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1.  Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications 
Redox Biology  2014;3:109-123.
Mitochondria are critically important in providing cellular energy ATP as well as their involvement in anti-oxidant defense, fat oxidation, intermediary metabolism and cell death processes. It is well-established that mitochondrial functions are suppressed when living cells or organisms are exposed to potentially toxic agents including alcohol, high fat diets, smoking and certain drugs or in many pathophysiological states through increased levels of oxidative/nitrative stress. Under elevated nitroxidative stress, cellular macromolecules proteins, DNA, and lipids can undergo different oxidative modifications, leading to disruption of their normal, sometimes critical, physiological functions. Recent reports also indicated that many mitochondrial proteins are modified via various post-translation modifications (PTMs) and primarily inactivated. Because of the recently-emerging information, in this review, we specifically focus on the mechanisms and roles of five major PTMs (namely oxidation, nitration, phosphorylation, acetylation, and adduct formation with lipid-peroxides, reactive metabolites, or advanced glycation end products) in experimental models of alcoholic and nonalcoholic fatty liver disease as well as acute hepatic injury caused by toxic compounds. We also highlight the role of the ethanol-inducible cytochrome P450-2E1 (CYP2E1) in some of these PTM changes. Finally, we discuss translational research opportunities with natural and/or synthetic anti-oxidants, which can prevent or delay the onset of mitochondrial dysfunction, fat accumulation and tissue injury.
Graphical abstract
Highlights
•Hepatotoxic agents including alcohol and high fat elevate nitroxidative stress.•Increased nitroxidative stress promotes post-translational protein modifications.•Post-translational protein modifications of many proteins lead to their inactivation.•Inactivation of mitochondrial proteins contributes to mitochondrial dysfunction.•Mitochondrial dysfunction contributes to necrotic or apoptotic tissue injury.
doi:10.1016/j.redox.2014.10.004
PMCID: PMC4297931  PMID: 25465468
AA-AGE, acetaldehyde-derived advanced glycation end product; ACR, acrolein; AFLD, alcoholic fatty liver disease; AGE-albumin, advanced glycation end product-albumin adduct; ALDH2, mitochondrial low-Km aldehyde dehydrogenase 2; AMPK, AMP-activated protein kinase; APAP, acetaminophen; Complex I, NADH-dependent ubiquinone oxidoreductase; Complex III, ubiquinone cytochrome bc1 oxidoreductase; Complex IV, cytochrome c oxidase; Complex V, ATP synthase; CYP2E1, ethanol-inducible cytochrome P450 2E1 isozyme; DILI, drug-induced liver injury; DTT, dithiothreitol; eNOS, endothelial NOS; ER, endoplasmic reticulum; ERK, extracellular signal regulated protein kinase; ETC, electron transport chain; Gpx, glutathione peroxidase; GSH, glutathione; 4-HNE, 4-hydroxynonenal; HIF, hypoxia-inducible factor; ICDH, isocitrate dehydrogenase; I-kB, inhibitor protein of NF-κB; iNOS, inducible nitric oxide synthase; I/R, ischemia–reperfusion; JNK, c-Jun N-terminal protein kinase; Keap1, Kelch-like ECH-associated protein 1; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MDMA, 3,4-methylenedioxymethamphetamine; MGO, methylglyoxal; mito-CP, mitochondria-targeted carboxy-proxyl; mitoQ, mitochondria-targeted ubiquinone; MPT, mitochondrial permeability transition; mtGSH, mitochondrial glutathione; NAC, N-acetylcysteine; NAFLD, nonalcoholic fatty liver disease; NF-κB, nuclear factor-κB; NAPQI, N-acetyl-p-benzoquinone imine; NEL-adduct, N-ethyllysine adduct; nNOS, neuronal NOS; NO, nitric oxide; Nrf2, nuclear factor (erythroid-derived 2)-like 2; 4-ONE, 4-oxonon-2-enal; p38K, p38 protein kinase; PGC1α, peroxisomal proliferator activated receptor gamma coactivator-1α; PKC, protein kinase C; Prx, peroxiredoxin; PTEN, lipid phosphatase and tensin homolog; RAGE, receptor for advanced glycation end product; RNS, reactive nitrogen species; ROS, reactive oxygen species; S-NO-Cys, S-nitrosylated Cys; SAMe, S-adenosyl-methionine; SOD, superoxide dismutase; SREBP, sterol regulated element binding protein; Thiolase, 3-ketoacyl-CoA thiolase; TIMP, tissue inhibitor of metalloproteinase 3; TPP+, triphenylphosphonium cation.; Nitroxidative stress; Redox; Post-translational modifications; Mitochondrial proteins; Mitochondrial dysfunction; Tissue injury
2.  Neuroprotective effects of berry fruits on neurodegenerative diseases 
Neural Regeneration Research  2014;9(16):1557-1566.
Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents.
doi:10.4103/1673-5374.139483
PMCID: PMC4192974  PMID: 25317174
nerve regeneration; berry fruit; neurodegenerative disease; neuroprotection; Alzheimer's disease; Parkinson's disease; review; neural regeneration
3.  Omega-3 Fatty Acids Could Alleviate the Risks of Traumatic Brain Injury – A Mini Review 
Traumatic brain injury (TBI) is an acquired brain trauma that occurs when any sudden trauma/injury causes damage to the brain. TBI is characterized by tissue damage and imbalance in the cerebral blood flow and metabolism. It has been established through laboratory experiments that the dietary supplementation of omega-3 fatty acids (FAs) could reduce the oxidative stress developed in brain due to TBI. The inclusion of omega-3 FA in diet could normalize the levels of brain-derived neurotrophic factor (BDNF), and thus, it could restore the survival of neuronal cells. BDNF improves the synaptic transmission by regulating synapsin 1 and cyclic adenosine monophosphate (cAMP) response element binding protein. The brain tissue analysis of TBI models supplemented with omega-3 polyunsaturated fatty acids (PUFAs) showed significantly reduced lipid peroxidation, nucleic acid and protein oxidation, thereby promoting neuronal and glial cell survival. Thus, omega-3 FA intake could be considered as a therapeutic option to reduce the secondary neuronal damages initiated by TBI.
doi:10.4103/2225-4110.130374
PMCID: PMC4003707  PMID: 24860731
Brain trauma; Neuronal damage; Omega-3 fatty acids; Oman; Traumatic brain injury
4.  HIV incidence from the first population-based cohort study in India 
BMC Infectious Diseases  2013;13:327.
Background
Understanding about who acquires new HIV infection and the determinants of why some persons get infected and others do not is fundamental to controlling HIV in the population. We assess HIV incidence and its associations in the population of a high HIV burden district in Andhra Pradesh state in southern India by a population-based longitudinal cohort study.
Methods
We re-surveyed a population-based cohort of 12,617 adults in Guntur district of Andhra Pradesh for which we had reported a baseline HIV prevalence of 1.72% (rural 1.64%, urban 1.89%) among the 15–49 years age group in 2004–2005. We conducted interviews to assess risk behaviour and performed HIV testing again in 2010–2011. We assessed the rate of new HIV infection and its associations using multiple logistic regression.
Results
The participation rate in the follow-up was 74.9% and 63.9% of the baseline rural and urban samples, respectively. Over a mean follow-up of 5.63 years, the incidence of HIV was 1.26 per 1000 person-years (95% CI 0.83-1.69), after adjusting for slight compositional bias in the follow-up sample. The incidence per 1000 person-years was higher among rural men (1.68) than urban men (0.85), and among rural women (1.28) than urban women (0.54). The strongest association with incidence was a HIV positive spouse in the baseline for both men (odds ratio 266, 95% CI 62–1137) and women (odds ratio 28, 95% CI 9–88). Among men the other significant associations with HIV incidence were frequent use of condom for sex over the past 6 months, non-circumcision, more than one lifetime woman sex partner or ever visited sex worker, and transport-related occupation; for women the other significant associations were having had HIV testing other than antenatal check-up, previously married but currently not, and tobacco use.
Conclusion
These first population-based cohort incidence data from India suggest that rural areas of high HIV burden states would need more attention to prevent new HIV infections, and that spouses of HIV positive persons and some other risk groups need to be targeted more effectively by HIV prevention programmes.
doi:10.1186/1471-2334-13-327
PMCID: PMC3722086  PMID: 23865751
HIV incidence; India; Population-based cohort; Rural; Spouse
5.  Identification of potential targets in Staphylococcus aureus N315 using computer aided protein data analysis 
Bioinformation  2013;9(4):187-192.
Staphylococcus aureus is a gram positive bacterium, responsible for both community-acquired and hospital-acquired infection, resulting in a mortality rate of 39%. 43.2% resistance to methicilin and emerging resistance to Fluroquinolone and Oxazolidinone, have evoked the necessity of the establishment of alternative and effective therapeutic approach to treat this bacteria. In this computational study, various database and online software are used to determine some specific targets of Staphylococcus aureus N315 other than those used by Penicillin, Quinolone and Oxazolidinone. For this purpose, among 302 essential proteins, 101 nonhomologous proteins were accrued and 64 proteins which are unique in several metabolic pathways of S. aureus were isolated by using metabolic pathway analysis tools. Furthermore, 7 essentially unique enzymes involved in exclusive metabolic pathways were revealed by this research, which can be potential drug target. Along with these important enzymes, 15 non-homologous proteins located on membrane were identified, which can play a vital role as potential therapeutic targets for the future researchers.
doi:10.6026/97320630009187
PMCID: PMC3602888  PMID: 23519164
Staphylococcus aureus; Essential proteins; Surface; Therapeutic targets
6.  An insight into the lignin peroxidase of Macrophomina phaseolina 
Bioinformation  2013;9(14):730-735.
Macrophomina phaseolina is one of the deadliest necrotrophic fungal pathogens that infect more than 500 plant species including major food, fiber, and oil crops all throughout the globe. It secretes a cocktail of ligninolytic enzymes along with other hydrolytic enzymes for degrading the woody lignocellulosic plant cell wall and penetrating into the host tissue. Among them, lignin peroxidase has been reported only in Phanerochaete chrysosporium so far. But interestingly, a recent study has revealed a second occurrence of lignin peroxidase in M. phaseolina. However, lignin peroxidases are of much significance biotechnologically because of their potential applications in bio-remedial waste treatment and in catalyzing difficult chemical transformations. Besides, this enzyme also possesses agricultural and environmental importance on account of their role in lignin biodegradation. In the present work, different properties of the lignin peroxidase of M. phaseolina along with predicting the 3-D structure and its active sites were investigated by the use of various computational tools. The data from this study will pave the way for more detailed exploration of this enzyme in wet lab and thereby facilitating the strategies to be designed against such deadly weapons of Macrophomina phaseolina. Furthermore, the insight of such a ligninolytic enzyme will contribute to the assessment of its potentiality as a bioremediation tool.
doi:10.6026/97320630009730
PMCID: PMC3746097  PMID: 23976830
Macrophomina phaseolina; Ligin peroxidase; lignin
7.  Phosphatidylserine-dependent neuroprotective signaling promoted by docosahexaenoic acid 
Enrichment of polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA, 22:6n–3), in the brain is known to be critical for optimal brain development and function. Mechanisms for DHA’s beneficial effects in the nervous system are not clearly understood at present. DHA is incorporated into the phospholipids in neuronal membranes, which in turn can influence not only the membrane chemical and physical properties but also the cell signaling involved in neuronal survival, proliferation and differentiation. Our studies have indicated that DHA supplementation promotes phosphatidylserine (PS) accumulation and inhibits neuronal cell death under challenged conditions, supporting a notion that DHA is an important neuroprotective agent. This article summarizes our findings on the DHA-mediated membrane-related signaling mechanisms that might explain some of the beneficial effects of DHA, particularly on neuronal survival.
doi:10.1016/j.plefa.2010.02.025
PMCID: PMC3383770  PMID: 20207120
8.  N-Docosahexaenoylethanolamide promotes development of hippocampal neurons 
The Biochemical journal  2011;435(2):327-336.
DHA (docosahexaenoic acid, C22:6,n−3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n−3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function.
doi:10.1042/BJ20102118
PMCID: PMC3169088  PMID: 21281269
docosahexaenoic acid (DHA); N-docosahexaenoylethanolamide (DEA); hippocampus; neurite growth; neuron; synaptogenesis
9.  Phosphatidylserine is a critical modulator for Akt activation 
The Journal of Cell Biology  2011;192(6):979-992.
Association of Akt with phosphatidylserine enhances binding to PIP3, inducing conformational changes in Akt that promote its phosphorylation-mediated activation.
Akt activation relies on the binding of Akt to phosphatidylinositol-3,4,5-trisphosphate (PIP3) in the membrane. Here, we demonstrate that Akt activation requires not only PIP3 but also membrane phosphatidylserine (PS). The extent of insulin-like growth factor–induced Akt activation and downstream signaling as well as cell survival under serum starvation conditions positively correlates with plasma membrane PS levels in living cells. PS promotes Akt-PIP3 binding, participates in PIP3-induced Akt interdomain conformational changes for T308 phosphorylation, and causes an open conformation that allows for S473 phosphorylation by mTORC2. PS interacts with specific residues in the pleckstrin homology (PH) and regulatory (RD) domains of Akt. Disruption of PS–Akt interaction by mutation impairs Akt signaling and increases susceptibility to cell death. These data identify a critical function of PS for Akt activation and cell survival, particularly in conditions with limited PIP3 availability. The novel molecular interaction mechanism for Akt activation suggests potential new targets for controlling Akt-dependent cell survival and proliferation.
doi:10.1083/jcb.201005100
PMCID: PMC3063130  PMID: 21402788
10.  The full-of-bacteria gene is required for phagosome maturation during immune defense in Drosophila 
The Journal of Cell Biology  2011;192(3):383-390.
Drosophila fob encodes a homolog of the Vps16 HOPS complex subunit, required for phagosome maturation and digestion of engulfed pathogens.
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a fatal recessive disorder caused by mutations in the VPS33B or VPS16B genes. Both encode homologues of the Vps33p and Vps16p subunits of the HOPS complex necessary for fusions of vacuoles in yeast. Here, we describe a mutation in the full-of-bacteria (fob) gene, which encodes Drosophila Vps16B. Flies null for fob are homozygous viable and fertile. They exhibit, however, a defect in their immune defense that renders them hypersensitive to infections with nonpathogenic bacteria. fob hemocytes (fly macrophages) engulf bacteria but fail to digest them. Phagosomes undergo early steps of maturation and transition to a Rab7-positive stage, but do not mature to fully acidified phagolysosomes. This reflects a specific requirement of fob in the fusion of phagosomes with late endosomes/lysosomes. In contrast, cargo of autophagosomes as well as endosomes exhibit normal lysosomal delivery in fob cells. These findings suggest that defects in phagosome maturation may contribute to symptoms of ARC patients including recurring infections.
doi:10.1083/jcb.201008119
PMCID: PMC3101095  PMID: 21282466
11.  Overexpression of heat shock protein 27 reduces cortical damage after cerebral ischemia 
Heat shock protein 27 (HSP27) has a major role in mediating survival responses to a range of central nervous system insults, functioning as a protein chaperone, an antioxidant, and through inhibition of cell death pathways. We have used transgenic mice overexpressing HSP27 (HSP27tg) to examine the role of HSP27 in cerebral ischemia, using model of permanent middle cerebral artery occlusion (MCAO). Infarct size was evaluated using multislice T2-weighted anatomical magnetic resonance imaging (MRI) after 24 h. A significant reduction of 30% in infarct size was detected in HSP27tg animals compared with wild-type (WT) littermates. To gain some insight into the mechanisms contributing to cell death and its attenuation by HSP27, we monitored the effect of induction of c-jun and ATF3 on tissue survival in MCAO and their effects on the expression of endogenous mouse HSP25 and HSP70. It is important that, the c-jun induction seen at 4 h tended to be localized to regions that were salvageable in HSP27tg mice but became infarcted in WT animals. Our results provide support for the powerful neuroprotective effects of HSP27 in cerebral ischemia.
doi:10.1038/jcbfm.2009.249
PMCID: PMC2949174  PMID: 19997117
focal ischemia; heat shock protein 27; MRI; permanent middle cerebral artery occlusion
12.  The SM Protein Car/Vps33A Regulates SNARE-mediated Trafficking to Lysosomes and Lysosome-related Organelles 
Molecular Biology of the Cell  2009;20(6):1705-1714.
The SM proteins Vps33A and Vps33B are believed to act in membrane fusions in endosomal pathways, but their specific roles are controversial. In Drosophila, Vps33A is the product of the carnation (car) gene. We generated a null allele of car to test its requirement for trafficking to different organelles. Complete loss of car function is lethal during larval development. Eye-specific loss of Car causes late, light-independent degeneration of photoreceptor cells. Earlier in these cells, two distinct phenotypes were detected. In young adults, autophagosomes amassed indicating that their fusion with lysosomes requires Car. In eye discs, endocytosed receptors and ligands accumulate in Rab7-positive prelysosomal compartments. The requirement of Car for late endosome-to-lysosome fusion in imaginal discs is specific as early endosomes are unaffected. Furthermore, lysosomal delivery is not restored by expression of dVps33B. This specificity reflects the distinct pattern of binding to different Syntaxins in vitro: dVps33B predominantly binds the early endosomal Avl and Car to dSyntaxin16. Consistent with a role in Car-mediated fusion, dSyntaxin16 is not restricted to Golgi membranes but also present on lysosomes.
doi:10.1091/mbc.E08-03-0282
PMCID: PMC2655250  PMID: 19158398
13.  Inhibition of Hb S Polymerization In Vitro by a Novel 15-mer EF Helix β73 His-Containing Peptide 
Biochemistry  2006;45(27):8358-8367.
Our mutational studies on HbS showed that the HbS β73His variant (β6Val and β73His) promoted polymerization, while HbS β73Leu (β6Val and β73Leu) inhibited polymerization. Based on these results, we speculated that EF-helix peptides containing β73His interact with β4Thr in HbS and compete with HbS, resulting in inhibition of HbS polymerization. We, therefore, studied inhibitory effects of 15-, 11-, 7- and 3-mer EF-helix peptides containing β73His on HbS polymerization. The delay time prior to HbS polymerization increased only in the presence of the 15-mer His peptide; the higher the amount, the longer the delay time. DIC image analysis also showed fiber elongation rate for HbS polymers decreased with increasing concentration of the 15-mer His peptide. In contrast, the same 15-mer-peptide containing β73Leu instead of His and peptides shorter than 11 amino acids containing β73His including His alone showed little effect on kinetics of polymerization and elongation of polymers. Analysis by protein-chip arrays showed that only the 15-mer β73His peptide interacted with HbS. CD spectra of the 15-mer β73His peptide did not show a specific helical structure, however, computer docking analysis suggested a lower energy for interaction of HbS with the 15-mer β73His peptide compared to peptides containing other amino acids at this position. These results suggest that the 15-mer β73His peptide interacts with HbS via the β4Thr in the βS-globin chain in HbS. This interaction may influence hydrogen bond interaction between β73Asp and β4Thr in HbS polymers and interfere in hydrophobic interactions of β6 Val leading to inhibition of HbS polymerization.
doi:10.1021/bi0604734
PMCID: PMC2593912  PMID: 16819835

Results 1-13 (13)