Impact of multiple sclerosis on male sexual and reproductive health.

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune neurodegenerative disease characterized by the destruction of myelin in the central nervous system, leading to significant health and quality of life burdens for patients. MS is most prevalent in younger individuals aged 20-40, a critical period when many patients hope to establish relationships and start families. While neurological disability, such as fatigue, sensory dysfunction, spasticity, and cognitive dysfunction, have been greatly improved with the advances in managing MS, physicians are frequently confronted with sexual and reproductive problems among younger male people with MS (PwMS). These issues mainly include erectile dysfunction, ejaculatory disorders, reduced libido, decreased sperm quality, and impaired male fertility. Despite recent studies indicating that MS negatively impacts the sexuality and fertility of male PwMS, these issues have not received sufficient attention. Genetic factors, autoimmunity, chronic inflammation, psychological factors, and the use of drugs may contribute to sexual/reproductive dysfunction in PwMS. However, like the overall understanding of MS pathophysiology, the complete mechanisms of its development remain unclear. In this study, we review the existing literature to summarize the range of sexual and reproductive issues unique to males with MS, explore potential underlying mechanisms, and aim to improve these issues in male PwMS. By shedding light on this overlooked aspect of MS, we hope to enhance the care and well-being of male PwMS facing these challenges.

Urinary SPP1 has potential as a non-invasive diagnostic marker for focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a type of chronic glomerular nephropathy showing characteristic glomerular sclerosis, diagnosed by kidney biopsy. However, it is difficult and expensive to monitor disease progression with repeated renal biopsy in clinical practice, and thus here we explored the feasibility of urine biomarkers as non-invasive diagnostic tools. We downloaded scRNA-seq datasets of 20 urine cell samples and 3 kidney tissues and obtained two gene lists encoding extracellular proteins for bioinformatic analysis; in addition, we identified key EP-Genes by immunohistochemical staining and performed bulk RNA sequencing with 12 urine samples. We report that urine cells and kidney cells were correlated. A total of 64 EP-Genes were acquired by intersecting genes of distal tubular cluster with extracellular proteins. Function enrichment analysis showed that EP-Genes might be involved in the immune response and extracellular components. Six key EP-Genes were identified and correlated with renal function. IMC showed that key EP-Genes were located mainly in tubules. Cross verification and examination of a urine RNAseq dataset showed that SPP1 had diagnostic potential for FSGS. The presence of urine SPP1 was primarily associated with macrophage infiltration in kidney, and the pathogenesis of FSGS may be related to innate immunity. Urinary cells seemed to be strongly similar to kidney cells. In summary, SPP1 levels reflect renal function and may have potential as a biomarker for non-invasive diagnosis of FSGS.

Nicotinamide N-Methyl Transferase as a Predictive Marker of Tubular Fibrosis in CKD.

Purpose: Chronic kidney disease (CKD) progression is complex. There are not standardized methods for predicting the prognosis of CKD. Nicotinamide N-methyltransferase (NNMT) has been shown to be associated with renal fibrosis. This study aimed to validate NNMT as a prognostic biomarker of progressive CKD. Patients and Methods: We explored the relationship between NNMT expression and CKD-related outcome variables using the NephroseqV5 and GEO databases. Additionally, a validation set of 37 CKD patients was enrolled to measure the correlation between NNMT expression levels and CKD outcomes. Furthermore, single-cell RNA sequencing data and the Human Protein Atlas were reanalyzed to investigate the expression specificity of NNMT in the kidney. Finally, to detect the status of NNMT expression with tubular fibrosis in vivo, we constructed a unilateral ureteral obstruction (UUO) mouse treated with an NNMT inhibitor. Results: Analyzing the datasets showed that NNMT was expressed mainly in proximal tubule compartments. And patients with high NNMT expression levels had a significantly lower overall survival rate compared to those with low NNMT expression levels (P = 0.013). NNMT was independent of prognosis factors in the multivariate Cox regression model, and the AUCs for CKD progression at 1, 3, and 5 years were 0.849, 0.775, and 0.877, respectively. Pathway enrichment analysis indicated that NNMT regulates the biological processes of tubulointerstitial fibrosis (TIF). In the validation group, NNMT levels were significantly higher in the CKD group combined with interstitial fibrosis. In vivo, NNMT was a high expression in the UUO group, peaking at postoperative day 21. Treatment with an NNMT inhibitor improved renal tubular interstitial fibrosis, and expression levels of FN, α-SMA, VIM, and TGF-ß1 were decreased compared with UUO (P < 0.05). Conclusion: NNMT was expressed mainly in tubular renal compartments, and associated with CKD prognosis. It holds potential as a diagnostic biomarker for tubular fibrosis in CKD.

Urinary PART1 and PLA2R1 Could Potentially Serve as Diagnostic Markers for Diabetic Kidney Disease Patients.

Background: Diabetic kidney disease (DKD) is a chronic renal disease which could eventually develop into renal failure. Though albuminuria and estimated glomerular filtration rate (eGFR) are helpful for the diagnosis of DKD, the lack of specific biomarkers reduces the efficiency of therapeutic interventions. Methods: Based on bulk-seq of 56 urine samples collected at different time points (including 11 acquired from DKD patients and 11 from healthy controls), in corporation of scRNA-seq data of urine samples and snRNA-seq data of renal punctures from DKD patients (retrieved from NCBI GEO Omnibus), urine-kidney specific genes were identified by Multiple Biological Information methods. Results: Forty urine-kidney specific genes/differentially expressed genes (DEGs) were identified to be highly related to kidney injury and proteinuria for the DKD patients. Most of these genes participate in regulating glucagon and apoptosis, among which, urinary PART1 (mainly derived from distal tubular cells) and PLA2R1 (podocyte cell surface marker) could be used together for the early diagnosis of DKD. Moreover, urinary PART1 was significantly associated with multiple clinical indicators, and remained stable over time in urine. Conclusion: Urinary PART1 and PLA2R1 could be shed lights on the discovery and development of non-invasive diagnostic method for DKD, especially in early stages.

High-dose-androgen-induced autophagic cell death to suppress the Enzalutamide-resistant prostate cancer growth via altering the circRNA-BCL2/miRNA-198/AMBRA1 signaling.

Androgen deprivation therapy (ADT) is a gold standard treatment for advanced PCa. However, most patients eventually develop the castration-resistant prostate cancer (CRPC) that progresses rapidly despite ongoing systemic androgen deprivation. While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients, the exact mechanism of this opposite effect remains unclear. Here we found that Enzalutamide-resistant (EnzR) CRPC cells can be suppressed by the high-dose-androgen (dihydrotestosterone, DHT). Mechanism dissection suggested that a high-dose-DHT can suppress the circular RNA-BCL2 (circRNA-BCL2) expression via transcriptional regulation of its host gene BCL2. The suppressed circRNA-BCL2 can then alter the expression of miRNA-198 to modulate the AMBRA1 expression via direct binding to the 3'UTR of AMBRA1 mRNA. The consequences of high-dose-DHT suppressed circRNA-BCL2/miRNA-198/AMBRA1 signaling likely result in induction of the autophagic cell death to suppress the EnzR CRPC cell growth. Preclinical studies using in vivo xenograft mouse models also demonstrated that AMBRA1-shRNA to suppress the autophagic cell death can weaken the effect of high-dose-DHT on EnzR CRPC tumors. Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future.

Clinical analysis of 103 cases of tuberculous meningitis complicated with hyponatremia in adults.

OBJECTIVE: Tuberculous meningitis (TBM) is a common infection of the central nervous system. TBM with hyponatremia is very common. If hyponatremia is not treated properly, it might affect the outcome of TBM patients. METHODS: We included 226 patients diagnosed with TBM who were admitted from August 2010 to August 2015 and retrospectively analyzed the clinical data of patients with and without hyponatremia. RESULTS: In total, 45.6% (103/226) patients had hyponatremia and 54.4% (123/226) patients did not have hyponatremia. Serum sodium and severity of TBM were independent prediction factors of poor outcomes in TBM. The prognosis of patients with hyponatremia was worse than that of patients without hyponatremia. The mortality was 3.9% (4/103) in the hyponatremia group, while 0% (0/123) in the non-hyponatremia group. The degree of hyponatremia was related to imaging, cerebrospinal fluid (CSF) cell count and protein, severity of TBM, time to correct hyponatremia, and prognosis. We analyzed the causes of hyponatremia and found syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was the most common cause (77.7%, 80/103), followed by cerebral salt wasting (CSW) (17.5%, 18/103). Comparing SIADH and CSW, there was a significant difference in mean blood pressure, albumin, and hematocrit, and no significant difference in demographic characteristics, imaging, CSF cell count and protein, severity, occurrence and correction time of hyponatremia, or prognosis. CONCLUSION: TBM with hyponatremia was dominated by moderate hyponatremia, which often manifested as SIADH. The more severe hyponatremia was, the longer the correction time of hyponatremia, which will affect the prognosis of TBM patients.

Sirt1 inhibits kidney stones formation by attenuating calcium oxalate-induced cell injury.

Cell injury is a necessary and critical event during CaOx kidney stone formation. Sirt1 exerts a number of pleiotropic effects, protecting against renal cell injury. This study aims to explore the relationship between Sirt1 and CaOx kidney stone formation and the underlying mechanism. Sirt1 expression in renal tissues or HK-2 cells was detected by Western blot, immunohistochemistry and immunofluorescence. Apoptosis in renal tissues was examined by TUNEL staining. Renal pathological changes and the crystals deposition were detected by hematoxylin-eosin and Von Kossa staining. Crystal-cell adhesion and cell injury in HK-2 cells were assessed by atomic absorption spectrometry and flow cytometry, respectively. Sirt1 expression in nephrolithiasis patients was downregulated and the level of apoptosis was increased. Further study found that Sirt1 expression was decreased in both in vivo and in vitro models. Interestingly, the levels of cell injury were elevated in vivo and in vitro models. Suppressing Sirt1 expression promoted COM-induced crystal-cell adhesion and exacerbated cell injury. In contrast, increasing the expression of Sirt1 by lentivirus transfection in vitro and resveratrol administration in vivo, alleviated crystal deposition and cell damage. Our findings suggest that Sirt1 could inhibit kidney stone formation, at least in part, through attenuating CaOx -induced cell injury.

Intestinal Klebsiella pneumoniae infection enhances susceptibility to epileptic seizure which can be reduced by microglia activation.

Epilepsy is a common nervous system disease, and the existing theory does not fully clarify its pathogenesis. Recent research suggests that intestinal microbes may be involved in the development of epilepsy, but which microbe is involved remains unclear. We used 16s rRNA sequencing to identify the most relevant gut microbe. To determine the relationship between this microbe and epilepsy, we used an animal model. In addition, western blotting and immunofluorescence, as well as inhibitor studies, were used to evaluate and confirm the role of microglia in this process. In this study, we first report an increase in gut Klebsiella pneumoniae in patients with epilepsy. Subsequently, animal studies revealed that Klebsiella pneumoniae in the intestinal tract affects seizure susceptibility and activates microglial cells to release inflammatory factors. Furthermore, the inflammatory response of microglial cells plays a protective role in the seizure susceptibility caused by an increased abundance of Klebsiella pneumoniae. Our results suggest that gut disruption may be involved in seizure regulation and microglia protect the brain against seizure under this condition. These findings provide a new perspective for research on the pathogenesis and prevention of epilepsy.

Melatonin Inhibits Migration and Invasion in LPS-Stimulated and -Unstimulated Prostate Cancer Cells Through Blocking Multiple EMT-Relative Pathways.

PURPOSE: Gram-negative bacteria are usually found in prostate cancer (PCa) tissues. This study aims to investigate the role of lipopolysaccharide (LPS), a glycolipid compound found in the outer membrane of gram-negative bacteria, on the migration and invasion of PCa cells, and to evaluate the protective effect of melatonin. MATERIALS AND METHODS: DU145, PC-3 and LNCaP cells were incubated with LPS in the presence or absence of melatonin. Wound healing and Transwell assays were used to analyze migration and invasion of PCa cells. RT-PCR and Western blotting were used to assess the mRNA and protein levels, respectively. Co-IP was used to analyze ß-catenin ubiquitination. RESULTS: Our results showed that LPS promoted migration and invasion of PCa cells. In addition, LPS stimulated inflammatory reaction and induced epithelial-mesenchymal transition (EMT) in PCa cells by activating several TLR4 downstream pathways. Specifically, LPS promoted NF-κB/IL-6/STAT3 signal transduction. In addition, LPS upregulated phosphorylation levels of cytoplasmic AKTSer473 and GSK-3ßSer9. Moreover, LPS induced phosphorylation of GSK-3ßSer9 in the "disruption complex", and then inhibited phosphorylation and ubiquitination of cytoplasmic ß-catenin, leading to ß-catenin nuclear translocation. Interestingly, melatonin inhibited invasion and migration not only in LPS-stimulated but also in LPS-unstimulated PCa cells. Melatonin suppressed PCa cells migration and invasion by blocking EMT mediated by IL-6/STAT3, AKT/GSK-3ß and ß-catenin pathways. CONCLUSION: This study provides evidence that melatonin inhibits migration and invasion through blocking multiple TLR4 downstream EMT-associated pathways both in LPS-stimulated and -unstimulated PCa cells. Our results provide new insights into the role of bacterial infection in PCa metastasis and a potential therapeutic agent.

The effect of three-dimensional nursing management on the respiratory exercise compliance and nursing efficiency in post-thoracotomy patients with acute pulmonary embolisms.

OBJECTIVE: To study the effect of the three-dimensional nursing management mode on compliance with respiratory function exercises and on the nursing efficiency in post-thoracotomy, acute pulmonary embolism (PE) patients. METHODS: A cohort of 20 post-thoracotomy patients with acute PE were equally and randomly divided into two groups. The patients in the experimental group underwent the three-dimensional nursing management mode, and the patients in the control group underwent ordinary nursing. The compliance with respiratory function exercises during the hospital stay and within 3 months after discharge was observed, and the efficiency of the three-dimensional nursing management mode was determined according to the patient recovery. RESULTS: The overall recovery effect in the experimental group was good, the respiratory function exercise effect was significant, and just one patient still had dyspnea after one week of nursing. There were 5 patients with chest tightness and chest pain and 7 patients with dyspnea in the control group. One patient died after a recurrence of the disease (P < 0.05). The total nursing efficiency was 90% in the experimental group and 30% in the control group (P < 0.05). Three months after discharge, the patients in the two groups were followed up, and a survey was conducted. In the experimental group, 14 patients and their families were very satisfied with the nursing. In the control group, 2 patients and their families were dissatisfied with the nursing, and the difference was statistically significant (P < 0.05). CONCLUSIONS: Three-dimensional nursing management with post-thoracotomy, acute pulmonary embolism patients contributes to improving the patients' compliance with respiratory function exercises and to the nursing efficiency. It can greatly improve the nursing efficiency, relieve patients' post-surgical pain, and can promote the formation of a good doctor-patient relationship to a certain extent.

ROS-mediated genotoxic stress is involved in NaAsO2-induced cell cycle arrest, stemness enhancement and chemoresistance of prostate cancer cells in a p53-independent manner.

Several epidemiological studies reported that chronic arsenic exposure increased risk of prostate cancer. This study aimed to investigate whether chronic NaAsO2 exposure elevates stemness and chemoresistance in prostate cancer cells. DU145 (wild-type p53) and PC-3 (p53-null) cells were exposed to NaAsO2 (2 µmol/L) for 30 generations. IC50s to docetaxel and cisplatin were increased in NaAsO2-exposed DU145 and PC-3 cells. The number of tumor spheres was elevated in NaAsO2-exposed DU145 and PC-3 cells. Nanog, SOX-2 and ALDH1A1, three markers of cancer stemness, were upregulated in NaAsO2-exposed PC-3 spheres. Moreover, NaAsO2-exposed DU145 and PC-3 cells were arrested in G2/M phase. Histone H2AX phosphorylation on Ser139, an indicator for DNA double-strand break, was upregulated in NaAsO2-exposed DU145 and PC-3 cells. ATM phosphorylation on Ser1981, a key sensor of genotoxic stress, was rapidly elevated in NaAsO2-exposed DU145 cells. Phosphor-p53, a downstream molecule of ATM signaling, and p21, a direct target of p53, were upregulated in NaAsO2-exposed DU145 cells. Unexpectedly, p21 was also elevated in NaAsO2-exposed p53-null PC-3 cells. Antioxidant NAC alleviated NaAsO2-induced ATM phosphorylation, cell cycle arrest, and subsequent stemness enhancement and chemoresistance in both DU145 and PC-3 cells. These results suggest that ROS-mediated genotoxic stress is involved in NaAsO2-induced cell cycle arrest, stemness enhancement and chemoresistance of prostate cancer cells in a p53-independent manner.

Calcitriol inhibits lipopolysaccharide-induced proliferation, migration and invasion of prostate cancer cells through suppressing STAT3 signal activation.

Increasing evidence suggests that infection promotes the initiation and progression of prostate cancer. This study investigated the effects of lipopolysaccharide (LPS), a major component of Gram-negative bacilli, on proliferation, migration and invasion of prostate cancer cells and the protective effects of 1α,25(OH)2D3 (calcitriol). PC-3 and DU145 cells were stimulated with LPS (2.0 µg/mL) in the presence or absence of 1α,25(OH)2D3 (100 nM). Our results shown that 1α,25(OH)2D3 reduced the proportion of S phase cells in LPS-stimulated PC-3 and DU145 cells, and down-regulated the nuclear protein levels of Cyclin D1 and PCNA in LPS-stimulated PC-3 cells. In addition, 1α,25(OH)2D3 inhibited migration and invasion, as determined by wound healing and transwell assay, in LPS-stimulated PC-3 and DU145 cells. Of interest, we observed that 1α,25(OH)2D3 inhibits NF-κB activation and subsequent synthesis and secretion of IL-6 and IL-8 by promoting VDR and NF-κB p65 interaction. Surprisingly, 1α,25(OH)2D3 blocks nuclear translocation of pSTAT3 by promoting physical interaction between VDR and pSTAT3 (Tyr705) in LPS-stimulated PC-3 and DU145 cells. These results suggest that 1α,25(OH)2D3 inhibits LPS-induced proliferation, migration and invasion in prostate cancer cells by directly and indirectly blocking STAT3 signal transduction.

Effects of a Portable Peritoneal Lavage Device on Dogs with Seawater-Immersed Open Abdominal Injury.

BACKGROUND: Seawater-immersed open abdominal injury is a special injury during marine activities. Effective warmed peritoneal lavage in the field early after injury is the key to treatment. This pilot study aimed at exploring the treatment effects of a self-developed portable peritoneal lavage device compared with conventional treatment model. MATERIAL AND METHODS: Beagle dogs were used to develop models of seawater-immersed open abdominal injury. A conventional lavage method or a novel peritoneal lavage device was used for lavage and rewarming. The vital signs, electrolyte, serum inflammatory cytokine expression levels, histological changes of mucosa, and microstructure variety of different groups were observed and compared before and after immersion and 2 h, 1 d, 3 d, and 5 d after lavage. RESULTS: The levels of TNF-α, IL-1ß, IL-8, IFN-γ, VEGF, and TGF-ß in the blood and the damage of tissues and cells in three groups were increased after immersion and decreased at the later points of time after lavage. The concentration of Na+, K+, Cl-, lactate, and lactate dehydrogenase in the plasma was significantly higher than that before immersion (P < 0.05), and the concentration of Ca2+ and HCO3 - and plasma pH decreased slightly (P < 0.05). The degree of tissue inflammation and mucosal injury in the delayed control group and device group was lower than the control group. CONCLUSIONS: Timely lavage and rewarming using a portable peritoneal lavage device reduced the inflammatory response of seawater-immersed open abdominal injury dogs and reduced the damage of multiple organs. The dogs recovered better and faster than the conventional treatment group.