7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD. VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20 mg/kg) and Donepezil (10 mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1ß, and NF-kß), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats. Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus. These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

In-vitro antioxidant and anti-inflammatory potential along with p.o. pharmacokinetic profile of key bioactive phytocompounds of Snow Mountain Garlic: a comparative analysis vis-à-vis normal garlic.

Snow mountain garlic (SMG) is a trans-Himalayan medicinal plant used in the traditional medicine system for several ailments, including inflammatory arthritis. Research studies are insufficient to validate its folk medicinal applications. In the present study, the comparative abundance of its key bioactive phytocompounds, viz., S-allyl-L-cysteine (SAC), alliin, and S-methyl-L-cysteine (SMC) against normal garlic were assessed using the LC-MS/MS-MRM method. In addition, the study also explored the antioxidant and anti-inflammatory potency of crude extract of SMG and purified signature phytocompounds (i.e., SMC, SAC, and alliin) in comparison with normal garlic and dexamethasone in LPS-stimulated RAW264.7 macrophage cells. The LC-MS/MS-MRM study revealed significant differences among SMG and normal garlic, viz., alliin 22.8-fold higher in SMG, and SMC could be detected only in SMG. In the bioassays, SMG extract and purified signature phytocompounds significantly downregulated oxidative damage in activated macrophages, boosting endogenous antioxidants' activity. SMG extract-treated macrophages significantly suppressed NF-κB expression and related inflammatory indicators such as cytokines, COX-2, iNOS, and NO. Notably, the observed anti-inflammatory and antioxidant bioactivities of SMG extract were comparable to signature phytocompounds and dexamethasone. In addition, SAC being uniformly found in SMG and normal garlic, its comparative pharmacokinetics was studied to validate the pharmacodynamic superiority of SMG over normal garlic. Significantly higher plasma concentrations (Cmax), half-life (t1/2), and area under curve (AUC) of SAC following SMG extract administration than normal garlic validated the proposed hypothesis. Thus, the abundance of bioactive phytocompounds and their better pharmacokinetics in SMG extract might be underlying its medicinal merits over normal garlic.

Alpha-Lipoic Acid Ameliorates Doxorubicin-Induced Cognitive Impairments by Modulating Neuroinflammation and Oxidative Stress via NRF-2/HO-1 Signaling Pathway in the Rat Hippocampus.

Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague-Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV-visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway.

Tetramethylpyrazine Attenuates Cognitive Impairment Via Suppressing Oxidative Stress, Neuroinflammation, and Apoptosis in Type 2 Diabetic Rats.

Cognitive dysfunction is an important complication observed in type 2 diabetes mellitus (T2DM) patients. Tetramethylpyrazine (TMP) is known to exhibit anti-diabetic and neuroprotective properties. Therefore, the present study aimed to investigate the possible therapeutic effects of TMP against type 2 diabetes-associated cognitive impairment in rats. High-fat diet (HFD) followed by a low dose of streptozotocin (35 mg/kg) was used to induce diabetes in Sprague-Dawley rats. TMP (20, 40, and 80 mg/kg) and Pioglitazone (10 mg/kg) were administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NOR) tests were used to assess memory function. Fasting blood glucose (FBG), lipid profile, HOMA-IR, glycosylated hemoglobin (HbA1c), and glucose tolerance were measured. Acetylcholinesterase (AChE) and choline acetytransferase (ChAT) activity, acetylcholine (ACh) levels, oxidative stress, apoptotic (Bcl-2, Bax, caspase-3), and inflammatory markers (TNF-α, IL-1ß, and NF-kß) were assessed. BDNF, p-AKT, and p-CREB levels were also measured. In the present work, we observed that treatment of diabetic rats with TMP alleviated learning and memory deficits, improved insulin sensitivity, and attenuated hyperglycemia and dyslipidemia. Furthermore, treatment with TMP increased BDNF, p-Akt, and p-CREB levels, normalized cholinergic dysfunction, and suppressed oxidative, inflammatory, and apoptotic markers in the hippocampus. Collectively, our results suggest that the TMP may be an effective neuroprotective agent in alleviating type 2 diabetes-associated cognitive deficits.

A comparative study of in-vitro and in-silico anti-candidal activity and GC-MS profiles of snow mountain garlic vs. normal garlic.

AIM: The study aimed to profile the volatile phytocomposition of snow mountain garlic (SMG) compared to normal garlic and investigate the anti-Candida efficacy against clinically relevant multi-drug resistant isolates of Candida species. METHODS AND RESULTS: Herein, SMG has shown significantly superior fungicidal power at 2x-MIC dose against C. albicans and C. glabrata in killing kinetic evaluation unlike the fungistatic effect of normal garlic. GC-MS headspace-based profiling of SMG showed 5 unique volatile compounds and a 5-fold higher content of saponins than normal garlic. In an in-silico analysis, cholesta-4,6-dien-3-ol,(3-beta) was uniquely identified in SMG as a potential inhibitor with high binding affinity to the active site of exo-1,3-betaglucan synthase, an established anti-candida drug target crucial for the biofilm matrix formation, thus suggesting a plausible anti-Candida mechanism. CONCLUSION: The in-vitro and in-silico studies have demonstrated the Candida-cidal and anti-biofilm activities of SMG, distinguishing it from the Candida-static efficacy of normal garlic. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report that identifies several phytochemical signatures of SMG along with a potential anti-Candida compound, that is cholesta-4,6-dien-3-ol,(3-beta)-, which appears worthy of detailed studies in the future to explore the utility of SMG as a fungal phytotherapy agent, especially against drug-resistant Candida sp.

Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice.

Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and luminal microbial community. The present study focuses on the effects' intra rectal administration of capsazepine (modulator of TRPA1/TRPV1 expressing peptidergic sensory neurons) on colonic mucus production and gut health. We performed histological analysis, gut permeability alteration, gene expression changes, metabolite profiling, and gut microbial abundance in the ileum, colon, and cecum content of these animals. Intra rectal administration of capsazepine modulates TRPA1/TRPV1-positive nociceptors (behavioral pain assays) and resulted in damaged mucosal lining, increased gut permeability, and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. These results suggest that caution must be exercised before employing TRPA1/TRPV1 modulation as a therapeutic option to alleviate pain caused due to IBD.

Naringenin Ameliorates Chronic Sleep Deprivation-Induced Pain via Sirtuin1 Inhibition.

Growing experimental evidences have suggested the reciprocal correlation between sleep deprivation and pain. Inflammation and oxidative stress are among the key pathways underlying this correlation. Therefore, the present study was aimed to assess the effect of antioxidant and anti-inflammatory compound naringenin (NGN) against chronic sleep deprivation (CSD)-induced mechanical and thermal hyperalgesia in female Swiss albino mice. In this study, mice were chronically sleep-deprived for 8 h a day for five days a week with the weekend as a free sleep period and continued for nine weeks using a modified multiple platform method. The pain behavioral tests were conducted at the end of the fourth week to assess the development of hyperalgesia followed by the administration of NGN and a combination of NGN with Sirtinol (SIR, a sirtuin1 inhibitor) till the end of the study. After nine weeks, pain behavioral tests, along with oxidative stress and inflammatory parameters in cortex and striatum, were assessed. Results indicated that CSD-induced hyperalgesia in mice accompanied by increased oxidative stress and inflammatory markers in cortex and striatum of the brain. NGN combatted the hyperalgesic response and also decreased levels of oxidative stress and inflammatory markers. Furthermore, the pharmacological effect of NGN was mitigated with SIR. Thus, the findings of the present study reveal that NGN is acting via sirtuin1 to exert its antinociceptive activity against CSD-induced hyperalgesia.

Neurobehavioral alterations in a mouse model of chronic partial sleep deprivation.

The night shift paradigm induces a state of chronic partial sleep deprivation (CPSD) and enhances the vulnerability to neuronal dysfunction. However, the specific neuronal impact of CPSD has not been thoroughly explored to date. In the current study, the night shift condition was mimicked in female Swiss albino mice. The classical sleep deprivation model, i.e., Modified Multiple Platform (MMP) method, was used for 8 h/day from Monday to Friday with Saturday and Sunday as a weekend off for nine weeks. Following nine weeks of night shift schedule, their neurobehavioral profile and physiological parameters were assessed along with the activity of the mitochondrial complexes, oxidative stress, serotonin levels, and inflammatory markers in the brain. Mice showed an overall hyperactive behavioral profile including hyperlocomotion, aggression, and stereotyped behavior accompanied by decreased activity of mitochondrial enzymes and serotonin levels, increased oxidative stress and inflammatory markers in whole brain homogenates. Collectively, the study points towards the occurrence of a hyperactive behavioral profile akin to mania and psychosis as a potential consequence of CPSD.

Dimethyl fumarate attenuates 2-VO-induced vascular dementia via activating the Nrf2 signaling pathway in rats.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia. METHODS: Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague-Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus. RESULTS: The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1ß, NF-κß, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment. CONCLUSION: Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia.

Evaluation of the in vitro and in vivo antioxidant potentials of food grade Phycocyanin.

Excessive generation of oxygen free radicals plays a pivotal role in destruction of biological molecules like DNA, proteins, lipids, carbohydrates and results in various pathologies including neuronal disorders. Antioxidant molecules from natural products are reported to have ability to mitigate their production or at least halt their progression and metastasis in the system. Different studies have been performed to spot antioxidants from natural sources and attempts have been made to integrate them in conventional therapy. In our present study, food grade Phycocyanin, a nutraceutical isolated from Spirulina platensis, has been evaluated for its in vitro and in vivo antioxidant potential using a battery of antioxidant assays viz. DPPH, TAC, FRAP, hydroxyl radical, hydrogen peroxide scavenging, SOD, GSH, and LPO assays. Reducing properties of Phycocyanin were also assessed by FRAC assay. For in vivo evaluation of antioxidant profile, animal model of intracerebroventricular administration of streptozotocin was employed. Levels of oxidative stress biomarkers were measured in cortex and hippocampal parts of brain. Results obtained depicted that Phycocyanin demonstrated a dose-dependent pattern in its efficacy, which indicates the presence of free radical scavenger moieties and possible role as a neuroprotective agent.

High fat-low protein diet induces metabolic alterations and cognitive dysfunction in female rats.

Approximately one-third of the world population is suffering from MetS, and the same is expected to rise in the years to come. Worldwide, most of the staple diets contain high amounts of carbohydrates, fats and comparatively low quantities of proteins. The goal of this study was to evaluate the effect of high fat-low protein diet in the development of the metabolic syndrome and associated cognitive deficits in the female rats. The rats fed with high fat-low protein diet (HFLPD) and 15% oral fructose solution for 24 weeks. Body weight, food intake, water intake, fasting blood glucose, oral glucose tolerance, glycosylated hemoglobin (HbA1C), and serum lipid profile were measured after every 4 weeks. Serum insulin, HOMA-IR index, rectal temperature, and systolic blood pressure were measured to confirm the manifestation of the hallmarks of metabolic syndrome. Behavioral tests for locomotion, anxiety, learning, and spatial memory were performed from the 12th week to till the end of the study. At the 24th week, oxidative stress assays and histopathology of liver, kidney, brain, and WAT were also performed. HFLPD significantly altered the physiologic and metabolic parameters which contributed to the manifestation of MetS. HFLPD also impaired the cognitive functions along with significant structural changes in the liver, kidney, WAT, and brain. The findings of this study reveal that HFLPD has the potential to induce the physiological, metabolic and histological alterations in rats, which eventually led to the development of MetS and also disrupted the cognitive functions in female rats.

Co-supplementation of isomalto-oligosaccharides potentiates metabolic health benefits of polyphenol-rich cranberry extract in high fat diet-fed mice via enhanced gut butyrate production.

PURPOSE: Cranberries are a rich source of polyphenolic antioxidants. Purified sugars or artificial sweeteners are being added to cranberry-based food products to mask tartness. Refined sugar and artificial sweeteners intake modulate gut microbiota and result in metabolic complications. We evaluated effects of isomalto-oligosaccharides (IMOs; sweet tasting non-digestible oligosaccharides) with cranberry extract (CRX) on high fat diet (HFD)-induced metabolic alterations in mice. METHODS: Male Swiss albino mice were fed normal chow or HFD (58% fat kcal), and were administered either CRX (200 mg/kg) alone or in combination with IMOs (1 g/kg). Cecal short-chain fatty acids, abundances of selected (1) butyrate producing, (2) metabolically beneficial, and (3) selective lipopolysaccharides producing gram negative gut bacteria were studied. Further, gut-related histological, biochemical, genomic changes along with circulating pro-/anti-inflammatory markers and systemic obesity-associated metabolic changes were studied. RESULTS: Co-supplementation of CRX and IMOs significantly improved cecal SCFAs, especially butyrate levels, selected butyrate-producing bacteria (clostridial cluster XIVa bacteria) and butyrate kinase expression in HFD-fed mice. The combination also significantly improved gut beneficial bacterial abundance, gut histology and related changes (colon mucin production, gut permeability) as compared to individual agents. It also prevented HFD-induced systemic and tissue inflammation, glucose intolerance and systemic obesity-associated metabolic changes in adipose tissue and liver. The combination of CRX and IMOs appeared more effective in the prevention of HFD-induced gut derangements. CONCLUSION: Combination of CRX and IMOs could be advantageous for normalization of metabolic alterations seen in diet-induced obesity via beneficial modulation of gastrointestinal health.

Vitamin D3 attenuates cognitive deficits and neuroinflammatory responses in ICV-STZ induced sporadic Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by intracellular neurofibrillary tangles and extracellular Aß deposition. Growing experimental evidence indicate diverse biological effects of vitamin D3 including antioxidant, neuroprotective, anti-inflammatory and cardiovascular benefits. However, the underlying neuroprotective mechanism of vitamin D3 is still largely elusive. Therefore, the present study was aimed to investigate the neuroprotective effects of vitamin D3 on ICV-STZ induced sporadic AD. Our study demonstrated that vitamin D3 pretreatment significantly improved spatial learning and memory functions and effectively mitigated ICV-STZ mediated neuronal oxidative stress, mitochondrial aberrations and improved cholinergic functions. Moreover, vitamin D3 attenuated hippocampal neuroinflammatory response and reduced neuronal death in cortex and hippocampus. Our findings indicated that prophylactic vitamin D3 supplementation ameliorated ICV-STZ mediated neurobehavioral alterations, oxidative stress and neuroinflammation thereby improving cholinergic functions and reversed degenerative changes in brain. Thus, our study further provides evidence for its therapeutic supplementation for various neurodegenerative disorders including AD.

Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice.

High fat diet (HFD)-induced alterations in gut microbiota and resultant 'leaky gut' phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1ß) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods.

Naringin Reverses Neurobehavioral and Biochemical Alterations in Intracerebroventricular Collagenase-Induced Intracerebral Hemorrhage in Rats.

Intracerebral hemorrhage (ICH) contributes to 10-15% of all strokes and is a high risk factor for morbidity and mortality as compared to other subtypes of stroke, that is, cerebral ischemia and subarachnoid hemorrhage. Oxidative stress (OS)-induced neuroinflammation and neuronal cell death contribute towards the hallmarks of ICH. Spared antioxidant levels, increased inflammatory cytokines and free radicals in ICH lead to neuronal death and exaggerate the hallmarks of ICH. Intracerebroventricular (ICV) collagenase (COL-induced neuronal cell damage and cognitive deficits form a widely recognized experimental model for ICH. Naringin (NGN), a natural antioxidant bioflavonoid, has shown potent neuroprotective effects in different neurodegenerative diseases. However, its potential is least explored in pathological conditions, such as hemorrhagic stroke. This study is aimed at exploring the protective effects of NGN against ICV-COL induced behavioral, neurological and memory deficits in rats. ICV-ICH was induced by single, unilateral intrastriatal injection of COL (1 IU in 2 µL, ICV) over 10 min. From 2nd day onwards, NGN was administered in three different doses (10, 20, and 40 mg/kg; p.o.). Animals were subjected to a battery of behavioral tests to assess behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Selitto and von Frey. Poststroke depression and memory deficits were estimated using forced swim test and Morris water maze test, respectively. Poststroke depression, neurological and cognitive deficits were mitigated dose dependently by NGN administration. NGN administration also attenuated the nitro-OS and restored tumor necrosis factor-α and endogenous antioxidant levels. Our research demonstrates that NGN has a protective effect against ICH-induced neurocognitive deficits, along with mitigation of oxido-nitrosative and inflammatory stress.

The novel role of ß-aescin in attenuating CCl4-induced hepatotoxicity in rats.

CONTEXT: ß-Aescin has anti-inflammatory, anti-oxidant and antiedematous properties. OBJECTIVE: The present study investigated the hepatoprotective effect and underlying mechanisms of ß-aescin in CCl4-induced liver damage. MATERIALS AND METHODS: Thirty-five Wistar rats were divided into six groups: normal control, CCl4 control, silymarin (50 mg/kg, p.o) and ß-aescin (0.9, 1.8 and 3.6 mg/kg, i.p.) treatment for 14 d. CCl4 (1 mL/kg, i.p. for 3 d) was administered to produce hepatic damage. Ponderal changes and liver marker enzymes were estimated. Hepatic oxidative and nitrosative stress was estimated by levels of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and nitrite/nitrate. Serum TGF-ß1 and TNF-α were estimated by ELISA technique. Hepatic collagen and histopathological studies were carried out. RESULTS: ß-Aescin (3.6 mg/kg) markedly decreased CCl4-induced increased levels of ALT, AST, ALP (71.77 versus 206.7, 71.39 versus 171.82, 121.20 versus 259 IU/L, respectively), total bilirubin (0.41 versus 1.35 mg/dL), TBARS (2.0 versus 8.83 nmol MDA/mg protein), nitrite/nitrate (352.50 versus 745.15 µg/mL) and increased CCl4-induced decreased GSH levels (0.095 versus 0.048 µmol/mg protein). ß-Aescin (3.6 mg/kg) induced focal regenerative changes in liver and markedly decreased TBARS (2.0 versus 8.83 nmol MDA/mg protein), nitrite/nitrate (352.50 versus 745.15 µg/mL), TGF-ß1 (92.28 versus 152.1 pg/mL), collagen content (110.75 versus 301.74 µmol/100 mg tissue) and TNF-α (92.82 versus 170.56 pg/mL) when compared with CCl4 control. DISCUSSION AND CONCLUSION: The findings suggest that ß-aescin has a protective effect on CCl4-induced liver injury, exhibited via its anti-inflammatory, antioxidative, antinitrosative and antifibrotic properties inducing repair regeneration of liver. Hence, it can be used as a promising hepatoprotective agent.

Hepatoprotective effect of trans-Chalcone on experimentally induced hepatic injury in rats: inhibition of hepatic inflammation and fibrosis.

The current study investigated the hepatoprotective effect of trans-Chalcone in carbon tetrachloride (CCl4) and paracetamol (PCM) induced liver damage in rats. Administration of CCl4 and PCM (1 mL/kg, i.p., 3 days, and 2 g/kg, p.o., single dose, respectively) produced hepatic injury. Ponderal changes (percent change in body mass and relative liver mass) and biochemical parameters (serum ALT, AST, ALP, bilirubin) were estimated. The markers of oxidative and nitrosative stress (TBARS, reduced GSH, nitrite and nitrate), hepatic fibrosis (TGF-ß1, collagen content), hepatic inflammation (TNF-α), and histopathological study were evaluated. trans-Chalcone (5, 10, and 20 mg/kg, i.p.) was found to be beneficial as demonstrated by significant reversal of liver histology by perceptible reduction of inflammatory cell infiltration with regenerative changes in hepatocytes. Improvement in percent change in body mass and significant reduction in relative liver mass were observed. Marked reduction in serum levels of ALT, AST, ALP, and bilirubin were noted. Decreases in TBARS and nitrites and nitrates and increases in reduced GSH levels were noted. Hepatic fibrosis and inflammation were significantly decreased. The findings indicate a novel hepatoprotective role for trans-Chalcone by improving hepatic injury by possible actions such as anti-oxidant, anti-nitrosative, anti-fibrotic, and anti-inflammatory. Hence, it can be used as promising hepatoprotective agent.

Calendula officinalis ameliorates l-arginine-induced acute necrotizing pancreatitis in rats.

CONTEXT: Calendula officinalis L. (Asteraceae) has been traditionally used in treating inflammation of internal organs, gastrointestinal tract ulcers and wound healing. OBJECTIVE: The present study investigates the effect of ethanol extract (95%) of Calendula officinalis flowers in l-arginine induced acute necrotizing pancreatitis in rats. MATERIALS AND METHODS: Rats were divided into four groups: normal control, l-arginine control, Calendula officinalis extract (COE) treated and melatonin treated (positive control), which were further divided into subgroups (24 h, day 3 and 14) according to time points. Two injections of l-arginine 2 g/kg i.p. at 1 h intervals were administered in l-arginine control, COE and melatonin-treated groups to produce acute necrotizing pancreatitis. Biochemical parameters [serum amylase, lipase, pancreatic amylase, nucleic acid content, total proteins, transforming growth factor-ß1 (TGF-ß1), collagen content, lipid peroxidation, reduced glutathione and nitrite/nitrate] and histopathological studies were carried out. RESULTS: COE treatment (400 mg/kg p.o.) was found to be beneficial. This was evidenced by significantly lowered histopathological scores (2 at day 14). Nucleic acid content (DNA 21.1 and RNA 5.44 mg/g pancreas), total proteins (0.66 mg/mL pancreas) and pancreatic amylase (1031.3 100 SU/g pancreas) were significantly improved. Marked reduction in pancreatic oxidative and nitrosative stress; collagen (122 µmoles/100 mg pancreas) and TGF-ß1 (118.56 pg/mL) levels were noted. Results obtained were comparable to those of positive control. DISCUSSION AND CONCLUSION: The beneficial effect of COE may be attributed to its antioxidant, antinitrosative and antifibrotic actions. Hence, the study concludes that COE promotes spontaneous repair and regeneration of the pancreas.

Distinct role of estrogen receptor-alpha and beta on postmenopausal diabetes-induced vascular dysfunction.

Estrogen is known to influence vascular functions and insulin sensitivity, but the relative contribution of estrogen receptor (ER) isoforms in postmenopausal diabetes-induced vascular dysfunction is unclear. The aim of the present study was to delineate the distinct role of estrogen receptor-α and beta ß on the vascular function in ovariectomized diabetic rats. Age matched 60 female sprague dawley rats (200-250g) were divided in nine groups. Bilateral ovariectomy was performed and streptozotocin was used to induce experimental diabetes. Rats were administered with 10µg/kg; s.c. of a nonselective estrogen receptor agonist, 17-ß estradiol (E2), selective ER-α agonist (4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol (PPT) and selective ER-ß agonist, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 4weeks after STZ injection. Treatment with selective ER-α agonist and E2 improved the impaired glycemic and lipid profile in ovariectomized diabetic rats, however selective ER-ß agonist did not show any effect. Vascular endothelial dysfunction was assessed by acetylcholine and sodium nitroprusside-induced endothelium dependent and independent relaxation in isolated rat aortic ring preparation as well as by electron microscopy of thoracic aorta. Further, serum thiobarbituric acid reactive substances, tumour necrotic factor-alpha and interleukin-1 beta and C-reactive protein were estimated to assess oxidative stress and vascular inflammation. Treatment with ER-α agonist markedly and E2 partially improved vascular function and endothelial integrity along with reduction in serum TBARS and inflammatory cytokines. However, ER-ß agonist did not show any improvement in vascular functions, oxidative stress or inflammation. These findings suggest that selective targeting of ER-α receptors results in vasculoprotection in the state of hypoestrogenicity and diabetes.

Efficiency of double layered microencapsulated probiotic to modulate proinflammatory molecular markers for the management of alcoholic liver disease.

Alcohol-related disorders are one of the challenging current health problems with medical, social, and economic consequences. Endotoxemia, oxidative stress, and release of a variety of inflammatory molecules are established mediators in alcoholic liver injury (ALD). Probiotics like L. plantarum though were reported to attenuate ALD, their in vivo health benefits are limited by their survival and sustenance in the adverse gut conditions. Therefore, to enhance their in vivo performance, chitosan coated alginate beads entrapping L. plantarum were prepared, characterized, and evaluated for their efficacy against ALD in rats. Following chronic alcohol exposure, rats developed endotoxemia, showed enhanced levels of liver enzyme markers, NF-κB levels, and increased cytokines such as TNF- α and IL12/p40 subunit, and reflected significant histological changes in the intestine and liver. However, cosupplementation with double layered microencapsulated probiotic significantly (P < 0.05) reduced the levels of endotoxemia, serum transaminases, NF-κB, and cytokines complemented with restoration of normal histoarchitecture of the intestine and liver. It is being documented here for the first time that the probiotics have the potential to inhibit IL-12/p40 subunit which is a recently explored potential marker for developing novel therapeutic agents. This study reveals that microencapsulation of probiotics may offer a biopharmacological basis for effective management of ALD.