Biomolecules最新文献

We previously reported that PRDM16 mediated the improvement in body composition in testosterone (T)-treated hypogonadal men by shifting adipogenesis to myogenesis. Previous preclinical studies suggest that Prdm16 regulates Runx2, an important osteoblastic transcription factor, expression and activity. However, the changes in PRDM16, and other genes/proteins involved in osteoblastogenesis with T therapy in hypogonadal men are unexplored. We investigated the role of PRDM16 in RUNX2 activation by measuring changes in gene expression in peripheral blood monocytes (PBMCs) and proteins in the serum of hypogonadal men after T therapy for 6 months. Likewise, we evaluated changes in the WNT10b-β-CATENIN signaling pathway by gene expression and protein analyses. We found significant increases in PRDM16 and RUNX2 expression in PBMCs together with significant increases in serum proteins at 6 months when compared to baseline. There were also increases in gene and protein expressions of WNT10b, and β-CATENIN at 6 months. Furthermore, we found a significant positive correlation between % changes in PRDM16 and WNT10b. Our results suggest that T therapy activates PRDM16, leading to enhanced signaling in the canonical WNT10b-β-CATENIN-RUNX2 pathway, the pathway involved in osteoblastogenesis. The above findings may account for the improvement in bone density and quality in hypogonadal men treated with T.

Mitochondrial ATP synthesis is driven by harnessing the electrochemical gradient of protons (proton motive force) across the mitochondrial inner membrane via the process of chemiosmosis. While there is consensus that the proton gradient is generated by components of the electron transport chain, the mechanism by which protons are supplied to ATP synthase remains controversial. As opposed to a global coupling model whereby protons diffuse into the intermembrane space, a localised coupling model predicts that protons remain closely associated with the lipid membrane prior to interaction with ATP synthase. Herein, a revised version of the chemiosmotic theory is proposed by introducing an RNA-based proton sink which aligns the release of sequestered protons to availability of ADP and Pi thereby maximising the efficiency of oxidative phosphorylation.

Bile salt hydrolase (BSH; EC 3.5.1.24) is the microbial enzyme that catalyzes the conversion of primary bile acids (BAs) into secondary ones, promoting microbial adaptation and modulating several host's biological functions. Probiotics with BSH activity are supposed to survive harsh intestinal conditions and exert a cholesterol-lowering effect. Here, Lacticaseibacillus rhamnosus strains (VB4 and VB1), isolated from the vaginal ecosystem, were submitted to a genomic survey, in vitro BSH activity, and BAs tolerance assay to unravel their probiotic potential as BAs modulators. The draft genomes of Lcb. rhamnosus VB4 and VB1 strains comprised 2769 and 2704 CDSs, respectively. Gene annotation revealed numerous strain-specific genes involved in metabolism and transport, as well as in DNA recombination. Each strain harbors a single bsh gene, encoding a C-N amide hydrolase, which conserved the essential residues required in the BSH core site. According to the results, compared to VB1, the VB4 strain tolerated better BAs stress and was more active in deconjugating BAs. However, BAs stress increased the bsh gene transcription in the VB1 strain but not in the VB4 strain, suggesting a partially nonlinear relationship between BSH activity and gene expression. In conclusion, despite the complexity of the BSH transcriptional system, the results support the VB4 strain as a promising BAs-deconjugating probiotic candidate.

Cancer's heterogeneity presents significant challenges in accurate diagnosis and effective treatment, including the complexity of identifying tumor subtypes and their diverse biological behaviors. This review examines how feature selection techniques address these challenges by improving the interpretability and performance of machine learning (ML) models in high-dimensional datasets. Feature selection methods-such as filter, wrapper, and embedded techniques-play a critical role in enhancing the precision of cancer diagnostics by identifying relevant biomarkers. The integration of multi-omics data and ML algorithms facilitates a more comprehensive understanding of tumor heterogeneity, advancing both diagnostics and personalized therapies. However, challenges such as ensuring data quality, mitigating overfitting, and addressing scalability remain critical limitations of these methods. Artificial intelligence (AI)-powered feature selection offers promising solutions to these issues by automating and refining the feature extraction process. This review highlights the transformative potential of these approaches while emphasizing future directions, including the incorporation of deep learning (DL) models and integrative multi-omics strategies for more robust and reproducible findings.

Background: Breast cancer is a heterogeneous malignant disease with a varying prognosis and is classified into four molecular subtypes. It remains one of the most prevalent cancers globally, with the tumor microenvironment playing a critical role in disease progression and patient outcomes.

Methods: This study evaluated tumor samples from 40 female patients with luminal A and B breast cancer, utilizing flow cytometry to phenotypically characterize the immune cells and tumor cells present within the tumor tissue.

Results: The luminal B-like tumor samples exhibited increased infiltration of CD4⁺ cells, regulatory T cells (Tregs), and Th17 cells and decreased levels of NK cells, γδ T cells, Th1 cells, and follicular T cells, which is indicative of a more immunosuppressive tumor microenvironment.

Conclusions: These findings suggest that luminal B-like tumors have a microenvironment that is less supportive of effective anti-tumor immune responses compared to luminal A tumors. This study enhances the understanding of the immunological differences between luminal subtypes of breast cancer and identifies potential new therapeutic targets and biomarkers that could drive advancements in precision medicine for breast cancer management.

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent two frequently observed clinical conditions. AKI is characterized by an abrupt decrease in glomerular filtration rate (GFR), generally associated with elevated serum creatinine (sCr), blood urea nitrogen (BUN), and electrolyte imbalances. This condition usually persists for approximately a week, causing a transient reduction in kidney function. If these abnormalities continue beyond 90 days, the condition is redefined as chronic kidney disease (CKD) or may advance to end-stage renal disease (ESRD). Recent research increasingly indicates that maladaptive repair mechanisms after AKI significantly contribute to the development of CKD. Thus, implementing early interventions to halt the progression from AKI to CKD has the potential to markedly improve patient outcomes. Although considerable research has been conducted, the exact mechanisms linking AKI to CKD are complex, and effective treatments remain limited. Kidney function is influenced by circadian rhythms, with the circadian gene Bmal1 being vital in managing these cycles. Recent research indicates that Bmal1 is significantly involved in the progression of both AKI and CKD. In this study, we conducted a retrospective analysis of Bmal1's role in AKI and CKD, reviewed recent research advancements, and investigated how Bmal1 influences the pathological mechanisms underlying the progression from AKI to CKD. Additionally, we highlighted gaps in the existing research and examined the potential of Bmal1 as a therapeutic target in kidney disease management. This work aims to provide meaningful insights for future studies on the role of the circadian gene Bmal1 in the transition from AKI to CKD, with the goal of identifying therapeutic approaches to mitigate kidney disease progression.

TMPRSS2, a human transmembrane protease enzyme, plays a crucial role in the spread of certain viruses, including influenza and coronaviruses. This enzyme promotes viral infection by cleaving viral glycoproteins, which helps viruses like SARS-CoV-2 and influenza A enter cells more effectively. Genetic differences in TMPRSS2 may affect people's susceptibility to COVID-19, underscoring the need for studies that consider diverse populations. Beyond infectious diseases, TMPRSS2 has also been linked to some cancers, suggesting it could be a valuable target for drug development. This review provides a summary of TMPRSS2 inhibitors currently under study, with some already in clinical trials to test their effectiveness against viral infections. As we uncover more about TMPRSS2's role in pathogenesis, it could open new doors for therapies to combat future outbreaks.

Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B') and, to a lesser extent, HSPA5 (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy.

Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate. In this study, we investigated the cytotoxic, proapoptotic, and anti-invasive effects of the synthetic indole phytoalexin MB-653. The antiproliferative effect was determined using an MTT assay, showing IC₅₀ values of 5.8 ± 0.3 μmol/L for HCT116 cells and 6.1 ± 2.1 μmol/L for Caco2 cells. Flow cytometry and Western blot analysis were employed to investigate the molecular mechanisms underlying cytotoxicity, proapoptotic action, and anti-invasion effects. The proapoptotic activity was evidenced by the activation of caspases 3 and 7, mitochondrial dysfunction, and an increased number of apoptotic cells, confirmed by annexin V/PI and AO/PI staining. Additionally, MB-653 induces dose-dependent G2/M phase cell cycle arrest, the cause of which could be cyclin B1/CDC2 complex dysfunction and/or a decrease in α-tubulin protein expression. Another important observation was that MB-653 modulated several signalling pathways associated with various cellular activities, including survival, proliferation, tumour invasiveness, metastasis, and epithelial-mesenchymal transition (EMT). We further demonstrated its safety for topical and parenteral application. To sum up, our results indicate the real potential of MB-653 in treating colorectal cancer.

In this article, we focus on kynurenic acid metabolism in neuropsychiatric disorders and the biochemical processes involved in memory and cognitive impairment, followed by different approaches in the fight against dementia. Kynurenic acid-a biochemical part of L-tryptophan catabolism-is synthesized from L-kynurenine by kynurenine aminotransferases. Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferases opens new therapeutic avenues for the treatment of memory impairment and dementia. The newly developed Helix pomatia snail model of memory can be used for the assessment of novel pharmacological approaches. Dietary supplementation with natural molecular/herbal extracts, exercise, and physical activity have significant impacts on endogenous pharmacology by reducing kynurenic acid synthesis, and these factors are likely to significantly modulate steady-state biological conditions and delay the negative consequences of aging, including the onset of pathological processes.