Cordycepin inhibits kidney injury by regulating GSK-3ß-mediated Nrf2 activation.

We explored the role and mechanism of cordycepin (COR) in inhibiting kidney injury. A mouse model of kidney injury was established using cisplatin (CDDP), and the kidney function, histopathology, and ferroptosis indices in mice were detected after intervening with COR. The targets of COR-ferroptosis-kidney injury were analyzed by network pharmacology, based on which the association between glycogen synthase kinase-3 beta (GSK-3ß) and COR was determined. HK-2 cells were cultured in vitro and treated separately with ferroptosis inducers erastin and CDDP. After the COR intervention, the level of ferroptosis was monitored. In vitro experiments found that COR could inhibit ferroptosis and CDDP-induced kidney injury. Network pharmacological analysis revealed that GSK-3ß was the target of COR. After inhibiting GSK-3ß expression, COR could not further inhibit the occurrence of ferroptosis. In vitro results also indicated that COR could inhibit ferroptosis in HK-2 cells. According to our findings, COR can ameliorate CDDP-induced kidney injury through GSK-3ß-mediated ferroptosis signaling. We identify new pharmacological effect and target for COR, the major component of Cordyceps sinensis.

Long noncoding RNA-LINC00478 promotes the progression of clear cell renal cell carcinoma through PBX3.

Long noncoding RNAs play an important regulatory role in the development and progression of tumors. Our study found that LINC00478 was upregulated in clear cell renal cell carcinoma (ccRCC), so we made an in-depth exploration into its mechanism. In Caki-2 cells, we established the oe-LINC00478 cell line overexpressing LINC00478, and established underexpressing sh-LINC00478 cell line by short hairpin RNA silencing. The abilities of oe-LINC00478 cell invasion and metastasis were significantly enhanced, and the cell proliferative potential was also improved. The cellular expressions of PBX3, CDCA8, and CDK2 were upregulated, while in the sh-LINC00478 cells, the proliferative potential and metastatic and invasive abilities were weakened. Similarly, we established the PBX3-overexpressing oe-PBX3 cell line and the PBX3-underexpressing sh-PBX3 cell line, finding that the PBX3 overexpression enhanced the metastatic and invasive abilities of Caki-2 cells. When we overexpressed LINC00478 in PBX3-knockout Caki-2-PBX3- / - cells, no significant changes were noted in the metastatic or invasive ability. Through RNA pull-down and RNA-binding protein immunoprecipitation assays, we found that LINC00478 could facilitate the transcription-translation processes of PBX3 by binding to it, thus further promoting the expression of downstream cyclins to exert its action. In animal experimentation, the oe-LINC00478 and sh-LINC00478 Caki-2 cells were separately seeded, revealing that the tumor volume was significantly larger in the oe-LINC00478 group than in the sh-LINC00478 group. This study finds that by promoting the PBX3 transcription, LINC00478 can further regulate the expressions of downstream cyclins, thereby facilitating the metastasis and invasion of ccRCC.

Short-term mortality risks among patients with non-metastatic bladder cancer.

BACKGROUND: Population-based analysis for the short-term non-bladder cancer related mortality among patients with non-metastatic bladder cancer is currently lacking. The objective of the current study was to assess and quantify cause of death after bladder cancer diagnosis. METHODS: The custom Surveillance, Epidemiology, and End Results (SEER) dataset for standardized mortality ratios (SMRs) was utilized to identify 24,074 patients who were diagnosed with nonmetastatic (M0) bladder cancer from 2014 to 2015. SMRs for causes of death were calculated. Risk factors for bladder cancer-specific mortality, competing mortality, second-cancer mortality, and noncancer mortality were determined using either multivariable Cox or competing risk regression models. RESULTS: Among all the 4179 (17.4%) deaths occurred during the follow-up period, almost half of them (44.2%) were attributed to non-bladder cancer cause, including second non-bladder cancer (10%) and other non-cancer causes (34.2%). The most common noncancer causes of death were heart diseases followed by chronic obstructive pulmonary disease. Patients had a higher risk of death from second malignancies (SMR, 1.59; 95% CI, 1.47-1.74) compared with death from first malignancies in the US general population, and also had higher risks of death from heart diseases (SMR, 1.29; 95% CI, 1.18-1.40) and chronic obstructive pulmonary disease (SMR, 1.52; 95% CI, 1.29-1.79) compared with the US general population. Additionally, some risk factors for competing second malignancies or noncancer mortality were determined, such as age, gender, marital status and treatment modalities. CONCLUSIONS: Death from non-bladder cancer cause contributed to almost half of all deaths in bladder cancer survivors during the short-term follow-up period. These findings can inform medical management and assist clinicians in counseling those survivors regarding their short-term health risks.

Secondary bladder stone caused by delayed penetration of the bladder by a pubic fracture: A case report and literature review.

Pelvic fractures sometimes lead to injuries of the urinary bladder, which commonly present as gross hematuria, dysuria and lower abdominal pain. As a type of urinary stone, bladder stones are usually secondary to lower urinary tract obstruction, such as benign prostatic hyperplasia, urethral stricture, and neurogenic bladder. The present case report examines an unusual case of a delayed pubic fracture penetrating the bladder, which caused a secondary bladder stone. A 53-year-old man was first hospitalized at The Second Hospital of Jiaxing (Jiaxing, China) in January 2020 because of trauma-induced bleeding in the scalp and abdominal pain. The patient underwent abdominal exploration and partial bowel resection, and his condition stabilized after surgery. After discharge, the patient had regular outpatient check-ups every 2-3 weeks. However, after 3 months, in April 2020, the patient was readmitted to the hospital because of frequent urination, an urgent need for urination and dysuria. Abdominal computed tomography imaging and cystoscopy revealed a pubic fracture that had penetrated the bladder wall, accompanied by a bladder stone. Subsequently, cystolithotomy was performed, which provided significant relief of symptoms once the catheter was removed after 2 weeks. Since then, the patient has been followed up until January 2023 and had remained asymptomatic. Bladder stones caused by necrotic bone fragmentation are rare. Bladder injuries resulting from pelvic fractures can have delayed onset; therefore, clinicians should be aware of the possibility of urogenital injury in such patients. It is crucial for clinicians to comprehend the potential mechanisms involved, analyze the clinical data of patients, closely monitor their condition and implement appropriate treatment measures when necessary.

M1 macrophage-derived exosomes synergistically enhance the anti- bladder cancer effect of gemcitabine.

Gemcitabine (GEM) is one of the first choice drugs for treating bladder cancer. In this study, we loaded M1 macrophage-derived exosomes (M1-Exo) with GEM by ultrasonication technique to derive an M1-Exo-GEM drug delivery system, and then explored its effects on bladder cancer. After inducing M1 polarization of macrophages in vitro, ultracentrifugation was performed to obtain M1-Exo, followed by construction of M1-Exo-GEM via ultrasonication technique. Mouse bladder cancer MB49 cells were chosen for study. CCK-8, PI staining and flow cytometry (FCM) assays were employed to assess the cell viability and apoptosis level. Inflammatory cytokines were detected by ELISA, while the protein expressions of Bcl-2, Bax and Caspase-3 were examined through Western-Blotting. After injecting M1-Exo-GEM into the tumor-bearing mouse model, the pathological changes were observed by H&E staining, the cancer cell damage was detected by TUNEL staining, and the apoptosis pathway activation was analyzed through immunohistochemical (IHC) staining and protein expression assays for Caspase-3 and Bax. Our results showed that M1-Exo and GEM had cytotoxic effects on MB49 cells, which increased the apoptosis level and the inflammatory cytokine expressions. Compared to M1-Exo and GEM, M1-Exo-GEM was significantly more cytotoxic to MB49 cells while markedly up-regulating the expressions of inflammatory cytokines. In the tumor-bearing mouse model, M1-Exo-GEM significantly inhibited tumor growth and damaged tumor cells, which outperformed GEM. Meanwhile, it also increased the tissue levels of inflammatory cytokines. This study finds that the drug delivery system composed of M1-Exo and GEM can act synergistically with GEM to exert cytotoxicity and induce inflammatory damage of bladder cancer cells.