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.

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.

Cutaneous Pharmacokinetics of Topically Applied Novel Dermatological Formulations.

Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.

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.

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. METHOD: 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.

Innovative Fusion of Probiotics and Mouth Fresheners: Investigating Unaltered Growth, Microscopic Analysis, and Mucoadhesive Strength.

Since ancient times, mouth fresheners in many different forms have been used throughout the world. Traditional knowledge describes the health benefits of mouth fresheners, and contemporary science is now investigating their benefits. Claims have been made that mouth fresheners not only improve digestion but also promote oral health. Similar, but in a more profound sense, probiotics offer astounding advantages in treating many disorders. In certain cases, probiotics also offer prophylactic effects. Numerous benefits for dental health are being studied for B. coagulans (MB-BCM9) and B. subtilis (MB-BSM12). In this current study, a probiotic and a mouth freshener were combined to ameliorate the impacts of both. The oral residence of probiotics was enhanced by employing mucoadhesive polymers. Numerous compositions were developed and evaluated for the unaltered growth of probiotics, along with other evaluations like microscopy, in vitro mucoadhesive strength, and stability studies. Xanthan gum and hydroxypropyl methylcellulose were used in the development of mucoadhesive probiotic powder by employing the lyophilization technique. More than five hours of residence time were observed in the in vitro study with goat oral mucosa. The enumeration study validated the label claims of MB-BCM9 and MB-BSM12. It also concluded that none of the components of the formulation had a detrimental effect on probiotics. In essence, the present work discloses the novel and stable formulation of a probiotic-based mouth freshener.

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.

DE-INTERACT: A machine-learning-based predictive tool for the drug-excipient interaction study during product development-Validation through paracetamol and vanillin as a case study.

The compatibility of drugs with excipients plays a crucial role in the prospective stability of pharmaceutical formulations. Apart from real-time stability studies, conventional analytical tools like DSC, FTIR, NMR, and chromatography help identify the possibilities of drug-excipient interactions. Machine learning can assist in developing a predictive tool for drug-excipient incompatibility. In the present work, PubChem Fingerprint is employed as the descriptor of compounds that thoroughly represents the drug's and excipient's chemistry. The 881-bit binary fingerprints of each drug and excipient make 1762 inputs, and one categorical output makes an instance in the dataset. A dataset of more than 3500 instances of drugs and excipients is carefully selected from peer-reviewed research papers. Rigorous training of the Artificial Neural Network (ANN) model was performed with maximum validation accuracy, minimum validation loss, and maximum validation precision as the checkpoints. The machine learning model (DE-Interact) was trained, achieving training and validation accuracies of 0.9930 and 0.9161, respectively. The performance of the DE-Interact model was evaluated by confirming three incompatible predictions by conventional analytical tools. Paracetamol with vanillin, paracetamol with methylparaben, and brinzolamide with polyethyleneglycol are these instances which are predicted as incompatible by the DE-Interact. DSC, FTIR, HPTLC, and HPLC analysis confirm the prediction. The present work offers a reliable DE-Interact tool for quick referencing while selecting excipients in formulation design.

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.

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.

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.

Review and Analysis of Massively Registered Clinical Trials of COVID-19 using the Text Mining Approach.

OBJECTIVE: Immediately after the outbreak of nCoV, many clinical trials are registered for COVID-19. The numbers of registrations are now raising inordinately. It is challenging to understand which research areas are explored in this massive pool of clinical studies. If such information can be compiled, then it is easy to explore new research studies for possible contributions in COVID-19 research. METHODS: In the present work, a text-mining technique of artificial intelligence is utilized to map the research domains explored through the clinical trials of COVID-19. With the help of the open-- source and graphical user interface-based tool, 3007 clinical trials are analyzed here. The dataset is acquired from the international clinical trial registry platform of WHO. With the help of hierarchical cluster analysis, the clinical trials were grouped according to their common research studies. These clusters are analyzed manually using their word clouds for understanding the scientific area of a particular cluster. The scientific fields of clinical studies are comprehensively reviewed and discussed based on this analysis. RESULTS: More than three-thousand clinical trials are grouped in 212 clusters by hierarchical cluster analysis. Manual intervention of these clusters using their individual word-cloud helped to identify various scientific areas which are explored in COVID19 related clinical studies. CONCLUSION: The text-mining is an easy and fastest way to explore many registered clinical trials. In our study, thirteen major clusters or research areas were identified in which the majority of clinical trials were registered. Many other uncategorized clinical studies were also identified as "miscellaneous studies". The clinical trials within the individual cluster were studied, and their research purposes are compiled comprehensively in the present work.

A Review and Analysis on Recent Advancements in Bubble Electrospinning Technology for Nanofiber Production.

BACKGROUND: Multiple applications of nanofiber in various segments of science and technology have sparked the interest of innovators to explore the innovative approaches for nanofiber production. The bubble electrospinning technique is the most versatile and simplest approach to scale up the production of nanofiber at the industrial level. Numerous patent applications have been filed with innovations and advancements in the field of bubble electrospinning technique. METHODS: In present work, different patent applications in the field of bubble electrospinning technique, which represents the advancement in bubble electrospinning technology, are searched and analyzed using various paid and free patent databases. The patent search results are compiled, analyzed and individual innovations are studied in detail to bring all the advancements hitherto in the bubble electrospinning technology under the purview of one review article. RESULTS: The "bubble ws3 electrospin" syntax in the structured search (TAC) facility of the patseer® has revealed most relevant patents on advancement in bubble electrospinning. After applying the family patent filter to the search result (33 patents), ten patents are selected for detailed study. The gist of the invention from each of the patent application or granted patent is recapitulated in this paper, along with their mosaics. CONCLUSION: Definite number of inventions are available in the field of bubble electrospinning technique. Inventions, which are disclosed, might have their pros and cons with respect to ease of acceptance by the industrial fraternity for large-scale production depending upon simplicity or complexity of the instrument. There is a profound scope of innovation in the bubble electrospinning technology in the areas like bubble stabilization, size and production rate control and much more.