Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)/ IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations.

In this study, novel substituted 1,3,5-triazine candidates (4a-d, 5a-j, and 6a-d) were designed as second-generation small molecules to act as dual IDH1 and IDH2 inhibitors according to the pharmacophoric features of both vorasidenib and enasidenib. Compounds 6a and 6b for leukemia cell lines showed from low to sub-micromolar GI50. Moreover, compounds 4c, 5f, and 6b described the frontier antitumor activity against THP1 and Kasumi Leukemia cancer cells with IC50 values of (10 and 12), (10.5 and 7), and (6.2 and 5.9) µg/mL, which were superior to those of cisplatin (25 and 28) µg/mL, respectively. Interestingly, compounds 4c, 6b, and 6d represented the best dual IDH1(R132H)/IDH2(R140Q) inhibitory potentials with IC50 values of (0.72 and 1.22), (0.12 and 0.93), and (0.50 and 1.28) µg/mL, respectively, compared to vorasidenib (0.02 and 0.08) µg/mL and enasidenib (0.33 and 1.80) µg/mL. Furthermore, the most active candidate (6b) has very promising inhibitory potentials towards HIF-1α, VEGF, and SDH, besides, a marked increase of ROS was observed as well. Besides, compound 6b induced the upregulation of P53, BAX, Caspases 3, 6, 8, and 9 proteins by 3.70, 1.99, 2.06, 1.73, 1.75, and 1.85-fold changes, respectively, and the downregulation for the BCL-2 protein by 0.55-fold change compared to the control. Besides, the in vivo behavior of compound 6b as an antitumor agent was evaluated in female mice bearing solid Ehrlich carcinoma tumors. Notably, compound 6b administration resulted in a prominent decrease in the weight and volume of the tumors, accompanied by improvements in biochemical, hematological, and histological parameters.

Repurposing the drug, amprolium as a novel molluscicide against the land snail (Eobania vermiculata).

Amprolium (AMP) is an organic compound used as a poultry anticoccidiostat. The aim of this work is to repurpose AMP to control the land snail, Eobania vermiculata in the laboratory and in the field. When snails treated with ½ LC50 of AMP, the levels of alkaline phosphatase (ALP), total lipids (TL), urea, creatinine, malondialdehyde (MDA), catalase (CAT), and nitric oxide (NO) were significantly increased, whereas the levels of acetylcholinesterase (AChE), total protein (TP), and glutathione (GSH) decreased. It also induced histopathological and ultrastructural changes in the digestive gland, hermaphrodite gland, kidney, mucus gland, and cerebral ganglion. Furthermore, scanning electron micrographs revealed various damages in the tegumental structures of the mantle-foot region of E. vermiculata snails. The field application demonstrated that the AMP spray caused reduced percentages in snail population of 75 and 84% after 7 and 14 days of treatment. In conclusion, because AMP disrupts the biology and physiology of the land snail, E. vermiculata, it can be used as an effective molluscicide.

Exploring chromone-2-carboxamide derivatives for triple-negative breast cancer targeting EGFR, FGFR3, and VEGF pathways: Design, synthesis, and preclinical insights.

Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA-MB-231, the triple-negative breast cancer cell line, was found to be the most sensitive, where the N-(2-furylmethylene) (15) and the α-methylated N-benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 µM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA-MB-231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0-G1 and G2-M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.

Anti-inflammatory and anti-oxidant activities of mesenchymal stem cells in chemically induced arthritic rats.

BACKGROUND: Mesenchymal stem cells (MSCs) have been extensively used as cell-based treatments for decades due to their anti-inflammatory, immunomodulatory, and healing abilities. The intent of our study was to determine the efficacy of MSCs in alleviating rheumatoid arthritis (RA) induced by Complete Freund's adjuvant (CFA) and to investigate the anti-inflammatory and antioxidant characteristics of MSCs. METHODS AND RESULTS: Intrapedally injecting 0.1 ml of CFA directly into the footpad of the right hind paw daily for 2 days was used to induce RA. Arthritic rats received four doses of MSCs (1 × 106 cells/rat/dose) intravenously through the lateral tail vein. Our results showed that arthritic rats treated with MSCs exhibited reduced levels of paw edema. Furthermore, arthritic rats treated with MSCs exhibited a significant decrease in the levels of RF, CRP, IL-1ß, TNF-α, IL-17 and ADAMTS-5, along with a significant increase in the levels of IL-4 and TIMP-3. Additionally, MSCs significantly reduced the expression of TGF-ß. Both the glutathione (GSH) content and antioxidant activity of GST were enhanced by MSCs, while LPO levels were suppressed. CONCLUSION: These findings provide further evidence that MSCs are valuable in treating RA, possibly due to their anti-inflammatory and anti-oxidative properties. Thus, MSCs have potential as a more effective therapeutic strategy for treating RA.

Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.

Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main  contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.

Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: the roles of oxidative stress, inflammation and cell apoptosis.

This study was designed to assess the preventive effects and to suggest the probable mechanisms of action of quercetin and naringein in diethylnitrosamine (DEN)/2-acetylaminofluorene (2AAF)-induced hepatocarcinogenesis in Wistar male rats. The chemical-induction of hepatocarcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg body weight (b.w.) twice/week for two weeks, followed by oral administration of 2AAF at 20 mg/kg body weight (b.w.) 4 times/week for 3 weeks. The DEN/2AAF-administered rats were co-treated with quercetin and naringenin at dose level of 10 mg/kg b. w. by oral gavage for 20 weeks. The treatment of DEN/2AAF-administered rats with quercetin and naringenin significantly prevented the elevations in serum levels of liver function indicators (ALT, AST, ALP, γ-GT, total bilirubin and albumin) and liver tumor biomarkers including AFP, CEA and CA19.9. The cancerous histological lesions and inflammatory cells infiltration in liver of DEN/2AAF-administered rats were remarkably suppressed by treatments with quercetin and naringenin. The hepatic oxidative stress markers including NO level and lipid peroxidation significantly decreased while the SOD, GPx and CAT activities and GSH content significantly increased in DEN/2AAF-administered rats treated with quercetin and naringenin when compared to DEN/2AFF-administered control rats. Furthermore, the lowered mRNA expression of liver IL-4, P53 and Bcl-2 in of DEN/2AAF-administered rats were significantly counteracted by treatment with quercetin and naringenin. Taken together, our results demonstrate that quercetin and naringenin may abate hepatocarcinogenesis via enhancement of anti-inflammatory, anti-oxidant and apoptotic actions.

A Novel ERK2 Degrader Z734 Induces Apoptosis of MCF-7 Cells via the HERC3/p53 Signaling Pathway.

Breast cancer is one of the leading causes of death worldwide, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as ERK inhibitors and degraders, have been intensively investigated. The targets of ERK participate in the regulation of critical cellular mechanisms and underpin the progression of anticancer therapy. In this study, we identified a novel small molecule, which we named Z734, as a new mitogen-activated protein kinase 1 (ERK2) degrader and demonstrated that Z734 inhibits cell growth by inducing p53-mediated apoptotic pathways in human breast cancer cells. Treatment with Z734 resulted in the inhibition of cancer cell proliferation, colony formation and migration invasion, as well as cancer cell death via apoptosis. In addition, the Co-IP and GST pulldown assays indicated that the HECT and RLD domains containing E3 ubiquitin protein ligase 3 (HERC3) could directly interact with ERK2 through the HECT domain, promoting ERK2 ubiquitination. We also observed a strong link between HERC3 and p53 for the modulation of apoptosis. HERC3 can increase the protein and phosphorylation levels of p53, which further promotes apoptotic activity. In a xenograft mouse model, the effect was obtained in a treatment group that combined Z734 with lapatinib compared with that of the single-treatment groups. In summary, our results indicated that Z734 actively controls the development of breast cancer through apoptosis, and HERC3 may mediate ERK2 and p53 signaling, which offers new potential targets for clinical therapy.

Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met.

c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.

Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer.

BACKGROUND: ErbB2 overexpression identifies a subset of breast cancer as ErbB2-positive and is frequently associated with poor clinical outcomes. As a membrane-embedded receptor tyrosine kinase, cell surface levels of ErbB2 are regulated dynamically by membrane physical properties. The present study aims to investigate the influence of membrane cholesterol contents on ErbB2 status and cellular responses to its tyrosine kinase inhibitors. METHODS: The cholesterol abundance was examined in ErbB2-positive breast cancer cells using filipin staining. Cellular ErbB2 localizations were investigated by immunofluorescence with altered membrane cholesterol contents. The inhibitory effects of the cholesterol-lowering drug lovastatin were assessed using cell proliferation, apoptosis, immunoblotting and immunofluorescence assays. The synergistic effects of lovastatin with the ErbB2 inhibitor lapatinib were evaluated using an ErbB2-positive breast cancer xenograft mouse model. RESULTS: Membrane cholesterol contents positively correlated with cell surface distribution of ErbB2 through increasing the rigidity and decreasing the fluidity of cell membranes. Reduction in cholesterol abundance assisted the internalization and degradation of ErbB2. The cholesterol-lowering drug lovastatin significantly potentiated the inhibitory effects of ErbB2 kinase inhibitors, accompanied with enhanced ErbB2 endocytosis. Lovastatin also synergized with lapatinib to strongly suppress the in vivo growth of ErbB2-positive breast cancer xenografts. CONCLUSION: The cell surface distribution of ErbB2 was closely regulated by membrane physical properties governed by cholesterol contents. The cholesterol-lowering medications can hence be exploited for potential combinatorial therapies with ErbB2 kinase inhibitors in the clinical treatment of ErbB2-positive breast cancer.

A Review on the Efficacy of Plant-derived Bio-active Compounds Curcumin and Aged Garlic Extract in Modulating Cancer and Age-related Diseases.

Aging is a process characterized by accumulating degenerative changes resulting in the death of an organism. Aging is mediated by various pathways that are directly linked to the individual's lifespan and are shunted for many age-related diseases. Many strategies for alleviating age-related diseases have been studied, which can target cells and molecules. Modern drugs such as Metformin, Rapamycin, and other drugs are used to reduce the effects of age-related diseases. Despite their beneficial activity, they possess some side effects which can limit their applications, mainly in older adults. Natural phytochemicals which have anti-aging activities have been studied by many researchers from a broader aspect and suggested that plant-based compounds can be a possible, direct, and practical way to treat age-related diseases which has enormous anti-aging activity. Also, studies indicated that the synergistic action of phytochemicals might enhance the biological effect rather than the individual or summative effects of natural compounds. Curcumin has an antioxidant property and is an effective scavenger of reactive oxygen species. Curcumin also has a beneficial role in many age-related diseases like diabetes, cardiovascular disease, neurological disorder, and cancer. Aged garlic extracts are also another bioactive component that has high antioxidant properties. Many studies demonstrated aged garlic extract, which has high antioxidant properties, could play a significant role in anti-aging and age-related diseases. The synergistic effect of these compounds can decrease the requirement of doses of a single drug, thus reducing its side effects caused by increased concentration of the single drug.

Uncovering the Therapeutic Potential of Phosphocreatine in Diabetic Retinopathy: Mitigating Mitochondrial Dysfunction and Apoptosis via JAK2/STAT3 Signaling Pathway.

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.

Phytochemicals, Antioxidant, and Antidiabetic Effects of Ranunculus hirtellus Aerial Parts and Roots: Methanol and Aqueous Extracts.

Ranunculus hirtellus, also known as crowfoot (buttercup), has a rich tradition of use in various biological contexts. While antibacterial studies on extracts from this plant have been conducted, the phytochemical composition, antioxidant properties, and antidiabetic effects remain unexplored. In this study, the phytochemical, antioxidant, and antidiabetic effects of its methanol and aqueous extracts were investigated. Our approach involved gas chromatography-mass spectrometry (GC/MS), alongside quantitative and qualitative methods, for phytochemical profiles. Additionally, concerning biological activities, the antioxidant effect was assessed through 2, 2-diphenyl-pieryl hydrazyl (DPPH) and 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays, while the antidiabetic effect was examined through the α-amylase inhibitory assay. The chloroform, ethyl acetate, and n-hexane extracts of R. hirtellus revealed the presence of 14 distinct compounds. In the methanol extract, sterols, quinones, glycosides, lactones, lignin, and flavonoids were identified. The aqueous extract contained sterols, alkaloids, glycosides, triterpenes, terpenoids, quinones, leucoanthocyanins, and lactones. The total flavonoid content (TFC), total phenolic content (TPC), total tannin content (TTC), and reducing sugar content (RDC) were determined in plant extracts, and a linear relationship was found between these parameters. Additionally, the TTC, TPC, and TFC values for both extracts hovered around 0.3786, 0.0476, and 0.1864 µg/mL, respectively, across all plant concentrations, while RDC ranged from 0.9336 to 1.0119 µg/mL in all four extracts. In vitro assays demonstrated dose-dependent antidiabetic activity in both methanolic and aqueous extracts by inhibiting α-amylase. Furthermore, the antioxidant activity observed in the DPPH assay was greater in the aqueous extract compared with the methanolic extract. In addition, the ethyl acetate extract exhibited the highest inhibition among chloroform and n-hexane in the ABTS assay. The results suggest that R. hirtellus can be a potential source of natural antioxidants and antidiabetic agents, and further studies are warranted to investigate the underlying mechanisms of its therapeutic effects.

Thorough examination of the potential biological implications of the cuproptosis-related gene LIPT2 in the prognosis and immunotherapy in pan-cancer.

OBJECTIVES: To elucidate the expression levels and prognostic value of the Lipoyltransferase 2 (LIPT2) gene in a pan-cancer view. METHODOLOGY: Our study comprehensively investigated the role of LIPT2 in pan-cancer, combining bioinformatics analyses with experimental validations. RESULTS: Analysis of LIPT2 mRNA expression across various cancers revealed a significant up-regulation in 18 tumor types and down-regulation in 8 types, indicating its diverse involvement. Prognostic assessment demonstrated a correlation between elevated LIPT2 expression and poorer outcomes in Overall Survival (OS) and Disease-Free Survival (DFS), particularly in Glioblastoma Multiforme (GBM), Liver Hepatocellular Carcinoma (LIHC), and Pheochromocytoma and Paraganglioma (PCPG). Protein expression analysis in GBM, LIHC, and PCPG affirmed a consistent increase in LIPT2 levels compared to normal tissues. Examining the methylation status in GBM, LIHC, and PCPG, we found reduced promoter methylation levels in tumor samples, suggesting a potential influence on LIPT2 function. Genetic mutation analysis using cBioPortal indicated a low mutation frequency (< 2%) in LIPT2 across GBM, LIHC, and PCPG. Immune correlation analysis unveiled a positive association between LIPT2 expression and infiltration levels of immune cells in GBM, LIHC, and PCPG. Single-cell analysis illustrated LIPT2's positive correlation with functional states, including angiogenesis and inflammation. Enrichment analysis identified LIPT2-associated processes and pathways, providing insights into its potential molecular mechanisms. Drug sensitivity analysis demonstrated that elevated LIPT2 expression conferred resistance to multiple compounds, while lower expression increased sensitivity. Finally, RT-qPCR validation in HCC cell lines confirmed the heightened expression of LIPT2 compared to a control cell line, reinforcing the bioinformatics findings. CONCLUSION: Overall, our study highlights LIPT2 as a versatile player in cancer, influencing diverse aspects from molecular processes to clinical outcomes across different cancer types.

UPLC-qTOF-MS phytochemical profile of Commiphora gileadensis leaf extract via integrated ultrasonic-microwave-assisted technique and synthesis of silver nanoparticles for enhanced antibacterial properties.

The utilization of metallic nanoparticles in bio-nanofabrication holds significant potential in the field of applied research. The current study applied and compared integrated ultrasonic-microwave-assisted extraction (US/MICE), ultrasonic extraction (USE), microwave-assisted extraction (MICE), and maceration (MAE) to extract total phenolic content (TPC). In addition, the study examined the antioxidant activity of Commiphora gileadensis (Cg) leaf. The results demonstrated that the TPC of US/MICE exhibited the maximum value at 59.34 ± 0.007 mg GAE/g DM. Furthermore, at a concentration of 10 µg/mL, TPC displayed a significant scavenging effect on DPPH (56.69 %), with an EC50 (6.48 µg/mL). Comprehensive metabolite profiling of the extract using UPLC-qTOF-MS/MS was performed to identify active agents. A total of 64 chromatographic peaks were found, out of which 60 were annotated. The most prevalent classes of metabolites found were polyphenols (including flavonoids and lignans), organic compounds and their derivatives, amides and amines, terpenes, and fatty acid derivatives. Transmission electron microscopy (TEM) revealed the aggregate size of the synthesized nanoparticles and the spherical shape of C. gileadensis-mediated silver nanoparticles (Cg-AgNPs). The nanoparticles had a particle size ranging from 7.7 to 42.9 nm. The Cg-AgNPs exhibited more inhibition zones against S. aureus and E. coli. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Cg-extract, AgNPs, and Cg-AgNPs were also tested. This study demonstrated the feasibility of using combined ultrasonic-microwave-assisted extraction to separate and extract chemicals from C. gileadensis on a large scale. These compounds have potential use in the pharmaceutical industry. Combining antibacterial and biocompatible properties in materials is vital for designing new materials for biomedical applications. Additionally, the results showed that the biocompatibility of the Ag-NPs using C. gileadensis extracts demonstrated outstanding antibacterial properties.

Pan-cancer analysis of HS6ST2: associations with prognosis, tumor immunity, and drug resistance.

OBJECTIVES: In this comprehensive study spanning 33 malignancies, we explored the differential expression and prognostic significance of Heparan sulfate 6-O-sulfotransferase 2 (HS6ST2). METHODS: TIMER2, UALCAN, and GEPIA2 were used for the expression analysis. cBioPortal was used for mutational analysis. CancerSEA, STRING, and DAVID, were employed for the single cell sequencing data analysis, protein-protein interaction network development, and gene enrichment analyses, respectively. GSCAlite and RT-qPCR were used for drug sensitivity and expression validation analysis. RESULTS: HS6ST2 exhibited significant (P < 0.05) overexpression in multiple cancers. Prognostically, elevated HS6ST2 expression was significantly associated with poor overall survival (OS) in patients with cervical squamous cell carcinoma (CESC), kidney chromophobe (KICH), lung adenocarcinoma (LUAD), and stomach adenocarcinoma (STAD), emphasizing its potential as a prognostic indicator in these cancers. Moreover, HS6ST2 expression correlated with pathological stages in CESC, KICH, LUAD, and STAD patients. Exploration of genetic alterations using cBioPortal unveiled distinct mutational landscapes, with low mutation frequencies in CESC, KICH, LUAD, and STAD. Additionally, reduced DNA methylation in CESC, KICH, LUAD, and STAD suggested a potential link between hypomethylation and heightened HS6ST2 expression. Analysis of immune cell infiltration revealed a positive correlation between HS6ST2 expression and the infiltration of CD8+ T and CD4+ T cells in CESC, KICH, LUAD, and STAD, highlighting its involvement in the tumor immunology processes. Single-cell functional states analysis demonstrated associations between HS6ST2 and diverse cellular processes. Moreover, gene enrichment analysis revealed the involvement HS6ST2 in crucial cellular activities. GSCAlite analysis underscored the potential of HS6ST2 as a therapeutic target, showing associations with drug sensitivity. Finally, experimental validation through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in LUAD tissues confirmed elevated HS6ST2 expression. CONCLUSION: Overall, this study provides a comprehensive understanding of HS6ST2 in CESC, KICH, LUAD, and STAD, emphasizing its potential as a prognostic biomarker and therapeutic target.

Decoding the DSCC1 gene as a pan-cancer biomarker in human cancers via comprehensive multi-omics analyses.

OBJECTIVES: While dysregulation of DSCC1 (DNA Replication And Sister Chromatid Cohesion 1) has been established in breast cancer and colorectal cancer, its associations with other tumors remain unclear. Therefore, this study was launched to explore the role of DSCC1 in pan-cancer. METHODOLOGY: In this study, we investigate the biological functions of DSCC1 across 33 solid tumors, elucidating its role in promoting oncogenesis and progression in various cancers through comprehensive analysis of multi-omics data. RESULTS: We conducted a comprehensive analysis of DSCC1 expression using RNA-seq data from TCGA and GTEx databases across 30 cancer types. Striking variations were observed, with significant overexpression of DSCC1 identified in numerous cancers. Elevated DSCC1 level was strongly associated with poorer prognosis, shorter survival, and advanced tumor stages in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), as indicated by Kaplan-Meier curves and GEPIA2 analysis. Further investigation into the molecular mechanisms revealed reduced DNA methylation in the DSCC1 promoter region in KIRP, LIHC, and LUAD, supporting enhanced RNA transcription. Protein expression analysis via the Human Protein Atlas (HPA) corroborated mRNA expression findings, showcasing elevated DSCC1 protein in KIRP, LIHC, and LUAD tissues. Mutational analysis using cBioPortal revealed alterations in 0.4% of KIRP, 17% of LIHC, and 5% of LUAD samples, predominantly characterized by amplification. Immune cell infiltration analysis demonstrated robust positive correlations between DSCC1 expression and CD8+ T cells, CD4+ T cells, and B cells, influencing the tumor microenvironment. STRING and gene enrichment analyses unveiled DSCC1's involvement in critical pathways, emphasizing its multifaceted impact. Notably, drug sensitivity analysis highlighted a significant correlation between DSCC1 mRNA expression and responses to 78 anticancer treatments, suggesting its potential as a predictive biomarker and therapeutic target for KIRP, LIHC, and LUAD. Finally, immunohistochemistry staining of clinical samples validated computational results, confirming elevated DSCC1 protein expression. CONCLUSION: Overall, this study provides comprehensive insights into the pivotal role of DSCC1 in KIRP, LIHC, and LUAD initiation, progression, and therapeutic responsiveness, laying the foundation for further investigations and personalized treatment strategies.

Unraveling the Anticancer Potential of Statins: Mechanisms and Clinical Significance.

Statins are an essential medication class in the treatment of lipid diseases because they inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. They reduce cholesterol levels and reduce the risk of cardiovascular disease in both primary and secondary prevention. In addition to their powerful pharmacologic suppression of cholesterol production, statins appear to have pleitropic effects in a wide variety of other diseases by modulating signaling pathways. In recent years, statins have seen a large increase in interest due to their putative anticancer effects. Statins appear to cause upregulation or inhibition in key pathways involved in cancer such as inhibition of proliferation, angiogenesis, and metastasis as well as reducing cancer stemness. Further, statins have been found to induce oxidative stress, cell cycle arrest, autophagy, and apoptosis of cancer cells. Interestingly, clinical studies have shown that statin use is associated with a decreased risk of cancer formation, lower cancer grade at diagnosis, reduction in the risk of local reoccurrence, and increasing survival in patients. Therefore, our objective in the present review is to summarize the findings of the publications on the underlying mechanisms of statins' anticancer effects and their clinical implications.

Functional studies of HLA and its role in SARS-CoV-2: Stimulating T cell response and vaccine development.

In the biological immune process, the major histocompatibility complex (MHC) plays an indispensable role in the expression of HLA molecules in the human body when viral infection activates the T-cell response to remove the virus. Since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2019, how to address and prevent SARS-CoV-2 has become a common problem facing all mankind. The T-cell immune response activated by MHC peptides is a way to construct a defense line and reduce the transmission and harm of the virus. Presentation of SARS-CoV-2 antigen is associated with different types of HLA phenotypes, and different HLA phenotypes induce different immune responses. The prediction of SARS-CoV-2 mutation information and the design of vaccines based on HLAs can effectively activate autoimmunity and cope with virus mutations, which can provide some references for the prevention and treatment of SARS-CoV-2.

The Pathogenic Role of Oxidative Stress, Cytokine Expression, and Impaired Hematological Indices in Diabetic Cardiovascular Diseases.

A simultaneous increase in the prevalence of diabetes mellitus (DM), a risk factor for cardiovascular diseases (CVDs), has contributed to the escalation of CVD related mortalities. To date, oxidative stress and inflammation are increasingly recognized as significant drivers of cardiovascular complications in patients with diabetes. Therefore, this study aims to explore the correlation between oxidative stress, inflammation, and hematological indices in diabetic patients with CVDs. Patients were allocated into five groups: healthy controls; nondiabetic patients with myocardial infarction; diabetic patients with myocardial infarction; nondiabetic patients with heart failure; and diabetic patients with heart failure. The results revealed that the malondialdehyde levels were increased; whereas superoxide dismutase enzyme activities were markedly reduced in all CVD groups compared with those of healthy controls. Although the mRNA expression levels of interleukin (IL)-6, IL-18, and IL-38 were significantly increased, those of the anti-inflammatory cytokine, IL-35, have been reduced in all CVD groups compared with healthy controls. Regarding hematological indices, hematocrit, red blood cell distribution width, mean platelet (PLT) volume, plateletcrit, PLT distribution width, leukocyte count, and PLT-to-lymphocyte and neutrophil-to-lymphocyte ratios were markedly increased in the diabetic and nondiabetic CVD groups compared with those of the healthy controls. Oxidative stress and cytokine biomarkers may play a significant role in the complications of diabetic cardiomyopathy. Moreover, hematological indices are particularly sensitive to systemic inflammatory changes and are novel markers for the early detection of diabetic cardiomyopathy.

Small molecule Z363 co-regulates TAF10 and MYC via the E3 ligase TRIP12 to suppress tumour growth.

BACKGROUND: The MYC oncoprotein, also known as the master regulator of genes, is a transcription factor that regulates numerous physiological processes, including cell cycle control, apoptosis, protein synthesis and cell adhesion, among others. MYC is overexpressed in approximately 70% of human cancers. Given its pervasive role in cancer biology, MYC down-regulation has become an attractive cancer treatment strategy. METHODS: The CRISPR/Cas9 method was used to produce KO cell models. Western blot was used to analyzed the expressions of MYC and TATA-binding proteinassociated factors 10 (TAF10) in cancer cells (MCF7, A549, HepG2 cells) Cell culture studies were performed to determine the mechanisms by which small molecules (Z363119456, Z363) affects MYC and TAF10 expressions and functions. Mouse studies were carried out to investigate the impact of Z363 regulation on tumor growth. RESULTS: Z363 activate Thyroid hormone Receptor-interacting Protein 12 (TRIP12), which phosphorylates MYC at Thr58, resulting in MYC ubiquitination and degradation and thereby regulating MYC target genes. Importantly, TRIP12 also induces TAF10 degradation, which reduces MYC protein levels. TRIP12, an E3 ligase, controls MYC levels both directly and indirectly by inhibiting MYC or TAF10 activity. CONCLUSIONS: In summary,these results demonstrate the anti-cancer properties of Z363, a small molecule that is co-regulated by TAF10 and MYC.