The Potential Role of Probiotics in the Management of Osteoarthritis Pain: Current Status and Future Prospects.

PURPOSE OF REVIEW: This narrative review article comprehensively explains the pathophysiology of osteoarthritis (OA) pain perception, how the gut microbiota is correlated with it, possible molecular pathways involved in probiotics-mediated OA pain reduction, limitations in the current research approaches, and future perspectives. RECENT FINDINGS: The initiation and progression of OA, including the development of chronic pain, is intricately associated with activation of the innate immune system and subsequent inflammatory responses. Trauma, lifestyle (e.g., obesity and metabolic disease), and chronic antibiotic treatment can disrupt commensal homeostasis of the human microbiome, thereby affecting intestinal integrity and promoting leakage of bacterial endotoxins and metabolites such as lipopolysaccharides (LPS) into circulation. Increased level of LPS is associated with knee osteophyte severity and joint pain. Both preclinical and clinical studies strongly suggest that probiotics may benefit patients with OA pain through positive gut microbiota modulation and attenuating low-grade inflammation via multiple pathways. Patent data also suggests increased interest in the development of new innovations that involve probiotic use for reducing OA and joint pain. Recent data suggest that probiotics are attracting more and more attention for OA pain management. The advancement of knowledge in this area may pave the way for developing different probiotic strains that can be used to support joint health, improve treatment outcomes in OA, and reduce the huge impact of the disease on healthcare systems worldwide.

Association between insulin and Nrf2 signalling pathway in Alzheimer's disease: A molecular landscape.

Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD.

Levosimendan: mechanistic insight and its diverse future aspects in cardiac care.

Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca2+) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust.

Structural Proteomics: Detection of Neurodegenerative Protein Modifications.

For decades now, neurodegenerative disorders have been explored, but their prompt detection is still very strenuous due to the complexity of the brain. This entails the demand for identification and development of clinical biomarkers in order to comply with the criteria of precision, specificity and repeatability. The use of rapidly evolving technologies such as Mass Spectrometry (MS) in proteomics has opened new ways to speed up the discovery of biomarkers, both for diagnostic and prognostic purposes. The wide range of possibilities for the detection of differentially expressed proteins in specific diseases has been opened by several novel proteomic techniques such as cross-linking mass spectrometry, hydrogen-deuterium exchange mass spectrometry, protein foot printing and more. Still, much research is required to give a deep insight into the complex system of the brain and its related disorders for unraveling prognostic and diagnostic biomarkers, which can be used to either enhance a certain function of our brain or to cure a particular disease/disorder. This review summarizes the latest developments in neuroproteomics and analyzes existing and potential directions for the discovery of biomarkers for neurodegenerative diseases.

Current Quest in Natural Bioactive Compounds for Alzheimer's Disease: Multi-Targeted-Designed-Ligand Based Approach with Preclinical and Clinical Based Evidence.

Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/ß secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.

Application of Contemporary Neuroproteomic Techniques in Unravelling Neurological Disorders.

Decades of research has stunned us with the very distinctive anatomy and physiology of our brain, and on the other hand, its complexity has always posed great difficulty in treating its dysfunction or damage. Understanding the brain under normal and, particularly in the diseased state, has always been very challenging and would have been impossible without proteomics. Neuroproteomic techniques have been extensively used for unraveling both dynamics and content of the proteome of our nervous system. This modern-day investigation and quantification of protein concentration and expression have given us a platform that enhances our knowledge on disease-associated processes and pathways modification and also leads to the identification of possible biomarkers that can be therapeutically targeted. With an increased interest in identifying and targeting possible biomarkers, this article focuses on describing applications of the much discussed neuroproteomics, with a significant role in the disease pathogenesis of some very common neurological disorders. This article will collectively discuss the use and relevance of neuroproteomics in a range of neurological diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and psychiatric disorders. We have also attempted to present the current successes and failures of the neuroproteomics approach on the results obtained from different clinical studies that targeted biomarkers associated with any particular neurological disorder.

Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease.

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-ß (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aß and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aß (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aß (1-42) level, GSK-3ß activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

Effect of statins on amyloidosis in the rodent models of Alzheimer's disease: Evidence from the preclinical meta-analysis.

INTRODUCTION: Previous studies have shown contrasting results in determining efficacy of statins against amyloid beta accumulation. The aim of this study was to assess the impact of statin in AD. METHOD: We searched PubMed and Embase for relevant preclinical studies. A meta-analysis of the statin's efficacy on amyloidosis and cognitive impairment was performed. Also, stratified analysis was performed on several covariates including the type of statin used, gender and age of rodents and duration of statin therapy, to account for the reported heterogeneity in the results obtained. The study protocol was registered in PROSPERO (CRD42018102557). RESULT: 17 studies including 22 comparisons, containing a sample size of 446 rodents, participated in the meta-analysis of statin's effect on overall Aß deposition. Although the effect of statin on overall Aß deposition was found to be protective (p < 0.00001) but as we categorized the efficacy of statin on different Aß species (soluble and insoluble Aß40/42) and Aß plaque load, we found that significance in the protection decreased. A stratified meta-analysis demonstrated a significant role in the duration of statin supplements and rodent's age on the heterogeneity of the results. Statin administered to rodents for the longest duration (>6 months) and younger rodents (<6 months of age) demonstrated significant efficacy of statin on Aß deposition. CONCLUSION: Statin showed reduction in Aß level but stratified analysis revealed that this effect of statin was dependent on rodent's age and duration of the treatment.

Role of AMP-activated protein kinase on cardio-metabolic abnormalities in the development of diabetic cardiomyopathy: A molecular landscape.

Cardiovascular complications associated with diabetes mellitus remains a leading cause of morbidity and mortality across the world. Diabetic cardiomyopathy is a descriptive pathology that in absence of co-morbidities such as hypertension, dyslipidemia initially characterized by cardiac stiffness, myocardial fibrosis, ventricular hypertrophy, and remodeling. These abnormalities further contribute to diastolic dysfunctions followed by systolic dysfunctions and eventually results in clinical heart failure (HF). The clinical outcomes associated with HF are considerably worse in patients with diabetes. The complexity of the pathogenesis and clinical features of diabetic cardiomyopathy raises serious questions in developing a therapeutic strategy to manage cardio-metabolic abnormalities. Despite extensive research in the past decade the compelling approaches to manage and treat diabetic cardiomyopathy are limited. AMP-Activated Protein Kinase (AMPK), a serine-threonine kinase, often referred to as cellular "metabolic master switch". During the development and progression of diabetic cardiomyopathy, a plethora of evidence demonstrate the beneficial role of AMPK on cardio-metabolic abnormalities including altered substrate utilization, impaired cardiac insulin metabolic signaling, mitochondrial dysfunction and oxidative stress, myocardial inflammation, increased accumulation of advanced glycation end-products, impaired cardiac calcium handling, maladaptive activation of the renin-angiotensin-aldosterone system, endoplasmic reticulum stress, myocardial fibrosis, ventricular hypertrophy, cardiac apoptosis, and impaired autophagy. Therefore, in this review, we have summarized the findings from pre-clinical and clinical studies and provided a collective overview of the pathophysiological mechanism and the regulatory role of AMPK on cardio-metabolic abnormalities during the development of diabetic cardiomyopathy.

No association between proton pump inhibitor use and risk of dementia: Evidence from a meta-analysis.

BACKGROUND AND AIM: A growing body of literature suggests the association between dementia risk and proton pump inhibitor (PPI) use. Therefore, we aimed to investigate the association between PPI use and dementia risk. METHODS: An extensive literature search was performed in PubMed, Embase, and Cochrane till March 31, 2019. All the studies (cohort and case-control) assessing the association between PPI use and dementia risk were eligible for inclusion. Articles were selected based on the screening of title and abstract, data were extracted, and risk of bias was assessed using Newcastle-Ottawa scale. The primary outcome was pooled risk of dementia among PPI user as compared with non-PPI user. Secondary outcomes include dementia risk based on subgroups. Statistical analysis was performed using review manager software. RESULTS: Twelve studies (eight cohort and four case-control) were found to be eligible for inclusion. Majority of the studies were of high quality. Dementia was diagnosed based on International Classification of Diseases 9/10 codes in majority of the included studies. PPI use was not associated with the dementia risk, with a pooled relative risk (RR) of 1.05 (95% confidence interval [CI]: 0.96-1.15), P = 0.31. Subgroup analysis based on study design (cohort: P = 0.14; case-control: P = 0.14), sex (RR 1.25 [95% CI: 0.97-1.60], P = 0.08), histamine 2 receptor antagonist blockers (P = 0.93), and Alzheimer's disease (RR 1.00 [95% CI: 0.91-1.09], P = 0.93) revealed no significant association between PPI use and dementia risk. CONCLUSION: We found no significant association between PPI use and the risk of dementia or Alzheimer's disease.

A novel therapeutic potential of cysteinyl leukotrienes and their receptors modulation in the neurological complications associated with Alzheimer's disease.

Cysteinyl leukotrienes (cysLTs) are member of eicosanoid inflammatory lipid mediators family produced by oxidation of arachidonic acid by action of the enzyme 5-lipoxygenase (5-LOX). 5-LOX is activated by enzyme 5-Lipoxygenase-activating protein (FLAP), which further lead to production of cysLTs i.e. leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4). CysLTs then produce their potent inflammatory actions by activating CysLT1 and CysLT2 receptors. Inhibitors of cysLTs are indicated in asthma, allergic rhinitis and other inflammatory disorders. Earlier studies have associated cysLTs and their receptors in several neurodegenerative disorders diseases like, multiple sclerosis, Parkinson's disease, Huntington's disease, epilepsy and Alzheimer's disease (AD). These inflammatory lipid mediators have previously shown effects on various aggravating factors of AD. However, not much data has been elucidated to test their role against AD clinically. Herein, through this review, we have provided the current and emerging information on the role of cysLTs and their receptors in various neurological complications responsible for the development of AD. In addition, literature evidences for the effect of cysLT inhibitors on distinct aspects of abnormalities in AD has also been reviewed. Promising advancement in understanding on the role of cysLTs on the various neuromodulatory processes and mechanisms may contribute to the development of newer and safer therapy for the treatment of AD in future.

Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Aß peptides in animal model of Alzheimer's disease.

With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-ß (1-42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Aß (1-42) peptides infused Wistar rats. ASX also significantly attenuated soluble Aß (1-42) level, IRS-S307 activity, GSK-3ß activity, TNF-α level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD.

Calcium channel blocker use reduces incident dementia risk in elderly hypertensive patients: A meta-analysis of prospective studies.

Calcium channel blockers (CCBs) are an established class of drug for the management of hypertension. Observational studies have found that CCB use is associated with a reduction in the risk of developing dementia; however, studies have variably linked the CCBs use with the risk of dementia. This meta-analysis aims to assess whether, in elderly hypertensive patients, the use of CCBs alters the risk of developing dementia. We searched PubMed, Embase and Cochrane from August 2013 to 21st August 2017. Studies were screened on the basis of title and abstract. Quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). The primary outcome was an estimate of the risk of dementia in elderly hypertensive CCBs users. The pooled relative risk (RR) was calculated using a generic inverse variance method. A subgroup analysis was also performed based on CCB class. Statistical analyses were performed using Review Manager Version 5.3. The meta-analysis included ten studies comprising 75,239 patients (53.16% female) with a median age and follow-up duration of 72.24 years and 8.21 years respectively. All of the studies were of high quality. The use of CCBs was associated with a significant reduction in the risk of developing dementia in elderly hypertensive patients (RR 0.70 [95% CI: 0.58-0.85] p = 0.0003) compared to those not using CCBs. In subgroup analysis we found that the dihydropyridine class was associated with a 44% [RR 0.56 (95% CI: 0.40-0.78) p = 0.0005] reduction in the dementia risk. The use of CCBs was associated with a significant reduction in the risk of developing dementia in elderly hypertensive patients.