Xinhua Zhang

Benign prostatic hyperplasia (BPH) is a highly prevalent, age-related disorder in men, defined by nonmalignant enlargement of the prostate, which results in bothersome lower urinary tract symptoms and impaired quality of life. Heat shock protein family A member 1 A (HSPA1A)/HSP70, as a molecular chaperone, plays a critical role in cellular stress protection, attenuating apoptosis and oxidative stress across various diseases. This study delineates the mechanistic framework by which HSP70 modulates mitochondrial quality control in BPH. In vitro and in vivo models reveal that lack of HSP70 triggers pronounced mitochondrial fragmentation, boosts reactive oxygen species accumulation, and disrupts mitochondrial membrane potential, resulting in enhanced apoptosis and alleviated BPH progression. Mechanistically, HSP70 facilitates PINK1/Parkin mediated mitophagy by promoting PINK1 autophosphorylation at Ser228, thereby enhancing the elimination of damaged mitochondria and suppressing mitochondrial apoptosis, while also orchestrating mitochondrial fission via regulation of DRP1 and MFF phosphorylation. HSPA1A is transcriptionally upregulated by HSF1, establishing an axis essential for mitophagy and apoptosis resistance in prostatic hyperplasia. Collectively, these findings position HSP70 as a central regulator of mitochondrial integrity and cell survival in BPH, and its manipulation holds translational promise for ameliorating prostatic hyperplasia.

Benign prostatic hyperplasia (BPH), prevalently in aging men, is characterized by aberrant cell death of prostate cells. Anoikis, a specific subtype of apoptosis, is triggered when cells detach from the extracellular matrix (ECM), in contrast, cells with anoikis resistance contribute to pathological processes such as unregulated cell proliferation and impaired cell death. However, the role of anoikis resistance in BPH pathogenesis remains poorly understood. In this study, an elevated anoikis resistance level was observed in BPH tissues compared to normal prostates. Furthermore, matrix metalloproteinase 7 (MMP7) was identified as a key regulator of anoikis resistance in hyperplastic prostatic epithelium. Under anoikis-inducing conditions, MMP7 promoted mitophagy via the PINK1-Parkin pathway, alleviated mitochondrial stress damage, and enhanced anoikis resistance in BPH-1 cells. Mechanistically, MMP7 interacted with VDAC1 and bound specifically to lysine residues K109 and K110, thereby inhibiting VDAC1 oligomerization and increasing the accumulation of VDAC1 monomers, which served as additional binding sites to Parkin-mediated polyubiquitination. Moreover, clinical data revealed that MMP7 expression levels correlated significantly with the International Prostate Symptom Score (IPSS) and nocturia frequency. Additionally, in vivo experiments demonstrated that inhibition of MMP7 suppressed mitophagy and markedly attenuated prostatic epithelial hyperplasia in a rat model BPH. Collectively, our findings clarify the functional role of the MMP7-VDAC1 axis in BPH pathogenesis and highlight its potential as a therapeutic target for BPH management.

Benign prostatic hyperplasia (BPH) is a common disease afflicting elderly males all over the world. The existing scientific research still has not completely clarified its etiology. Pleiotrophin (PTN) is a developmental regulatory protein involved in various biological processes. This study aimed to elucidate the expression, biological function, and underlying mechanism of PTN in the onset and progression of BPH. Human prostate tissues, cell lines, rat models and PTN-knockout mice models were utilized. PTN knockdown, PTN overexpression, and estradiol cell models were established. The qRT-PCR, Western Blot, flow cytometry, CCK-8 assay, collagen gel contraction assay, co-immunoprecipitation, immunofluorescence, H&E, Masson’s trichrome, immunohistochemical staining, TUNEL assay and tissue micro-array analysis were performed during in vivo and in vitro experiments. Our current data validated that PTN is localized in stroma and epithelium of the prostate, with stronger expression in BPH tissues. Functionally, silenced PTN promoted cell apoptosis while it inhibited cell proliferation, cell contraction and fibrosis. Consistently, overexpression of PTN suppressed cell apoptosis, and facilitated cell proliferation, cell contraction, as well as fibrosis. More importantly, AKT phosphorylation and RhoA/ROCK1/2 axis were confirmed to be involved in the regulation of prostate biological processes by PTN. Moreover, estradiol treatment could enhance PTN expression and modulate downstream biological process. Also, PTN expression was correlated with prostate volume (PV), fPSA and the ratio of fPSA/tPSA. Finally, recombinant PTN induced prostatic hyperplasia in rats, PTN knockout suppressed BPH in mice, and estradiol treatment upregulated PTN expression. These results further confirm the crucial role of PTN in BPH onset and progression. Our current study demonstrates that PTN is of significance in the onset and development of BPH and may be a new target for the treatment of BPH.

Background and objects: Benign prostatic hyperplasia (BPH) is a common disease that impairs the life quality of elderly men. The close relationship of BPH and diabetes has been generally established, however, the exact molecular mechanism remains unclear. Midline-1 (MID1) is an E3 ubiquitin ligase belonging to Tripartite Motif family and its involvement in the initiation and progression of many diseases, such as diabetic kidney disease has been well accepted. This study aims to illuminate the potential impact of high glucose (HG) on prostatic cells and elucidate the molecular role of MID1 in the development of BPH.Methods: In this work, human prostate specimens and cultured human prostate cell lines (BPH-1 and WPMY-1) were employed. The impact of HG treatment on these two lines was assessed and the expression and localization of MID1, along with its potential downstream target protein phosphatase 2A (PP2A), were determined using multiple experimental methods. MID1-overexpressing cell models were further used to investigate the function of MID1 in regulating inflammation, fibrosis and epithelial-mesenchymal transition (EMT).Results: Herein we demonstrate diabetic individuals with BPH had lower expression of MID1 and higher expression of the catalytic subunit of PP2A (PP2Ac), larger prostate volume, higher international prostate symptom score (IPSS) and lower Qmax than non-diabetic groups. On a cellular level, HG treatment inhibited the expression of MID1, thus stimulating cellular proliferation and triggering EMT, fibrosis and inflammation of two prostatic cells via enhanced WNT/β-catenin signaling.Conclusions: In general, our novel data demonstrate targeting MID1 might be a promising area of medical treatment for patients with both BPH and diabetes.

Benign prostatic hyperplasia (BPH) is a prevalent disorder in aging males. It is investigated whether heat shock protein family A member 1A (HSPA1A), a cytoprotective chaperone induced under stress, has been implicated in the development of BPH. RNA‐sequencing and single‐cell sequencing analyses revealed significant upregulation of HSPA1A in BPH compared to controls. In vitro experiments elucidated that HSPA1A was localized in prostatic epithelium and stroma, with upregulated expression in BPH tissues. Moreover, HSPA1A silencing augmented apoptosis and reactive oxygen species (ROS) accumulation, inhibiting proliferation via ERK/JNK activation, while overexpression reversed these effects in prostatic BPH‐1 and WPMY‐1 cells. Additionally, ERK1/2 suppression with U0126 rescued the effects of HSPA1A silencing. In vivo, testosterone‐induced BPH (T‐BPH) rat models treated with the HSPA1A antagonist KNK437 exhibited prostatic atrophy and molecular changes consistent with reduced HSPA1A activity. Finally, we conducted a tissue microarray (TMA) analysis of 139 BPH specimens from Zhongnan Hospital of Wuhan University, which revealed a positive correlation between HSPA1A expression and clinical parameters, including prostate volume (PV), tPSA, fPSA, and IPSS. In conclusion, our findings suggested that HSPA1A attenuated apoptosis and oxidative stress through the ERK/JNK signaling pathway, contributing to BPH pathogenesis.

Clear cell renal cell carcinoma is a prevalent urological malignancy, imposing substantial burdens on both patients and society. In our study, we used bioinformatics methods to select four putative target genes associated with EMT and prognosis and developed a nomogram model which could accurately predicting 5-year patient survival rates. We further analyzed proteome and single-cell data and selected PLCG2 and TMEM38A for the following experiments. Overexpression models of PLCG2 and TMEM38A were generated in Caki-1 and 786-O cell lines using plasmids. The in vitro experiments demonstrated that both of them exerted pro-apoptotic effects on Caki-1 and 786-O cells, inducing G2/M phase arrest, inhibiting proliferation, and suppressing EMT. In summary, we identified potential tumor suppressor factors and stratified ccRCC patients into high-risk and low-risk groups based on these factors. Furthermore, we elucidated the impact of PLCG2 and TMEM38A in Caki-1 and 786-O cell lines, offering novel avenues for therapeutic target exploration.

Benign prostatic hyperplasia (BPH) represents a prevalent etiology of lower urinary tract symptoms (LUTS) in the male population, clinically defined by a non-malignant proliferation of prostatic tissue. While BPH exhibits a high prevalence among older male populations globally, the precise underlying mechanisms contributing to its development remain incompletely elucidated. Mitochondria, essential organelles within eukaryotic cells, are critical for cellular bioenergetics, the regulation of reactive oxygen species (ROS) generation, and the modulation of cell death pathways. The maintenance of mitochondrial homeostasis involves a complex interplay of processes. By synthesizing previous literature, this review discusses mitochondrial homeostasis in prostate glands and the role of mitochondrial dysfunction in the context of BPH. Furthermore, the review delved into each dimension of mitochondrial dysfunction in the specific etiology of BPH, highlighting its impact on cell survival, apoptosis, ferroptosis, oxidative stress and androgen receptor (AR). Overall, this review aims to unveil the crosstalk between mitochondrial dysfunction and BPH and identify intrinsic mechanisms.

Benign prostatic hyperplasia (BPH) is a prevalent condition affecting the male urinary system, with its molecular mechanisms of pathogenesis remaining unclear. Y-27632, a non-isoform-selective Rho kinase inhibitor, has shown therapeutic potential in various diseases but its effects on static factors and fibrosis in BPH remain unexplored. This study investigated human prostate tissues, human prostate cell lines, and BPH rat model using immunofluorescence, flow cytometry, quantitative reverse transcription polymerase chain reaction, western blotting, and cell counting kit-8. ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters. Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while induced cell apoptosis in a dose-dependent manner. Moreover, knockdown of either ROCK isoform inhibited fibrosis and EMT, induced apoptosis, while ROCK overexpression had the opposite effects. ROCK downregulation inhibited the β-catenin signaling pathway (such as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while inhibiting TGF-β/Smad_2/3 signaling. At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis in BPH model rats to some extent. Our study sheds light on the therapeutic potential of Y-27632 in regulating prostate cell growth, fibrosis and EMT, and demonstrates for the first time the regulatory effect of ROCK isoforms on prostate cells, providing the basis for future research of ROCK isoform-selective inhibitors.

Introduction: Benign prostatic hyperplasia (BPH) is a common pathologic process in aging men, and the contraction of the prostatic smooth muscles (SMs) in the stroma plays a vital role in this pathogenesis, leading to lower urinary tract symptoms (LUTSs). The isoforms of both the SM myosin (SMM) and non-muscle myosin (NMM) are associated with the contraction type of the prostatic SMs, but the mechanism has not been fully elucidated. Methods: We collected prostate tissues from 30 BPH patients receiving surgical treatments, and normal human prostate samples were obtained from 12 brain-dead men. A testosterone-induced (T-induced) rat model was built, and the epithelial hyperplastic prostates were harvested. Competitive RT-PCR was used to detect the expression of SMM isoforms. We investigated the contractility of human prostate strips in vitro in an organ bath. Results: The results regarding the comparisons of SMM isoforms varied between rat models and human samples. In comparison with T-induced rats and controls, competitive RT-PCR failed to show any statistically significant difference regarding the compositions of SMM isoforms. For human prostates samples, BPH patients expressed more SM-1 isoforms (66.8% vs. 60.0%, p < 0.001) and myosin light chain-17b (MLC_17b) (35.9% vs. 28.5%, p < 0.05) when compared to young donors. There was a significant decrease in prostate myosin heavy chain (MHC) expression in BPH patients, with a 66.4% decrease in MHC at the mRNA level and a 51.2% decrease at the protein level. The upregulated expression of non-muscle myosin heavy chain-B (NMMHC-B) was 1.6-fold at the mRNA level and 2.1-fold at the protein level. The organ bath study showed that isolated prostate strips from BPH patients produced slower tonic contraction compared to normal humans. Conclusion: In this study, we claim that in the enlarged prostates of patients undergoing surgeries, MHC expression significantly decreased compared to normal tissues, with elevated levels of SM-1, MLC_17b, and NMMHC-B isoforms. Modifications in SMM and NMM might play a role in the tonic contractile properties of prostatic SMs and the development of LUTS/BPH. Understanding this mechanism might provide insights into the origins of LUTS/BPH and facilitate the identification of novel therapeutic targets.