Superoxide dismutase and neurological disorders.

Superoxide dismutase (SOD) is a common antioxidant enzyme found majorly in living cells. The main physiological role of SOD is detoxification and maintain the redox balance, acts as a first line of defence against Reactive nitrogen species (RNS), Reactive oxygen species (ROS), and other such potentially hazardous molecules. SOD catalyses the conversion of superoxide anion free radicals (O 2 -.) into molecular oxygen (O 2) and hydrogen peroxide (H 2O 2) in the cells. Superoxide dismutases (SODs) are expressed in neurons and glial cells throughout the CNS both intracellularly and extracellularly. Endogenous oxidative stress (OS) linked with enlarged production of reactive oxygen metabolites (ROMs), inflammation, deregulation of redox balance, mitochondrial dysfunction and bioenergetic crisis are found to be prerequisite for neuronal loss in neurological diseases. Clinical and genetic studies indicate a direct correlation between mutations in SOD gene and neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). Therefore, inhibitors of OS are considered as an optimistic approach to prevent neuronal loss. SOD mimetics like Metalloporphyrin Mn (II)-cyclic polyamines, Nitroxides and Mn (III)- Salen complexes are designed and used as therapeutic extensively in the treatment of neurological disorders. SODs and SOD mimetics are promising future therapeutics in the field of various diseases with OS-mediated pathology.

Protective effects of fecal microbiota transplantation against ischemic stroke and other neurological disorders: an update.

The bidirectional communication between the gut and brain or gut-brain axis is regulated by several gut microbes and microbial derived metabolites, such as short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides. The Gut microbiota (GM) produce neuroactives, specifically neurotransmitters that modulates local and central neuronal brain functions. An imbalance between intestinal commensals and pathobionts leads to a disruption in the gut microbiota or dysbiosis, which affects intestinal barrier integrity and gut-immune and neuroimmune systems. Currently, fecal microbiota transplantation (FMT) is recommended for the treatment of recurrent Clostridioides difficile infection. FMT elicits its action by ameliorating inflammatory responses through the restoration of microbial composition and functionality. Thus, FMT may be a potential therapeutic option in suppressing neuroinflammation in post-stroke conditions and other neurological disorders involving the neuroimmune axis. Specifically, FMT protects against ischemic injury by decreasing IL-17, IFN-γ, Bax, and increasing Bcl-2 expression. Interestingly, FMT improves cognitive function by lowering amyloid-ß accumulation and upregulating synaptic marker (PSD-95, synapsin-1) expression in Alzheimer's disease. In Parkinson's disease, FMT was shown to inhibit the expression of TLR4 and NF-κB. In this review article, we have summarized the potential sources and methods of administration of FMT and its impact on neuroimmune and cognitive functions. We also provide a comprehensive update on the beneficial effects of FMT in various neurological disorders by undertaking a detailed interrogation of the preclinical and clinical published literature.

Role of the Gut Bacteria-Derived Metabolite Phenylacetylglutamine in Health and Diseases.

Over the past few decades, it has been well established that gut microbiota-derived metabolites can disrupt gut function, thus resulting in an array of diseases. Notably, phenylacetylglutamine (PAGln), a bacterial derived metabolite, has recently gained attention due to its role in the initiation and progression of cardiovascular and cerebrovascular diseases. This meta-organismal metabolite PAGln is a byproduct of amino acid acetylation of its precursor phenylacetic acid (PAA) from a range of dietary sources like egg, meat, dairy products, etc. The microbiota-dependent metabolism of phenylalanine produces PAA, which is a crucial intermediate that is catalyzed by diverse microbial catalytic pathways. PAA conjugates with glutamine and glycine in the liver and kidney to predominantly form phenylacetylglutamine in humans and phenylacetylglycine in rodents. PAGln is associated with thrombosis as it enhances platelet activation mediated through the GPCRs receptors α2A, α2B, and ß2 ADRs, thereby aggravating the pathological conditions. Clinical evidence suggests that elevated levels of PAGln are associated with pathology of cardiovascular, cerebrovascular, and neurological diseases. This Review further consolidates the microbial/biochemical synthesis of PAGln and discusses its role in the above pathophysiologies.

Trimethylamine-N-oxide and cerebral stroke risk: A review.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced by the action of gut microbiota and the hepatic enzyme Flavin Mono­oxygenase 3 (FMO3). TMAO level has a positive correlation with the risk of cardiovascular events, including stroke, and their level is influenced mainly by dietary choice and the action of liver enzyme FMO3. TMAO plays a role in the development of atherosclerosis plaque, which is one of the causative factors of the stroke event. Preclinical and clinical investigations on the TMAO and associated stroke risk, severity, and outcomes are summarised in this review. In addition, mechanisms of TMAO-driven vascular dysfunction are also discussed, such as inflammation, oxidative stress, thrombus and foam cell formation, altered cholesterol and bile acid metabolism, etc. Post-stroke inflammatory cascades involving activation of immune cells, i.e., microglia and astrocytes, result in Blood-brain-barrier (BBB) disruption, allowing TMAO to infiltrate the brain and further aggravate inflammation. This event occurs as a result of the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway through the release of inflammatory cytokines and chemokines that further aggravate the BBB and initiate further recruitment of immune cells in the brain. Thus, it's likely that maintaining TMAO levels and associated gut microbiota could be a promising approach for treating and improving stroke complications.

Polyphenols, Autophagy and Neurodegenerative Diseases: A Review.

Polyphenols are secondary metabolites from plant origin and are shown to possess a wide range of therapeutic benefits. They are also reported as regulators of autophagy, inflammation and neurodegeneration. The autophagy pathway is vital in degrading outdated organelles, proteins and other cellular wastes. The dysregulation of autophagy causes proteinopathies, mitochondrial dysfunction and neuroinflammation thereby contributing to neurodegeneration. Evidence reveals that polyphenols improve autophagy by clearing misfolded proteins in the neurons, suppress neuroinflammation and oxidative stress and also protect from neurodegeneration. This review is an attempt to summarize the mechanism of action of polyphenols in modulating autophagy and their involvement in pathways such as mTOR, AMPK, SIRT-1 and ERK. It is evident that polyphenols cause an increase in the levels of autophagic proteins such as beclin-1, microtubule-associated protein light chain (LC3 I and II), sirtuin 1 (SIRT1), etc. Although it is apparent that polyphenols regulate autophagy, the exact interaction of polyphenols with autophagy markers is not known. These data require further research and will be beneficial in supporting polyphenol supplementation as a potential alternative treatment for regulating autophagy in neurodegenerative diseases.

An Integrated Review of Carpal Tunnel Syndrome: New Insights to an Old Problem.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy characterized by pain, numbness, and impaired function of the hand due to compression of the median nerve at the level of the wrist. Although CTS can develop from repetitive strain, injury, or medical conditions, there are also congenital and genetic risk factors that can predispose individuals to the condition. With respect to anatomical factors, some individuals are born with a smaller carpal tunnel, which increases their susceptibility to median nerve compression. Variations in specific genes, such as those encoding proteins involved in extracellular matrix remodeling, inflammation, and nerve function, have also been linked to an increased risk for CTS. CTS is associated with a high cost of health care maintenance and loss of work productivity. Therefore, it is vital that primary care physicians fully understand the anatomy, epidemiology, pathophysiology, etiology, and risk factors of CTS, so they can be proactive in prevention, diagnosing, and guiding proper treatment. This integrated review also provides insights into how biological, genetic, environmental, and occupational factors interact with structural elements to determine who is most likely to acquire and suffer from CTS. Keeping health practitioners abreast of all the factors that could impact CTS should go a long way in decreasing the health care and socioeconomic burden of CTS.

The Role of a Gut Microbial-Derived Metabolite, Trimethylamine N-Oxide (TMAO), in Neurological Disorders.

Trimethylamine lyases are expressed in a wide range of intestinal microbiota which metabolize dietary nutrients like choline, betaine, and L-carnitine to form trimethylamine (TMA). Trimethylamine N-oxide (TMAO) is an oxidative product of trimethylamine (TMA) catalyzed by the action of flavin monooxygenases (FMO) in the liver. Higher levels of TMAO in the plasma and cerebrospinal fluid (CSF) have been shown to contribute to the development of risk factors and actively promote the pathogenesis of metabolic, cardiovascular, and cerebrovascular diseases. The investigations on the harmful effects of TMAO in the development and progression of neurodegenerative and sleep disorders are summarized in this manuscript. Clinical investigations on the role of TMAO in predicting risk factors and prognostic factors in patients with neurological disorders are also summarized. It is observed that the mechanisms underlying TMAO-mediated pathogenesis include activation of inflammatory signaling pathways such as nuclear factor kappa B (NF-κß), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, and MAPK/JNK in the periphery and brain. Data suggests that TMAO levels increase with age-related cognitive dysfunction and also induce mitochondrial dysfunction, oxidative stress, neuronal senescence, and synaptic damage in the brain. Further research into the relationships between dietary food consumption and gut microbiota-dependent TMAO levels could provide novel therapeutic options for neurological illnesses.

An Overview of Parkinson's Disease: Curcumin as a Possible Alternative Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain and basal ganglia, followed by dopamine deficiency in the brain. Dopamine plays a crucial role in motor coordination, memory, and cognition; its decrease in PD leads to dyskinesia, cognitive deficits, and depression. In addition, the formation of alpha-synuclein protein aggregates (Lewy bodies) causes further damage to the CNS. Current treatment options include dopamine precursors, inhibitors of dopamine metabolism, upregulation of autophagy, adenosine A2A antagonists, and surgical intervention as a last resort. A challenge arises from a progressive decrease in treatment efficacy as the disease progresses and this necessitates exploration of adjunctive treatments. Epidemiological studies suggest that the prevalence of PD varies between ethnic groups of Caucasians, Asians, and African Americans. Notably, the prevalence of PD is lower in countries of Southeastern Asia including India. The differences in the diet of various ethnic groups may suggest an origin for this difference in the prevalence of PD. One staple ingredient in traditional Asian cuisine is turmeric. Curcuma longa, popularly known as turmeric, is an orange tuberous rhizome that has been used for centuries in traditional Indian cuisine and traditional medicine. Turmeric contains curcumin, a potent antioxidant that scavenges reactive oxygen species and chelates toxic metals. Curcumin has been proposed to be a neuroprotective agent due to its potent antioxidative properties. Though preliminary studies in animal model systems have suggested a protective effect of curcumin on dopaminergic neurons, the direct benefits of curcumin on the progress of PD remains poorly understood. In this review, we explore the promising use of curcumin as an adjunct to conventional PD treatments in order to enhance treatment and improve outcomes.

The Role of Gut Dysbiosis in the Pathophysiology of Neuropsychiatric Disorders.

Mounting evidence shows that the complex gut microbial ecosystem in the human gastrointestinal (GI) tract regulates the physiology of the central nervous system (CNS) via microbiota and the gut-brain (MGB) axis. The GI microbial ecosystem communicates with the brain through the neuroendocrine, immune, and autonomic nervous systems. Recent studies have bolstered the involvement of dysfunctional MGB axis signaling in the pathophysiology of several neurodegenerative, neurodevelopmental, and neuropsychiatric disorders (NPDs). Several investigations on the dynamic microbial system and genetic-environmental interactions with the gut microbiota (GM) have shown that changes in the composition, diversity and/or functions of gut microbes (termed "gut dysbiosis" (GD)) affect neuropsychiatric health by inducing alterations in the signaling pathways of the MGB axis. Interestingly, both preclinical and clinical evidence shows a positive correlation between GD and the pathogenesis and progression of NPDs. Long-term GD leads to overstimulation of hypothalamic-pituitary-adrenal (HPA) axis and the neuroimmune system, along with altered neurotransmitter levels, resulting in dysfunctional signal transduction, inflammation, increased oxidative stress (OS), mitochondrial dysfunction, and neuronal death. Further studies on the MGB axis have highlighted the significance of GM in the development of brain regions specific to stress-related behaviors, including depression and anxiety, and the immune system in the early life. GD-mediated deregulation of the MGB axis imbalances host homeostasis significantly by disrupting the integrity of the intestinal and blood-brain barrier (BBB), mucus secretion, and gut immune and brain immune functions. This review collates evidence on the potential interaction between GD and NPDs from preclinical and clinical data. Additionally, we summarize the use of non-therapeutic modulators such as pro-, pre-, syn- and post-biotics, and specific diets or fecal microbiota transplantation (FMT), which are promising targets for the management of NPDs.

Antimicrobial agents' utilization and cost pattern in an Intensive Care Unit of a Teaching Hospital in South India.

BACKGROUND AND AIMS: High utilization and inappropriate usage of antimicrobial agents (AMAs) in an Intensive Care Unit (ICU) increases resistant organisms, morbidity, mortality, and treatment cost. Prescription audit and active feedback are a proven method to check the irrational prescription. Measuring drug utilization in DDD/100 bed-days is proposed by the WHO to analyze and compare the utilization of drugs. Data of AMAs utilization are required for planning an antibiotic policy and for follow-up of intervention strategies. Hence, in this study, we proposed to evaluate the utilization pattern and cost analysis of AMA used in the ICU. METHODOLOGY: A prospective observational study was conducted for 1 year from January 1, 2014, to December 31, 2014, and the data were obtained from the ICU of a tertiary care hospital. The demographic data, disease data, relevant investigation, the utilization of different classes of AMAs (WHO-ATC classification) as well as individual drugs and their costs were recorded. RESULTS: One thousand eight hundred and sixty-two prescriptions of AMAs were recorded during the study period with an average of 1.73 ± 0.04 prescriptions/patient. About 80.4% patients were prescribed AMAs during admission. Ceftriaxone (22.77%) was the most commonly prescribed AMA followed by piperacillin/tazobactam (15.79%), metronidazole (12%), amoxicillin/clavulanic acid (6.44%), and azithromycin (4.34%). Ceftriaxone, piperacillin/tazobactam, metronidazole, and linezolid were the five maximally utilized AMAs with 38.52, 19.22, 14.34, 8.76, and 8.16 DDD/100 bed-days respectively. An average cost of AMAs used per patient was 2213 Indian rupees (INR). CONCLUSION: A high utilization of AMAs and a high cost of treatment were noticed which was comparable to other published data, though an increased use of newer AMAs such as linezolid, clindamycin, meropenem, colistin was noticed.

A Study of Attitude and Knowledge of the Psychiatry Resident Doctors toward Clinician-Pharmaceutical Industry Interaction.

BACKGROUND: Pharmaceutical industry and clinicians are the two important stakeholders in the modern-day health care. However, concerns have been expressed about the lack of congruence between the goals of these two. AIMS: The current study aimed at exploring the knowledge and attitude of the psychiatry resident doctors toward the clinician-pharmaceutical industry interaction and also at exploring the knowledge of the residents about the new Medical Council of India guidelines on this issue. MATERIALS AND METHODS: The survey was conducted among psychiatry residents. Descriptive statistics with frequency distribution was carried out by using SPSS version 17.0. RESULTS: It had a good response rate of around 90%. The survey reveals the knowledge and attitude of the psychiatry residents toward the psychiatrist-pharmaceutical industry interaction. CONCLUSIONS: The survey provides understanding in knowledge and attitude of the psychiatry residents towards the psychiatrist-pharmaceutical industry interaction.