Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing–like response of ECM–receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)–tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Bladder cancer is one of the most commonly diagnosed and fatal malignancies of the urinary tract. Noncoding RNAs have been reported to be new biomarkers and effective treatment targets for bladder cancer. In the present study, we identified a novel bladder cancer-related circRNA-miRNA-mRNA network, the circ_0004463/miR-380-3p/FOXO1 axis. circ_0004463 is significantly downregulated, whereas miR-380-3p is upregulated in bladder carcinoma tissue samples and cells. circ_0004463 acts as a tumor suppressor by inhibiting bladder cancer cell proliferation. Genes that negatively correlated with miR-380-3p and genes that miR-380-3p might target are enriched in mitochondrial respiration chain-related pathways. miR-380-3p promotes the proliferation of bladder cancer cells and mitochondrial respiration by acting as an oncogenic miRNA. circ_0004463 competes with FOXO1 for miR-380-3p binding to counteract miR-380-3p-mediated repression of FOXO1. Circ_0004463 overexpression inhibits cancer cell proliferation and mitochondrial respiration in bladder cancer cell lines, while miR-380-3p overexpression dramatically reverses the roles of circ_0004463 overexpression. In conclusion, the circ_0004463/miR-380-3p/FOXO1 axis could regulate mitochondrial respiration and bladder cancer cell apoptosis via FOXO1 signaling.

Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists. We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs. Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies. This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.

Background: Age-related macular degeneration (AMD) is the most common cause of visual disorders in the aged population and is characterized by the formation of retinal pigment epithelium (RPE) deposits and dysfunction/death of the RPE and photoreceptors. It is supposed that both oxidative stress and inflammation play a critical role in the pathogenesis of AMD. The development of therapeutic strategies against oxidative stress and inflammation in AMD is urgently needed. Rubus suavissimus S. Lee (RS), a medicinal plant growing in the southwest region of China, has been used as an herbal tea and medicine for various diseases. Methods: In this project, we evaluate the therapeutic potential of RS extract for AMD. We prepared RS extracts from dried leaves, which contained the main functional compounds. Results: RS extract significantly increased cell viability, upregulated the expression of antioxidant genes, lowered the generation of malondialdehyde and reactive oxygen species, and suppressed inflammation in H2O2-treated human RPE cells. In the in vivo study, treatment with RS extract attenuated body weight gain, lowered cholesterol and triglyceride levels in the liver and serum, increased antioxidant capacity, and alleviated inflammation in the retina and RPE/choroid of mice fed a high-fat diet. Conclusions: Our findings suggest that RS extract offers therapeutic potential for treating AMD patients.

To evaluate the performance of Grayscale Ultrasound (GSU), Color Doppler Ultrasound/Power Doppler Ultrasound (CDU/PDU), Transrectal Real-Time Tissue Elastography (TRTE) and Contrast-Enhanced Ultrasound (CEUS) in the diagnosis of Prostate Cancer (PCa). All analyzed patients underwent GSU, CDU/PDU, TRTE and CEUS examinations before radical prostatectomy. Receiver Operating Characteristic (ROC) curves were drawn, and the Areas Under the Curve (AUCs) were calculated for the four ultrasonic modalities alone and in combination. Binary logistic analysis was used to evaluate the predictive value of lesion features observed with the 4 modalities. The results of the chi-square test showed that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate of TRTE for diagnosing PCa were higher than those of CEUS (p-values were < 0.05 for all). The ROC curves analysis showed that the diagnostic performance of TRTE for PCa was better than that of CEUS (p = 0.046). Moreover, the diagnostic performance of the combination of four ultrasonic technologies (AUC = 0.873) was significantly better than that of any technology alone. Multivariate binary logistic regression analysis showed that enhancement strength on CEUS, presence of a blue area on TRTE and total serum Prostate Specific Antigen (PSA) level were independent predictors for prostate malignancy. The diagnostic performance of TRTE was higher than that of CEUS. Early hyperenhancement on CEUS and stiffness on TRTE had high predictive value for the diagnosis of PCa. The combination of multiple ultrasonic modalities can significantly improve the positive diagnostic rate for PCa over that of a single ultrasonic mode.