Biomarkers: Role and Scope in Neurological Disorders.

Neurological disorders pose a great threat to social health and are a major cause for mortality and morbidity. Effective drug development complemented with the improved drug therapy has made considerable progress towards easing symptoms associated with neurological illnesses, yet poor diagnosis and imprecise understanding of these disorders has led to imperfect treatment options. The scenario is complicated by the inability to extrapolate results of cell culture studies and transgenic models to clinical applications which has stagnated the process of improving drug therapy. In this context, the development of biomarkers has been viewed as beneficial to easing various pathological complications. A biomarker is measured and evaluated in order to gauge the physiological process or a pathological progression of a disease and such a marker can also indicate the clinical or pharmacological response to a therapeutic intervention. The development and identification of biomarkers for neurological disorders involves several issues including the complexity of the brain, unresolved discrepant data from experimental and clinical studies, poor clinical diagnostics, lack of functional endpoints, and high cost and complexity of techniques yet research in the area of biomarkers is highly desired. The present work describes existing biomarkers for various neurological disorders, provides support for the idea that biomarker development may ease our understanding underlying pathophysiology of these disorders and help to design and explore therapeutic targets for effective intervention.

Comparison of cardiac autonomic function across complete glycaemic spectrum.

OBJECTIVES: Autonomic imbalance is attributed as key mechanism altering metabolic regulation in diabetes mellitus. In view of controversial reports on autonomic function in FDRD and prediabetes, we aimed to assess and compare the autonomic function across the complete glycaemic spectrum in Indian population. METHODS: Short term heart rate variability and cardiac autonomic reactivity tests - blood pressure and heart rate response to orthostatic tolerance and deep breathing exercise, and diastolic response to isometric handgrip exercise were recorded in normoglycemic apparently healthy individual, normoglycemic first degree relatives of diabetes, prediabetes and diabetes individuals. RESULTS: Resting heart rate is significantly higher in FDRD, prediabetes and diabetes as compared to controls (control < FDRD = prediabetes = diabetes). Total power, LF power (control < FDRD < prediabetes = diabetes) and HF power (control < FDRD < prediabetes < diabetes) decreased along the glycaemic spectrum. Time-domain variables of HRV (SDNN, RMSSD, NN50, pNN50) were reduced as we move along the glycaemic spectrum (control < FDRD < prediabetes = diabetes). Cardiac autonomic function reactivity parameters such as 30:15 ratio and E:I ratio are decreased in prediabetes and diabetes group as compared to control and FDRD group (control = FDRD < prediabetes = diabetes). Diastolic response to isometric hand grip increases along the glycaemic spectrum starting from FDRD (control < FDRD < prediabetes = diabetes). CONCLUSIONS: Autonomic dysfunction is observed even in first degree relatives of diabetes. Autonomic dysfunction increases as we move along the glycaemic spectrum (control < FDRD < prediabetes < diabetes).

Structural characterization of glutamyl-tRNA synthetase (GluRS) from Plasmodium falciparum.

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in protein translation machinery that provide the charged tRNAs needed for protein synthesis. Over the past decades, aaRSs have been studied as anti-parasitic, anti-bacterial, and anti-fungal drug targets. This study focused on the cytoplasmic glutamyl-tRNA synthetase (GluRS) from Plasmodium falciparum, which belongs to class Ib in aaRSs. GluRS unlike most other aaRSs requires tRNA to activate its cognate amino acid substrate L-Glutamate (L-Glu), and fails to form an intermediate adenylate complex in the absence of tRNA. The crystal structures of the Apo, ATP, and ADP-bound forms of Plasmodium falciparum glutamyl-tRNA synthetase (PfGluRS) were solved at 2.1 Å, 2.2 Å, and 2.8 Å respectively. The structural comparison of the Apo- and ATP-bound holo-forms of PfGluRS showed considerable conformational changes in the loop regions around the ATP-binding pocket of the enzyme. Biophysical characterization of the PfGluRS showed binding of the enzyme substrates L-Gluand ATP.. The sequence and structural conservation were evident across GluRS compared to other species. The structural dissection of the PfGluRS gives insight into the critical residues involved in the binding of ATP substrate, which can be harvested to develop new antimalarial drugs.

COVID-19-induced Stress in Health-care Workers: Effect of 8-week Common Yoga Protocol on Autonomic Function and Inflammatory and Oxidative Stress Markers.

Background: COVID-19 pandemic posed a huge stress on health-care givers affecting their physical and mental health. Wellness strategies like yoga can improve flexibility, resilience, and outlook. Aim: The present study explored the effect of 8-week standard common yoga protocol (CYP) intervention on autonomic functions, emotional stress, oxidative stress, and inflammation markers in the nurse group of health-care givers. Materials and Methods: It is a randomized controlled trial where 50 nurses underwent CYP and 50 participated as controls. Anthropometric parameters, cardiovascular parameters, autonomic function including time and frequency domain parameters, biochemical parameters, and psychological stress using the questionnaire were assessed before and after 8-week CYP. Results: Total 88 nurses completed the study with 42 and 46 participants, respectively, in the CYP and control groups. CYP intervention resulted in a significant reduction in cardiovascular parameters systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse pressure, and rate pressure product (P < 0.001, P < 0.001, P < 0.001, P < 0.001, and P = 0.002, respectively), perceived stress score and Depression, Anxiety, and Stress Scale psychological variables of depression, anxiety, and stress, and serum lipid parameters compared to the control group. CYP significantly increased total power, low frequency, high frequency, root mean square of successive differences between adjacent NN intervals, change in successive normal sinus (NN) intervals exceeds 50 ms, and pNN50% (P < 0.001, P = 0.006, P = 0.006, P = 0.039, P < 0.001, and P = 0.013, respectively) suggesting improved resting autonomic modulation and parasympathodominance due to higher vagal efferent activity. There were significant reductions in serum cortisol, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 in both the groups. Serum telomerase significantly reduced (P = 0.024) and total antioxidant capacity (P = 0.036) increased in the CYP group post intervention. Conclusion: CYP intervention was beneficial in improving psychophysiological, autonomic, and biochemical profile of the nurse group of health-care workers.

Analysis of Prediagnostic Circulating Levels of Gonadotropins and Androgens with Risk of Epithelial Ovarian Cancer.

Background Prevailing experimental and epidemiological evidence supports the role of circulating endogenous sex steroid hormones in the pathogenesis of ovarian carcinogenesis by dysregulation of cell differentiation, proliferation, and apoptosis but is scarce and inconclusive. Objectives This article evaluates the role of circulating levels of gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and androgens (testosterone, dehydroepiandrosterone-sulfate [DHEA-S]) for the risk of epithelial ovarian cancer in a case-control approach using samples collected in advance of clinical diagnosis. Materials and Methods A total of 100 epithelial ovarian cancer (EOC) patients and 100 healthy female controls were consequently enrolled in this hospital-based case-control study. Serum FSH, LH, testosterone, and DHEA-S were measured based on the principle of electrochemiluminescence immunoassay. Suitable descriptive statistics were used for different variables. Results Median values of FSH (58.9 vs. 45.5 IU/L, p = 0.02) and DHEA-S (163.43 vs. 142.2 ug/dL, p = 0.03) were significantly high in EOC patients compared with controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH and DHEA-S concentrations, and the results revealed that the highest third tertile of FSH (> 72.6 IU/L; OR = 3.0, confidence interval [CI] = 1.24-7.29, p trend = 0.04) and DHEA-S (> 194.2 ug/dL; OR = 3.8, CI = 1.26-11.61, p trend = 0.03) were significantly associated with increased risk of ovarian cancer in postmenopausal and premenopausal women, respectively. The statistically significant trend observed for FSH in postmenopausal women, remained only for the subgroup with menopause duration greater than 10 years (OR = 5.9, CI = 1.33-26.66, p trend = 0.04). FSH and DHEA-S concentrations and ovarian cancer risk were internally consistent with groups defined by oral contraceptive pill use, hormone replacement therapy, and smoking. However, no evidence was found for the association between serum LH and testosterone level with the occurrence of ovarian tumorigenesis. Conclusion Prediagnostic circulating concentration of FSH and DHEA-S unveiled a significant positive association with augmented risk of EOC, thus might serve as a predictive marker for the susceptibility to ovarian carcinogenesis and should be added in the screening profile of EOC for early recognition and scheduling necessary interventions/management strategies.

A single amino acid substitution alters activity and specificity in Plasmodium falciparum aspartyl & asparaginyl-tRNA synthetases.

The specificity of each aminoacyl-tRNA synthetase (aaRS) for its cognate amino acid ensures correct tRNA esterification and allows fidelity in protein synthesis. The aaRSs discriminate based on the chemical properties of their amino acid substrates and structural features of the binding pockets. In this study, we characterized aspartyl-(DRS) and asparaginyl-tRNA synthetase (NRS) from Plasmodium falciparum to determine the basis of their specificity towards L-asp and L-asn respectively. The negatively charged L-asp and its analogue L-asn differ only in their side-chain groups i.e., -OH and -NH2. Further, the amino acid binding sites are highly conserved within these two enzymes. Analysis of the substrate (L-asp/L-asn) binding sites across species revealed two highly conserved residues in PfDRS (D408 and K372) and PfNRS (E395 and L360) that are involved in recognition of the Oδ2/Nδ2 of L-asp/L-asn respectively. These residues were mutated and swapped between the D408→E in PfDRS and the corresponding E395→D in PfNRS. A similar approach was employed for residue number K372→L in PfDRS and L360→K in PfNRS. The mutated PfDRSD408E retained its enzymatic activity during step 1 of aminoacylation reaction towards L-asp and L-asn and esterified tRNAAsp with L-asp like wild type enzyme, while the PfDRSK372L was rendered enzymatically inactive. The correspondingly mutated PfNRSE395D was enzymatically inactive. The mutated PfNRSL360K had an altered specificity and esterified tRNAAsn with non-cognate amino acid L-asp and not L-asn. These data suggest that the residue K372 is crucial for the enzymatic activity of PfDRS while the residue L360 in PfNRS imparts specificity towards L-asn.

Therapeutic implications of sonic hedgehog pathway in metabolic disorders: Novel target for effective treatment.

Hedgehog, a developmental morphogen, and its downstream signalling have recently been associated with metabolic control. Sonic hedgehog signalling (Shh) is a significant pathway that regulates various events during the growth and development of embryos. The dysregulation of the Shh pathway has been implicated in many physiological and pathological processes, including adipocyte differentiation, cancer, diabetes and obesity. Researchers have proved that pharmacological modulation of the Shh pathway might help to improve better outcomes in metabolic disorders. A systemic review was conducted through various search engines to understand the molecular nature of Shh Pathway in Metabolic Disorders and its therapeutic implication in the future. However, we could find that by studying the crosstalk between various pathways, such as Wnt/ ß-catenin, TGF (transforming growth factor ß), mTOR, and notch with Sonic hedgehog, a close link between the pathogenesis of different metabolic disorders. Understanding the importance of these molecular interlinking networks will provide a rational basis that influences its activity. This article discusses the changes and modifications that happen due to up-or down-regulation of various transcription factors in the Shh pathway. The study attempts to provide a complete overview of the main signalling events involved with canonical and non-canonical Hedgehog signalling and the increasingly complicated regulatory modalities related to Hedgehog for regulating metabolism. Further, it investigates the possible approaches needed to treat metabolic disorders for better results.

Effect of Resonance Breathing on Heart Rate Variability and Cognitive Functions in Young Adults: A Randomised Controlled Study.

INTRODUCTION: Heart rate variability (HRV) is an important physiological biomarker of wellbeing, mood, and adaptation, and hence improvements in HRV signify improved health, mood, and adaptation to stress. Resonance breathing has consistently been shown to increase HRV, mood, and adaptability. The study investigated the effects of four-week training of resonance breathing in young adults on HRV, stress, and cognition functions. METHODS: The randomized controlled study was conducted on young men (18-30 years) after obtaining Institutional Ethics Committee approval and written informed consent from the participants. Participants were randomly divided into two groups: the control group and the resonance breathing (RB) group. Baseline parameters, along with heart rate variability, trail tests for cognition, and perceived stress level, were assessed in both groups. After undergoing four weeks of training, the intervention group practiced deep breathing at the resonance frequency for 20 minutes per day for four weeks, whereas the control group did not. All parameters were recorded again after four weeks of resonance breathing. RESULTS: No difference was observed in the HRV parameters in the control group at baseline and four weeks after the baseline recording (p>0.05). In the intervention group, there was a significant improvement in the HRV parameters, the standard deviation of the normal-to-normal interval (SDNN), the proportion derived by dividing NN50 by the total number of NN intervals (pNN50), and total power, after practicing four weeks of resonance breathing (p<0.05). A significant difference in these parameters was also observed in the control and intervention groups after four weeks (p<0.05). There was a significant improvement in the Trails A and B test performance in the intervention group after practicing for four weeks of RB. Similarly, the perceived stress score decreased significantly in the RB group in comparison to its baseline value as well as the control group value.  Conclusion: Increased parasympathetic and decreased sympathetic activity were observed after practicing 20 minutes of resonance frequency breathing every day for four weeks. It also improved cognition and reduced perceived stress levels among young adults. It is recommended that young adults should practice deep breathing at the resonance frequency for a few minutes every day. This would allay anxiety and stress, improve their cognitive performance, and also reduce their cardiovascular morbidity.

Kynurenine Metabolism and Alzheimer's Disease: The Potential Targets and Approaches.

L-tryptophan, an essential amino acid, regulates protein homeostasis and plays a role in neurotransmitter-mediated physiological events. It also influences age-associated neurological alterations and neurodegenerative changes. The metabolism of tryptophan is carried majorly through the kynurenine route, leading to the production of several pharmacologically active enzymes, substrates, and metabolites. These metabolites and enzymes influence a variety of physiological and pathological outcomes of the majority of systems, including endocrine, haemopoietic, gastrointestinal, immunomodulatory, inflammatory, bioenergetic metabolism, and neuronal functions. An extensive literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on the kynurenine metabolites that influence cellular redox potential, immunoregulatory mechanisms, inflammatory pathways, cell survival channels, and cellular communication in close association with several neurodegenerative changes. The imbalanced state of kynurenine pathways has found a close association to several pathological disorders, including HIV infections, cancer, autoimmune disorders, neurodegenerative and neurological disorders including Parkinson's disease, epilepsy and has found special attention in Alzheimer's disease (AD). Kynurenine pathway (KP) is intricately linked to AD pathogenesis owing to the influence of kynurenine metabolites on excitotoxic neurotransmission, oxidative stress, uptake of neurotransmitters, and modulation of neuroinflammation, amyloid aggregation, microtubule disruption, and their ability to induce a state of dysbiosis. Pharmacological modulation of KP pathways has shown encouraging results, indicating that it may be a viable and explorable target for the therapy of AD.

Shaping the gut microbiota by bioactive phytochemicals: An emerging approach for the prevention and treatment of human diseases.

The human digestive tract is the cottage to trillions of live microorganisms, which regulate health and illness. A healthy Gut Microbiota (GM) is necessary for preventing microbial growth, body growth, obesity, cancer, diabetes, and enhancing immunity. The equilibrium in GM's composition and the presence/absence of critical species enable specific responses to be essential for the host's better health condition. Research evidences revealed that the dietary plants and their bioactive phytochemicals (BPs) play an extensive and critical role in shaping the GM to get beneficial health effects. BPs are also known to improve gastrointestinal health and reduce the risk of several diseases by modulating GM-mediated cellular and molecular processes. Regular intake of BPs-rich vegetables, fruits, and herbal preparations promotes probiotic bacteria, including Bifidobacteria and Lactobacillus species, while inhibiting unwanted gut residents' development Escherichia coli, and Salmonella typhimurium etc. Upon consumption, BPs contact the GM that gets transformed before being absorbed from the gastrointestinal tract. Biotransformation of BPs by GM is linked with the enhancement of bioactivity/toxicity diminishment of the BPs compared to parental phytochemicals. Therefore, the current review focuses on the role of BPs in shaping GM for the prevention and treatment of human diseases.

Apoptotic Pathways and Alzheimer's Disease: Probing Therapeutic Potential.

Apoptosis is an intrinsic biochemical, cellular process that regulates cell death and is crucial for cell survival, cellular homeostasis, and maintaining the optimum functional status. Apoptosis in a predetermined and programmed manner regulates several molecular events, including cell turnover, embryonic development, and immune system functions but may be the exclusive contributor to several disorders, including neurodegenerative manifestations, when it functions in an aberrant and disorganized manner. Alzheimer's disease (AD) is a fatal, chronic neurodegenerative disorder where apoptosis has a compelling and divergent role. The well-characterized pathological features of AD, including extracellular plaques of amyloid-beta, intracellular hyperphosphorylated tangles of tau protein (NFTs), inflammation, mitochondrial dysfunction, oxidative stress, and excitotoxic cell death, also instigate an abnormal apoptotic cascade in susceptible brain regions (cerebral cortex, hippocampus). The apoptotic players in these regions affect cellular organelles (mitochondria and endoplasmic reticulum), interact with trophic factors, and several pathways, including PI3K/AKT, JNK, MAPK, mTOR signalling. This dysregulated apoptotic cascade end with an abnormal neuronal loss which is a primary event that may precede the other events of AD progression and correlates well with the degree of dementia. The present review provides insight into the diverse and versatile apoptotic mechanisms that are indispensable for neuronal survival and constitute an integral part of the pathological progression of AD. Identification of potential targets (restoring apoptotic and antiapoptotic balance, caspases, TRADD, RIPK1, FADD, TNFα, etc.) may be valuable and advantageous to decide the fate of neurons and to develop potential therapeutics for treatment of AD.

Delayed Gastric Emptying among Indian Patients with Non-Diabetic Chronic Kidney Disease.

INTRODUCTION: Upper gastrointestinal symptoms such as nausea, vomiting, abdominal bloating, and poor appetite are more frequent among chronic kidney disease (CKD) patients and may contribute to poor nutritional intake and malnutrition. Delayed gastric emptying (GE), one of the important contributors to these symptoms, has not been evaluated systematically in different stages of non-diabetic CKD, among Indian patients. MATERIALS AND METHODS: This hospital-based, cross-sectional analytical study aimed to find out the frequency of delayed GE in non-diabetic CKD (stages: 3,4,5) patients and also to study the correlation between delayed GE and symptoms of gastroparesis, autonomic neuropathy and nutritional parameters. Patients were subjected to evaluation of symptoms of gastroparesis by standardized questionnaire (gastroparesis cardinal symptom index), nutritional status (by anthropometric measures and serum albumin), autonomic function by heart rate variability (HRV) and GE by gastric scintigraphy with a standardized solid rice idli (savory cake) meal labeled with technetium-99m sulfur colloid. RESULTS: Of the 89 non-diabetic CKD (stages-3,4,5) patients evaluated, 22 (≈25%) had delayed GE and 8 (≈9%) rapid GE. Prevalence of delayed GE was higher among stage 5 (15/49, 31%) compared to stages 3 and 4 (7/40, 17.5%), though the difference was statistically insignificant. There was no association between delayed GE and symptoms of gastroparesis and autonomic neuropathy. Though not statistically significant, nutritional parameters (body mass index, skinfold thickness, and serum albumin) were poorer in the delayed GE group compared to the rest. CONCLUSION: Delayed GE, irrespective of symptoms, may contribute to malnutrition and hence should be looked for in non-diabetic CKD patients with unexplained malnutrition.

Dysbiosis and Alzheimer's Disease: A Role for Chronic Stress?

Alzheimer's disease (AD) is an incurable, neuropsychiatric, pathological condition that deteriorates the worth of geriatric lives. AD is characterized by aggregated senile amyloid plaques, neurofibrillary tangles, neuronal loss, gliosis, oxidative stress, neurotransmitter dysfunction, and bioenergetic deficits. The changes in GIT composition and harmony have been recognized as a decisive and interesting player in neuronal pathologies including AD. Microbiota control and influence the oxidoreductase status, inflammation, immune system, and the endocrine system through which it may have an impact on the cognitive domain. The altered and malfunctioned state of microbiota is associated with minor infections to complicated illnesses that include psychosis and neurodegeneration, and several studies show that microbiota regulates neuronal plasticity and neuronal development. The altered state of microbiota (dysbiosis) may affect behavior, stress response, and cognitive functions. Chronic stress-mediated pathological progression also has a well-defined role that intermingles at various physiological levels and directly impacts the pathological advancement of AD. Chronic stress-modulated alterations affect the well-established pathological markers of AD but also affect the gut-brain axis through the mediation of various downstream signaling mechanisms that modulate the microbial commensals of GIT. The extensive literature reports that chronic stressors affect the composition, metabolic activities, and physiological role of microbiota in various capacities. The present manuscript aims to elucidate mechanistic pathways through which stress induces dysbiosis, which in turn escalates the neuropathological cascade of AD. The stress-dysbiosis axis appears a feasible zone of work in the direction of treatment of AD.

Stressed mitochondria: A target to intrude alzheimer's disease.

Alzheimer's disease (AD) is the inoperable, incapacitating, neuropsychiatric, and degenerative manifestation that drastically affects human life quality. The current medications target extra-neuronal senile plaques, oxidative stress, neuroinflammation, intraneuronal neurofibrillary tangles, cholinergic deficits, and excitotoxicity. Among novel pathways and targets, bioenergetic and resultant mitochondrial dysfunction has been recognized as essential factors that decide the neuronal fate and consequent neurodegeneration in AD. The crucial attributes of mitochondria, including bioenergesis, signaling, sensing, integrating, and transmitting biological signals contribute to optimum networking of neuronal dynamics and make them indispensable for cell survival. In AD, mitochondrial dysfunction and mitophagy are a preliminary and critical event that aggravates the pathological cascade. Stress is known to promote and exaggerate the neuropathological alteration during neurodegeneration and metabolic impairments, especially in the cortico-limbic system, besides adversely affecting the normal physiology and mitochondrial dynamics. Stress involves the allocation of energy resources for neuronal survival. Chronic and aggravated stress response leads to excessive release of glucocorticoids by activation of the hypothalamic-pituitaryadrenal (HPA) axis. By acting through their receptors, glucocorticoids influence adverse mitochondrial changes and alter mtDNA transcription, mtRNA expression, hippocampal mitochondrial network, and ultimately mitochondrial physiology. Chronic stress also affects mitochondrial dynamics by changing metabolic and neuro-endocrinal signalling, aggravating oxidative stress, provoking inflammatory mediators, altering tropic factors, influencing gene expression, and modifying epigenetic pathways. Thus, exploring chronic stress-induced glucocorticoid dysregulation and resultant bio-behavioral and psychosomatic mitochondrial alterations may be a feasible narrative to investigate and unravel the mysterious pathobiology of AD.

Assessment of vascular function in complete glycaemic spectrum.

Purpose: The present study was conceived to delineate the point of vascular dysfunction along the glycemic spectrum (normoglycemic individuals with no family history of diabetes, normoglycemic individuals with family history of diabetes, prediabetic individuals, and diabetic individuals).Materials and Methods: In this cross-sectional comparative study, we enrolled 252 participants of both gender in the age group of 30-50 years. They were classified based on their family history of diabetes and glycemic status into four groups along the glycemic spectrum as mentioned above. We measured flow-mediated dilation (FMD) from brachial artery and vascular function biomarkers such as enthothelin-1 (ET-1), von Willbrand Factor (vWF), Vascular Endothelial Growth Factor (VEGF) to assess the vascular function. The comparison of data between groups were done using One Way ANOVA/Kruskal-Wallis followed by post-hoc analysis using LSD/Mann-Whitney U Test depending on the normality of the data. Spearman correlation was done between vascular function and plasma glucose levels to identify its relationship. Linear regression was carried out to identify the factors influencing the FMD across the glycemic spectrum.Results: We observed that vascular function negatively correlated with blood glucose levels. However, endothelin-1 and vWF derangement was there even in normoglycemic first degree relatives of diabetes (FDRD) and the derangement increased in prediabetes and diabetes. Physiological dysfunction in terms of decreased flow-mediated dilation starts from prediabetes only. VEGF derangement is found only in diabetic individuals.Conclusion: Vascular dysfunction is found even in normoglycemic FDRD and the derangement increased and compounded with the advancement of disease.

Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer's disease.

AIM: Insulin has a well-established role in cognition, neuronal detoxification and synaptic plasticity. Insulin transduction affect neurotransmitter functions, influence bioenergetics and regulate neuronal survival through regulating glucose energy metabolism and downward pathways. METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out with the help of the keywords like "Alzheimer's disease; Hypometabolism; Oxidative stress; energy failure in AD, Insulin; Insulin resistance; Bioenergetics" till June 2020. The review was conducted using the above keywords to collect the latest articles and to understand the nature of the extensive work carried out on insulin resistance and bioenergetic manifestations in Alzheimer's disease. KEY FINDINGS: The article sheds light on insulin resistance mediated hypometabolic state on pathological progression of AD. The disrupted insulin signaling has pathological outcome in form of disturbed glucose homeostasis, altered bioenergetic state which increases build-up of senile plaques (Aß), neurofibrillary tangles (τ), decline in transportation of glucose and activation of inflammatory pathways. The mechanistic link of insulin resistant state with therapeutically explorable potential transduction pathways is the focus of the reviewed work. SIGNIFICANCE: The present work opines that the mechanism by which the insulin resistance mediates dysregulation of bioenergetics and progresses to neurodegenerative state holds the tangible potential to succeed in the development of novel dementia therapies. Further, hypometabolic complications and altered insulin signaling may be explored as a mechanistic relation between bioenergetic deficits and AD.

Effect of Yoga Therapy on Disease Activity, Inflammatory Markers, and Heart Rate Variability in Patients with Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease. Antirheumatoid treatment reduces disease activity and inflammation, but not all patients respond to treatment. Autonomic dysfunction is common in RA leading to frequent cardiovascular complications. Yoga therapy may be useful in these patients, but there are little data on the effect of yoga on disease activity, inflammatory markers, and heart rate variability (HRV). Objectives: This study assessed the effect of 12-week yoga therapy on disease activity, inflammatory markers, and HRV in patients with RA. Materials and Methods: This randomized control trial was conducted on newly diagnosed RA patients attending outpatient services at the Department of Clinical Immunology, JIPMER. One hundred and sixty-six participants were randomized into two groups: the control group (CG) (n = 83) and yoga group (YG) (n = 83). Yoga therapy was administered to participants in the YG for 12 weeks, along with standard medical treatment. The CG received only standard medical treatment. Primary outcomes were disease activity score 28, interleukin-1α (IL-1α), IL-6, tumor necrosis factor-α (TNF-α), cortisol, and HRV parameters. All parameters were measured at baseline and after 12 weeks. Results: Disease activity significantly decreased in both groups after 12 weeks, but it was reduced more in YG, which was statistically significant (p < 0.05). In both YG and CG, IL-1α, IL-6, TNF-α, and cortisol decreased after 12 weeks, but IL-1α and cortisol decreased more significantly in YG than in CG. Low-frequency component expressed as normalized unit (LFnu) and the low-frequency/high-frequency (LF-HF) ratio decreased significantly, and total power and HF component expressed as normalized unit (HFnu) increased significantly in the YG compared with CG. Conclusion: Twelve-week yoga therapy, if given along with standard medical treatment, significantly reduces disease activity and improves sympathovagal balance in RA patients.

Alzheimer's Disorder: Epigenetic Connection and Associated Risk Factors.

The gene based therapeutics and drug targets have shown incredible and appreciable advances in alleviating human sufferings and complexities. Epigenetics simply means above genetics or which controls the organism beyond genetics. At present it is very clear that all characteristics of an individual are not determined by DNA alone, rather the environment, stress, life style and nutrition play a vital part in determining the response of an organism. Thus, nature (genetic makeup) and nurture (exposure) play equally important roles in the responses observed, both at the cellular and organism levels. Epigenetics influence plethora of complications at cellular and molecular levels that includes cancer, metabolic and cardiovascular complications including neurological (psychosis) and neurodegenerative disorders (Alzheimer's disease, Parkinson disease etc.). The epigenetic mechanisms include DNA methylation, histone modification and non coding RNA which have substantial impact on progression and pathways linked to Alzheimer's disease. The epigenetic mechanism gets deregulated in Alzheimer's disease and is characterized by DNA hyper methylation, deacetylation of histones and general repressed chromatin state which alter gene expression at the transcription level by upregulation, downregulation or silencing of genes. Thus, the processes or modulators of these epigenetic processes have shown vast potential as a therapeutic target in Alzheimer's disease.

Navigating Alzheimer's Disease via Chronic Stress: The Role of Glucocorticoids.

Alzheimer's disease (AD) is a chronic intensifying incurable progressive disease leading to neurological deterioration manifested as impairment of memory and executive brain functioning affecting the physical ability like intellectual brilliance, common sense in patients. The recent therapeutic approach in Alzheimer's disease is only the symptomatic relief further emerging the need for therapeutic strategies to be targeted in managing the underlying silent killing progression of dreaded pathology. Therefore, the current research direction is focused on identifying the molecular mechanisms leading to the evolution of the understanding of the neuropathology of Alzheimer's disease. The resultant saturation in the area of current targets (amyloid ß, τ Protein, oxidative stress etc.) has led the scientific community to rethink of the mechanistic neurodegenerative pathways and reprogram the current research directions. Although, the role of stress has been recognized for many years and contributing to the development of cognitive impairment, the area of stress has got the much-needed impetus recently and is being recognized as a modifiable menace for AD. Stress is an unavoidable human experience that can be resolved and normalized but chronic activation of stress pathways unsettle the physiological status. Chronic stress mediated activation of neuroendocrine stimulation is generally linked to a high risk of developing AD. Chronic stress-driven physiological dysregulation and hypercortisolemia intermingle at the neuronal level and leads to functional (hypometabolism, excitotoxicity, inflammation) and anatomical remodeling of the brain architecture (senile plaques, τ tangles, hippocampal atrophy, retraction of spines) ending with severe cognitive deterioration. The present review is an effort to collect the most pertinent evidence that support chronic stress as a realistic and modifiable therapeutic earmark for AD and to advocate glucocorticoid receptors as therapeutic interventions.