Among tumor microenvironment (TME), the entire metabolic characteristics of tumor-resident cells are reprogrammed to benefit the expansion of tumor cells, which count on glutamine in large part to fuel the tricarboxylic acid cycle for energy generation and anabolic metabolism support. Endothelial cells that are abducted by tumor cells to form a pathological tumor vascular network for constructing the hypoxic immunosuppressive TME, also rely on glutaminolysis as the "engine" of angiogenesis. Additionally, the glutamine metabolic preference benefits the polarization of TAMs towards pro-tumoral M2 phenotype as well. Herein, we developed a type of siRNA micelleplexes (MH@siGLS1) to reverse immunosuppressive TME by targeting glutaminolysis within tumor-resident cells for tumor vasculature normalization- and TAMs repolarization-enhanced photo-immunotherapy. Tumor cell starvation and antioxidant system destruction achieved by MH@siGLS1-mediated glutaminolysis inhibition could promote photodynamic therapy efficacy, which was available to trigger immunogenic cell death for adaptive antitumor immune responses. Meanwhile, glutaminolysis inhibition of tumor endothelial cells and TAMs could realize tumor vascular normalization and TAMs repolarization for antitumor immunity amplification. This study provides a unique perspective on cancer treatments by focusing on the interrelations of metabolic characteristics and the biofunctions of various cell types within TME.

Prostate cancer is the most prevalent malignant tumor among men, ranking first in incidence and second in mortality globally. Novel hormone therapies (NHT) targeting the androgen receptor (AR) pathway have become the standard of care for metastatic prostate cancer. This review offers a comprehensive overview of NHT, including abiraterone, enzalutamide, apalutamide, darolutamide, and rezvilutamide, which have demonstrated efficacy in delaying disease progression and improving patient survival and quality of life. Nevertheless, resistance to NHT remains a critical challenge. The mechanisms underlying resistance are complex, involving AR gene amplification, mutations, splice variants, increased intratumoral androgens, and AR-independent pathways such as the glucocorticoid receptor, neuroendocrine differentiation, DNA repair defects, autophagy, immune evasion, and activation of alternative signaling pathways. This review discusses these resistance mechanisms and examines strategies to counteract them, including sequential treatment with novel AR-targeted drugs, chemotherapy, poly ADP-ribose polymerase inhibitors, radionuclide therapy, bipolar androgen therapy, and approaches targeting specific resistance pathways. Future research should prioritize elucidating the molecular basis of NHT resistance, optimizing existing therapeutic strategies, and developing more effective combination regimens. Additionally, advanced sequencing technologies and resistance research models should be leveraged to identify novel therapeutic targets and improve drug delivery efficiencies. These advancements hold the potential to overcome NHT resistance and significantly enhance the management and prognosis of patients with advanced prostate cancer.

This study was designed to investigate the effect of silencing microtubule-affinity regulating kinase 4(MARK4)on the apoptosis,inflammatory cytokine release and intestinal barrier protein expression of FHC cells in a lipopolysaccharide(LPS)-induced ulcerative colitis(UC)model,and the underlying molecular mechanisms.Western blot analysis was used to measure the expression levels of MARK4 and apoptosis-related factors including Caspase-1,NLRP3,and GSDMD in colon tissues from both UC patients and healthy individuals,as well as in LPS-induced FHC cell inflammation model.FHC cells was transfected with shRNA to silence MARK4.In control(normal FHC cells),LPS(LPS-stimulated FHC cells),and MARK4-silenced+LPS(shRNA-and LPS-treated FHC cells)groups,the expression levels of Caspase-1,NLRP3,GSDMD,intestinal barrier proteins,and NF-κB pathway-related proteins were assessed by Western blotting.ELISA and RT-qPCR were used to measure the expression levels of inflammatory cytokines IL-1β,IL-6,and TNF-α;flow cytometry was utilized to assess apoptosis.Data showed that both in UC patient colon tissues and the in vitro LPS-induced FHC cell UC inflammation model,there was a significant increase in the expression of MARK4 and apoptosis-related proteins including NLRP3,Caspase-1,and GSDMD.Silencing MARK4 inhibited the expression of these apoptosis-related proteins and downregulated the inflammatory cytokines IL-1β,IL-6,and TNF-α in LPS-induced FHC cells.Silencing MARK4 also reduced apoptosis,increased the expression of intestinal barrier proteins ZO-1,Occludin,and upregulated Claudin2.Gene Set Enrichment Analysis(GSEA)indicated a positive correlation between MARK4 and the NF-κB signaling pathway.Furthermore,silencing of MARK4 inhibited the expression levels of p-P65 and p-IKKα in the NF-κB pathway.In conclusion,MARK4 is significantly upregulated in UC tissues and cells.Silencing MARK4 inhibits the activation of the NF-κB signaling pathway,thereby inhibiting the apoptosis and inflammatory factor expression of UC cells.Thus,MARK4 could be a potential therapeutic target for UC patients.

BACKGROUND:Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system mediated by T cells.The Toll-like receptors(TLRs)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway plays an important role in the development of the disease.Exploring the specific mechanism of the signaling pathway is essential for further treatment of the disease and improving the prognosis of patients. OBJECTIVE:To review the TLRs/MyD88/NF-κB signaling pathway and its role in multiple sclerosis/experimental autoimmune encephalomyelitis models,which provides new ideas and strategies for the treatment of multiple sclerosis by inhibiting the TLRs/MyD88/NF-κB signaling pathway. METHODS:The literature related to the topic from January 2002 to December 2022 was searched in CNKI,WanFang and PubMed databases.A total of 61 articles were finally included for analysis. RESULTS AND CONCLUSION:The TLRs/MyD88/NF-κB signaling pathway is an important pathway that triggers a pro-inflammatory immune response.The TLRs/MyD88/NF-κB signaling pathway plays an important role in the development of multiple sclerosis by regulating the antigen presentation of dendritic cells,destroying the integrity of the blood-brain barrier,and promoting the activation of T cells,B cells and microglia.By targeting TLRs,MyD88 and NF-κB molecules,inhibiting the activation or signal transduction of TLRs,MyD88 and NF-κB,and reducing the secretion of pro-inflammatory factors,multiple sclerosis can be treated.Animal studies have shown that active ingredients of traditional Chinese medicines,such as flavonoids and glycosides,and traditional Chinese medicine compound formulas,such as Buyang Huanwu Tang,can also treat experimental autoimmune encephalomyelitis by regulating the TLRs/MyD88/NF-κB signaling pathway,which points to the direction of searching for medicines targeting the TLRs/MyD88/NF-κB signaling pathway for the treatment of multiple sclerosis.

Objective To explore the mechanisms of circadian rhythm disorder(CRD)on behavior and testicular spermatogenic capacity in adolescent mice.Methods Thirty SPF grade C57 mice were selected and randomly di-vided into the control and CRD groups with 15 mice in each group.The control group kept 12 h dark/12 h bright circulating light,and the CRD group kept 24 h light.The trial lasted for 61 days.The growth curves of mice in each group were counted;the elevated plus maze test and open field test were performed to detect mice behavior;neuronal morphology was visualized by Nissl staining.The distribution of ionized calcium-binding adapter molecule 1(Iba1)and neuron-specific nuclear protein(NeuN)in the hypothalamus were detected by immunofluorescence and Western blot.Expression of testosterone synthesis-related genes steroidogenic acute regulatory protein(StAR)and hydroxy-delta-5-steroid dehydrogenase,3 beta-and steroid delta-isomerase 1(HSD3B1)and spermatogenesis-related genes gametogenetin binding protein 2(GGNBP2)and deleted in azoospermia-like(DAZL)were deter-mined by RT-qPCR.Results The weight of the CRD group was significantly higher than that of control group at 61 days;in the elevated plus maze test,the time,frequency,and percentage of time in the open arm of the CRD group were significantly less than those of the control group;in the open field test,there was no significant differ-ence in movement distance between the two groups;however,the residence time of the central area in the CRD group was significantly less than that in the control group;the frequency of entering the central area in the CRD group was significantly less than that in the control group.Nissl staining results showed that the positive cells in the CRD group were significantly lower than the control group.Immunofluorescence and Western blot results showed that Iba1 protein expression was up-regulated and NeuN protein expression was down-regulated in the hypothalamus of the CRD group.In the RT-qPCR experiment,the expression of HSD3B1 in the CRD group was significantly low-er than that of the control group;the expression of GGNBP2 and DAZL in the CRD group was significantly lower than that in the control group.Conclusion The CRD treatment can not only lead to depressive behavior in adoles-cent mice but also reduce the development of reproductive system in male adolescent mice.

Background: The objective of this study was to investigate the impact of robot-assisted surgery (RA) on the risk of new vertebral compression fracture (NVCF) and bone cement leakage in patients with osteoporotic vertebral compression fractures (OVCF) after percutaneous vertebral augmentation (PVA), including percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP). Methods: A meta-analysis was performed to evaluate the clinical outcomes and adverse effects of RA-PVA versus fluoroscopy-assisted (FA)-PVA in patients with OVCF. A validation cohort of 385 patients who underwent PVP or PKP was retrospectively analyzed.In addition, we attempted to create well-calibrated nomograms to estimate the risk of NVCF and bone cement leakage. Results: The meta-analysis revealed that the incidence of NVCF and bone cement leakage was significantly lower in RA-PVA than in FA-PVA. The validation cohort confirmed that RA-PVA provided better results than FA-PVA in terms of NVCF and bone cement leakage. Conclusions The meta-analysis and the validation cohort suggest that RA reduced the risk of NVCF and bone cement leakage in patients with OVCF after PVA. The nomograms are accurate and easy-to-implement methods for clinicians to estimate the risk of NVCF and bone cement leakage after PVA.

Background: The objective of this study was to investigate the impact of robot-assisted surgery (RA) on the risk of new vertebral compression fracture (NVCF) and bone cement leakage in patients with osteoporotic vertebral compression fractures (OVCF) after percutaneous vertebral augmentation (PVA), including percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP). Methods: A meta-analysis was performed to evaluate the clinical outcomes and adverse effects of RA-PVA versus fluoroscopy-assisted (FA)-PVA in patients with OVCF. A validation cohort of 385 patients who underwent PVP or PKP was retrospectively analyzed.In addition, we attempted to create well-calibrated nomograms to estimate the risk of NVCF and bone cement leakage. Results: The meta-analysis revealed that the incidence of NVCF and bone cement leakage was significantly lower in RA-PVA than in FA-PVA. The validation cohort confirmed that RA-PVA provided better results than FA-PVA in terms of NVCF and bone cement leakage. Conclusions The meta-analysis and the validation cohort suggest that RA reduced the risk of NVCF and bone cement leakage in patients with OVCF after PVA. The nomograms are accurate and easy-to-implement methods for clinicians to estimate the risk of NVCF and bone cement leakage after PVA.

Background: The objective of this study was to investigate the impact of robot-assisted surgery (RA) on the risk of new vertebral compression fracture (NVCF) and bone cement leakage in patients with osteoporotic vertebral compression fractures (OVCF) after percutaneous vertebral augmentation (PVA), including percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP). Methods: A meta-analysis was performed to evaluate the clinical outcomes and adverse effects of RA-PVA versus fluoroscopy-assisted (FA)-PVA in patients with OVCF. A validation cohort of 385 patients who underwent PVP or PKP was retrospectively analyzed.In addition, we attempted to create well-calibrated nomograms to estimate the risk of NVCF and bone cement leakage. Results: The meta-analysis revealed that the incidence of NVCF and bone cement leakage was significantly lower in RA-PVA than in FA-PVA. The validation cohort confirmed that RA-PVA provided better results than FA-PVA in terms of NVCF and bone cement leakage. Conclusions The meta-analysis and the validation cohort suggest that RA reduced the risk of NVCF and bone cement leakage in patients with OVCF after PVA. The nomograms are accurate and easy-to-implement methods for clinicians to estimate the risk of NVCF and bone cement leakage after PVA.

Background: The objective of this study was to investigate the impact of robot-assisted surgery (RA) on the risk of new vertebral compression fracture (NVCF) and bone cement leakage in patients with osteoporotic vertebral compression fractures (OVCF) after percutaneous vertebral augmentation (PVA), including percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP). Methods: A meta-analysis was performed to evaluate the clinical outcomes and adverse effects of RA-PVA versus fluoroscopy-assisted (FA)-PVA in patients with OVCF. A validation cohort of 385 patients who underwent PVP or PKP was retrospectively analyzed.In addition, we attempted to create well-calibrated nomograms to estimate the risk of NVCF and bone cement leakage. Results: The meta-analysis revealed that the incidence of NVCF and bone cement leakage was significantly lower in RA-PVA than in FA-PVA. The validation cohort confirmed that RA-PVA provided better results than FA-PVA in terms of NVCF and bone cement leakage. Conclusions The meta-analysis and the validation cohort suggest that RA reduced the risk of NVCF and bone cement leakage in patients with OVCF after PVA. The nomograms are accurate and easy-to-implement methods for clinicians to estimate the risk of NVCF and bone cement leakage after PVA.