Repetitive transcranial magnetic stimulation for post-stroke non-fluent aphasia: a systematic review and meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) on language function in patients with non-fluent aphasia post-stroke. Methods: We selected randomized clinical trials (RCT) that involved stroke patients with non-fluent aphasia, whose intervention was rTMS vs. no therapy or other therapy. Two researchers autonomously reviewed the literature based on the specified criteria for inclusion and exclusion and completed the process of data extraction, data verification, and quality evaluation. Meta-analysis was performed using RevMan 5.4 and Stata MP 17, while the assessment of risk of bias was carried out utilizing the Risk of Bias version 2 tool (RoB2). Results: The meta-analysis involved 47 RCTs, encompassing 2,190 patients overall. The indexes indicated that rTMS has the potential to decrease the severity of non-fluent aphasia in stroke patients, including improvement of the capability of repetition, naming, and spontaneous language. The determination of BDNF in the serum of patients was also increased. In addition, rTMS reduced the likelihood of depression in stroke patients. Conclusion: To summarize the relevant studies, rTMS has significant effects on improving the language abilities of stroke patients suffering from non-fluent aphasia, including the abilities of repetition, naming, and spontaneous language.

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.

The Social Inequality of Music: University Students from a Higher Social Class Are More Likely to Build Relationships and Feel Happiness Through Music.

The relationship between young people's music use and well-being has gained extensive interest in recent years. The relationship-building function of music is one of its most important functions. While many studies have documented the positive effects of this function, there is a lack of research discussing this topic from the perspective of social stratification. This study sampled 691(63.8% male, M age = 19.43, SD = 1.42) Chinese university students to examine the social class differences among university students in acquiring well-being through the relationship-building function of music. The results revealed that university students from a higher social class are more likely to acquire well-being through the relationship-building function of music. In addition, interdependent self-construal plays a moderating role in the mediating model. The mediating effect was only significant when university students have a higher level of interdependent self-construal. These results indicated social class differences among university students in the building of relationships with music, underscoring the need for future research and interventions to address social inequality in the context of music's functions.

Comprehensive analysis indicated that NDE1 is a potential biomarker for pan-cancer and promotes bladder cancer progression.

BACKGROUND: The nuclear distribution E homologue 1 (NDE1) is a crucial dynein binding partner. The NDE1 protein has the potential to disrupt the normal functioning of centrosomes, leading to a compromised ability to generate spindles and ensure precise separation of chromosomes during cell division. The potential consequences of this phenomenon include genomic instability, malignant transformation and the proliferation of neoplastic growths. However, studies examining the connection between NDE1 and cancer is still very rare. METHODS: The expression level, prognostic impact, gene change, DNA methylation, protein interaction, mRNA m6A modification, ceRNA network, associated gene and function enrichment, and immune-related effects of NDE1 in pan-cancer were examined using a range of online analytic tools and the R software package. The CCK-8 test, transwell assay, scratch assay and colony formation assay were used to confirm the effects of NDE1 on the proliferation, invasion and metastasis of bladder cancer cells. RESULTS: Numerous tumour types have elevated NDE1, which is linked to a bad prognosis. NDE1 is an excellent diagnostic tool for many different types of cancer. Numerous malignancies have been linked to genetic changes in NDE1. NDE1 was connected to TMB, MSI, several immunological checkpoint genes and immune cell infiltration. NDE1 is linked to a number of immunological subtypes. NDE1 could affect how well immunotherapy works to treat different types of cancer. NDE1 was mostly associated with cell cycle, chromosomal segregation, DNA replication and mitotic segregation, according to GO and KEGG analyses. NDE1 physically binds to PAFAH1B1 and DCTN1, respectively. The proliferation, invasion and metastasis of bladder cancer cells may be prevented by NDE1 knockdown. Furthermore, knockdown of NDE1 promoted the apoptosis of bladder cancer cells. CONCLUSION: High expression of NDE1 is present in a variety of tumours, which is linked to a bad prognosis for cancer. Knockdown of NDE1 inhibited the proliferation, invasion and metastasis of bladder cancer cells, and promoted the apoptosis. For a number of malignancies, NDE1 may be a biomarker for immunotherapy and prognosis.

The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-induced kidney injury.

Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.

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.

STAT6 promoting oxalate crystal deposition-induced renal fibrosis by mediating macrophage-to-myofibroblast transition via inhibiting fatty acid oxidation.

OBJECTIVE AND DESIGN: Kidney stones commonly occur with a 50% recurrence rate within 5 years, and can elevate the risk of chronic kidney disease. Macrophage-to-myofibroblast transition (MMT) is a newly discovered mechanism that leads to progressive fibrosis in different forms of kidney disease. In this study, we aimed to investigate the role of MMT in renal fibrosis in glyoxylate-induced kidney stone mice and the mechanism by which signal transducer and activator of transcription 6 (STAT6) regulates MMT. METHODS: We collected non-functioning kidneys from patients with stones, established glyoxylate-induced calcium oxalate stone mice model and treated AS1517499 every other day in the treatment group, and constructed a STAT6-knockout RAW264.7 cell line. We first screened the enrichment pathway of the model by transcriptome sequencing; detected renal injury and fibrosis by hematoxylin eosin staining, Von Kossa staining and Sirius red staining; detected MMT levels by multiplexed immunofluorescence and flow cytometry; and verified the binding site of STAT6 at the PPARα promoter by chromatin immunoprecipitation. Fatty acid oxidation (FAO) and fibrosis-related genes were detected by western blot and real-time quantitative polymerase chain reaction. RESULTS: In this study, we found that FAO was downregulated, macrophages converted to myofibroblasts, and STAT6 expression was elevated in stone patients and glyoxylate-induced kidney stone mice. The promotion of FAO in macrophages attenuated MMT and upregulated fibrosis-related genes induced by calcium oxalate treatment. Further, inhibition of peroxisome proliferator-activated receptor-α (PPARα) eliminated the effect of STAT6 deletion on FAO and fibrosis-associated protein expression. Pharmacological inhibition of STAT6 also prevented the development of renal injury, lipid accumulation, MMT, and renal fibrosis. Mechanistically, STAT6 transcriptionally represses PPARα and FAO through cis-inducible elements located in the promoter region of the gene, thereby promoting MMT and renal fibrosis. CONCLUSIONS: These findings establish a role for STAT6 in kidney stone injury-induced renal fibrosis, and suggest that STAT6 may be a therapeutic target for progressive renal fibrosis in patients with nephrolithiasis.

YAP/ACSL4 Pathway-Mediated Ferroptosis Promotes Renal Fibrosis in the Presence of Kidney Stones.

The potential association between calcium oxalate stones and renal fibrosis has been extensively investigated; however, the underlying mechanisms remain unclear. Ferroptosis is a novel form of cell death characterized by iron-dependent lipid peroxidation and regulated by acyl coenzyme A synthase long-chain family member 4 (ACSL4). Yes-associated protein (YAP), a transcriptional co-activator in the Hippo pathway, promotes ferroptosis by modulating ACSL4 expression. Nevertheless, the involvement of YAP-ACSL4 axis-mediated ferroptosis in calcium oxalate crystal deposition-induced renal fibrosis and its molecular mechanisms have not been elucidated. In this study, we investigated ACSL4 expression and ferroptosis activation in the kidney tissues of patients with calcium oxalate stones and in mice using single-cell sequencing, transcriptome RNA sequencing, immunohistochemical analysis, and Western blot analysis. In vivo and in vitro experiments demonstrated that inhibiting ferroptosis or ACSL4 mitigated calcium oxalate crystal-induced renal fibrosis. Furthermore, YAP expression was elevated in the kidney tissues of patients with calcium oxalate stones and in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines. Mechanistically, in calcium oxalate crystal-stimulated human renal tubular epithelial cell lines, activated YAP translocated to the nucleus and enhanced ACSL4 expression, consequently inducing cellular ferroptosis. Moreover, YAP silencing suppressed ferroptosis by downregulating ACSL4 expression, thereby attenuating calcium oxalate crystal-induced renal fibrosis. Conclusively, our findings suggest that YAP-ACSL4-mediated ferroptosis represents an important mechanism underlying the induction of renal fibrosis by calcium oxalate crystal deposition. Targeting the YAP-ACSL4 axis and ferroptosis may therefore hold promise as a potential therapeutic approach for preventing renal fibrosis in patients with kidney stones.

Comprehensive analysis reveals XCL2 as a cancer prognosis and immune infiltration-related biomarker.

BACKGROUND: X-C Motif Chemokine Ligand 2 (XCL2) is a 114 amino acid, structurally conserved chemokine involved in activating cytotoxic T cells. However, the pathophysiological mechanisms of XCL2 protein in various disease conditions, particularly cancer, remain poorly understood. METHODS: Bioinformatics was used to detect the expression of XCL2, the relationship between survival time and XCL2 in BLCA patients, the mutational status of XCL2, the role of XCL2 in the tumor immune microenvironment, and the sensitivity of XCL2-targeted drugs in 33 cancers. In vitro experiments were conducted to investigate the chemotactic effects of XCL2 expression on M1-type macrophages in human specimens and in isolated cancer cells. RESULTS: XCL2 expression was downregulated in tumor tissues and closely associated with the prognosis of human cancers. Furthermore, XCL2 affects DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) in human cancers. The expression level of XCL2 significantly correlated with infiltrated immune cells, immunological pathways, and other immune markers. More importantly, we found that XCL2 was positively associated with T lymphocytes and macrophages in the transcriptome and single-cell sequencing data. Using multiple immunofluorescence staining, we found that the expression level of XCL2 was upregulated in many cells in pan-cancer samples, and the number of M1 macrophage marker CD68 and INOS-positive cells increased. 786O, U251, and MDA-MB-231 cells could recruit more M1 macrophages in vitro after overexpressing XCL2. CONCLUSIONS: Our results reveal that XCL2 could act as a vital chemokine in pan-cancer and provide new targets and concepts for cancer treatment.

DUSP2 affects bladder cancer prognosis by down-regulating MEK/ERK and P38 MAPK signaling pathways through PTPN7.

BACKGROUND: As one of the leading causes of cancer death worldwide, bladder cancer (BCa) ranks 12th in incidence rate. Dual Specific Phosphatase 2 (DUSP2) is a member of the bispecific protein phosphatase subfamily. DUSP2 is closely related to the prognosis of cancer, but the role of DUSP2 in bladder cancer is still unclear. This study aims to explore how DUSP2 affects the prognosis of bladder cancer and clarify the important mechanism in bladder cancer. METHODS: Bioinformatics and experiments have detected the anti-tumor effect of DUSP2. Construct a DUSP2 overexpression cell model, and then use protein blotting experiments to verify the efficiency of transfection. The effects of DUSP2 on proliferation, metastasis, apoptosis, epithelial mesenchymal transition (EMT) and immune invasion of bladder cancer cells were detected in vitro or in vivo. In addition, the mechanism of DUSP2 regulating MEK/ERK through PTPN7 pathway and P38 MAPK inhibiting the progression of bladder cancer was also discussed. RESULTS: The expression of DUSP2 was down regulated in bladder cancer samples and cell lines. The overexpression of DUSP2 inhibits the proliferation, metastasis and immune microenvironment of bladder cancer cells. In addition, we confirmed that DUSP2 regulates MEK/ERK and P38 MAPK through PTPN7 pathway to inhibit the progression of bladder cancer. CONCLUSION: DUSP2 inhibits the progression of bladder cancer by regulating PTPN7. These results suggest that DUSP2/PTPN7/MEK/ERK pathway may become a new therapeutic target for bladder cancer.

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.

Classification and clinical significance of the posterior group of renal calyces.

To study the anatomical orientation of the posterior group of calyces based on reconstructed images of computerized tomography urography (CTU) and provide a novel classification with its clinical significance. Clinical data of a total of 1321 patients, who underwent CTU examination in our hospital were retrospectively analyzed. Among these, a total of 2642 3-dimensional reconstructed images of CTU scans were considered in this study. Based on the morphology of the renal calyces and the influence on the establishment of surgical access, the posterior group renal calyces are classified into 3 major types including pot-belly type, classically branched and elongated branched. The classically branched type is further classified into 3 sub-types: a, b and c, based on the association of minor calyces of the posterior group to the major calyces. Type a is derived from 1 group of major calyces only, type b is derived from 2 groups of major calyces simultaneously, and type c is derived from 3 groups of major calyces simultaneously. Statistical findings revealed that all kidneys possess posterior group calyces. The percentage of occurrence of pot-belly type, classically branched and elongated branched is 8.06%, 73.13%, and 18.81%, respectively. The anatomical typing of the classical branching type occurred in 19.36%, 68.17%, and 12.47% for types a, b, and c, respectively. In this study, the posterior group calyces were found to be present across all patients. The posterior group calyces were highest in the classical branching type, of which anatomical typing was highest in type b. The typing of the posterior group of calyces could provide an anatomical basis for percutaneous nephrolithotomy (PCNL) puncture from the posterior group.

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.

Overexpression of sirtuin 1 attenuates calcium oxalate-induced kidney injury by promoting macrophage polarization.

Sirtuin 1 (SIRT1) protein is involved in macrophage differentiation, while NOTCH signaling affects inflammation and macrophage polarization. Inflammation and macrophage infiltration are typical processes that accompany kidney stone formation. However, the role and mechanism of SIRT1 in renal tubular epithelial cell injury caused by calcium oxalate (CaOx) deposition and the relationship between SIRT1 and the NOTCH signaling pathway in this urological disorder are unclear. This study investigated whether SIRT1 promotes macrophage polarization to inhibit CaOx crystal deposition and reduce renal tubular epithelial cell injury. Public single-cell sequencing data, RT-qPCR, immunostaining approaches, and Western blotting showed decreased SIRT1 expression in macrophages treated with CaOx or exposed to kidney stones. Macrophages overexpressing SIRT1 differentiated towards the anti-inflammatory M2 phenotype, significantly inhibiting apoptosis and alleviating injury in the kidneys of mice with hyperoxaluria. Conversely, decreased SIRT1 expression in CaOx-treated macrophages triggered Notch signaling pathway activation, promoting macrophage polarization towards the pro-inflammatory M1 phenotype. Our results suggest that SIRT1 promotes macrophage polarization towards the M2 phenotype by repressing the NOTCH signaling pathway, which reduces CaOx crystal deposition, apoptosis, and damage in the kidney. Therefore, we propose SIRT1 as a potential target for preventing disease progression in patients with kidney stones.

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.

Gut microbiota in patients with kidney stones: a systematic review and meta-analysis.

BACKGROUND: Mounting evidence indicates that the gut microbiome (GMB) plays an essential role in kidney stone (KS) formation. In this study, we conducted a systematic review and meta-analysis to compare the composition of gut microbiota in kidney stone patients and healthy individuals, and further understand the role of gut microbiota in nephrolithiasis. RESULTS: Six databases were searched to find taxonomy-based comparison studies on the GMB until September 2022. Meta-analyses were performed using RevMan 5.3 to estimate the overall relative abundance of gut microbiota in KS patients and healthy subjects. Eight studies were included with 356 nephrolithiasis patients and 347 healthy subjects. The meta-analysis suggested that KS patients had a higher abundance of Bacteroides (35.11% vs 21.25%, Z = 3.56, P = 0.0004) and Escherichia_Shigella (4.39% vs 1.78%, Z = 3.23, P = 0.001), and a lower abundance of Prevotella_9 (8.41% vs 10.65%, Z = 4.49, P < 0.00001). Qualitative analysis revealed that beta-diversity was different between the two groups (P < 0.05); Ten taxa (Bacteroides, Phascolarctobacterium, Faecalibacterium, Flavobacterium, Akkermansia, Lactobacillus, Escherichia coli, Rhodobacter and Gordonia) helped the detection of kidney stones (P < 0.05); Genes or protein families of the GMB involved in oxalate degradation, glycan synthesis, and energy metabolism were altered in patients (P < 0.05). CONCLUSIONS: There is a characteristic gut microbiota dysbiosis in kidney stone patients. Individualized therapies like microbial supplementation, probiotic or synbiotic preparations and adjusted diet patterns based on individual gut microbial characteristics of patients may be more effective in preventing stone formation and recurrence.

Histone H3K27 methyltransferase EZH2 regulates apoptotic and inflammatory responses in sepsis-induced AKI.

Rationale: The role of histone methylation modifications in renal disease, particularly in sepsis-induced acute kidney injury (AKI), remains unclear. This study aims to investigate the potential involvement of the histone methyltransferase zeste homolog 2 (EZH2) in sepsis-induced AKI and its impact on apoptosis and inflammation. Methods: We first examined the expression of EZH2 in the kidney of sepsis-induced AKI (LPS injection) mice and LPS-stimulated tubular epithelial cells. We next constructed the EZH2 knockout mice to further confirm the effects of EZH2 on apoptosis and inflammatory response in AKI. And the inflammatory level of epithelial cells can be reflected by detecting chemokines and the chemotaxis of macrophages. Subsequently, we constructed the EZH2 knocked-down cells again and performed Chromatin Immunoprecipitation sequencing to screen out the target genes regulated by EZH2 and the enrichment pathway. Then we confirmed the EZH2 target gene and its regulatory pathway in vivo and in vitro experiments. Experimental results were finally confirmed using another in vivo model of sepsis-induced AKI (cecal perforation ligation). Results: The study found that EZH2 was upregulated in sepsis-induced AKI and that silencing EZH2 could reduce renal tubular injury by decreasing apoptosis and inflammatory response of tubular epithelial cells. EZH2 knockout mice showed significantly reduced renal inflammation and macrophage infiltration. Chromatin immunoprecipitation sequencing and polymerase chain reaction identified Sox9 as a target of EZH2. EZH2 was found to be enriched on the promoter of Sox9. Silencing EZH2 resulted in a significant increase in the transcriptional level of Sox9 and activation of the Wnt/ß-catenin signaling pathway. The study further reversed the effects of EZH2 silencing by silencing Sox9 or administering the Wnt/ß-catenin inhibitor icg001. It was also found that Sox9 positively regulated the expression of ß-catenin and its downstream pathway-related genes. Finally, the study showed that the EZH2 inhibitor 3-deazaneplanocin A significantly alleviated sepsis-induced AKI. Conclusion: Our results indicate that silencing EZH2 can protect renal function by relieving transcriptional inhibition of Sox9, activating the Wnt/ß-catenin pathway, and attenuating tubular epithelial apoptosis and inflammatory response of the renal interstitium. These results highlight the potential therapeutic value of targeting EZH2 in sepsis-induced AKI.

Evaluation of retinal microcirculation alterations using OCTA in hyperopic ametropic amblyopia patients before and after treatment.

PURPOSE: We aimed to compare retinal microcirculation in hyperopic ametropic amblyopia patients before and after treatment and in healthy children using optical coherence tomography angiography (OCTA), and to explore the pathogenesis of hyperopic ametropic amblyopia. METHODS: Eighteen patients with hyperopic ametropic amblyopia aged 4-8 years were selected as the patient group, and 18 age-matched healthy children were randomly selected as controls. The foveal avascular zone (FAZ) area, perimeter and circularity, vessel density (VD) and perfusion density (PD) of macular superficial retinal capillary plexus, macular thickness, peripapillary retinal nerve fiber layer thickness, and ganglion cell-inner plexiform layer thickness were compared between both groups. After 6 months of amblyopia treatment, the same parameters were measured again. RESULTS: The VD and PD in the central, inner, inner nasal, and inner inferior regions in hyperopic ametropic amblyopia were lower than in the control group after adjustment for axial length. After 6 months of treatment, the VD increased significantly, except in the outer nasal and outer inferior regions. The PD in the central (p < 0.001), inner superior (p = 0.001), inner inferior (p = 0.011) and inner temporal (p = 0.026) regions increased. The FAZ perimeter and circularity significantly differed between the groups. After 6 months of treatment, the FAZ area and perimeter decreased, but circularity increased. CONCLUSION: Hyperopic ametropic amblyopia eyes showed a significant decrease in vessel and perfusion densities. After amblyopia treatment, the vessel and perfusion densities of patients with hyperopic ametropic amblyopia increased, suggesting that abnormalities in the microvascular system are a pathogenic factor of amblyopia.

Evaluation of retinal microcirculation alterations using optical coherence tomography angiography in patients with hyperopia ametropic amblyopia: A case-control study.

Given that there are controversial findings regarding vessel density in amblyopia, we quantified retinal microcirculation using optical coherence tomography angiography and compared it between hyperopic ametropic amblyopia eyes and age-matched control eyes. This case-control study was conducted from March 2021 to March 2022 at the Affiliated Eye Hospital of Nanchang University, Nanchang, China. Both groups included 72 eyes. Foveal avascular zone area, circularity and perimeter, perfusion density and vessel density of macular superficial retinal capillary plexus, macular thickness, macular volume, peripapillary retinal nerve fiber layer thickness, and ganglion cell-inner plexiform layer thickness were compared between hyperopia ametropic amblyopia eyes and age-matched control eyes. Additionally, best-corrected visual acuity, maximum corneal curvature, minimum corneal curvature, and anterior chamber depth were measured. In the hyperopia ametropic amblyopia eyes and control eyes, vessel density was 7.51 ± 2.13 and 9.91 ± 2.71 mm-1 in the central, 17.20 ± 1.38 and 18.25 ± 1.37 mm-1 in the inner, and 17.90 ± 0.88 and 18.43 ± 0.97 mm-1 in the full regions, respectively. The perfusion densities were 0.17 ± 0.06 and 0.23 ± 0.07 in the central, 0.41 ± 0.05 and 0.44 ± 0.03 in the inner, and 0.44 ± 0.03 and 0.46 ± 0.02 in the full regions, respectively. The central macular thicknesses of hyperopia ametropic amblyopia and control eyes were 240.04 ± 20.11 and 235.08 ± 24.41 µm, respectively. Foveal avascular zone perimeter and circularity (P < .043 and P = .001) significantly differed between the 2 groups. Hyperopia ametropic amblyopia eyes showed lower appreciably in vessel and perfusion densities, which could be one of the major pathophysiological mechanisms of hyperopia ametropic amblyopia and provide a new direction for the diagnosis and treatment of amblyopia.