Role of oxidative stress in diabetes-induced complications and their management with antioxidants.

Diabetes mellitus (DM) is a huge global health issue and one of the most studied diseases, with a large global prevalence. Oxidative stress is a cytotoxic consequence of the excessive development of ROS and suppression of the antioxidant defense system for ROS elimination, which accelerates the progression of diabetes complications such as diabetic neuropathy, retinopathy, and nephropathy. Hyperglycaemia induced oxidative stress causes the activation of seven major pathways implicated in the pathogenesis of diabetic complications. These pathways increase the production of ROS and RNS, which contributes to dysregulated autophagy, gene expression changes, and the development of numerous pro-inflammatory mediators which may eventually lead to diabetic complications. This review will illustrate that oxidative stress plays a vital role in the pathogenesis of diabetic complications, and the use of antioxidants will help to reduce oxidative stress and thus may alleviate diabetic complications.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Gut microbiota and Autism Spectrum Disorder: From pathogenesis to potential therapeutic perspectives.

Autism is a complex neurodevelopmental disorder which disrupts communication, social and interactive skills followed by appearance of repetitive behavior. The underlying etiology remains incomprehensible but genetic and environmental factors play a key role. Accumulated evidence shows that alteration in level of gut microbes and their metabolites are not only linked to gastrointestinal problems but also to autism. So far the mix of microbes that is present in the gut affects human health in numerous ways through extensive bacterial-mammalian cometabolism and has a marked influence over health via gut-brain-microbial interactions. Healthy microbiota may even ease the symptoms of autism, as microbial balance influences brain development through the neuroendocrine, neuroimmune, and autonomic nervous systems. In this article, we focused on reviewing the correlation between gut microbiota and their metabolites on symptoms of autism by utilizing prebiotics, probiotics and herbal remedies to target gut microflora hence autism.

Protective effect of Grewia asiatica leaves extract in animal models of epilepsy and anxiety.

Grewia asiatica Linn. is a well-known plant for its nutritional and therapeutic attributes. It has been mentioned in ancient Indian literature as Rasayana due to its stimulant and tonic effects. Thus, present investigation was carried out to evaluate the antiepileptic and anxiolytic action of G. asiatica Linn. leaves using animal models. Methanol extract at dose levels of 100 and 200 mg/kg was capable of providing protection against both pentylenetetrazole and maximal electroshock induced seizures in mice. Extract also showed significant anxiolytic activity in elevated plus maze, light/dark box and mirror chamber mice models at same dose levels. Results of this study indicated that the methanol extract of leaves of G. asiatica plant possess significant antiepileptic and anxiolytic effect.

Reconnoitering the transformative journey of minocycline from an antibiotic to an antiepileptic drug.

Minocycline, a second-generation tetracycline antibiotic is being widely tested in animals as well as clinical settings for the management of multiple neurological disorders. The drug has shown to exert protective action in a multitude of neurological disorders including spinal-cord injury, stroke, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Being highly lipophilic, minocycline easily penetrates the blood brain barrier and is claimed to have excellent oral absorption (~100% bioavailability). Minocycline possesses anti-inflammatory, immunomodulatory, and anti-apoptotic properties, thereby supporting its use in treating neurological disorders. The article henceforth reviews all the recent advances in the transformation of this antibiotic into a potential antiepileptic/antiepileptogenic agent. The article also gives an account of all the clinical trials undertaken till now validating the antiepileptic potential of minocycline. Based on the reported studies, minocycline seems to be an important molecule for treating epilepsy. However, the practical therapeutic implementations of this molecule require extensive mechanism-based in-vitro (cell culture) and in-vivo (animal models) studies followed by its testing in randomized, placebo controlled and double-blind clinical trials in large population as well as in different form of epilepsies.

Hepatoprotective effect of Physalis divaricata in paracetamol induced hepatotoxicity: In vitro, in silico and in vivo analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalis divaricata D. Don. is an erect weed of family Solanaceae. The root extract of this plant is used by the indigenous communities of Sub-Himalayan region of Uttarakhand, India for the treatment of liver disorders. AIM OF THE STUDY: To evaluate hepatoprotective potential of P. divaricata in paracetamol (PCM) induced hepatotoxicity in rats. MATERIALS AND METHODS: The dried roots of P. divaricata were subjected to extraction using different solvents. The chloroform extract, methanol extract and bioactive aqueous fraction of methanol extract were evaluated for hepatoprotective effect. After initial in vitro screening, all extracts were screened for hepatoprotective potential in PCM (3 g/kg p.o) induced hepatotoxicity. Following PCM administration, extracts were administered orally for 7 days in increasing dose concentrations. All the animals were euthanized on eighth day, serum and liver tissues were collected and subjected to various biochemical and histopathological analysis. Aqueous fraction of methanol extract was further analyzed using LC- MS analysis. RESULTS: Methanol extract and its bioactive aqueous fraction exhibited significant and better in vitro antioxidant and antiproliferative activity as compared to chloroform extract. PCM treatment caused hepatotoxicity as assessed by altered levels of various hepatic biomarkers (increase in the levels of ALT, AST, ALP, albumin, triglycerides, cholesterol, TBARS, and AOPPs as well as decrease in GSH and TrxR levels) along with histopathological changes (portal to portal bridging, necrosis, and inflammation). Methanolic extract (200, 400 and 800 mg/kg) and its aqueous fraction treatment (25, 50 and 100 mg/kg) significantly restored elevated hepatic biomarkers, oxidative stress, and protected normal hepato-architecture. LC-MS analysis of aqueous fraction showed presence of rutin and kaempferol. In silico analysis further showed the capability of rutin to make complex with TNF-α and block its interaction with the target site. CONCLUSION: Aqueous fraction showed maximum hepatoprotective potential as conceived through in vitro and in vivo studies. Presence of rutin may explain hepatoprotective potential of P. divaricata.

Protective effect of vanillic acid against diabetes and diabetic nephropathy by attenuating oxidative stress and upregulation of NF-κB, TNF-α and COX-2 proteins in rats.

Diabetes is the most prevalent disorder in the world characterized by uncontrolled high blood glucose levels and nephropathy is one of the chief complications allied with hyperglycemia. Vanillic acid; the main bioactive compound derived from natural sources such as vegetables, fruits and plants possesses various pharmacological activities such as antioxidant, anti-inflammatory and anti-proliferative. The current study was designed to investigate the antidiabetic and renoprotective effects of vanillic acid by its various pharmacological activities. Streptozotocin (50 mg/kg)/nicotinamide (110 mg/kg) was used to induce diabetes in rats. Oral administration of vanillic acid once daily for 6 weeks (25, 50 and 100 mg/kg) significantly reduced the hyperglycemia, increased liver enzymes and normalized lipid profile that was altered in diabetic rats. Moreover, vanillic acid attenuated the impaired renal function as evidenced by a reduction in serum creatinine, urea, uric acid and urinary microproteinuria levels with a concomitant increase in urinary creatinine clearance in the nephropathic rats. Diabetic rats showed a marked increase in thiobarbituric acid reactive substances (TBARS) and superoxide anion generation (SAG) along with decreased reduced glutathione (GSH) in the renal tissue which was ameliorated in the vanillic acid-treated rats. Histopathologically, vanillic acid treatment was associated with reduced damage with normalized structural changes in renal tissue. Furthermore, treatment groups showed the suppression of upregulation of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, cyclo-oxygenase (COX)-2 and up-regulation of Nuclear factor-erythroid 2-related factor 2 (Nrf-2) in the renal tissue. In conclusion, vanillic acid's ameliorative impact on diabetic nephropathic rats may be attributed to its powerful free radical scavenging property, down-regulation of NF-κB, TNF-α, COX-2 and up-regulation of Nrf-2 proteins in renal tissue.

A Comprehensive Review on Medicinal Herbs and Novel Formulations for the Prevention of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases reported in the aging population across the globe. About 46.8 million people are reported to have dementia, and AD is mainly responsible for dementia in aged people. Alzheimer's disease (AD) is thought to occur due to the accumulation of ß-amyloid (Aß) in the neocortex portion of the brain, nitric oxide mediated dysfunctioning of blood-brain barrier, reduced activity of serine racemase enzyme, cell cycle disturbances, damage of N-methyl-D-aspartate (NMDA) receptors and glutamatergic neurotransmission. Modern treatment methods target the pathways responsible for the disease. To date, solely symptomatic treatments exist for this disease, all making an attempt to counterbalance the neurotransmitter disturbance. Treatments able to prevent or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. Effective treatments entail a better indulgence of the herbal bioactives by novel drug delivery systems. The herbal bioactive administered by novel drug delivery systems have proved beneficial in treating this disease. This review provides detailed information about the role of medicinal plants and their formulations in treating Alzheimer's disease which will be highly beneficial for the researchers working in this area.

Protective role of Phyllanthusfraternus in alloxan-induced diabetes in rats.

BACKGROUND: Phyllanthusfraternus is a pantropical weed of family phyllanthaceae, mainly found in northeast India. It has been used in the folklore medicine of Manipur tribe for treating type 2 diabetes. OBJECTIVE: The present study was commenced to evaluate the anti-diabetic and renoprotective potential of P.fraternus (aerial parts) in alloxan-induced diabetes in rats. MATERIALS AND METHODS: Alloxan (130 mg/kg, ip) was used for the induction of diabetes in adult male wistar rats. Animals with blood glucose level greater than 280 mg/dL were treated once daily for 14 days with various test extracts. The biochemical parameters were measured from serum on the 15th day post-treatment. Necropsy samples harvested from pancreas and kidneys were examined for histopathological changes in these organs. RESULTS: Alloxan-induced diabetes not only caused significant increases in blood glucose, triglycerides, total cholesterol, creatinine and urea levels, but also provoked high oxidative stress in pancreas and kidneys. Profound morphological injuries were observed in islets of Langerhans and kidneys of diabetic animals. Administration of methanol extract (200 and 400 mg/kg) and mother liquor (200 and 400 mg/kg) ameliorate the elevated levels of blood glucose, triglycerides, total cholesterol as well as other biochemical parameters, but highest reduction in blood glucose concentration was observed with the largest dose of ethyl acetate fraction (400 mg/kg) of P.fraternus. Histopathological examination of pancreas and kidneys also exhibited greater protection by treatment with acetate fraction (400 mg/kg). The HPLC analysis showed the presence of four polyphenols such as catechin, gallic acid, caffeic acid and ellagic acid in ethyl acetate fraction of P. fraternus during HPLC analysis. CONCLUSION: The results suggest that polyphenols present in P.fraternus may be responsible for the anti-diabetic and renoprotective activity in rats. Such protective effects of could be mediated through flavonol-induced anti-oxidant and anti-inflammatory activities in the pancreas and kidneys.

Molecular targets in cancer prevention by 4-(methylthio)butyl isothiocyanate - A comprehensive review.

The consumption of cruciferous vegetables rich in isothiocyanates has long been associated with a reduced risk of various types of cancer. 4-(methylthio)butyl isothiocyanate also called erucin is an isothiocyanate present in appreciable quantity in the seeds of Eruca sativa Mill. plant. Although the literature has revealed its protective effects via inducing phase II enzymes and inhibiting carcinogen activating phase I enzymes, recent studies also suggest that, it inhibits the proliferation of cancer cells by altering the telomerase activity, dynamics of microtubules, expression of histone deacetylases, and other molecular pathways. With this in mind, the emphasis has been made to review the molecular targets involved in cancer prevention by 4-(methylthio)butyl isothiocyanate.

Alternative treatment strategies for neuropathic pain: Role of Indian medicinal plants and compounds of plant origin-A review.

Neuropathic pain is a complex, chronic pain state accompanied by tissue injury and nerve damage. This important health issue constitutes a challenge for the modern medicine worldwide. The management of neuropathic pain remains a major clinical challenge, pertaining to an inadequate understanding of pathophysiological mechanisms of neuropathic pain. Various classes of drugs have been reported effective for the management of neuropathic pain viz. opiates, tricyclic antidepressants, and antiepileptic agents. However, association of adverse effects with these drugs hinders their confident prescription in people with neuropathic pain. Recently, various medicinal plants have been reported effective for the management of neuropathic pain. So, it may be prudent to look beyond synthetic drugs pertaining to their unprecedented pharmacotherapeutic effects with lesser adverse effects. The extensive literature review has been carried out from databases such as Science direct, Scifinder, Wiley online library, PubMed, Research gate, Google scholar and Chemical Abstracts. The list of Traditional Indian Medicinal plants (TIMPs) and isolated compounds have been compiled which have been reported effective as an alternative therapy for the management of neuropathic pain. This helps the researchers to discover some novel therapeutic agents against neuropathic pain.

Ameliorative potential of Alstonia scholaris (Linn.) R. Br. against chronic constriction injury-induced neuropathic pain in rats.

BACKGROUND: Alstonia scholaris commonly known as 'Saptaparni' is an Indian traditional medicinal plant used in Ayurveda. It is commonly used to treat various disorders like asthma, bronchitis, diarrhea, dysentery and malaria. In folklore medicine the milky juice of the plant is applied on wounds and ulcers to treat pain, ear ache and also in rheumatic pains. AIM: The present study was designed to investigate the potential of A. scholaris R. Br. in chronic constriction injury of sciatic nerve (CCI) induced neuropathic pain in rats. METHODS: Peripheral neuropathy was induced by chronic constriction injury of sciatic nerve. The behavioral parameters like mechanical and thermal hyperalgesia and cold allodynia were assessed on the 14th day. Tissue parameters like total protein, thiobarbituric acid reactive substances, reduced glutathione, myeloperoxidase, total calcium and TNF-α were assessed to check biochemical changes. Chloroform and methanol extract of A. scholaris leaves (100 and 200 mg/kg) and pregabalin (10 mg/kg, as positive control) were administered orally for 14 consecutive days starting from the day of surgery. RESULTS: CCI resulted in significant development of mechanical hyperalgesia, heat hyperalgesia and cold allodynia along with alteration in the biochemical changes. Administration of methanol extract at 200 mg/kg significantly attenuated the CCI induced change in nociceptive threshold and biochemical changes which was comparable to that of pregabalin. The high-performance liquid chromatography (HPLC) of the bioactive methanol extract revealed the presence of different types of flavonoids such as gallic acid, catechin, epicatechin, ellagic acid and kaempferol, in which kaempferol was observed to be in higher concentration. CONCLUSION: Methanol extract (200 mg/kg) of A. scholaris showed the ameliorative effect in CCI induced neuropathic pain which may be due to the presence of kaempferol and attributed to its anti-oxidative and anti-inflammatory properties.