Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.

Xiao M, et al. World J Mens Health. 2024 Oct;42:e97. https://doi.org/10.5534/wjmh.240126

Introduction: Low-intensity pulsed ultrasound (LIPUS) is a type of specific ultrasound that is delivered at low intensity and generated in pulsed wave mode. Previous studies have demonstrated the therapeutic applications of LIPUS in the healing or regeneration of several tissues. However, research on LIPUS therapy for erectile dysfunction (ED) is still limited. Objectives: This literature review aims to summarize the clinical trials, clinical applications, and the molecular mechanisms of LIPUS in ameliorating ED. Methods: A comprehensive literature search was conducted in PubMed and MEDLINE using the keywords: “low-intensity pulsed ultrasound,” “erectile dysfunction,” “treatment,” “clinical trials,” and “mechanism.” Results: LIPUS significantly improved erectile function in patients with mild-to-moderate ED in all of the clinical trials. Notably, no adverse events were reported in any of the studies. In addition, LIPUS was shown to promote erectile function mainly via the regeneration of cavernous nerves, the corpus cavernosum endothelium or smooth muscles, as well as via the activation of stem cells. Conclusion: LIPUS has demonstrated safety and efficacy in the treatment of ED based on clinical trials, and the mechanisms that are involved in these effects have been elucidated via basic studies. Although most clinical studies have lacked placebo-controlled groups and have included limited sample sizes, LIPUS therapy is still a promising area in ED research. However, it should be noted that the studies were conducted in China, which may limit the generalizability of the findings.

The high prevalence of diabetes mellitus-induced erectile dysfunction (DMED) in males and the limited efficacy of existing therapies necessitate deeper mechanistic insights. We identify pathological lactate accumulation in the corpus cavernosum as a major driver of DMED in male mice, promoting structural degeneration and smooth muscle cell loss. Mechanistically, transcriptional repression and functional impairment of fructose-1,6-bisphosphatase 1 (Fbp1), a rate-limiting gluconeogenic enzyme, underlie this lactate accumulation. Epigenetic profiling revealed suppression of Fbp1 transcription associated with histone H3 lysine 9 trimethylation and histone H3 lysine 27 trimethylation. Palmitoylation at the FBP1 Cys282 residue, catalyzed by zinc finger DHHC-type containing 13, further disrupted its gluconeogenic function, exacerbating lactate accumulation. To rescue these defects, we engineered lipid nanoparticles loaded with the Fbp1-C282S mutant mRNA, restoring FBP1 expression, blocking pathological palmitoylation, and ultimately improving erectile function in diabetic male mice. Here, our study in male mice identifies cavernosal lactate accumulation as a central pathological factor, elucidates its molecular regulation, and provide a targeted therapeutic strategy for DMED.

Background: The poor clinical situation of type 2 diabetes-induced erectile dysfunction (T2DMED) creates an urgent need for new therapeutic targets. Aim: To reveal the conserved molecular mechanism of T2DMED across species. Methods: T2DMED rat and mouse models were constructed to extract mRNA from corpus cavernosum for high-throughput sequencing. The differentially expressed genes (DEGs) were analyzed and the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Protein–Protein Interaction Networks were performed by bioinformatics methods. Immunohistochemistry, immunofluorescence, hematoxylin- eosin and Masson staining were used for subsequent verification. Outcomes: Cross-species transcriptomics of T2DMED rats and mice were analyzed and validated. Results: Gene expression patterns in normal corpus cavernosum of mice and rats showed a strong correlation (r = 0.75, P < 2.2 × 10-16), with a total of 15 691 homologous genes identified. In both species, 553 homologous down-regulated DEGs were identified, mainly enriched in pathways related to smooth muscle and mitochondrial functions, as revealed by KEGG and GO analyses. Immunohistochemistry and immunofluorescence confirmed the decreased expression of α-smooth muscle actin and Uqcr10 in cavernosum tissues of T2DMED mice and rats. Additionally, 239 homologous up-regulated DEGs were identified, which were enriched in the Wnt signaling pathway and extracellular matrix composition. Subsequent experiments confirmed increased β-catenin expression and significant collagen accumulation, indicating fibrosis in T2DMED. Clinical implications: To provide a new direction for improving the erectile ability of patients with T2DMED. Strengths and limitations: The main strength is that cross-species transcriptomic sequencing has revealed the conserved molecular mechanisms of T2DMED. The main limitation is the lack of further validation in the T2DMED patients. Conclusions: Cross-species transcriptomic comparisons may offer a novel strategy for uncovering the underlying mechanisms and identifying therapeutic targets for T2DMED.