Integrated in-silico and in-vitro assessments of HDAC6 inhibitor efficacy in mitigating amyloid beta pathology in Alzheimer's disease.

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (Aß) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for Aß degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased Aß build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing Aß load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating Aß accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma.

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 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.

Futuristic approach to cancer treatment.

Cancer is becoming one of the deadliest disease in both developed as well as developing countries and continuous effort is being made to find innovative therapies for myriad types of cancers that afflict the human body. Therapeutic options for cancer have grown exponentially over the time but we are quite a way off from finding a magic bullet that can help cure cancer and based on the current evidence we may never find a catch all cure ever and it becomes crucial that we keep on innovating and find multiple ways to attack the menace of this dreaded disease. Many patients suffer recurrence of disease and require second-line or in some cases more than two lines of treatment. In this review article we have discussed the available therapies along with the newer advancements that have been made in cancer therapy. Latest developments in treatment of various cancers that have been discussed include gene editing using CRISPR/Cas9, theranostics, viral mediated therapy, artificial intelligence, tumor infiltrating lymphocyte therapy, etc.

Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits.

BACKGROUND: It is well accepted that PI3k/Akt signaling pathway is a potential therapeutic window which regulates metabolism and energy homeostasis within the brain, and is an important mediator of normal neuronal physiological functions. Dysregulation of this pathway results in impaired insulin signaling, learning and memory and neuronal survival. OBJECTIVES: Elucidating the role of everolimus in intracerebroventricular (ICV) streptozotocin induced Insulin/IGF-1 dependent PI3K/Akt/mTOR pathway dysregulation and associated neurobehavioral deficits. METHODS: Rats were administered with streptozotocin (3 mg/kg) intracerebroventricular, followed by administration of everolimus (1 mg/kg) orally for 21 days. After that, Morris water maze and passive avoidance tests were performed for assessment of memory. Animals were sacrificed to evaluate brain insulin pathway dysfunction, neurotrophic, apoptotic, inflammatory, and biochemical markers in rat brain. To elucidate the mechanism of action of everolimus, PI3K inhibitor, wortmannin was administered in the presence of everolimus in one group. RESULTS: Streptozotocin administration resulted in a significant decrease of brain insulin, insulin growth factor-1 levels, and alterations in behavioral, neurotrophic (BDNF), inflammatory (TNF-α), apoptotic (NF-κB, Bcl2 and Bax) and biochemical (AChE and ChAT assay) parameters in comparison to sham group rats. Everolimus significantly mitigated the deleterious behavioral, biochemical, and molecular changes in rats having central insulin dysfunction. However, the protective effect of everolimus was completely abolished when it was administered in the presence of wortmannin. CONCLUSION: Findings from the study reveal that mTOR inhibitors can be an important treatment strategy for neurobehavioral deficits occurring due to central insulin pathway dysfunction. Protective effect of drugs is via modulation of PI3K/Akt pathway.

Role of protein tyrosine phosphatase 1B inhibitor in central insulin resistance and associated cognitive deficits.

BACKGROUND: Protein tyrosine phosphatase 1B (PTP1B) inhibitors are potential candidates for the treatment of peripheral insulin resistance and diabetes mellitus. Similar to peripheral action within the brain also, PTP1B activation impairs insulin signaling pathways. Activation of PTP1B in brain also accentuates neuroinflammation, oxidative stress and decreases neurotrophic factors in various brain dysfunctions including cognitive decline. OBJECTIVES: The main objective of our study was to elucidate the role of alendronate, a potent PTP1B inhibitor (blood brain barrier crossing bisphosphonate) in central insulin resistance and associated memory deficits. METHODOLOGY: To induce central insulin resistance, streptozotocin (3 mg/kg) intracerebroventricular (ICV) was administered in two alternate days (1st and 3rd). After 21 days, memory was assessed via using the passive avoidance and Morris water maze paradigm. At the end of behavioral studies, animals were sacrificed to assess a variety of biochemical and molecular parameters in the hippocampus and cerebral cortex region of the brain. Treatment drug alendronate (3 mg/kg/day, p.o) and standard drug donepezil (3 mg/kg/i.p.) were administered from the 3rd day of STZ administration till the end of the study. Inhibition of PTP1B activates phosphoinsotide-3 kinase (PI3 K) (down-stream regulator of insulin signaling pathway).Thus, to illuminate the mechanism of action of alendronate, PI3 K inhibitor, wortmannin was administered in presence of alendronate in one group. RESULTS: Administration of alendronate to ICV streprozotocin treated rats resulted in modulation of the insulin signaling pathway and associated behavioral, biochemical and molecular changes in central insulin resistance. However, the protective effect of alendronate was entirely vanished when it was administered in the presence of wortmannin. CONCLUSION: Alendronate can be an important treatment strategy in central insulin signaling pathway dysfunction and associated cognitive deficits. Protective effect of alendronate is via modulation of PI3-K/Akt signaling pathway.

Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review.

BACKGROUND: SARS-CoV-2, which majorly affects the lungs and respiratory tract is thought due to dysregulation of the immune system which causes an immense imbalance of the cytokines. However, till now no standard treatment has been developed in treating the disease. On the other hand, it becomes important to prevent the acute respiratory tract infection due to COVID-19 which is the most dangerous phase leading to increased mortality. Hence this systematic review has been framed by pooling the available data of the use of stem cells in SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS. METHODS: 6 literature databases (PubMed, EMBASE, Scopus, Google Scholar, Clinicaltrials.gov, and Clinical trial registry of India) were searched for relevant studies till 10th August 2020 using keywords stem cells, mesenchymal stem cells, cell therapy, SARS CoV-2, SARS Coronavirus, Coronavirus 2, COVID-19, nCoV-19, Novel Coronavirus, MERS CoV, ARDS, acute respiratory distress syndrome. RESULTS: The observations of this systematic review suggest capability of MSCs in reducing the systemic inflammation and protecting against SARS-CoV-2 as evidenced by the available clinical data. CONCLUSION: MSCs can overcome the clinical challenges currently faced by SARS-CoV-2 infected patients, specifically who are seriously ill and not responding to conventional therapies. Though the available clinical data is motivating, still predicting the therapeutic potential of MSCs will be too early in COVID-19. Hence, further studies in a larger cohort of patients becomes a prerequisite to validate their potential efficacy.

Clinically relevant cell culture models and their significance in isolation, pathogenesis, vaccine development, repurposing and screening of new drugs for SARS-CoV-2: a systematic review.

BACKGROUND: In-Vitro/Cellular evidence is the backbone and vital proof of concept during the development of novel therapeutics as well as drugs repurposing against COVID-19. Choosing an ideal in-vitro model is vital as the virus entry is through ACE2, CD147, and TMPRSS2 dependant and very specific. In this regard, this is the first systematic review addressing the importance of specific cell lines used as potential in-vitro models in the isolation, pathogenesis, and therapeutics for SARS-COV-2. METHODS: We searched 17 literature databases with appropriate keywords, and identified 1173 non-duplicate studies. In the present study, 71 articles are included after a careful, thorough screening of the titles and their abstracts for possible inclusion using predefined inclusion/exclusion criteria (PRISMA Guidelines). RESULTS: In the current study, we compiled cell culture-based studies for SARS-CoV-2 and found the best compatible In-Vitro models for SARS-CoV-2 (Vero, VeroE6, HEK293 as well as its variants, Huh-7, Calu-3 2B4, and Caco2). Among other essential cell lines used include LLC-MK2, MDCKII, BHK-21, HepG2, A549,T cell leukemia (MT-2), stems cells based cell line DYR0100for differentiation assays, and embryo-specific NIH3T3 cell line for vaccine production. CONCLUSION: The Present study provides a detailed summary of all the drugs/compounds screened for drug repurposing and discovery purpose using the in-vitro models for SARS-CoV-2 along with isolation, pathogenesis and vaccine production. This study also suggests that after careful evaluation of all the cell line based studies, Kidney cells (VeroE6, HEK293 along with their clones), liver Huh-7cells, respiratory Calu-3 cells, and intestinal Caco-2 are the most widely used in-vitro models for SARS-CoV-2.

Molecular diagnosis of COVID-19 in different biologic matrix, their diagnostic validity and clinical relevance: A systematic review.

Due to COVID 19 outbreak many studies are being conducted for therapeutic strategies and vaccines but detection methods play an important role in the containment of the disease. Hence, this systematic review aims to evaluate the effectiveness of the molecular detection techniques in COVID-19. For framing the systematic review 6 literature databases (PubMed, EMBASE, OVID, Web of Science, Scopus and Google Scholar) were searched for relevant studies and articles were screened for relevant content till 25th April 2020. Observations from this systematic review reveal the utility of RT-PCR with serological testing as one such method cannot correlate with accurate results. Availability of point of care devices do not conform to sensitivity and specificity in comparison to the conventional methods due to lack of clinical investigations. Pivotal aim of molecular and serological research is the development of detection methods that can support the clinical decision making of patients suspected with SARS-CoV-2. However, none of the methods were 100% sensitive and specific; hence additional studies are required to overcome the challenges addressed here. We hope that the present article with its observations and suggestions will assist the researchers to realize this vision in future.

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.

In silico docking and comparative ADMET profile of different glycogen synthase kinase 3 beta inhibitors as the potential leads for the development of anti-Alzheimer drug therapy.

Glycogen synthase kinase 3 beta (GSK3 ß) plays a key role in pathologic hyper phosphorylation of tau and plays an important role in the pathogenesis of Alzheimer's disease. In the present study, we have screened a set of potential hits in in silico platform to gain insight regarding binding profile with the target (GSK3 ß) from molecular docking, ADME/T, and molecular dynamics (MD) simulations. The three screened compounds 6-BIBEO, 6-BIO, and SB216763 topped the docking score chart when subjected to hard scoring function extraprecision of GLIDE. The active site dynamics study through MD simulations provides insights on residues Asp133, Val135, and Ile62 which are in a state of minimum deviation from their mean special position while they interact with the respective ligands. The same molecules also displayed favorable pharmacokinetic profile, negative Ames test and falls correctly within drug-likeliness rules. These agents can be taken forward further for the development of anti-Alzheimer's drug therapy.

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.