Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions.

"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.

ITF2357 regulates NF-κB signaling pathway to protect barrier integrity in retinal pigment epithelial cells.

The robust integrity of the retinal pigment epithelium (RPE), which contributes to the outer brain retina barrier (oBRB), is compromised in several retinal degenerative and vascular disorders, including diabetic macular edema (DME). This study evaluates the role of a new generation of histone deacetylase inhibitor (HDACi), ITF2357, in regulating outer blood-retinal barrier function and investigates the underlying mechanism of action in inhibiting TNFα-induced damage to RPE integrity. Using the immortalized RPE cell line (ARPE-19), ITF2357 was found to be non-toxic between 50 nM and 5 µM concentrations. When applied as a pre-treatment in conjunction with an inflammatory cytokine, TNFα, the HDACi was safe and effective in preventing epithelial permeability by fortifying tight junction (ZO-1, -2, -3, occludin, claudin-1, -2, -3, -5, -19) and adherens junction (E-cadherin, Nectin-1) protein expression post-TNFα stress. Mechanistically, ITF2357 depicted a late action at 24 h via attenuating IKK, IκBα, and p65 phosphorylation and ameliorated the expression of IL-1ß, IL-6, and MCP-1. Also, ITF2357 delayed IκBα synthesis and turnover. The use of Bay 11-7082 and MG132 further uncovered a possible role for ITF2357 in non-canonical NF-κB activation. Overall, this study revealed the protection effects of ITF2357 by regulating the turnover of tight and adherens junction proteins and modulating NF-κB signaling pathway in the presence of an inflammatory stressor, making it a potential therapeutic application for retinal vascular diseases such as DME with compromised outer blood-retinal barrier.

Pathophysiology, diagnosis, and herbal medicine-based therapeutic implication of rheumatoid arthritis: an overview.

Rheumatoid arthritis (RA) stands as an autoimmune disorder characterized by chronic joint inflammation, resulting in profound physiological alterations within the body. Affecting approximately 0.4-1.3% of the global population, this condition poses significant challenges as current therapeutic approaches primarily offer symptomatic relief, with the prospect of complete recovery remaining elusive. This review delves into the contemporary advancements in understanding the pathophysiology, diagnosis, and the therapeutic potential of herbal medicine in managing RA. Notably, early diagnosis during the initial stages emerges as the pivotal determinant for successful recovery post-treatment. Utilizing tools such as Magnetic Resonance Imaging (MRI), anti-citrullinated peptide antibody markers, and radiography proves crucial in pinpointing the diagnosis of RA with precision. Unveiling the intricate pathophysiological mechanisms of RA has paved the way for innovative therapeutic interventions, incorporating plant extracts and isolated phytoconstituents. In the realm of pharmacological therapy for RA, specific disease-modifying antirheumatic drugs have showcased commendable efficacy. However, this conventional approach is not without its drawbacks, as it is often associated with various side effects. The integration of methodological strategies, encompassing both pharmacological and plant-based herbal therapies, presents a promising avenue for achieving substantive recovery. This integrated approach not only addresses the symptoms but also strives to tackle the underlying causes of RA, fostering a more comprehensive and sustainable path towards healing.

Targeting Peroxisome Proliferator-Activated Receptor-ß/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy.

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-ß/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-ß/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-ß/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-ß/δ.

Understanding CFTR Functionality: A Comprehensive Review of Tests and Modulator Therapy in Cystic Fibrosis.

Cystic fibrosis is a genetic disorder inherited in an autosomal recessive manner. It is caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7, which leads to abnormal regulation of chloride and bicarbonate ions in cells that line organs like the lungs and pancreas. The CFTR protein plays a crucial role in regulating chloride ion flow, and its absence or malfunction causes the production of thick mucus that affects several organs. There are more than 2000 identified mutations that are classified into seven categories based on their dysfunction mechanisms. In this article, we have conducted a thorough examination and consolidation of the diverse array of tests essential for the quantification of CFTR functionality. Furthermore, we have engaged in a comprehensive discourse regarding the recent advancements in CFTR modulator therapy, a pivotal approach utilized for the management of cystic fibrosis, alongside its concomitant relevance in evaluating CFTR functionality.

Investigating the effect of wall material and pressure homogenisation on encapsulation parameters and thermal stability in chia seed oil microcapsules.

AIM: To evaluate the effect of different wall material (WM) matrices followed by homogenisation to encapsulate chia seed oil (CSO) using freeze drying technology. METHODS: CSO was encapsulated using three ratios (100/0, 50/50, and 100/0) of two WM matrices: MTS/WPC (modified tapioca starch-whey protein concentrate) and MD/WPC (maltodextrin-whey protein concentrate). The evaluation included encapsulation efficiency (EE), oxidative stability, and α-linolenic acid (ALA) retention. Homogenised microcapsules (-H) were then assessed for storage and thermal stability, along with cumulative oil release. RESULTS: The MD-WPC-H 50/50 microcapsules had superior EE (97.32%), higher ALA retention (60.2%), storage stability (up to 30 days), higher thermal stability (up to 700 °C), and desirable oil release in simulated condition. CONCLUSION: Selecting suitable WM and homogenisation is key for improving EE, storage, thermal stability, and targeted release. The CSO microcapsule can serve as a functional ingredient to improve the quality of diverse food products.

Artificial viruses: A nanotechnology based approach.

OBJECTIVES: The main objective of this work was to review and summarise the detailed literature available on viral nanoparticle and the strategies utilised for their manufacture along with their applications as therapeutic agents. DATA ACQUISITION: The reported literature related to development and application of virus nanoparticles have been collected from electronic data bases like ScienceDirect, google scholar, PubMed by using key words like "viral nanoparticles", "targeted drug delivery" and "vaccines" and related combinations. RESULT: From the detailed literature survey, virus nanoparticles were identified as carriers for the targeted delivery. Due to the presence of nanostructures in virus nanoparticles, these protect the drugs from the degradation in the gastrointestinal tract and in case of the delivery of gene medicine, they carry the nucleic acids to the target/susceptible host cells. Thus, artificial viruses are utilised for targeted delivery to specific organ in biomedical and biotechnological areas. CONCLUSION: Thus, virus nanoparticles can be considered as viable option as drug/gene carrier in various healthcare sectors especially drug delivery and vaccine and can be explored further in future for the development of better drug delivery techniques.

Remote Assessment of ADHD Symptoms Based on Mobile Game Performance in Children with ADHD: A Proof of Concept.

The use of game-based digital medicine is gaining increasing interest in helping children with ADHD to improve their attention outside the clinical setting. In this process, it is important to continue monitoring children's responses to the use of digital medicine. In this work, we introduce novel digital markers and an analytic pipeline to estimate ADHD-related symptomatic levels during the self-administration of attention games. The digital markers, capturing the children's characteristics of attention and inattention spans, were extracted and translated into clinically-accepted measures of ADHD symptoms, specifically the ADHD-Rating Scale (ADHD-RS) and Child Behavior Checklist (CBCL). To validate the feasibility of our approach, we collected game-specific performance data from 15 children with ADHD, which was used to train machine learning-based regression models to estimate their corresponding ADHD-RS and CBCL scores. Our experiment results showed mean absolute errors of 5.14 and 4.05 points between the actual and estimated ADHD-RS and CBCL scores respectively. This study enables new clinical and research opportunities for accurate longitudinal assessment of symptomatic levels of ADHD via an interactive means of playing mobile games.

Thiazolidinedione as a Promising Medicinal Scaffold for the Treatment of Type 2 Diabetes.

BACKGROUND: Thiazolidinediones, also known as glitazones, are considered as biologically active scaffold and a well-established class of anti-diabetic agents for the treatment of type 2 diabetes mellitus. Thiazolidinediones act by reducing insulin resistance through elevated peripheral glucose disposal and glucose production. These molecules activate peroxisome proliferated activated receptor (PPARγ), one of the sub-types of PPARs, and a diverse group of its hybrid have also shown numerous therapeutic activities along with antidiabetic activity. OBJECTIVE: The objective of this review was to collect and summarize the research related to the medicinal potential, structure-activity relationship and safety aspects of thiazolidinedione analogues designed and investigated in type 2 diabetes during the last two decades. METHODS: The mentioned objective was achieved by collecting and reviewing the research manuscripts, review articles, and patents from PubMed, Science Direct, Embase, google scholar and journals related to the topic from different publishers like Wiley, Springer, Elsevier, Taylor and Francis, Indian and International government patent sites etc. Results: The thiazolidinedione scaffold has been a focus of research in the design and synthesis of novel derivatives for the management of type 2 diabetes, specifically in the case of insulin resistance. The complications like fluid retention, idiosyncratic hepatotoxicity, weight gain and congestive heart failure in the case of trosiglitazone, and pioglitazone have restricted their use. The newer analogues have been synthesized by different research groups to attain better efficacy and less side effects. CONCLUSION: Thus, the potential of thiazolidinediones in terms of their chemical evolution, action on nuclear receptors, aldose reductase and free fatty acid receptor 1 is well established. The newer TZD analogues with better safety profiles and tolerability will soon be available in the market for common use without further delay.

Development and characterization of rice bran-gum Arabic based encapsulated biofertilizer for enhanced shelf life and controlled bacterial release.

Introduction: Currently, microbe-based approaches are being tested to address nutrient deficiencies and enhance nutrient use efficiency in crops. However, these bioinoculants have been unsuccessful at the commercial level due to differences in field and in-vivo conditions. Thus, to enhance bacterial stability, microbial formulations are considered, which will provide an appropriate microenvironment and protection to the bacteria ensuring better rhizospheric-colonization. Methods: The present study aimed to develop a phosphobacterium-based encapsulated biofertilizer using the ion-chelation method, wherein a bacterial strain, Myroid gitamensis was mixed with a composite solution containing rice bran (RB), gum Arabic (GA), tricalcium phosphate, and alginate to develop low-cost and slow-release microbeads. The developed microbead was studied for encapsulation efficiency, shape, size, external morphology, shelf-life, soil release behavior, and biodegradability and characterized using SEM, FTIR, and XRD. Further, the wheat growth-promoting potential of microbeads was studied. Results: The developed microbeads showed an encapsulation efficiency of 94.11%. The air-dried beads stored at 4°C were favorable for bacterial survival for upto 6 months. Microbeads showed 99.75% degradation within 110 days of incubation showing the bio-sustainable nature of the beads. The application of dried formulations to the pot-grown wheat seedlings resulted in a higher germination rate, shoot length, root length, fresh weight, dry weight of the seedlings, and higher potassium and phosphorus uptake in wheat. Discussion: This study, for the first time, provides evidence that compared to liquid biofertilizers, the RB-GA encapsulated bacteria have better potential of enhancing wheat growth and can be foreseen as a future fertilizer option for wheat.

Black garlic particles as a natural pigment and emulsifier in a Pickering emulsion based low fat innovative mayonnaise: Improved rheology and bioactivity.

Black garlic is rich in brown pigments and Maillard reaction products are known for antioxidant activity and health promoting effects. In the present investigation, we report a facile strategy for fabricating low-fat innovative mayonnaise (IM) using black garlic particles (BGP) as a natural pigment, and a functional ingredient. Whey protein concentrate and high methoxyl pectin at optimized concentrations were utilized for fabricating an IM which served as a control. IM5 and IM10 were ternary composites constituting whey protein, high methoxyl pectin along with BGP (@5 and 10% respectively). The formulation IM10 (BGP @10%) showed high firmness and low spreadability quotient, hence IM5 was taken forward for fabrication for two more variants namely IM-J (using low methoxyl pectin (LMP) from jackfruit peels) and IM-C (LMP from citrus). The effect of BGP and LMP on the functional quality of IM was confirmed through zeta potential, antioxidant activity, textural, rheological, and microscopic evaluation. Fluorescence microscopy confirmed the presence of solid particles over the fat phase of IM, while interaction of pectin and whey proteins was demonstrated through fluorescence emission spectroscopy which clearly displayed stabilization of IM through the formation of Pickering emulsion. Pronounced difference in color and flavor score with BGP established high sensory scores in IM5, IM-J, and IM-C. Rheology supported the stabilizing effects of LMP in IM-J and IM-C in terms of speedy recovery of thixotropy, with recovering storage modulus (G'). Enhanced viscosity of IM-C and IM-J further corroborated the dual effect of LMP and BGP in improving emulsifying and functional quality of IM. Enhanced oxidative stability of IM was established by reduced peroxide and Totox values. Overall our results suggest the promising applications of black garlic as functional ingredient in protein and pectin based Pickering emulsions.

Unleashing the bioactive potential of Capsicum chinense cv Bhut Jolokia: a comparison of microwave- and ultrasound-mediated extraction techniques for lipophilic capsaicin.

This study investigated the extraction of capsaicin from Capsicum chinense cv Bhut Jolokia using rice bran oil (RBO) as a 'green solvent' via microwave- and ultrasound-mediated techniques (MME and UME) as an alternative to hazardous organic solvents. Extraction conditions were optimised using MME at 180 and 300 W for 2 and 8 min and UME at 300 and 400 W for 10 and 30 min. The maximum capsaicin yield obtained was 12.47 mg/mL, with a corresponding gamma oryzanol content of 8.46 mg/mL. The peroxide value of the extract (capsaicin-infused RBO) was found to be within permissible limits as per Codex Alimentarius specifications. Results strongly suggest the potential of RBO as a novel solvent for extraction of capsaicin. The capsaicin-enriched oil can be used as a functional food ingredient due to its health-promoting properties.

Prudent tactics to sail the boat of PARP inhibitors as therapeutics for diverse malignancies.

INTRODUCTION: PARP inhibitors block the DNA-repairing mechanism of PARP and represent a promising class of anti-cancer therapy. The last decade has witnessed FDA approvals of several PARP inhibitors, with some undergoing advanced-stage clinical investigation. Medicinal chemists have invested much effort to expand the structure pool of PARP inhibitors. Issues associated with the use of PARP inhibitors that make their standing disconcerting in the pharmaceutical sector have been addressed via the design of new structural assemblages. AREA COVERED: In this review, the authors present a detailed account of the medicinal chemistry campaigns conducted in the recent past for the construction of PARP1/PARP2 inhibitors, PARP1 biased inhibitors, and PARP targeting bifunctional inhibitors as well as PARP targeting degraders (PROTACs). Limitations associated with FDA-approved PARP inhibitors and strategies to outwit the limitations are also discussed. EXPERT OPINION: The PARP inhibitory field has been rejuvenated with numerous tractable entries in the last decade. With numerous magic bullets in hand coupled with unfolded tactics to outwit the notoriety of cancer cells developing resistance toward PARP inhibitors, the dominance of PARP inhibitors as a sagacious option of targeted therapy is highly likely to be witnessed soon.

Nivalenol Mycotoxin Concerns in Foods: An Overview on Occurrence, Impact on Human and Animal Health and Its Detection and Management Strategies.

Mycotoxins are secondary metabolites produced by fungi that infect a wide range of foods worldwide. Nivalenol (NIV), a type B trichothecene produced by numerous Fusarium species, has the ability to infect a variety of foods both in the field and during post-harvest handling and management. NIV is frequently found in cereal and cereal-based goods, and its strong cytotoxicity poses major concerns for both human and animal health. To address these issues, this review briefly overviews the sources, occurrence, chemistry and biosynthesis of NIV. Additionally, a brief overview of several sophisticated detection and management techniques is included, along with the implications of processing and environmental factors on the formation of NIV. This review's main goal is to offer trustworthy and current information on NIV as a mycotoxin concern in foods, with potential mitigation measures to assure food safety and security.

Interrogation of superior vena cava by deep transgastric transesophageal echocardiography imaging: Clinical applications.

The advantages of intraoperative deep transgastric interrogation by transesophageal echocardiography (TEE) of the superior vena cava (SVC) in comparison to the standard bicaval view was studied in pediatric cardiac surgical cases. The view was found to be helpful in obtaining additional data in pediatric cardiac surgical patients.

A Targeted Metabolomics Approach to Study Secondary Metabolites and Antioxidant Activity in 'Kinnow Mandarin' during Advanced Fruit Maturity.

In this study, we investigated the impact of harvest maturity stages and contrasting growing climates on secondary metabolites in Kinnow mandarin. Fruit samples were harvested at six harvest maturity stages (M1−M6) from two distinct growing locations falling under subtropical−arid (STA) and subtropical−humid (STH) climates. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique was employed to identify and quantify secondary metabolites in the fruit juice. A total of 31 polyphenolics and 4 limonoids, with significant differences (p < 0.05) in their concentration, were determined. With advancing maturity, phenolic acids and antioxidant activity were found to increase, whereas flavonoids and limonoids decreased in concentration. There was a transient increase in the concentration of some polyphenolics such as hesperidin, naringin, narirutin, naringenin, neoeriocitrin, rutin, nobiletin and tangeretin, and limonoid aglycones such as limonin and nomilin at mid-maturity stage (M3) which coincided with prevailing low temperature and frost events at growing locations. A higher concentration of limonin and polyphenolics was observed for fruit grown under STH climates in comparison to those grown under STA climates. The data indicate that fruit metabolism during advanced stages of maturation under distinct climatic conditions is fundamental to the flavor, nutrition and processing quality of Kinnow mandarin. This information can help in understanding the optimum maturity stage and preferable climate to source fruits with maximum functional compounds, less bitterness and high consumer acceptability.

Coral red beads and arthritis.

We report a patient presenting with cutaneous papulonodular lesions associated with painful stiff joints. Histopathological examination showed positivity for CD68 and CD45. There was no atypia.