Biomolecules & biomedicine最新文献

Immune checkpoint inhibitors produce durable antitumor effects in various cancers, but not all patients respond. High tumor mutational burden (TMB) is a known predictor of clinical benefit. In this study, we focused on the MHC-I-dependent neoantigen presentation pathway to enhance predictive capabilities beyond TMB. Using pan-cancer immunogenomic analyses of somatic mutation data from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we analyzed 33 cancer types. Objective response rates (ORRs) to PD-1/PD-L1 inhibitors were evaluated in relation to immune characteristics, including TMB, neoantigen load, MHC-I gene expression, and CD8+ T cell fraction. Spearman’s rank correlation was used to assess these relationships. TMB showed the strongest correlation with ORR (r = 0.783, P = 2.17 × 10⁻⁵). However, integrating TMB, HLA-A expression, and CD8+ T cell fraction significantly improved predictive accuracy (r = 0.865, P = 1.80 × 10⁻⁶). Validation in external cohorts confirmed these findings, revealing notable differences in MHC-I pathway activity between responders and non-responders to immunotherapy. Our results demonstrate that the MHC-I antigen presentation pathway is strongly associated with response to PD-1/PD-L1 inhibitors. Importantly, combining antigen expression, processing, presentation, and recognition features provides superior predictive power compared to TMB alone. This integrated approach could improve treatment outcome predictions and advance personalized immunotherapy strategies.

Inhibiting ferroptosis represents a promising strategy for managing neuronal injury caused by intracerebral hemorrhage (ICH). Platelet factor 4 (PF4), a chemokine with diverse biological functions, has an unclear role in ICH and its impact on neuronal ferroptosis. To investigate this, a hemin-induced injury model was established in PC12 cells in vitro, and an ICH model was created in vivo using IV collagenase injection. Hemin-treated PC12 cells were co-cultured with recombinant mouse PF4 (Rm-PF4) protein to examine the effects of PF4 on ferroptosis. Additionally, Rm-PF4 was administered intraperitoneally to ICH mice, and its influence on neurological dysfunction, brain edema, and neuronal ferroptosis was evaluated. Western blot analysis was employed to assess PF4 levels, CXCR3/phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway activation, and ferroptosis-related protein expression. PF4 levels were found to be reduced in both perihematomal brain tissues of ICH mice and hemin-treated PC12 cells. Treatment with Rm-PF4 decreased ferrous ion, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, effectively inhibiting ferroptosis in PC12 cells. Furthermore, Rm-PF4 administration alleviated neurological dysfunction, neuronal damage, and brain edema while suppressing neuronal ferroptosis in ICH mice. Mechanistically, Rm-PF4 activated the CXCR3/PI3K/AKT/Nrf2 pathway, and this protective effect was diminished by a CXCR3 antagonist in both ICH mice and hemin-treated PC12 cells. In conclusion, PF4 mitigates ICH-induced neuronal ferroptosis in mouse models and PC12 cells by activating the CXCR3/PI3K/AKT/Nrf2 pathway.

The Wnt signaling pathway is one of the most important and critical signaling pathways for maintaining cellular functions, such as cell proliferation and differentiation. Increasing evidence substantiates that the Wnt signaling pathway also plays a significant role in the regulation of bone formation in osteoporosis. Accordingly, inhibitors of this pathway, such as sclerostin, Dickkopf-1 (DKK1), WNT inhibitory factor 1 (WIF1), and secreted frizzled-related proteins (SFRPs), have a negative regulatory role in bone formation and may serve as effective therapeutic targets for osteoporosis. This review examines the mechanisms of action of Wnt signaling pathway inhibitors in osteoporosis, the relationship between the Wnt pathway and its inhibitors, and new molecular targets for osteoporosis treatment. Overall, the regulatory mechanisms of Wnt pathway inhibitors are summarized to provide scientific and theoretical guidance for the treatment and prevention of osteoporosis.

Vulvovaginal candidiasis (VVC) is a common fungal infection caused primarily by Candida albicans, characterized by inflammation and discomfort, often requiring effective therapeutic strategies to reduce fungal load and inflammation. This study aimed to explore the therapeutic effects and underlying mechanisms of combining aspirin (ASP) and itraconazole (ITR) in treating vulvovaginal candidiasis (VVC) through activation of the NF-κB signaling pathway. Clinical isolates of Candida albicans were selected, and the M27-A4 microbroth dilution method was used for in vitro drug sensitivity testing. A VVC model was established, and after three days of continuous administration, fungal load, inflammatory factors, and pathway protein expression were analyzed using Gram staining, plate counting, glycogen (PAS) staining, ELISA, and qPCR. The results of the in vitro drug sensitivity tests revealed that the MIC50 values of ASP and ITR were significantly reduced when the two drugs were combined. In animal experiments, the VVC model group exhibited a substantial vaginal fungal load compared to the blank control group. This was accompanied by elevated levels of inflammatory factors (IL-1β, IL-6, and TNF-α) in serum and vaginal lavage fluid, increased phosphorylation of p65 and IκBα, and upregulation of p65 and IκBα mRNA expression in vaginal tissue. Treatment with the ASP and ITR combination significantly reduced vaginal fungal load, decreased levels of IL-1β, IL-6, and TNF-α, and suppressed the phosphorylation of p65 and IκBα in serum and vaginal lavage fluid. Additionally, the mRNA expression of p65 and IκBα in vaginal tissue was downregulated. These findings suggest that the combination of ASP and ITR is effective in treating VVC. The therapeutic effect may be attributed to the inhibition of IL-1β, IL-6, and TNF-α production by downregulating NF-κB signaling pathway proteins.

The role of the C15orf48 gene in lung cancer is not well understood. This study aimed to investigate the effect of C15orf48 in non-small cell lung cancer (NSCLC). Bioinformatics analyses were performed using Oncomine, The Cancer Genome Atlas (TCGA), Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Immunohistochemical staining was used to detect C15orf48 expression in tissue microarrays. Cellular assays, including CCK8, colony formation, wound healing, transwell migration, flow cytometry, and cell adhesion, were conducted to assess cell viability, proliferation, invasion, and apoptosis. A xenograft tumor model was used to examine tumor growth, and Western blotting was used to detect protein expression. C15orf48 expression was significantly upregulated in tumor tissues compared to normal tissues and was associated with poor prognosis. Knockdown of C15orf48 in A549 and H1299 cells reduced proliferation, invasion, and adhesion while increasing apoptosis. C15orf48 knockdown also inhibited tumor growth in vivo and was associated with immune cell infiltration. Although C15orf48 expression correlated with the epithelial-mesenchymal transition (EMT) score, no significant differences were observed. GSEA identified the NF-κB signaling pathway as a key pathway involved. Proteins PLAUR, IKBα, IL-1RN, ICAM1, and TMPRSS4 showed decreased expression in the shC15orf48 group compared to the shCtrl group. We concluded that C15orf48 promotes NSCLC progression, potentially through immune cell infiltration and the NF-κB signaling pathway.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type (WT) mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using H&E staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression.

Cardiac arrest (CA) remains a critical global health issue with high rates of mortality and morbidity. Accurate prediction of neurological outcomes in post-CA patients is essential for optimizing management strategies. Optic nerve sheath diameter (ONSD) and near-infrared spectroscopy (NIRS) are emerging as promising tools for evaluating brain oxygenation and intracranial pressure. However, the potential benefits of combining these methods for improved prognostic accuracy have not been thoroughly explored. This study investigates whether the combined use of ultrasonographic ONSD and NIRS measurements enhances the prediction of neurological outcomes after CA. In this prospective study, ONSD measurements were obtained three times at 24-hour intervals, while regional hemoglobin oxygen saturation (rSO2) using NIRS was recorded twice. Neurological outcomes were assessed using the Full Outline of Unresponsiveness (FOUR) and Cerebral Performance Categories (CPC) scores for both early and late evaluations. Results indicated that 47.5% of patients had poor outcomes and 52.5% had good outcomes based on the FOUR score, while 65% had poor outcomes and 35% had good outcomes according to the CPC score. The combination of ONSD and NIRS measurements showed superior prognostic performance compared to either method alone. While standalone NIRS measurements taken after 24 hours exhibited limited predictive value, combining ONSD and NIRS provided a more reliable approach for neurological assessment in the short-term following CA. This integrated method may improve prognostic accuracy and support better clinical decision-making.

Ferroptosis plays a crucial role in the secondary pathophysiological damage to brain tissue surrounding hematomas after intracerebral hemorrhage (ICH). While platelet factor 4 (PF4) is known to promote regeneration following peripheral nerve injury, its role in brain tissue repair after cerebral hemorrhage remains unclear. In this study, Hemin-induced PC12 cells were treated with various inhibitors and assessed for viability, oxidative stress, and ferroptosis using a combination of assays, including CCK-8 (Cell Counting Kit-8), EdU (5-Ethynyl-2’-deoxyuridine), flow cytometry, and immunofluorescence. ICH cells were also treated with recombinant PF4 (Rm-PF4) and a CXCR3 antagonist (AMG487) to investigate the mechanism by which Rm-PF4 influences Hemin-induced PC12 cell injury and inflammation. Subsequently, ICH mouse models were established via collagenase injection. Neurological function in these mice was evaluated using the Cylinder and Corner tests. Histopathological damage to brain tissue was analyzed through HE, TUNEL, and Nissl staining, as well as immunohistochemistry, to further explore the role of Rm-PF4 in controlling neuroinflammation in vivo. Results showed that Rm-PF4 inhibited Hemin-mediated ferroptosis-induced PC12 cell damage and inflammation by activating the CXCR3/AKT1/SLC7A11 signaling pathway. Blocking the CXCR3/AKT1/SLC7A11 pathway partially reversed PF4's protective effects on Hemin-induced PC12 cells. In ICH mice, pro-inflammatory marker CD16 (3rd day) and anti-inflammatory marker Arg1 (7th day) were significantly decreased and increased, respectively (p<0.05). IL-6, TNF-α, and IL-1β levels were down-regulated in brain tissues after Rm-PF4 injection, which was significantly reversed by AMG487. PF4 inhibits ferroptosis after ICH reduced PC12 cell damage and the inflammatory response via activating the CXCR3/AKT1/SLC7A11 pathway.

Hyperoside (HYP) exhibits diverse pharmacological effects and holds potential for enhancing chemotherapy sensitivity. However, few studies have reported the impact of HYP on the malignant progression of esophageal carcinoma (EC) and its sensitivity to radiotherapy. The impact of HYP on the viability of EC cells (TE-1 and KYSE-150) was assessed using Cell Counting Kit-8 (CCK-8) assays. The biological characteristics and radiosensitivity of EC cells following HYP treatment were evaluated through clone formation experiments, flow cytometry, scratch wound-healing assays, and transwell migration and invasion assays. Western blot analysis was performed to determine the levels of proteins associated with cell death and epithelial-mesenchymal transition (EMT), as well as to explore whether HYP interferes with the radiosensitivity of EC cells via the  STAT3/AKT/ERK pathways. Finally, a subcutaneous graft tumor model was constructed to investigate the effects of HYP and X-ray treatments on in vivo tumor growth. The findings indicated a dose-dependent decrease in the survival rate of KYSE-150 and TE-1 cells following HYP treatment. HYP treatment also inhibited cell proliferation, invasion, migration, and EMT, while increasing the apoptotic rate and radiosensitivity of the cells. Notably, HYP suppressed the malignant progression of EC and enhanced radiosensitivity via the STAT3/AKT/ERK pathway. Moreover, HYP impaired the growth of EC tumors in mice, with the combined HYP and X-ray treatment exerting a stronger inhibitory effect. In conclusion, HYP increases the radiosensitivity of esophageal carcinoma cells, offering considerable promise for application in the clinical treatment of EC.

This review examines hormone replacement therapy (HRT) in cases of surgical menopause following gynecological malignancies. It aims to capture current knowledge, summarize recent findings, and provide recommendations for clinical settings. Unlike natural menopause, surgical menopause occurs abruptly, without an adjustment period, and is associated with a notably higher risk of fractures, arthritis, cognitive decline, dementia, Parkinson's disease, and various metabolic disorders affecting glucose and lipid levels-all of which contribute to an increased risk of major cardiovascular events. In 2017, The North American Menopause Society recommended that, barring contraindications, HRT should be initiated in women who enter surgical menopause before age 45. If these women do not experience vasomotor symptoms or other issues, HRT should be maintained consistently at least until age 52. This guideline reflects contemporary knowledge and is the result of a multidisciplinary consensus, based on a review of existing literature and several randomized clinical trials focusing on women who have survived gynecological cancers and whose quality of life is significantly impacted by surgical or early menopause. Estrogen supplementation is particularly beneficial, as it is linked to marked improvements in quality of life, including delayed onset of chronic cardiovascular issues, reduced fracture risk, enhanced cognitive function, reduced inflammation, and improved self-esteem, as well as better social and work performance. Clinical implementation of HRT, however, requires a highly individualized approach. This approach must consider the type and stage of malignancy, histopathological characteristics, risk factors for recurrence (such as diet, concurrent medications, medical history, and genetic predispositions), and a thorough assessment of the potential benefits and risks of HRT, as well as the patient's personal wishes and expectations.