Impact of GSK-3ß and CK-1δ on Wnt signaling pathway in alzheimer disease: A dual target approach.

Alzheimer's disease (AD) is an enigmatic neurological illness that offers few treatment options. Recent exploration has highlighted the crucial connection of the Wnt signaling pathway in AD pathogenesis, shedding light on potential therapeutic targets. The present study focuses on the dual targeting of glycogen synthase kinase-3ß (GSK-3ß) and casein kinase-1δ (CK-1δ) within the framework of the Wnt signaling pathway as a possible technique for AD intervention. GSK-3ß and CK-1δ are multifunctional kinases known for their roles in tau hyperphosphorylation, amyloid processing, and synaptic dysfunction, all of which are major hallmarks of Alzheimer's disease. They are intricately linked to Wnt signaling, which plays a pivotal part in sustaining neuronal function and synaptic plasticity. Dysregulation of the Wnt pathway in AD contributes to cognitive decline and neurodegeneration. This review delves into the molecular mechanisms by which GSK-3ß and CK-1δ impact the Wnt signaling pathway, elucidating their roles in AD pathogenesis. We discuss the potential of small-molecule inhibitors along with their SAR studies along with the multi-targetd approach targeting GSK-3ß and CK-1δ to modulate Wnt signaling and mitigate AD-related pathology. In summary, the dual targeting of GSK-3ß and CK-1δ within the framework of the Wnt signaling pathway presents an innovative and promising avenue for future AD therapies, offering new hope for patients and caregivers in the quest to combat this challenging condition.

Discovery of VEGFR inhibitors through virtual screening and energy assessment.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is crucial in promoting tumor angiogenesis and cancer metastasis. Thus, inhibition of VEGFR-2 has appeared as a good tactic for cancer treatment. To find out novel VEGFR-2 inhibitors, first, the PDB structure of VEGFR-2, 6GQO, was selected based on atomic nonlocal environment assessment (ANOLEA) and PROCHECK assessment. 6GQO was then further used for structure-based virtual screening (SBVS) of different molecular databases, including US-FDA approved drugs, US-FDA withdrawn drugs, may bridge, MDPI, and Specs databases using Glide. Based on SBVS, receptor fit, drug-like filters, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of 427877 compounds, the best 22 hits were selected. From the 22 hits, hit 5 complex with 6GQO was put through molecular mechanics/generalized born surface area (MM/GBSA) study and hERG binding. The MM/GBSA study revealed that hit 5 possesses lesser binding free energy with more inferior stability in the receptor pocket than the reference compound. The VEGFR-2 inhibition assay of hit 5 disclosed an IC50 of 165.23 nM against VEGFR-2, which can be possibly enhanced through structural modifications.

Drugs acting on the renin-angiotensin-aldosterone system (RAAS) and deaths of COVID-19 patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are two of the most commonly used antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS). Previous research has shown that RAAS inhibitors increase the expression of angiotensin-converting enzyme, a cellular receptor for the severe acute respiratory syndrome coronavirus 2, raising concerns that the use of ACEi and ARBs in hypertensive patients may increase COVID-19 patient mortality. Therefore, the main aim of the current study was to find out the role of drugs acting on RAAS, particularly ACEi/ARBs in the deaths of COVID-19 patients. RESULTS: In total, 68 studies were found to be appropriate, reporting a total of 128,078 subjects. The odds ratio was found to be 1.14 [0.95, 1.36], which indicates the non-significant association of ACEi/ARBs with mortality of COVID-19 patients. Further, the association of individual ACEi/ARBs with mortality of COVID-19 patients was also found non-significant. The sensitivity analysis results have shown no significant effect of outliers on the outcome. CONCLUSIONS: Based on available evidence, ACEi/ARB were not significantly associated with deaths of COVID-19 patients.

Next-generation sequencing in the biodiversity conservation of endangered medicinal plants.

Medicinal plants have been used as traditional herbal medicines in the treatment of various types of diseases. However, the increased demand for these plants highlights the importance of conservation specifically for endangered species. Significant advancements in next-generation sequencing (NGS) technologies have accelerated medicinal plant research while reducing costs and time demands. NGS systems enable high-throughput whole genome sequencing as well as direct RNA sequencing and transcriptome analysis. The sequence data sets created can be used in a variety of areas of study, including biodiversity conservation, comparative genomics, transcriptomic analysis, single cell mining, metagenomics, epigenetics, molecular marker discovery, multi genome sequencing, and so on. Commercial sequencing service providers are constantly working to improve technologies to address bioinformatics problems in NGS data analysis. Several genome sequencing projects on medicinal plants have been completed recently and a few more are in the works. In some medicinal plants, massive NGS-based data has been developed. In the present review, we have attempted to briefly discuss advancements in NGS technology on medicinally essential plants in India. The review will also provide ideas for applying NGS technologies for exploring genomes of various endangered medicinal plants whose genome sequences are not normally available and thus provides valuable insights for the conservation of these vulnerable species.

Quinoline-derivatives as privileged scaffolds for medicinal and pharmaceutical chemists: A comprehensive review.

The quinoline scaffolds are privileged for their numerous biological activities in the pharmaceutical field. This moiety constitutes a well-known space in several marketed preparations. The quinoline scaffolds gained attention in modern days being an important chemical moiety in the identification, designing, and synthesis of novel potent derivatives. The current review is developed to shine the light on critical and significant insights on the quinoline derivatives possessing diverse biological activities such as analgesic, anti-inflammatory, antialzheimer, anti-convulsant, anti-oxidant, antimicrobial, anti-cancer activities and so on. A detailed summary of quinoline ring from its origin to the recent advancements regarding its synthesis, green chemistry approaches, patented methods, and its marketed drugs is presented in the review. We attempted to review the literature compiling the critical information that has potential to encourage fellow researchers and scientists for the design and development of quinoline scaffold based active molecules that have improved therapeutic performance along with profound pharmacological properties.

Menstrual hygiene practices and associated factors among Indian adolescent girls: a meta-analysis.

BACKGROUND: Menstrual hygiene management (MHM) and practices by adolescent females of low and middle-income countries (LMICs) are a severe public health issue. The current systematic review and meta-analysis aimed to estimate the pooled proportion of the hygiene practices, menstrual problems with their associated factors, and the effectiveness of educational interventions on menstrual hygiene among adolescent school girls in India. METHODS: PRISMA checklist and PICO guidelines were used to screen the scientific literature from 2011 to 2021. The Newcastle-Ottawa Scale was used to assess the quality of studies. Four themes were developed for data analysis, including hygiene practices, type of absorbent used, menstruation associated morbidities and interventions performed regarding menstruation. Eighty-four relevant studies were included and a meta-analysis, including subgroup analysis, was performed. RESULTS: Pooled data revealed a statistically significant increase in sanitary pad usage "(SMD = 48.83, 95% CI = 41.38-57.62, p < 0.00001)" and increased perineum practices during menstruation "(SMD = 55.77, 95% CI = 44.27-70.26, p < 0.00001)". Results also reported that most prevalent disorders are dysmenorrhea "(SMD = 60.24, 95% CI = 50.41-70.06, p < 0.0001)", Pre-menstrual symptoms "(SMD = 62.67, 95% CI = 46.83-78.50, p < 0.00001)", Oligomenorrhea "(SMD = 23.57, CI = 18.05-29.10, p < 0.00001), Menorrhagia "(SMD = 25.67, CI = 3.86-47.47, p < 0.00001)", PCOS "(SMD = 5.50, CI = 0.60-10.40, p < 0.00001)", and Polymenorrhea "(SMD = 4.90, CI = 1.87-12.81, p < 0.0001)". A statistically significant improvement in knowledge "(SMD = 2.06, 95% CI = 0.75-3.36, p < 0.00001)" and practice "(SMD = 1.26, 95% CI = 0.13-2.65, p < 0.00001)" on menstruation was observed. Infections of the reproductive system and their repercussions can be avoided with better awareness and safe menstruation practices. CONCLUSIONS: Learning about menstrual hygiene and health is essential for adolescent girls' health education to continue working and maintaining hygienic habits. Infections of the reproductive system and their repercussions can be avoided with better awareness and safe menstruation practices.

Menstrual hygiene management (MHM) and practices by adolescent females of low and middle-income countries (LMICs) are severe problems for girls, parents, society, and policymakers. Menstrual-related problems are widespread among adolescent girls in India. Different menstrual abnormalities are found in different populations, suggesting socio-cultural and regional variation. Menstrual abnormalities and disorders are frequently linked to physical, mental, social, psychological, and reproductive issues, affecting adolescents' daily lives and their families lives by various psychosocial problems such as anxiety. We have the intention to compile, summarise, and critically analyse peer-reviewed and published scientific evidence from 2011 to 2021 on menstrual hygiene management methods used, most typical menstrual morbidities and their associated factors among Indian adolescent girls, and to evaluate the evidence for existing interventions like educational programs and absorbent distribution. Program planners and policymakers could use the findings of this study to build relevant initiatives to incorporate safe MHM in the country so that interventions can be designed taking into account the current needs of adolescent girls to reduce menstrual morbidities and improve their quality of life. A statistically significant improvement in knowledge and practice on menstruation was observed. Learning about menstrual hygiene and health is an essential aspect of adolescent girls' health education to continue working and maintaining hygienic habits. Infections of the reproductive system and their repercussions can be avoided with better awareness and safe menstruation practices.

Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer.

Cancer, a fatal disease, is also one of the main causes of death worldwide. Despite various developments to prevent and treat cancer, the side effects of anticancer drugs remain a major concern. Ascorbic acid is an essential vitamin required by our bodies for normal physiological function and also has antioxidant and anticancer activity. Although the body cannot synthesize ascorbic acid, it is abundant in nature through foods and other natural sources and also exists as a nutritional food supplement. In anticancer drug development, ascorbic acid has played an important role by inhibiting the development of cancer through various mechanisms, including scavenging reactive oxygen species (ROS), selectively producing ROS and encouraging their cytotoxicity against tumour cells, preventing glucose metabolism, serving as an epigenetic regulator, and regulating the expression of HIF in tumour cells. Several ascorbic acid analogues have been produced to date for their anticancer and antioxidant activity. The current review summarizes the mechanisms behind ascorbic acid's antitumor activity, presents a compilation of its derivatives and their biological activity as anticancer agents, and discusses delivery systems such as liposomes, nanoparticles against cancer, and patents on ascorbic acid as anticancer agents.

An updated review on the role of the CXCL8-CXCR1/2 axis in the progression and metastasis of breast cancer.

Chronic inflammation is a major factor in tumor growth and progression. Cancer cells secrete C-X-C chemokine ligand 8 (CXCL8) along with its receptor C-X-C chemokine receptor 1 (CXCR1) and chemokine receptor 2 (CXCR2). It plays a significant role in the activation and trafficking of inflammatory mediators, tumor proliferation and interferes in breast cancer development by controlling cell adhesion, proliferation, migration, and metastasis. This axis also plays a significant role in driving different cancers and melanomas, including breast cancer progression, by controlling stem cell masses. Few small-molecule CXCR1/2 inhibitors and CXCL8 releasing inhibitors have been identified in the past two decades that bind these receptors in their inactive forms and blocks their signaling as well as the biological activities associated with inflammation. Inhibitors of certain inflammatory molecules are projected to be more efficient in different inflammatory diseases. Preclinical trials indicate that patients may be benefitted from combined treatment with targeted drugs, chemotherapies, and immunotherapies. Thus, targeting the CXCL8-CXCR1/2 signaling axis in breast cancer could be a promising approach for its therapeutics. This review examines the roles of the CXCL8-CXCR1/2 signaling axis and how it is implicated in the tumor microenvironment in breast cancer. In addition, we also discuss the potential role of the CXCL8-CXCR1/2 axis in targeted therapeutics for breast cancer.

Therapeutic opportunities of edible antiviral plants for COVID-19.

The pandemic of Serious Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) that produces corona virus disease (COVID-19) has challenged the entire mankind by rapidly spreading globally in 210 countries affecting over 25 million people and about 1 million deaths worldwide. It continues to spread, afflicting the health system globally. So far there is no remedy for the ailment and the available antiviral regimens have been unsatisfactory for the clinical outcomes and the mode of treatment has been mainly supportive for the prevention of COVID-19-induced morbidity and mortality. From the time immortal the traditional plant-based ethno-medicines have provided the leads for the treatment of infectious diseases. Phytopharmaceuticals have provided potential and less toxic antiviral drugs as compared to conventional modern therapeutics which are associated with severe toxicities. The ethnopharmacological knowledge about plants has provided food supplements and nutraceuticals as a promise for prevention and treatment of the current pandemic. In this review article, we have attempted to comprehend the information about the edible medicinal plant materials with potential antiviral activity specifically against RNA virus which additionally possess property to improve immunity along with external and internal respiration and exhibit anti-inflammatory properties for the prevention and treatment of the disease. This will open an arena for the development of novel nutraceutical herbal formulations as an alternative therapy that can be used for the prevention and treatment of COVID-19.

Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection.

Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.

Delineating clinical characteristics and comorbidities among 206 COVID-19 deceased patients in India: Emerging significance of renin angiotensin system derangement.

AIM: While there are rampant deaths reported worldwide due to novel corona virus (COVID-19) on one side, hypertension, diabetes and renal failure are emerging comorbidities with mortality risk due to respiratory failure on the other side. The link of these morbidities with renin angiotensin system (RAS) and angiotensin converting enzyme-2 (ACE2) as the site of the multiplication of COVID-19 has widely been accepted. The objective of this research report was to delineate the clinical characteristics with COVID-19 infection with RAS and to consider its significance not just for the search of novel antiviral drugs, but for the management and prevention of death of patients with COVID-19. METHODS: It was a retrospective case series analysis of demographic and clinical data with associated comorbidities of 206 deaths reported in India up to 10th April 2020. The data were available from the official release from Ministry of Health and Family welfare, Government of India. This was followed by a literature search to correlate the available evidence for their possible relationship with RAS. RESULTS: The demographic data were consistent with those reported from other countries. The death (53.4%) was more common in patients with age above 60 years and men (69.3%) were more susceptible as compared to women (30.68%).We found that 50.5% of the deceased patients had pre-existing comorbidities. Diabetes and hypertension were the major comorbidities in 27.8% and 22.1% of the deceased cases respectively. Although respiratory and cardiac problems were prevalent at the time of death, the pre-existing pulmonary disease was comparatively less prevalent. Only 13.6% of the deceased were having pre-existing respiratory problems and 6.2% had cardiac ailments. We could correlate the reports that RAS plays a significant role in the prognosis of the disease. CONCLUSIONS: Patients with cardiovascular diseases, diabetes mellitus and hypertension are at greater risk for developing COVID-19 infection. There may be massive derangement of the entire RAS after the attack of COVID-19 and hence, patients with these pre-existing comorbidities and on ACE inhibitors or angiotensin receptor blockers should be monitored carefully considering the role of RAS in the prognosis of COVID-19 infections.

Synthesis and in vivo diuretic activity of some novel pyrimidine derivatives.

A series of 1,6-dihydropyrimidine-2-amine derivatives and 1,6-dihydropyrimidine-2-thiol derivatives were synthesized by the reaction of substituted 1,3-diphenylprop-2-en-1-one (chalcones) with guanidine hydrochloride and thiourea, respectively. All the synthesized compounds were in good agreement with elemental and spectral data. The synthesized compounds were screened in vivo for diuretic activity. The four compounds 2d, 2e, 3d and 3e, which showed moderate to good diuretic activity, were evaluated for their toxicity studies and none of the compounds showed any toxicity of the liver as compared with control. However, compounds 3e and 3d showed diuretic properties more than that of standard (acetazolamide) and were long acting. Overall, compound 3e, 6-(2,6-dichlorophenyl)-4-(pyridin-2-yl)-1,6-dihydropyrimidine-2-thiol, was found to be the most promising candidate of the series.

Pyrazoline bearing benzimidazoles: search for anticancer agent.

2-acetyl benzimidazole was allowed to react with substituted aromatic aldehydes to get desired intermediate chalcones (2a-g), the cyclocondensation of these intermediates with hydrazine hydrate and phenyl hydrazine in two separate reactions yielded pyrazoline derivatives (3a-g &4a-g respectively). Among the synthesize compounds, six compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, (4f) 2-[5-(3,4-dimethoxyphenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-1H-benzimidazole (NSC 748326) was found to be the most active candidate of the series and selected for further evaluation at five dose level screening.