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Abstract Pregnenolone is a key intermediate in the biosynthesis of many steroid hormones and neuroprotective steroids. Sulfotransferase family cytosolic 2B member 1 (SULT2B1a) has been reported to be highly selective to sulfate pregnenolone. This study aimed to clarify the effect of missense single nucleotide polymorphisms (SNPs) of the human SULT2B1 gene on the sulfating activity of coded SULT2B1a allozymes toward Pregnenolone. To investigate the effects of single nucleotide polymorphisms of the SULT2B1 gene on the sulfation of pregnenolone by SULT2B1a allozymes, 13 recombinant SULT2B1a allozymes were generated, expressed, and purified using established procedures. Human SULT2B1a SNPs were identified by a comprehensive database search. 13 SULT2B1a nonsynonymous missense coding SNPs (cSNPs) were selected, and site-directed mutagenesis was used to generate the corresponding cDNAs, packaged in pGEX-2TK expression vector, encoding these 13 SULT2B1a allozymes, which were bacterially expressed in BL21 E. coli cells and purified by glutathione-Sepharose affinity chromatography. Purified SULT2B1a allozymes were analyzed for sulfating activities towards pregnenolone. In comparison with the wild-type SULT2B1a, of the 13 allozymes, 11 showed reduced activity toward pregnenolone at 0.1 µM. Specifically, P134L and R259Q allozymes, reported to be involved in autosomal-recessive congenital ichthyosis, displayed low activity (1–10%) toward pregnenolone. The findings of this study may demonstrate the impact of genetic polymorphism on the sulfation of pregnenolone in individuals with different SULT2B1 genotypes.

Objective: Lung cancer (LC) has the highest mortality rate globally. Most chemotherapeutic medicines now in use are cytotoxic, prompting the search for novel compounds with anticancer properties and improved safety profiles for normal cells. Dipeptidyl peptidase-4 inhibitors have demonstrated anticancer effects and apoptotic properties by specifically inhibiting dipeptidyl peptidase-4, a glycoprotein found in various organs that support the spread of cancer and tumor formation. Based on that, this study aimed to evaluate the cytotoxicity and apoptotic activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line (A549) alone and in combination with cisplatin (CP). Methods: A549 cells were categorized into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA treated cells (1:1 ratio), and CP plus LINA treated cells (1:1 ratio). After 72 hours of incubation, cell viability (or cytotoxicity) and concentration required to inhibit 50% of cell viability (IC50) for each group were determined using an MTT assay. This method is safe and easy to use, has more reproducibility, and is commonly used for cell viability and cytotoxicity tests. Later, A549 cells were cultured in six flasks and exposed to the IC50 for 36 hours. Afterward, the cells were harvested and centrifuged, and the supernatant was removed. The remaining cell pellets were collected and lysed using a lysis buffer to measure B-cell lymphoma type 2 (BCL-2) levels with ELISA test kits. The data was collected and subjected to statistical analysis techniques. Results: MTT assay results determined that SITA and LINA significantly increased A549 cell cytotoxicity compared to the control group (P<0.0001). Moreover, combining SITA or LINA with CP showed markedly increased antitumor efficacy and more significant cytotoxicity directed toward A549 cells. Additionally, these combinations highly reduced IC50 in comparison to monotherapy. Considerably, both drugs showed remarkable apoptotic activity on A549 cells when used alone or combined with CP by decreasing BCL2 levels. Consequently, it potentiates apoptotic effects and cytotoxicity of CP against cancer cells. Interestingly, Lina was more potent than Sita regarding cytotoxicity and apoptotic activity on A549 cells. Conclusion: SITA and Lina exhibited significant cytotoxic and apoptotic effects against A549 cells through the induction of apoptosis. Notably, the results suggest a potential synergistic anticancer impact on CP. [ABSTRACT FROM AUTHOR]

Lung cancer has the highest global fatality rate of all cancers, and most existing therapies have a wide range of toxic effects. This necessitates searching for new medications with potential anticancer properties and a better safety profile against normal cells. Dipeptidyl peptidase-4 (DPP4) inhibitors have recently shown anticancer efficacy in various malignancies such as colorectal, prostate, and renal cancer. Therefore, this study investigated the anticancer activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line A549 alone and in combination with cisplatin (CP). A549 cells were divided into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA-treated cells (ratio 1:1), and CP plus LINA-treated cells (ratio 1:1). After 72 hours of incubation, a 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) test was used to determine cell viability and the concentration of 50% inhibition for cell viability (IC50) for each group. A549 cells were later seeded in six flasks and treated with the resulting IC50; cell pellets were collected and lysed to determine the malondialdehyde (MDA) level using ELISA kits. SITA and LINA therapy dramatically reduced A549 cell viability compared to the control (P < 0.0001), with results comparable to CP. When SITA and LINA were combined with CP, they demonstrated significantly higher anticancer efficacy than when used alone. Notably, both medicines lowered MDA levels when taken alone or in combination with CP. SITA and LINA showed promising anticancer and antioxidant activity against A549 cells. This may indicate a potential synergistic anticancer effect with CP. [ABSTRACT FROM AUTHOR]

Lung cancer possesses the most significant worldwide mortality rate among all types of tumors, and the majority of current treatments exhibit a broad spectrum of adverse reactions. This requires investigating novel drugs that can inhibit the growth of cancer cells while minimizing harm to normal cells. Recent studies have demonstrated that Dipeptidyl peptidase-4 (DPP4) inhibitors can effectively suppress the growth of cancer cells in several types of malignancies, including colorectal, prostate, and kidney cancers. Hence, this study evaluated the effectiveness of sitagliptin in suppressing the proliferation of lung carcinoma cells (A549) alone as well as in conjunction with cisplatin. A549 cells were divided into four groups: control (untreated cells), cells treated with cisplatin, cells treated with sitagliptin, and cells treated with cisplatin plus sitagliptin combination (ratio 1:1). After incubation for 72 hours, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl2H-tetrazolium bromide (MTT) test was utilized to evaluate cell viability percent and concentration of 50% inhibition for cell viability (IC50) for each group. Then, A549 cells were cultured into four flasks and exposed to the IC50 concentration. The resulting cell pellets were gathered and subjected to lysis to assess the malondialdehyde (MDA) level using ELISA kits. The vitality of A549 cells was significantly reduced by Sitagliptin therapy compared to the control (P < 0.0001). When the combination of sitagliptin and cisplatin was administered, it exhibited markedly superior anticancer effectiveness compared to their usage alone. Significantly, sitagliptin reduced MDA levels, whether used individually or in combination with cisplatin. As a result, sitagliptin exhibited significant anticancer and antioxidant properties against A549 cells. This suggests a possible synergistic anticancer effect with cisplatin. [ABSTRACT FROM AUTHOR]

Introduction In the human body, the adrenal cortex constitutes a major site for the biosynthesis and secretionofa varietyof steroid hormones including pregnenolone, dehydroepiandrosterone (DHEA), and androstenedione (Turcu et al. 2014). [...], The cytosolic sulfotransferase (SULT) SULT2A1 is known to mediate the sulfation of DHEA as well as some other hydroxysteroids such aspregnenolone. The present study was designedtoinvestigate how genetic polymorphismsof the human SULT2A1 gene may affect the sulfation of DHEA and pregnenolone. Online databases were systematically searched to identify human SULT2A1 single nucleotide polymorphisms (SNPs). Of the 98 SULT2A1 non-synonymous coding SNPs identified, seven were selected for further investigation. Site-directed mutagenesis was used to generate cDNAs encoding these seven SULT2A1 allozymes, which were expressed in BL21 Escherichia coli cells and purified by glutathione-Sepharose affinity chromatography. Enzymatic assays revealed that purified SULT2A1 allozymes displayed differential sulfating activity toward both DHEA and pregnenolone. Kinetic analyses showed further differential catalytic efficiency and substrate affinity of the SULT2A1 allozymes, in comparison with wild-type SULT2A1. These findings provided useful information concerning the effects of genetic polymorphisms on the sulfating activity of SULT2A1 allozymes. Key words: single nucleotide polymorphisms, cytosolic sulfotransferase, SULT, SULT2A1, sulfation, dehydroepiandrosterone, DHEA, pregnenolone. La sulfotransferase (SULT) cytosolique SULT2A1 est connue pour catalyser la sulfatation de la dehydroepiandrosterone (DHEA) de meme que d&apos;autres hydroxysteroides comme la pregnenolone. La presente etude a ete concue pour examiner comment les polymorphismes genetiques du gene SULT2A1 humain peuvent affecter la sulfatation de la DHEA et de la pregnenolone. Des bases de donnees en ligne ont ete systematiquement fouillees afin d&apos;identifier des polymorphismes mononucleotidiques (SNP) deSULT2A1 humain. Des 98 SNP codants non-synonymes de SULT2A1 identifies, sept ont ete choisis pour des etudes plus approfondies.La mutagenese dirigee aete utilisee pour generer des ADNc codant ces sept allozymes de SULT2A1, qui ont ete exprimees chez Escherichia coli BL21 et purifiees par chromatographie d&apos;affinite sur glutathion-Sepharose. Les dosages enzymatiques ont revele que les allozymes de SULT2A1 purifiees presentaient des activites de sulfatation differentielles envers la DHEA et la pregnenolone. Les analyses cinetiques ont en outre montre la differenciation de l&apos;efficacite catalytique et de l&apos;affinite pour les substrats des allozymes de SULT2A1, comparativement a SULT2A1 sauvage. Ces resultats ont fourni une information utile en ce qui concerne les effets des polymorphismes genetiques sur l&apos;activite de sulfatation des allozymes de SULT2A1. [Traduit par la Redaction] Mots-cles : polymorphismes mononucleotidiques, sulfotransferase cytosolique, SULT, SULT2A1, sulfatation, dehydroepiandrosterone, DHEA, pregnenolone.

Abstract New ways for comparing and bounding strongly ( s , m ) $(s,m)$ -convex functions using Caputo fractional derivatives and Caputo-Fabrizio integral operators are explored. These operators generalize some classic inequalities of Hermite-Hadamard for functions with strongly ( s , m ) $(s,m)$ -convex derivatives. The findings are also applied to special functions and means involving the digamma function. Additionally, we relate our findings to applications in biomedicine, engineering, robotics, the automotive industry, and electronics.

Abstract Breast cancer is one of the most common causes of death in women in the modern world. Cancerous tissue detection in histopathological images relies on complex features related to tissue structure and staining properties. Convolutional neural network (CNN) models like ResNet50, Inception‐V1, and VGG‐16, while useful in many applications, cannot capture the patterns of cell layers and staining properties. Most previous approaches, such as stain normalization and instance‐based vision transformers, either miss important features or do not process the whole image effectively. Therefore, a deep fusion‐based vision Transformer model (DFViT) that combines CNNs and transformers for better feature extraction is proposed. DFViT captures local and global patterns more effectively by fusing RGB and stain‐normalized images. Trained and tested on several datasets, such as BreakHis, breast cancer histology (BACH), and UCSC cancer genomics (UC), the results demonstrate outstanding accuracy, F1 score, precision, and recall, setting a new milestone in histopathological image analysis for diagnosing breast cancer.

Polycystic ovary syndrome (PCOS) is the most common endocrinology disorder affecting women of reproductive age, characterized by irregular menstruation, androgen overproduction and insulin resistance. Peroxisome proliferator-activated receptor-gamma (PPARG) is one of the essential modulators of ovarian steroid hormone synthesis and lipid metabolism. Precision medicine and targeted therapy have emerged as practical therapeutic approaches, focusing on specific molecules/pathways to minimize side effects and improve outcomes. This study aimed to identify potential Indonesian phytoconstituents that inhibit PPARG both from a pharmacokinetic and pharmacodynamic perspective based on the in silico approach. Data of 6776 phytoconstituents from the Indonesian Medicinal Plant Database were screened for compounds with Pa>0.3 as “Insulin Sensitivity”, “Lipid metabolism”, and “Anti-inflammation” using PASSOnline. We performed pharmacokinetic profile prediction using SwissADME based on Lipinski criteria. Molecular docking was carried out with PPARG as the target proteins, utilizing PyMol, Pyrx, and Discovery Studio to evaluate top-hit compounds with the highest binding affinity. Through in silico screening and molecular docking, Quercitol exhibited superior binding with the protein target compared to the control ligands and metformin. Quercitol also met the Lipinski criteria, showing favourable bioavailability as a drug candidate. Hence, these findings will provide a theoretical basis for further studies as regards drugs targeting PPARG in PCOS.

As the financialization issue is getting more and more attention, the behavioral motives and effects behind this appearance should not be ignored, and it is of great practical significance for the high-quality development of China's real economy to explore the impact and mechanism of the financialization trend on the investment and financing maturity mismatch of China's real enterprises. Using sample data of Chinese A-share listed companies from 2013 to 2020, this article empirically examines the impact of financialization on the investment and financing maturity structure from a new perspective of asset classification by using a fixed-effect model, and explores the mechanism of the financial regulatory environment's moderating effect on the relationship between the two mentioned above. The study shows that: there is an inverted U-shaped nonlinear relationship between the financialization of investment income and fixed income and “maturity mismatch “. The term mismatch of investment and financing increases with the degree of financialization, after reaching the critical point, it eases with the deepening of financialization. However, the specific point of view is different. In the sample interval, the investment income financialization exacerbates the investment and financing maturity mismatch more obviously; the fixed income financialization inhibits the investment and financing maturity mismatch more obviously. Under the different perspectives of the firms' ownership nature, financing constraints, and principal-agent problems, there are differences in the impact of firms' allocation of different types of financial assets on the investment and financing term structure. In addition, the regulatory effect of financial supervision weakens the inverted U-shaped relationship of investment income financialization with investment and financing maturity mismatch; it enhances the inverted U-shaped relationship between fixed income financialization and investment and financing maturity mismatch. In general, financial supervision has had a significant positive effect on investment and financing maturity mismatches. The findings have important policy implications in terms of corporate real investment, financial market development, and financial regulation, which can help promote China's economic development and stability.

We propose a new definition of the γ-convex stochastic processes (CSP) using center and radius (CR) order with the notion of interval valued functions (C.RI.V). By utilizing this definition and Mean-Square Fractional Integrals, we generalize fractional Hermite–Hadamard–Mercer-type inclusions for generalized C.RI.V versions of convex, tgs-convex, P-convex, exponential-type convex, Godunova–Levin convex, s-convex, Godunova–Levin s-convex, h-convex, n-polynomial convex, and fractional n-polynomial (CSP). Also, our work uses interesting examples of C.RI.V(CSP) with Python-programmed graphs to validate our findings using an extension of Mercer’s inclusions with applications related to entropy and information theory.

A variety of bacteria, yeasts, and fungi colonize the aerial parts of plants termed as phyllosphere. Study of phylloshpere has gained considerable attention focusing on new non-invasive methods and bio-control agents of plant-associated microorganisms. The present study was designed to isolate microbes from phyllosphere of Olea europaea and assess their biofilm forming ability. Further, correlation between biofilm formation and ultraviolet (UV) radiation was observed. In total, four strains L1, L2, L3 and L4 were screened and purified from phyllosphere of O. europaea. Biochemical characterization and 16srRNA sequencing identified these strains as Erwinia herbicola (MN905123), Micrococcus luteus (MN905159), Pseudomonas syringae (MN905161) and Bacillus subtilis (MN905164). Physiological characterization revealed that strains exhibited optimum growth at pH 7 and temperature 37°C. Biofilm formation showed B. subtilis as the strongest biofilm former. Afterwards, UV radiation at various time intervals i.e., 3, 4, and 15 minutes indicated that bacterial biofilm was resistant upto 10 minutes UV exposure. A significant decrease (p=0.01) in biofilm formation of mutant strains was observed after 15 minutes UV exposure thus pointing towards significantly reduced activity of the DNA repair gene. This study provided evidence that environments exposed to desiccation and/ambient UV radiations could principally select for highly resistant microbial biofilms organisms against ionizing radiations, enabling these to withstand extreme conditions. [ABSTRACT FROM AUTHOR]

BackgroundGlaucoma is a leading cause of irreversible blindness globally and for decades, Molteno and Ahmed glaucoma implants, operating on different mechanisms, have been used to treat complicated glaucoma with varying success.ObjectiveTo assess the safety and efficacy of the Molteno glaucoma implant (MGI) versus the Ahmed glaucoma valve (AGV) in patients with complicated glaucoma.MethodsWe comprehensively searched PubMed, Google Scholar, Cochrane Library and Science Direct) from inception till July 2023 and studies comparing patients with MGI and those with AGV in patients with complicated glaucoma. The primary outcome was intra-ocular pressure reduction at different time intervals. Secondary outcomes included surgical success rate, hypertensive phase, anti-glaucoma medication (AGM) and total complications. ResultsIn this meta-analysis, four studies were included with a patient population of 257 with refractory, neovascular or advanced uncontrolled glaucoma. Postoperative intra-ocular pressure reduction did not show significant difference between the two groups (MD: -1.34, 95% CI [-2.78, 0.09]). From the secondary outcomes, surgical success rate (RR: 0.88, 95% CI [0.51,1.53]), hypertensive phase (RR: 0.74, 95% CI [0.39,1.40]) were insignificant. Postoperative anti-glaucoma medication (MD: -0.07, 95% CI [-0.79, -0.65] and total complications (RR:1.36, 95% CI [1.07, 1.72]) were significant. ConclusionNo significant difference was observed between the patients with MGI and AGV for the primary outcome. From the secondary outcome, AGV was associated with reduced anti-glaucoma medication use and significantly lowered the number of complications.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=475539, identifier CRD42023475539.