An in silico drug repurposing approach to identify HDAC1 inhibitors against glioblastoma.

Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.

Evaluation of efficacy and safety of glucosamine sulfate, chondroitin sulfate, and their combination regimen in the management of knee osteoarthritis: a systematic review and meta-analysis.

AIM: This study was aimed to assess the efficacy and safety of two oral Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOAs)-Glucosamine Sulfate, Chondroitin Sulfate, and their combination regimen in the management of knee osteoarthritis (KOA). METHODS: This systematic review was conducted according to PRISMA 2020 guidelines. A detailed literature search was performed from 03/1994 to 31/12/2022 using various electronic databases including PubMed, Embase, Cochrane Library, and Google Scholar, using the search terms-Glucosamine sulfate (GS), Chondroitin sulfate (CS), Knee osteoarthritis, Joint pain, Joint disease, and Joint structure, for literature concerning glucosamine, chondroitin, and their combination in knee osteoarthritis treatment. Cochrane Collaboration's Risk assessment tool (version 5.4.1) was used for assessing the risk of bias and the quality of the literature. The data was extracted from the included studies and subjected to statistical analysis to determine the beneficial effect of Glucosamine Sulfate, Chondroitin Sulfate, and their combination. RESULTS: Twenty-five randomized controlled trials (RCTs) were included in this systematic review. In short, exclusively 9 RCTs for GS, 13 RCTs for CS, and 3 RCTs for the combination of GS and CS. All these studies had their treatment groups compared with placebo. In the meta-analysis, CS showed a significant reduction in pain intensity, and improved physical function compared to the placebo; GS showed a significant reduction in tibiofemoral joint space narrowing. While the combination of GS and CS showed neither a reduction in pain intensity, nor any improvement in the physical function. However, the combination exhibited a non-significant reduction in joint space narrowing. In the safety evaluation, both CS and GS have shown good safety profile and were well tolerated. CONCLUSION: This meta-analysis revealed that the CS (with decreased pain intensity and improvement in the physical function), and GS (with significant reduction in the joint space narrowing) have significant therapeutic benefits. However, their combination did not significantly improve the symptoms or modify the disease. This may be due to the limited trials that are available on the combination of the sulfate forms of the intervention. Hence, there is a scope for conducting multicentric randomised controlled trials to evaluate and conclude the therapeutic role of CS and GS combination in the management of KOA.

New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation.

Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders.

Mechanisms Behind the Pharmacological Application of Biochanin-A: A review.

This review was aimed at summarizing the cellular and molecular mechanisms behind the various pharmacological actions of biochanin-A. Many studies have been reported claiming its application in cancers, metabolic disorders, airway hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard to hormone-dependent cancers like breast, prostate, and other malignancies like pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment options, biochanin-A revealed agreeable results in arresting cancer development. Biochanin-A has also shown therapeutic benefits when administered for neurological disorders, diabetes, hyperlipidaemia, and other chronic diseases/disorders. Isoflavones are considered phenomenal due to their high efficiency in modifying the physiological functions of the human body. Biochanin-A is one among the prominent isoflavones found in soy (glycine max), red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency in modulating vital cellular mechanisms in various diseases. It has been popular for ages among menopausal women in controlling symptoms. In view of the multi-targeted functions of biochanin-A, it is essential to summarize it's mechanism of action in various disorders. The safety and efficacy of biochanin-A needs to be established in clinical trials involving human subjects. Biochanin-A might be able to modify various systems of the human body like the cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable effect on hormonal cancers and other cancers. Many types of research on biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic cancers, have shown a positive impact. Through modulating oxidative stress, SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms biochanin-A produces anti-diabetic action. The diverse molecular mechanistic pathways involved in the pharmacological ability of biochanin-A indicate that it is a very promising molecule and can play a major impact in modifying several physiological functions.

Sesamol combats diabetogenic effects of atorvastatin through GLUT-4 expression and improved pancreatic viability.

Statin-associated diabetes (SAD) is an issue that has come to light after a series of recent clinical trials that has led to the issue of a black box warning for statins by the US FDA. However, the benefit of statin outweighs its risk. Nevertheless, experiments have been conducted to identify the mechanism by which statins aggravate the risk of diabetes only in a select population who bear the risk factors of obesity, sedentary lifestyle, hypertension, and other associated risk factors of lifestyle disorders. In this study, the possibility of utilization of a phyto-molecule, sesamol, for its ability to combat statin-associated diabetes using atorvastatin as the agent of choice has been explored. MMP assay and western blot was conducted to investigate the effects of atorvastatin on apoptotic cascade with sesamol as a protective agent was conducted in MIN-6 cells. Effect of the combination was tested in L6 cells with 2-NBDG uptake assay and as well as western blot for GLUT-4. A diet-induced hypercholesterolemia model was developed in an in vivo model animals and treated with atorvastatin and sesamol with histopathological analysis being carried out to evaluate the apoptotic markers and GLUT-4 presence. It was found that sesamol can combat pancreatic beta cell apoptosis via the internal apoptotic pathway activated by atorvastatin. With regards to muscle cells, sesamol could improve the GLUT-4 vesical production, but not improve glucose uptake which is inhibited by atorvastatin. These findings are further confirmed by animal studies. These findings indicate that sesamol can serve as a prototype molecule for further development and investigation of similar compounds to tackle SAD.

Current Drug Targets in Alzheimer's Associated Memory Impairment: A Comprehensive Review.

Alzheimer's disease (AD) is the most prevalent form of dementia among geriatrics. It is a progressive, degenerative neurologic disorder that causes memory and cognition loss. The accumulation of amyloid fibrils and neurofibrillary tangles in the brain of AD patients is a distinguishing feature of the disease. Therefore, most of the current therapeutic goals are targeting inhibition of beta-amyloid synthesis and aggregation as well as tau phosphorylation and aggregation. There is also a loss of the cholinergic neurons in the basal forebrain, and first-generation therapeutic agents were primarily focused on compensating for this loss of neurons. However, cholinesterase inhibitors can only alleviate cognitive symptoms of AD and cannot reduce the progression of the disease. Understanding the molecular and cellular changes associated with AD pathology has advanced significantly in recent decades. The etiology of AD is complex, with a substantial portion of sporadic AD emerging from unknown reasons and a lesser proportion of early-onset familial AD (FAD) caused by a mutation in several genes, such as the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. Hence, efforts are being made to discover novel strategies for these targets for AD therapy. A new generation of AChE and BChE inhibitors is currently being explored and evaluated in human clinical trials for AD symptomatic treatment. Other approaches for slowing the progression of AD include serotonergic modulation, H3 receptor antagonism, phosphodiesterase, COX-2, and MAO-B inhibition. The present review provides an insight into the possible therapeutic strategies and their molecular mechanisms, enlightening the perception of classical and future treatment approaches.

Treatments for psoriasis: A journey from classical to advanced therapies. How far have we reached?

Psoriasis is considered an autoimmune, inflammatory disorder with a genetic basis. The underlying aetiology is yet unclear. Evidence suggests the congregation of immune cells and their secreted inflammatory cytokines, leukocytes, and other inflammation-promoting factors in large amounts within the epidermal layers of the skin, driving an inflammatory milieu. Although psoriasis is not a fatal condition, patients experience severe pain and suffering. It has a debilitating effect on the physiological and psychological state of the patient. Its distinguishing features are inflammation, formation of plaques on the skin and hyperproliferation of keratinocytes. Therapeutic strategies for treating psoriasis witnessed a radical improvement from traditional therapies to the approval of specific therapies like biologics and small molecules. The emerging evidence about new pharmacological targets and mechanisms in psoriasis has widened the scope for expanding therapeutic strategies. Our review discusses the existing treatments for plaque psoriasis and updates on therapies based on novel pharmacological targets in clinical development.

Amelioration of high-fat diet (HFD) + CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction.

Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1-8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (- 26.31 to - 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within - 750.70 to - 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p < 0.05) changes in lipid profile and anti-oxidant parameters (Catalase, SOD, GSH, nitrite, and LPO) and plasma insulin levels. NMJ-3 treatment also reduced inflammation, fibrosis, and necrosis in liver samples.

ABO phenotype and SARS-CoV-2 infection: Is there any correlation?

COVID-19 is the currently evolving viral disease worldwide. It mainly targets the respiratory organs, tissues and causes illness. A plethora of studies has been performing to bring proper treatment and prevent people from the infection. Likewise, susceptibility to some infectious diseases has been associated with blood group phenotypes. The co-relationship of blood group with the occurrence of SARS-CoV-2 infection and death has been examined in numerous studies. This review explained the described studies regarding the correlation of blood group and the other essential factors with COVID-19.

Beta-Caryophyllene, a CB2R Selective Agonist, Protects Against Cognitive Impairment Caused by Neuro-inflammation and Not in Dementia Due to Ageing Induced by Mitochondrial Dysfunction.

BACKGROUND: Dementia is a neurodegenerative disorder majorly evidenced by cognitive impairment. Although there are many types of dementia, the common underlying etiological factors in all the types are neuro-inflammation or aging induced apoptosis. ß-caryophyllene, a cannabinoid type-2 receptor agonist, has been reported to have promising neuroprotective effects in cerebral ischemia and neuro-inflammation. OBJECTIVE: In the present study, we evaluated the effects of ß-caryophyllene against animal models of dementia whose etiology mimicked neuro-inflammation and aging. METHODS: Two doses (50 and 100 mg/kg of body weight) of ß-caryophyllene given orally were tested against AlCl3-induced dementia in male Sprague Dawley (SD) rats using the Morris water maze test. Subsequently, the effect of the drug was assessed for episodic memory in female SD rats using novel object recognition task in doxorubicin-induced neuro-inflammation and chemobrain model. Moreover, its effects were evaluated in D-galactose-induced mitochondrial dysfunction leading to dementia. RESULTS: ß-caryophyllene, at both doses, showed significant improvement in memory when assessed using parameters like target quadrant entries, escape latency and path efficiency in the Morris water maze test for spatial memory. In the doxorubicin-induced chemobrain model, ß-caryophyllene at 100 mg/kg significantly elevated acetylcholinesterase and catalase levels and lowered lipid peroxidation compared to the disease control. In the novel object recognition task, ß-caryophyllene at 100 mg/kg significantly improved recognition index and discrimination index in the treated animals compared to the disease control, with a significant increase in catalase and a decrease in lipid peroxidation in both hippocampus and frontal cortex. However, in the D-galactose-induced mitochondrial dysfunction model, ß-caryophyllene failed to show positive effects when spatial memory was assessed. It also failed to improve D-galactose-induced diminished mitochondrial complex I and II activities. CONCLUSION: Hence, we conclude that ß-caryophyllene at 100 mg/kg protects against dementia induced by neuro-inflammation with no effect on neuronal aging induced by mitochondrial dysfunction.

Role of Statins in New-onset Diabetes Mellitus: The Underlying Cause, Mechanisms Involved, and Strategies to Combat.

Statins have transformed the treatment of cardiovascular diseases through primary and secondary prevention of events. Despite the success of statin's management of cardiovascular conditions, certain clinical trials, reviews, and meta-analysis point out that statins have the propensity to induce diabetes. The risk further increases with intensive statin therapy or in patients with diabetes. A proper mechanism for the induction of the diabetic condition has not yet been determined. The involvement of statin with beta cells in insulin secretion and peripheral cells in insulin resistance has been widely studied and established. The present review provides an update on the recent understanding of statin-induced diabetes. This covers the origin of statins, their development, possible mechanisms that explain the adverse effects in glucose homeostasis, and probable targets to remedy the condition.

In silico Study to Evaluate the Antiviral Activity of Novel Structures against 3C-like Protease of Novel Coronavirus (COVID-19) and SARS-CoV.

BACKGROUND: Globally, over 4.3 million laboratory confirmed cases of COVID-19 have been reported from over 105 countries. No FDA approved antiviral is available for the treatment of this infection. Zhavoronkov et al., with their generative chemistry pipeline, have generated structures that can be potential novel drug-like inhibitors for COVID-19, provided they are validated. 3C-like protease (3CLP) is a homodimeric cysteine protease that is present in coronaviruses. Interestingly, 3CLP is 96.1% structurally similar between SARS-CoV and SARS-CoV-2. OBJECTIVE: To evaluate interaction of generated structures with 3CLP of SARS-CoV (RCSB PDB ID: 4MDS). METHODS: Crystal structure of human SARS-CoV with a non-covalent inhibitor with resolution: 1.598 Å was obtained and molecular docking was performed to evaluate the interaction with generated structures. The MM-GBSA and IFD-SP were performed to narrow down to the structures with better binding energy and IFD score. The ADME analysis was performed on top 5 hits and further MD simulation was employed for top 2 hits. RESULTS: In XP docking, IFD-SP and molecular dynamic simulation studies, the top 2 hits 32 and 61 showed interaction with key amino acid residue GLU166. Structure 61, also showed interaction with HIS164. These interactions of generated structure 32 and 61, with GLU166 and HIS164, indicate the binding of the selected drug within the close proximity of 3CLP. In the MD simulation, the protein- ligand complex of 4MDS and structure 61 was found to be more stable for 10ns. CONCLUSION: These identified structures can be further assessed for their antiviral activity to combat SARS-CoV and COVID-19.

Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study.

Neprilysin (NEP) is a neutral endopeptidase with diverse physiological roles in the body. NEP's role in degradation of diverse classes of peptides such as amyloid beta, natriuretic peptide, substance P, angiotensin, endothelins, etc., is associated with pathologies of alzheimer's, kidney and heart diseases, obesity, diabetes and certain malignancies. Hence, the functional inhibition of NEP in the above systems can be a good therapeutic target. In the present study, in-silico drug repurposing approach was used to identify NEP inhibitors. Molecular docking was carried out using GLIDE tool. 2934 drugs from the ZINC12 database were screened using high throughput virtual screening (HTVS) followed by standard precision (SP) and extra precision (XP) docking. Based on the XP docking score and ligand interaction, the top 8 hits were subjected to free ligand binding energy calculation, to filter out 4 hits (ZINC000000001427, ZINC000001533877, ZINC000000601283, and ZINC000003831594). Further, induced fit docking-standard precision (IFD-SP) and molecular dynamics (MD) studies were performed. The results obtained from MD studies suggest that ZINC000000601283-NEP and ZINC000003831594-NEP complexes were most stable for 20ns simulation period as compared to ZINC000001533877-NEP and ZINC000000001427-NEP complexes. Interestingly, ZINC000000601283 and ZINC000003831594 showed similarity in binding with the reported NEP inhibitor sacubitrilat. Findings from this study suggest that ZINC000000601283 and ZINC000003831594 may act as NEP inhibitors. In future studies, the role of ZINC000000601283 and ZINC000003831594 in NEP inhibition should be tested in biological systems to evaluate therapeutic effect in NEP associated pathological conditions.

Tumour suppression through modulation of neprilysin signaling: A comprehensive review.

Peptidases are emerging as promising drug targets in tumour suppression. Neprilysin, also known as neutral endopeptidase, is a cell surface peptidase that degrades various peptides such as angiotensin II, endothelin I, Substance P, etc., and reduces their local concentration. Neprilysin is expressed in various tissues such as kidney, prostate, lung, breast, brain, intestine, adrenal gland, etc. The tumour-suppressor mechanisms of neprilysin include its peptidase activity that degrades mitogenic growth factors such as fibroblast growth factor-2 and insulin-like growth factors, and the protein-protein interaction of neprilysin with phosphatase and tensin homolog, focal adhesion kinase, ezrin/radixin/moesin, and phosphoinositide 3-kinase. Studies have shown that the levels of neprilysin play an important role in malignancies. NEP is downregulated in prostate, renal, lung, breast, urothelial, cervical, hepatic cancers, etc. Histone deacetylation and hypermethylation of the neprilysin promoter region are the common mechanisms involved in the downregulation of neprilysin. Downregulation of the peptidase promotes angiogenesis, cell survival and cell migration. This review presents an overview of the role of neprilysin in malignancy, the tumour suppression mechanisms of neprilysin, the epigenetic mechanisms responsible for downregulation of neprilysin, and the potential pharmacological approaches to upregulate neprilysin levels and its activity.

Rutin Protects against Doxorubicin-Induced Cognitive Dysfunction While Retaining the Anticancer Potential of Dox in a Murine Model of N-Methyl-N-Nitrosourea - Induced Mammary Carcinoma.

Chemobrain is a significant post-chemotherapy complication for which no approved treatments are available. We had previously identified that rutin inhibits doxorubicin (Dox-) -induced cognitive decline in healthy rats. However, it was important to also establish that it does so in rats with mammary carcinoma without compromising Dox's antitumor potential. Mammary carcinoma was induced in female rats by intraperitonial administration of N-methyl-N-nitrosourea (i.p.). Rats that developed mammary carcinoma were treated with Dox after pretreatment with vehicle or rutin. After Dox exposure (50 days), episodic and spatial memory was assessed using the novel object recognition task and the Morris water maze, respectively. Tumor progression was evaluated by measurement of tumor weight and volume and histological analysis. Blood samples were collected to estimate hematological parameters. Oxidative status and TNF-α levels were estimated in brain homogenates. Dox treatment significantly reduced tumor size and volume. Pretreatment with rutin did not significantly alter Dox's tumor suppression potential, suggesting that it does not influence Dox's anticancer activity. In addition, rutin ameliorated Dox-induced cognitive decline, myelosuppression, and brain oxidative stress. The present study indicates that rutin protects against Dox-induced cognitive decline and myelosuppression without affecting its antitumor potential.

Persistent attenuation of brain oxidative stress through aging in perinatal maternal separated rat pups supplemented with choline and docosahexaenoic acid or Clitoria ternatea aqueous root extract.

INTRODUCTION: Perinatal maternal separation stress (PMSS) induces brain lipid peroxidation and reduction in endogenous antioxidants. The present study was designed to assess the brain oxidative stress (MDA) and protein thiol levels through various stages of aging in PMSS rat pups supplemented with choline with docosahexaenoic acid (DHA) or Clitoria ternatea (Linn) aqueous root extract (CTR). MATERIAL AND METHODS: Study groups, control, PMSS, PMSS + choline with DHA, PMSS + CTR (n = 6/group) were included in the study. Pups of PMSS groups were separated from their mothers for a period of 6 h/day for 30 days. PMSS + supplemented groups were treated as appropriate during the same period. Rats were sacrificed on day 30, 60, 90, 210 and 360. Brains were processed for MDA and protein thiol levels. RESULTS: Brain MDA levels were significantly increased in PMSS rats at day 30, 60 (p < 0.001), 90 (p < 0.01) and attenuated in PMSS pups supplemented with choline with DHA and CTR at day 30, 60 (p < 0.01), 90 (p < 0.01, p < 0.05) and 360 (p < 0.001) when compared to the same in age-matched controls and PMSS rats, respectively. Alternatively, brain protein thiol levels in PMSS rats were reduced in all age groups when compared to the same in age-matched controls. A significant increase in brain thiol levels was observed in supplemented groups at day 60 (p < 0.01) and 210 (p < 0.01, p < 0.05) when compared to the same in age-matched PMSS rats. CONCLUSIONS: PMSS causes enhanced brain lipid peroxidation (MDA levels) and reduces endogenous antioxidants. Supplementation of choline and DHA or CTR during PMSS in rats persistently attenuates brain oxidative stress through aging.

Combined Administration of Monosodium Glutamate and High Sucrose Diet Accelerates the Induction of Type 2 Diabetes, Vascular Dysfunction, and Memory Impairment in Rats.

In this study, we aimed to develop an experimental animal model for type 2 diabetes mellitus (T2DM) using a combination of monosodium glutamate (MSG) and high sucrose diet (HSD). Young male Wistar rats (20-30 g) were injected with MSG (2 or 4 mg/g, i.p. for 4 days). These rats were also fed an HSD, while the control group was fed a starch diet (SFD) for 150 days. Parameters assessed periodically were body weight, feed intake, blood glucose level, and oral glucose tolerance test (OGTT), lipid profile, liver and kidney function tests, skeletal muscle glucose uptake, cognitive function tests, and microvascular changes using isolated rat aorta. Histological changes in pancreas, liver, and kidney tissue were assessed using hematoxylin and eosin staining, whereas brain tissue was assessed using cresyl violet stain. Feeding MSG in combination with HSD in rats significantly increased body weight, and produced hyperglycemia, dyslipidemia, and hyperinsulinemia. Animals developed frank diabetic complications, which included insulin resistance in skeletal muscle, hypertension, vascular dysfunction, nephropathy, and dementia. Histological studies revealed neuronal loss with necrotic bodies in the brain, reduction in glomerular count in kidney, and severe hypertrophy and hyperplasia in the islets of Langerhans. These results indicate the successful induction of type-2 diabetes along with several diabetic complications by combining MSG with HSD.

Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats: An in vitro and in vivo preclinical paradigm.

From our lab, among the nineteen heterocyclic homoprostanoids (HHPs), three derivatives (compounds 3, 3b and 3c) exerted antioxidant and anti-inflammatory activity. Present study is an extension of the earlier work, and, is designed to establish their therapeutic potential in monoarthritis in rats. In addition, their possible mechanism of action would be investigated. A battery of in vitro tests such as lipopolysaccharide (LPS)-induced nitrite (NO)/reactive oxygen species (ROS) and NO/interleukin (IL)-6 generation in murine macrophages and whole blood (WhB), respectively were conducted. Later, in vitro cyclooxygenase (COX) enzyme inhibitory activity was also evaluated. All the tested compounds showed comparable efficacy against ROS and NO in LPS-stimulated murine macrophages. However, compound 3 did not exert inhibitory effect on LPS-induced NO/IL-6 generation in WhB assay. Compounds (3b and 3c) inhibited the NO generation in LPS-stimulated WhB. However, only compound 3b reversed the raised IL-6 levels in this assay. None of the test compounds inhibited COX iso-enzymes in the in vitro assay. All three HHPs showed comparable efficacy against carrageenan-induced paw inflammation. However, none of them exhibited any dose-dependent effect in this model. Based upon previous reports, compound 3c was explored against adjuvant-induced monoarthritis (AIA) in male Sprague-Dawley rats, where it exerted promising therapeutic effect. In addition to radiological and histological examinations of tibio-tarsal joint, various parameters such as chronic inflammation/pain, clinical score, interleukin (IL)-6 levels and complete blood cell profile were evaluated in AIA rats. Chronic treatment with 3c halted the disease progression in rats, improved the overall health of animals, as demonstrated by haematological, clinical scoring and joint examinations (radiological and histopathological). Inhibitory effect on elevated IL-6 in AIA rats suggested the possible mechanism of 3c on cytokine signalling. Overall, the study supports the anti-arthritic potential of compound 3c.

Insulin Protects against Brain Oxidative Stress with an Apparent Effect on Episodic Memory in Doxorubicin-Induced Cognitive Dysfunction in Wistar Rats.

The present study was aimed at assessing the protective effect of insulin against doxorubicin (DOX)-induced cognitive dysfunction in Wistar rats. Cognitive function for episodic memory was assessed by a novel object recognition task (NORT) in male Wistar rats. Oxidative stress markers-SOD, catalase, glutathione, and lipid peroxidation-in the hippocampus and frontal cortex were assessed using colorimetric methods. Doxorubicin treatment (2.5 mg/kg, i.p., every 5 days for 50 days) reduced recognition and discriminative indices in NORT with increased oxidative stress in the brain. A nonhypoglycemic dose of insulin (0.5 IU/kg, i.p.) significantly reduced brain oxidative stress (MDA) induced by doxorubicin with an increase in the antioxidant defense systems (SOD, catalase, and GSH). Rats treated with combined insulin and DOX spent comparatively more time with the novel object when compared to the non-novel objects; however, the observed difference was not statistically significant. An apparent improvement (p < 0.26) in recognition of the novel object was observed against the damage induced by doxorubicin. These results suggest that insulin reduces brain oxidative stress and apparently improves doxorubicin-induced cognitive dysfunction in Wistar rats.

Sodium valproate enhances doxorubicin-induced cognitive dysfunction in Wistar rats.

BACKGROUND: Increasing number of scientific reports have highlighted the role of histone acetylation/deacetylation in neurodegenerative conditions, including chemotherapy-induced cognitive dysfunction (also known as chemobrain). Multiple sources state that increased activity of histone deacetylases (HDACs) play a detrimental role in chemobrain. In the present study, sodium valproate, a well-known HDAC inhibitor, was explored for its neuroprotective potential against chemobrain development. METHODS: Doxorubicin (DOX), a chemotherapeutic agent, was used to induce chemobrain in experimental animals while treating with sodium valproate simultaneously. The animals were subjected to novel object recognition test (NORT) in order to assess their cognitive status and further, brain antioxidant levels were estimated. The animal body weights and survival were noted throughout the period of the study. Blood parameters such as red blood cell count, white blood cell count and haemoglobin levels were also measured. RESULTS: Our findings are in contradiction to the known neuroprotective properties of valproic acid. We observed that sodium valproate failed to prevent chemobrain development in DOX treated animals. In fact, treatment with sodium valproate dose dependently worsened cognitive status in DOX treated animals including their brain antioxidant status, possibly leading to neuronal damage through free radical induced toxicity. CONCLUSION: The present study highlights the caution that needs to be exercised in projecting HDAC inhibitors as in vivo neuroprotective agents, due to the complexity of existing neurological pathways and the diverse roles of histone deacetylases.