Yingbo Dai

Fibrotic diseases involve increased mechanical stress due to extracellular matrix deposition, significantly altering cellular metabolism. However, a systematic understanding of how mechanical force regulates lipid metabolism across different molecular layers remains limited. We employed an integrated multi-omics approach, including transcriptomics, Ribo-seq, proteomics, and lipidomics, to comprehensively assess the effects of mechanical stretch on lipid metabolism in human cavernous fibroblasts. Our analysis revealed that while mechanical force elicits complex multi-layered responses, post-translational regulation predominantly drives this lipid metabolic reprogramming. Lipidomics identified a significant reduction in fatty acids and an upregulation of ganglioside. Key genes central to this mechanosensitive metabolic shift were pinpointed. This study demonstrates that mechanical force hierarchically reprograms lipid metabolism. The shift from fatty acids to ganglioside underscores a key metabolic adaptation in fibroblasts. Targeting the identified critical genes may offer a promising therapeutic strategy for fibrosis-related diseases.

Background: Cisplatin-based chemotherapy remains the standard treatment for advanced bladder cancer (BC); however, nephrotoxicity and chemoresistance limit its clinical application. Baicalin, a flavonoid metabolite derived from the botanical drug, Scutellaria baicalensis Georgi , has been reported to induces autophagy in BC. However, its regulatory effect on autophagic flux under cisplatin treatment remains unclear. Materials and Methods: We used cell counting kit (CCK)-8 and 5-ethynyl-2′-deoxyuridine (EdU) assays to explore the role of baicalin in enhancing the sensitivity of BC cells in vitro . The underlying mechanisms were explored using transmission electron microscopy, western blotting, and immunofluorescence, and these findings were validated in vivo. Results: CCK-8 and EdU assays indicated that baicalin significantly enhanced the therapeutic effect of cisplatin and reduced its half maximal inhibitory concentration (IC ₅₀ ) value. Baicalin also inhibited the migration and invasion of BC cells. Western blotting indicated that baicalin suppressed cisplatin-induced autophagy by inhibiting autophagic flux, as evidenced by a reduction in the fusion of autophagosomes and lysosomes, along with decreased expression of lysosomal proteins LAMP1, LAMP2, CTSD, and CTSB. The results of the experiment in vivo showed that baicalin enhanced the anti-cancer effect of cisplatin. Tumor size in the combination group was significantly smaller than that in the cisplatin group. Conclusion: Baicalin enhanced the sensitivity of BC cells to cisplatin by inhibiting autophagic flux through lysosomal activity suppression. This study provides a potential botanical drug candidate for chemosensitization during BC chemotherapy.

Purpose: This study aimed to compare the differences in kidney stone recurrence between typical primary hyperparathyroidism (TPHPT) and normocalcemic primary hyperparathyroidism (NPHPT) patients who did not receive parathyroidectomy (PTX) treatment. Materials and methods: We conducted a retrospective analysis of patients hospitalized for surgical management of kidney stones between September 2015 and March 2023. Patients’ demographic data, blood test parameters, stone parameters, and surgical interventions were collected. Based on serum calcium and parathyroid hormone (PTH) levels, patients were categorized into TPHPT, NPHPT, and control groups. Postoperative stone recurrence was assessed during follow-up. Results: A total of 288 patients (139 males and 149 females) were analyzed, with 96 patients in each group. PTH and serum calcium levels were significantly higher in the TPHPT group than in both NPHPT and control groups (P < 0.001). The recurrence probability of kidney stones after surgery was higher in patients with both TPHPT and NPHPT than in the control group (42.7 vs 19.8% and 36.5 vs 19.8%, P < 0.05, respectively). However, no significant difference was found between TPHPT and NPHPT groups (P > 0.05). After adjusting for covariates, the Cox regression analysis revealed that NPHPT was a risk factor for kidney stone recurrence (HR: 2.31, 95% CI: 1.26–4.26, P = 0.007). Conclusions: Patients with TPHPT and NPHPT who have not undergone PTX treatment both exhibit a higher recurrence rate of kidney stones, with no significant difference between the two groups. Nevertheless, clinicians should place more emphasis on the recurrence of kidney stones in patients with NPHPT.

Cuproptosis, a copper‐dependent cell death mechanism driven by tricarboxylic acid (TCA) cycle collapse, shows limited efficacy in hypoxic or glycolytic renal cell carcinoma (RCC). Here, through systematic screening of 688 glycolysis inhibitors combined with elesclomol (ES), we identified PIK‐III as a potent cuproptosis sensitiser. Multi‐omics analysis revealed that PIK‐III restores sensitivity by rewiring thiamine metabolism. Mechanistically, PIK‐III induces macropinocytosis, enabling thiamine uptake to replenish thiamine pyrophosphate (TPP), which activates pyruvate dehydrogenase E1‐alpha 1 (PDHA1) and redirects pyruvate into the TCA cycle. Concurrently, ES‐induced DLAT oligomerisation disrupts TCA flux, creating a metabolic crisis. In vivo, PIK‐III synergises with ES to suppress tumour growth in xenograft and patient‐derived models without systemic toxicity. Our work uncovers a metabolic vulnerability in cuproptosis‐resistant RCC and positions PIK‐III as a therapeutic candidate to overcome resistance via dual targeting of thiamine transport and mitochondrial dysfunction.

Key Points: Keratin 20 was upregulated earlier than kidney injury molecule 1 in AKI, and its proximal tubule–specific deletion aggravated kidney dysfunction in mouse models. Keratin 20 competed with apoptosis-linked gene-2-interacting protein X for peroxiredoxin 2 binding, thereby decreasing the exosomal secretion of peroxiredoxin 2 and inhibiting ferroptosis in kidney tubular cells. Background: AKI is a prevalent clinical syndrome with insufficient kidney function. Keratin 20 (KRT20), a component of intermediate filaments, is widely recognized as a biomarker of kidney tubular injury, yet its exact function in kidney disease remains uncertain. Methods: RNA sequencing data from a mouse model of ischemia/reperfusion-induced AKI were analyzed to assess KRT20 transcript levels. The effect of specific Krt20 knockout in renal proximal tubule cells ( Krt20 ^PTKO ) was subsequently examined in two distinct AKI mouse models. Luciferase reporter assays and chromatin immunoprecipitation–PCR was used to identify transcription factors regulating KRT20 expression, whereas immunoprecipitation followed by mass spectrometry elucidated the downstream targets of KRT20. In addition, the clinical significance of KRT20 and peroxiredoxin 2 (PRDX2) was evaluated in patients with acute tubular necrosis. Results: KRT20 was significantly upregulated in renal proximal tubule cells during the early phase of AKI, preceding the induction of kidney injury molecule 1 expression. This upregulation was mediated by FBJ Murine Osteosarcoma Viral Oncogene Homolog B in both ischemia/reperfusion and cisplatin-induced AKI models. Renal proximal tubule cell–specific knockout of Krt20 exacerbated the kidney injury during AKI. Mechanistically, KRT20 protected against AKI by sequestering PRDX2, an antioxidant protein, and inhibiting the exosomal secretion of PRDX2, eventually preventing ferroptosis in kidney tubular cells. Further analysis revealed that apoptosis-linked gene-2-interacting protein X facilitated PRDX2 exosomal release, whereas KRT20 competed with apoptosis-linked gene-2-interacting protein X for binding to the N -terminal domain of PRDX2, thereby retaining PRDX2 intracellularly. Finally, the expression levels of KRT20 and PRDX2 were correlated with kidney injury severity and kidney function decline in clinical samples. Conclusions: These findings indicate that KRT20 was upregulated in the early stages of AKI, serving to protect kidney tubule cells by sequestering PRDX2 and inhibiting ferroptosis.

Summary Purpose This study aimed to describe the clinical characteristics and summarize the treatment outcomes in epididymitis patients with abscess formation. Material and methods From February 2016 to August 2022, epididymitis was diagnosed in 442 patients in the outpatient setting or emergency department. Patient information and laboratory data were extracted from electronic medical records. The treatment was analyzed. Results A total of 24 epididymitis patients developed abscess formation. Pain was the most common symptoms and abscess rupture was presented in 8 patients. A causative microorganism was more likely to be positively detected in caput epididymitis than corpus or caudal epididymitis in both urine culture and abscess culture (p = 0.023 and p = 0.038, respectively). All patients received a complete course of antimicrobial therapy. Conclusion Abscess formation is a severe disease condition of epididymitis, and requires systemic treatment including complete antimicrobial therapy, abscess incision and drainage and even epididymectomy or epididymo-orchiectomy. Caput epididymitis is more likely to be combined with orchitis, and easier to detect pathogenic microorganisms.

Leydig cells' (LCs') senescence is an important reason for the decline of testicular function in elderly men. Cellular communication network factor 5 (CCN5) regulates lipid metabolism and cellular fibrosis through multiple mechanisms. However, its role in LCs' aging and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects and molecular mechanisms by which CCN5 drives aging phenotypes in LCs and to evaluate the potential of targeting CCN5 as a therapeutic strategy for testicular aging. CCN5 expression was located in LCs and elevated in aged testis. Overexpression of CCN5 led to LCs' aging and testis dysfunction. Extracellularly, CCN5 activated β-catenin and SMAD2/3 phosphorylation, promoting the expression of fibrosis-related genes. Intracellularly, CCN5 did not affect de novo cholesterol synthesis-related genes but changed the balance of cholesterol transporters. CCN5 bound to and reduced ring finger protein 213 (RNF213) protein levels. RNF213 knockdown activated forkhead box O, p16, and p21, resulting in SA-β-gal activation, reduced cell proliferation, and lipid droplet loss. In aged mice, CCN5 knockdown improved testicular atrophy, restored lipid droplet content and testosterone synthesis, and enhanced physical endurance and sexual behavior. In summary, CCN5 drives LCs' aging and testicular dysfunction maybe via promoting fibrosis and lipid droplet loss. Targeting CCN5 offers a promising strategy to treat testicular aging and associated reproductive endocrine disorders.

According to increasing evidence, high‑density lipoproteins (HDLs) may raise prostate‑specific antigen (PSA) levels in the prostate. The link between HDL‑cholesterol (C) and PSA, on the other hand, is debatable and challenging. Hence, the present study examined the relationship between HDL‑C and PSA in men using the National Health and Nutrition Examination Survey (NHANES) database. NHANES data were extracted for five cycles from 2001 to 2010. The data used for analysis included PSA concentrations, sociodemographic and laboratory data. After the screening, 6,669 out of 52,195 participants were included in the present study. Participants were divided into four groups based on HDL‑C quartiles. Categorical and continuous variables using weighted chi‑square tests and linear regression models were analysed to compare differences between groups. A total of three weighted multivariate linear regression models were constructed and the association between HDL‑C and PSA using a smoothed curve fit was assessed. In the present study, unadjusted and adjusted multivariate linear regression models revealed a significant positive association between PSA concentrations and serum HDL‑C levels. Specifically, each unit increase in HDL‑C ratio was associated with an increase in PSA concentration by 0.470 ng/ml (P<0.001) in the unadjusted model. In minimally adjusted models, accounting for socioeconomic and demographic factors, this association remained significant, with an increase of 0.408 ng/ml per unit increase in serum HDL‑C (P<0.001). Furthermore, the stratified analysis revealed various impacts based on socioeconomic status and HDL‑C levels, with a significant interaction between household income and HDL‑C levels (P=0.037). Exclusion of subjects with low HDL‑C levels strengthened the association, revealing a significant increase in PSA concentration with higher HDL‑C levels (0.50 ng/ml per 1 mmol/l increase, P=0.009). The findings of the present study suggest a nuanced relationship between HDL‑C levels, socioeconomic factors, and PSA concentrations, highlighting the potential importance of considering these factors in prostate cancer (Pca) screening and risk assessment. The present study found a positive association between serum HDL‑C and PSA concentrations in adult men in the United States without a Pca diagnosis.