S100A9 promotes renal calcium oxalate stone formation via activating the TLR4-p38/MAPK-LCN2 signaling pathway.

OBJECTIVES: To explore the role of S100A9 protein in renal calcium oxalate (CaOx) stone formation. METHODS: CaOx nephrocalcinosis mice were established via intraperitoneal injection of glyoxylate. They were treated with S100A9 deficiency, Paquinimod, or p38 MAPK-IN-1. Vonkossa staining was conducted to observe the deposition of CaOx crystals. Renal expression of inflammation, macrophage polarization, and injury markers was detected using immunohistochemistry and qPCR. Effects of S100A9 on renal tubular epithelial cells (HK-2) were explored by transcriptome sequencing. The mechanism of how S100A9 regulated lipocalin 2 (LCN2) was studied through Western Blot. Flow cytometry was performed to detect the influence of LCN2 on macrophages polarization. RESULTS: S100A9 deficiency inhibited the renal deposition of CaOx crystals in nephrocalcinosis mice. S100A9 upregulated the expression of LCN2 in HK-2 cells via activating the TLR4-p38/MAPK pathway. LCN2 promoted the migration and M1 polarization of macrophages. S100A9 deficiency downregulated the renal expression of LCN2, IL1-ß, Kim-1, F4/80, and CD80 in nephrocalcinosis mice. Paquinimod and p38 MAPK-IN-1 both inhibited the renal deposition of CaOx crystals and downregulated the expression of LCN2, IL1-ß, Kim-1, F4/80, iNOS, and CD68 in nephrocalcinosis mice. CONCLUSIONS: S100A9 promotes renal inflammatory injury by activating the TLR4-p38/MAPK-LCN2 pathway and then contributes to CaOx stone formation.

Inflammatory factors and the risk of urolithiasis: a bidirectional Mendelian randomization study.

Background: Urolithiasis is a prevalent condition encountered in urology. Over the past decade, its global incidence has been on an upward trajectory; paired with a high recurrence rate, this presents considerable health and economic burdens. Although inflammatory factors are pivotal in the onset and progression of urolithiasis, their causal linkages remain elusive. Method: Mendelian randomization (MR) is predicated upon genome-wide association studies (GWASs). It integrates bioinformatics analyses to reveal causal relationships between exposures and outcomes, rendering it an effective method with minimized bias. Drawing from a publicly accessible GWAS meta-analysis comprising 8,293 samples, we identified 41 genetic variations associated with inflammatory cytokines as instrumental variables. Outcome data on upper urinary tract stones, which included renal and ureteral stones (9,713 cases and 366,693 controls), and lower urinary tract stones, including bladder and urethral stones (1,398 cases and 366,693 controls), were derived from the FinnGen Consortium R9 dataset. By leveraging the bidirectional MR methodology, we aimed to decipher the causal interplay between inflammatory markers and urolithiasis. Results: Our study comprehensively elucidated the association between genetic inflammatory markers and urolithiasis via bidirectional Mendelian randomization. Post-MR analysis of the 41 genetic inflammation markers revealed that elevated levels of circulating interleukin-2 (IL-2) (OR = 0.921, 95% CI = 0.848-0.999) suggest a reduced risk for renal stone disease, while heightened stem cell growth factor beta (SCGF-ß) (OR = 1.150, 95% CI = 1.009-1.310) and diminished macrophage inflammatory protein 1 beta (MIP-1ß) (OR = 0.863, 95% CI = 0.779-0.956) levels suggest an augmented risk for lower urinary tract stones. Furthermore, renal stone disease appeared to elevate IL-2 (ß = 0.145, 95% CI = 0.013-0.276) and cutaneous T cell-attracting chemokine (CTACK) (ß = 0.145, 95% CI = 0.013-0.276) levels in the bloodstream, whereas lower urinary tract stones were linked to a surge in interleukin-5 (IL-5) (ß = 0.142, 95% CI = 0.057-0.226), interleukin-7 (IL-7) (ß = 0.108, 95% CI = 0.024-0.192), interleukin-8 (IL-8) (ß = 0.127, 95% CI = 0.044-0.210), growth regulated oncogene alpha (GRO-α) (ß = 0.086, 95% CI = 0.004-0.169), monokine induced by interferon-gamma (MIG) (ß = 0.099, 95% CI = 0.008-0.191) and macrophage inflammatory protein 1 alpha (MIP-1α) (ß = 0.126, 95% CI = 0.044-0.208) levels. Conclusion: These discoveries intimate the instrumental role of IL-2 in the onset and progression of upper urinary tract stones. SCGF-ß and MIP-1ß influence the development of lower urinary tract stones. Urolithiasis also impacts the expression of cytokines such as IL-2, CTACK, IL-5, IL-7, IL-8, GRO-α, MIG, and MIP-1α. There is a pressing need for further investigation to ascertain whether these biomarkers can be harnessed to prevent or treat urolithiasis.

Bacterial lipopolysaccharide-related genes are involved in the invasion and recurrence of prostate cancer and are related to immune escape based on bioinformatics analysis.

Background: The composition of the tumor microbial microenvironment participates in the whole process of tumor disease. However, due to the limitations of the current technical level, the depth and breadth of the impact of microorganisms on tumors have not been fully recognized, especially in prostate cancer (PCa). Therefore, the purpose of this study is to explore the role and mechanism of the prostate microbiome in PCa based on bacterial lipopolysaccharide (LPS)-related genes by means of bioinformatics. Methods: The Comparative Toxicogenomics Database (CTD) was used to find bacterial LPS- related genes. PCa expression profile data and clinical data were acquired from TCGA, GTEx, and GEO. The differentially expressed LPS-related hub genes (LRHG) were obtained by Venn diagram, and gene set enrichment analysis (GSEA) was used to investigate the putative molecular mechanism of LRHG. The immune infiltration score of malignancies was investigated using single-sample gene set enrichment analysis (ssGSEA). Using univariate and multivariate Cox regression analysis, a prognostic risk score model and nomogram were developed. Results: 6 LRHG were screened. LRHG were involved in functional phenotypes such as tumor invasion, fat metabolism, sex hormone response, DNA repair, apoptosis, and immunoregulation. And it can regulate the immune microenvironment in the tumor by influencing the antigen presentation of immune cells in the tumor. And a prognostic risk score and the nomogram, which were based on LRHG, showed that the low-risk score has a protective effect on patients. Conclusion: Microorganisms in the PCa microenvironment may use complex mechanism and networks to regulate the occurrence and development of PCa. Bacterial lipopolysaccharide-related genes can help build a reliable prognostic model and predict progression-free survival in patients with prostate cancer.

Pregnancy complicated with adrenal adenoma causing ACTH-independent Cushing's syndrome, accompanied by obstetric antiphospholipid syndrome and severe pre-eclampsia: case report and literature review.

This case report shares the management experience of a patient with pregnancy combined with adrenal adenoma causing ACTH-independent Cushing's syndrome (CS), accompanied by obstetric antiphospholipid syndrome (OAPS) and severe pre-eclampsia. The case was a 26-year-old that presented with typical clinical symptoms and signs of CS. The patient had a history of 4 spontaneous abortions in the last 4 years. The 24-hour urinary free cortisol was significantly increased, an abnormal cortisol circadian rhythm was demonstrated by a high late-night salivary cortisol, blood ACTH was suppressed (< 1ng/dL), anticardiolipin antibody was positive, and imaging examination showed an adrenal tumor. The patient underwent laparoscopic adrenal tumor resection under general anesthesia at 23 weeks of gestation. The tumor was pathologically confirmed to be an adrenocortical adenoma. The patient underwent a cesarean section at 39 weeks of gestation to give birth to a healthy baby girl with an Apgar score of 10. Pregnancy complicated by CS is clinically rare, easily masked by normal physiological changes of pregnancy, and is difficult to diagnose. The determination of 24-hour urinary free cortisol, the circadian rhythm of serum cortisol, ultrasound, and MRI can be helpful in the diagnosis of CS during pregnancy. Surgery is the first choice for the treatment of CS during pregnancy. As a subtype of antiphospholipid syndrome, patients with OAPS are prone to thrombotic events and recurrent miscarriages if not treated accordingly. To our knowledge no cases of CS with OAPS and severe pre-eclampsia have been reported. We summarize the experience of the treatment of this patient and review the literature to improve clinicians' awareness of this disease.

Potential role of gut microbiota in prostate cancer: immunity, metabolites, pathways of action?

The gut microbiota helps to reveal the relationship between diseases, but the role of gut microbiota in prostate cancer (PCa) is still unclear. Recent studies have found that the composition and abundance of specific gut microbiota are significantly different between PCa and non-PCa, and the gut microbiota may have common and unique characteristics between different diseases. Intestinal microorganisms are affected by various factors and interact with the host in a variety of ways. In the complex interaction model, the regulation of intestinal microbial metabolites and the host immune system is particularly important, and they play a key role in maintaining the ecological balance of intestinal microorganisms and metabolites. However, specific changes in the composition of intestinal microflora may promote intestinal mucosal immune imbalance, leading to the formation of tumors. Therefore, this review analyzes the immune regulation of intestinal flora and the production of metabolites, as well as their effects and mechanisms on tumors, and briefly summarizes that specific intestinal flora can play an indirect role in PCa through their metabolites, genes, immunity, and pharmacology, and directly participate in the occurrence, development, and treatment of tumors through bacterial and toxin translocation. We also discussed markers of high risk PCa for intestinal microbiota screening and the possibility of probiotic ingestion and fecal microbiota transplantation, in order to provide better treatment options for clinic patients. Finally, after summarizing a number of studies, we found that changes in immunity, metabolites.

A ß-carboline derivative-based nickel(ii) complex as a potential antitumor agent: synthesis, characterization, and cytotoxicity.

A novel nickel(ii) complex of 6-methoxy-1-pyridine-ß-carboline (4a) was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC50 values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 µM), lower than those of ligand 4 and cisplatin. Furthermore, 4a (6 µM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that 4a induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca2+]c levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered via executive molecular caspase-9 and caspase-3. In short, 4a exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.