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The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in Sprague‒Dawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue.

Canonical transient receptor potential (TRPC) channels contribute to calcium homeostasis, which is involved in penile vascular contractility and erectile dysfunction (ED) pathophysiology. We evaluated the impact of TRPC5 inhibition on endothelial function in penile vascular tissue from aging rats and ED patients and its effect on the relaxant efficacy of PDE5 inhibitors. TRPC inhibitor-induced endothelial and neurogenic relaxations were evaluated in corpus cavernosum (RCC) from a rat model of aging-related ED and in human penile resistance arteries (HPRAs) and corpus cavernosum (HCC) from ED patients and organ donors (NoED). The TRPC5 inhibitor, AC1903, was more effective than TRPC3 and TRPC4 inhibitors in relaxing aged RCC and HCC and HPRA from ED patients. In addition to enhancing endothelial and neurogenic relaxations in RCC from aged animals, AC1903 improved endothelium-dependent relaxation in both HCC and HPRA from ED patients but not in tissues from NoED. Cavernosal expression of TRPC5 was not different between ED and NoED subjects. AC1903 potentiated relaxations to the PDE5 inhibitor, tadalafil, in HCC/HPRA from ED patients. TRPC5 inhibition improved penile vascular function in aged rats and patients with ED. TRPC5 inhibition could be a potential therapeutic target for ED, particularly when combined with PDE5 inhibitors to enhance treatment outcomes.

Diabetes is an incurable, chronic disease that can lead to many complications, including angiopathy, peripheral neuropathy, and erectile dysfunction (ED). The angiopoietin-Tie2 signaling pathway plays a critical role in blood vessel development, formation, remodeling, and peripheral nerve regeneration. Therefore, strategies for activating the Tie2 signaling pathway have been developed as potential therapies for neurovascular diseases. Here, we developed a human Tie2-agonistic antibody (MT-100) that not only resists Ang-2 antagonism and activates Tie2 signaling but also regulates a novel target, sushi repeat-containing protein X-linked 2 (Srpx2). This regulation led to the survival of vascular and neuronal cells, a reduction in the production of reactive oxygen species (ROS), activation of the PI3K/AKT/eNOS signaling pathway, increased expression of neurotrophic factors, and ultimately alleviation of ED in diabetic mice. Our findings not only provide conclusive evidence that MT-100 is a promising therapeutic strategy for the treatment of diabetic ED but also suggest it has substantial clinical applications for other complications associated with diabetes. New Antibody Activates Tie2 to Combat Diabetic Complications Erectile dysfunction is a condition where men have difficulty maintaining an erection. It is common among men with diabetes, often due to severe damage to blood vessels. Researchers found a need for better therapies for diabetic ED. They created a new humanized antibody, MT-100, which targets the Tie2 receptor. The Tie2 receptor is important for keeping blood vessels stable and protecting nerves. In their study, they tested MT-100 on diabetic mice. After injecting MT-100, the mice showed better erectile function due to improved blood vessel and nerve growth. MT-100 also helped cells survive and reduced oxidative stress, which is damage caused by harmful molecules. The study suggests MT-100 could be a promising treatment for diabetic ED by supporting blood vessel and nerve health. Future studies might look at MT-100 for other blood vessel diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Abstract Context Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty. Objective This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys. Methods We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence. Results Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases. Conclusion Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.

This study aims to explore the impact of Nesfatin-1 on type 2 diabetic erectile dysfunction (T2DMED) and its underlying mechanism in regulating the phenotypic switching of corpus cavernosum smooth muscle cells (CCSMCs). Twenty-four 4-week-old male C57 wild-type mice were randomly assigned to the control group, model group, and Nesfatin-1 treatment group. Monitoring included body weight, blood glucose levels, and penile cavernous pressure (ICP). Histochemistry and Western blot analyses were conducted to assess the expressions of α-SMA, OPN, and factors related to the PI3K/AKT/mTOR signaling pathway. CCSMCs were categorized into the control group, high glucose and high oleic acid group (GO group), Nesfatin-1 treatment group (GO+N group), sildenafil positive control group (GO+S group), and PI3K inhibitor group (GO+N+E group). Changes in phenotypic markers, cell morphology, and the PI3K/AKT/mTOR signaling pathway were observed in each group. (1) Nesfatin-1 significantly ameliorated the body size, body weight, blood glucose, glucose tolerance, and insulin resistance in T2DMED mice. (2) Following Nesfatin-1 treatment, the ICP/MSBP ratio and the peak of the ICP curve demonstrated a significant increase. (3) Nesfatin-1 significantly enhanced smooth muscle and reduced collagen fibers in the corpus cavernosum. (4) Nesfatin-1 notably increased α-SMA expression and decreased OPN expression in CCSMCs. (5) Nesfatin-1 elevated PI3K, p-AKT/AKT, and p-mTOR/mTOR levels in penile cavernous tissue. Nesfatin-1 not only effectively improves body weight and blood glucose levels in diabetic mice but also enhances erectile function and regulates the phenotypic switching of corpus cavernosum smooth muscle. The potential mechanism involves Nesfatin-1 activating the PI3K/AKT/mTOR signaling pathway to induce the conversion of CCSMCs to a contractile phenotype.

The baculum, a bone in the penis of many mammal species, shows an astonishing level of morphological divergence between species. Despite hundreds of years of interest, biologists have been unable to directly test its function. The goal of the current study is to uncover molecular details that could allow selective disruption of the baculum while allowing normal sexual differentiation and skeletal development. We compare patterns of androgen receptor binding and single cell gene expression in the developing penis, forelimbs and hindlimbs of mice. We identified chondrocytes in all three tissue types, but those from the developing penis show several unique features, including a population of chondrocytes that express both Runt-related transcription factor 2 ( Runx2 ) and Androgen receptor ( Ar ). By combining a Runx2 -Cre allele with a floxed Ar allele in mice, we selectively knocked out androgen signaling in late chondrocytes, resulting in a range of defects in baculum morphology. Males with the most disrupted bacula were unable to copulate, and their bacula appears to be disconnected from the corpus cavernosum muscle. Our study provides insights into the diversity of molecular mechanisms leading to bone and offers the first opportunity to directly test the function of the baculum.

Background Cavernous nerve injury (CNI) is a prominent etiological factor in the development of erectile dysfunction (ED). Nevertheless, the underlying pathophysiological mechanisms of CNI-induced ED (CNI-ED) are not fully elucidated. Galectin-3 (Gal-3), an indicator of inflammation and fibrosis, has been implicated in the pathogenesis of arteriogenic ED. In this study, we investigate the role of Gal-3 in CNI-ED and explore the potential mechanisms by which adipose-derived mesenchymal stem cell exosomes (ADSC-Exo) ameliorate CNI-ED. Methods We established a bilateral CNI (BCNI) rat model and evaluated erectile function using intracavernous pressure (ICP), mean arterial pressure (MAP), and infrared ray thermography (IRT). The expression level of Gal-3 was measured in the major pelvic ganglia (MPG), penile corpus cavernosum, and cultured cells, with its expression modulated by lentiviral vectors. A combination of experimental approaches, including western blot, immunofluorescence, and flow cytometry analysis, were employed to investigate the role of Gal-3 in the progression of CNI-ED. Additionally, the potential molecular mechanisms by which ADSC-Exo ameliorates CNI-ED were explored. Results Our findings indicated that the expression of Gal-3 is significantly upregulated in the MPG and penile corpus cavernosum of BCNI rats. This upregulation was accompanied by oxidative stress and activation of the TLR4/MyD88/NF-κB signaling pathway. Following lentiviral knockdown of Gal-3, erectile function in BCNI rats was improved. Moreover, ADSC-Exo transplantation inhibited Gal-3 expression and the related inflammatory profibrotic cascades. Conclusions Collectively, this study demonstrates that upregulation of Gal-3 promotes the pathogenesis of CNI-ED by triggering oxidative stress and inflammatory profibrotic cascades and highlights the therapeutic potential of ADSC-Exo in restoring erectile function via Gal-3 inhibition. Graphical Abstract

Erectile dysfunction (ED) is the most prevalent consequences in men with diabetes mellitus (DM). Recent studies demonstrates that neutrophil extracellular traps (NETs) play important roles in DM and its complications. Nevertheless, whether NETs are involved in ED remains unknown. This work intended to explore the role and mechanisms of NETs in ED in the context of DM. Here, we observed that NET generation and pyroptosis were promoted in DM rats with ED compared with controls. Mechanistically, NETs facilitated NLRP3 inflammasome activation and subsequently triggered pyroptosis under high glucose stress, ultimately leading to ED. Intriguingly, DNase I (a NET degrading agent) alleviated ED and corpus cavernosum injury in DM rats. Overall, NETs might induce ED in DM by promoting NLRP3-mediated pyroptosis in the corpus cavernosum.

Background Erectile dysfunction (ED) is an important cause of reduced quality of life for men and their partners. A common pathological feature across various types of ED, including diabetes mellitus-induced ED (DMED) and bilateral cavernous nerve injury-induced ED (CNIED), is the loss of endothelial cells (ECs) and smooth muscle cells (SMCs) in the corpus cavernosum (CC). Stem cell-based therapies have garnered attention due to their potential to differentiate into specialized cell types, offering promise for the treatment of ED. Fibroblasts (FBs), the most abundant cell type in the CC, have raised considerable interest in recent years. However, the functional role of FBs in the progression of ED remains unclear. Methods We established DMED and CNIED animal models and performed single-cell RNA sequencing (scRNA-seq) to analyze cell subsets within the pathological environments of these two ED types. To further investigate the cellular landscape, we combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify specific FB subsets in the CC. Results scRNA-seq revealed a distinct subset of FBs that overexpress both Sca1 and PDGFRa. CytoTRACE analysis and Gene Set Enrichment Analysis (GSEA) indicated that PDGFRa + Sca1 + FBs may be associated with angiogenesis and possess the potential to differentiate into ECs and SMCs. Immunofluorescence analysis confirmed that PDGFRa + Sca1 + FBs were localized to the vessel walls, with co-localization of Sca1 and PDGFRa observed with markers for SMCs and ECs. Our findings shed light on the role of PDGFRa + Sca1 + FBs in the CC, demonstrating their involvement in angiogenesis and vascular repair. The depletion of these FBs in disease conditions may contribute to the exhaustion of ECs and SMCs, providing new insights into the pathogenesis of ED. Conclusion These results open potential avenues for novel therapeutic strategies aimed at targeting PDGFRa + Sca1 + FBs to restore vascular function in ED.

The lost DNA that makes us human A computational survey of the human genome has identified more than 500 human-specific genomic deletions that remove sequences that are highly conserved between chimpanzees and other animals. These are genomic changes that are likely to have contributed to unique features of human biology. Most of the deleted sequences are located in the non-coding regions of the genome. The human deletions are enriched near genes involved in neural development and steroid hormone signalling, consistent with previous suggestions that regulatory changes near key developmental control genes may have important roles in human evolution. Specific examples of human-specific deletions include one that affects penile anatomy and another relating to brain size. This study searched for putative regulatory mutations specific to the human lineage by looking for sequences that are highly conserved between chimpanzees and other species, but are not present in the human genome. The 500-odd human-specific deletions tend to lie in non-coding DNA stretches and near genes involved in steroid hormone signalling and neural function. This is illustrated with two examples, one of which affects penile anatomy whereas the other affects brain size. Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown 1 . Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes 2 , 3 , 4 , 5 . Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species 6 , 7 , 8 . Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor ( AR ) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage 9 , 10 . Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma ( GADD45G ) 11 , 12 , a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations 6 , 7 , 8 and inactivation events 13 long proposed to have an important role in human evolutionary divergence.