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1.  Designing and screening of universal drug from neem (Azadirachta indica) and standard drug chemicals against influenza virus nucleoprotein 
Background
Different strains of influenza virus are affecting a large number of people worldwide. Many synthetic antiviral medicines are available for influenza virus in the market. But still there is a need for the development of universal drugs against these strains of influenza virus.
Methods
For this purpose conserved residues within the influenza virus nucleoprotein have been retrieved. The drugs, previously known to have antiviral properties, were screened to identify the best candidate universal drug against Influenza virus strains. Compounds from leaf extracts of neem, were also screened to identify the natural drugs without side effects.
Result
Molecular docking identified three potential compounds (Nimbaflavone, Rutin, and Hyperoside) having perfect binding with reported conserved residues (ASP302, SER50) of influenza virus nucleoprotein that is involved in the binding of drugs. Further analysis showed Hyperoside as a universal drug against various influenza strains. Some chemical drugs were also evaluated through screening against nucleoprotein. The results showed six drugs (OMS, CBX, LGH, Naproxen, BMS-883559, and BMS-885838) which were interacting with same conserved residues (ASP302, TYR52, SER50, GLY288, SER376, and ARG99) as were found in the case of neem phytochemicals. Hyperoside from neem leaf extract along with drugs LGH, Naproxen, BMS-885838, and BMS-883559 showed best interactions with conserved residues of nucleoprotein.
Conclusion
The compound Hyperoside from neem leaf extract along with drugs LGH, Naproxen, BMS-885838, and BMS-883559 showed best interactions with conserved residues of nucleoprotein. So these compounds have been identified for their potential against influenza strains to be utilized as a universal drug.
doi:10.1186/s12906-016-1469-2
PMCID: PMC5162082  PMID: 27986088
Influenza virus; Nucleoprotein; Neem leaf extract; Molecular docking; Universal drug
2.  Stray notes on two phthirapteran species occurring on Indian grey Horn Bill, Tockus birostris Scopoli (Coraciformes: Bucerotidae) 
Two phthirapteran species (an amblyceran Chapinia clayae and an ischnoceran, Buceroemersonia clarkei) were recovered from eight Indian grey Horn Bills, during 2009 in district Rampur (India). The occurrence of B. clarkei on Indian birds has not been noted earlier. The population characteristics of both the species have been recorded. On the basis of crop contents C. clayae appeared to be a probable haematophagous. The egg chorion of B. clarkei appeared smooth that of C.clayae bears sculpturing.
doi:10.1007/s12639-013-0409-z
PMCID: PMC4675591  PMID: 26688647
Buceroemersonia clarkei; Chapinia clayae; Indian grey Horn Bill lice; Mallophaga; Phthiraptera; Tockus birostris
3.  Amplicon-Based RNA Interference Targeting V2 Gene of Cotton Leaf Curl Kokhran Virus-Burewala Strain Can Provide Resistance in Transgenic Cotton Plants 
Molecular Biotechnology  2016;58(12):807-820.
The conserved coat or V2 gene of begomoviruses is responsible for viral movement in the plant cells. RNAi technology was used to silence V2 gene for resistance against these viruses in transgenic plants. The transformation of the RNAi-based gene construct targeting V2 gene of CLCuKoV-Bur, cloned under 35S promoter, was done in two elite cotton varieties MNH-786 and VH-289 using shoot apex cut method of gene transformation. The transformation efficiency was found to be 3.75 and 2.88 % in MNH-786 and VH-289, respectively. Confirmation of successful transformation was done through PCR in T 0, T 1, and T 2 generations using gene-specific primers. Transgenic cotton plants were categorized on the basis of the virus disease index in T 1 generation. Copy number and transgene location were observed using FISH and karyotyping in T 2 generation which confirmed random integration of V2 RNAi amplicon at chromosome 6 and 16. Real-time quantitative PCR analyses of promising transgenic lines showed low virus titer compared to wild-type control plants upon challenging them with viruliferous whiteflies in a contained environment. From the results, it was concluded that amplicon V2 RNAi construct was able to limit virus replication and can be used to control CLCuV in the field.
doi:10.1007/s12033-016-9980-8
PMCID: PMC5102983  PMID: 27757798
Gene transformation; siRNA; CLCuD; Begomovirus; V2 ORF; Knockdown
4.  Population levels of Phthiraptera on domestic ducks (Anas platyrhynchos) (Anseriformes: Anatidae) 
Three phthirapteran species (two Ischnocera and one Amblycera) were recovered from hundred ducks in district Bareilly and Rampur during 2011–2012. Prevalence of Anaticola crassicornis was comparatively higher (31 %) than that of Anatoecus dentatus (16 %) and Holomenpon leucoxanthum (28 %). However, the intensity of infestation of H. leucoxanthum (22.89) remained higher than the other two species. Distribution pattern of all lice were skewed but negative binomial model was not found to be a good fit. Sex ratios of all three species were skewed in favour of females (A. crassicornis—1:1.23, H. leucoxanthum—1:1.19, A. dentatus—1:1.72) and nymphal population exceeded the adult population (A. crassicornis—1:1.26, H. leucoxanthum—1:1.12, A. dentatus—1:1.61).
doi:10.1007/s12639-013-0398-y
PMCID: PMC4554582  PMID: 26345073
Phthiraptera; Lice; Ischnocera; Amblycera; Prevalence
5.  Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity 
Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation–induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration–approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia–reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure.
doi:10.1165/rcmb.2014-0005OC
PMCID: PMC4491118  PMID: 25188881
chlorine; inhalation; cardiac; sarcoendoplasmic reticulum Ca2+ATPase; ranolazine
7.  Inhaled matters of the heart 
Inhalations of atmospheric pollutants, especially particulate matters, are known to cause severe cardiac effects and to exacerbate preexisting heart disease. Heart failure is an important sequellae of gaseous inhalation such as that of carbon monoxide. Similarly, other gases such as sulphur dioxide are known to cause detrimental cardiovascular events. However, mechanisms of these cardiac toxicities are so far unknown. Increased susceptibility of the heart to oxidative stress may play a role. Low levels of antioxidants in the heart as compared to other organs and high levels of reactive oxygen species produced due to the high energetic demand and metabolic rate in cardiac muscle are important in rendering this susceptibility. Acute inhalation of high concentrations of halogen gases is often fatal. Severe respiratory injury and distress occurs upon inhalation of halogens gases, such as chlorine and bromine; however, studies on their cardiac effects are scant. We have demonstrated that inhalation of high concentrations of halogen gases cause significant cardiac injury, dysfunction, and failure that can be critical in causing mortalities following exposures. Our studies also demonstrated that cardiac dysfunction occurs as a result of a direct insult independent of coexisting hypoxia, since it is not fully reversed by oxygen supplementation. Therefore, studies on offsite organ effects of inhaled toxic gases can impact development of treatment strategies upon accidental or deliberate exposures to these agents. Here we summarize the knowledge of cardiovascular effects of common inhaled toxic gases with the intent to highlight the importance of consideration of cardiac symptoms while treating the victims.
doi:10.14800/crm.997
PMCID: PMC4672864  PMID: 26665179
Inhaled gases; halogens; sulphur dioxide; cardiac dysfunction
8.  Stanniocalcin-1 is induced by Hypoxia Inducible Factor in Rat Alveolar Epithelial Cells 
Alveolar type II (ATII) cells remain differentiated and express surfactant proteins when cultured at an air-liquid (A/L) interface. When cultured under submerged conditions, ATII cells dedifferentiate and change their gene expression profile. We have previously shown that gene expression under submerged conditions is regulated by hypoxia inducible factor (HIF) signaling due to focal hypoxia resulting from ATII cell metabolism. Herein, we sought to further define gene expression changes in ATII cells cultured under submerged conditions. We performed a genome wide microarray on RNA extracted from rat ATII cells cultured under submerged conditions for 24–48 h after switching from an A/L interface. We found significant alterations in gene expression, including upregulation of the HIF target genes stanniocalcin-1 (STC1), tyrosine hydroxylase (Th), enolase (Eno) 2, and matrix metalloproteinase (MMP) 13, and we verified upregulation of these genes by RT-PCR. Because STC1, a highly evolutionarily conserved glycoprotein with anti-inflammatory, anti-apoptotic, anti-oxidant, and wound healing properties, is widely expressed in the lung, we further explored the potential functions of STC1 in the alveolar epithelium. We found that STC1 was induced by hypoxia and HIF in rat ATII cells, and this induction occurred rapidly and reversibly. We also showed that recombinant human STC1 (rhSTC1) enhanced cell motility with extended lamellipodia formation in alveolar epithelial cell (AEC) monolayers but did not inhibit the oxidative damage induced by LPS. We also confirmed that STC1 was upregulated by hypoxia and HIF in human lung epithelial cells. In this study, we have found that several HIF target genes including STC1 are upregulated in AECs by a submerged condition, that STC1 is regulated by hypoxia and HIF, that this regulation is rapidly and reversibly, and that STC1 enhances wound healing moderately in AEC monolayers. However, STC1 did not inhibit oxidative damage in rat AECs stimulated by LPS in vitro. Therefore, alterations in gene expression by ATII cells under submerged conditions including STC1 were largely induced by hypoxia and HIF, which may be relevant to our understanding of the pathogenesis of various lung diseases in which the alveolar epithelium is exposed to relative hypoxia.
doi:10.1016/j.bbrc.2014.09.060
PMCID: PMC4188510  PMID: 25251473
HIF; STC1; Gene expression; Alveolar epithelial cells
9.  Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation 
Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway–capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot–degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and α2-antiplasmin. Measurement of tissue-specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide–induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and α2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM.
doi:10.1165/rcmb.2014-0012OC
PMCID: PMC4189487  PMID: 24796565
sulfur mustard; lung injury; plasminogen activator inhibitor-1; α2-antiplasmin; thrombin activatable fibrinolysis inhibitor
10.  Chlorine inhalation-induced myocardial depression and failure 
Physiological Reports  2015;3(6):e12439.
Victims of chlorine (Cl2) inhalation that die demonstrate significant cardiac pathology. However, a gap exists in the understanding of Cl2-induced cardiac dysfunction. This study was performed to characterize cardiac dysfunction occurring after Cl2 exposure in rats at concentrations mimicking accidental human exposures (in the range of 500 or 600 ppm for 30 min). Inhalation of 500 ppm Cl2 for 30 min resulted in increased lactate in the coronary sinus of the rats suggesting an increase in anaerobic metabolism by the heart. There was also an attenuation of myocardial contractile force in an ex vivo (Langendorff technique) retrograde perfused heart preparation. After 20 h of return to room air, Cl2 exposure at 500 ppm was associated with a reduction in systolic and diastolic blood pressure as well echocardiographic/Doppler evidence of significant left ventricular systolic and diastolic dysfunction. Cl2 exposure at 600 ppm (30 min) was associated with biventricular failure (observed at 2 h after exposure) and death. Cardiac mechanical dysfunction persisted despite increasing the inspired oxygen fraction concentration in Cl2-exposed rats (500 ppm) to ameliorate hypoxia that occurs after Cl2 inhalation. Similarly ex vivo cardiac mechanical dysfunction was reproduced by sole exposure to chloramine (a potential circulating Cl2 reactant product). These results suggest an independent and distinctive role of Cl2 (and its reactants) in inducing cardiac toxicity and potentially contributing to mortality.
doi:10.14814/phy2.12439
PMCID: PMC4510636  PMID: 26109193
Coronary sinus; echocardiography; halogen; left ventricular dysfunction
11.  Quinoline based furanones and their nitrogen analogues: Docking, synthesis and biological evaluation 
A small library of twenty-four quinoline based butenolides also known as furanones and their nitrogen analogues was prepared by using two different aroylpropionic acids, viz. 3-(2-naphthoyl)propionic acid (3) and 3-(biphenyl-4-yl)propionic acid (4), as starting materials. The 3-aroylpropionic acids were reacted with different 6-substituted-2-chloroquinolin-3-carbaldehydes (2a–d) to obtain the corresponding furan-2(3H)-ones (5a–h). The purified and characterized furanones were then converted into their corresponding 2(3H)-pyrrolones (6a–h) and N-benzyl-pyrrol-2(3H)-ones (7a–h). The antimicrobial activities of the title compounds were evaluated against two strains of each Gram +ve (Staphylococcus aureus and Bacillus subtilis), Gram −ve bacteria (Escherichia coli and Pseudomonas aeruginosa) and against fungal strains of Aspergillus niger and Aspergillus flavus. In vivo anti-inflammatory potential of the title compounds was investigated by standard method. Majority of the compounds showed significant antibacterial activity against both the Gram +ve strains. Eight most potent anti-inflammatory compounds (5b, 5d, 5h, 6b, 7b, 7d, 7f, 7h) which exhibited >53% inhibition in edema, were also screened for their in vivo analgesic activity. All the tested compounds were found to have significant reduction in ulcerogenic action but only three compounds (5d, 5h and 7h) showed comparable analgesic activity to standard drug, diclofenac. The results were also validated using in silico approach and maximum mol doc score was obtained for compounds 7a–h. On comparing the in vivo and in silico anti-inflammatory results of synthesized compounds, N-benzyl pyrrolones (7a–h) emerged as the potent anti-inflammatory agents. It was also observed that compounds that possess electron withdrawing group such as —Cl or NO2 are more biologically active.
doi:10.1016/j.jsps.2015.05.002
PMCID: PMC5094435  PMID: 27829814
In silico; Butenolide; Pyrrolone; Antimicrobial; Analgesic; Anti-inflammatory
12.  Stem Cell Research in Pakistan; Past, Present and Future 
Background and Objectives
Stem cells have proved to have great therapeutic potential as stem cell treatment is replacing traditional ways of treatment in different disorders like cancer, aplastic anemia, stroke, heart disorders. The developed and developing countries are investing differently in this area of research so research output and clinical translation of research greatly vary among developed and developing countries. Present study was done to investigate the current status of stem cells research in Pakistan and ways to improve it.
Results
Many advanced countries (USA, UK and Canada etc.) are investing heavily in stem cell research and treatment. Different developing countries like Iran, Turkey and India are also following the developed countries and investing a lot in stem cells research. Pakistan is also making efforts in establishing this field to get desired benefits but unfortunately the progress is at very low pace. If Government plays an active role along with private sector, stem cell research in Pakistan can be boosted up. The numbers of publications from Pakistan are very less compared to developed and neighboring countries and Pakistan also has very less number of institutes working in this area of research.
Conclusions
Stem cells research is at its initial stages in Pakistan and there is great need to bring Government, academia and industry together so they could make serious efforts to promote research in this very important field. This will help millions of patients suffering from incurable disorders and will also reduce economic loss.
doi:10.15283/ijsc.2015.8.1.1
PMCID: PMC4445703  PMID: 26019749
Stem cells; Publications; Stem cells institute; Pakistan
13.  bHLH106 Integrates Functions of Multiple Genes through Their G-Box to Confer Salt Tolerance on Arabidopsis 
PLoS ONE  2015;10(5):e0126872.
An activation-tagging methodology was applied to dedifferentiated calli of Arabidopsis to identify new genes involved in salt tolerance. This identified salt tolerant callus 8 (stc8) as a gene encoding the basic helix-loop-helix transcription factor bHLH106. bHLH106-knockout (KO) lines were more sensitive to NaCl, KCl, LiCl, ABA, and low temperatures than the wild-type. Back-transformation of the KO line rescued its phenotype, and over-expression (OX) of bHLH106 in differentiated plants exhibited tolerance to NaCl. Green fluorescent protein (GFP) fused with bHLH106 revealed that it was localized to the nucleus. Prepared bHLH106 protein was subjected to electrophoresis mobility shift assays against E-box sequences (5'-CANNTG-3'). The G-box sequence 5'-CACGTG-3' had the strongest interaction with bHLH106. bHLH106-OX lines were transcriptomically analyzed, and resultant up- and down-regulated genes selected on the criterion of presence of a G-box sequence. There were 198 genes positively regulated by bHLH106 and 36 genes negatively regulated; these genes possessed one or more G-box sequences in their promoter regions. Many of these genes are known to be involved in abiotic stress response. It is concluded that bHLH106 locates at a branching point in the abiotic stress response network by interacting directly to the G-box in genes conferring salt tolerance on plants.
doi:10.1371/journal.pone.0126872
PMCID: PMC4433118  PMID: 25978450
14.  Genome-Wide Screening of Salt Tolerant Genes by Activation-Tagging Using Dedifferentiated Calli of Arabidopsis and Its Application to Finding Gene for Myo-Inositol-1-P-Synthase 
PLoS ONE  2015;10(5):e0115502.
Salinity represents a major abiotic stress factor that can adversely limit the production, quality and geographical distribution of crops. In this study we focused on dedifferentiated calli with fundamental cell functions, the salt tolerance of which had not been previously examined. The experimental approach was based on activation tagging without regeneration of plants for the identification of salt-tolerant mutants of Arabidopsis. Among 62,000 transformed calli that were screened, 18 potential mutants resistant to 150 mM NaCl were obtained. Thermal asymmetric interlaced (TAIL)-PCR was performed to determine the location of T-DNA integration in the genome. In one line, referred to as salt tolerant callus 1 (stc1), expression of a gene [At4g39800: myo-inositol-1-P-synthase 1 (MIPS1)] was considerably enhanced in calli. Plants regenerated from calli showed tolerance to salt in germination and subsequent growth. Retransformation of wild-type Arabidopsis with MIPS1 conferred salt tolerance, indicating that MIPS1 is the causal gene. The over-expression of MIPS1 increased the content of total inositol. The involvement of MIPS1 in salt tolerance through the fundamental cell growth has been proved in Arabidopsis.
doi:10.1371/journal.pone.0115502
PMCID: PMC4433338  PMID: 25978457
15.  Development of response surface methodology for optimization of extraction parameters and quantitative estimation of embelin from Embelia ribes Burm by high performance liquid chromatography 
Pharmacognosy Magazine  2015;11(Suppl 1):S166-S172.
Background:
Embelia ribes Burm is widely used medicinal plant for the treatment of different types of disorders in the Indian traditional systems of medicine.
Objective:
The present work was aimed to optimize the extraction parameters of embelin from E. ribes fruits and also to quantify embelin content in different extracts of the plant.
Materials and Methods:
Optimization of extraction parameters such as solvent: drug ratio, temperature and time were carried out by response surface methodology (RSM). Quantitative estimation of embelin in different extracts of E. ribes fruits was done through high performance liquid chromatography.
Results:
The optimal conditions determined for extraction of embelin through RSM were; extraction time (27.50 min), extraction temperature 45°C and solvent: drug ratio (8:1). Under the optimized conditions, the embelin yield (32.71%) was equitable to the expected yield (31.07%, P > 0.05). These results showed that the developed model is satisfactory and suitable for the extraction process of embelin. The analysis of variance showed a high goodness of model fit and the accomplishment of the RSM method for improving embelin extraction from the fruits of E. ribes.
Conclusion:
It is concluded that this may be a useful method for the extraction and quantitative estimation of embelin from the fruits of E. ribes.
doi:10.4103/0973-1296.157722
PMCID: PMC4461957  PMID: 26109763
Embelia ribes; response surface methodology; reverse phase-high performance liquid chromatography; ultrasonic-assisted extraction
16.  A cost-benefit analysis of twice-daily consultant ward rounds and clinical input on investigation and pharmacy costs in a major teaching hospital in the UK 
BMJ Open  2015;5(4):e007367.
Objectives
Misuse of investigations, medications and hospital beds is costing the National Health Service (NHS) billions of pounds with little evidence that approaches centred on reducing overuse are sustainable. Our previous study demonstrated that twice-daily consultant ward rounds reduce inpatient length of stay and suggested a reduction in overuse of investigations and medications. This study aims to assess the impact of daily consultant ward rounds on the use of investigations and medications and estimate the potential cost benefit.
Settings
The study was performed on two medical wards in a major city university teaching hospital in Liverpool, UK, receiving acute admissions from medical assessment and emergency departments.
Participants and intervention
The total number of patients admitted, investigations performed and pharmacy costs incurred were collected for 2 years before and following a change in the working practice of consultants from twice-weekly to twice-daily consultant ward rounds on the two medical wards.
Outcome measures
We performed a cost-benefit analysis to assess the net amount of money saved by reducing inappropriate investigations and pharmacy drug use following the intervention.
Results
Despite a 70% increase in patient throughput (p<0.01) the investigations and pharmacy, costs per patient reduced by 50% over a 12-month period (p<0.01) and were sustained for the next 12 months. The reduction in investigations and medication use did not have any effect on the readmission or mortality rate (p=NS), whereas, the length of stay was almost halved (p<0.01). Daily senior clinician input resulted in a net cost saving of £336 528 per year following the intervention.
Conclusions
Daily consultant input has a significant impact on reducing the inappropriate use of investigations and pharmacy costs saving the NHS more than £650K on the two wards over a 2-year period.
doi:10.1136/bmjopen-2014-007367
PMCID: PMC4390722  PMID: 25854972
Inappropriate investigations; Cost-benefit; Quality iimprovement; Decision making; Ward rounds
17.  Optogenetics Applications for Treating Spinal Cord Injury 
Asian Spine Journal  2015;9(2):299-305.
Cases of spinal cord injury (SCI) are increasing all over the world; and in USA alone, there are 273,000 patients, which not only leads to morbidity and mortality but also results in a great economic burden. Many approaches are being used at the pre-clinical and clinical level to treat SCI including therapeutic agents, surgical decompression, stem cell therapy etc. Recently, a new approach called optogenetics has emerged in which light sensitive proteins are used to switch neurons on and off, and this approach has great potential to be used as therapy due to its specificity and rapid response in milliseconds. Few animal studies have been performed so far in which the respiratory and bladder function of rats was restored through the use of optogenetics. On the basis of promising results obtained, in the future, this approach can prove to be a valuable tool to treat patients with SCI.
doi:10.4184/asj.2015.9.2.299
PMCID: PMC4404549  PMID: 25901246
Optogenetics; Spinal cord injury; Photostimulation; Stem cells; Regeneration
18.  Synthesis, molecular properties, toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents 
The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives (3a–k) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives (3a–k) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine (3g), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine (3i) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine (3j) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number (3i) emerged as a potential candidate for further research as it obeyed Lipinski’s rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening.
doi:10.1016/j.jsps.2015.02.008
PMCID: PMC4720031  PMID: 26903774
Imidazolidine; Indomethacin; Anti-inflammatory; Analgesic
19.  Molecular docking based screening of neem-derived compounds with the NS1 protein of Influenza virus 
Bioinformation  2015;11(7):359-365.
Different strains of influenza virus are affecting a large number of people worldwide to combat with Influenza virus destruction, numerous synthetic antiviral medicines are available for influenza virus in the market. But still there was a need for the development of drug which will target all the strains of influenza virus. For this purpose conserved residues within the influenza virus NS1 protein have been found by aligning all the available sequences of existing strains from the national center of biotechnology information(NCBI) protein database. The compounds from leaf extracts of neem (Azadirachta indica), previously known to have antiviral properties, were virtually screened to identify side effects free natural drug. Molecular docking identified eight potential compounds (Tetratriacontane, 127-40-2, 6-o-ACETYLNIMBANDIOL, Rutin, Tiplasinin, Hyperoside, ( )- Nimocinolide and Quercitrin) found to have perfect binding with reported conserved residues (R19, R35, S42 and D39) of influenza virus NS1 protein involved in the binding of drugs. From, further analysis 6-o-ACETYLNIMBANDIOL, Rutin and Tiplasinin were found as drug against influenza strains because their binding residues were conserved in all strains. The potential of neem chemical against influenza virus has best been highlighted through this study and it provides direction for further consideration of these products for in-vivo and in-vitro validations.
Abbreviations
NS1 protein - Non Structural 1 protein
NA - Neuraminidase, HA - Hemagglutinin, M - Matrix, 127-40-2 - 4-[(1E, 3E, 5E,7Z, 9E, 11E, 13E, 15E, 17E)-18-(4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17- nonaenyl]-3, 5, 5-trimethylcyclohex-3-en-1-ol, Quercitrin 2 - (3,4-dihydroxyphenyl)-5,7-dihydroxy-3- [(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxychromen-4-one, Tiplasinin 2 - [1-benzyl-5-[4-(trifluoromethoxy) phenyl] indol-3-yl]-2-oxoacetic acid, Hyperoside 2 - (3,4-dihydroxyphenyl)-5,7-dihydroxy-3- [(2S,3R,4S,5R,6R)-3, 4, 5-trihydroxy-6- (hydroxymethyl)oxan-2- yl]oxychromen-4-one LGH 4-(2-chloro-4-nitrophenyl)piperazin-1-yl][3-(2-methoxyphenyl)-5-methyl-1,2-oxazol-4-yl]methanone, nRUTIN 2 - (3, 4-dihydroxyphenyl) -5, 7-dihydroxy-3-[(2S, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-[[(2R, 3R, 4R, 5R, 6S)-3,4,5-trihydroxy- 6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one.
doi:10.6026/97320630011359
PMCID: PMC4546996  PMID: 26339153
Influenza virus; NS1 protein; Neem leaf extract; Molecular docking
20.  In silico study for diversing the molecular pathway of pigment formation: an alternative to manual coloring in cotton fibers 
Diversity of colors in flowers and fruits is largely due to anthocyanin pigments. The flavonoid/anthocyanin pathway has been most extensively studied. Dihydroflavonol 4-reductase (DFR) is a vital enzyme of the flavonoid pathway which displays major impact on the formation of anthocyanins, flavan 3-ols and flavonols. The substrate specificity of the DFR was found to play a crucial role in determination of type of anthocyanidins. Altering the flavonoid/anthocyanin pathway through genetic engineering to develop color of our own choice is an exciting subject of future research. In the present study, comparison among four DFR genes (Gossypium hirsutum, Iris × hollandica, Ang. DFRI and DFRII), sequence alignment for homology as well as protein modeling and docking is demonstrated. Estimation of catalytic sites, prediction of substrate preference and protein docking were the key features of this article. For specific substrate uptake, a proline rich region and positions 12 plus 26 along with other positions emphasizing the 26-amino acid residue region (132–157) was tested. Results showed that proline rich region position 12, 26, and 132–157 plays an important role in selective attachment of DFRs with respective substrates. Further, “Expasy ProtParam tool” results showed that Iris × hollandica DFR amino acids (Asn 9: Asp 23) are favorable for reducing DHQ and DHM thus accumulating delphinidin, while Gossypium hirsutum DFR has (Asn 13: Asp 21) hypothesized to consume DHK. Protein docking data showed that amino acid residues in above mentioned positions were just involved in attachment of DFR with substrate and had no role in specific substrate uptake. Advanced bioinformatics analysis has revealed that all above mentioned positions have role in substrate attachment. For substrate specificity, other residues region is involved. It will help in color manipulations in different plant species.
doi:10.3389/fpls.2015.00751
PMCID: PMC4584984  PMID: 26442064
anthocyanin; DFR; delphinidin; cytochromes and flavonoid 3′; 5′-hydroxylase
21.  Metastasis: Other Side of the Coin 
Frontiers in Oncology  2015;5:163.
doi:10.3389/fonc.2015.00163
PMCID: PMC4523785  PMID: 26301201
regression; immune system; nervous system; dilution; proliferation
22.  Assessment of Microbial Load of Un-pasteurized Fruit Juices and in vitro Antibacterial Potential of Honey Against Bacterial Isolates 
The development of resistance in bacteria against commonly used antibiotics/drugs is of considerable medical significance. Aim of this study was to determine the microbial load of un-pasteurized packed fruit juices sold in Lahore city and to determine antibacterial activity of five different honey samples against isolated bacteria. Unpasteurized fruit juice samples (n=60) were collected from street vendors. All the samples were subjected to Total viable count (TVC), Staphylococcal count (SC) and Coliform count (CC). One hundred and ten strains of bacteria were isolated from various fruit juices and identified on the basis of cultural characters, morphology and biochemical characters. Mean TVCs, SCs and CCs of juices (6.80±1.91, 5.45±1.06 and 3.25±1.25 log10 CFU/ml respectively) were non-significant with standard permissible limits (p<0.05). Among all the fruit juices, 66.66% of samples had TVC more than 4 log10 CFU/ml, 51.66% of samples had SC more than 3 log10 CFU/ml and 46.66% of samples had CC more than 2 log10 CFU/ml. Among the bacillus isolates purified, were Bacillus alvei, Bacillus subtilis, Bacillus polymyxa, Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, Escherichia coli and Enterobecter. All five different types of honey samples used in this study showed antibacterial activity against B. alvei, B. polymyxa, B. subtilis and S. aureus and no activity against P. aeruginosa, K. pneumonia, Enterobecter and E. coli. It is concluded that microbial load in unpasteurized fruit juices is significantly higher than standard permissible limits which insinuates its possible role in spoilage and food borne illnesses. Periodic monitoring of packed fruit juices should be carried out to make them safe for consumption. Honey can be used as an alternative for treatment of various infections, especially those caused by antibiotic resistant bacteria.
doi:10.2174/1874285801509010026
PMCID: PMC4676039  PMID: 26668658
Antibacterial activity; contamination; honey; hygienic quality; microorganism; Unpasteurized fruit juices
23.  In-Silico Determination of Insecticidal Potential of Vip3Aa-Cry1Ac Fusion Protein Against Lepidopteran Targets Using Molecular Docking 
Study and research of Bt (Bacillus thuringiensis) transgenic plants have opened new ways to combat insect pests. Over the decades, however, insect pests, especially the Lepidopteran, have developed tolerance against Bt delta-endotoxins. Such issues can be addressed through the development of novel toxins with greater toxicity and affinity against a broad range of insect receptors. In this computational study, functional domains of Bacillus thuringiensis crystal delta-endotoxin (Cry1Ac) insecticidal protein and vegetative insecticidal protein (Vip3Aa) have been fused to develop a broad-range Vip3Aa-Cry1Ac fusion protein. Cry1Ac and Vip3Aa are non-homologous insecticidal proteins possessing receptors against different targets within the midgut of insects. The insecticidal proteins were fused to broaden the insecticidal activity. Molecular docking analysis of the fusion protein against aminopeptidase-N (APN) and cadherin receptors of five Lepidopteran insects (Agrotis ipsilon, Helicoverpa armigera, Pectinophora gossypiella, Spodoptera exigua, and Spodoptera litura) revealed that the Ser290, Ser293, Leu337, Thr340, and Arg437 residues of the fusion protein are involved in the interaction with insect receptors. The Helicoverpa armigera cadherin receptor, however, showed no interaction, which might be due to either loss or burial of interactive residues inside the fusion protein. These findings revealed that the Vip3Aa-Cry1Ac fusion protein has a strong affinity against Lepidopteran insect receptors and hence has a potential to be an efficient broad-range insecticidal protein.
doi:10.3389/fpls.2015.01081
PMCID: PMC4667078  PMID: 26697037
Vip3Aa; Cry1Ac; fusion protein; Lepidopteran; homology modeling; molecular docking
24.  Menacanthus palmai, a new species of chewing louse (Menoponidae: Amblycera: Phthiraptera) from the Coturnix coromandelica 
The new species Menacanthus palmai collected from Coturnix coromandelica (Gmelin), in Rampur district (UP), India, is described and illustrated. Morphologically the new species is close to M. abdominalis from Coturnix coturnix but differs in having long pointed ventral processes on the postero-medial angles of the second to fifth pleurites. Furthermore, these two species also differ in the number of tergal and sternal abdominal setae, and the morphology of the male genitalia. Another species, Menacanthus pallipes from C. chinensis, does not have ventral processes on the postero-medial angles of pleurites.
doi:10.1007/s12639-012-0179-z
PMCID: PMC3793084  PMID: 24431583
Chewing lice; Biting lice; New louse; Louse taxonomy; Menacanthus
25.  Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation 
Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence.
Methods
Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, were instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin.
Results
Airway obstruction in the form of fibrin-containing casts were evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid.
Conclusions
Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury.
doi:10.1016/j.taap.2013.05.020
PMCID: PMC3775856  PMID: 23727623
Sulfur mustard; inhalation; lung injury; TFPI; airway; coagulation

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