New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity.

Depression is highly prevalent globally, however, currently available medications face challenges such as low response rates and short duration of efficacy. Additionally, depression mostly accompany other psychiatric disorders, further progressing to major depressive disorder without long-term effective management. Thus, sustained antidepressant strategies are urgently needed. Recently, ketamine and psilocybin gained attention as potential sustained antidepressants. Review of recent studies highlights that synaptic plasticity changes as key events of downstream long-lasting changes in sustained antidepressant effect. This underscores the significance of synaptic plasticity in sustained antidepressant effect. Moreover, neurexins, key molecules involved in the regulation of synaptic plasticity, act as critical links between synaptic plasticity and sustained antidepressant effects, involving mechanisms including protein level, selective splicing, epigenetics, astrocytes, positional redistribution and protein structure. Based on the regulation of synaptic plasticity by neurexins, several drugs with potential for sustained antidepressant effect are also discussed. Focusing on neurexins in regulating synaptic plasticity promises much for further understanding underlying mechanisms of sustained antidepressant and the next step in new drug development. This research represents a highly promising future research direction.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

TRIM26 inhibits clear cell renal cell carcinoma progression through destabilizing ETK and thus inactivation of AKT/mTOR signaling.

BACKGROUND: Tripartite motif-containing 26 (TRIM26), a member of the TRIM protein family, exerts dual function in several types of cancer. Nevertheless, the precise role of TRIM26 in clear cell renal cell carcinoma (ccRCC) has not been investigated. METHODS: The expression of TRIM26 in ccRCC tissues and cell lines were examined through the use of public resources and experimental validation. The impacts of TRIM26 on cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process were determined via CCK-8, colony formation, EdU incorporation, wound healing, Transwell invasion, Western blot, and Immunofluorescence assays. RNA-seq followed by bioinformatic analyses were used to identify the downstream pathway of TRIM26. The interaction between TRIM26 and ETK was assessed by co-immunoprecipitation, qRT-PCR, Western blot, cycloheximide (CHX) chase, and in vivo ubiquitination assays. RESULTS: We have shown that TRIM26 exhibits a downregulation in both ccRCC tissues and cell lines. Furthermore, this decreased expression of TRIM26 is closely linked to unfavorable overall survival and diseases-free survival outcomes among ccRCC patients. Gain- and loss-of-function experiments demonstrated that increasing the expression of TRIM26 suppressed the proliferation, migration, invasion, and EMT process of ccRCC cells. Conversely, reducing the expression of TRIM26 had the opposite effects. RNA sequencing, coupled with bioinformatic analysis, revealed a significant enrichment of the mTOR signaling pathway in the control group compared to the group with TRIM26 overexpression. This finding was then confirmed by a western blot assay. Subsequent examination revealed that TRMI26 had a direct interaction with ETK, a non-receptor tyrosine kinase. This interaction facilitated the ubiquitination and degradation of ETK, resulting in the deactivation of the AKT/mTOR signaling pathway in ccRCC. ETK overexpression counteracted the inhibitory effects of TRIM26 overexpression on cell proliferation, migration, and invasion. CONCLUSION: Our results have shown a novel mechanism by which TRIM26 hinders the advancement of ccRCC by binding to and destabilizing ETK, thus leading to the deactivation of AKT/mTOR signaling. TRIM26 shows promise as both a therapeutic target and prognostic biomarker for ccRCC patients.

Causal associations of immune cells with benign prostatic hyperplasia: insights from a Mendelian randomization study.

BACKGROUND: Previous research has focused on the association between immune cells and the development of benign prostatic hyperplasia (BPH). Nevertheless, the causal relationships in this context remain uncertain. METHODS: This study employed a comprehensive and systematic two-sample Mendelian randomization (MR) analysis to determine the causal relationships between immunophenotypes and BPH. We examined the causal associations between 731 immunophenotypes and the risk of BPH by utilizing publicly available genetic data. Integrated sensitivity analyses were performed to validate the robustness, assess heterogeneity, and examine horizontal pleiotropy in the results. RESULTS: We discovered that 38 immunophenotypes have a causal effect on BPH. Subsequently, four of these immunophenotypes underwent verification using weighted median, weighted mode, and inverse variance weighted (IVW) algorithms, which included CD19 on CD24+ CD27+, CD19 on naive-mature B cell, HLA DR on CD14- CD16+ and HLA DR+ T cell%lymphocyte. Furthermore, BPH exhibited a significant association with three immunophenotypes: CD19 on IgD+ CD38dim (ß = -0.152, 95% CI = 0.746-0.989, P = 0.034), CD19 on IgD+ (ß = -0.167, 95% CI = 0.737-0.973, P = 0.019), and CD19 on naive-mature B cell (ß = -0.166, 95% CI = 0.737-0.972, P = 0.018). CONCLUSIONS: Our study provides valuable insights for future clinical investigations by establishing a significant association between immune cells and BPH.

AURKB promotes bladder cancer progression by deregulating the p53 DNA damage response pathway via MAD2L2.

BACKGROUND: Bladder cancer (BC) is the most common urinary tract malignancy. Aurora kinase B (AURKB), a component of the chromosomal passenger protein complex, affects chromosomal segregation during cell division. Mitotic arrest-deficient 2-like protein 2 (MAD2L2) interacts with various proteins and contributes to genomic integrity. Both AURKB and MAD2L2 are overexpressed in various human cancers and have synergistic oncogenic effects; therefore, they are regarded as emerging therapeutic targets for cancer. However, the relationship between these factors and the mechanisms underlying their oncogenic activity in BC remains largely unknown. The present study aimed to explore the interactions between AURKB and MAD2L2 and how they affect BC progression via the DNA damage response (DDR) pathway. METHODS: Bioinformatics was used to analyze the expression, prognostic value, and pro-tumoral function of AURKB in patients with BC. CCK-8 assay, colony-forming assay, flow cytometry, SA-ß-gal staining, wound healing assay, and transwell chamber experiments were performed to test the viability, cell cycle progression, senescence, and migration and invasion abilities of BC cells in vitro. A nude mouse xenograft assay was performed to test the tumorigenesis ability of BC cells in vivo. The expression and interaction of proteins and the occurrence of the senescence-associated secretory phenotype were detected using western blot analysis, co-immunoprecipitation assay, and RT-qPCR. RESULTS: AURKB was highly expressed and associated with prognosis in patients with BC. AURKB expression was positively correlated with MAD2L2 expression. We confirmed that AURKB interacts with, and modulates the expression of, MAD2L2 in BC cells. AURKB knockdown suppressed the proliferation, migration, and invasion abilities of, and cell cycle progression in, BC cells, inducing senescence in these cells. The effects of AURKB knockdown were rescued by MAD2L2 overexpression in vitro and in vivo. The effects of MAD2L2 knockdown were similar to those of AURKB knockdown. Furthermore, p53 ablation rescued the MAD2L2 knockdown-induced suppression of BC cell proliferation and cell cycle arrest and senescence in BC cells. CONCLUSIONS: AURKB activates MAD2L2 expression to downregulate the p53 DDR pathway, thereby promoting BC progression. Thus, AURKB may serve as a potential molecular marker and a novel anticancer therapeutic target for BC.

Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present and process antigens in PRAD has not been investigated. In this study, antigen presentation and process-related CAFs (APPCAFs) were identified using bioinformatics, and the clinical implications of APPCAF-related signatures in PRAD were investigated. METHODS: SMART technology was used to sequence the transcriptome of primary CAFs isolated from patients undergoing different treatments. Differential expression gene (DEG) screening was conducted. A CD4 + T-cell early activation assay was used to assess the activation degree of CD4 + T cells. The datasets of PRAD were obtained from The Cancer Genome Atlas (TCGA) database and NCBI Gene Expression Omnibus (GEO), and the list of 431 antigen presentation and process-related genes was obtained from the InnateDB database. Subsequently, APP-related CAFs were identified by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses were performed to depict the biological functions. A risk signature based on APPCAF-related genes (APPCAFRS) was developed by least absolute shrinkage and selection operator (LASSO) regression analysis, and the independence of the risk score as a prognostic factor was evaluated by univariate and multivariate Cox regression analyses. Furthermore, a biochemical recurrence-free survival (BCRFS)-related nomogram was established, and immune-related characteristics were assessed using the ssGSEA function. The immune treatment response in PRAD was further analyzed by the Tumor Immune Dysfunction and Exclusion (TIDE) tool. The expression levels of hub genes in APPCAFRS were verified in cell models. RESULTS: There were 134 upregulated and 147 downregulated genes, totaling 281 differentially expressed genes among the primary CAFs. The functions and pathways of 147 downregulated DEGs were significantly enriched in antigen processing and presentation processes, MHC class II protein complex and transport vesicle, MHC class II protein complex binding, and intestinal immune network for IgA production. Androgen withdrawal diminished the activation effect of CAFs on T cells. NMF clustering of CAFs was performed by APPRGs, and pseudotime analysis yielded the antigen presentation and process-related CAF subtype CTSK + MRC2 + CAF-C1. CTSK + MRC2 + CAF-C1 cells exhibited ligand‒receptor connections with epithelial cells and T cells. Additionally, we found a strong association between CTSK + MRC2 + CAF-C1 cells and inflammatory CAFs. Through differential gene expression analysis of the CTSK + MRC2 + CAF-C1 and NoneAPP-CAF-C2 subgroups, 55 significant DEGs were identified, namely, APPCAFRGs. Based on the expression profiles of APPCAFRGs, we divided the TCGA-PRAD cohort into two clusters using NMF consistent cluster analysis, with the genetic coefficient serving as the evaluation index. Four APPCAFRGs, THBS2, DPT, COL5A1, and MARCKS, were used to develop a prognostic signature capable of predicting BCR occurrence in PRAD patients. Subsequently, a nomogram with stability and accuracy in predicting BCR was constructed based on Gleason grade (p = n.s.), PSA (p < 0.001), T stage (p < 0.05), and risk score (p < 0.01). The analysis of immune infiltration showed a positive correlation between the abundance of resting memory CD4 + T cells, M1 macrophages, resting dendritic cells, and the risk score. In addition, the mRNA expression levels of THBS2, DPT, COL5A1, and MARCKS in the cell models were consistent with the results of the bioinformatics analysis. CONCLUSIONS: APPCAFRS based on four potential APPCAFRGs was developed, and their interaction with the immune microenvironment may play a crucial role in the progression to castration resistance of PRAD. This novel approach provides valuable insights into the pathogenesis of PRAD and offers unexplored targets for future research.

Fatty Oil of Descurainia Sophia Nanoparticles Improve Monocrotaline-Induced Pulmonary Hypertension in Rats Through PLC/IP3R/Ca2+ Signaling Pathway.

Purpose: Fatty oil of Descurainia Sophia (OIL) has poor stability and low solubility, which limits its pharmacological effects. We hypothesized that fatty oil nanoparticles (OIL-NPs) could overcome this limitation. The protective effect of OIL-NPs against monocrotaline-induced lung injury in rats was studied. Methods: We prepared OIL-NPs by wrapping fatty oil with polylactic-polyglycolide nanoparticles (PLGA-NPs) and conducted in vivo and in vitro experiments to explore its anti-pulmonary hypertension (PH) effect. In vitro, we induced malignant proliferation of pulmonary artery smooth muscle cells (RPASMC) using anoxic chambers, and studied the effects of OIL-NPs on the malignant proliferation of RPASMC cells and phospholipase C (PLC)/inositol triphosphate receptor (IP3R)/Ca2+ signal pathways. In vivo, we used small animal echocardiography, flow cytometry, immunohistochemistry, western blotting (WB), polymerase chain reaction (PCR) and metabolomics to explore the effects of OIL-NPs on the heart and lung pathological damage and PLC/IP3R/Ca2+ signal pathway of pulmonary hypertension rats. Results: We prepared fatty into OIL-NPs. In vitro, OIL-NPs could improve the mitochondrial function and inhibit the malignant proliferation of RPASMC cells by inhibiting the PLC/IP3R/Ca2+signal pathway. In vivo, OIL-NPs could reduce the pulmonary artery pressure of rats and alleviate the pathological injury and inflammatory reaction of heart and lung by inhibiting the PLC/IP3R/Ca2+ signal pathway. Conclusion: OIL-NPs have anti-pulmonary hypertension effect, and the mechanism may be related to the inhibition of PLC/IP3R/Ca2+signal pathway.

BMAL1 inhibits renal fibrosis and renal interstitial inflammation by targeting the ERK1/2/ELK-1/Egr-1 axis.

RATIONALE: Renal fibrosis and renal interstitial inflammation due to hydronephrosis are associated with progressive chronic kidney disease (CKD). The clock gene BMAL1 is thought to be involved in various diseases, including hypertension, diabetes, etc. However, little is known about how BMAL1 regulates renal fibrosis and renal interstitial inflammation in obstructed kidneys. METHODS: The expression level of BMAL1 in UUO was examined using the GEO database. Lentivirus, siRNA and adeno-associated virus were used to modulate BMAL1 levels in HK-2 cells and mouse kidney. qRT-PCR, immunofluorescence staining, histological analysis, ELISA and Western blot were used to determine the level of fibrin deposition and the release of inflammatory factors. Immunofluorescence staining and western blotting were used to examine the interaction between BMAL1 and the ERK1/2/ELK-1/Egr-1 axis. RESULTS: Bioinformatics analysis and in vivo experiments in this study showed that the expression level of BMAL1 in UUO model kidneys was higher than that in normal kidneys. We then found that downregulation of BMAL1 promoted the production of extracellular matrix (ECM) proteins and proinflammatory factors in vivo and in vitro, whereas upregulation inhibited this process. In addition, we demonstrated that the ERK1/2/ELK-1/Egr-1 axis is an important pathway for BMAL1 to play a regulatory role, and the use of PD98059 abolished the promoting effect of down-regulation of BMAL1 on fibrosis and inflammation. CONCLUSIONS: Our findings suggest that BAML1 can target the ERK1/2/ELK-1/Egr-1 axis to suppress fibrotic progression and inflammatory events in obstructed kidneys, thereby inhibiting the development of CKD.

Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty.

BACKGROUND: Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM: To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS: A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS: The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION: In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.

Preparation, structural characteristics and antioxidant activity of polysaccharide and its metal chelates from the peel of Dioscorea oppositifolia L.

Two metal chelates of Dioscorea oppositifolia L. peel polysaccharides (DTP) were prepared: iron chelate (DTP-Fe) and zinc chelate (DTP-Zn). The physicochemical properties of the polysaccharide and its metal chelates were assessed by UV-Vis absorption spectroscopy, Fourier-transform infra-red spectroscopy, scanning electron microscopy, and thermogravimetric analysis. Antioxidant activities were evaluated by DPPH, ABTS + and hydroxyl radical scavenging assays. According to ICP-MS, the iron content of DTP-Fe was 9.47%, while the zinc content of DTP-Zn was 4.02%. The antioxidant capacity of DTP-Fe increased with the increase of concentration, and its overall activity was higher than that of DTP and DTP-Zn. This polysaccharide-iron chelate can be developed and utilised as an antioxidant and multifunctional iron supplement. DTP-Zn showed the potential to be a natural antioxidant and zinc supplement food.

Prognostic and immunological roles of IL18RAP in human cancers.

Across several cancers, IL18 receptor accessory protein (IL18RAP) is abnormally expressed, and this abnormality is related to tumor immunity and heterogeneous clinical outcomes. In this study, based on bioinformatics analysis, we discovered that IL18RAP is related to the human tumor microenvironment and promotes various immune cells infiltration. Additionally, the multiple immunofluorescence staining revealed that with the increased expression of IL18RAP, the number of infiltrated M1 macrophages increased. This finding was confirmed by coculture migration analysis using three human cancer cell lines (MDA-MB-231, U251, and HepG2) with IL18RAP knockdown. We discovered a positive link between IL18RAP and the majority of immunostimulators, immunoinhibitors, major histocompatibility complex (MHC) molecules, chemokines, and chemokine receptor genes using Spearman correlation analysis. Additionally, functional IL18RAP's gene set enrichment analysis (GSEA) revealed that it is related to a variety of immunological processes, such as positive regulation of interferon gamma production and positive regulation of NK cell-mediated immunity. Moreover, we used single-cell RNA sequencing analysis to detect that IL18RAP was mainly expressed in immune cells, and HALLMARK analysis confirmed that the INF-γ gene set expression was upregulated in CD8Tex cells. In addition, in human and mouse cancer cohorts, we found that the level of IL18RAP can predict the immunotherapy response. In short, our study showed that IL18RAP is a new tumor biomarker and may become a potential immunotherapeutic target in cancer.

Simultaneous thulium laser resection of the prostate and transperineal prostate biopsy in clinically diagnosed metastatic prostate cancer with bladder outlet obstruction.

Metastatic prostate cancer (mPCa) patients complicated with bladder outlet obstruction (BOO) are often referred to a urologist. Androgen deprivation therapy (ADT) combined with indwelling catheter usually be the initial management. To retrospectively analysis the safety and efficacy of simultaneous thulium laser resection of the prostate (TmLRP) and transperineal prostate biopsy in metastatic prostate cancer with bladder outlet obstruction. From January 2016 to December 2021, 67 clinically diagnosed mPCa with BOO patients were included in this study. All patients were preoperatively assessed with international prostate symptom score (IPSS), QoL, serum prostate-specific antigen (PSA), prostate volume evaluation by transrectal ultrasound, postvoid residual urine volume (PVR), and maximum flow rate (Qmax). Preoperative and perioperative parameters at 1-, 3-, and 6-month follow-up were also evaluated. All complications were recorded. Simultaneous TmLRP and transperineal prostate biopsy had obvious advantages for clinically diagnosed mPCa patients with BOO, including short overall operation time (52 ± 23.3 min), little hemoglobin decrease (0.6 ± 0.7 g/l), and short hospital stay (average 3.8 days). In addition, simultaneous TmLRP and transperineal prostate biopsy also brought them significant improvement on IPSS, QoL score, Qmax, and PVR volume (P < 0.001) at 1-, 3-, and 6-month follow-up after operation compared to preoperative parameters. Complications were in a low incidence. Simultaneous TmLRP and transperineal prostate biopsy is a bloodless operation with immediate effect and little perioperative complication. Importantly, it is a promising technology in the diagnosis and treatment of clinically diagnosed mPCa patients with BOO.

Biocompatibility and efficacy of prostatic urethral lift in benign prostate hyperplasia: an in vivo and in vitro study.

The study aimed to assess the biocompatibility and efficacy of a prostatic urethral lift (PUL) for benign prostatic hyperplasia (BPH). Human BPH-1 cells were co-cultured with implant anchors and sutures, and cytotoxicity was measured. Scanning electron microscopy (SEM) was used to observe adhesion and growth of cells and to evaluate implant biocompatibility. Fifteen male beagle dogs were randomly assigned to the surgical (n = 9) or sham-operated (n = 6) groups. The surgical group underwent cystotomy, and PUL was used to insert two implants in each lobe of the prostate to compress the enlarged prostate and dilate the urethra; the sham group underwent cystotomy without implant insertion. Compared with the control group, no significant difference in cell viability among the groups with different co-culture times of implant anchors and sutures (P > 0.05) was observed. SEM revealed good adhesion and growth of prostate cells on the implants. Improvements in urine flow rates remained stable at 7, 28, and 180 days after surgery, and the urethral diameter in the prostate region was significantly increased compared with that before surgery. PUL is a biocompatible and effective treatment for BPH, improving the urine flow rate without causing inflammation, tissue damage, or cytotoxic effects. Here, the basis for further PUL application was provided.

Rapamycin and Low-dose IL-2 Mediate an Immunosuppressive Microenvironment to Inhibit Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

MTHFD2 promotes PD-L1 expression via activation of the JAK/STAT signalling pathway in bladder cancer.

Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC.

FLRT2 suppresses bladder cancer progression through inducing ferroptosis.

Bladder cancer is a common tumour worldwide and exhibits a poor prognosis. Fibronectin leucine rich transmembrane protein 2 (FLRT2) is associated with the regulation of multiple tumours; however, its function in human bladder cancer remain unclear. Herein, we found that FLRT2 level was reduced in human bladder cancer and that higher FLRT2 level predicted lower survival rate. FLRT2 overexpression inhibited, while FLRT2 silence facilitated tumour cell growth, migration and invasion. Mechanistic studies revealed that FLRT2 elevated acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, increased lipid peroxidation and subsequently facilitated ferroptosis of human bladder cancer cells. In summary, we demonstrate that FLRT2 elevates ACSL4 expression to facilitate lipid peroxidation and subsequently triggers ferroptosis, thereby inhibiting the malignant phenotype of human bladder cancer cells. Overall, we identify FLRT2 as a tumour suppressor gene.

Clinical Efficacy of Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes: A Meta-analysis.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat type 2 diabetes mellitus (T2DM), which have been considered at the same treatment pattern point as basal insulin (BI). Thus, comprehensively comparing these drugs is conducive to informing the treatment decisions. In this context, this work was developed to evaluate the clinical efficacy and safety of GLP-1 RAs by comparing them with basal insulin. GLP-1 RAs were compared with basal insulin in adults with T2DM with inadequate oral anti-hyperglycemic drug control by searching related literature from MEDLINE, EMBASE, CENTRAL, and PubMed databases, which were published from established the datasets to October 2022. Data on hemoglobin A1c, body weight, and blood glucose were extracted and analyzed. The MD values of HbA1C, weight, and fasting blood glucose (FBG) change were -0.02, -1.37, and -1.68, respectively. Meanwhile, the OR of the hypoglycemia ratio was 0.33. In conclusion, GLP-1 RAs exhibited a great effect on blood glucose and weight control and a better effect on FBG control.

Identification and validation of cancer-associated fibroblast-related subtypes and the prognosis model of biochemical recurrence in prostate cancer based on single-cell and bulk RNA sequencing.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an essential component of the tumor immune microenvironment that are involved in extracellular matrix (ECM) remodeling. We aim to investigate the characteristics of CAFs in prostate cancer and develop a biochemical recurrence (BCR)-related CAF signature for predicting the prognosis of PCa patients. METHODS: The bulk RNA-seq and relevant clinical information were obtained from the TCGA and GEO databases, respectively. The infiltration scores of CAFs in prostate cancer patients were calculated using the MCP counter and EPIC algorithms. The single-cell RNA sequencing (scRNA-seq) was downloaded from the GEO database. Subsequently, univariate Cox regression analysis was employed to identify prognostic genes associated with CAFs. We identified two subtypes (C1 and C2) of prostate cancer that were associated with CAFs via non-negative matrix factorization (NMF) clustering. In addition, the BCR-related CAF signatures were constructed using Lasso regression analysis. Finally, a nomogram model was established based on the risk score and clinical characteristics of the patients. RESULTS: Initially, we found that patients with high CAF infiltration scores had shorter biochemical recurrence-free survival (BCRFS) times. Subsequently, CAFs in four pairs of tumors and paracancerous tissues were identified. We discovered 253 significantly differentially expressed genes, of which 13 had prognostic significance. Using NMF clustering, we divided PCa patients into C1 and C2 subgroups, with the C1 subgroup having a worse prognosis and substantially enriched cell cycle, homologous recombination, and mismatch repair pathways. Furthermore, a BCR-related CAFs signature was established. Multivariate COX regression analysis confirmed that the BCR-related CAFs signature was an independent prognostic factor for BCR in PCa. In addition, the nomogram was based on the clinical characteristics and risk scores of the patient and demonstrated high accuracy and reliability for predicting BCR. Lastly, our findings indicate that the risk score may be a useful tool for predicting PCa patients' sensitivity to immunotherapy and drug treatment. CONCLUSION: NMF clustering based on CAF-related genes revealed distinct TME immune characteristics between groups. The BCR-related CAF signature accurately predicted prognosis and immunotherapy response in prostate cancer patients, offering a promising new approach to cancer treatment.

p53 deacetylation alleviates calcium oxalate deposition-induced renal fibrosis by inhibiting ferroptosis.

Calcium oxalate (CaOx) stones are among the most common types of kidney stones and are associated with renal tubular damage, interstitial fibrosis, and chronic kidney disease. The mechanism of CaOx crystal-induced renal fibrosis remains unknown. Ferroptosis, a type of regulated cell death, is characterised by iron-dependent lipid peroxidation, and the tumour suppressor p53 is a key regulator of ferroptosis. In the present study, our results demonstrated that ferroptosis was significantly activated in patients with nephrolithiasis and hyperoxaluric mice as well as verified the protective effects of ferroptosis inhibition on CaOx crystal-induced renal fibrosis. Moreover, the single-cell sequencing database, RNA-sequencing, and western blot analysis revealed that the expression of p53 was increased in patients with chronic kidney disease and the oxalate-stimulated human renal tubular epithelial cell line, HK-2. Additionally, the acetylation of p53 was enhanced by oxalate stimulation in HK-2 cells. Mechanistically, we found that the induction of p53 deacetylation, owing to either the SRT1720-induced activation of deacetylase sirtuin 1 or the triple mutation of p53, inhibited ferroptosis and alleviated renal fibrosis caused by CaOx crystals. We conclude that ferroptosis is one of the critical mechanisms contributing to CaOx crystal-induced renal fibrosis, and the pharmacological induction of ferroptosis via sirtuin 1-mediated p53 deacetylation may be a potential target for preventing renal fibrosis in patients with nephrolithiasis.