-Readi, Mahmoud Z. | Eid, Safaa Y. | Wink, Michael | Isa, Ahmed M. | Alnuaim, Lulu | Almutawa, Johara | Abu-Rafae, Basim | Alasiri, Saleh | Binsaleh, Saleh | Nazam, Nazia | Lone, Mohamad I. | Ahmad, Waseem | Ansari, Shakeel A. | Alqahtani, Mohamed H.
BMC Genomics  2016;17(Suppl 6):487.
Table of contents
O1 Regulation of genes by telomere length over long distances
Jerry W. Shay
O2 The microtubule destabilizer KIF2A regulates the postnatal establishment of neuronal circuits in addition to prenatal cell survival, cell migration, and axon elongation, and its loss leading to malformation of cortical development and severe epilepsy
Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G. Chaudhary, Mohammed Al-Qahtani, Nobutaka Hirokawa
O3 Integration of metagenomics and metabolomics in gut microbiome research
Maryam Goudarzi, Albert J. Fornace Jr.
O4 A unique integrated system to discern pathogenesis of central nervous system tumors
Saleh Baeesa, Deema Hussain, Mohammed Bangash, Fahad Alghamdi, Hans-Juergen Schulten, Angel Carracedo, Ishaq Khan, Hanadi Qashqari, Nawal Madkhali, Mohamad Saka, Kulvinder S. Saini, Awatif Jamal, Jaudah Al-Maghrabi, Adel Abuzenadah, Adeel Chaudhary, Mohammed Al Qahtani, Ghazi Damanhouri
O5 RPL27A is a target of miR-595 and deficiency contributes to ribosomal dysgenesis
Heba Alkhatabi
O6 Next generation DNA sequencing panels for haemostatic and platelet disorders and for Fanconi anaemia in routine diagnostic service
Anne Goodeve, Laura Crookes, Nikolas Niksic, Nicholas Beauchamp
O7 Targeted sequencing panels and their utilization in personalized medicine
Adel M. Abuzenadah
O8 International biobanking in the era of precision medicine
Jim Vaught
O9 Biobank and biodata for clinical and forensic applications
Bruce Budowle, Mourad Assidi, Abdelbaset Buhmeida
O10 Tissue microarray technique: a powerful adjunct tool for molecular profiling of solid tumors
Jaudah Al-Maghrabi
O11 The CEGMR biobanking unit: achievements, challenges and future plans
Abdelbaset Buhmeida, Mourad Assidi, Leena Merdad
O12 Phylomedicine of tumors
Sudhir Kumar, Sayaka Miura, Karen Gomez
O13 Clinical implementation of pharmacogenomics for colorectal cancer treatment
Angel Carracedo, Mahmood Rasool
O14 From association to causality: translation of GWAS findings for genomic medicine
Ahmed Rebai
O15 E-GRASP: an interactive database and web application for efficient analysis of disease-associated genetic information
Sajjad Karim, Hend F Nour Eldin, Heba Abusamra, Elham M Alhathli, Nada Salem, Mohammed H Al-Qahtani, Sudhir Kumar
O16 The supercomputer facility “AZIZ” at KAU: utility and future prospects
Hossam Faheem
O17 New research into the causes of male infertility
Ashok Agarwa
O18 The Klinefelter syndrome: recent progress in pathophysiology and management
Eberhard Nieschlag, Joachim Wistuba, Oliver S. Damm, Mohd A. Beg, Taha A. Abdel-Meguid, Hisham A. Mosli, Osama S. Bajouh, Adel M. Abuzenadah, Mohammed H. Al-Qahtani
O19 A new look to reproductive medicine in the era of genomics
Serdar Coskun
P1 Wnt signalling receptors expression in Saudi breast cancer patients
Muhammad Abu-Elmagd, Abdelbaset Buhmeida, Ashraf Dallol, Jaudah Al-Maghrabi, Sahar Hakamy, Wejdan Al-Qahtani, Asia Al-Harbi, Shireen Hussain, Mourad Assidi, Mohammed Al-Qahtani, Adel Abuzenadah
P2 Analysis of oxidative stress interactome during spermatogenesis: a systems biology approach to reproduction
Burak Ozkosem, Rick DuBois
P3 Interleukin-18 gene variants are strongly associated with idiopathic recurrent pregnancy loss.
Safia S Messaoudi, Maryam T Dandana, Touhami Mahjoub, Wassim Y Almawi
P4 Effect of environmental factors on gene-gene and gene-environment reactions: model and theoretical study applied to environmental interventions using genotype
S. Abdalla, M. Nabil Al-Aama
P5 Genomics and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumor
Asmaa Elzawahry, Tsuyoshi Takahashi, Sachiyo Mimaki, Eisaku Furukawa, Rie Nakatsuka, Isao Kurosaka, Takahiko Nishigaki, Hiromi Nakamura, Satoshi Serada, Tetsuji Naka, Seiichi Hirota, Tatsuhiro Shibata, Katsuya Tsuchihara, Toshirou Nishida, Mamoru Kato
P6 In-Silico analysis of putative HCV epitopes against Pakistani human leukocyte antigen background: an approach towards development of future vaccines for Pakistani population
Sajid Mehmood, Naeem Mahmood Ashraf, Awais Asif, Muhammad Bilal, Malik Siddique Mehmood, Aadil Hussain
P7 Inhibition of AChE and BuChE with the natural compounds of Bacopa monerri for the treatment of Alzheimer’s disease: a bioinformatics approach
Qazi Mohammad Sajid Jamal, Mughees Uddin Siddiqui, Mohammad A. Alzohairy, Mohammad A. Al Karaawi
P8 Her2 expression in urothelial cell carcinoma of the bladder in Saudi Arabia
Taoufik Nedjadi, Jaudah Al-Maghrabi, Mourad Assidi, Heba Al-Khattabi, Adel Al-Ammari, Ahmed Al-Sayyad, Abdelbaset Buhmeida, Mohammed Al-Qahtani
P9 Association of angiotensinogen single nucleotide polymorphisms with Preeclampsia in patients from North Africa
Hédia Zitouni, Nozha Raguema, Marwa Ben Ali, Wided Malah, Raja Lfalah, Wassim Almawi, Touhami Mahjoub
P10 Systems biology analysis reveals relations between normal skin, benign nevi and malignant melanoma
Mohammed Elanbari, Andrey Ptitsyn
P11 The apoptotic effect of thymoquinone in Jurkat cells
Sana Mahjoub, Rabeb El Ghali, Bechir Achour, Nidhal Ben Amor, Mourad Assidi, Brahim N'siri, Hamid Morjani
P12 Sonic hedgehog contributes in bladder cancer invasion in Saudi Arabia
Taoufik Nedjadi, Adel Al-Ammari, Ahmed Al-Sayyad, Nada Salem, Esam Azhar, Jaudah Al-Maghrabi
P13 Association of Interleukin 18 gene promoter polymorphisms - 607A/C and -137 G/C with colorectal cancer onset in a sample of Tunisian population
Vera Chayeb, Maryam Dendena, Hedia Zitouni, Khedija Zouari-Limayem, Touhami Mahjoub
P14 Pathological expression of interleukin-6, -11, leukemia inhibitory factor and their receptors in tubal gestation with and without tubal cytomegalovirus infection
Bassem Refaat, Ahmed M Ashshi, Sarah A Batwa
P15 Phenotypic and genetic profiling of avian pathogenic and human diarrhegenic Escherichia coli in Egypt
Hazem Ramadan, Amal Awad, Ahmed Ateya
P16 Cancer-targeting dual gene virotherapy as a promising therapeutic strategy for treatment of hepatocellular carcinoma
Adel Galal Ahmed El-Shemi, Ahmad Ashshi, Mohammed Basalamah, Youjin Na, Chae-Ok YUN
P17 Cancer dual gene therapy with oncolytic adenoviruses expressing TRAIL and IL-12 transgenes markedly eradicated human hepatocellular carcinoma both in vitro and in vivo
Adel Galal Ahmed El-Shemi, Ahmad Ashshi, Mohammed Basalamah, Youjin Na, Chae-Ok Yun
P18 Therapy with paricalcitol attenuates tumor growth and augments tumoricidal and anti-oncogenic effects of 5-fluorouracil on animal model of colon cancer
Adel Galal El-Shemi, Bassem Refaat, Osama Kensara, Amr Abdelfattah
P19 The effects of Rubus idaeus extract on normal human lymphocytes and cancer cell line
Batol Imran Dheeb, Mohammed M. F. Al-Halbosiy, Rghad Kadhim Al lihabi, Basim Mohammed Khashman
P20 Etanercept, a TNF-alpha inhibitor, alleviates mechanical hypersensitivity and spontaneous pain in a rat model of chemotherapy-induced neuropathic pain
Djouhri, Laiche, Chaudhary Adeel, Nedjadi, Taoufik
P21 Sleeping beauty mutagenesis system identified genes and neuronal transcription factor network involved in pediatric solid tumour (medulloblastoma)
Hani Al-Afghani, Maria Łastowska, Haya H Al-Balool, Harsh Sheth, Emma Mercer, Jonathan M Coxhead, Chris PF Redfern, Heiko Peters, Alastair D Burt, Mauro Santibanez-Koref, Chris M Bacon, Louis Chesler, Alistair G Rust, David J Adams, Daniel Williamson, Steven C Clifford, Michael S Jackson
P22 Involvement of interleukin-1 in vitiligo pathogenesis
Mala Singh, Mohmmad Shoab Mansuri, Shahnawaz D. Jadeja, Hima Patel, Yogesh S. Marfatia, Rasheedunnisa Begum
P23 Cytogenetics abnormalities in 12,884 referred population for chromosomal analysis and the role of FISH in refining the diagnosis (cytogenetic experience 2004-2013)
Amal M Mohamed, Alaa K Kamel, Nivin A Helmy, Sayda A Hammad, Hesham F Kayed, Marwa I Shehab, Assad El Gerzawy, Maha M. Ead, Ola M Ead, Mona Mekkawy, Innas Mazen, Mona El-Ruby
P24 Analysis of binding properties of angiotensin-converting enzyme 2 through in silico method
S. M. A. Shahid, Qazi Mohammad Sajid Jamal, J. M. Arif, Mohtashim Lohani
P25 Relationship of genetics markers cis and trans to the β-S globin gene with fetal hemoglobin expression in Tunisian sickle cell patients
Moumni Imen, Chaouch Leila, Ouragini Houyem, Douzi Kais, Chaouachi Dorra Mellouli Fethi, Bejaoui Mohamed, Abbes Salem
P26 Analysis of estrogen receptor alpha gene polymorphisms in breast cancer: link to genetic predisposition in Sudanese women
Areeg Faggad, Amanuel T Gebreslasie, Hani Y Zaki, Badreldin E Abdalla
P27 KCNQI gene polymorphism and its association with CVD and T2DM in the Saudi population
Maha S AlShammari, Rhaya Al-Ali, Nader Al-Balawi , Mansour Al-Enazi, Ali Al-Muraikhi, Fadi Busaleh, Ali Al-Sahwan, Francis Borgio, Abdulazeez Sayyed, Amein Al-Ali, Sadananda Acharya
P28 Clinical, neuroimaging and cytogenetic study of a patient with microcephaly capillary malformation syndrome
Maha S. Zaki, Hala T. El-Bassyouni, Marwa I. Shehab
P29 Altered expression of CD200R1 on dendritic cells of patients with inflammatory bowel diseases: in silico investigations and clinical evaluations
Mohammed F. Elshal, Kaleemuddin M., Alia M. Aldahlawi, Omar Saadah,
J. Philip McCoy
P30 Development of real time PCR diagnostic protocol specific for the Saudi Arabian H1N1 viral strains
Adel E El-Tarras, Nabil S Awad, Abdulla A Alharthi, Mohamed M M Ibrahim
P31 Identification of novel genetic variations affecting Osteoarthritis patients
Haneen S Alsehli, Ashraf Dallol, Abdullah M Gari, Mohammed M Abbas, Roaa A Kadam, Mazen M. Gari, Mohmmed H Alkaff, Adel M Abuzenadah, Mamdooh A Gari
P32 An integrated database of GWAS SNVs and their evolutionary properties
Heba Abusamra, Sajjad Karim, Hend F Nour eldin, Elham M Alhathli, Nada Salem, Sudhir Kumar, Mohammed H Al-Qahtani
P33 Familial hypercholesterolemia in Saudi Arabia: prime time for a national registry and genetic analysis
Fatima A. Moradi, Omran M. Rashidi, Zuhier A. Awan
P34 Comparative genomics and network-based analyses of early hepatocellular carcinoma
Ibrahim Hamza Kaya, Olfat Al-Harazi, Dilek Colak
P35 A TALEN-based oncolytic viral vector approach to knock out ABCB1 gene mediated chemoresistance in cancer stem cells
Nabila A Alkousi, Takis Athanasopoulos
P36 Cartilage differentiation and gene expression of synovial fluid mesenchymal stem cells derived from osteoarthritis patients
Afnan O Bahmaid, Etimad A Alhwait, Mamdooh A Gari, Haneen S Alsehli, Mohammed M Abbas, Mohammed H Alkaf, Roaa Kadam, Ashraf Dallol, Gauthaman Kalamegam
P37 E-GRASP: Adding an evolutionary component to the genome-wide repository of associations (GRASP) resource
Hend F Nour Eldin, Sajjad Karim, Heba Abusamra, Elham Alhathli, Nada Salem, Mohammed H Al-Qahtani, Sudhir Kumar
P38 Screening of AGL gene mutation in Saudi family with glycogen storage disease Type III
Salma N Alsayed, Fawziah H Aljohani, Samaher M Habeeb, Rawan A Almashali, Sulman Basit, Samia M Ahmed
P39 High throughput proteomic data suggest modulation of cAMP dependent protein kinase A and mitochondrial function in infertile patients with varicocele
Rakesh Sharma, Ashok Agarwal, Damayanthi Durairajanayagam, Luna Samanta, Muhammad Abu-Elmagd, Adel M. Abuzenadah, Edmund S. Sabanegh, Mourad Assidi, Mohammed Al-Qahtani
P40 Significant protein profile alterations in men with primary and secondary infertility
Ashok Agarwal, Rakesh Sharma, Luna Samanta, Damayanthi Durairajanayagam, Mourad Assidi, Muhammad Abu-Elmagd, Mohammed Al-Qahtani, Adel M. Abuzenadah, Edmund S. Sabanegh
P41 Spermatozoa maturation in infertile patients involves compromised expression of heat shock proteins
Luna Samanta, Ashok Agarwal, Rakesh Sharma, Zhihong Cui, Mourad Assidi, Adel M. Abuzenadah, Muhammad Abu-Elmagd, Mohammed Al-Qahtani
P42 Array comparative genomic hybridization approach to search genomic answers for spontaneous recurrent abortion in Saudi Arabia
Alaa A Alboogmi, Nuha A Alansari, Maha M Al-Quaiti, Fai T Ashgan, Afnan Bandah, Hasan S Jamal, Abdullraheem Rozi, Zeenat Mirza, Adel M Abuzenadah, Sajjad Karim, Mohammed H Al-Qahtani
P43 Global gene expression profiling of Saudi kidney cancer patients
Sajjad Karim, Hans-Juergen Schulten, Ahmad J Al Sayyad, Hasan MA Farsi, Jaudah A Al-Maghrabi, Zeenat Mirza, Reem Alotibi, Alaa Al-Ahmadi, Nuha A Alansari, Alaa A Albogmi, Maha M Al-Quaiti, Fai T Ashgan, Afnan Bandah, Mohammed H Al-Qahtani
P44 Downregulated StAR gene and male reproductive dysfunction caused by nifedipine and ethosuximide
Rasha A Ebiya, Samia M Darwish, Metwally M. Montaser
P45 Clustering based gene expression feature selection method: A computational approach to enrich the classifier efficiency of differentially expressed genes
Heba Abusamra, Vladimir B. Bajic
P46 Prognostic significance of Osteopontin expression profile in colorectal carcinoma
Jaudah Al-Maghrabi, Wafaey Gomaa, Mehenaz Hanbazazh, Mahmoud Al-Ahwal, Asia Al-Harbi, Wejdan Al-Qahtani, Saher Hakamy, Ghali Baba, Abdelbaset Buhmeida, Mohammed Al-Qahtani
P47 High Glypican-3 expression pattern predicts longer disease-specific survival in colorectal carcinoma
Jaudah Al-Maghrabi, Abdullah Al-Harbi, Mahmoud Al-Ahwal, Asia Al-Harbi, Wejdan Al-Qahtani, Sahar Hakamy, Ghalia Baba, Abdelbaset Buhmeida, Mohammed Al-Qahtani
P48 An evolutionary re-assessment of GWAS single nucleotide variants implicated in the Cholesterol traits
Elham M Alhathli, Sajjad Karim, Nada Salem, Hend Nour Eldin, Heba Abusamra, Sudhir Kumar, Mohammed H Al-Qahtani
P49 Derivation and characterization of human Wharton’s jelly stem cells (hWJSCs) in vitro for future therapeutic applications
Aisha A Alyamani, Gauthaman Kalamegam, Etimad A Alhwait, Mamdooh A Gari, Mohammed M Abbas, Mohammed H Alkaf, Haneen S Alsehli, Roaa A Kadam, Mohammed Al-Qahtani
P50 Attitudes of healthcare students toward biomedical research in the post-genomic era
Rawan Gadi, Abdelbaset Buhmeida, Mourad Assidi , Adeel Chaudhary, Leena Merdad
P51 Evaluation of the immunomodulatory effects of thymoquinone on human bone marrow mesenchymal stem cells (BM-MSCs) from osteoarthritic patients
Saadiah M Alfakeeh, Etimad A Alhwait, Mamdooh A Gari, Mohammed M Abbas, Mohammed H Alkaf, Haneen S Alsehli, Roaa Kadam, Gauthaman Kalamegam
P52 Implication of IL-10 and IL-28 polymorphism with successful anti-HCV therapy and viral clearance
Rubi Ghazala, Shilu Mathew, M.Haroon Hamed, Mourad Assidi, Mohammed Al-Qahtani, Ishtiaq Qadri
P53 Selection of flavonoids against obesity protein (FTO) using in silico and in vitro approaches
Shilu Mathew, Lobna Mira, Manal Shaabad, Shireen Hussain, Mourad Assidi, Muhammad Abu-Elmagd, Mohammed Al-Qahtani
P54 Computational selection and in vitro validation of flavonoids as new antidepressant agents
Shilu Mathew, Manal Shaabad, Lobna Mira, Shireen Hussain, Mourad Assidi, Muhammad Abu-Elmagd, Mohammed Al-Qahtani
P55 In Silico prediction and prioritization of aging candidate genes associated with
progressive telomere shortening
Ahmed Rebai, Mourad Assidi, Abdelbaset Buhmeida, Muhammad Abu-Elmagd, Ashraf Dallol, Jerry W Shay
P56 Identification of new cancer testis antigen genes in diverse types of malignant human tumour cells
Mikhlid H Almutairi
P57 More comprehensive forensic genetic marker analyses for accurate human remains identification using massively parallel sequencing (MPS)
Angie Ambers, Jennifer Churchill, Jonathan King, Monika Stoljarova, Harrell Gill-King, Mourad Assidi, Muhammad Abu-Elmagd, Abdelbaset Buhmeida, Muhammad Al-Qatani, Bruce Budowle
P58 Flow cytometry approach towards treatment men infertility in Saudi Arabia
Muhammad Abu-Elmagd, Farid Ahmed, Ashraf Dallol, Mourad Assidi, Taha Abo Almagd, Sahar Hakamy, Ashok Agarwal, Muhammad Al-Qahtani, Adel Abuzenadah
P59 Tissue microarray based validation of CyclinD1 expression in renal cell carcinoma of Saudi kidney patients
Sajjad Karim, Hans-Juergen Schulten, Ahmad J Al Sayyad, Hasan MA Farsi, Jaudah A Al-Maghrabi, Abdelbaset Buhmaida, Zeenat Mirza, Reem Alotibi, Alaa Al-Ahmadi, Nuha A Alansari, Alaa A Albogmi, Maha M Al-Quaiti, Fai T Ashgan, Afnan Bandah, Mohammed H Al-Qahtani
P60 Assessment of gold nanoparticles in molecular diagnostics and DNA damage studies
Rukhsana Satar, Mahmood Rasool, Waseem Ahmad, Nazia Nazam, Mohamad I Lone, Muhammad I Naseer, Mohammad S Jamal, Syed K Zaidi, Peter N Pushparaj, Mohammad A Jafri, Shakeel A Ansari, Mohammed H Alqahtani
P61 Surfing the biospecimen management and processing workflow at CEGMR Biobank
Hanan Bashier, Abrar Al Qahtani, Shilu Mathew, Amal M. Nour, Heba Alkhatabi, Adel M. Abu Zenadah, Abdelbaset Buhmeida, Mourad Assidi, Muhammed Al Qahtani
P62 Autism Spectrum Disorder: knowledge, attitude and awareness in Jeddah, Kingdom of Saudi Arabia
Muhammad Faheem, Shilu Mathew, Shiny Mathew, Peter Natesan Pushparaj, Mohammad H. Al-Qahtani
P63 Simultaneous genetic screening of the coagulation pathway genes using the Thromboscan targeted sequencing panel
Hani A. Alhadrami, Ashraf Dallol, Adel Abuzenadah
P64 Genome wide array comparative genomic hybridization analysis in patients with syndromic congenital heart defects
Ibtessam R. Hussein, Adeel G. Chaudhary, Rima S Bader, Randa Bassiouni, Maha Alquaiti, Fai Ashgan, Hans Schulten, Mohamed Nabil Alama, Mohammad H. Al Qahtani
P65 Toxocogenetic evaluation of 1, 2-Dichloroethane in bone marrow, blood and cells of immune system using conventional, molecular and flowcytometric approaches
Mohammad I Lone, Nazia Nizam, Waseem Ahmad, Mohammad A Jafri, Mahmood Rasool, Shakeel A Ansari, Muhammed H Al-Qahtani
P66 Molecular cytogenetic diagnosis of sexual development disorders in newborn: A case of ambiguous genitalia
Eradah Alshihri, Muhammad Abu-Elmagd, Lina Alharbi, Mourad Assidi, Mohammed Al-Qahtani
P67 Identification of disease specific gene expression clusters and pathways in hepatocellular carcinoma using In Silico methodologies
Shilu Mathew, Peter Pushparaj Natesan, Muhammed Al Qahtani
P68 Human Wharton’s Jelly stem cell conditioned medium inhibits primary ovarian cancer cells in vitro: Identification of probable targets and mechanisms using systems biology
Gauthaman Kalamegam, Peter Natesan Pushparaj, Fazal Khan, Roaa Kadam, Farid Ahmed, Mourad Assidi, Khalid Hussain Wali Sait, Nisreen Anfinan, Mohammed Al Qahtani
P69 Mutation spectrum of ASPM (Abnormal Spindle-like, Microcephaly-associated) gene in Saudi Arabian population
Muhammad I Naseer, Adeel G Chaudhary, Mohammad S Jamal, Shilu Mathew, Lobna S Mira, Peter N Pushparaj, Shakeel A Ansari, Mahmood Rasool, Mohammed H AlQahtani
P70 Identification and characterization of novel genes and mutations of primary microcephaly in Saudi Arabian population
Muhammad I Naseer, Adeel G Chaudhary, Shilu Mathew, Lobna S Mira, Mohammad S Jamal, Sameera Sogaty, Randa I Bassiouni, Mahmood Rasool, Mohammed H AlQahtani
P71 Molecular genetic analysis of hereditary nonpolyposis colorectal cancer (Lynch Syndrome) in Saudi Arabian population
Mahmood Rasool, Shakeel A Ansari, Mohammad S Jamal, Peter N Pushparaj, Abdulrahman MS Sibiani, Waseem Ahmad, Abdelbaset Buhmeida, Mohammad A Jafri, Mohiuddin K Warsi, Muhammad I Naseer, Mohammed H Al-Qahtani
P72 Function predication of hypothetical proteins from genome database of chlamydia trachomatis
Rubi, Kundan Kumar, Ahmad AT Naqvi, Faizan Ahmad, Md I Hassan, Mohammad S Jamal, Mahmood Rasool, Mohammed H AlQahtani
P73 Transcription factors as novel molecular targets for skin cancer
Ashraf Ali, Jummanah Jarullah, Mahmood Rasool, Abdelbasit Buhmeida, Shahida Khan, Ghufrana Abdussami, Maryam Mahfooz, Mohammad A Kamal, Ghazi A Damanhouri, Mohammad S Jamal
P74 An In Silico analysis of Plumbagin binding to apoptosis executioner: Caspase-3 and Caspase-7
Bushra Jarullah, Jummanah Jarullah, Mohammad SS Jarullah, Ashraf Ali, Mahmood Rasool, Mohammad S Jamal
P75 Single cell genomics applications for preimplantation genetic screening optimization: Comparative analysis of whole genome amplification technologies
Mourad Assidi, Muhammad Abu-Elmagd, Osama Bajouh, Peter Natesan Pushparaj, Mohammed Al-Qahtani, Adel Abuzenadah
P76 ZFP36 regulates miRs-34a in anti-IgM triggered immature B cells
Mohammad S Jamal, Jummanah Jarullah, Abdulah EA Mathkoor, Hashim MA Alsalmi, Anas MM Oun, Ghazi A Damanhauri, Mahmood Rasool, Mohammed H AlQahtani
P77 Identification of a novel mutation in the STAMBP gene in a family with microcephaly-capillary malformation syndrome
Muhammad I. Naseer, Mahmood Rasool, Sameera Sogaty, Adeel G. Chudhary, Yousif A. Abutalib, Daniele Merico, Susan Walker, Christian R. Marshall, Mehdi Zarrei, Stephen W. Scherer, Mohammad H. Al-Qahtani
P78 Copy number variations in Saudi patients with intellectual disability and epilepsy
Muhammad I. Naseer, Muhammad Faheem, Adeel G. Chaudhary, Mahmood Rasool, Gauthaman Kalamegam, Fai Talal Ashgan, Mourad Assidi, Farid Ahmed, Syed Kashif Zaidi, Mohammed M. Jan, Mohammad H. Al-Qahtani
P79 Prognostic significance of CD44 expression profile in colorectal carcinoma
Maryam Al-Zahrani, Sahira Lary, Sahar Hakamy, Ashraf Dallol, Mahmoud Al-Ahwal, Jaudah Al-Maghrabi, Emmanuel Dermitzakis, Adel Abuzenadah, Abdelbaset Buhmeida, Mohammed Al-Qahtani
P80 Association of the endothelial nitric oxide synthase (eNOS) gene G894T polymorphism with hypertension risk and complications
Abeer A Al-refai, Mona Saleh, Rehab I Yassien, Mahmmoud Kamel, Rabab M Habeb
P81 SNPs array to screen genetic variation among diabetic patients
Najlaa Filimban, Ashraf Dallol, Nadia Ghannam, Mohammed Al-Qahtani, Adel Mohammed Abuzenadah
P82 Detection and genotyping of Helicobacter pylori among gastric cancer patients from Saudi Arabian population
Fehmida Bibi, Sana Akhtar, Esam I. Azhar, Muhammad Yasir, Muhammad I. Nasser, Asif A. Jiman-Fatani, Ali Sawan
P83 Antimicrobial drug resistance and molecular detection of susceptibility to Fluoroquinolones among clinical isolates of Salmonella species from Jeddah-Saudi Arabia
Ruaa A Lahzah, Asho Ali
P84 Identification of the toxic and virulence nature of MAP1138c protein of Mycobacterium avium subsp. paratuberculosis
Syed A Hassan, Seyed E Hasnain, Iftikhar A Tayubi, Hamza A Abujabal, Alaa O Magrabi
P85 In vitro and in silico evaluation of miR137 in human breast cancer
Fazal Khan, Gauthaman Kalamegam, Peter Natesan Pushparaj, Adel Abuzenada, Taha Abduallah Kumosani, Elie Barbour, Mohammed Al-Qahtani
P86 Auruka gene is over-expressed in Saudi breast cancer
Manal Shabaad, Shilu Mathew, Ashraf Dallol, Adnan Merdad, Abdelbaset Buhmeida, Mohammed Al-Qahtani
P87 The potential of immunogenomics in personalized healthcare
Mourad Assidi, Muhammad Abu-Elmagd, Kalamegam Gauthaman, Mamdooh Gari, Adeel Chaudhary, Adel Abuzenadah, Peter Natesan Pushparaj, Mohammed Al-Qahtani
P88 In Silico physiochemical and structural characterization of a putative ORF MAP0591 and its implication in the pathogenesis of Mycobacterium paratuberculosis in ruminants and humans
Syed A Hassan, Iftikhar A Tayubi, Hani MA Aljahdali
P89 Effects of heat shock on human bone marrow mesenchymal stem cells (BM-MSCs): Implications in regenerative medicine
Reham Al Nono, Mamdooh Gari, Haneen Alsehli, Farid Ahmed, Mohammed Abbas, Gauthaman Kalamegam, Mohammed Al-Qahtani
P90 In Silico analyses of the molecular targets of Resveratrol unravels its importance in mast cell mediated allergic responses
Shilu Mathew, Fazal Khan, Mahmood Rasool, Mohammed Sarwar Jamal, Muhammad Imran Naseer, Zeenat Mirza, Sajjad Karim, Shakeel Ansari, Mourad Assidi, Gauthaman Kalamegam, Mamdooh Gari, Adeel Chaudhary, Adel Abuzenadah, Peter Natesan Pushparaj, Mohammed Al-Qahtani
P91 Effects of environmental particulate matter on bone-marrow mesenchymal stem cells
Muhammad Abu-Elmagd, Gauthaman Kalamegam, Roaa Kadam, Mansour A Alghamdi, Magdy Shamy, Max Costa, Mamdouh I Khoder, Mourad Assidi, Peter Natesan Pushparaj, Mamdooh Gari, Mohammed Al-Qahtani
P92 Distinctive charge clusters in human virus proteomes
Najla Kharrat, Sabrine Belmabrouk, Rania Abdelhedi, Riadh Benmarzoug, Mourad Assidi, Mohammed H. Al Qahtani, Ahmed Rebai
P93 In vitro experimental model and approach in identification of new biomarkers of inflammatory forms of arthritis
Ghazi Dhamanhouri, Peter Natesan Pushparaj, Abdelwahab Noorwali, Mohammad Khalid Alwasiyah, Afnan Bahamaid, Saadiah Alfakeeh, Aisha Alyamani, Haneen Alsehli, Mohammed Abbas, Mamdooh Gari, Ali Mobasheri, Gauthaman Kalamegam, Mohammed Al-Qahtani
P94 Molecular docking of GABAA receptor subunit γ-2 with novel anti-epileptic compounds
Muhammad Faheem, Shilu Mathew, Peter Natesan Pushparaj, Mohammad H. Al-Qahtani
P95 Breast cancer knowledge, awareness, and practices among Saudi females residing in Jeddah
Shilu Mathew, Muhammad Faheem, Shiny Mathew, Peter Natesan Pushparaj, Mohammad H. Al-Qahtani
P96 Anti-inflammatory role of Sesamin by Attenuation of Iba1/TNF-α/ICAM-1/iNOS signaling in Diabetic Retinopathy
Mohammad Sarwar Jamal, Syed Kashif Zaidi, Raziuddin Khan, Kanchan Bhatia, Mohammed H. Al-Qahtani, Saif Ahmad
P97 Identification of drug lead molecule against vp35 protein of Ebola virus: An In-Silico approach
Iftikhar AslamTayubi, Manish Tripathi, Syed Asif Hassan, Rahul Shrivastava
P98 An approach to personalized medicine from SNP-calling through disease analysis using whole exome-sequencing of three sub-continental populations
Iftikhar A Tayubi, Syed Hassan, Hamza A.S Abujabal
P99 Low versus high frequency of Glucose –6 – Phosphate Dehydrogenase (G6PD) deficiency in urban against tribal population of Gujarat – A signal to natural selection
Ishani Shah, Bushra Jarullah, Mohammad S Jamal, Jummanah Jarullah
P100 Spontaneous preterm birth and single nucleotide gene polymorphisms: a recent update
Ishfaq A Sheikh, Ejaz Ahmad, Mohammad S Jamal, Mohd Rehan, Muhammad Abu-Elmagd, Iftikhar A Tayubi, Samera F AlBasri, Osama S Bajouh, Rola F Turki, Adel M Abuzenadah, Ghazi A Damanhouri, Mohd A Beg, Mohammed Al-Qahtani
P101 Prevalence of congenital heart diseases among Down syndrome cases in Saudi Arabia: role of molecular genetics in the pathogenesis
Sahar AF Hammoudah, Khalid M AlHarbi, Lama M El-Attar, Ahmed MZ Darwish
P102 Combinatorial efficacy of specific pathway inhibitors in breast cancer cells
Sara M Ibrahim, Ashraf Dallol, Hani Choudhry, Adel Abuzenadah, Jalaludden Awlia, Adeel Chaudhary, Farid Ahmed, Mohammed Al-Qahtani
P103 MiR-143 and miR-145 cluster as potential replacement medicine for the treatment of cancer
Mohammad A Jafri, Muhammad Abu-Elmagd, Mourad Assidi, Mohammed Al-Qahtani
P104 Metagenomic profile of gut microbiota during pregnancy in Saudi population
Imran khan, Muhammad Yasir, Esam I. Azhar, Sameera Al-basri, Elie Barbour, Taha Kumosani
P105 Exploration of anticancer targets of selected metabolites of Phoenix dactylifera L. using systems biological approaches
Fazal Khan, Gauthaman Kalamegam, Peter Natesan Pushparaj, Adel Abuzenada, Taha Abduallah Kumosani, Elie Barbour
P106 CD226 and CD40 gene polymorphism in susceptibility to Juvenile rheumatoid arthritis in Egyptian patients
Heba M. EL Sayed, Eman A. Hafez
P107 Paediatric exome sequencing in autism spectrum disorder ascertained in Saudi families
Hans-Juergen Schulten, Aisha Hassan Elaimi, Ibtessam R Hussein, Randa Ibrahim Bassiouni, Mohammad Khalid Alwasiyah, Richard F Wintle, Adeel Chaudhary, Stephen W Scherer, Mohammed Al-Qahtani
P108 Crystal structure of the complex formed between Phospholipase A2 and the central core hydrophobic fragment of Alzheimer’s β- amyloid peptide: a reductionist approach
Zeenat Mirza, Vikram Gopalakrishna Pillai, Sajjad Karim, Sujata Sharma, Punit Kaur, Alagiri Srinivasan, Tej P Singh, Mohammed Al-Qahtani
P109 Differential expression profiling between meningiomas from female and male patients
Reem Alotibi, Alaa Al-Ahmadi, Fatima Al-Adwani, Deema Hussein, Sajjad Karim, Mona Al-Sharif, Awatif Jamal, Fahad Al-Ghamdi, Jaudah Al-Maghrabi, Saleh S Baeesa, Mohammed Bangash, Adeel Chaudhary, Hans-Juergen Schulten, Mohammed Al-Qahtani
P110 Neurospheres as models of early brain development and therapeutics
Muhammad Faheem, Peter Natesan Pushparaj, Shilu Mathew, Taha Abdullah Kumosani, Gauthaman Kalamegam, Mohammed Al-Qahtani
P111 Identification of a recurrent causative missense mutation p.(W577C) at the LDLR exon 12 in familial hypercholesterolemia affected Saudi families
Faisal A Al-Allaf, Zainularifeen Abduljaleel, Abdullah Alashwal, Mohiuddin M. Taher, Abdellatif Bouazzaoui, Halah Abalkhail, Faisal A. Ba-Hammam, Mohammad Athar
P112 Epithelial ovarian carcinoma (EOC): Systems oncological approach to identify diagnostic, prognostic and therapeutic biomarkers
Gauthaman Kalamegam, Peter Natesan Pushparaj, Muhammad Abu-Elmagd, Farid Ahmed Khalid HussainWali Sait, Nisreen Anfinan, Mamdooh Gari, Adeel Chaudhary, Adel Abuzenadah, Mourad Assidi, Mohammed Al-Qahtani
P113 Crohn’s disease phenotype in northern Tunisian population
Naira Ben Mami, Yosr Z Haffani, Mouna Medhioub, Lamine Hamzaoui, Ameur Cherif, Msadok Azouz
P114 Establishment of In Silico approaches to decipher the potential toxicity and mechanism of action of drug candidates and environmental agents
Gauthaman Kalamegam, Fazal Khan, Shilu Mathew, Mohammed Imran Nasser, Mahmood Rasool, Farid Ahmed, Peter Natesan Pushparaj, Mohammed Al-Qahtani
P115 1q Gain predicts poor prognosis marker for young breast cancer patients
Shereen A Turkistany, Lina M Al-harbi, Ashraf Dallol, Jamal Sabir, Adeel Chaudhary, Adel Abuzenadah
P116 Disorders of sex chromosomes in a diagnostic genomic medicine unit in Saudi Arabia: Prevalence, diagnosis and future guidelines
Basmah Al-Madoudi, Bayan Al-Aslani, Khulud Al-Harbi, Rwan Al-Jahdali, Hanadi Qudaih, Emad Al Hamzy, Mourad Assidi, Mohammed Al Qahtani
P117 Combination of WYE354 and Sunitinib demonstrate synergistic inhibition of acute myeloid leukemia in vitro
Asad M Ilyas, Youssri Ahmed, Mamdooh Gari, Farid Ahmed, Mohammed Alqahtani
P118 Integrated use of evolutionary information in GWAS reveals important SNPs in Asthma
Nada Salem, Sajjad Karim, Elham M Alhathli, Heba Abusamra, Hend F Nour Eldin, Mohammed H Al-Qahtani, Sudhir Kumar
P119 Assessment of BRAF, IDH1, IDH2, and EGFR mutations in a series of primary brain tumors
Fatima Al-Adwani, Deema Hussein, Mona Al-Sharif, Awatif Jamal, Fahad Al-Ghamdi, Jaudah Al-Maghrabi, Saleh S Baeesa, Mohammed Bangash, Adeel Chaudhary, Mohammed Al-Qahtani, Hans-Juergen Schulten
P120 Expression profiles distinguish oligodendrogliomas from glioblastoma multiformes with or without oligodendroglioma component
Alaa Alamandi, Reem Alotibi, Deema Hussein, Sajjad Karim, Jaudah Al-Maghrabi, Fahad Al-Ghamdi, Awatif Jamal, Saleh S Baeesa, Mohammed Bangash, Adeel Chaudhary, Hans-Juergen Schulten, Mohammed Al-Qahtani
P121 Hierarchical clustering in thyroid goiters and hyperplastic lesions
Ohoud Subhi, Nadia Bagatian, Sajjad Karim, Adel Al-Johari, Osman Abdel Al-Hamour, Hosam Al-Aradati, Abdulmonem Al-Mutawa, Faisal Al-Mashat, Jaudah Al-Maghrabi, Hans-Juergen Schulten, Mohammad Al-Qahtani
P122 Differential expression analysis in thyroiditis and papillary thyroid carcinomas with or without coexisting thyroiditis
Nadia Bagatian, Ohoud Subhi, Sajjad Karim, Adel Al-Johari, Osman Abdel Al-Hamour, Abdulmonem Al-Mutawa, Hosam Al-Aradati, Faisal Al-Mashat, Mohammad Al-Qahtani, Hans-Juergen Schulten, Jaudah Al-Maghrabi
P123 Metagenomic analysis of waste water microbiome in Sausdi Arabia
Muhammad W shah, Muhammad Yasir, Esam I Azhar, Saad Al-Masoodi
P124 Molecular characterization of Helicobacter pylori from faecal samples of Tunisian patients with gastric cancer
Yosr Z Haffani, Msadok Azouz, Emna Khamla, Chaima Jlassi, Ahmed S. Masmoudi, Ameur Cherif, Lassaad Belbahri
P125 Diagnostic application of the oncoscan© panel for the identification of hereditary cancer syndrome
Shadi Al-Khayyat, Roba Attas, Atlal Abu-Sanad, Mohammed Abuzinadah, Adnan MerdadAshraf Dallol, Adeel Chaudhary, Mohammed Al-Qahtani, Adel Abuzenadah
P126 Characterization of clinical and neurocognitive features in a family with a novel OGT gene missense mutation c. 1193G > A/ (p. Ala319Thr)
Habib Bouazzi, Carlos Trujillo, Mohammad Khalid Alwasiyah, Mohammed Al-Qahtani
P127 Case report: a rare homozygous deletion mutation of TMEM70 gene associated with 3-Methylglutaconic Aciduria and cataract in a Saudi patient
Maha Alotaibi, Rami Nassir
P128 Isolation and purification of antimicrobial milk proteins
Ishfaq A Sheikh, Mohammad A Kamal, Essam H Jiffri, Ghulam M Ashraf, Mohd A Beg
P129 Integrated analysis reveals association of ATP8B1 gene with colorectal cancer
Mohammad A Aziz, Rizwan Ali, Mahmood Rasool, Mohammad S Jamal, Nusaibah samman, Ghufrana Abdussami, Sathish Periyasamy, Mohiuddin K Warsi, Mohammed Aldress, Majed Al Otaibi, Zeyad Al Yousef, Mohamed Boudjelal, Abdelbasit Buhmeida, Mohammed H Al-Qahtani, Ibrahim AlAbdulkarim
P130 Implication of IL-10 and IL-28 polymorphism with successful anti-HCV therapy and viral clearance
Rubi Ghazala, Shilu Mathew, M. Haroon Hamed, Mourad Assidi, Mohammed Al-Qahtani, Ishtiaq Qadri
P131 Interactions of endocrine disruptor di-(2-ethylhexyl) phthalate (DEHP) and its metabolite mono-2-ethylhexyl phthalate (MEHP) with progesterone receptor
Ishfaq A Sheikh, Muhammad Abu-Elmagd, Rola F Turki, Ghazi A Damanhouri, Mohd A. Beg
P132 Association of HCV nucleotide polymorphism in the development of hepatocellular carcinoma
Mohd Suhail, Abid Qureshi, Adil Jamal, Peter Natesan Pushparaj, Mohammad Al-Qahtani, Ishtiaq Qadri
P133 Gene expression profiling by DNA microarrays in colon cancer treated with chelidonine alkaloid
Mahmoud Z El-Readi, Safaa Y Eid, Michael Wink
P134 Successful in vitro fertilization after eight failed trials
Ahmed M. Isa, Lulu Alnuaim, Johara Almutawa, Basim Abu-Rafae, Saleh Alasiri, Saleh Binsaleh
P135 Genetic sensitivity analysis using SCGE, cell cycle and mitochondrial membrane potential in OPs stressed leukocytes in Rattus norvegicus through flow cytometric input
Nazia Nazam, Mohamad I Lone, Waseem Ahmad, Shakeel A Ansari, Mohamed H Alqahtani
doi:10.1186/s12864-016-2858-0
PMCID: PMC4959372  PMID: 27454254
4.  Inflammatory arthritis in caspase-1 gene deficient mice: Contribution of proteinase 3 for caspase-1-independent production of bioactive IL-1β 
Arthritis and rheumatism  2009;60(12):3651-3662.
Objective
Caspase-1 is a known cysteine proteases and is a critical component of the inflammasome. Caspase-1 and neutrophil serine proteases, such as proteinase 3 (PR3) can process pro-IL-1β a crucial cytokine linked to the pathogenesis of rheumatoid arthritis, but their relative importance is unknown.
Methods
To this end we induced acute and chronic arthritis in caspase-1−/− mice and investigated the lack of caspase-1 on joint swelling, cartilage metabolism and joint pathology. In addition, caspase-1 activity was inhibited in mice lacking active cysteine proteases and evaluated the effect of dual blockade of caspase-1 and serine proteinase on arthritis severity and joint pathology.
Results
Surprisingly, caspase-1−/− mice developed joint swelling similar to wild-type mice in models of neutrophil-dominated arthritis. Joint fluid concentrations of bioactive IL-1β were comparable in caspase-1−/− mice and controls. In contrast, induction of chronic arthritis with minimal numbers of neutrophils in caspase-1−/− mice lead to reduced joint inflammation and cartilage damage, implying caspase-1 dependence. In mice lacking neutrophil serine PR3, inhibition caspase-1 activity results in decreased bioactive IL-1β concentrations in synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR-3 and caspase-1 lead to protection against cartilage and bone destruction.
Conclusions
We conclude that caspase-1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis the lack of caspase-1 results in reduced joint pathology. This study implies that caspase-1 inhibitors are not able to interfere with the whole spectrum of IL-1β production and hence may be of therapeutic value only in inflammatory conditions where limited numbers of neutrophils are present.
doi:10.1002/art.25006
PMCID: PMC2993325  PMID: 19950280
5.  Reduced Lipoapoptosis, Hedgehog Pathway Activation, and Fibrosis in Caspase-2 deficient Mice with Nonalcoholic Steatohepatitis 
Gut  2014;64(7):1148-1157.
Objective
Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg. DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis.
Design
Caspase-2 was localized in liver biopsies from NASH patients. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild type (WT) and caspase-2 deficient mice. Lipotoxicity was modeled in vitro using hepatocytes derived from WT and caspase-2 deficient mice.
Results
We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localized in injured hepatocytes and its expression was markedly up-regulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of pro-fibrogenic Hedgehog target genes in mice, and blocked production of Hedgehog ligands in cultured hepatocytes.
Conclusion
These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo, for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.
doi:10.1136/gutjnl-2014-307362
PMCID: PMC4303564  PMID: 25053716
nonalcoholic steatohepatitis; caspase-2; apoptosis; fibrosis
6.  The Enigmatic Roles of Caspases in Tumor Development 
Cancers  2010;2(4):1952-1979.
One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may even promote tumor development. Moreover, experimental evidence suggests that caspases might play non-apoptotic roles in processes that are crucial for tumorigenesis, such as cell proliferation, migration, or invasion. We thus propose a model wherein caspases are preserved in tumor cells due to their functional contributions to development and progression of tumors.
doi:10.3390/cancers2041952
PMCID: PMC3840446  PMID: 24281211
caspase; cancer; apoptosis; tumor suppressor; non-apoptotic functions; mutations; LOH
7.  Comparison of activated caspase detection methods in the gentamicin-treated chick cochlea 
Hearing research  2008;240(1-2):1-11.
Aminoglycoside antibiotics induce caspase-dependent apoptotic death in cochlear hair cells. Apoptosis, a regulated form of cell death, can be induced by many stressors, which activate signaling pathways that result in the controlled dismantling of the affected cell. The caspase family of proteases is activated in the apoptotic signaling pathway and is responsible for cellular destruction. The initiator caspase-9 and the effector caspase-3 are both activated in chick cochlear hair cells following aminoglycoside exposure. We have analyzed caspase activation in the avian cochlea during gentamicin-induced hair cell death to compare two different methods of caspase detection: caspase antibodies and CaspaTag kits. Caspase antibodies bind to the cleaved activated form of caspase-9 or caspase-3 in specific locations in fixed tissue. CaspaTag is a fluorescent inhibitor that binds to a reactive cysteine residue on the large subunit of the caspase heterodimer in unfixed tissue.
To induce cochlear hair cell loss, 1-2 week-old chickens received a single injection of gentamicin (300 mg/kg). Chicks were sacrificed 24, 30, 42, 48, 72, or 96 h after injection. Cochleae were dissected and labeled for activated caspase-9 or caspase-3 using either caspase-directed antibodies or CaspaTag kits. Ears were co-labeled with either phalloidin or myosin VI to visualize hair cells and to determine the progression of cochlear damage. The timing of caspase activation was similar for both assays; however, caspase-9 and caspase-3 antibodies labeled only those cells currently undergoing apoptotic cell death. Conversely, CaspaTag-labeled all the cells that have undergone apoptotic cell death and ejection from the sensory epithelium, in addition to those that are currently in the cell death process. This makes CaspaTag ideal for showing an overall pattern or level of cell death over a period of time, while caspase antibodies provide a snapshot of cell death at a specific time point.
doi:10.1016/j.heares.2008.03.003
PMCID: PMC2430666  PMID: 18487027
Apoptosis; Caspase; Avian; Aminoglycoside; Cochlea; Gentamicin; Hair cells
8.  Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17 
Carcinogenesis  2015;36(11):1372-1380.
Summary
The increased incidence and multiplicity of solar simulated light-induced skin papillomas and elevated expression of keratin-17 in casapse-7 knock-out mice reflects a novel insight into the role of caspase-7-mediated cleavage of keratin-17 and subsequent induction of apoptosis in preventing skin photocarcinogenesis.
Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17.
doi:10.1093/carcin/bgv110
PMCID: PMC4635665  PMID: 26271098
9.  Caspase-1-Dependent and -Independent Cell Death Pathways in Burkholderia pseudomallei Infection of Macrophages 
PLoS Pathogens  2014;10(3):e1003986.
The cytosolic pathogen Burkholderia pseudomallei and causative agent of melioidosis has been shown to regulate IL-1β and IL-18 production through NOD-like receptor NLRP3 and pyroptosis via NLRC4. Downstream signalling pathways of those receptors and other cell death mechanisms induced during B. pseudomallei infection have not been addressed so far in detail. Furthermore, the role of B. pseudomallei factors in inflammasome activation is still ill defined. In the present study we show that caspase-1 processing and pyroptosis is exclusively dependent on NLRC4, but not on NLRP3 in the early phase of macrophage infection, whereas at later time points caspase-1 activation and cell death is NLRC4- independent. In the early phase we identified an activation pathway involving caspases-9, -7 and PARP downstream of NLRC4 and caspase-1. Analyses of caspase-1/11-deficient infected macrophages revealed a strong induction of apoptosis, which is dependent on activation of apoptotic initiator and effector caspases. The early activation pathway of caspase-1 in macrophages was markedly reduced or completely abolished after infection with a B. pseudomallei flagellin FliC or a T3SS3 BsaU mutant. Studies using cells transfected with the wild-type and mutated T3SS3 effector protein BopE indicated also a role of this protein in caspase-1 processing. A T3SS3 inner rod protein BsaK mutant failed to activate caspase-1, revealed higher intracellular counts, reduced cell death and IL-1β secretion during early but not during late macrophage infection compared to the wild-type. Intranasal infection of BALB/c mice with the BsaK mutant displayed a strongly decreased mortality, lower bacterial loads in organs, and reduced levels of IL-1β, myeloperoxidase and neutrophils in bronchoalveolar lavage fluid. In conclusion, our results indicate a major role for a functional T3SS3 in early NLRC4-mediated caspase-1 activation and pyroptosis and a contribution of late caspase-1-dependent and -independent cell death mechanisms in the pathogenesis of B. pseudomallei infection.
Author Summary
Inflammasome activation is important for host defence against bacterial infection. Many gram-negative pathogens use secretion systems to inject bacterial proteins such as flagellin or structural components of the secretion machinery itself into the host cytosol leading to caspase-1 activation and pyroptotic cell death. However, little is known about the B. pseudomallei factors that trigger caspase-1 activation as well as downstream signalling pathways and effector mechanisms of caspase-1. Here, we identified the B. pseudomallei T3SS3 inner rod protein BsaK as an early activator of caspase-1-dependent cell death and IL-1β secretion in primary macrophages and as a virulence factor in murine melioidosis. We could show that upon infection of macrophages, caspase-7 is activated downstream of the NLRC4/caspase-1 inflammasome and requires caspase-9 processing. Although caspase-7 was essential for cleavage of the DNA damage sensor PARP during pyroptosis, it did neither contribute to cytokine production nor B. pseudomallei growth restriction by promoting early macrophage death. In addition to a rapid NLRC4/caspase-1- dependent induction of pyroptosis in wild-type macrophages, we observed a delayed activation of classical apoptosis in macrophages lacking caspase-1/11. Thus, initiation of different cell death pathways seems to be an effective strategy to limit intracellular B. pseudomallei infection.
doi:10.1371/journal.ppat.1003986
PMCID: PMC3953413  PMID: 24626296
10.  Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release 
BMC Neuroscience  2005;6:13.
Background
Apoptosis plays a key role in cell death observed in neurodegenerative diseases marked by a progressive loss of neurons as seen in Alzheimer's disease. Although the exact cause of apoptosis is not known, a number of factors such as free radicals, insufficient levels of nerve growth factors and excessive levels of glutamate have been implicated. We and others, have previously reported that in a stable HT22 neuronal cell line, glutamate induces apoptosis as indicated by DNA fragmentation and up- and down-regulation of Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic) genes respectively. Furthermore, these changes were reversed/inhibited by estrogens. Several lines of evidence also indicate that a family of cysteine proteases (caspases) appear to play a critical role in neuronal apoptosis. The purpose of the present study is to determine in primary cultures of cortical cells, if glutamate-induced neuronal apoptosis and its inhibition by estrogens involve changes in caspase-3 protease and whether this process is mediated by Fas receptor and/or mitochondrial signal transduction pathways involving release of cytochrome c.
Results
In primary cultures of rat cortical cells, glutamate induced apoptosis that was associated with enhanced DNA fragmentation, morphological changes, and up-regulation of pro-caspase-3. Exposure of cortical cells to glutamate resulted in a time-dependent cell death and an increase in caspase-3 protein levels. Although the increase in caspase-3 levels was evident after 3 h, cell death was only significantly increased after 6 h. Treatment of cells for 6 h with 1 to 20 mM glutamate resulted in a 35 to 45% cell death that was associated with a 45 to 65% increase in the expression of caspase-3 protein. Pretreatment with caspase-3-protease inhibitor z-DEVD or pan-caspase inhibitor z-VAD significantly decreased glutamate-induced cell death of cortical cells. Exposure of cells to glutamate for 6 h in the presence or absence of 17β-estradiol or Δ8, 17β-estradiol (10 nM-10 μM) resulted in the prevention of cell death and was associated with a significant dose-dependent decrease in caspase-3 protein levels, with Δ8, 17β-E2 being more potent than 17β-E2. Protein levels of Fas receptor remained unchanged in the presence of glutamate. In contrast, treatment with glutamate induced, in a time-dependent manner, the release of cytochrome c into the cytosol. Cytosolic cytochrome c increased as early as 1.5 h after glutamate treatment and these levels were 5 fold higher after 6 h, compared to levels in the untreated cells. Concomitant with these changes, the levels of cytochrome c in mitochondria decreased significantly. Both 17β-E2 and Δ8, 17β-E2 reduced the release of cytochrome c from mitochondria into the cytosol and this decrease in cytosolic cytochrome c was associated with inhibition of glutamate-induced cell death.
Conclusion
In the primary cortical cells, glutamate-induced apoptosis is accompanied by up-regulation of caspase-3 and its activity is blocked by caspase protease inhibitors. These effects of glutamate on caspase-3 appear to be independent of changes in Fas receptor, but are associated with the rapid release of mitochondrial cytochrome c, which precedes changes in caspase-3 protein levels leading to apoptotic cell death. This process was differentially inhibited by estrogens with the novel equine estrogen Δ8, 17β-E2 being more potent than 17β-E2. To our knowledge, this is the first study to demonstrate that equine estrogens can prevent glutamate-induced translocation of cytochrome c from mitochondria to cytosol in rat primary cortical cells.
doi:10.1186/1471-2202-6-13
PMCID: PMC555946  PMID: 15730564
11.  The Inflammasome-Mediated Caspase-1 Activation Controls Adipocyte Differentiation and Insulin Sensitivity 
Cell metabolism  2010;12(6):593-605.
SUMMARY
Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1β and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1β and IL-18 requires cleavage by caspase-1, a cysteine protease regulated by a protein complex called the inflammasome. We demonstrate that the inflamma-some/caspase-1 governs adipocyte differentiation and insulin sensitivity. Caspase-1 is upregulated during adipocyte differentiation and directs adipocytes toward a more insulin-resistant phenotype. Treatment of differentiating adipocytes with recombinant IL-1β and IL-18, or blocking their effects by inhibitors, reveals that the effects of caspase-1 on adipocyte differentiation are largely conveyed by IL-1β. Caspase-1 and IL-1β activity in adipose tissue is increased both in diet-induced and genetically induced obese animal models. Conversely, mice deficient in caspase-1 are more insulin sensitive as compared to wild-type animals. In addition, differentiation of preadipocytes isolated from caspase-1−/− or NLRP3−/− mice resulted in more metabolically active fat cells. In vivo, treatment of obese mice with a caspase-1 inhibitor significantly increases their insulin sensitivity. Indirect calorimetry analysis revealed higher fat oxidation rates in caspase-1−/− animals. In conclusion, the inflammasome is an important regulator of adipocyte function and insulin sensitivity, and caspase-1 inhibition may represent a novel therapeutic target in clinical conditions associated with obesity and insulin resistance.
doi:10.1016/j.cmet.2010.11.011
PMCID: PMC3683568  PMID: 21109192
12.  DECREASED EXPRESSION LEVEL OF APOPTOSIS-RELATED GENES AND/OR PROTEINS IN SKELETAL MUSCLES, BUT NOT IN HEARTS, OF GROWTH HORMONE RECEPTOR KNOCKOUT MICE 
The long-lived growth hormone (GH) receptor knockout (GHRKO; KO) mice are GH resistant due to targeted disruption of the GH receptor (Ghr) gene. Apoptosis is a physiological process in which cells play an active role in their own death and is a normal component of the development and health of multicellular organisms. Aging is associated with the progressive loss of strength of skeletal and heart muscles. Calorie restriction (CR) is a well known experimental model to delay aging and increase lifespan. The aim of the study was to examine the expression of the following apoptosis-related genes: caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, p53 and cytochrome c1 (cyc1) in the skeletal muscles and hearts of female normal and GHRKO mice, fed ad libitum or subjected to 40% CR for 6 months, starting at 2 months of age. Moreover, skeletal muscle caspase-3, caspase-9, caspase-8, bax, bcl-2, Smac/DIABLO, Apaf-1, bad, phospho-bad (pbad), phospho-p53 (pp53) and cytochrome c (cyc) protein expression levels were assessed.
Results
Expression of caspase-3, caspase-9, bax and Smac/DIABLO genes and proteins was decreased in GHRKO’s skeletal muscles. The Apaf-1 protein expression also was diminished in this tissue. In contrast, bcl-2 and pbad protein levels were increased in skeletal muscles in knockouts. No changes were demonstrated for the examined genes expression in GHRKO’s hearts except for the increased level of cyc1 mRNA. CR did not alter the expression of the examined genes and proteins in skeletal muscles of knockouts vs. normal (N) mice. In heart homogenates, CR increased caspase-3 mRNA level as compared to ad libitum (AL) mice.
Conclusion
decreased expression of certain pro-apoptotic genes and/or proteins may constitute the potential mechanism of prolonged longevity in GHRKO mice, protecting these animals from aging; this potential beneficial mechanism is not affected by calorie restriction.
doi:10.1258/ebm.2010.010202
PMCID: PMC3703836  PMID: 21321312
13.  Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo 
Cell Death and Differentiation  2014;22(5):719-730.
Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2-deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo.
doi:10.1038/cdd.2014.159
PMCID: PMC4392070  PMID: 25301067
14.  Leptin attenuates cardiac apoptosis after chronic ischaemic injury 
Cardiovascular Research  2009;83(2):313-324.
Aims
We have previously shown that activation of leptin signalling in the heart reduces cardiac morbidity and mortality after myocardial infarction (MI). In the present study, we tested the hypothesis that leptin signalling limits cardiac apoptosis after MI through activation of signal transducer and activator of transcription (STAT)-3 responsive anti-apoptotic genes, including B-cell lymphoma (bcl)-2 and survivin, that serve to downregulate the activity of caspase-3.
Methods and results
Hearts from C57BL/6J and three groups of leptin-deficient Ob/Ob mice (food-restricted, ad libitum, and leptin-repleted) were examined 4 weeks after permanent left coronary artery ligation or sham operation. Inflammatory and apoptotic cell number was determined in cardiac sections by immunostaining. Expression of cardiac bcl-2, survivin, and pro and active caspase-3 was determined and correlated with in vitro caspase-3 activity. In the absence of MI, both lean and obese leptin-deficient mice exhibited increased cardiac apoptosis compared with wild-type mice. After MI, the highest rates of apoptosis were seen in the infarcted tissue of lean and obese Ob/Ob mice. Further, leptin-deficient hearts, as well as hearts from wild-type mice treated with the STAT-3 inhibitor WP1066, exhibited blunted anti-apoptotic bcl-2 and survivin gene expression, and increased caspase-3 protein expression and activity. The increased caspase-3 activity and apoptosis in hearts of leptin-deficient mice after MI was significantly attenuated in Ob/Ob mice replete with leptin, reducing apoptosis to levels comparable to that observed in wild-type mice after MI.
Conclusion
These results demonstrate that intact leptin signalling post-MI acts through STAT-3 to increase anti-apoptotic bcl-2 and survivin gene expression and reduces caspase-3 activity, consistent with a cardioprotective role of leptin in the setting of chronic ischaemic injury.
doi:10.1093/cvr/cvp071
PMCID: PMC2701718  PMID: 19233863
Apoptosis; Leptin; Survivin; bcl-2; Heart failure
15.  Caspase-8 tyrosine-380 phosphorylation inhibits CD95 DISC function by preventing procaspase-8 maturation and cycling within the complex 
Oncogene  2016;35(43):5629-5640.
Caspase-8 is a key initiator of apoptotic cell death where it functions as the apical protease in death receptor-mediated apoptosis triggered via the death-inducing signalling complex (DISC). However, the observation that caspase-8 is upregulated in many common tumour types led to the discovery of alternative non-apoptotic, pro-survival functions, many of which are contingent on phosphorylation of a tyrosine residue (Y380) found in the linker region between the two catalytic domains of the enzyme. Furthermore, Src-mediated Y380 phosphorylation leads to increased resistance to CD95-induced apoptosis; however, the mechanism underlying this impaired response to extrinsic apoptotic stimuli has not been identified. Consequently, we have employed a number of model systems to further dissect this protective mechanism. First, using an in vitro DISC model together with recombinant procaspase-8 variants, we show that Y380 phosphorylation inhibits procaspase-8 activation at the CD95 DISC, thereby preventing downstream activation of the caspase cascade. Second, we validated this finding in a cellular context using transfected neuroblastoma cell lines deficient in caspase-8. Reconstitution of these lines with phosphomimetic-caspase-8 results in increased resistance to CD95-mediated apoptosis and enhanced cell migration. When the in vitro DISC is assembled in the presence of cell lysate, caspase-8 Y380 phosphorylation attenuates DISC activity by inhibiting procaspase-8 autoproteolytic activity but not recruitment or homodimerization of caspase-8 within the complex. Once incorporated into the DISC, phosphorylated caspase-8 is unable to be released from the complex; this inhibits further cycling and release of active catalytic subunits into the cytoplasm, thus resulting in increased apoptotic resistance. Taken together, our novel findings expand our understanding of the key mechanisms underlying the anti-apoptotic functions of caspase-8 which may act as a critical block to existing antitumour therapies. Importantly, reversal or inhibition of caspase-8 phosphorylation may prove a valuable avenue to explore for sensitization of resistant tumours to extrinsic apoptotic stimuli.
doi:10.1038/onc.2016.99
PMCID: PMC5095593  PMID: 27109099
16.  Prostaglandin F2alpha- and FAS-activating antibody-induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice 
We recently demonstrated that caspase-3 is important for apoptosis during spontaneous involution of the corpus luteum (CL). These studies tested if prostaglandin F2α (PGF2α) or FAS regulated luteal regression, utilize a caspase-3 dependent pathway to execute luteal cell apoptosis, and if the two receptors work via independent or potentially shared intracellular signaling components/pathways to activate caspase-3. Wild-type (WT) or caspase-3 deficient female mice, 25–26 days old, were given 10 IU equine chorionic gonadotropin (eCG) intraperitoneally (IP) followed by 10 IU human chorionic gonadotropin (hCG) IP 46 h later to synchronize ovulation. The animals were then injected with IgG (2 micrograms, i.v.), the FAS-activating antibody Jo2 (2 micrograms, i.v.), or PGF2α (10 micrograms, i.p.) at 24 or 48 h post-ovulation. Ovaries from each group were collected 8 h later for assessment of active caspase-3 enzyme and apoptosis (measured by the TUNEL assay) in the CL. Regardless of genotype or treatment, CL in ovaries collected from mice injected 24 h after ovulation showed no evidence of active caspase-3 or apoptosis. However, PGF2α or Jo2 at 48 h post-ovulation and collected 8 h later induced caspase-3 activation in 13.2 ± 1.8% and 13.7 ± 2.2 % of the cells, respectively and resulted in 16.35 ± 0.7% (PGF2α) and 14.3 ± 2.5% TUNEL-positive cells when compared to 1.48 ± 0.8% of cells CL in IgG treated controls. In contrast, CL in ovaries collected from caspase-3 deficient mice whether treated with PGF2α , Jo2, or control IgG at 48 h post-ovulation showed little evidence of active caspase-3 or apoptosis. CL of WT mice treated with Jo2 at 48 h post-ovulation had an 8-fold increase in the activity of caspase-8, an activator of caspase-3 that is coupled to the FAS death receptor. Somewhat unexpectedly, however, treatment of WT mice with PGF2α at 48 h post-ovulation resulted in a 22-fold increase in caspase-8 activity in the CL, despite the fact that the receptor for PGF2α has not been shown to be directly coupled to caspase-8 recruitment and activation. We hypothesize that PGF2α initiates luteolysis in vivo, at least in part, by increasing the bioactivity or bioavailability of cytokines, such as FasL and that multiple endocrine factors work in concert to activate caspase-3-driven apoptosis during luteolysis.
doi:10.1186/1477-7827-1-15
PMCID: PMC152637  PMID: 12657159
17.  Recql5 protects against lipopolysaccharide/D-galactosamine-induced liver injury in mice 
World Journal of Gastroenterology : WJG  2015;21(36):10375-10384.
AIM: To investigate the effects of Recql5 deficiency on liver injury induced by lipopolysaccharide/D-galactosamine (LPS/D-Gal).
METHODS: Liver injury was induced in wild type (WT) or Recql5-deficient mice using LPS/D-Gal, and assessed by histological, serum transaminases, and mortality analyses. Hepatocellular apoptosis was quantified by transferase dUTP nick end labeling assay and Western blot analysis of cleaved caspase-3. Liver inflammatory chemokine and cytochrome P450 expression was analyzed by quantitative reverse transcription-PCR. Neutrophil infiltration was evaluated by myeloperoxidase activity. Expression and phosphorylation of ERK, JNK, p65, and H2A.X was determined by Western blot. Oxidative stress was evaluated by measuring malondialdehyde production and nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity.
RESULTS: Following LPS/D-Gal exposure, Recql5-deficient mice exhibited enhanced liver injury, as evidenced by more severe hepatic hemorrhage, higher serum aspartate transaminase and alanine transaminase levels, and lower survival rate. As compared to WT mice, Recql5-deficient mice showed an increased number of apoptotic hepatocytes and higher cleaved caspase-3 levels. Recql5-deficient mice exhibited increased DNA damage, as evidenced by increased γ-H2A.X levels. Inflammatory cytokine levels, neutrophil infiltration, and ERK phosphorylation were also significantly increased in the knockout mice. Additionally, Recql5-deficicent mice exhibited increased malondialdehyde production and elevated inducible nitric oxide synthase, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activity, indicative of enhanced oxidative stress. Moreover, CYP450 expression was significantly downregulated in Recql5-deficient mice after LPS/D-Gal treatment.
CONCLUSION: Recql5 protects the liver against LPS/D-Gal-induced injury through suppression of hepatocyte apoptosis and oxidative stress and modulation of CYP450 expression.
doi:10.3748/wjg.v21.i36.10375
PMCID: PMC4579884  PMID: 26420964
Recql5; Liver injury; Apoptosis; Oxidative stress; CYP450
18.  The Pro-Apoptotic BH3-only, Bcl-2 Family Member Puma Is Critical for Acute Ethanol-Induced Neuronal Apoptosis 
Synaptogenesis in humans occurs in the last trimester of gestation and in the first few years of life whereas it occurs in the postnatal period in rodents. A single exposure of neonatal rodents to ethanol during this period evokes extensive neuronal apoptosis. Previous studies indicate that ethanol triggers the intrinsic apoptotic pathway in neurons and that this requires the multi-BH domain, pro-apoptotic Bcl-2 family member Bax. To define the upstream regulators of this apoptotic pathway, we examined the possible roles of p53 and a subclass of pro-apoptotic Bcl-2 family members (i.e. the BH3 domain-only proteins) in neonatal wild-type and gene-targeted mice that lack these cell death inducers. Acute ethanol exposure produced greater caspase-3 activation and neuronal apoptosis in wild type mice than in saline-treated littermate controls. Loss of Puma resulted in marked protection from ethanol-induced caspase-3 activation and apoptosis. Although Puma expression has been reported to be regulated by p53, p53-deficient mice exhibited a similar extent of ethanol-induced caspase-3 activation and neuronal apoptosis as wild-type mice. Mice deficient in other pro-apoptotic BH3-only proteins, including Noxa, Bim or Hrk, showed no significant protection from ethanol-induced neuronal apoptosis. Collectively, these studies indicate a p53-independent, Bax- and Puma-dependent mechanism of neuronal apoptosis and identify Puma as a possible molecular target for inhibiting the effects of intrauterine ethanol exposure in humans.
doi:10.1097/NEN.0b013e3181a9d524
PMCID: PMC2745204  PMID: 19535997
Apoptosis; Bax; BH3-only; Caspase-3; Ethanol; Noxa; p53; Puma
19.  Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis 
Kinetic modeling, phase diagrams analysis, and quantitative single-cell experiments are combined to investigate how multiple factors, including the XIAP:caspase-3 ratio and ligand concentration, regulate receptor-mediated apoptosis.
Based on protein expression levels, Lyapunov-based phase diagrams predict which pathways are required for a cell to undergo receptor-mediated cell death.Multiple inter-dependent factors, including the XIAP:caspase-3 ratio and ligand concentration, regulate the requirement for mitochondrial outer membrane permeabilization during receptor-mediated apoptosis.The E3 ubiquitin ligase activity of XIAP is essential for maintaining the ‘snap-action' regulation of effector caspase activity.Cell-to-cell variability in protein expression gives rise to mixed phenotypes in cell lines that map close to boundaries (separatrices) identified by Lyapunov exponent analysis.
In mammalian cells, extrinsic (receptor-mediated) apoptosis is triggered by binding of extracellular death ligands such as tumor necrosis factor (TNF) and TRAIL (TNF-related apoptosis-inducing ligand) to cognate receptors. When death receptors are activated, death inducing signaling complexes (DISCs) assemble causing activation and cleavage of initiator pro-caspases-8 and -10, which then cleave effector pro-caspases-3 and -7 in a multi-enzyme cascade (Riedl and Shi, 2004). Active effector caspases digest essential cellular proteins and activate the CAD nucleases that cleave genomic DNA, thereby killing cells. This cascade of DISC assembly followed by initiator and then effector caspase activation is sufficient to kill so-called type I cells (e.g. B lymphocytes), but most cell types exhibit a type II behavior in which mitochondrial outer membrane permeabilization (MOMP) is an essential step in the march to death (Scaffidi et al, 1998; Barnhart et al, 2003; Letai, 2008). Identifying factors that determine whether cells are type I or II is of practical and theoretical interest. From a practical perspective, whether a cell requires MOMP for apoptosis determines the potency of Bcl2 and similar oncogenes, the efficacy of anti-Bcl2 drugs such as navitoclax (ABT-263), and the sensitivity of cells to TRAIL and anti-TRAIL receptor antibodies, which are also investigational anti-cancer drugs (Newsom-Davis et al, 2009). From a theoretical perspective, the type I versus II choice exemplifies a common situation in mammalian cells in which overlapping signaling pathways play a greater or lesser role in controlling cell fate depending on cell type: it is remarkable that a simple three-step (receptor→initiator caspase→effector caspase) process is sufficient to trigger apoptosis in some cell types but that a much more complex route involving MOMP is required in others.
Attempts to understand why some cells require MOMP for cell death and others do not have identified differences in the oligomeric state of death ligand receptors and the efficiency of DISC formation as important variables. In cells in which DISCs form efficiently, initiator caspases are cleaved rapidly and sufficient effector pro-caspases are processed into their active forms to kill cells (type I cells; Scaffidi et al, 1999b). In type II cells, DISC formation seems to be less efficient, and it has been proposed that MOMP is required to amplify weak initiator caspase signals and thereby generate lethal effector caspase levels (Barnhart et al, 2003). However, it has recently become apparent that XIAP also plays a role in type I versus II choice: in XIAP knockout mice, liver cells switch from a type II to a type I phenotype (Jost et al, 2009) and XIAP is observed to be involved in the survival of type I cells treated with death ligands in culture (Maas et al, 2010).
In this paper, we attempt to place these observations in a quantitative context by analyzing a computational model of extrinsic cell death using a method drawn from dynamical system analysis, direct finite-time Lyapunov exponent (DLE) analysis. Our implementation of DLE analysis relates changes in the concentrations of protein in a model to an outcome several hours later. We computed DLEs for six regulators of apoptosis over a range of concentrations determined experimentally to represent a natural range of variation in parental or genetically modified tumor cell lines. This generated a phase space onto which individual cell lines could be mapped using quantitative immunoblotting data. Cell-to-cell variation was estimated by flow cytometry and also mapped onto the phase space. The most interesting regions of the space were those in which a small change in one or more initial protein concentration resulted in a dramatic change in phenotype. Such a boundary or separatrix was observed in slices of phase space corresponding XIAP versus pro-caspase-3 concentration (the [XIAP]:[caspase-3] ratio). In cells in which the ratio is low, a type I phenotype is predicted to occur; when the ratio is high, a type II phenotype is favored; and in cell lines that lie close to the separatrix, cell-to-cell variability is expected, with some cells exhibiting a type I phenotype and others a type II behavior. DLE analysis shows that the [XIAP]:[caspase-3] ratio is not the only controlling factor in type I versus II control: as receptor activity or ligand concentration increase, the position of the separatrix changes so as to expand the region in which the type I phenotype is favored.
We tested these predictions by manipulating XIAP and ligand levels in multiple cell lines and then followed cell death by imaging, flow cytometry, or clonogenic assays. We observed that when XIAP was knocked out (by homologous recombination) in the HCT116 colorectal cancer line, cells shifted from a pure type II to a type I phenotype, as predicted from the DLE phase diagram. SKW6.4 B-cell lymphoma cells were predicted to lie at a position in phase space that is insensitive to XIAP levels (within the range achievable by over-expression) and we confirmed this experimentally. Finally, T47D breast cancer cells were predicted—and observed—to straddle the separatrix and to exhibit cell-to-cell variability in fate, with some cells showing a type I and others a type II phenotype. As the concentration of TRAIL was increased, the ratio of type I to type II T47D cells increased, confirming the prediction that this ratio is controlled in a multi-factorial manner.
To extend our approach to mutations that change protein activity rather than protein level, we simulated the effects of changing rate constants that control ubiquitylation of caspase-3 following its binding to XIAP. We generated cells carrying a truncated form of XIAP that lacks the RING domain (XIAPΔRING) and cannot mediate the ubiquitylation of caspase-3 (this truncation leaves the affinity of XIAP for caspase-3 unchanged). We predicted and demonstrated experimentally that expression of XIAPΔRING disrupts normal snap-action control over caspase-3 activation. Our findings not only advance understanding of extrinsic apoptosis but also constitute a proof of principle for an approach to quantitative modeling of dynamic regulatory processes in diverse cell types.
Receptor-mediated apoptosis proceeds via two pathways: one requiring only a cascade of initiator and effector caspases (type I behavior) and the second requiring an initiator–effector caspase cascade and mitochondrial outer membrane permeabilization (type II behavior). Here, we investigate factors controlling type I versus II phenotypes by performing Lyapunov exponent analysis of an ODE-based model of cell death. The resulting phase diagrams predict that the ratio of XIAP to pro-caspase-3 concentrations plays a key regulatory role: type I behavior predominates when the ratio is low and type II behavior when the ratio is high. Cell-to-cell variability in phenotype is observed when the ratio is close to the type I versus II boundary. By positioning multiple tumor cell lines on the phase diagram we confirm these predictions. We also extend phase space analysis to mutations affecting the rate of caspase-3 ubiquitylation by XIAP, predicting and showing that such mutations abolish all-or-none control over activation of effector caspases. Thus, phase diagrams derived from Lyapunov exponent analysis represent a means to study multi-factorial control over a complex biochemical pathway.
doi:10.1038/msb.2011.85
PMCID: PMC3261706  PMID: 22108795
apoptosis; caspases; dynamical systems analysis; kinetic modeling; XIAP
20.  Non-apoptotic functions of caspase-7 during osteogenesis 
Cell Death & Disease  2014;5(8):e1366-.
Caspase-3 and -7 are generally known for their central role in the execution of apoptosis. However, their function is not limited to apoptosis and under specific conditions activation has been linked to proliferation or differentiation of specialised cell types. In the present study, we followed the localisation of the activated form of caspase-7 during intramembranous (alveolar and mandibular bones) and endochondral (long bones of limbs) ossification in mice. In both bone types, the activated form of caspase-7 was detected from the beginning of ossification during embryonic development and persisted postnatally. The bone status was investigated by microCT in both wild-type and caspase-7-deficient adult mice. Intramembranous bone in mutant mice displayed a statistically significant decrease in volume while the mineral density was not altered. Conversely, endochondral bone showed constant volume but a significant decrease in mineral density in caspase-7 knock-out mice. Cleaved caspase-7 was present in a number of cells that did not show signs of apoptosis. PCR array analysis of the mandibular bone of caspase-7-deficient versus wild-type mice pointed to a significant decrease in mRNA levels for Msx1 and Smad1 in early bone formation. These observations might explain the decrease in the alveolar bone volume of adult knock-out mice. In conclusion, this study is the first to report a non-apoptotic function of caspase-7 in osteogenesis and also demonstrates further specificities in endochondral versus intramembranous ossification.
doi:10.1038/cddis.2014.330
PMCID: PMC4454305  PMID: 25118926
21.  Listeria monocytogenes Infection in Caspase-11-Deficient Mice  
Infection and Immunity  2002;70(5):2657-2664.
Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1β [IL-1β]-converting enzyme), Cas11 is directly involved in the maturation of IL-1β and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11−/−) mice during infection with Listeria monocytogenes. Cas11−/− and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11−/− and wild-type mice infected with Listeria had similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1β levels were similar in Cas11−/− mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11−/− mice were deficient in the production of gamma interferon. IL-1β responses in Cas11−/− were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1β were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.
doi:10.1128/IAI.70.5.2657-2664.2002
PMCID: PMC127953  PMID: 11953408
22.  Retina Is Protected by Neuroserpin from Ischemic/Reperfusion-Induced Injury Independent of Tissue-Type Plasminogen Activator 
PLoS ONE  2015;10(7):e0130440.
The purpose of the present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) on acute retinal ischemic/reperfusion-induced (IR) injury. An IR injury model was established by elevating intraocular pressure (IOP) for 60 minutes in wild type and tPA-deficient (tPA-/-) mice. Prior to IR injury, 1 μL of 20 μmol/L NSP or an equal volume of bovine serum albumin (BSA) was intravitreally administered. Retinal function was evaluated by electroretinograph (ERG) and the number of apoptotic neurons was determined via TUNEL labeling. Caspase-3, -8, -9,poly (ADP-ribose) polymerase (PARP)and their cleaved forms were subsequently analyzed. It was found that IR injury significantly damaged retinal function, inducing apoptosis in the retina, while NSP attenuated the loss of retinal function and significantly reduced the number of apoptotic neurons in both wild type and tPA-/- mice. The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA-/- mice. NSP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3. It was therefore concluded that the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator.
doi:10.1371/journal.pone.0130440
PMCID: PMC4503687  PMID: 26176694
23.  Caspase-Dependent Inhibition of Mousepox Replication by gzmB 
PLoS ONE  2009;4(10):e7512.
Background
Ectromelia virus is a natural mouse pathogen, causing mousepox. The cytotoxic T (Tc) cell granule serine-protease, granzyme B, is important for its control, but the underlying mechanism is unknown. Using ex vivo virus immune Tc cells, we have previously shown that granzyme B is able to activate several independent pro-apoptotic pathways, including those mediated by Bid/Bak/Bax and caspases-3/-7, in target cells pulsed with Tc cell determinants.
Methods and Findings
Here we analysed the physiological relevance of those pro-apoptotic pathways in ectromelia infection, by incubating ectromelia-immune ex vivo Tc cells from granzyme A deficient (GzmB+ Tc cells) or granzyme A and granzyme B deficient (GzmA×B−/− Tc cell) mice with ectromelia-infected target cells. We found that gzmB-induced apoptosis was totally blocked in ectromelia infected or peptide pulsed cells lacking caspases-3/-7. However ectromelia inhibited only partially apoptosis in cells deficient for Bid/Bak/Bax and not at all when both pathways were operative suggesting that the virus is able to interfere with apoptosis induced by gzmB in case not all pathways are activated. Importantly, inhibition of viral replication in vitro, as seen with wild type cells, was not affected by the lack of Bid/Bak/Bax but was significantly reduced in caspase-3/-7-deficient cells. Both caspase dependent processes were strictly dependent on gzmB, since Tc cells, lacking both gzms, neither induced apoptosis nor reduced viral titers.
Significance
Out findings present the first evidence on the biological importance of the independent gzmB-inducible pro-apoptotic pathways in a physiological relevant virus infection model.
doi:10.1371/journal.pone.0007512
PMCID: PMC2759507  PMID: 19838298
24.  Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice 
Cell Death Discovery  2016;2:16009-.
Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2−/−) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2−/− mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18–22 months) male Casp2−/− mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2−/− mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2−/− mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2−/− mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.
doi:10.1038/cddiscovery.2016.9
PMCID: PMC4979492  PMID: 27551503
25.  Caspase-7: a protease involved in apoptosis and inflammation 
Caspase-7 was considered to be redundant with caspase-3 because these related cystein proteases share an optimal peptide recognition sequence and have several endogenous protein substrates in common. In addition, both caspases are proteolytically activated by the initiator caspases-8 and -9 during death receptor- and DNA-damage-induced apoptosis, respectively. However, a growing body of biochemical and physiological data indicate that caspase-7 also differs in significant ways from caspase-3. For instance, several substrates are specifically cleaved by caspase-7, but not caspase-3. Moreover, caspase-7 activation requires caspase-1 inflammasomes under inflammatory conditions, while caspase-3 processing proceeds independently of caspase-1. Finally, caspase-7 deficient mice are resistant to endotoxemia, whereas caspase-3 knockout mice are susceptible. These findings suggest that specifically interfering with caspase-7 activation may hold therapeutic value for the treatment of cancer and inflammatory ailments.
doi:10.1016/j.biocel.2009.09.013
PMCID: PMC2787741  PMID: 19782763
caspase-7; caspase-3; apoptosis; inflammation

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