Mathematical modelling of Alzheimer's disease biomarkers: Targeting Amyloid beta, Tau protein, Apolipoprotein E and Apoptotic pathways.

Introduction: The kinetics of brain cell death in Alzheimer's disease (AD) is being studied using mathematical models. These mathematical models utilize techniques like differential equations, stochastic processes, and network theory to explore crucial signalling pathways and interactions between different cell types. One crucial area of research is the intentional cell death known as apoptosis, which is crucial for the nervous system. The main purpose behind the mathematical modelling of this is for identification of which biomarkers and pathways are most influential in the progression of AD. In addition, we can also predict the natural history of the disease, by which we can make early diagnosis. Mathematical modelling of AD: Current mathematical models include the Apolipoprotein E (APOE) Gene Model, the Tau Protein Kinetics Model, and the Amyloid Beta Peptide Kinetic Model. The Bcl-2 and Bax apoptosis theories postulate that the balance of pro- and anti-apoptotic proteins in cells determines whether a cell experiences apoptosis, where the Bcl-2 model, depicts the interaction of pro- and anti-apoptotic proteins, it is also being used in research on cell death in a range of cell types, including neurons and glial cells. How peptides are produced and eliminated in the brain is explained by the Amyloid beta Peptide (Aß) Kinetics Model. The tau protein kinetics model focuses on production, aggregation, and clearance of tau protein processes, which are hypothesized to be involved in AD. The APOE gene model investigates the connection between the risk of Alzheimer's disease and the APOE gene. These models have been used to predict how Alzheimer's disease would develop and to evaluate how different inhibitors will affect the illness's course. Conclusion: These mathematical models reflect physiological meaningful characteristics and demonstrates robust fits to training data. Incorporating biomarkers like Aß, Tau, APOE and markers of neuronal loss and cognitive impairment can generate sound predictions of biomarker trajectories over time in Alzheimer's disease.

Eco-friendly Approaches to Chromene Derivatives: A Comprehensive Review of Green Synthesis Strategies.

Synthetic routes of chromene are an area of thrust research due to its wide application as pigments, agrochemicals, cosmetics, and an important nucleus scaffold for various pharmaco-logically active drugs. The chromene nucleus is an important moiety for the discovery of new drug candidates owing to its broad range of pharmacological actions like antitumor, anti-inflammatory, antiviral, and many others. However, traditional synthesis techniques frequently use unsafe reagents and produce hazardous waste, presenting environmental issues. The eco-friendly production of chromene derivatives utilizes sustainable raw materials, non-toxic cata-lysts, and gentle reaction conditions to reduce ecological consequences. Innovative methods like microwave irradiation, ultrasound synthesis, the use of environmentally friendly solvents, a cata-lyst-based approach with minimal environmental impact, and mechanochemistry-mediated syn-thesis are implemented. These approaches provide benefits in scalability, cost-effectiveness, and ease of purification. This review compiles and presents various recently reported green synthetic strategies of chromene and its derivatives and gives the reader a clear idea of the detailed and crit-ical aspects of various synthetic protocols described.

Gynostemma pentaphyllum Makino exerts cardioprotective effects by improving hemodynamic, biochemical and histopathological changes through activation of PI3K signalling in isoproterenol-induced myocardial infarction in rats.

OBJECTIVES: To evaluate the cardioprotective effects of Gynostemma pentaphyllum Makino in isoproterenol-induced myocardial infarction in rats and to evaluate the role of phosphatidylinositol 3-kinases (PI3K) in cardioprotection. METHODS: The protective effect of the hydroalcoholic leaf extract of Gynostemma pentaphyllum (LEGP) on the heart was investigated against isoproterenol (ISO)-induced MI in rats. Preliminary phytochemical screening was performed followed by molecular docking. For the in vivo studies Wistar albino rats (Male) were divided among different groups. Different parameters were evaluated such as heart weight index, Electrocardiogram (ECG) analysis, triphenyl tetrazolium chloride assay, cardiac enzyme markers, oxidative stress, antioxidant enzymes, PI3K levels, and histopathology of cardiac tissue. RESULTS: Results showed that LEGP improved the electrocardiogram, reduced infarct size, and decreased the levels of cardiac enzyme markers and oxidative stress, while antioxidant enzymes and PI3K levels were increased. CONCLUSION: LEGP protected the heart against ISO-induced MI in rats by improving hemodynamic, biochemical and histological attributes. These protective effects were produced by the phytoconstituents of the LEGP through modulation of the PI3K signalling pathway.

Outcomes Among Racial and Ethnic Minority Patients With Advanced Cancers in Phase 1 Trials: A Meta-Analysis.

Importance: Patients from racial and ethnic minority groups (eg, Asian, Hispanic, and non-Hispanic Black patients) have low representation in clinical trials, especially in phase 1 trials in cancer. These trials represent valuable options for patients with advanced cancer who experience disease progression with standard therapy. Objective: To determine whether the benefit of enrollment to phase 1 cancer trials extends to Asian, Hispanic, and non-Hispanic Black patients as much as it does for non-Hispanic White patients. Data Sources: Patient records at a single institution from January 1999 to December 2016 were reviewed. Treatment-related responses, toxic effects, and deaths were recorded. Study Selection: All phase 1 studies were included. Data Extraction and Synthesis: Data underwent independent extraction by multiple observers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The primary outcome was overall survival (OS), assessed using univariate and multivariable time-to-event analyses. Results: A total of 738 patients (median [range], 60 [22-93] years; 467 [63.3] female) including 197 Hispanic patients (26.7%), 238 non-Hispanic Black patients (32.2%), and 282 non-Hispanic White patients (38.2%), were enrolled in 64 phase 1 trials, including 33 cytotoxic trials (51.5%), 21 biologic trials (32.8%), and 10 combined therapy trials (15.6%). The primary cancer diagnoses were colorectal (187 patients [25.3%]), ovarian (141 patients [19.1%]), lung (58 patients [7.9%]), uterine (49 patients [6.6%]), and breast (41 patients [5.6%]). Patients underwent a median (range) of 3 (0-13) therapies prior to trial enrollment. Among 558 patients evaluated for response, the clinical benefit rate (ie, stable disease plus response rates) was 49.1%, and the overall response rate was 6.5%. Grade 3 or 4 nonhematological toxic effects were observed in 27.8% (95% CI, 24.6%-31.3%) of patients and grade 3 or 4 hematological toxic effects were observed in 19.7% (95% CI, 17.0%-22.8%) of patients. The treatment-related mortality rate was 0.9% (95% CI, 0.4%-1.9%). Median OS was 9.6 (95% CI, 8.2-11.0) months among Hispanic patients, 8.3 (95% CI, 6.7-10.4) months among non-Hispanic Black patients, and 9.8 (95% CI, 8.5-11.4) months among non-Hispanic White patients (P = .13). In a multivariable analysis, age older than 60 years, Eastern Cooperative Oncology Group performance status score of 2 or greater, more than 2 metastatic sites, lactate dehydrogenase grade 1 or 2, grade 2 or greater low albumin, grade 1 or greater total bilirubin, and grade 2 or greater anemia were associated with worse prognosis, whereas leukocytosis greater than grade 1 was associated with better OS. Conclusions and Relevance: In this meta-analysis assessing outcomes in phase 1 cancer trials among patients from racial and ethnic minority groups, Hispanic and non-Hispanic Black patients had benefits similar to those of non-Hispanic White patients.

Structural Insights of PD-1/PD-L1 Axis: An In silico Approach.

BACKGROUND: Interaction of PD-1 protein (present on immune T-cell) with its ligand PD-L1 (over-expressed on cancerous cell) makes the cancerous cell survive and thrive. The association of PD-1/PD-L1 represents a classical protein-protein interaction (PPI), where receptor and ligand binding through a large flat surface. Blocking the PD-1/PDL-1 complex formation can restore the normal immune mechanism, thereby destroying cancerous cells. However, the PD-1/PDL1 interactions are only partially characterized. OBJECTIVE: We aim to comprehend the time-dependent behavior of PD-1 upon its binding with PD-L1. METHODS: The current work focuses on a molecular dynamics simulation (MDs) simulation study of apo and ligand bound PD-1. RESULTS: Our simulation reveals the flexible nature of the PD-1, both in apo and bound form. Moreover, the current study also differentiates the type of strong and weak interactions which could be targeted to overcome the complex formation. CONCLUSION: The current article could provide a valuable structural insight about the target protein (PD-1) and its ligand (PD-L1) which could open new opportunities in developing small molecule inhibitors (SMIs) targeting either PD-1 or PD-L1.

Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review.

Background and Purpose: The blood-brain barrier (BBB), a critical interface of specialized endothelial cells, plays a pivotal role in regulating molecular and ion transport between the central nervous system (CNS) and systemic circulation. Experimental Approach: This review aims to delve into the intricate architecture and functions of the BBB while addressing challenges associated with delivering therapeutics to the brain. Historical milestones and contemporary insights underscore the BBB's significance in protecting the CNS. Key Results: Innovative approaches for enhanced drug transport include intranasal delivery exploiting olfactory and trigeminal pathways, as well as techniques like temporary BBB opening through chemicals, receptors, or focused ultrasound. These avenues hold the potential to reshape conventional drug delivery paradigms and address the limitations posed by the BBB's selectivity. Conclusion: This review underscores the vital role of the BBB in maintaining CNS health and emphasizes the importance of effective drug delivery through this barrier. Nanoparticles emerge as promising candidates to overcome BBB limitations and potentially revolutionize the treatment of CNS disorders. As research progresses, the application of nanomaterials shows immense potential for advancing neurological therapeutics, albeit with careful consideration of safety aspects.

Decrypting the multifaceted peripheral neuropathy based on molecular pathology and therapeutics: a comprehensive review.

CONTEXT: Peripheral neuropathy (PN) is a multifaceted complication characterized by nerve damage due to oxidative stress, inflammatory mediators, and dysregulated metabolic processes. Early PN manifests as sensory changes that develop progressively in a "stocking and glove" pattern. METHODS AND MECHANISMS: A thorough review of literature has been done to find the molecular pathology, clinical trials that have been conducted to screen the effects of different drugs, current treatments and novel approaches used in PN therapy. Diabetic neuropathy occurs due to altered protein kinase C activity, elevated polyol pathway activity in neurons, and Schwann cells-induced hyperglycemia. Other causes involve chemotherapy exposure, autoimmune ailments, and chronic ethanol intake. CONCLUSION: Symptomatic treatments for neuropathic pain include use of tricyclic antidepressants, anticonvulsants, and acetyl-L-carnitine. Patients will have new hope if clinicians focus on novel therapies including gene therapy, neuromodulation techniques, and cannabidiol as an alternative to traditional medications, as management is still not ideal.

Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

Investigating the Antioxidant Capacity of Newly Synthesized Flavonoids via DPPH Assay.

BACKGROUND: Numerous naturally occurring and artificially synthesized flavonoids have garnered attention for their impressive ability to combat oxidative stress and scavenge free radicals when evaluated in laboratory settings. The core aim of our investigation revolved around assessing the antioxidant potential of a diverse range of synthesized flavonoids through in vitro experiments. METHOD: We crafted 29 distinct flavonoids using the aldol condensation mechanism via a chalcone intermediate to accomplish this. We meticulously characterized these newly formed compounds using a variety of spectroscopic techniques. We employed the widely recognized DPPH free radical method for the crucial antioxidant evaluation, a benchmark in such studies. RESULT: The radical scavenging efficacy of our synthesized flavonoids was then meticulously compared to that of the positive control, ascorbic acid, renowned for its antioxidant prowess, and the IC50 values for each compound were calculated and examined. Surprisingly, our results showed that the flavonoids we tested had a wide range of antioxidant activity, with IC50 values that ranged from 75.8 ± 8.30 to 397 ± 25.10 µg/mL. CONCLUSION: Intriguingly, compounds US5, US13, US16, US17, US18, and US21 outshone even ascorbic acid in their antioxidant potential, displaying remarkable scavenging abilities against free radicals. This discovery holds promise for further exploration of these compounds as potential antioxidants with potential applications in health and wellness.

Emerging green synthetic routes for thiazole and its derivatives: Current perspectives.

This review article provides an overview of the green synthesis of thiazole derivatives, emphasizing sustainable and environmentally friendly methodologies. Thiazole derivatives possess significant value and find diverse applications across various fields. However, conventional synthesis methods often involve hazardous reagents and generate substantial waste, posing environmental concerns. The green synthesis of thiazole derivatives employs renewable starting materials, nontoxic catalysts, and mild reaction conditions to minimize environmental impact. Innovative techniques such as microwave irradiation, ultrasound synthesis, green solvents, a green catalyst-based approach, and mechanochemistry-mediated synthesis are employed, offering advantages in terms of scalability, cost-effectiveness, and purification simplicity. The resulting thiazole derivatives exhibit comparable or enhanced biological activities, showcasing the feasibility and practicality of green synthesis in drug discovery. This review paper underscores the importance of sustainable approaches in functional molecular synthesis and encourages further research in this domain.

Molecular pathology and therapeutics of the diabetic foot ulcer; comprehensive reviews.

Diabetes mellitus (DM) is a chronic metabolic condition linked to high blood sugar levels. Diabetes causes complications like neuropathy, nephropathy, and retinopathy. Diabetes foot ulcer (DFU) is a significant and serious wound healing issue resulting from uncontrolled DM. The main causes of the development of the DFU are oxidative stress brought on by the NO moiety, release of pro-inflammatory cytokines like tumour necrosis factor (TNF)-α and interleukin (IL-1), cellular dysfunction, and pathogenic microorganisms including staphylococcus and streptococcus species. The two main types of wounds that are prevalent in DFU patients are neuropathic and neuroischemic. If this wound is not properly treated or cared for, a lower limb may have to be amputated. There are several therapy options for DFU, including antibiotics, debridement, dressings, nano formulations, and growth factor preparations like PDGF-BB, to help the wound heal and prevent amputation. Other novel approaches involved the use of nerve taps, microneedle patches, nanotechnology-based formulations and stem cell applications to promote healing. There are possibilities of drug repurposing for the DFU treatment based on targeting specific enzymes. This article summarises the current pathophysiological aspects of DFU and its probable future targets.

A Review of the Therapeutic Importance of Indole Scaffold in Drug Discovery.

Indole is known as a versatile heterocyclic building block for its multiple pharmacological activities and has a high probability of success in the race for drug candidates. Many natural products, alkaloids, and bioactive heterocycles contain indole as the active principle pharmacophore. These encourage the researchers to explore it as a lead in the drug development process. The current manuscript will serve as a torchbearer for understanding the structurally diverse class of indole derivatives with extensive pharmacological activity. The current manuscript describes the intermediates and their functional groups responsible for superior biological activity compared to the standard. The review is written to help researchers to choose leads against their target but also to provide crucial insight into the design of a hybrid pharmacophore-based approach in drug design with enhanced potential. The present reviews on the indole derivatives correlate the structures with biological activities as well as essential pharmacophores, which were highlighted. The discussion was explored under challenging targets like dengue, chikungunya (anti-viral), antihypertensive, diuretic, immunomodulator, CNS stimulant, antihyperlipidemic, antiarrhythmic, anti-Alzheimer's, and neuroprotective, along with anticancer, antitubercular, antimicrobial, anti-HIV, antimalarial, anti-inflammatory, antileishmanial, antianthelmintic, and enzyme inhibitors. So, this review includes a discussion of 19 different pharmacological targets for indole derivatives that could be utilized to derive extensive information needed for ligand-based drug design. The article will guide the researchers in the selection, design of lead and pharmacophore, and ligand-based drug design using indole moiety.

Atorvastatin's Reduction of Alzheimer's Disease and Possible Alteration of Cognitive Function in Midlife as well as its Treatment.

Over the past 20 years, advances in the field of pathogenesis have inspired researchers to look into novel pharmacological therapeutics that are more focused on the pathophysiological events of the disease (AD). This review article discussed the prior use of statins for the prevention of Alzheimer's disease, which can help prevent the disease. Other drugs, such as memantine and donepezil, are available, but they cannot prevent the onset of AD in middle age. Based on available clinical data, the valuable effects of statins are mediated by alteration of ß-amyloid (Aß) and tau metabolism, genetic and lifestyle risk factors, along with other clinical aspects of AD. These findings suggested that using statins in middle age may help to prevent Alzheimer's disease by modifying genetic and non-genetic risk factors in later stages of life. In the present review, we elaborated upon the modification of risk factors and amyloid metabolism in the development and progression of AD and their modulation through atorvastatin. Future directions in the research and treatment of Alzheimer's disease patients include the use of antisense oligonucleotides (ASO) to change target expression, and researchers discovered decreased markers of oxidative stress in tissues affected by tau pathology in response to RNA interference treatment.

Xenobots: Applications in Drug Discovery.

This review work discusses the applications of xenobots in drug discovery. These are the world's first tiny robots that are living. Robots are built of metals and other things that benefit humans to solve various issues; however, in this case, small xenobots were built utilizing Xenopus laevis, frog embryonic stem cells in the blastocyte stage. Xenobots were created by combining bioscience, artificial intelligence, and computer science. Artificial intelligence constructs several forms of design in an in vitro, In-silico model, after which software analyzes the structure; the most substantial and most noticeable forms are filtered out. Later in vivo development create the design of the Petri plate using the MMR solution and makes the same form as the in silico approach. Ultimately evaluation done based on the behavior, movement, function, and features of xenobots. Xenobots are employed in medical research, pharmaceutical research to evaluate novel dosage forms, also useful for biotechnological and environmental research. Xenobots can be utilized to cure neurodegenerative disorders such as Alzheimer's, Parkinson's disease, and cancer-related issues because of their selfrepairing properties, which allow them to repair normal damaged cells, and convey drugs to their specific target, and reduce cytotoxicity in mostly malignancy circumstances. In the future, new approaches will be employed to treat chronic illnesses and their complications.

Probiotic Formulations: A Patent Landscaping Using the Text Mining Approach.

The outstanding research outcomes and registrations of myriads of probiotic strains have flooded the health market with various innovative probiotic-based products and their patents. The study of patented formulations of probiotics can give an overall insight into its existing application. A landscaping review of patents for probiotic-based preparations is presented in the current work. The patent search was performed over commercially available patent databased and analysis tool-PatSeer Pro®. Search strings containing words "Formulation" and "Composition" resulted in more than 3700 patents. Landscaping review of 400 + patents from the last 20 years (2000-2020) was performed using the Text-Mining approach. Text-Mining helped to identify 19 technological clusters which represent these patents. These clusters include the patents of probiotic preparations on animal feed, human food, cosmetics, antimicrobial, antidiabetic, arthritis, etc. A review of this massive number of patents unveiled many exciting preparations. Probiotic-based innovative products for depression, diabetes, Parkinson's, tumor, acne, and animal husbandry are reviewed comprehensively. The present work also unravels a few new-flanged products like probiotic layered condoms, products for acute alcoholism, and traditional Chinese medicine with probiotics. The patent landscape of probiotic-based preparations has presented a whole scenario of probiotic-based preparations. It has also revealed many unexplored areas where innovation can be excelled.

Pharmacological Study of A3 Adenosine Receptor agonist (AB Meca) in Xenograft Lung Cancer Model in Mice through In Silico and In Vivo Approach: Targeting TNF-α.

BACKGROUND: Lung cancer is the leading cause of mortality in India. Adenosine Receptor (AR) has emerged as a novel cancer-specific target. A3AR levels are upregulated in various tumor cells, which may mean that the specific AR may act as a biological marker and target specific ligands leading to cell growth inhibition. AIM: Our aim was to study the efficacy of the adenosine receptor agonist, AB MECA, by in silico (molecular docking) and in vitro (human cancer cells in xenografted mice) studies. METHODS: Molecular docking on the AB-meca and TNF-α was performed using AutoDock. A549 Human lung cancer 2 ×106 cells per microliter per mouse injected via intrabronchial route. Rat TNF-α level was assessed by ELISA method. RESULTS: AB Meca's predicted binding energy (beng) with TNF-α was 97.13 kcal/mol, and the compatible docking result of a small molecular inhibitor with TNF-α native ligand beng was 85.76 kcal/mol. In vivo, a single dose of lung cancer cell A549 is being researched to potentiate tumor development. Doxorubicin and A3AR agonist therapies have lowered TNF-alpha levels that were associated with in silico function. The A3AR Agonist showed myeloprotective effects in the groups treated along with doxorubicin. CONCLUSION: AB MECA's higher binding energy (beng) with TNF-α mediated reduction of tumor growth in our lung cancer in vivo model suggested that it may be an effective therapy for lung cancer.

In Vitro Cytotoxicity and Aromatase Inhibitory Activity of Flavonoids: Synthesis, Molecular Docking and In silico ADME Prediction.

BACKGROUND: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. OBJECTIVE: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. METHODS: 39 Flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In silico ADME properties were checked by QikProp software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. RESULTS: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 µM, 1.636 µM, 16.08 µM, 22.02 µM, 15.75 µM, 0.345 µM and 16.08 µM, respectively, compared with the reference drug letrozole. The in vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 µM and 0.36 µM, respectively. CONCLUSION: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 µM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

Development of Natural Bioactive Alkaloids: Anticancer Perspective.

Cancer is a frightful disease that still poses a 'nightmare' worldwide, causing millions of casualties annually imposing one of the human race's greatest health-care challenges that entail a pragmatic treatment strategy. Plants are repositories for new chemical entities and have a promising cancer research path, supplying 60% of the anticancer agents currently used. However, plants and plant-derived products revolutionize the field, as they are quick, cleaner, eco-friendly, low-cost, effective, and less toxic than conventional treatment methods. Alkaloids are important chemical compounds that serve as a rich reservoir for drug discovery and development. However, some alkaloids derived from natural herbs display anti-proliferation and antimetastatic activity on different forms of cancer both in vitro and in vivo. Alkaloids have also been widely formulated as anticancer medications, such as camptothecin and vinblastine. Based on the information in the literature, this review focuses on the naturally-derived bioactive alkaloids with prospective anticancer properties. Still, more research and clinical trials are required before final recommendations can be made on specific alkaloids.

Role of Natural and Synthetic Flavonoids as Potential Aromatase Inhibitors in Breast Cancer: Structure-Activity Relationship Perspective.

World Health Organization categorized breast cancer as one of the leading cancer types in females worldwide, and its treatment remains challenging. Accumulated evidence suggested the role of estrogen and its metabolites in pre- and post-menopausal women. Upregulation of estrogen-dependent aromatase is significantly involved in the pathogenesis of breast cancer. Several aromatase inhibitors, such as exemestane, formestane, and letrozole, are being used clinically, owing to their estrogen suppression role. Apart from these drugs, several other molecules, such as natural and synthetic flavonoids, have been reported widely for a similar biological activity. However, some reasonable modifications are required for these structures to achieve desired efficacy and to alleviate toxicity. Designing a novel aromatase inhibitor will be possible if we can establish a rational correlation between the chemistry and biological features of the existing molecules. The benzopyranone- ring system, present in the flavonoid molecules, has been reported as a pharmacophore due to its inhibitory activity on aromatase, which helps repress breast cancer progression. This essential feature has been utilized to modify several natural flavonoids into 5 and 7 hydroxy/methoxy flavone, 4-imidazolyl/triazolyl flavone, 5,4'- diamino flavone, 7,8- benzo-4-imidazolyl flavone, α-naphthoflavone, and 2-azole/thiazolyl isoflavone derivatives. These scaffolds have been considered in this review for meticulous study in aspects of the structure-activity relationship for aromatase inhibitory activity, and it would likely pave the way for designing a potential lead candidate in the future.

Predictors of clinically relevant differences between noninvasive versus arterial blood pressure.

OBJECTIVE: Blood pressure (BP) measurements are important for managing patients with hypertensive emergencies (HE). Previous studies showed that there was significant difference between IABP and NIBP but no information whether these differences changed management. Our study investigated the factors associated with the differences affecting BP management of patients with HE. METHODS: This was a retrospective study involving adult patients admitted to a resuscitation unit. We screened all patients who received IABP upon admission between 06/01/2017 and 12/31/2017 as sample size calculation recommended 64 patients. Primary outcome was the clinical relevance of the difference of IABP vs. NIBP, which was defined as having both: a) difference of 10 mm of mercury (mmHg), and b) resulting in possible change of blood pressure managements according to treatment guidelines. We performed backward stepwise multivariable logistic regression to measure associations. RESULTS: We analyzed 147 patients whose mean age was 69 (±16) years and included 69 (47%) patients with spontaneous intracerebral hemorrhage (sICH). Mean difference between IABP and NIBP was 21 (±16) mmHg while 41 (28%) patients who had difference affecting managements. In multivariable regression, sICH (Odd Ratios 13.5, 95%CI 2.3-79.5, p-value < 0.001) was significantly associated with clinically relevant difference between the two modalities of BP monitoring. CONCLUSIONS: There was a large difference between IABP and NIBP among patients with hypertensive emergencies. Up to 30% of patients had clinically relevant differences. Patients with sICH were more likely to have differences affecting BP management. Further studies are needed to confirm our observation.