Overview of multifunctional Tregs in cardiovascular disease: From insights into cellular functions to clinical implications.

Regulatory T cells (Tregs) are crucial in regulating T-cell-mediated immune responses. Numerous studies have shown that dysfunction or decreased numbers of Tregs may be involved in inflammatory cardiovascular diseases (CVDs) such as atherosclerosis, hypertension, myocardial infarction, myocarditis, cardiomyopathy, valvular heart diseases, heart failure, and abdominal aortic aneurysm. Tregs can help to ameliorate CVDs by suppressing excessive inflammation through various mechanisms, including inhibition of T cells and B cells, inhibition of macrophage-induced inflammation, inhibition of dendritic cells and foam cell formation, and induction of anti-inflammatory macrophages. Enhancing or restoring the immunosuppressive activity of Tregs may thus serve as a fundamental immunotherapy to treat hypertension and CVDs. However, the precise molecular mechanisms underlying the Tregs-induced protection against hypertension and CVDs remain to be investigated. This review focuses on recent advances in our understanding of Tregs subsets and function in CVDs. In addition, we discuss promising strategies for using Tregs through various pharmacological approaches to treat hypertension and CVDs.

Vapor and Light Responsive Biocompatible Soft Actuator.

Bioinspired smart polymeric materials that undergo three-dimensional shape deformation in response to specific stimuli have gained significant attention in the field of soft robotics and intelligent devices. Despite the substantial advancements in soft robotics, there is a growing demand for the design of multistimuli-responsive soft actuators using a single layer of material due to its reduced complexity and ease of manufacturing and durability. Here, we report the actuation characteristics of a single-layer, dual-responsive soft actuator that overcomes the commonly encountered delamination issues often associated with bilayer systems by incorporating PEDOT:PSS with cassava starch. This soft actuator exhibits deformations in response to various solvent vapors, such as water, alcohol, and acetone. Remarkably, it demonstrates opposite deformations upon exposure to water and alcohol vapors. Additionally, the actuator responds to light triggers and folds upon exposure to sunlight and infrared light. The degree of folding can be precisely controlled by adjusting the intensity of the light source. Furthermore, the periodic geometric patterns imposed on the surface of the actuator provide an additional handle to control the bending axis. For proof of concept, we leverage the actuation capabilities of our actuator to showcase a range of potential applications, including its usage in wearable textiles, crawler robots, smart curtains, push-and-pull machines, and smart lifts.

Responsive soft actuator: harnessing multi-vapor, light, and magnetic field stimuli.

Bioinspired soft actuators, capable of undergoing shape deformation in response to external triggers, hold great potential in fields such as soft robotics, artificial muscles, drug delivery, and smart switches. However, their widespread application is hindered by limitations in responsiveness, durability, and complex fabrication processes. In this study, we propose a new approach to tackle these challenges by developing a single-layer soft actuator that responds to multiple stimuli using a straightforward solution-casting method. This actuator comprises bio-polymer gelatin, bio-compatible PEDOT:PSS, and iron oxide (Fe3O4) nanoparticles. Our actuator exhibits responsiveness to a range of organic solvent vapors, including water vapor, light, and magnetic fields. Notably, it exhibits rapid and reversible bending in distinct directions in response to different vapors, bending upwards in the presence of water vapor and downwards in the presence of alcohol vapor. Moreover, exposure to infrared (IR) light induces a bending toward the light source. The incorporation of magnet-responsive Fe3O4 nanoparticles induces multi-functionality in the actuator. The actuation characteristics of the actuator are controlled by leveraging its responsiveness to dual stimuli, such as water vapor and magnetic fields, as well as light and magnetic fields. For the proof of concept, we showcase several potential applications of our multi-stimuli responsive soft actuator, including magnet-triggered electrical switches, cargo transportation, soft grippers, targeted drug delivery, energy harvesting, and bio-mimicry.

PIDA-promoted metal-free [3 + 2] heteroannulation of ß-ketothioamides with 4-hydroxy coumarins: chemo-/regioselective access to furo[3,2-c]chromen-4-ones at room temperature.

Herein, we report a viable protocol to access furo[3,2-c]chromen-4-ones by engaging easily accessible 4-hydroxy coumarins as a three-atom CCO unit and thioamides as a C2 coupling partner, mediated by phenyliodine(III) diacetate (PIDA) at room temperature in a highly efficient and pot-/step-economical manner. This strategy not only avoids potential toxicity and tiresome workup conditions, but also features operational simplicity, a broad substrate scope, good functional group tolerance, high yields, easy scalability and exclusive selectivity. A mechanistic study has shown that this metal-free reaction is triggered by PIDA via activation of the ß-carbon of 4-hydroxy coumarin, followed by a nucleophilic addition/intramolecular cyclization/dethiohydration cascade. High-resolution mass spectra (HRMS) study confirms the key intermediates involved during the course of the reaction, elucidating the reaction pathways, and demonstrates the excellent regio- and chemoselectivity of this approach.

Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans.

BACKGROUND: Proteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age-related diseases. RESULTS: This study introduces a novel heat-killed Levilactobacillus brevis strain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-type Caenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of-function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptor sqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1, ilys-1, cnc-2, spp-9, spp-21, clec-47, and clec-266) and antioxidation (sod-3 and gst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors. CONCLUSION: Our research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin-signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.

Prevalence of non-communicable disease risk factors among nursing staff in a low and middle-income country: A cross-sectional digital survey-based study.

AIM: To assess the prevalence of non-communicable disease risk factors among the nursing staff and educate them on prevention. BACKGROUND: Nursing staff is integral to the Indian community healthcare systems. Recent studies report a high prevalence of non-communicable diseases in Indian nursing staff. Therefore, data on the prevalence of non-communicable disease risk factors among nursing staff are crucial for education on prevention. DESIGN: A cross-sectional digital survey-based study. METHOD: We invited 4435 nursing staff to attend our online survey. We used a customized questionnaire for data collection, including a digitized version of the Community-Based Assessment Checklist form. A score of >4 was considered high risk and warranted screening. RESULT: Among 682 nursing staff who attended, 70% had never undergone screening for non-communicable diseases. The prevalence of non-communicable disease risk factors was significantly higher in male nursing staff. In addition, logistic regression analysis showed that age, tobacco and alcohol use, increased waist circumference, physical inactivity and family history of non-communicable diseases were significant risk factors among nursing staff. CONCLUSION: The study findings suggest that the nursing staff have suboptimal self-health concerns on non-communicable diseases. This situation warrants continued medical education, awareness campaigns on adopting a healthy lifestyle and health promotion.

Film Coating of Phosphorylated Mandua Starch on Matrix Tablets for pH-Sensitive Release of Mesalamine.

Chemically modified mandua starch was successfully synthesized and applied to coat mesalamine-loaded matrix tablets. The coating material was an aqueous dispersion of mandua starch modified by sodium trimetaphosphate and sodium tripolyphosphate. To investigate the colon-targeting release competence, chemically modified mandua starch film-coated mesalamine tablets were produced using the wet granulation method followed by dip coating. The effect of the coating on the colon-targeted release of the resultant delivery system was inspected in healthy human volunteers and rabbits using roentgenography. The results show that drug release was controlled when the coating level was 10% w/w. The release percentage in the upper gastric phase (pH 1.2, simulated gastric fluid) was less than 6% and reached up to 59.51% w/w after 14 h in simulated colonic fluid. In addition to in vivo roentgenographic studies in healthy rabbits, human volunteer studies proved the colon targeting efficiency of the formulation. These results clearly demonstrated that chemically modified mandua starch has high effectiveness as a novel aqueous coating material for controlled release or colon targeting.

Intestinal Parasitic Infection in Children and Adolescents With Ocular Diseases: The Prevalence, Spectrum, and Effect of Lockdown During the COVID-19 Pandemic.

INTRODUCTION: People with visual impairments and blindness face challenges in performing regular tasks such as maintaining proper sanitation, which makes them vulnerable to intestinal parasitic infections. AIMS AND OBJECTIVES: This study aims to examine the prevalence and distribution of intestinal parasitic infections in children and adolescents with ocular diseases and to assess if the lockdown during the COVID-19 pandemic affected these rates. METHODS: This retrospective, hospital record-based study was conducted among children and adolescents attending the Regional Institute of Ophthalmology in Kolkata, India. It involved routine stool examinations as part of their treatment during 2019-2020. Early morning stool specimens were collected and brought to the institute laboratory in containers. Stools were examined under a microscope for cysts, ova, parasites, and adult worms. Findings were recorded in the laboratory record book. These data were then extracted into a spreadsheet and analyzed using IBM SPSS Statistics for Windows, Version 26 (Released 2019; IBM Corp., Armonk, New York). RESULTS: The prevalence of intestinal parasitic infections was 8.59% (59 out of 687 patients). Among those 59 positive cases, Ascaris lumbricoides, Giardia lamblia, Entamoeba histolytica, Trichuris trichiura, Taenia spp., Enterobius vermicularis, and Isospora belli were detected in 27 (45.8%), 15 (25.4%), 8 (13.6%), 6 (10.2%), 3 (5.1%), 2 (3.4%), and 1 (1.7%) patients, respectively. The positivity rate of stool samples was higher from September and thereafter from January to March. The sample positivity rate was higher post-pandemic and lockdown, but not statistically significant (11.5% vs. 5.3%; χ²=4.044, df=1, p=0.44). CONCLUSION: Ascaris lumbricoides was the most commonly observed intestinal parasite in children and adolescents with ocular disease in our setting. Seasonal variation was noted with higher case positivity at the end of the rainy season and thereafter in winter. Therefore, we propose to strengthen the routine deworming program during this period in Eastern India. Higher sample positivity after the pandemic may be attributed to school closures during the lockdown period, which might have caused some children to miss their routine deworming medication.

Multivapor-Responsive Controlled Actuation of Starch-Based Soft Actuators.

Multivapor-responsive biocompatible soft actuators have immense potential for applications in soft robotics and medical technology. We report fast, fully reversible, and multivapor-responsive controlled actuation of a pure cassava-starch-based film. Notably, this starch-based actuator sustains its actuated state for over 60 min with a continuous supply of water vapor. The durability of the film and repeatability of the actuation performance have been established upon subjecting the film to more than 1400 actuation cycles in the presence of water vapor. The starch-based actuators exhibit intriguing antagonistic actuation characteristics when exposed to different solvent vapors. In particular, they bend upward in response to water vapor and downward when exposed to ethanol vapor. This fascinating behavior opens up new possibilities for controlling the magnitude and direction of actuation by manipulating the ratio of water to ethanol in the binary solution. Additionally, the control of the bending axis of the starch-based actuator, when exposed to water vapor, is achieved by imprinting-orientated patterns on the surface of the starch film. The effect of microstructure, postsynthesis annealing, and pH of the starch solution on the actuation performance of the starch film is studied in detail. Our starch-based actuator can lift 10 times its own weight upon exposure to ethanol vapor. It can generate force ∼4.2 mN upon exposure to water vapor. To illustrate the vast potential of our cassava-starch-based actuators, we have showcased various proof-of-concept applications, ranging from biomimicry to crawling robots, locomotion near perspiring human skin, bidirectional electric switches, ventilation in the presence of toxic vapors, and smart lifting systems. These applications significantly broaden the practical uses of these starch-based actuators in the field of soft robotics.

Statistical modelling, optimization, and mechanistic exploration of novel ureolytic Enterobacter hormaechei IITISM-SA3 in cadmium immobilization under microbial inclusive and cell-free conditions through microbially induced calcite precipitation.

The study aimed to evaluate the potential of a novel isolated ureolytic Enterobacter hormaechei IITISM-SA3 in cadmium bioremoval through MICP. The optimization and modelling of the biotic and abiotic factors affecting the process of mineralization were also performed. In addition, the underlying mechanism of MICP-driven Cd mineralization under microbial-inclusive and cell-free conditions was revealed and supported through the characterization of the bio-precipitates obtained using various characterization techniques. The results indicated that the isolate could remove 97.18% Cd2+ of 11.4 ppm under optimized conditions of 36.86 h, pH 7.63, and biomass dose of 1.75 ml. Besides, the presence and absence of bacterial cells were found to influence both the morphologies and crystalline structures of precipitates. The precipitates obtained under microbial-inclusive conditions showed typical rhombohedral crystalline structures of the composition comprising CaCO3, CdCO3, and 0.67Ca0.33CdCO3. However, the crystalline nature of the precipitate reduced to a nano-sized granular structure in cell-free media. Unlike the cadmium mineralization process under microbial-inclusive media, where bacterial cells serve as nucleation sites for crystallization, the carbonate precipitation effectively captures Cd2+ through co-precipitation, chemisorption, or alternative mechanisms involving interactions between metal ions and CaCO3 under cell-free conditions. The findings presented suggest that using cell-free culture supernatant enriched with carbonate ions provides an avenue that could be harnessed for sustainable metal remediation.

Mutagenic Azido Impurities in Drug Substances: A Perspective.

Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)3 Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives.

Immunomodulatory and AntiOxidant Potential of Polyherbal Dhatryadi Rasayana in the Form of Churna and Granules.

Dhatryadi Rasayana revitalizes the human body and helps in maintaining health with the elimination of ill effects of various diseases. The effective delivery systems for Rasayana may affect the profound effect of active principles in the body. The present study deals with investigation and evaluation of phytochemical constituents, physicochemical characteristics, along with antioxidant and immunomodulatory effects of Dhatryadi Rasayana in churna (powder) and granule formulations. Dhatryadi Rasayana churna and its granules were studied for various physicochemical parameters, e.g., moisture content, ash-value, acid-insoluble ash content, water-soluble extractive, alcohol-soluble extractive, bulk density, tapped density, angle of repose, Carr's index, Hausner's ratio, total sugar, reducing sugar, non-reducing sugar, heavy metals, total microbial load, etc. In vitro antioxidant potential of Dhatryadi Rasayana churna and its granules was determined by scavenging the DPPH and FRAP assays. The immunomodulatory activities of Dhatryadi Rasayana churna and its granules were studied in Wistar albino rats and the complete blood count (CBC), delayed-type hypersensitivity reaction (DTH), and hemagglutination antibody titer were assessed. Dhatryadi Rasayana churna contained alkaloids (0.50 ± 0.298% w/w), tannins (9.84 ± 1.527% w/w), saponins (4.18 ± 2.126% w/w), and flavonoids (9.34 ± 1.026% w/w), while its granules contained 11.08 ± 2.468% w/w total tannins, 2.40 ± 1.132% w/w alkaloids, and 12.46 ± 2.645% w/w total flavonoids. The DPPH scavenging effect was determined by IC50 (churna - 23.89 µg/mL; granules - 9.33 µg/mL), and the antioxidant capacity assessed by FRAP was 77.0 mmol/100 g equivalent of ascorbic acid for churna and 50 mmol/100 g equivalent of ascorbic acid for granules. Dhatryadi Rasayana churna and its granules reflected a significant immunostimulatory effect on both the cell-mediated and humoral immune systems in Wistar albino rats. Moreover, churna and granules of Dhatryadi Rasayana revealed significant antioxidant and immunomodulatory activities and these may be applied for treating different diseases as well as improving the immunity of the body.

Design, synthesis, biological assessment and molecular modeling studies of novel imidazothiazole-thiazolidinone hybrids as potential anticancer and anti-inflammatory agents.

A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (4a, 4b, 4c) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound 4c was found to be most active and displayed IC50 value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC50 value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds 4a, 4b and 4c were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds 4b and 4c. Hepatotoxicity studies of compounds 4b and 4c also showed normal architecture of hepatocytes. Compounds 4a-g and 5a-d were also evaluated for their in-vitro anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds 4a-d and 5a-b showed promising activity and were selected for in-vivo inflammatory activity against carrageenan rat paw edema test. Among these compounds, 4b was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound 4b also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds 4c and 4b could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity.

Comprehensive molecular analysis of driver mutations in non-small cell lung carcinomas and its correlation with PD-L1 expression, An Indian perspective.

BACKGROUND: The understanding of molecular mechanisms involved in non-small cell lung carcinoma (NSCLC) has revolutionized significantly in the recent years. These have helped to develop personalized management strategies by identifying specific molecular alterations such as mutations in EGFR, ROS1, BRAF, ERBB2, MET, ALK, and KRAS genes. These mutations are targetable ensuring a better clinical outcome. Next-generation sequencing (NGS) methodology is the recommended technique for the identification of driver mutations in the five hot-spot genes (EGFR, ALK, ROS1, MET, and BRAF) involved in the NSCLC. NGS has numerous advantages including multiplexing, tissue conservation, identification of rare and novel variants, and reduced cost over the sequential single gene testing. Herein, we sought to demonstrate the mutational profile in NSCLC and their clinicopathologic correlation in a contemporary cohort of Indian NSCLC patients. Additionally, we studied the correlation of oncogenic driver mutations with PD-L1 status in these patients. MATERIALS AND METHODS: Five fifty-two stage IV NSCLC patients (adenocarcinoma=490; squamous cell carcinoma=51; adenosquamous carcinoma=5; large cell carcinoma=2; sarcomatoid carcinoma=3; spindle cell carcinoma=1) underwent broad molecular profiling by a custom-made, targeted DNA- and RNA-based five hot-spot genes lung cancer panel (EGFR, ALK, ROS1, BRAF, and MET), compatible with the NGS Ion S5 system. The mutations were correlated with the clinicopathologic characteristics. Additionally, PD-L1 expression status, available on 252 tumors, was correlated with the oncogenic drivers. RESULTS: Validation of the 5 gene panel yielded the following results: a) specificity of 99.74%; b) sensitivity of 100% for single nucleotide variants (SNVs) (>5% variant allele frequency, VAF), indels (>10% VAF) and fusions; c) 100% intra- and inter-run reproducibility; d) 88% inter-laboratory agreement. Validated panel was then used to analyze clinical samples. Sixty percentage tumors harbored either one (54.71%) or multiple (3.26%) mutations. EGFR and BRAF V600E mutations, ALK and ROS1 rearrangements, and MET exon 14 skipping mutation were observed in 38.41% (n = 212) and 2.72% (n = 15) patients, 12.14% (n = 67) and 3.62% (n = 20) patients, and 1.09% (n = 6) patients, respectively. EGFR exon 19 deletion accounted for 52.83% of all mutations, followed by L858R (35.85%), T790M (5.19%), exon 20 insertions (6.6%), and other rare mutations (G719X, L861Q, S768I) (9.91%). Concurrent EGFR with ALK, EGFR with ROS1, EGFR with MET, and EGFR with BRAF were observed in 10, 4, 1, and 3 patients, respectively. PD-L1 was expressed in 134 patients (53.2%). Exon 19 deletion was more prevalent in PD-L1 negative tumors whereas exon 21 substitution (L858R) was seen more in PD-L1 positive tumors. CONCLUSIONS: This is one of the largest cohorts of NSCLC for comprehensive targeted mutational profiling and correlation with the PD-L1 expression. The mutations are more prevalent in non-smoker females for all genes, except ALK (non-smoker males). MET and BRAF mutations are more common in elderly population whereas EGFR mutations, and ALK and ROS1 genes rearrangements are more prevalent in younger population. The most common histopathologic subtype/feature associated with various mutations was as follows: acinar with EGFR, solid with ALK, macronucleoli with ROS1, signet ring with MET, and micropapillary with BRAF.

Targeting HIF-1α in sickle cell disease and cancer: unraveling therapeutic opportunities and risks.

INTRODUCTION: HIF-1α, a key player in medical science, holds immense significance in therapeutic approaches. This review delves into its complex dynamics, emphasizing the delicate balance required for its modulation. HIF-1α stands as a cornerstone in medical research, its role extending to therapeutic strategies. This review explores the intricate interplay surrounding HIF-1α, highlighting its critical involvement and the necessity for cautious modulation. AREAS COVERED: In sickle cell disease (SCD), HIF-1α's potential to augment fetal hemoglobin (HbF) production and mitigate symptoms is underscored. Furthermore, its role in cancer is examined, particularly its influence on survival in hypoxic tumor microenvironments, angiogenesis, and metastasis. The discussion extends to the intricate relationship between HIF-1α modulation and cancer risks in SCD patients, emphasizing the importance of balancing therapeutic benefits and potential hazards. EXPERT OPINION: Managing HIF-1α modulation in SCD patients requires a nuanced approach, considering therapeutic potential alongside associated risks, especially in exacerbating cancer risks. An evolutionary perspective adds depth, highlighting adaptations in populations adapted to low-oxygen environments and aligning cancer cell metabolism with primitive cells. The role of HIF-1α as a therapeutic target is discussed within the context of complex cancer biology and metabolism, acknowledging varied responses across diverse cancers influenced by intricate evolutionary adaptations.

Scalable imaging-free spatial genomics through computational reconstruction.

Tissue organization arises from the coordinated molecular programs of cells. Spatial genomics maps cells and their molecular programs within the spatial context of tissues. However, current methods measure spatial information through imaging or direct registration, which often require specialized equipment and are limited in scale. Here, we developed an imaging-free spatial transcriptomics method that uses molecular diffusion patterns to computationally reconstruct spatial data. To do so, we utilize a simple experimental protocol on two dimensional barcode arrays to establish an interaction network between barcodes via molecular diffusion. Sequencing these interactions generates a high dimensional matrix of interactions between different spatial barcodes. Then, we perform dimensionality reduction to regenerate a two-dimensional manifold, which represents the spatial locations of the barcode arrays. Surprisingly, we found that the UMAP algorithm, with minimal modifications can faithfully successfully reconstruct the arrays. We demonstrated that this method is compatible with capture array based spatial transcriptomics/genomics methods, Slide-seq and Slide-tags, with high fidelity. We systematically explore the fidelity of the reconstruction through comparisons with experimentally derived ground truth data, and demonstrate that reconstruction generates high quality spatial genomics data. We also scaled this technique to reconstruct high-resolution spatial information over areas up to 1.2 centimeters. This computational reconstruction method effectively converts spatial genomics measurements to molecular biology, enabling spatial transcriptomics with high accessibility, and scalability.

PTSA-induced synthesis, in silico and nano study of novel ethylquinolin-thiazolo-triazole in cervical cancer.

Aim: p-Toluenesulfonic acid-(PTSA) and grinding-induced novel synthesis of ethylquinolin-thiazolo-triazole derivatives was performed using green chemistry. Materials & methods: Development of a nanoconjugate drug-delivery system of ethylquinolin-thiazolo-triazole was carried out with D-α-tocopheryl polyethylene glycol succinate (TPGS) and the formulation was further characterized by transmission electron microscopy, atomic force microscopy, dynamic light scattering and in vitro drug release assay. The effect of 3a nanoparticles was assessed against a cervical cancer cell line (HeLa) through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect on apoptosis was determined. Results & discussion: The 3a nanoparticles triggered the apoptotic mode of cell death after increasing the intracellular reactive oxygen level by enhancing cellular uptake of micelles. Furthermore, in silico studies revealed higher absorption, distribution, metabolism, elimination and toxicity properties and bioavailability of the enzyme tyrosine protein kinase. Conclusion: The 3a nanoparticles enhanced the therapeutic potential and have higher potential for targeted drug delivery against cervical cancer.

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Preclinical evaluation of dalbergin loaded PLGA-galactose-modified nanoparticles against hepatocellular carcinoma via inhibition of the AKT/NF-κB signaling pathway.

Prior research has shown the effectiveness of dalbergin (DL), dalbergin nanoformulation (DLF), and dalbergin-loaded PLGA-galactose-modified nanoparticles (DLMF) in treating hepatocellular carcinoma (HCC) cells. The present investigation constructs upon our previous research and delves into the molecular mechanisms contributing to the anticancer effects of DLF and DLMF. This study examined the anti-cancer effects of DL, DLF, and DLMF by diethyl nitrosamine (DEN)-induced HCC model in albino Wistar rats. In addition, we performed biochemical, antioxidant, lipid profile tests, and histological studies of liver tissue. The anticancer efficacy of DLMF is equivalent to that of 5-fluorouracil, a commercially available therapy for HCC. Immunoblotting studies revealed a reduction in the expression of many apoptotic markers, such as p53, BAX, and Cyt-C, in HCC. Conversely, the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3 was elevated. Nevertheless, the administration of DL, DLF, and DLMF effectively controlled the levels of these apoptotic markers, resulting in a considerable decrease in the expression of Bcl-2, TNF-α, NFκB, p-AKT, and STAT-3. Specifically, the activation of TNF-alpha and STAT-3 triggers the signalling pathways that include the Bcl-2 family of proteins, Cyt-C, caspase 3, and 9. This ultimately leads to apoptosis and the suppression of cell growth. Furthermore, metabolomic analysis using 1H NMR indicated that the metabolites of animals reverted to normal levels after the treatment.