Exploring Astrocytes Involvement and Glutamate Induced Neuroinflammation in Chlorpyrifos-Induced Paradigm Of Autism Spectrum Disorders (ASD).

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

Insight into the pathophysiological advances and molecular mechanisms underlying cerebral stroke: current status.

Molecular pathways involved in cerebral stroke are diverse. The major pathophysiological events that are observed in stroke comprises of excitotoxicity, oxidative stress, mitochondrial damage, endoplasmic reticulum stress, cellular acidosis, blood-brain barrier disruption, neuronal swelling and neuronal network mutilation. Various biomolecules are involved in these pathways and several major proteins are upregulated and/or suppressed following stroke. Different types of receptors, ion channels and transporters are activated. Fluctuations in levels of various ions and neurotransmitters have been observed. Cells involved in immune responses and various mediators involved in neuro-inflammation get upregulated progressing the pathogenesis of the disease. Despite of enormity of the problem, there is not a single therapy that can limit infarction and neurological disability due to stroke. This is because of poor understanding of the complex interplay between these pathophysiological processes. This review focuses upon the past to present research on pathophysiological events that are involved in stroke and various factors that are leading to neuronal death following cerebral stroke. This will pave a way to researchers for developing new potent therapeutics that can aid in the treatment of cerebral stroke.

SEW2871 reduces seizures via the sphingosine 1-phosphate receptor-1 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug-refractory epilepsy.

Epilepsy is a prevalent neurological disorder characterized by neuronal hypersynchronous discharge in the brain, leading to central nervous system (CNS) dysfunction. Despite the availability of anti-epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine-1-phosphate-receptor 1 (S1PR1) in drug-resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)-resistant pentylenetetrazol (PTZ)-kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi-drug resistance 1 (MDR1) and multi-drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB + PTZ for 62 days to develop a drug-resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75 mg/kg, intraperitoneally [i.p.]) was administered for 14 days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose-dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation-induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark-stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.

Evaluation of prescriptions from tertiary care hospitals across India for deviations from treatment guidelines & their potential consequences.

BACKGROUND OBJECTIVES: Irrational prescribing practices have major consequences on patient safety and also increase the economic burden. Real-life examples of impact of irrational prescription have potential to improve prescribing practices. In this context, the present study aimed to capture and evaluate the prevalence of deviations from treatment guidelines in the prescriptions, potential consequence/s of the deviations and corrective actions recommended by clinicians. METHODS: It was a cross-sectional observational study conducted in the outpatient departments of tertiary care hospitals in India wherein the 13 Indian Council of Medical Research Rational Use of Medicines Centres are located. Prescriptions not compliant with the standard treatment guidelines and incomplete prescriptions with respect to formulation, dose, duration and frequency were labelled as 'prescriptions having deviations'. A deviation that could result in a drug interaction, lack of response, increased cost, preventable adverse drug reaction (ADR) and/or antimicrobial resistance was labelled as an 'unacceptable deviation'. RESULTS: Against all the prescriptions assessed, about one tenth of them (475/4838; 9.8%) had unacceptable deviations. However, in 2667/4838 (55.1%) prescriptions, the clinicians had adhered to the treatment guidelines. Two thousand one hundred and seventy-one prescriptions had deviations, of which 475 (21.9%) had unacceptable deviations with pantoprazole (n=54), rabeprazole+domperidone (n=35) and oral enzyme preparations (n=24) as the most frequently prescribed drugs and upper respiratory tract infection (URTI) and hypertension as most common diseases with unacceptable deviations. The potential consequences of deviations were increase in cost (n=301), ADRs (n=254), drug interactions (n=81), lack of therapeutic response (n=77) and antimicrobial resistance (n=72). Major corrective actions proposed for consideration were issuance of an administrative order (n=196) and conducting online training programme (n=108). INTERPRETATION CONCLUSIONS: The overall prevalence of deviations found was 45 per cent of which unacceptable deviations was estimated to be 9.8 per cent. To minimize the deviations, clinicians recommended online training on rational prescribing and administrative directives as potential interventions.

Pattern of Medical Device Adverse Events in a Tertiary Care Hospital in Northern India: An Ambispective Study.

BACKGROUND: Knowledge about the pattern of adverse events caused by medical devices (MDs) is limited in India. We aimed to assess the pattern of MD adverse events (MDAEs) in a tertiary hospital in Northern India. MATERIALS AND METHODS: This descriptive study was conducted ambispectively at various clinical departments of PGIMER, Chandigarh. We followed the guidelines edged by the Materiovigilance Program of India (MvPI) to conduct this study. The prospective study (PS) was done from January to December 2020, with a concurrent retrospective study (RS) proceeding to 3 years to learn more about the reporting culture, demographics, notification status, risk class of defective devices, and the type of adverse events. RESULTS: We received 224 MDAE in the PS and identified 413 MDAE in the RS. Reporting of adverse events to the national MvPI was negligible in the RS. In the PS, nurses reported the majority of MDAEs (65%), followed by doctors (30%). The occurrence of MDAE was higher in males (PS; 52%, RS; 57%) and age groups between 21 and 30 years (PS; 19.1%, RS; 23.2%) in both studies. MDAEs were frequent in low- to moderate-risk devices (class B: 66%) in the PS, while it was documented only for high-risk devices (class C: 51% and class D: 49%) in the RS. Most of the serious adverse events (SAEs) were reported among moderate to high-risk devices, and an increased frequency of SAE (60.4%) was observed among nonnotified MDs. The overall incidence of near-miss events was 14%. CONCLUSION: Knowledge of MDAEs and reporting of defective devices to regulatory authorities is essential to prevent further incidence. Adverse events caused by MDs are ubiquitous irrespective of their risk classification, notification status, and patient demographic factors. Accelerated reporting of MDAE by all cadre of healthcare professionals is urgently required to safeguard the health of Indians.

Gmx_qk: An Automated Protein/Protein-Ligand Complex Simulation Workflow Bridged to MM/PBSA, Based on Gromacs and Zenity-Dependent GUI for Beginners in MD Simulation Study.

Open-source MD simulation tools provide academics and low-income countries with the ability to compete in drug discovery advancements. Gromacs is a well-known and established MD simulation tool, among others. Although command-line tools offer full flexibility to users, they require expertise and familiarity with the UNIX operating system. In this context, we have developed an automated bash workflow that enables users with minimal knowledge of UNIX or command-line tools to run protein/protein-ligand complex simulations bridged to MM/PBSA calculations. The workflow provides information to the user using Zenity widgets and requires minimal intervention, such as energy minimization, simulation duration, and output file naming. It initiates MD simulations within a few seconds (energy minimization, NVT, NPT, and MD) after taking input files and parameters, which takes 20-30 min in a command-line-based protocol. The single workflow also helps users to produce reproducible research results with fewer errors. The workflow is available at the GitHub repository: https://github.com/harry-maan/gmx_qk.

Estimating the Cost of Delivering Tobacco Cessation Intervention Package at Noncommunicable Disease Clinics in Two Districts of North India.

INTRODUCTION: Integrated care is likely to improve outcomes in strained healthcare systems while limiting costs. NCD clinics were introduced under the "National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Disease, and Stroke" (NPCDCS) in India; however, there is limited literature on the costs of delivering tobacco cessation interventions within NPCDCS. One of the study's objectives was to estimate the cost of delivering a culturally specific patient-centric behavioral intervention package in two district-level NCD clinics in Punjab, India. METHODS: Costing was undertaken using the health systems perspective. A top-down or financial costing approach and a bottom-up or activity-based approach were employed at each step of development and implementation. The opportunity cost was used to include the cost of human resources, infrastructure, and capital resources used. All infrastructure and capital costs were annualized using a 3% annual discount rate. Four additional scenarios were built up concerning three major components to reduce costs further when rolled out on a large scale. RESULTS: The cost of intervention package development, human resource training, and unit cost of implementation were estimated to be INR 6,47,827 (USD 8,874); INR 134,002 (USD 1810); and INR 272 (USD 3.67), respectively. Based on our sensitivity analysis results, the service delivery cost varied from INR 184 (USD 2.48) to INR 326 (USD 4.40) per patient. CONCLUSION: The development costs of the intervention package accounted for the majority proportion of the total cost. Of the total unit cost of implementation, the telephonic follow-up, human resources, and capital resources were the major contributory components. IMPLICATIONS: The current study aims to fill gaps by estimating the unit-level health systems cost of a culturally sensitive, disease-specific, and patient-centric tobacco cessation intervention package delivered at the outpatient settings of NCD clinics at the secondary level hospital, which represents a major link in the health care system of India. Findings from this study could be used to provide supportive evidence to policymakers and program managers for rolling out such interventions in established NCD clinics through the NPCDCS program of the Indian Government.

PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling.

The protein kinase R-like endoplasmic reticulum kinase/eukaryotic initiation factor 2ɑ (PERK/eIF2α), the branch of unfolded protein response (UPR), is responsible for transient arrest in translation to counter the enhanced levels of misfolded or unfolded proteins in the endoplasmic reticulum (ER) following any acute condition. In neurological disorders, overactivation of PERK-P/eIF2-P signaling, leads to a prolonged decline in global protein synthesis resulting in synaptic failure and neuronal death. Our study has shown, PERK/ATF4/CHOP pathway gets activated following cerebral ischemia in rats. We have further demonstrated, PERK inhibitor, GSK2606414 ameliorates ischemia induced neuronal damage by preventing additional neuronal loss, minimizing brain infarct, reducing brain edema, and preventing neurological symptoms from appearing. GSK2606414 was found to improve the neurobehavioral deficits and reduce the pyknotic neurons in ischemic rats. Also, it decreased glial activation and apoptotic protein mRNA expression while enhanced the synaptic protein mRNA expression in rat brain following cerebral ischemia. In conclusion, our findings suggest that PERK/ATF4/CHOP activation play a vital role in cerebral ischemia. Thus, PERK inhibitor, GSK2606414 might be a potential neuroprotective agent in cerebral ischemia.

Usage Pattern of Fixed-dose Combinations at ICMR Network of Rational Use of Medicine Centres across India: Recommendations for Policymakers and Prescribers.

AIM: Irrational use of medicines is a global problem. In India, one contributing factor is the availability of a large number of fixed-dose combinations (FDCs). To improve rational use and to strengthen policies, it is important to assess the usage patterns and rationality of FDCs. METHODS: This study was conducted as part of a 1-year prospective cross-sectional analysis of prescriptions in the outpatient clinics of broad specialities from 13 tertiary care hospitals across India. Five most commonly prescribed FDCs in each center were analyzed. In addition, all the prescribed FDCs were classified as per the Kokate Committee classification and it was noted whether any of the FDCs were irrational or banned as per the reference lists released by regulatory authorities. RESULTS: A total of 4,838 prescriptions were analyzed. Of these, 2,093 (43.3%) prescriptions had at least one FDC. These 2,093 prescriptions had 366 different FDCs. Of the 366 FDCs, 241 were rational; 10 were irrational; 14 required further data generation; and the remaining 96 FDCs could not be categorized into any of the above. Vitamins and minerals/supplements, antibacterial for systemic use, and drugs for gastroesophageal reflux disease (GERD) and peptic ulcer were the most used FDCs. CONCLUSION: Based on the finding that some prescriptions contained irrational FDCs, it is recommended that a rigorous, regular, and uniform method of evaluation be implemented to approve/ban FDCs and that prescribers be periodically notified about the status of the bans.

Screening and identification of phytochemical drug molecules against mutant BRCA1 receptor of breast cancer using computational approaches.

The American Cancer Society claims that breast cancer is the second most significant cause of cancer-related death, with over one million women diagnosed each year. Breast cancer linked to the BRCA1 gene has a significant risk of mortality and recurrence and is susceptible to alteration or over-expression, which can lead to hereditary breast cancer. Given the shortage of effective and possibly curative treatments for breast cancer, the present study combined molecular and computational analysis to find prospective phytochemical substances that can suppress the mutant gene (BRCA1) that causes the disease. Virtual screening and Molecular docking approaches are utilized to find probable phytochemicals from the ZINC database. The 3D structure of mutant BRCA1 protein with the id 3PXB was extracted from the NCBI-PDB. Top 10 phytochemical compounds shortlisted based on molecular docking score between - 11.6 and - 13.0. Following the ADMET properties, only three (ZINC000085490903 = - 12.50, ZINC000085490832 = - 12.44, and ZINC000070454071 = - 11.681) of the 10 selected compounds have drug-like properties. The molecular dynamic simulation study of the top three potential phytochemicals showed stabilized RMSD and RMSF values as compared to the APO form of the BRCA1 receptor. Further, trajectory analysis revealed that approximately similar radius of gyration score tends to the compactness of complex structure, and principal component and cross-correlation analysis suggest that the residues move in a strong correlation. Thermostability of the target complex (B-factor) provides information on the stable energy minimized structure. The findings suggest that the top three ligands show potential as breast cancer inhibitors.

Dental pulp stem cell secretome ameliorates d-galactose induced accelerated aging in rat model.

Advancing age is associated with several diseases and disorders due to multiorgan atrophy. The increasing proportion of elderly humans demands the identification of means to counteract aging and age-associated disorders. There is an increased depletion of stem cells in the aged organs, resulting in their inability to repair the damage and hence organ degeneration. Stem cell therapy has been implicated in counteracting aging and shown promise. However, the use of stem cells encounters several side effects and complications such as handling and storage of the cells for transplantation purpose. Stem cells secretome has proven to be of significant importance in a variety of disorders. In this study, we have shown that secretome derived from dental pulp stem cells (DPSCs) can reverse the age-associated degeneration induced by chronic exposure to d-galactose in a rat model. The secretome was able to increase muscle grip strength and animal activity. Secretome also improved the kidney function and hepatic biochemistry similar to healthy controls as evaluated by renal function test and Fourier-transform infrared spectroscopy. We also showed that secretome reduced the levels of monoamine oxidase and acetylcholinesterase in the brain and liver, indicating aging reversal. Finally, proteomic profiling of DPSCs secretome revealed the presence of 13 proteins which have antiaging functions. Thus, our study provides first proof of concept that DPSCs secretome can render protection against d-galactose induced accelerated aging.

Oral Atenolol versus Propranolol in the Treatment of Infantile Hemangioma: A Systematic Review and Meta-Analysis.

Background: Infantile hemangioma (IH) is the most common benign vascular tumor of infancy. Propranolol is considered first-line therapy for IH. However, it is associated with side effects. Therefore, there was a need for alternative therapy. Atenolol, a selective b1-blocker may be free from such side effects. Hence, the present study aims to develop a more accurate estimate of the safety and efficacy of atenolol compared to propranolol in the treatment of IH. Methodology: A search of various literature databases (PubMed, Embase, Ovid, Scopus, Cochrane Central, CINAHL, Web of Science, and Google Scholar) was done to identify studies which compared propranolol versus atenolol in the treatment of IH. The combined odds ratio along with corresponding 95% confidence intervals (CIs) were evaluated using a fixed-effects model. Results: A total of 300 articles were screened of which five studies including 116 patients in atenolol arm and 138 patients in the propranolol arm were analyzed. Atenolol was comparable to propranolol in terms of efficacy as no significant difference was seen between both the treatment arms in terms of hemangioma activity score (mean difference 0.25 [95% CI;‒0.21, 0.71]) and complete response (odds ratio [OR] =0.43; 95% CI; 0.17, 1.11; P = 0.08,). Atenolol therapy was better than propranolol in terms of safety, i.e., serious/potentially serious side effect, (OR = 0.11; 95% CI; 0.02, 0.51; P = 0.005) and wheezing/bronchial hyperreactivity (OR = 0.11; 95% CI; 0.02, 0.51; P = 0.005). Conclusion: The present meta-analysis provides evidence that atenolol has got a comparable efficacy and better safety profile with propranolol.

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis.

BACKGROUND & OBJECTIVES: Hydroxychloroquine (HCQ), reported to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in in vitro studies, has been recommended for prophylaxis of COVID-19 in healthcare workers (HCWs). The objective of this study was to assess short-term adverse events (AEs) of HCQ in HCWs. METHODS: This cross-sectional study among consenting HCWs taking prophylaxis and working in hospitals with COVID-19 patients used online forms to collect details of HCWs, comorbidities, prophylactic drugs used and AEs after the first dose of HCQ. Verification of dose and AEs was done by personal contact. Multivariate logistic regression analysis was done to determine the effect of age, gender and dose of HCQ on AE. RESULTS: Of the 1303 HCWs included, 98.4 per cent (n=1282) took HCQ and 66 per cent (n=861) took 800 mg as first day's dose. Among the 19.9 per cent (n=259) reporting AEs, 1.5 per cent (n=20) took treatment for AE, none were hospitalized and three discontinued HCQ. Gastrointestinal AEs were the most common (172, 13.2%), with less in older [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.89], with more in females (OR 2.46, 95% CI 1.78-3.38) and in those taking a total dose of 800 mg on day one compared to a lower dose. Hypoglycaemia (1.1%, n=14), cardiovascular events (0.7%, n=9) and other AEs were minimal. INTERPRETATION & CONCLUSIONS: HCQ prophylaxis first dose was well tolerated among HCWs as evidenced by a low discontinuation. For adverse effects, a small number required treatment, and none required hospitalization. The study had limitations of convenience sampling and lack of laboratory and electrocardiography confirmation of AEs.

Promising traditional Indian medicinal plants for the management of novel Coronavirus disease: A systematic review.

Traditional Indian medical practices (Ayurveda, Siddha, Unani, and homeopathy) are a vast reservoir of knowledge about medicinal plants. The promising pharmacological properties of these plants have paved the way for developing therapy against novel Coronavirus (CoV) infection. The current review will summarize published works of literature on the effects of traditional Indian medicinal plants against acute respiratory infection (COVID-19, SARS, Influenza, and Respiratory syncytial virus infection) and registered clinical trials of traditional Indian herbal medicines in COVID-19. The current study aims to comprehensively evaluate the data of traditional Indian medicinal plants to warrant their use in COVID-19 management. PubMed, Embase, and Cochrane databases were searched along with different clinical trial databases. A total of 22 relevant traditional Indian medicinal plants (35 relevant studies) were included in the current study having potential antiviral properties against virus-induced respiratory illness along with promising immunomodulatory and thrombolytic properties. Further, 36 randomized and nonrandomized registered clinical trials were also included that were aimed at evaluating the efficacy of herbal plants or their formulations in COVID-19 management. The antiviral, immunomodulatory, and thrombolytic activities of the traditional Indian medicinal plants laid down a strong rationale for their use in developing therapies against SARS-CoV-2 infection. The study identified some important potential traditional Indian medicinal herbs such as Ocimum tenuiflorum, Tinospora cordifolia, Achyranthes bidentata, Cinnamomum cassia, Cydonia oblonga, Embelin ribes, Justicia adhatoda, Momordica charantia, Withania somnifera, Zingiber officinale, Camphor, and Kabusura kudineer, which could be used in therapeutic strategies against SARS-CoV-2 infection.

Metformin ameliorates the status epilepticus- induced hippocampal pathology through possible mTOR modulation.

The initial precipitating injury such as SE progresses to chronic epilepsy through multiple epileptogenic processes. Early epileptogenic events are generally characterized by neuroinflammation, neurodegeneration and abnormal neurogenesis in the hippocampus. Metformin has exhibited anti-inflammatory and neuroprotective properties in numerous studies. The current study attempts to investigate the effect of metformin on seizure-induced inflammation and neuronal degeneration, and the involvement of the mTOR pathway. Status epilepticus (SE) was induced in male Wistar rats with systemic administration of Lithium (127 mg/kg) and Pilocarpine (30 mg/kg). In test rats, Metformin 100 mg/kg or 200 mg/kg was administered orally for 7 days, followed by SE induction. Results indicate that metformin did not alter the SE profile significantly which was evident by the behavioural scoring and electroencephalogram (EEG) recordings. However, metformin 200 mg/kg attenuated the SE-induced glial activation (p < 0.01), up regulated mRNA levels of proinflammatory cytokines (p < 0.001) and chemokines (p < 0.001) and enhanced BBB permeability (p < 0.05). In addition, metformin ameliorated the insult-induced region-specific neuronal damage (p < 0.01) and restored the hippocampal neuronal density. Metformin significantly inhibited phosphorylated S6 ribosomal protein (phospho-S6rp) (p < 0.05), thus demonstrating that the beneficial effects might be partly mediated by the mTOR pathway. The study thus reiterates that mTOR signalling is one of the mechanisms involved in inflammation and neurodegeneration in early epileptogenesis following SE.

Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer's disease.

Alzheimer's disease (AD) is a major contributor of dementia leading to the degeneration of neurons in the brain with major symptoms like loss of memory and learning. Many evidences suggest the involvement of neuroinflammation in the pathology of AD. Cytokines including TNF-α and IL-6 are also found increasing the BACE1 activity and expression of NFκB resulting in generation of Aß in AD brain. Following the interaction of Aß with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPARγ agonists like pioglitazone increases the phagocytosis of Aß and reduces inflammatory cytokine IL-1ß. Celecoxib and roficoxib like selective COX-2 inhibitors also ameliorate neuroinflammation. Non-selective COX inhibitor indomethacin is also potent inhibitor of inflammatory mediators released from microglia. Mitophagy process is considered quite helpful in reducing inflammation due to microglia as it promotes the phagocytosis of over activated microglial cells and other inflammatory cells. Mitophagy induction is also beneficial in the removal of damaged mitochondria and reduction of infiltration of inflammatory molecules at the site of accumulation of the damaged mitochondria. Targeting these pathways and eventually ameliorating the activation of microglia can mitigate neuroinflammation and come out as a better therapeutic option for the treatment of Alzheimer's disease.

Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: A systematic review and meta-analysis.

Following the demonstration of the efficacy of hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 in vitro, many trials started to evaluate its efficacy in clinical settings. However, no systematic review and meta-analysis have addressed the issue of the safety and efficacy of hydroxychloroquine (HCQ) in coronavirus disease 2019. We conducted a systematic review and meta-analysis with the objectives of evaluation of safety and efficacy of HCQ alone or in combination in terms of "time to clinical cure," "virological cure," "death or clinical worsening of disease," "radiological progression," and safety. RevMan was used for meta-analysis. We searched 16 literature databases out of which seven studies (n = 1358) were included in the systematic review. In terms of clinical cure, two studies reported possible benefit in "time to body temperature normalization" and one study reported less "cough days" in the HCQ arm. Treatment with HCQ resulted in less number of cases showing the radiological progression of lung disease (odds ratio [OR], 0.31, 95% confidence interval [CI], 0.11-0.9). No difference was observed in virological cure (OR, 2.37, 95% CI, 0.13-44.53), death or clinical worsening of disease (OR, 1.37, 95% CI, 1.37-21.97), and safety (OR, 2.19, 95% CI, 0.59-8.18), when compared with the control/conventional treatment. Five studies reported either the safety or efficacy of HCQ + azithromycin. Although seems safe and effective, more data are required for a definitive conclusion. HCQ seems to be promising in terms of less number of cases with radiological progression with a comparable safety profile to control/conventional treatment. We need more data to come to a definite conclusion.

Role of TRPV1/TRPV3 channels in olanzapine-induced metabolic alteration: Possible involvement in hypothalamic energy-sensing, appetite regulation, inflammation and mesolimbic pathway.

Atypical antipsychotics (AAPs) have the tendency of inducing severe metabolic alterations like obesity, diabetes mellitus, insulin resistance, dyslipidemia and cardiovascular complications. These alterations have been attributed to altered hypothalamic appetite regulation, energy sensing, insulin/leptin signaling, inflammatory reactions and active reward anticipation. Line of evidence suggests that transient receptor potential vanilloid type 1 and 3 (TRPV1 and TRPV3) channels are emerging targets in treatment of obesity, diabetes mellitus and could modulate feed intake. The present study was aimed to investigate the putative role TRPV1/TRPV3 in olanzapine-induced metabolic alterations in mice. Female BALB/c mice were treated with olanzapine for six weeks to induce metabolic alterations. Non-selective TRPV1/TRPV3 antagonist (ruthenium red) and selective TRPV1 (capsazepine) and TRPV3 antagonists (2,2-diphenyltetrahydrofuran or DPTHF) were used to investigate the involvement of TRPV1/TRPV3 in chronic olanzapine-induced metabolic alterations. These metabolic alterations were differentially reversed by ruthenium red and capsazepine, while DPTHF didn't show any significant effect. Olanzapine treatment also altered the mRNA expression of hypothalamic appetite-regulating and nutrient-sensing factors, inflammatory genes and TRPV1/TRPV3, which were reversed with ruthenium red and capsazepine treatment. Furthermore, olanzapine treatment also increased expression of TRPV1/TRPV3 in nucleus accumbens (NAc), TRPV3 expression in ventral tegmental area (VTA), which were reversed by the respective antagonists. However, DPTHF treatment showed reduced feed intake in olanzapine treated mice, which might be due to TRPV3 specific antagonism and reduced hedonic feed intake. In conclusion, our results suggested the putative role TRPV1 in hypothalamic dysregulations and TRPV3 in the mesolimbic pathway; both regulate feeding in olanzapine treated mice.

Therapeutic options for management of Hori's nevus: A systematic review.

Hori's nevus is a pigmentation disorder reported mainly in middle-aged Asian women. There is no systematic review addressing its pharmacotherapy. The population for our systematic review was patients with a clinical/histological diagnosis of Hori's nevus (both sex, any age group). We screened five literature databases using relevant keywords. All RCTs, observational studies and case series mentioning at least one intervention and outcome of that intervention were included. Nineteen studies were included in the final systematic review from total 680 identified nonduplicate records. Different forms of laser (alexandrite laser [QSAL and PSAL], Nd:YAG laser [QSNYL high fluence, low fluence, 532 followed by 1064 nm], Er: YAG and Nd:YAG combination, ruby laser [QSRL], CO2 laser followed by QSRL) and dermabrasion were found to be useful in treatment of Hori' nevus. Among alexandrite lasers, PSAL is more efficacious and safe than QSAL. In case of high fluence QSNYL, hyperpigmentation rate is quite high while low fluence QSNYL requires more number of treatment sessions. The combined 1064 nm + 532 nm protocol is better in terms of efficacy and safety. Er:YAG + Nd:YAG combination have similar efficacy and added advantage of synergistic action and no adverse event.

Premature graying of hair: Risk factors, co-morbid conditions, pharmacotherapy and reversal-A systematic review and meta-analysis.

Premature graying of hair (PGH) being a very common entity for which pharmacotherapy and reversibility are not properly addressed. Therefore, this systematic review was conducted to address these issues. For this relevant study were selected from various databases including PubMed, EMBASE, OVID, Web of science, Scopus, and Google Scholar till January 20, 2019. Studies which reported risk factors, co-morbid conditions associated with PGH, its pharmacotherapy and reversal were included in the study. Although many risk factors are reported in literature, smoking, vitamin deficiency (B12, folic acid, and B7), mineral deficiency (low serum calcium and serum ferritin) are found to be associated with PGH. Other important risk factors are family history of PGH, obesity, high B.P, lack of exercise, drugs, genetic syndromes, dyslipidemia, thyroid disorders, hyperuricemia, and alteration in liver function. PGH is found to be an important marker of CAD, more so in case of smoker. Among different pharmacotherapeutic management options, low grade recommendation (2A) is given to calcium pantothenate, PABA, calcium pantothenate + PABA combination. Anu-tailam is the only herbal agent evaluated in clinical research settings. Finally, treating the accompanying pathologies led to the reversal of the disease in many cases.