Amelioration of Repeated Restraint Stress-Induced Behavioral Deficits and Hippocampal Anomalies with Taurine Treatment in Mice.

Taurine, an essential neutraceutical, has been reported to exhibit antioxidant and anti-inflammatory properties. Substantial evidence indicates that prolonged stress is one of the leading causes of psychological and physiological anomalies. Restraint stress (RS) rat model is the most widely used experimental model for the induction of chronic psycho-emotional stress. In the present study, Swiss albino male mice were restrained for 6 h/day for 28 consecutive days. Animals were divided into four groups: control, RS, RS + taurine, and taurine control group. Taurine, a potent antioxidant, was administered (200 mg/kg) orally along with RS for 28 days. The taurine intervention significantly restored the RS-induced neurobehavioral alterations evident by the elevated plus-maze, Morris water maze test, forced swim test, tail suspension test, and a sucrose preference test. Moreover, taurine significantly prevented hippocampal oxidative stress (lipid peroxidation, reduced glutathione, and nitrite) and other neurochemical (acetylcholinesterase, and IL-1ß) anomalies. Using western blotting analyses, we demonstrate that taurine treatment significantly ameliorated the alterations in Brain-derived neurotrophic factor, caspase-3, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) level in the hippocampus. Thus, Taurine effectively inhibited RS-induced oxidative stress, neuroinflammation, and apoptosis via a mechanism involving the inhibition of the NF-κB signaling pathway. In summary, our study is the first to demonstrate that NF-κB and caspase-3 inhibition, as well as BDNF augmentation, was involved in neuroprotective potential of taurine against RS-induced behavioural anomalies.

Differential effect of NDGA on cisplatin-induced nephrotoxicity in Spargue-Dawley rats.

Context: Nephrotoxicity is a highly manifested complication in cancer patients undergoing cisplatin therapy. Oxidative stress, nitrosative stress, and inflammation are the major patho-mechanisms of cisplatin-induced nephrotoxicity. Objective: The purpose of this study was to determine the protective effect of pretreatment and post-treatment of nordihydroguaiarectic acid (NDGA) on cisplatin-induced nephrotoxicity. Material and methods: Cisplatin-induced renal damage was accessed by biochemical estimation of nephrotoxicity markers, oxidative and nitrosative stress whereas inflammatory markers were accessed by ELISA technique. Results and conclusion: Cisplatin administration had resulted in renal injury associated with oxidative stress, nitrosative stress as evident by increased MDA, ROS, and nitrite level with decreased antioxidants such as SOD, catalase and, glutathione. Furthermore, cisplatin treated animals exhibited a noticeable pro-inflammatory response with the substantial increase in renal levels of TNF-α, IL-1ß, and IL-6 and decrease in the renal level of IL-10. NDGA pretreatment did not lead to significantly rise in oxidative stress, nitrosative stress, and inflammation along with restored the level of IL-10 in the kidney and preserved renal function. Moreover, NDGA post-treatment also presented nephroprotective effects, but the effects were not as positive as compared to NDGA pretreatment. In conclusion, these results indicate that NDGA pretreatment is renoprotective while on the other hand NDGA post-treatment is not so effective in cisplatin-induced nephrotoxicity.

Nyctanthes arbor-tristis leaf extract ameliorates hyperlipidemia- and hyperglycemia-associated nephrotoxicity by improving anti-oxidant and anti-inflammatory status in high-fat diet-streptozotocin-induced diabetic rats.

Type 2 diabetes is a multifactorial disorder coupled with impaired glucose tolerance, diminished insulin sensitivity and hyperlipidemia. Incessant hyperglycemia and hyperlipidemia led a towering risk to develop cardiovascular hitches with end-stage renal failure. Leaves of Nyctanthes arbor-tristis L. (NAT) (family: Oleaceae) is traditionally used by tribes of Assam for various ailments without proper scientific validation and appropriate mechanism of action for its activity. Hence, we aimed to evaluate the mechanism involved in the hypoglycemic and hypolipidemic effects of NAT leaves in high-fat diet (HFD)-streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were fed with in-house prepared high-fat diet (HFD) for a period of 4 weeks to create insulin resistance. Streptozotocin was injected intraperitoneally to these rats to cause ß-cell destructions to create a model of type 2 diabetes. Our results have shown that NAT extract has a dose-dependent hypoglycemic and hypolipidemic activity in controlling the early biochemical parameters of kidney and lipids. Moreover, the extract has anti-oxidant and anti-inflammatory activities which were more pronounced at a dose of 400 mg/kg body weight. NAT treatment group also restored the normal architecture of the kidney and aorta tissue. GC-MS data analysis revealed the presence of several active compounds which are directly or indirectly responsible for its anti-diabetic and anti-hyperlipidemic activity. The apparent mechanism of NAT for its nephroprotection may be due to the suppression of hyperglycemia-mediated oxidative stress and amelioration of inflammatory cascades allied with NF-kB activation.

Sodium Phenylbutyrate and Edaravone Abrogate Chronic Restraint Stress-Induced Behavioral Deficits: Implication of Oxido-Nitrosative, Endoplasmic Reticulum Stress Cascade, and Neuroinflammation.

Chronic stress exposure can produce deleterious effects on the hippocampus (HC) which eventually leads to cognitive impairment and depression. Endoplasmic reticulum (ER) stress has been reported as one of the major culprits in the development of stress-induced cognitive impairment and depression. We investigated the neuroprotective efficacy of sodium phenylbutyrate (SPB), an ER stress inhibitor, and edaravone, a free radical scavenger, against chronic restraint stress (CRS)-induced cognitive deficits and anxiety- and depressive-like behavior in mice. Adult male Swiss albino mice were restrained for 6 h/day for 28 days and injected (i.p.) with SPB (40 and 120 mg/kg) or edaravone (3 and 10 mg/kg) for the last seven days. After stress cessation, the anxiety- and depressive-like behavior along with spatial learning and memory were examined. Furthermore, oxido-nitrosative stress, proinflammatory cytokines, and gene expression level of ER stress-related genes were assessed in HC and prefrontal cortex (PFC). CRS-exposed mice showed anxiety- and depressive-like behavior, which was significantly improved by SPB and edaravone treatment. In addition, SPB and edaravone treatment significantly alleviated CRS-induced spatial learning and memory impairment. Furthermore, CRS-evoked oxido-nitrosative stress, neuroinflammation, and depletion of Brain-derived neurotrophic factor were significantly ameliorated by SPB and edaravone treatment. We found significant up-regulation of ER stress-related genes in both HC and PFC regions, which were suppressed by SPB and edaravone treatment in CRS mice. Our study provides evidence that SPB and edaravone exerted neuroprotective effects on CRS-induced cognitive deficits and anxiety- and depressive-like behavior, which is possibly coupled with inhibition of oxido-nitrosative stress, neuroinflammation, and ER stress cascade.

Molecular and biochemical evidence on the protective effects of quercetin in isoproterenol-induced acute myocardial injury in rats.

Cardioprotection represents one of the most important and realistic aspects of preventive therapy today. Quercetin, a naturally occurring dietary flavone, has been studied extensively for its antioxidant properties. The objective of present study is to find out the cardioprotective activity and to explore the underlying mechanisms of quercetin pretreatment (50 mg/kg body weight, orally) for 14 days against isoproterenol (ISO; 100 mg/kg body weight, subcutaneously) induced myocardial infarction in Wistar rats. Cardiac diagnostic markers, oxidative stress, inflammatory cytokines, histopathology along with gene expression analysis of calpain 1 and 2 were carried out in experimental rats. Quercetin pretreatment showed protective effects on heart by significantly attenuating the ISO-induced oxidative stress, inflammation, protecting heart architecture, and by downregulation of the expression of calpain. Overall, these findings revealed the cardio-protective potential of quercetin and its mechanism of action against ISO-induced MI in rats.

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD.

Baicalein protects isoproterenol induced myocardial ischemic injury in male Wistar rats by mitigating oxidative stress and inflammation.

OBJECTIVE: The aim of the present study was to investigate the cardioprotective effects of baicalein, main bioactive constituent from roots of Scutellaria baicalensis and Scutellaria lateriflora, on isoproterenol (ISO) induced acute myocardial infarction model in rats and to explore the underlying mechanisms. METHOD: Rats were treated with baicalein (50 mg/kg and 100 mg/kg) orally for 14 days and on 13th and 14th day, myocardial injury was induced by ISO injection (100 mg/kg, subcutaneous) at an interval of 24 h. RESULT: Our study showed that ISO administration resulted in significant elevations in the levels of cardiac injury biomarkers such as cardiac troponin I, creatine kinase-MB, AST and ALT. Concentrations of reactive nitrogen species and reactive oxygen species in the heart tissue increased significantly while antioxidant enzymes level declined. The levels of tissue pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 were significantly increased after ISO administration. Pretreatment with baicalein significantly reversed these alterations induced by ISO administration. Exploration of the underlying mechanisms of protective effect of baicalein pretreatment revealed that it repressed the expression of nuclear factor kappa B and restored the ISO induced elevation of pro-inflammatory cytokines, oxidative and nitrosative stress. We found that baicalein pretreatment enhanced the level of antioxidant defense enzymes like SOD, catalase and GSH. Furthermore, the present study also demonstrated cardioprotective effects of baicalein by the histopathological findings. CONCLUSION: Taken together, our findings demonstrated that baicalein pretreatment might have a potential benefit in prevention and terminating ischemic heart diseases like myocardial infarction.

Morin Hydrate Mitigates Cisplatin-Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice.

Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

Emergence of vanA gene among vancomycin-resistant enterococci in a tertiary care hospital of North - East India.

BACKGROUND & OBJECTIVES: Vancomycin-resistant enterococci (VRE) have become one of the most challenging nosocomial pathogens with the rapid spread of the multi-drug resistant strain with limited therapeutic options. It is a matter of concern due to its ability to transfer vancomycin resistant gene to other organisms. The present study was undertaken to determine the emergence of vancomycin-resistant enterococci and the vanA gene among the isolates in a tertiary care hospital of North-East India. METHODS: A total of 67 consecutive enterococcal isolates from different clinical samples were collected and identified by using the standard methods. Antibiogram was done by disk diffusion method and VRE was screened by the disk diffusion and vancomycin supplement agar dilution method. The minimum inhibitory concentration (MIC) value for vancomycin was determined by E-test. The VRE isolates were analyzed by PCR for vanA gene. RESULTS: A total of 54 (81%) Enterococcus faecalis and 13 (19%) E. faecium were detected among the clinical isolates and 16 (24%) were VRE. The VRE isolates were multidrug resistant and linezolid resistance was also found to be in three. MIC range to vancomycin was 16-32 µg/ml among the VRE. The vanA gene was found in nine of 16 VRE isolates. INTERPRETATION & CONCLUSIONS: Emergence of VRE and presence of vanA in a tertiary care hospital setting in North-East India indicate toward a need for implementing infection control policies and active surveillance.

Animal models of myocardial infarction: Mainstay in clinical translation.

Preclinical models with high prognostic power are a prerequisite for translational research. The closer the similarity of a model to myocardial infarction (MI), the higher is the prognostic value for clinical trials. An ideal MI model should present cardinal signs and pathology that resemble the human disease. The increasing understanding of MI stratification and etiology, however, complicates the choice of animal model for preclinical studies. An ultimate animal model, relevant to address all MI related pathophysiology is yet to be developed. However, many of the existing MI models comprising small and large animals are useful in answering specific questions. An appropriate MI model should be selected after considering both the context of the research question and the model properties. This review addresses the strengths, and limitations of current MI models for translational research.

Prevalence and identification of extended spectrum ß-lactamases (ESBL) in Escherichia coli isolated from a tertiary care hospital in North-East India.

Extended-spectrum ß-lactamases (ESBLs) are rapidly evolving group of ß-lactamase enzymes produced by the Gram negative bacteria. In this study, we determined the antimicrobial sensitivity pattern of Escherichia coli isolates and prevalence of TEM, SHV and CTX-M genes in ESBL positive E. coli isolated from the patients admitted to a tertiary care hospital in North-East India. A total of 85 multidrug-resistant isolates of E. coli obtained from clinical samples; urine (n = 80), sputum (n = 3), body fluid (n = 1), vaginal discharge (n = 1) were screened for resistance to third generation cephalosporins. ESBL production in resistant isolates was determined by double disk synergy test (DDST) and phenotypic confirmatory test (PCT). ESBL positive isolates were subjected to PCR for detection of TEM, SHV and CTX-M genes. Imipenem was found to be most effective against E. coli (susceptible isolates 96.47%) while ciprofloxacin was the least effective antibiotic (resistant isolates 60%). Among 33 ESBL positive isolates confirmed via PCT, preponderance in female population (60.6%) was noted. The most prevalent gene was bla(SHV) (63.04%) followed by bla(TEM) and bla(CTX-M) (60.86 and 54.34%, respectively) in ESBL positive E. coli. Most of the extensively used antibiotics, appear to be ineffective against the ever-mutating bacteria. This resistance urges cautious antimicrobial management on priority. Further, it helps in effectively designing the chemotherapeutic regimen for patients of a particular geographic area.

Anxiolytic and anticonvulsant activity of methanol extract of leaves of Alternanthera brasiliana (L.) Kuntze (Amaranthaceae) in laboratory animals.

Anxiety related disorders are the most common mental illnesses and major cause of disability in man. Anxiolytic activity of methanol extract of leaves of A. brasiliana (L.) Kuntze (MEAB) was evaluated using hole board (HB), open field (OF), elevated plus maze (EPM) and light/dark exploration test (LDE) in mice. Its locomotor activity was studied using actophotometer and anticonvulsant effect was studied using maximal electroshock-induced seizures and pentylenetetrazole-induced seizures in mice. Single oral administration of MEAB at different doses (100, 300 and 600 mg/kg, ip) significantly increased the number and duration of head poking in the HB test; rearing, assisted rearing and number of square traveled in the OF test; entries and time spent in open arm in the EPM test; time spent in lighted box, and numbers of crossings and transfer latency time in the LDE test. There was significant reduction in the time spent in close arm in the EPM test and time spent in dark box in LDE test. In the actophotometer, the activity count was reduced in MEAB and diazepam treated group than control group. All the three doses of the extract significantly reduced the duration of seizures induced by pentylenetetrazole (chemoshock convulsion). However, the extract did not show any appreciable effect in electroshock convulsion model. The results of the present study suggest promising anxiolytic and anticonvulsant activity of MEAB which might be accredited to different phytoconstituents like alkaloids, steroids and triterpenes present in the methanol extract of A. brasiliana.

Differential modulation of GR signaling and HDACs in the development of resilient/vulnerable phenotype and antidepressant-like response of vorinostat.

The present study explored the antidepressant potential of vorinostat (VOR) against chronic social defeat stress (CSDS) in mice. Since this model has the remarkable capacity to delineate the resilient and the defeated mice, we also looked for their molecular deviations. Defeated mice showed classical phenotypic alterations such as anhedonia, social avoidance, anxiety and despair. Whereas, resilient mice were immune to the development of those. Both defeated and resilient mice demonstrated marked CORT elevation in blood. Development of resilience vs. defeat to CSDS was found to be associated with the differential nuclear levels of GR, HDAC3 and HDAC6 in the hippocampus. Activation of a stress responsive adaptive mechanism involving these mediators at the nuclear level might be offering resilience while maladaptive mechanisms leading to defeat. Interestingly, an elevated hippocampal HDAC6 level in defeated mice was also observed, which was restored by VOR treatment. Further studies will be necessary to delineate the HDAC6 associated antidepressant mechanisms. As HDAC3 and HDAC6 are crucial mediators of GR signaling, further molecular studies may aid in understanding the basis of development of resilience to target MDD with new prospective.

7,8-Dihydroxyflavone alleviated the high-fat diet and alcohol-induced memory impairment: behavioral, biochemical and molecular evidence.

RATIONALE: Alcoholism and obesity impart a deleterious impact on human health and affects the quality of life. Chronic consumption of alcohol and western diet has been reported to cause memory deficits. 7,8-dihydroxyflavone (7,8-DHF), a TrkB agonist, comprises antioxidant and anti-inflammatory properties in treating various neurological disorders. OBJECTIVES: The current study was aimed to determine the protective effect and molecular mechanism of 7,8-DHF against alcohol and high-fat diet (HFD)-induced memory deficits in rats. METHODS: The adult male Wistar rats were given alcohol (3-15%) and HFD ad libitum for 12 weeks in different experimental groups. 7,8-DHF (5 mg/kg) was intraperitoneally injected daily for the last 4 weeks (9th-12th week). RESULTS: The alcohol and HFD administration caused cognitive impairment as evaluated through the Morris water maze (MWM) test in alcohol, HFD, and alcohol + HFD-fed animals. The last 4-week treatment of 7,8-DHF (5 mg/kg; i.p.) attenuated alcohol and HFD-induced memory loss. 7,8-DHF treatment also restored the glutathione (GSH) level along with attenuation of nitrite, malondialdehyde content (markers of oxidative and nitrosative stress), and reduction of the acetylcholinesterase activity in the hippocampus of alcohol and HFD-fed animals. Furthermore, the administration of 7,8-DHF caused downregulation of NF-κB, iNOS, and caspase-3 and upregulation of Nrf2, HO-1, and BDNF mRNA level in rat hippocampus. CONCLUSION: 7,8-DHF administration conferred beneficial effects against alcohol and HFD-induced memory deficit via its unique antioxidant, anti-inflammatory, anti-apoptotic potential, along with the activation of TrkB/BDNF signaling pathway in the hippocampus.

An Overview of the Heterogeneity of Major Depressive Disorder: Current Knowledge and Future Prospective.

Major depressive disorder (MDD) is estimated to impose maximum debilitating effects on the society by 2030, with its critical effects on health, functioning, quality of life and concomitant high levels of morbidity and mortality. Yet, the disease is inadequately understood, diagnosed and treated. Moreover, with the recent drastic rise in the pace of life, stress has materialized as one of the most potent environmental factors for depression. In this scenario, it is important to understand the modern pathogenetic hypotheses and mechanisms, and possibly try to shift from the traditional approaches in depression therapy. These include the elaboration of pathophysiological changes in heterogeneous systems such as genetic, epigenetic, serotonergic, noradrenergic, gammaaminobutyric acid, glutamatergic and endocannabinoid systems, neurotrophic factors, HPA axis, immune system as well as cellular stress mechanisms. These components interact with each other in a complex matrix and further elucidation of their mechanism and cascade pathways are needed. This might aid in the identification of MDD subtypes as well as the development of sophisticated biomarkers. Further, characterization might also aid in developing multitargeted therapies that hold much promise as compared to the conventional monoamine based treatment. New candidate pharmacons, refined psychotherapeutic modalities, advanced neuro-surgical and imaging techniques as well as the implementation of pharmacokinetic, pharmacogenetic prescribing guidelines constitute the emerging expanses of MDD treatment.

Cognitive Improvement by Vorinostat through Modulation of Endoplasmic Reticulum Stress in a Corticosterone-Induced Chronic Stress Model in Mice.

Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of existing drugs in a new pharmacology class is the safest and cheapest option for treatment instead of new drug discovery. Vorinostat (VOR) is the first histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous T-cell lymphoma by the U.S. FDA. VOR follows the rule of five and is reported to cross the blood-brain barrier. Therefore, we aimed to evaluate the procognitive potential of VOR (25 mg/kg) administered by intraperitoneal (ip) route in a stress-based model of chronic corticosterone (CORT) injections (20 mg/kg, subcutaneously (sc)). The study comprised six groups. Normal mice were administered vehicle (VEH) (days 1-21, sc) in the first group, VOR (days 8-21, 25 mg/kg, ip) in the second group, and fluoxetine (FLX) (days 8-21, 15 mg/kg, oral) in the third group. Mice in the remaining three groups were given 20 mg/kg (sc) CORT for 21 days, and VOR (days 8-21, 25 mg/kg, ip) or FLX (days 8-21, 15 mg/kg, oral) was additionally administered to the treatment groups. Behavioral tests such as Morris water maze test, novel object recognition test, and object in place test were performed at the end of the dosing schedule to assess cognition. After behavior tests, mice were sacrificed, and hippocampus was separated from brain tissue for reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry studies. VOR treatment attenuated endoplasmic reticulum (ER) stress in CORT mice as evident from the reduction in DNA damage-inducible transcript 3 (Ddit3) (gene encoding CHOP), caspase 12 (Casp12), and calpain-2 (Capn2) mRNA levels, and cleaved caspase 3 (CASP3) protein expression. Bax inhibitor-1 (BI-1) was significantly increased in VOR-treated CORT mice. VOR also reversed CORT induced increase in HDAC2 level in the CA3 region. The protective effects of VOR were comparable to that of FLX in CORT mice. Thus, VOR has the potential to reverse cognitive dysfunction via modulation of ER stress markers and HDAC2.

Anxiolytic effect of hydroethanolic extract of Drymaria cordata L Willd.

Drymaria cordata hydroethanolic extract (DCHE) at 25, 50 and 100 mg/kg (p.o.) was administered to study anxiolytic effect. Different models for anxiolytic activity viz. Hole board, Open field, Elevated plus maze, Light/dark exploration model were used. In the hole board model, there was dose dependent and significant increase in the numbers of head pokes and the time of head dipping in the treated groups in comparison to the vehicle. In open field test, the number of rearing, assisted rearing and numbers of squares traversed increased significantly. Similarly, in elevated plus maze test, there was significant increase in the time spent and number of entries in open arm as compared to the time spent and number of entries in closed arm in dose dependent manner. In light/dark exploration test, another model for anxiolytic activity, the time spent in lit box, number of crossing and the latency period increased significantly with reduction in time spent in dark box after treatment with DCHE. The presence of phytochemicals viz. triterpenes, diterpenes, steroids and tannins might contribute to its anxiolytic activity.

Hepatoprotective potential of 7,8-Dihydroxyflavone against alcohol and high-fat diet induced liver toxicity via attenuation of oxido-nitrosative stress and NF-κB activation.

BACKGROUND: Fatty liver diseases are the most common and major health concern arises from the modern lifestyle and alcohol (ethanol) abuse. The prevalence of non-alcoholic fatty liver diseases (NAFLD) has been observed prominently in obese and diabetic individuals, while alcoholic liver disease is common in alcoholic persons. Fatty liver disease, such as steatohepatitis, leads to fibrosis, cirrhosis and eventually hepatocellular carcinoma. The present study was designed to investigate the effect of 7,8-Dihydroxyflavone (7,8-DHF) against high-fat diet (HFD) and ethanol (EtOH)-induced hepatotoxicity in rats. METHODS: Male Wistar rats (150-200 g) were fed HFD (58% calories from fat) and EtOH (3-15% in drinking water) for 12 weeks. 7,8-DHF was administered intraperitoneally at the dose of 5 mg/kg/day for the last four weeks. After 12 weeks, biochemical, ELISA, RT-PCR, and histological studies have been carried out. RESULTS: Biochemical analyses revealed the involvement of oxidative stress and inflammation in the liver of HFD and EtOH-fed rats. 7,8-DHF treatment significantly reduced HFD and EtOH-induced oxidative stress as evidenced by the reduction of lipid peroxidation and augmentation of reduced glutathione level. Moreover, IL-1ß level was found significantly reduced in 7,8-DHF treated EtOH, HFD and EtOH+HFD groups. The semi-quantitative RT-PCR results indicated down-regulation of Nrf-2 and HO-1 and up-regulation of NF-κB and iNOS mRNA expression level in the liver of HFD and EtOH-fed rats, which was ameliorated by 7,8-DHF treatment. CONCLUSION: The present study suggested that 7,8-DHF could be an effective pharmacological intervention in combating HFD and EtOH-induced hepatotoxicity.

Ameliorative effect of fisetin against lipopolysaccharide and restraint stress-induced behavioral deficits via modulation of NF-κB and IDO-1.

BACKGROUND: Fisetin, a plant active polyphenol, is well known for its antioxidant and free radical scavenging activities. The present study was designed to explore the detailed molecular mechanism underlying its neuroprotective effects. METHODS: The young male mice were either administered a single dose of lipopolysaccharide (0.83 mg/kg) or subjected to restraint stress (6 h per day for 28 days) to induce behavioral deficits in different groups. Fisetin (15 mg/kg) was orally administered for the last 14 days of the study. RESULTS: Lipopolysaccharide (LPS) as well as restraint stress (RS) exposure caused behavioral alterations (anxiety and depressive-like behavior). Gene expression analysis showed upregulation of nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and indoleamine 2,3-dioxygenase (IDO)-1 gene expression along with downregulation of Nrf-2 (nuclear factor erythroid 2-related factor 2), HO-1 (heme oxygenase-1), and ChAT (choline acetyltransferase) gene expression level in RS and RS+LPS groups. Fisetin administration significantly ameliorated behavioral and neurochemical deficits in LPS, RS, and RS+LPS groups. CONCLUSION: These findings clearly indicated that fisetin administration improved behavioral functions and suppressed the NF-κB and IDO-1 (indoleamine 2,3-dioxygenase) activation along with their antioxidant effect, suggesting fisetin as an intriguing nutraceutical for the management of inflammation-associated neurological disorders.

Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer's Disease-Like Complications of Diabetes.

Diabetes is a risk factor for Alzheimer's disease and it is associated with significant memory loss. In the present study, we hypothesized that the soluble epoxide hydrolase (sEH) inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl)-urea (also known as TPPU) could alleviate diabetes-aggravated Alzheimer's disease-like symptoms by improving memory and cognition, and reducing the oxidative stress and inflammation associated with this condition. Also, we evaluated the effect of edaravone, an antioxidant on diabetes-induced Alzheimer's-like complications and the additive effect of docosahexaenoic acid (DHA) on the efficacy of TPPU. Diabetes was induced in male Sprague-Dawley rats by intraperitoneally administering streptozotocin (STZ). Six weeks after induction of diabetes, animals were either treated with vehicle, edaravone (3 or 10 mg/kg), TPPU (1 mg/kg) or TPPU (1 mg/kg) + DHA (100 mg/kg) for 2 weeks. The results demonstrate that the treatments increased the memory response of diabetic rats, in comparison to untreated diabetic rats. Indeed, DHA + TPPU were more effective than TPPU alone in reducing the symptoms monitored. All drug treatments reduced oxidative stress and minimized inflammation in the brain of diabetic rats. Expression of the amyloid precursor protein (APP) was increased in the brain of diabetic rats. Treatment with edaravone (10 mg/kg), TPPU or TPPU + DHA minimized the level of APP. The activity of acetylcholinesterase (AChE) which metabolizes acetylcholine was increased in the brain of diabetic rats. All the treatments except edaravone (3 mg/kg) were effective in decreasing the activity of AChE and TPPU + DHA was more efficacious than TPPU alone. Intriguingly, the histological changes in hippocampus after treatment with TPPU + DHA showed significant protection of neurons against STZ-induced neuronal damage. Overall, we found that DHA improved the efficacy of TPPU in increasing neuronal survival and memory, decreasing oxidative stress and inflammation possibly by stabilizing anti-inflammatory and neuroprotective epoxides of DHA. In the future, further evaluating the detailed mechanisms of action of sEH inhibitor and DHA could help to develop a strategy for the management of Alzheimer's-like complications in diabetes.