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Background: The adulteration of milk is an important issue that needs to be addressed because of its deleterious effects on health. Detection of adulterants in milk can be done in laboratories or by purchasing adulteration detection kits. There are few home-based rapid tests to detect common milk adulterants, which are less known by our community. Objectives of this study were to estimate the proportion of milk adulteration and to identify common adulterants, to determine the association of milk adulteration with gastrointestinal and renal diseases; and also to validate rapid home-based tests by comparing its result with standard milk adulteration detection kit. Materials and Methods: A community-based study was conducted on 330 medical and paramedical staff. Collected milk samples during family visits were tested by standard milk adulteration detection tests and rapid home-based tests. Results: Among 330 tested milk samples, 233 samples were adulterated with one or more than one adulterant. The most common adulteration observed was the addition of water to milk, followed by detergent, urea, and neutralizer. The specificity of the rapid tests was found to be almost 100% in the detection of water and detergent in milk and accuracy was above 80%; with “substantial agreement” (kappa = 0.7) between rapid tests and standard tests on kappa statistics. Conclusion: The present study has identified a large extent of milk adulteration and common adulterants, which may have harmful effects on health. The utility of home-based rapid tests is clearly proven to detect common adulterants.

Current research aims to assess the therapeutic impact of Mucuna pruriens seed extract on PROTAMIN (PRM) I and II gene expression and hormones in chlorpromazine-induced endocrine disruptions and reproductive toxicity in male rats. Thirty male Wistar rats were categorized into five groups: the negative control group, rats that received distilled water for 52 days; the induction group, rats that received (20 mg/kg) of chlorpromazine for 52 days; and three treatment groups that were pretreated with chlorpromazine (similar to the induction group) that received a low, medium, and high dose of Mucuna pruriens (500, 1000, and 2000 mg/kg, respectively). Serum samples were collected to measure testosterone, FSH (follicular stimulating hormone), LH (luteinizing hormone), and prolactin serum levels using the ELISA technique. Tissue samples were collected to measure PRM I and II gene expression and for histopathological study. The PRM I and II genes were significantly downregulated in the chlorpromazine-treated group. These genes were also significantly upregulated in Mucuna pruriens-treated groups. The Mucuna pruriens-treated groups revealed a significant rise in serum LH, testosterone, and FSH concentrations, decreased serum prolactin, and improved histology of testicular damage compared to the induction group. In conclusion, the endocrine disruption and hormonal changes induced by chlorpromazine improved when Mucuna pruriens was administered, improving the impairment in gene expression and hormones.

Abstract Background Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. Methods 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. Results Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p

Abstract Background Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear. Objectives We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy. Methods We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory’s 99th -percentile upper limit of normal (xULN). Results 4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs.

Abstract Background Policy research aims to provide evidence to inform government policy decisions about health and social care. Engaging and involving the public and patients in this work is widely recognised as essential. Research funders prioritise equality, diversity and inclusion (EDI) in patient and public involvement and engagement (PPIE), but people who are most likely to experience poor outcomes are also those least likely to be involved in research. This paper describes our experience of setting out to understand how to overcome barriers to EDI in PPIE in the research carried out by the National Institute for Health and Care Research (NIHR) Policy Research Unit in Maternal and Neonatal Health and Care (PRU-MNHC), in a PPIE consultation project we called The Listening Series. Methods We convened five video-recorded online discussion groups involving 20 individuals advocating for groups who are under-represented in our research. Those taking part included people working with Black and Asian women and families, young parents, those from socially deprived backgrounds, and women and families with physical and learning disabilities. Discussions focussed on practical solutions to addressing challenges to people being excluded, and how to improve EDI in our research. Learning and reflection Five key themes were identified: ‘build trust’; ‘involve us from the beginning’; ‘show us impact’; ‘use clear, appropriate and inclusive communication’; and ‘imagine life in our shoes’. We used the learning to create a guidance document for researchers and an accompanying 15-minute film. We also took practical steps to embed the learning strategically by expanding our Task Group for PPIE in the PRU-MNHC to include four Listening Series invitees with a remit to champion EDI in our research and ensure that it is embedded in our PPIE activities. We continue to reflect on and work to address the associated challenges. Conclusions The Listening Series helped us rethink our processes for inclusion to go beyond traditional methods of involvement and engagement. The themes identified pose challenges that require time, resource and empathic engagement from researchers to be meaningfully resolved. This has implications for policy makers and research funders who need to consider this in their processes.

Creep is a complex behavior of concrete since it induces different stages of response under loading and unloading with time. It represents the time-dependent strain as a result of a constant sustained load applied with time. In cementitious materials such as engineered cementitious composite concrete, ECC, the loaded cement paste is the principal source of creep strain. Therefore, investigating the overall creep behavior, under the loading and unloading stages, will be beneficial in providing data for the performance of ECC concrete. The test for compressional creep strain is done according to the ASTM C- 512 under controlled temperature (21 oC) and relative humidity (40%). In this research, the loading stage lasted for 9 months, and the unloading stage lasted 3 months. The total creep strain, creep coefficient, and specific creep were recorded for six ECC concrete mixes. The mixes have two strength levels, 30 and 60 MPa at 28 days, and contain polypropylene and polyvinyl alcohol fibers. Results revealed significant enhancement, and lower creep behavior, in mixes including fibers compared to plain mixes. The best promising results for the creep coefficient and specific creep were recorded when using mixes of 60 MPa containing polyvinyl alcohol fibers compared to plain mixes.

Abstract Centrin1 gene deleted Leishmania donovani parasite (LdCen1 −/− ) was developed and extensively tested experimentally as an intracellular stage-specific attenuated and immunoprotective live parasite vaccine candidate ex vivo using human PBMCs and in vivo in animals. Here we report manufacturing and pre-clinical evaluation of current Good-Laboratory Practice (cGLP) grade LdCen1 −/− parasites, as a prerequisite before proceeding with clinical trials. We screened three batches of LdCen1 −/− parasites manufactured in bioreactors under cGLP conditions, for their consistency in genetic stability, attenuation, and safety. One such batch was preclinically tested using human PBMCs and animals (hamsters and dogs) for its safety and protective immunogenicity. The immunogenicity of the CGLP grade LdCen1 −/− parasites was similar to one grown under laboratory conditions. The cGLP grade LdCen1 −/− parasites were found to be safe and non-toxic in hamsters and dogs even at 3 times the anticipated vaccine dose. When PBMCs from healed visceral leishmaniasis (VL) cases were infected with cGLP LdCen1 −/− , there was a significant increase in the stimulation of cytokines that contribute to protective responses against VL. This effect, measured by multiplex ELISA, was greater than that observed in PBMCs from healthy individuals. These results suggest that cGLP grade LdCen1 −/− manufactured under cGMP complaint conditions can be suitable for future clinical trials.

Abstract Estimating runoff at ground-mounted solar photovoltaic (PV) installations is challenging because of the disconnected nature of impervious solar panels and the pervious ground surface underneath and between panel rows. There is a need for improved tools to estimate how low impact development practices at these solar installations affect stormwater runoff. The objective of this study was to develop an innovative spreadsheet-based runoff calculator that rapidly estimates stormwater runoff from ground-mounted solar PV sites. The calculator is built on a 2-D hydrologic model (Hydrus-2D/3D) calibrated and validated using experimental data from five commercial solar farms in Colorado, Georgia, Minnesota, New York, and Oregon. The Hydrus-2D/3D hydrologic model was then used to generate nomographs for stormwater runoff that were incorporated into an easy-to-use Excel-based solar farm runoff calculator. This calculator allows for rapid estimation of NRCS stormwater runoff curve number (CN) values at solar farms by considering several complex factors unique to PV installations including: soil and topographic characteristics, surface cover, disconnected impervious surface factors associated with various solar panel designs, and climatic factors. The solar farm runoff calculator quickly estimates runoff CN for pre- and post-construction scenarios, and can estimate actual depth of runoff based on a user-specified 24-h design storm depth. Factors that have the most significant impact on stormwater runoff include design storm return frequency, soil texture, soil bulk density, and soil depth. Ground surface cover has a moderate impact on stormwater runoff, and factors that have a lesser impact on stormwater runoff include slope and array size, spacing and orientation on the landscape. The runoff calculator allows for accurate estimates of runoff generated by disconnected impervious surfaces and low impact development practices at solar farms as affected by a wide range of site-specific conditions.

Background The primary objective worldwide during the coronavirus disease 2019 (COVID-19) pandemic had been controlling disease transmission. However, lockdown measures used to mitigate transmission affected human behavior and altered lifestyles, with a likely impact on chronic non-communicable diseases. More than a year into the pandemic, substantial peer-reviewed literature emerged on altered lifestyles following the varying lockdown measures imposed globally to control the virus spread. We explored the impact of lockdown measures on six lifestyle factors, namely diet, physical activity, sleep, stress, social connectedness, and the use of tobacco, alcohol, or other harmful substances. Methods We comprehensively searched PubMed and the World Health Organization’s global literature database on COVID-19 and retrieved 649 relevant articles for the narrative review. A critical interpretative synthesis of the articles was performed. Results Most of the articles included in the review identified the negative effect of lockdown measures on each of the lifestyle factors in many parts of the world. Encouraging lifestyle trends were also highlighted in a few articles. Such trends can positively influence the outcome of lifestyle-related chronic diseases, such as obesity and diabetes. Conclusions The lockdown associated with COVID-19 has largely had a negative impact on the lifestyles of individuals and communities across many countries and cultures. However, some individuals and communities also initiated positive lifestyle-related behavioral changes. If the knowledge generated by studying the impact of COVID-19-related lockdowns on the six lifestyle factors is further consolidated, it could improve chronic disease outcomes. This will help better understand lifestyle behaviors amidst crises and assist in redesigning extreme public health measures such as lockdowns.. It is up to governments, communities, and healthcare/academic entities to derive benefit from lessons learned from the pandemic, with the ultimate objective of better educating and promoting healthy lifestyles among communities.

IntroductionFamilial hypercholesterolemia, the highly prevalent form of dyslipidemia, is a well-known risk factor for premature heart disease and stroke worldwide. Statins, which inhibit 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, are the first-choice treatment for dyslipidemias, and have been effective in reducing the risk of stroke and myocardial infarction. However, emerging evidence indicates that statins may increase the incidence of new-onset type 2 diabetes by reducing β-cell mass and function. Notably, past in vitro reports studying the effects of statins on β-cells were performed without including free fatty acids in the model. This factor should have been addressed since these agents are used to treat individuals with hyperlipidemia.MethodsHere, we used a mouse insulinoma MIN6 β-cell culture model to assess the efficacy, cytotoxicity, and insulin-suppressive effects of simvastatin and pravastatin in the presence of palmitic, linoleic, and oleic acids cocktail to mimic mixed lipids challenge in a biologically relevant setting.Results and discussionOur findings indicate that simvastatin was more effective in lowering intracellular cholesterol but was more cytotoxic as compared to pravastatin. Similarly, simvastatin exhibited a higher suppression of total insulin content and insulin secretion. Both drugs suppressed insulin secretion in phases 1 and 2, dose-dependently. No significant effect was observed on mitochondrial respiration. More importantly, elution experiments showed that insulin content diminution by simvastatin treatment was reversible, while exogenous mevalonate did not improve total insulin content. This suggests that simvastatin's influence on insulin content is independent of its specific inhibitory action on HMG-CoA reductase. In conclusion, our study identified that simvastatin was more effective in lowering intracellular cholesterol, albeit it was more toxic and suppressive of β-cells function. Notably, this suppression was found to be reversible.

BackgroundDengue virus (DENV) infection, spread by Aedes aegypti mosquitoes, is a significant public health concern in tropical and subtropical regions. Among the four distinct serotypes of DENV (DENV-1 to DENV-4), DENV-2 is associated with the highest number of fatalities worldwide. However, there is no specific treatment available for dengue patients caused by DENV-2.ObjectiveThis study aimed to identify inhibitory phytocompounds in silico in Vernonia cinerea (V. cinerea), a widely used traditional medicinal plant, for treating DENV-2 associated illnesses.MethodsThe chemical structures of 17 compounds from V. cinerea were sourced from the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) database. These compounds underwent geometry optimization, were screened against nonstructural protein 1 (NSP1) of DENV-2, and further validated through molecular dynamics simulations (MDS). Baicalein, an established drug against DENV-2, was used for validation in molecular screening, MDS, and MM-GBSA analyses.ResultsAmong these compounds, Beta-amyrin, Beta-amyrin acetate, Chrysoeriol, Isoorientin, and Luteolin showed promising potential as inhibitors of the NSP1 of DENV-2, supported by the results of thermodynamic properties, molecular orbitals, electrostatic potentials, spectral data and molecular screening. Besides, these compounds adhered to the Lipinski’s “rule of 5”, showing no hepatotoxicity/cytotoxicity, with mixed mutagenicity, immunotoxicity, and carcinogenicity. Furthermore, final validation through MDS confirmed their potential, demonstrating stable tendencies with significant inhibitory activities against NSP1 of DENV-2 over the control drug Baicalein. Among the screened compounds, Chrysoeriol emerged as the most promising inhibitor of NSP1 of DENV-2, followed by Luteolin and Isoorientin.ConclusionTaken together, our results suggest that Chrysoeriol is the best inhibitor of NSP1 of DENV-2, which could be evaluated as a therapeutic agent or a lead compound to treat and manage DENV-2 infections.

BackgroundThe Kuwaiti and Qatari populations have a high prevalence of obesity, a major risk factor for various metabolic disorders. Previous studies have independently explored mitochondrial DNA (mtDNA) variations and their association with obesity in these populations. This study aims to investigate the role of mtDNA haplogroups and variants in obesity risk among these Gulf populations.MethodsWhole exome sequencing data from 1,112 participants (348 Kuwaitis and 764 Qataris) were analyzed for mtDNA variants. Participants were classified as obese or non-obese based on body mass index (BMI). Association analyses were performed to examine the relationship between mtDNA haplogroups and obesity, adjusting for covariates such as age and sex.ResultsHaplogroup R was found to be protective against obesity, with an odds ratio (OR) of 0.69 (p = 0.045). This association remained significant after adjusting for age and sex (OR = 0.694; 95% CI: 0.482-0.997; p = 0.048). Several mtDNA variants, particularly those involved in mitochondrial energy metabolism, showed nominal associations with obesity, but these did not remain significant after correcting for multiple testing.ConclusionHaplogroup R consistently demonstrates a protective association against obesity in both Kuwaiti and Qatari populations, highlighting its potential as a biomarker for obesity risk in the Gulf region. However, further research with larger sample sizes is needed to validate these findings and clarify the role of mtDNA variants in obesity.

IntroductionIncreasing evidence from human and animal model studies indicates the significant role of microRNAs (miRNAs) in pancreatic beta cell function, insulin signaling, immune responses, and pathogenesis of type 1 diabetes (T1D).MethodsWe aimed, using next-generation sequencing, to screen miRNAs from peripheral blood mononuclear cells of eight independent Kuwaiti-Arab families with T1D affected siblings, consisting of 18 T1D patients and 18 unaffected members, characterized by no parent-to-child inheritance pattern.ResultsOur analysis revealed 20 miRNAs that are differentially expressed in T1D patients compared with healthy controls. Module-based weighted gene co-expression network analysis prioritized key consensus miRNAs in T1D pathogenesis. These included hsa-miR-320a-3p, hsa-miR-139-3p, hsa-miR-200-3p, hsa-miR-99b-5p and hsa-miR-6808-3p. Functional enrichment analysis of differentially expressed miRNAs indicated that PI3K-AKT is one of the key pathways perturbed in T1D. Gene ontology analysis of hub miRNAs also implicated PI3K-AKT, along with mTOR, MAPK, and interleukin signaling pathways, in T1D. Using quantitative RT-PCR, we validated one of the key predicted miRNA-target gene-transcription factor networks in an extended cohort of children with new-onset T1D positive for islet autoantibodies. Our analysis revealed that hsa-miR-320a-3p and its key targets, including PTEN, AKT1, BCL2, FOXO1 and MYC, are dysregulated in T1D, along with their interacting partners namely BLIMP3, GSK3B, CAV1, CXCL3, TGFB, and IL10. Receiver Operating Characteristic analysis highlighted the diagnostic potential of hsa-miR-320a-3p, CAV1, GSK3B and MYC for T1D.DiscussionOur study presents a novel link between hsa-miR-320a-3p and T1D, and highlights its key regulatory role in the network of mRNA markers and transcription factors involved in T1D pathogenesis.

Objective: This study explores the frequency of human leukocyte antigen (HLA) genes, particularly HLA-B alleles, within the Kuwaiti population. We aim to identify alleles with known associations to adverse drug reactions (ADRs) based on existing literature. We focus on the HLA-B gene due to its well-documented associations with severe cutaneous adverse reactions and the extensive pharmacogenetic research supporting its clinical relevance.MethodsWe utilized the HLA-HD tool to extract, annotate, and analyse HLA-B alleles from the exome data of 561 Kuwaiti individuals, sequenced on the Illumina HiSeq platform. HLA typing was conducted using the HLA-HD tool with a reference panel from the IPD-IMGT/HLA database. The major HLA-B pharmacogenetic markers were obtained from the HLA Adverse Drug Reaction Database, focusing on alleles with significant ADR associations in published literature.ResultsThe distribution of HLA-B alleles in the Kuwaiti population revealed that the most frequent alleles were HLA-B*50:01 (10.52%), HLA-B*51:01 (9.89%), HLA-B*08:01 (6.06%), HLA-B*52:01 (4.55%), HLA-B*18:01 (3.92%), and HLA-B*41:01 (3.65%). Notably, alleles HLA-B*13:01, HLA-B*13:02, HLA-B*15:02, HLA-B*15:13, HLA-B*35:02, HLA-B*35:05, HLA-B*38:01, HLA-B*40:02, HLA-B*44:03, HLA-B*51:01, HLA-B*57:01 and HLA-B*58:01 were identified with known associations to various ADRs. For example, HLA-B*51:01 was associated with clindamycin, phenobarbital, and phenytoin, and was found in 18% of individuals.ConclusionOur study enriches the regional genetic landscape by delineating HLA-B allele variations within Kuwait and across the Arabian Peninsula. This genetic insight, along with the identification of markers previously linked to drug hypersensitivity, provides a foundation for future pharmacogenetic research and potential personalized medicine strategies in the region.

Background Reduced estimated glomerular filtration rate (eGFR) is associated with lower use of invasive management and increased mortality after acute coronary syndrome (ACS). The reasons for this are unclear.Methods A retrospective clinical cohort study was performed using data from the English National Institute for Health Research Health Informatics Collaborative (2010–2017). Multivariable logistic regression was used to investigate whether eGFR

The study proposed the removal of Brilliant Green, a cationic dye, by adsorption process from wastewater solution utilizing a low-cost adsorbent such as Nutraceutical Industrial Pepper Seed Spent (NIPSS). The study comprises an investigation of the parametric influence on the adsorption process. The parameters identified are pH, dye concentration, process temperature, quantity of the adsorbent, and particle size. The study of statistics found from experiments was carried out by incorporating Freundlich, Brouers-Sotolongo, Langmuir, Toth, Sips, Jovanovic, and Redlich-Peterson isotherm models. The adsorption kinetics were determined by implementing pseudo-first-order and second-order models, diffusion film models, and Dumwald-Wagner and Weber-Morris models. The experimental adsorption capacity qe was found to be about 130 mg/g. This value was closest to the maximum adsorption of 144.6mg/g predicted by the Brouers-Sotolongo isotherm which had a correlation coefficient (R2) of 0.998. The adsorption kinetics data was confirmed to be a pseudo-second-order model. The change in free energy, enthalpy change, and entropy change were vital thermodynamic factors in concluding that adsorption is almost spontaneous and endothermic process. Change in enthalpy (ΔH°) reduced value indicates the physical nature of the process. The adsorption of BG dye on the adsorbent surface was authenticated by FTIR spectroscopy and SEM imaging. A Central Composite Design (CCD) Quadratic model under Response Surface Methodology (RSM) was implemented for statistical optimization of adsorption capacity for the five parameters studied, namely, time, temperature, concentration of the dye, weight of the adsorbent, and pH. Software Design Expert 7.0 was used to evaluate 3D contour plots. The process of optimization yielded a value of 350 mg/g. Thus, incrementing the adsorption process by 84.2 %. The study provides insights on various dye and adsorbent interaction possibilities and derives that NIPSS is an efficient adsorbent to extract BG dye from wastewater solutions.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Background The primary objective worldwide during the coronavirus disease 2019 (COVID-19) pandemic had been controlling disease transmission. However, lockdown measures used to mitigate transmission affected human behavior and altered lifestyles, with a likely impact on chronic non-communicable diseases. More than a year into the pandemic, substantial peer-reviewed literature emerged on altered lifestyles following the varying lockdown measures imposed globally to control the virus spread. We explored the impact of lockdown measures on six lifestyle factors, namely diet, physical activity, sleep, stress, social connectedness, and the use of tobacco, alcohol, or other harmful substances. Methods We comprehensively searched PubMed and the World Health Organization’s global literature database on COVID-19 and retrieved 649 relevant articles for the narrative review. A critical interpretative synthesis of the articles was performed. Results Most of the articles included in the review identified the negative effect of lockdown measures on each of the lifestyle factors in many parts of the world. Encouraging lifestyle trends were also highlighted in a few articles. Such trends can positively influence the outcome of lifestyle-related chronic diseases, such as obesity and diabetes. Conclusions The lockdown associated with COVID-19 has largely had a negative impact on the lifestyles of individuals and communities across many countries and cultures. However, some individuals and communities also initiated positive lifestyle-related behavioral changes. If the knowledge generated by studying the impact of COVID-19-related lockdowns on the six lifestyle factors is further consolidated, it could improve chronic disease outcomes. This will help better understand lifestyle behaviors amidst crises and assist in redesigning extreme public health measures such as lockdowns.. It is up to governments, communities, and healthcare/academic entities to derive benefit from lessons learned from the pandemic, with the ultimate objective of better educating and promoting healthy lifestyles among communities.

Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression. Using a well-established MDA-MB-231 breast cancer model, we found that the synergy between TGF-β and TNF-α led to MMP-9 upregulation at the transcriptional and translational levels, compared to treatments with each agent alone. Our in vitro findings are corroborated by co-expression of elevated MMP-9 with TGF-β and TNF-α in human breast cancer tissues. Mechanistically, we found that the MMP-9 upregulation driven by TGF-β/TNF-α cooperativity was attenuated by selective inhibition of the TGF-βRI/Smad3 pathway. Comparable outcomes were observed upon inhibition of TGF-β-induced phosphorylation of Smad2/3 and p38. As expected, the cells defective in Smad2/3 or p38-mediated signaling did not exhibit this synergistic induction of MMP-9. Importantly, the inhibition of histone methylation but not acetylation dampened the synergistic MMP-9 expression. Histone modification profiling further identified the H3K36me2 as an epigenetic regulatory mark of this synergy. Moreover, TGF-β/TNF-α co-stimulation led to increased levels of the transcriptionally permissive dimethylation mark at H3K36 in the MMP-9 promoter. Comparable outcomes were noted in cells deficient in NSD2 histone methyltransferase. In conclusion, our findings support a cooperativity model in which TGF-β could amplify the TNF-α-mediated MMP-9 production via chromatin remodeling and facilitate breast cancer invasion and metastasis.

BackgroundCoronavirus disease 2019 (COVID-19) caused by the coronavirus SARS-CoV-2, has emerged as a rapidly spreading contagious disease across the globe. Recent studies showed that people with diabetes mellitus, severe obesity, and cardiovascular disease are at higher risk of mortality from COVID-19. It has been suggested that the increased risk is due to the chronic inflammatory state associated with type 2 diabetes. This study aimed to evaluate the efficacy of pioglitazone, a strong insulin sensitizer with anti-inflammatory properties, in improving the clinical outcomes of patients with type 2 diabetes admitted with moderate–severe COVID-19.MethodWe enrolled 350 patients with type 2 diabetes who were admitted to hospitals in Qatar and Kuwait with COVID-19. Patients were randomized to receive, in a double-blind fashion, pioglitazone (n = 189) or a matching placebo (n = 161) for 28 days. The study had two primary outcomes: (1) the incidence of a composite outcome composed of (a) the requirement for mechanical ventilation, (b) death, and (c) myocardial damage; and (2) an increase in C-reactive protein (CRP) levels.ResultsThe first primary outcome occurred in 28 participants (8%), and the secondary outcome occurred in 17. Treatment with pioglitazone showed a significant reduction in interleukin (IL)-3 levels compared with placebo treatment (mean (SD) 2.73 (± 2.14) [95% CI: 0.02, 1.1], p = 0.043 vs. 2.28 (± 1.67) [95% CI: − 0.23, 0.86], p = 0.3, respectively), with no effect seen in the levels of other inflammatory markers. Even though not significant, a few of the patients on pioglitazone exhibited serum troponin levels > 3 times higher than the normal range seen in patients on placebo. On the other hand, more patients on pioglitazone were admitted to the ICU than those with placebo, and no significant difference in the CRP reduction was observed between the two groups.ConclusionThe results of the present study demonstrate that pioglitazone treatment did not independently provide any additional clinical benefit to patients with type 2 diabetes admitted with a COVID-19 infection.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT04604223.

Non-steroidal anti-inflammatory drugs like paracetamol, which have strong antibacterial and analgesic properties, are frequently employed in medicine. On the other hand, fulminant liver necrosis and other adverse reactions can result from paracetamol exposure. The development of useful analytical techniques is therefore necessary to identify and quantify paracetamol. Green determination techniques have been thoroughly studied in the last few years because of their simplicity, increased sensitivity and selectivity, and cost-effectiveness. The development of determination methods for quantification the presence of paracetamol in drugs and biological products has advanced, as this review details. The advancement in techniques for the selective detection of paracetamol during the past years was studied. In particular, the emphasis is on the inventive aspects brought about by spectrophotometry, chromatography, and automated devices. There is a lot of reviews on this topic, but no one has assessed the greenness of paracetamol determination approaches in biological samples. The two greenness scales were utilized for calculating the results. Analytical GREEnness Calculator (AGREE) and Complementary Green Analytical Procedure Index (ComplexGAPI) are simple, free, and sensitive programs.

Introduction: The current research was conducted to estimate the loss of crestal bone using the flap and flapless method for implant placement. Materials and Methods: Forty participants who fulfilled the addition criteria were chosen for this research. All participants were then categorized equally into two study groups, that is, with and without undergoing flap surgery. Statistical evaluation was performed using the Mann-Whitney U-test. Results: Flapless implant placement showed lesser crestal bone loss. Conclusion: Compared to flap surgery, seamless implant implantation showed less loss of crestal bone.

Objectives: This study was conducted to evaluate the efficacy of turmeric, ashwagandha, and aloe vera in the management of oral lichen planus (OLP) lesion. Materials and Methods: Thirty patients with histologically confirmed symptomatic OLP with gingival presentation were included in this comparative investigation. Three groups of participants were created: Group I consisted of turmeric; group II included ashwagandha; and group III included aloe vera. For 3 weeks in a row, they were told to apply topical treatments twice a day. The patients were recalled for 4 to evaluate the cessation of symptoms. Result: The participants in all the groups showed a considerable improvement in the burning lesion size and pain after 4 months of follow-up. Conclusion: For the treatment of OLP, turmeric, ashwagandha, and aloe vera can be useful as substitute topical medications, particularly for those who are not responsive to topical corticosteroids.