Combination of disulfiram and Copper-Cysteamine nanoparticles induces mitochondria damage and promotes apoptosis in endometrial cancer.

Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, Cu3Cl(SR)2 (R[bond, double bond]CH2CH2NH2), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing in vitro experiments utilizing Ishikawa cells, in vivo studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 µM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant in vivo anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.

Nanomaterials Solutions for Contraception: Concerns, Advances, and Prospects.

Preventing unintentional pregnancy is one of the goals of a global public health policy to minimize effects on individuals, families, and society. Various contraceptive formulations with high effectiveness and acceptance, including intrauterine devices, hormonal patches for females, and condoms and vasectomy for males, have been developed and adopted over the last decades. However, distinct breakthroughs of contraceptive techniques have not yet been achieved, while the associated long-term adverse effects are insurmountable, such as endocrine system disorder along with hormone administration, invasive ligation, and slowly restored fertility after removal of intrauterine devices. Spurred by developments of nanomaterials and bionanotechnologies, advanced contraceptives could be fulfilled via nanomaterial solutions with much safer and more controllable and effective approaches to meet various and specific needs for women and men at different reproductive stages. Nanomedicine techniques have been extended to develop contraceptive methods, such as the targeted drug delivery and controlled release of hormone using nanocarriers for females and physical stimulation assisted vasectomy using functional nanomaterials via photothermal treatment or magnetic hyperthermia for males. Nanomaterial solutions for advanced contraceptives offer significantly improved biosafety, noninvasive administration, and controllable reversibility. This review summarizes the nanomaterial solutions to female and male contraceptives including the working mechanisms, clinical concerns, and their merits and demerits. This work also reviewed the nanomaterials that have been adopted in contraceptive applications. In addition, we further discuss safety considerations and future perspectives of nanomaterials in nanostrategy development for next-generation contraceptives. We expect that nanomaterials would potentially replace conventional materials for contraception in the near future.

Bioinformatic Analysis Combined With Experimental Validation Reveals Novel Hub Genes and Pathways Associated With Focal Segmental Glomerulosclerosis.

Background: Focal segmental glomerulosclerosis (FSGS) is a type of nephrotic syndrome leading to end-stage renal disease, and this study aimed to explore the hub genes and pathways associated with FSGS to identify potential diagnostic and therapeutic targets. Methods: We downloaded the microarray datasets GSE121233 and GSE129973 from the Gene Expression Omnibus (GEO) database. The datasets comprise 25 FSGS samples and 25 normal samples. The differential expression genes (DEGs) were identified using the R package "limma". Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the database for Annotation, Visualization and Integrated Discovery (DAVID) to identify the pathways and functional annotation of the DEGs. The protein-protein interaction (PPI) was constructed based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized using Cytoscape software. The hub genes of the DEGs were then evaluated using the cytoHubba plugin of Cytoscape. The expression of the hub genes was validated by quantitative real-time polymerase chain reaction (qRT-PCR) using the FSGS rat model, and receiver operating characteristic (ROC) curve analysis was performed to validate the accuracy of these hub genes. Results: A total of 45 DEGs including 18 upregulated and 27 downregulated DEGs, were identified in the two GSE datasets (GSE121233 and GSE129973). Among them, five hub genes with a high degree of connectivity were selected. From the PPI network, of the top five hub genes, FN1 was upregulated, while ALB, EGF, TTR, and KNG1 were downregulated. The qRT-PCR analysis of FSGS rats confirmed that the expression of FN1 was upregulated and that of EGF and TTR was downregulated. The ROC analysis indicated that FN1, EGF, and TTR showed considerable diagnostic efficiency for FSGS. Conclusion: Three novel FSGS-specific genes were identified through bioinformatic analysis combined with experimental validation, which may promote our understanding of the molecular underpinning of FSGS and provide potential therapeutic targets for the clinical management.

Wnt4 is significantly upregulated during the early phases of cisplatin-induced acute kidney injury.

Wnt4 is a secreted growth factor associated with renal tubulogenesis. Our previous studies identified that renal and urinary Wnt4 are upregulated following ischemia-reperfusion injury in mice, but the roles of Wnt4 in other forms of acute kidney injury (AKI) remain unclear. Here, we investigated the changes in Wnt4 expression using a cisplatin-induced AKI model. We found that renal and urinary Wnt4 expression increased as early as 12 hours, peaked at day 4 following cisplatin-induced AKI and was closely correlated with histopathological alterations. By contrast, the serum creatinine level was significantly elevated until day 3, indicating that Wnt4 is more sensitive to early tubular injury than serum creatinine. In addition, renal Wnt4 was co-stained with aquaporin-1 and thiazide-sensitive NaCl cotransporter, suggesting that Wnt4 can detect both proximal and distal tubular injuries. These data were further confirmed in a clinical study. Increased urinary Wnt4 expression was detected earlier than serum creatinine and eGFR in patients with contrast-induced AKI after vascular intervention. This study is the first to demonstrate that increased expression of renal and urinary Wnt4 can be detected earlier than serum creatinine after drug-induced AKI. In particular, urinary Wnt4 can potentially serve as a noninvasive biomarker for monitoring patients with tubular injury.

Urine anti-PLA2R antibody is a novel biomarker of idiopathic membranous nephropathy.

Since urine samples more directly reflect kidney alterations and damage than blood samples, we investigated whether urine anti-PLA2R antibody (uPLA2R-Ab) could be utilized similarly to serum anti-PLA2R antibody (sPLA2R-Ab) as a noninvasive biomarker of idiopathic membranous nephropathy (IMN). In this study, we performed a qualitative analysis using an indirect immunofluorescence test (IIFT) and measured uPLA2R-Ab and sPLA2R-Ab concentrations using an enzyme-linked immunosorbent assay (ELISA) in 28 patients with biopsy-proven IMN and 12 patients with secondary membranous nephropathy (SMN). Overall, 64.3% (n=18) of patients with IMN had IIFT-positive sPLA2R-Ab, 67.9% (n=19) of patients with IMN had IIFT-positive uPLA2R-Ab, and none of the SMN patients had IIFT-positive sPLA2R-Ab or uPLA2R-Ab. The titers of the anti-PLA2R antibody from the IMN patients in the urine (10.72±22.24 RU/µmol, presented as uPLA2R-Ab/urine creatinine) and serum (107.36±140.93 RU/ml) were higher than those from the SMN patients (0.51±0.46 RU/µmol, 0.008±0.029 RU/ml, respectively, p<0.05). Statistical analyses indicated that there were positive correlations between uPLA2R-Ab and gPLA2R, sPLA2R-Ab or urinary protein and negative correlations between uPLA2R-Ab and serum albumin in patients with IMN. In conclusion, uPLA2R-Ab is a novel biomarker of IMN. sPLA2R-Ab combined with uPLA2R-Ab might be more helpful for diagnosis and activity in PLA2R associated MN.

Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis.

Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/ß-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/ß-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.

Wnt4 is a novel biomarker for the early detection of kidney tubular injury after ischemia/reperfusion injury.

Earlier intervention after acute kidney injury would promote better outcomes. Our previous study found that Wnt proteins are promptly upregulated after ischemic kidney injury. Thus, we assessed whether Wnt4 could be an early and sensitive biomarker of tubular injury. We subjected mice to bilateral ischemia/reperfusion injury (IRI). Kidney and urinary Wnt4 expression showed an early increase at 3 hours and increased further at 24 hours post-IRI and was closely correlated with histopathological alterations. Serum creatinine slightly increased at 6 hours, indicating that it was less sensitive than Wnt4 expression. These data were further confirmed by clinical study. Both kidney and urinary Wnt4 expression were significantly increased in patients diagnosed with biopsy-proven minimal change disease (MCD) with tubular injury, all of whom nevertheless had normal estimated glomerular filtration rate (eGFR) and serum creatinine. The increased Wnt4 expression also strongly correlated with histopathological alterations in these MCD patients. In conclusion, this is the first demonstration that increases in both kidney and urinary Wnt4 expression can be detected more sensitively and earlier than serum creatinine after kidney injury. In particular, urinary Wnt4 could be a potential noninvasive biomarker for the early detection of tubular injury.

Serum Anti-PLA2R Antibody Predicts Treatment Outcome in Idiopathic Membranous Nephropathy.

BACKGROUND: M-type phospholipase A2 receptor (PLA2R) has been identified as the major target antigen in idiopathic membranous nephropathy (IMN). However, the role of glomerular PLA2R (gPLA2R) and the associations of serum anti-PLA2R antibody (sPLA2R-Ab) titre with diagnosis, treatment and prognosis in IMN need to be further investigated. METHODS: We screened 148 consecutive patients with biopsy-proven membranous nephropathy (MN; 113 with IMN and 35 with secondary MN (SMN)) who were followed up for ≤20 months. Serum and urine samples were simultaneously collected at different time points. The levels of sPLA2R-Ab were detected using immunofluorescence and enzyme-linked immunosorbent assay. gPLA2R was assessed by immunofluorescence. RESULTS: Most patients with IMN displayed both gPLA2R and sPLA2R-Ab positive (85.8 and 82.3%, respectively). In contrast, very few patients with SMN showed either gPLA2R or sPLA2R-Ab positive. The sPLA2R-Ab titre, not gPLA2R, was significantly correlated with proteinuria. Surprisingly, changes in sPLA2R-Ab titre occurred earlier and faster than proteinuria in patients who were followed up for ≤20 months during the whole period of observation. Survival analysis of IMN patients indicated a significant association between sPLA2R-Ab titre and outcome, whereas, no significant difference was observed between the gPLA2R intensity and outcome. CONCLUSIONS: These data indicate that sPLA2R-Ab might be a better biomarker for IMN diagnosis and treatment outcome. In addition, monitoring sPLA2R-Ab titre may assist in determining when to initiate the administration of immunosuppressive agents and in evaluating treatment efficacy.

Angiopoietin-Like-4, a Potential Target of Tacrolimus, Predicts Earlier Podocyte Injury in Minimal Change Disease.

Podocyte injury plays central roles in proteinuria and kidney dysfunction, therefore, identifying specific biomarker to evaluate earlier podocyte injury is highly desirable. Podocyte-secreted angiopoietin-like-4 (Angptl4) mediates proteinuria in different types of podocytopathy. In the present study, we established an experimental minimal change disease (MCD) rat model, induced by adriamycin (ADR) and resulted in definite podocyte injury, to identify the dynamic changes in Angptl4 expression. We also investigated the direct effects of tacrolimus on Angptl4 and podocyte repair. We determined that the glomerular Angptl4 expression was rapidly upregulated and reached a peak earlier than desmin, an injured podocyte marker, in the ADR rats. Furthermore, this upregulation occurred prior to heavy proteinuria and was accompanied by increased urinary Angptl4. We observed that the Angptl4 upregulation occurred only when podocyte was mainly damaged since we didn't observe little Angptl4 upregulation in MsPGN patients. In addition, we observed the glomerular Angptl4 mainly located in injured podocytes rather than normal podocytes. Moreover, we found that tacrolimus treatment significantly promoted podocyte repair and reduced glomerular and urinary Angptl4 expression at an earlier stage with a significant serum Angptl4 upregulation. And similar results were confirmed in MCD patients. In conclusion, this study represents the first investigation to demonstrate that Angptl4 can predict podocyte injury at earlier stages in MCD and the identification of earlier podocyte injury biomarkers could facilitate the prompt diagnosis and treatment of patients with podocytopathy, as well as determination of the prognosis and treatment efficacy in these diseases.

Respiratory viruses in hospitalized children with acute lower respiratory tract infections in harbin, China.

This study investigated the prevalence of respiratory viruses, including respiratory syncytial virus (RSV), influenza virus types A and B (Flu A/B), parainfluenza virus (Para) 1-3, and adenovirus (Ad), in hospitalized children with acute lower respiratory tract infections (ALRIs). Immunofluorescence assays identified viral etiology in 412 patients younger than 16 years old. The overall viral isolation rate was 63.1% (260/412). The RSV was detected in 25.0%, Flu A/B in 19.4%, Para 1-3 in 14.6%, and Ad in 4.1% of the total sample. Multiple viruses were detected in 6.6% of the study population. Most viral infections occurred in the first 5 years of life, and the incidence of viral infection peaked during early spring and winter. Infection with Ad often resulted in the development of severe pneumonia in older children, and during the summer. The sequences of the isolated Ad hexons belonged to species B, and were closely related to the Gomen strain isolated in the United States in the 1950s. The study results will help determine the etiologic agents of ALRI in children and establish prevention and treatment programs.