Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERß)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Current Insights into Carpal Tunnel Syndrome: Clinical Strategies for Prevention and Treatment.

BACKGROUND: Carpal tunnel syndrome (CTS) is a condition that is caused by medial nerve compression, resulting in symptoms such as numbness, tightness, or weakness in the hand. OBJECTIVES: The aim of the study was to find out the genetic modulation, mechanism, available treatment, and recommendation for carpal tunnel syndrome at its specific stage. METHODS: Almost 200 papers were searched for this review article, and 145 articles were selected. The literature was collected from different sources like Google scholar, PubMed, a directory of open-access journals, and science.gov by using keywords, such as treatment, risk factors, recommendation, and clinical features of carpal tunnel syndrome. RESULTS: The most efficient non-surgical treatment is methylprednisolone acetate, which reduces inflammation by acting on the glucocorticoid receptor in conjunction with immunofilling. It has also been used successfully as a second-line drug for the treatment of patients with mild or moderate conditions in order to provide relief. New non-pharmacological options include laser therapy in acupuncture, transcutaneous electric nerve stimulation (TENS), and sham therapy. Modern treatments like TENS, laser therapy, splints, and injections of methylprednisolone acetate have been demonstrated to be helpful in sporadic situations. For patients with mild and moderate problems, more research should be conducted that includes the combination of these surgical and non-surgical treatments. CONCLUSION: We propose a multifunctional panel construct and define standard data items for future research into carpal tunnel syndrome. A discussion on idiopathic carpal tunnel syndrome, risk factors, combination of therapies, using guidelines-based recommendations and treatment should be initiated.

Unravelling the Crosstalk between Estrogen deficiency and Gut-biota Dysbiosis in the development of Diabetes Mellitus.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the ß-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin-sphingolipid pathway in an animal model of pharmacoresistant epilepsy.

BACKGROUND: The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats. MATERIALS AND METHODS: PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury. RESULTS: Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy. CONCLUSION: The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.

Discussing pathologic mechanisms of Diabetic retinopathy & therapeutic potentials of curcumin and ß-glucogallin in the management of Diabetic retinopathy.

Diabetic retinopathy (DR) is a form of retinal microangiopathy that occurs as a result of long-term Diabetes mellitus (DM). Patients with Diabetes mellitus typically suffer from DR as a progression of the disease that may be due to initiation and dysregulation of pathways like the polyol, hexosamine, the AGE/RAGE, and the PKC pathway, which all have negative impacts on eye health and vision. In this review, various databases, including PubMed, Google Scholar, Web of Science, and Science Direct, were scoured for data relevant to the aforementioned title. The three most common therapies for DR today are retinal photocoagulation, anti-vascular endothelial growth factor (VEGF) therapy, and vitrectomy, however, there are a number of drawbacks and limits to these methods. So, it is of critical importance and profound interest to discover treatments that may successfully address the pathogenesis of DR. Curcumin and ß-glucogallin are the two potent compounds of natural origin that are already being used in various nutraceutical formulations for several ailments. They have been shown potent antiapoptotic, anti-inflammatory, antioxidant, anticancer, and pro-vascular function benefits in animal experiments. Their parent plant species have been used for generations by practitioners of traditional herbal medicine for the treatment and prevention of various eye ailments. In this review, we will discuss about pathophysiology of Diabetic retinopathy and the therapeutic potentials of curcumin and ß-glucogallin one of the principal compounds from Curcuma longa and Emblica officinalis in Diabetic retinopathy.

Pre-clinical Aspects and Contemporary Treatments of Parkinson's Disease.

BACKGROUND: After Alzheimer's disease, the second slot for the most common neurodegenerative disease, is occupied by Parkinson's disease. The symptoms of Parkinson's are classified as motor symptoms and non-motor symptoms. Motor symptoms involve rigidity, tremors, bradykinesia, and postural instability. Non-motor symptoms consist of cognitive dysfunction, salivation, lacrimation, etc. Objectives: The objectives of this study are to find out the most recent treatment options for Parkinson's disease. METHODS: Research and review papers are collected from different databases like Google Scholar, PubMed, Mendeley, Scopus, Science Open, and the Directory of Open Access Journals using different keywords such as "Parkinson's disease, biomarkers, animal models". RESULTS: Currently, various novel therapeutics have been emerging for PD. These may include treatments that may control the symptoms without causing any other severe side effects with already available treatments. Better therapies such as gene therapies, cell-based treatments, and regenerative therapies, which may evolve over time, can be a better therapeutic option. CONCLUSION: There is a need for the development of novel and potential therapeutic strategies that offer fewer side effects to patients. Several clinical, biochemical, and imaging markers that are noteworthy in Parkinson's disease examination have been discussed here. Current work in the field of Parkinson's disease has developed a variety of significant small animal models, such as viral vector models and seeding models, including the insertion of preformed fibrils of alpha-synuclein. The brief concepts regarding risk factors, pathogenesis, clinical diagnosis, and emerging treatments of PD are discussed in this review article.

Recent Advances in the Prevention and Management of Monkeypox Viral Infection in Humans.

BACKGROUND: There have been several neglected infectious pathogens that have reemerged in the last few decades, including the monkeypox virus, a virus from the orthopoxviral genus that causes monkeypox and is transmitted between animals and humans. The human monkeypox outbreak has spread to several different countries. Because of the outbreak's unusually high case count and lack of connections to endemic nations, there are concerns that the monkeypox transmission pattern may have changed. OBJECTIVE: The current study aimed to provide recent advancements in the prevention and management of the monkeypox virus in humans. METHODOLOGY: We have highlighted recent advancements in the prevention and management of the monkeypox virus in humans in this work. RESULTS: For the treatment and prevention of monkeypox, new medications and vaccinations are being used, and more study is needed to understand the epidemiology, biology, and ecology of the virus in endemic regions and stop future global outbreaks. Vaccines available in the market for the treatment of viruses are JYNEOS and ACAM2000. Some of the antiviral drugs, such as tecovirimat, brincidofovir, cidofovir, trifluridine, and vaccinia immune globulin, are used for the treatment of the monkeypox virus. Some of the vaccines, such as NIOCH-14, Cidofovir, CMX-001, and ST-246, are currently in clinical trials. CONCLUSION: We have, herein, covered features of monkeypox viral biology that are important for risk assessment and getting ready for an outbreak of the monkeypox virus, with a focus on recent advances in knowledge of the virus's host range, evolutionary potential, and potential targets for neutralization.

Investigation of Pancreatic-beta cells Role in the Biological Process of Ageing.

BACKGROUND: Cellular senescence is associated with the formation and progression of a range of illnesses, including ageing and metabolic disorders such as diabetes mellitus and pancreatic beta cell dysfunction. Ageing and reduced glucose tolerance are interconnected. Often, Diabetes is becoming more common, which is concerning since it raises the risk of a variety of age-dependent disorders such as cardiovascular disease, cancer, Parkinson's disease, stroke, and Alzheimer's disease. OBJECTIVES: The objectives of this study are to find out the most recent research on how ageing affects the functions of pancreatic beta cells, beta cell mass, beta cell senescence, mitochondrial dysfunction, and hormonal imbalance. METHODS: Various research and review manuscripts are gathered from various records such as Google Scholar, PubMed, Mendeley, Scopus, Science Open, the Directory of Open Access Journals, and the Education Resources Information Centre, using different terms like "Diabetes, cellular senescence, beta cells, ageing, insulin, glucose". RESULTS: In this review, we research novel targets in order to discover new strategies to treat diabetes. Abnormal glucose homeostasis and type 2 diabetes mellitus in the elderly may aid in the development of novel medicines to delay or prevent diabetes onset, improve quality of life, and, finally, increase life duration. CONCLUSION: Aging accelerates beta cell senescence by generating premature cell senescence, which is mostly mediated by high glucose levels. Despite higher plasma glucose levels, hepatic gluconeogenesis accelerates and adipose tissue lipolysis rises, resulting in an increase in free fatty acid levels in the blood and worsening insulin resistance throughout the body.

Structural-Based Virtual Screening of FDA-Approved Drugs Repository for NSP16 Inhibitors, Essential for SARS-COV-2 Invasion Into Host Cells: Elucidation From MM/PBSA Calculation.

NSP16 is one of the structural proteins of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) necessary for its entrance to the host cells. It exhibits 2'O-methyl-transferase (2'O-MTase) activity of NSP16 using methyl group from S-adenosyl methionine (SAM) by methylating the 5-end of virally encoded mRNAs and shields viral RNA, and also controls its replication as well as infection. In the present study, we used in silico approaches of drug repurposing to target and inhibit the SAM binding site in NSP16 using Food and Drug Administration (FDA)-approved small molecules set from Drug Bank database. Among the 2 456 FDA-approved molecules, framycetin, paromomycin, and amikacin were found to be significant binders against the SAM binding cryptic pocket of NSP16 with docking score of -13.708, -14.997 and -15.841 kcal/mol, respectively. Classical molecular dynamics (MD) simulation and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculation depicted that all these three framycetin, paromomycin, and amikacin might be promising therapeutic leads towards SARS-CoV-2 infections via host immune escape inhibition pathway.

A systematic review for the development of Alzheimer's disease in in vitro models: a focus on different inducing agents.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer's disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer's disease developed using chemicals and environmental agents are instrumental in providing insights into the disease's pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.

A preliminary study to evaluate the behavior of Indian population toward E-pharmacy.

The use of the Internet has increased exponentially for buying as well as selling of goods. Even the purchase of medications online is no exception. Owing to its benefits, there are certain risk factors in purchase of online medicines. Currently, the data on the use of Internet pharmacies are limited. Thus, the main objective of our study is to assess the knowledge, attitude, and practices (KAP) of Indian population toward E-pharmacy in India carried out in the Department of Pharmacology, PGIMER, Chandigarh. A KAP questionnaire was prepared which was distributed to the participants through Google Forms and a URL sent to them. This questionnaire was divided into four sections including demographics, occupation, income, and use of the Internet to measure the alertness toward the online purchase of medicines. A total of 322 responses were collected, out of which only 268 (83.2%) participants were aware of online pharmacy. The awareness was more in males and that too in urban population. Among the respondents, majority of the users prefer to buy medicines offline (81%, n = 217) which can be due to poor quality of medicines and lack of trustworthy websites. The utmost reason for buying the medicine online was deficiency of availability in the market and differences in the prices. The most preferred drugs respondents were willing to buy online were prescription drugs followed by cosmetics and dietary supplements. In conclusion, of our results, most of the people use the Internet to search for the medications online who prefer to consult the physicians before buying. Therefore, the future of online pharmacy can be improved if there will be some set guidelines, awareness, and knowledge among the users.

Yogic Neti-Kriya Using Povidone Iodine: Can it have a Preventive Role Against SARS-CoV-2 Infection Gateway?

During this COVID-19 pandemic, except steroid, none of the therapeutic measures have showed any evidence of efficacy. Traditionally jala-neti using lukewarm salted water remains a yogic way of maintaining upper airway hygiene. Saline irrigation decreases the concentration of inflammatory mediators (e.g. histamine, leukotriene etc.) in nasal secretions, reduces the severity and frequency of sinusitis, reduce need of antibiotic therapy and restores competency of nasal mucosa. Jala-neti is an integral part of six cleansing techniques of yogic kriyas practised in India since thousands of years. Jala-neti can clean the upper airways, prevents colonization of infectious agents, removes foreign bodies, prevents stasis of mucous and subsequently enhances the drainage of paranasal sinuses and maintain health. Regular practice of Jala neti improves nasal symptoms and overall health status of patients with sinusitis. Jala-neti sample can even be used for COVID-19 diagnosis. Povidone iodine (PVP-I) has been utilized as a time tested antimicrobial agent with broad spectrum coverage against wide range of bacteria and viruses. Anti-SARS-CoV-2 action of PVP-I was seen at a concentration as low as 0.45%. PVP-I is generally well tolerated upto 5%, however nasal ciliotoxicity is reported at this concentration, however, this toxicity is not reported with lower concentrations(1.25% and 0.5%). So, theoretically, by using neti-kriya with povidone iodine (0.5-1%) as irrigation solution can combine and enhance the protection against COVID-19 and this can be an important armor in the fight against COVID-19. However, this hypothesis needs to be validated in real life clinical trial scenario before implementing.

Valproic Acid and Propionic Acid Modulated Mechanical Pathways Associated with Autism Spectrum Disorder at Prenatal and Neonatal Exposure.

Autism spectrum disorder (ASD) is a composite disorder of brain development with uncertain etiology and pathophysiology. Genetic factors are important in ASD causation, although environmental factors are also involved in ASD pathophysiology. Environmental factors might affect the genetic processes of brain development through the modulation of molecular pathways that might be involved with ASD. Valproic acid and propionic acid are the major environmental factors that serve as medicine and food preservative. VPA is used as an anti-epileptic medicine, but it has adverse effects on pregnant women and alters the developmental patterns of the embryo. It is a multi- targeting agent and affects 5-HT, GABA, etc. PPA is a secondary metabolite of gut microbiota that is commonly used as a food preservative. PPA plays a significant role in ASD causation by altering the several developmental molecular pathways like PTEN/Akt, mTOR/Gskß, Cytokines activated pathways, etc., at the prenatal and neonatal stage. Moreover, ASD complexity might be increased by other important factors like vitamin A deficiency. Vitamin A is important for cortical brain development and neuronal cell differentiation. Additionally, several important genes such as RELN, Lhx2, CREB, IL-6, NMDA, BDNF, etc., are also altered in ASD and involved in brain development, central nervous system, and enteric nervous system. These genes affect neuronal differentiation, hyperactivity, oxidative stress, oxytocin, and GABA imbalance lead to improper behavior in autistic individuals. These genes are also studied in VPA and PPA ASD-like animal models. In this review, we explored the mechanical pathways that might be altered with VPA and PPA exposures at the embryonic developmental stage or neonatal developmental stage.

Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R).

INTRODUCTION: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein. MATERIALS AND METHODS: Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). RESULTS AND DISCUSSION: Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better. CONCLUSION: We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.

Neuroprotective effect of bone marrow-derived mesenchymal stem cell secretome in 6-OHDA-induced Parkinson's disease.

Aim: The aim of the study was to evaluate the neuroprotective effect of bone marrow stem cell secretome in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Materials & methods: Secretome prepared from mesenchymal stem cells of 3-month-old rats was injected daily for 7 days between days 7 and 14 after 6-OHDA administration. After 14 days, various neurobehavioral parameters were conducted. These behavioral parameters were further correlated with biochemical and molecular findings. Results & conclusion: Impaired neurobehavioral parameters and increased inflammatory, oxidative stress and apoptotic markers in the 6-OHDA group were significantly modulated by secretome-treated rats. In conclusion, mesenchymal stem cell-derived secretome could be further explored for the management of Parkinson's disease.

Evaluation of the in vitro and in vivo antioxidant potentials of food grade Phycocyanin.

Excessive generation of oxygen free radicals plays a pivotal role in destruction of biological molecules like DNA, proteins, lipids, carbohydrates and results in various pathologies including neuronal disorders. Antioxidant molecules from natural products are reported to have ability to mitigate their production or at least halt their progression and metastasis in the system. Different studies have been performed to spot antioxidants from natural sources and attempts have been made to integrate them in conventional therapy. In our present study, food grade Phycocyanin, a nutraceutical isolated from Spirulina platensis, has been evaluated for its in vitro and in vivo antioxidant potential using a battery of antioxidant assays viz. DPPH, TAC, FRAP, hydroxyl radical, hydrogen peroxide scavenging, SOD, GSH, and LPO assays. Reducing properties of Phycocyanin were also assessed by FRAC assay. For in vivo evaluation of antioxidant profile, animal model of intracerebroventricular administration of streptozotocin was employed. Levels of oxidative stress biomarkers were measured in cortex and hippocampal parts of brain. Results obtained depicted that Phycocyanin demonstrated a dose-dependent pattern in its efficacy, which indicates the presence of free radical scavenger moieties and possible role as a neuroprotective agent.

Rhino-orbital-cerebral-mucormycosis in COVID-19: A systematic review.

Since the onset of COVID-19 pandemic, parallel opportunistic infections have also been emerging as another disease spectrum. Among all these opportunistic infection, mucormycosis has become a matter of concern with its rapid increase of cases with rapid spread as compared to pre-COVID-19 era. Cases have been reported in post-COVID-19-related immune suppression along with the presence of comorbidity which adds on the deadly outcome. There is no systematic review addressing the issue of COVID-19-associated mucormycosis. This is the first systematic review of published studies of mucormycosis associated with COVID-19. The aim was to analyze the real scenario of the disease statement including all the published studies from first November 2019 to 30th June to analyze the contemporary epidemiology, clinical manifestations, risk factor, prognosis, and treatment outcome of COVID-19 associated rhino-orbito-cerebral-mucormycosis. A comprehensive literature search was done in following databases, namely, PubMed, Google Scholar, Scopus, and EMBASE using keywords mucormycosis, rhino orbital cerebral mucormycosis, COVID-19, and SARS-CoV-2 (from November 01, 2019 to June 30, 2021). Our study shows that, while corticosteroids have proved to be lifesaving in severe to critical COVID-19 patients, its indiscriminate use has come with its price of rhino-orbito-cerebral mucormycosis epidemic, especially in India especially in patients with preexisting diabetes mellitus with higher mortality. Corticosteroid use should be monitored and all COVID-19 patients should be closely evaluated/monitored for sequelae of immunosuppression following treatment.

Construction of time-response curve for neuronal and vascular endothelial dysfunction in ovariectomized rats.

BACKGROUND: Studies have shown that there is a critical time period to start hormone therapy after the loss of ovarian function during menopause. The length of estrogen deprivation may evolve different pathophysiological manifestations. OBJECTIVE: The aim of the present study was to investigate behavioral, biochemical, and molecular alterations at different time points after surgical menopause with an aim and identify various pathophysiological targets to exploit "window of opportunity" and to design newer therapeutic modalities for menopause-associated neurobehavioral and vascular deficits. MATERIALS AND METHODS: Bilateral ovariectomy was performed to induce surgical menopause and estrogen deficiency state. Menopause-associated neuronal and vascular dysfunctions were noted after 1, 2, and 3 months of the study. RESULTS: Neuronal and vascular endothelial dysfunction post ovariectomy revealed that behavioral, biochemical, molecular, and vascular endothelial dysfunction appeared after 1 month of ovariectomy except hyperglycemia, which occurs after 3 months. CONCLUSIONS: Time-response studies measuring behavioral, biochemical, and molecular markers at various time points after ovariectomy reveal that there is a fast onset of neuronal and vascular complications, but the duration of insulin resistance is a relatively late phenomenon.