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.

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.

Nrf2 Signaling Pathway: a Potential Therapeutic Target in Combating Oxidative Stress and Neurotoxicity in Chemotherapy-Induced Cognitive Impairment.

Chemotherapy-induced cognitive impairment (CICI) is one of the major adverse effects of antineoplastic drugs, which decrease the quality of life in cancer survivors. Extensive experimental and clinical research suggests that chemotherapeutic drugs generate an enormous amount of reactive oxygen species (ROS), contributing to oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, and neuronal death, eventually leading to CICI. Despite the progress in exploring different pathological mechanisms of CICI, effective treatment to prevent CICI progression has not been developed yet. Nrf2 is the principal transcription factor that regulates cellular redox balance and inflammation-related gene expression. Emerging evidence suggests that upregulation of Nrf2 and its target genes could suppress oxidative stress, and neuroinflammation, restore BBB integrity, and increase neurogenesis. This review discusses the role of Nrf2 in CICI, how it responds to oxidative stress, inflammation, neurotoxicity, and potential Nrf2 activators that could be used to enhance Nrf2 activation in CICI.

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.

α7nAChR activation protects against oxidative stress, neuroinflammation and central insulin resistance in ICV-STZ induced sporadic Alzheimer's disease.

Central insulin resistance is considered as one of the pathological hallmarks of Alzheimer's disease (AD), similar to formation of amyloid plaques and neurofibrillary tangles (NFT). Activation of α7nAChR by GTS-21 has been indicated to reverse peripheral insulin resistance and exert neuroprotection. Therefore, the aim of the present study was to determine the effect of α7nAChR agonist (GTS-21) on intracerebroventricular administration of streptozotocin (ICV-STZ)-induced oxidative stress, neuroinflammation, cholinergic dysfunction, central insulin resistance and cognitive deficits. GTS-21 (1, 4 and 8 mg/kg; i.p.) was administered for 21 days following bilateral ICV-STZ administration (3 mg/kg) in C57BL/6 mice. Neurobehavioral assessments were performed using Morris water maze (MWM) and novel object recognition (NOR). Inflammatory markers (TNF-α, IL-6 and IL-1ß) were determined using ELISA. Oxido-nitrosative stress (GSH, MDA and nitrite) and cholinergic activity (acetylcholine esterase and choline acetyltransferase) were estimated in the cortex and hippocampus through biochemical methods. Gene expression of insulin receptor (IR), IRS1, IRS2, BACE1, APP, PI3-K, AKT and GSK3ß were determined by q-RT-PCR. ICV-STZ administration induced memory impairment, increased oxidative stress and neuroinflammation, and caused cholinergic dysfunction. Our results demonstrated that activation of α7nAChR by GTS-21 treatment improved memory in MWM and NOR test. Moreover, GTS-21 treatment significantly decreased oxido-nitrosative stress, inflammatory markers and cholinergic dysfunction in cortex and hippocampus. Finally, GTS-21 treatment restored ICV-STZ induced downregulation of IR, IRS1, IRS2, PI3-k, Akt and attenuated GSK3ß, APP and BACE-1 indicating improved insulin signalling. Therefore, activation of α7nAChR through GTS-21 might be the potential target for the amelioration of central insulin resistance induced AD.

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.

Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits.

BACKGROUND: It is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival. OBJECTIVES: Elucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF-1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits. METHODS: Rats were administered with streptozotocin (3 mg/kg) intracerebroventricular, followed by administration of everolimus (1 mg/kg) orally for 21 days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group. RESULTS: Streptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor-1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF-α), apoptotic (NF-κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin. CONCLUSION: Findings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.

Short-chain fatty acids increase intracellular calcium levels and enhance gut hormone release from STC-1 cells via transient receptor potential Ankyrin1.

Short-chain fatty acids (SCFAs), metabolites of colonic bacterial fermentation of complex carbohydrates, are closely related to the release of gut hormones. In this study, we examined the involvement of transient receptor potential ankyrin 1 (TRPA1) in SCFA-induced increase in intracellular calcium ([Ca2+ ]i ) and its impact on gut hormone secretion using naturally TRPA1 expressing intestinal secretin tumour cell-1 (STC-1) cell line. Individual SCFAs and their physiological mix enhanced calcium influx in TRPA1-dependent manner. SCFA mix also significantly increased membrane expression of TRPA1. Gene expression studies revealed that SCFA mix elevated the expression of genes involved in calcium-activated calcineurin pathway in TRPA1-dependent manner and cAMP-regulated transcriptional co-activators (CRTC) pathway independent to TRPA1. Genes representing synaptic vesicular exocytosis and gut hormone precursors were significantly elevated with SCFA mix treatment. Treatment with TRPA1 antagonist HC-030031 markedly reduced these effects. The release of gut hormones was elevated with 10 mm SCFA mix in TRPA1 dependent manner. Our in vivo prebiotic study results suggested presence of an environment conducive to increase in gut hormone secretion. Overall, our findings provide an evidence for the possible role of TRPA1 in SCFA-induced increase in gut hormone secretion, hence another mechanism of action for prebiotics.

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.

Astaxanthin attenuates oxidative stress and inflammatory responses in complete Freund-adjuvant-induced arthritis in rats.

BACKGROUND: Astaxanthin (ATX), a natural xanthophyll carotenoid, has shown to exert significant protective effects against various diseases via its antioxidant and anti-inflammatory properties. However, its potential role in arthritis is still not reported. Therefore, the aim of the present study was to investigate the potential anti-arthritic properties of ATX against complete Freund's adjuvant (CFA)-induced arthritis rats. METHODS: Adjuvant arthritis was induced by single intraplantar injection of complete Freund's adjuvant (CFA) in the left hind paw of adult female Wistar rats. ATX (25, 50 and 100 mg/kg) and indomethacin (5 mg/kg) were given orally from days 14 to 28. The anti-arthritic activity was evaluated through various nociceptive behavioral tests (mechanical allodynia, mechanical hyperalgesia, cold allodynia, and thermal hyperalgesia), paw edema assessment, and arthritis scores. Serum tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and cyclic citrullinated peptide (CCP) antibody levels were assessed. Moreover, malondialdehyde (MDA), nitrite, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were also evaluated. RESULTS: Oral administration of ATX (50 and 100 mg/kg) exhibited significant anti-arthritic activity via enhancing the nociceptive threshold, reducing paw edema and improving arthritis scores. Moreover, ATX treatment also markedly suppressed inflammatory and oxidative mediators in adjuvant-administered rats. CONCLUSIONS: Our findings suggest that ATX possesses potential anti-arthritic activity, which could be attributed to its anti-inflammatory and antioxidant properties.

Selective ER-α agonist alleviates vascular endothelial dysfunction in ovariectomized type 2 diabetic rats.

Postmenopausal diabetic women represent a specific risk group with a greater incidence of vascular deficits as compared with age-matched men or non-diabetic women. 17ß-estradiol is the mainstay therapy for menopause and associated complications; however, its vasculoprotective effect is lost in women with diabetes. Although, exact mechanism of dichotomous effect of estrogen has not been delineated but it may be due to, differential activation of ER-α and ß during disease conditions such as diabetes. Thus main objective of our study was to characterize the specific estrogen receptor which could be selectively targeted to achieve vasculoprotection in postmenopausal diabetic situation. A significant impairment in glycemic and lipid profile, decreased ACh-induced endothelium dependent relaxation, impaired endothelial integrity, and rise in inflammatory and oxidative stress markers were observed in ovariectomized type 2 diabetic rats as compared to sham rats. These markers were further correlated with aortic eNOS levels. Treatment with selective ER-α receptor agonist markedly while 17ß-estradiol partially ameliorated these alterations along with enhanced aortic eNOS levels. However, ER-ß agonist did not show any effect. Our data suggests that selective ER-α activation could be an important pharmacological target, to mimic the beneficial effect of estradiol in cardiovascular disorders, especially in postmenopausal diabetic state.

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.

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.

Effect of mesenchymal stem cells and galantamine nanoparticles in rat model of Alzheimer's disease.

AIM: The present study investigated the efficacy of bone marrow-derived mesenchymal stem cells (BM-MSCs) in combination with galantamine hydrobromide-loaded solid lipid nanoparticles (GH-SLNs) in intracerebroventricular (ICV)-isoproterenol-induced rat model of Alzheimer's disease. MATERIALS & METHODS: BM-MSCs were harvested by dissecting femur and tibia of 8-10-week-old Wistar rats. 1 × 10(6) cells were administered intravenously once in ICV-isoproterenol-induced rats followed by GH-SLNs (5 mg/kg) for 3 weeks. RESULTS & CONCLUSION: ICV-isoproterenol resulted in significant memory deficit. The results demonstrated rapid regain of memory in isoproterenol-induced amnesic rats, following single intravenous administration of BM-MSCs and oral administration of GH-SLNs for 21 days. The combination of BM-MSCs and GH-SLNs produced a more pronounced protective effect, therefore, could be explored for the management of Alzheimer's disease.

Phytochemicals: Potential in Management of Climacteric Neurobiology.

Menopause jeopardizes the integrity of brain and makes it vulnerable to various diseases, both of psychiatric and degenerative nature. Exogenous estrogen supplementation confers neuroprotection but the results of Women's Health Initiative (WHI), Million Women Study (MWS) and incidence of endometrial cancer, breast cancer and venous thromboembolism reported with estrogen use have engendered doubts over its clinical translation for postmenopausal neurological disorders. Scientific community and general public have started recognizing the protective potential of phytochemicals in climacteric medicine. These phytochemicals are plant-derived, non-steroidal bioactive estrogenic compounds. Emerging preclinical studies have suggested that these phytochemicals display potential benefits in mitigating postmenopausal depression, anxiety, cerebral ischemia and cognitive dysfunction. Thus, the aim of present review is: a) to give an overview of neuroprotective action of estrogen, b) to address the chemical and pharmacological features of various classes of phytoestrogens, and c) to present preclinical and clinical evidence of effect of phytoestrogens on climacteric neurobiology with their possible mechanisms of action.

Protective effect of Mimosa pudica L. in an L-arginine model of acute necrotising pancreatitis in rats.

Mimosa pudica is used in traditional medicine for treating various disorders such as inflammatory conditions, diarrhoea, insomnia, alopecia, urogenital infections and wounds. The present study investigated the effect of M. pudica extract (MPE) on L-arginine-induced acute necrotising pancreatitis in rats. The ethanolic extract of M. pudica leaves was studied for the presence of quercetin and gallic acid using high-performance liquid chromatography. Four groups were employed-normal control rats, L-arginine control rats (two intraperitoneal [i.p.] injections of 2 g/kg at an interval of 1 h), MPE-treated rats (400 mg/kg orally) and melatonin-treated rats (positive control 10 mg/kg i.p.), which were further divided into subgroups according to time points (24 h, 3 days and 14 days). Serum amylase, lipase, tumour necrosis factor-α (TNF-α), pancreatic amylase, nucleic acid content, protein, transforming growth factor-ß1 (TGF-ß1), thiobarbituric reactive substances, glutathione, nitrite/nitrate, collagen content and histopathological examination were carried out. MPE significantly improved acute necrotising pancreatitis by modulating diagnostic markers of pancreatitis such as serum lipase and pancreatic amylase, inflammation (TNF-α), and oxidative and nitrosative stress. Moreover, MPE administration induced regenerative changes in the pancreas evidenced by increased levels of pancreatic proteins, nucleic acid content and histopathology report. In addition, MPE improved TGF-ß1 and collagen levels thereby preventing fibrosis. The current investigation indicates the novel role of MPE in reducing the severity of acute necrotising pancreatitis by plausible mechanisms such as anti-inflammatory and anti-fibrotic activity and by promoting repair and regeneration of the pancreas.

Cinnamaldehyde supplementation prevents fasting-induced hyperphagia, lipid accumulation, and inflammation in high-fat diet-fed mice.

Cinnamaldehyde, a bioactive component of cinnamon, is increasingly gaining interest for its preventive and therapeutic effects against metabolic complications like type-2 diabetes. This study is an attempt to understand the effect of cinnamaldehyde in high-fat diet (HFD)-associated increase in fasting-induced hyperphagia and related hormone levels, adipose tissue lipolysis and inflammation, and selected cecal microbial count in mice. Cinnamaldehyde, at 40 µM dose, prevented lipid accumulation and altered gene expression toward lipolytic phenotype in 3T3-L1 preadipocyte cell lines. In vivo, cinnamaldehyde coadministration prevented HFD-induced body weight gain, decreased fasting-induced hyperphagia, as well as circulating leptin and leptin/ghrelin ratio. In addition to that, cinnamaldehyde altered serum biochemical parameters related to lipolysis, that is, glycerol and free fatty acid levels. At transcriptional level, cinnamaldehyde increased anorectic gene expression in hypothalamus and lipolytic gene expression in visceral white adipose tissue. Furthermore, cinnamaldehyde also decreased serum IL-1ß and inflammatory gene expression in visceral white adipose tissue. However, cinnamaldehyde did not modulate the population of selected gut microbial (Lactobacillus, Bifidibaceria, and Roseburia) count in cecal content. In conclusion, cinnamaldehyde increased adipose tissue lipolysis, decreased fasting-induced hyperphagia, normalized circulating levels of leptin/ghrelin ratio, and reduced inflammation in HFD-fed mice, which augurs well for its antiobesity role.

Lycopene abrogates Aß(1-42)-mediated neuroinflammatory cascade in an experimental model of Alzheimer's disease.

BACKGROUND: Neuroinflammation characterized by glial activation and release of proinflammatory mediators is considered to play a critical role in the pathogenesis of Alzheimer's disease (AD). ß-Amyloid1-42 (Aß1-42)-induced learning and memory impairment in rats is believed to be associated with neuronal inflammation. OBJECTIVES: The present study was designed to investigate the effect of lycopene, a potent antioxidant and anti-inflammatory carotenoid, in intracerebroventricular (i.c.v.) Aß1-42-induced neuroinflammatory cascade along with learning and memory impairment in rats. MATERIAL AND METHODS: I.c.v. Aß1-42 was injected bilaterally followed by treatment with lycopene or rivastigmine for 14 days. Morris water maze and elevated plus maze tests were used to assess the memory function. Rats were sacrificed and brains harvested to evaluate various biochemical parameters and mitochondrial complex activities in postmitochondrial supernatant fractions of cerebral cortex and hippocampus of rat brains. The levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), tumor growth factor ß (TGF-ß), nuclear factor-κB (NF-κB) and caspase-3 were assessed by enzyme-linked immunosorbent assay analysis. RESULTS: Lycopene remediated Aß-induced learning and memory deficits in a dose-dependent manner. Aß1-42-induced mitochondrial dysfunction along with surge of proinflammatory cytokines TNF-α, TGF-ß and IL-1ß as well as NF-κB and caspase-3 activity in rat brain was significantly reduced with lycopene treatment. CONCLUSION: The amelioration of Aß1-42-induced spatial learning and memory impairment by lycopene could be linked, at least in part, to the inhibition of NF-κB activity and the down-regulation of expression of neuroinflammatory cytokines, suggesting that lycopene may be a potential candidate for AD treatment.