MT-100, a human Tie2-agonistic antibody, improves penile neurovasculature in diabetic mice via the novel target Srpx2.

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.

Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate.

Introduction: Despite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both and models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.

Role of pericytes in regulating penile angiogenesis and nerve regeneration.

Pericytes are multifunctional mural cells that surround the abluminal wall of endothelial cells and are associated with vascular development, vascular permeability, and angiogenesis. Additionally, pericytes demonstrate stem cell-like properties and contribute to neuroinflammatory processes. Pericytes have been extensively studied in the central nervous system.

Heparin-binding epidermal growth factor-like growth factor improves erectile function in streptozotocin-induced diabetic mice.

Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) serves as a pro-angiogenic factor; however, there is to our knowledge currently no reported research on the relationship between HB-EGF and diabetic erectile dysfunction (ED).

Aim: In this study we aimed to determine whether HB-EGF can improve the erectile function of streptozotocin-induced diabetic mice and to explore the related mechanisms.

Methods: Eight-week-old male C57BL/6 mice were used for diabetes induction.

Argonaute 2 restored erectile function and corpus cavernosum mitochondrial function by reducing apoptosis in a mouse model of cavernous nerve injury.

Purpose: To determine whether the overexpression of the Argonaute RNA-induced silencing complex catalytic component 2 (Ago2) improves erectile function in mice after cavernous nerve injury (CNI).

Materials And Methods: Lentiviruses containing open reading frame (ORF) mouse clone (Ago2 O/E) were used to overexpress Ago2, and lentiviruses ORF negative control particles (NC) were used as a negative control. Three days before preparing the CNI model, we injected lentiviruses into the penises of 8-week-old male C57BL/6 mice.

Single-cell transcriptome analysis of cavernous tissues reveals the key roles of pericytes in diabetic erectile dysfunction.

Erectile dysfunction (ED) affects a significant proportion of men aged 40-70 and is caused by cavernous tissue dysfunction. Presently, the most common treatment for ED is phosphodiesterase 5 inhibitors; however, this is less effective in patients with severe vascular disease such as diabetic ED. Therefore, there is a need for development of new treatment, which requires a better understanding of the cavernous microenvironment and cell-cell communications under diabetic condition.

Photobiomodulation as a Potential Therapy for Erectile Function: A Preclinical Study in a Cavernous Nerve Injury Model.

Purpose: To identify the optimal photobiomodulation (PBM) parameters using molecular, histological, and erectile function analysis in cavernous nerve injury.

Materials And Methods: A cavernous nerve injury was induced in 8-week-old C57BL/6J male mice that were subsequently divided randomly into age-matched control groups. Erectile function tests, penile histology, and Western blotting were performed 2 weeks after surgery and PBM treatment.

FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway.

The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are not well known. Here, we identify a potentially novel function of FLRT2 in preventing endothelial cell senescence and vascular aging. We found that FLRT2 expression was lower in cultured senescent endothelial cells as well as in aged rat and human vascular tissues.

Fibroblasts enable penile erection.

Perivascular fibroblasts may underlie erectile dysfunction.

Regenerative therapies as a potential treatment of erectile dysfunction.

Erectile dysfunction (ED) is the most common sexual dysfunction disease in adult males. ED can be caused by many factors, such as vascular disease, neuropathy, metabolic disturbances, psychosocial causes, and side effects of medications. Although current oral phosphodiesterase type 5 inhibitors can achieve a certain effect, they cause temporary dilatation of blood vessels with no curative treatment effects.

BMP2 restores erectile dysfunction through neurovascular regeneration and fibrosis reduction in diabetic mice.

Background: The odds of erectile dysfunction are three times more prevalent in diabetes. Severe peripheral vascular and neural damage in diabetic patients responds poorly to phosphodiesterase-5 (PDE5) inhibitors. However, bone morphogenetic protein 2 is known to be involved in angiogenesis.

Crystal structure of LRG1 and the functional significance of LRG1 glycan for LPHN2 activation.

The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFβ signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2.

Vactosertib, TGF-β receptor I inhibitor, augments the sensitization of the anti-cancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) exhibits a pronounced extracellular matrix (ECM)-rich response, which is produced by an excessive amount of transforming growth factor β (TGF-β), resulting in tumor progression and metastasis. In addition, TGF-β signaling contributes to rapidly acquired resistance and incomplete response to gemcitabine. Recently, selective inhibitors of the TGF-β signaling pathway have shown promise in PDAC treatment, particularly as an option for augmenting responses to chemotherapy.

Melatonin and Exercise Counteract Sarcopenic Obesity through Preservation of Satellite Cell Function.

Sarcopenic obesity (SO) is characterized by atrophic skeletal muscle impairment (sarcopenia) and obesity, which is associated with adverse outcomes of morbidity and mortality in elderly people. We investigated the effects of melatonin and exercise training on SO in 32-week-old senescence-accelerated mouse-prone-8 (SAMP8) mice fed a normal diet or a high-fat diet for 16 weeks. Melatonin, exercise, or melatonin and exercise for 8 weeks displayed reductions in the SO-induced impairment of skeletal muscle function and atrophy.

Argonaute 2 Restores Erectile Function by Enhancing Angiogenesis and Reducing Reactive Oxygen Species Production in Streptozotocin (STZ)-Induced Type-1 Diabetic Mice.

Severe vascular and nerve damage from diabetes is a leading cause of erectile dysfunction (ED) and poor response to oral phosphodiesterase 5 inhibitors. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. In the present study, we report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions.

A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity.

Heat Shock Protein 70 in Penile Neurovascular Regeneration Requires Cystathionine Gamma-Lyase.

Purpose: Diabetes mellitus, one of the major causes of erectile dysfunction, leads to a poor response to phosphodiesterase-5 inhibitors. Heat shock protein 70 (Hsp70), a ubiquitous molecular chaperone, is known to play a role in cell survival and neuroprotection. Here, we aimed to assess whether and how Hsp70 improves erectile function in diabetic mice.

IGFBP5 antisense and short hairpin RNA (shRNA) constructs improve erectile function by inducing cavernosum angiogenesis in diabetic mice.

Background: The incidence of diabetic erectile dysfunction (ED) is rapidly increasing, and due to the severe angiopathy caused by diabetes, current drugs are ineffective at treating ED. Insulin-like growth factor-binding protein 5 (IGFBP5) promotes cell death and induces apoptosis in various cell types.

Objectives: To evaluate the effectiveness of IGFBP5 knockdown in improving erectile function in diabetic mice.

Pericyte-derived extracellular vesicle-mimetic nanovesicles ameliorate erectile dysfunction via lipocalin 2 in diabetic mice.

Diabetes mellitus is one of the main causes of erectile dysfunction (ED). Men with diabetic ED do not respond well to oral phosphodiesterase-5 inhibitors owing to neurovascular dysfunction. Pericyte-derived extracellular vesicle-mimetic nanovesicles (PC-NVs) are known to promote nerve regeneration in a mouse model of cavernous nerve injury.

Efficacy of Low-Intensity Extracorporeal Shock Wave Treatment in Erectile Dysfunction Following Radical Prostatectomy: A Systematic Review and Meta-Analysis.

Erectile dysfunction (ED) is a well-known complication of radical prostatectomy (RP). Oral 5-phosphodiesterase inhibitors are currently the most widely used penile rehabilitation treatment for ED following RP, but they are less effective than for those with general ED. Low-intensity extracorporeal shock wave treatment (LI-ESWT), causing a biological change that induces neovascularization, has recently been used as a treatment for ED.

Latrophilin-2 is a novel receptor of LRG1 that rescues vascular and neurological abnormalities and restores diabetic erectile function.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM.

Pericyte‑derived extracellular vesicles‑mimetic nanovesicles improves peripheral nerve regeneration in mouse models of sciatic nerve transection.

Pericyte‑derived extracellular vesicle‑mimetic nanovesicles (PC‑NVs) play an important role in the improvement of erectile function after cavernous nerve injury. However, the impact of PC‑NVs on the peripheral nervous system (PNS), such as the sciatic nerve, is unclear. In this study, PC‑NVs were isolated from mouse cavernous pericytes (MCPs).

RNA-sequencing profiling analysis of pericyte-derived extracellular vesicle-mimetic nanovesicles-regulated genes in primary cultured fibroblasts from normal and Peyronie's disease penile tunica albuginea.

Background: Peyronie's disease (PD) is a severe fibrotic disease of the tunica albuginea that causes penis curvature and leads to penile pain, deformity, and erectile dysfunction. The role of pericytes in the pathogenesis of fibrosis has recently been determined. Extracellular vesicle (EV)-mimetic nanovesicles (NVs) have attracted attention regarding intercellular communication between cells in the field of fibrosis.