scholarly journals MYPT1 reduction is a novel pathogenic factor of erectile dysfunction

2020 ◽  
Author(s):  
Wei Zhao ◽  
Jie Sun ◽  
Liang-Yu Yao ◽  
Ye-Qiong Li ◽  
Cai-Ping Chen ◽  
...  
Keyword(s):  
Erectile Dysfunction ◽  
Knockout Mice ◽  
Smooth Muscles ◽  
Muscle Dysfunction ◽  
Pathogenic Factor ◽  
E3 Ligases ◽  
Penile Artery ◽  
Novel Strategy ◽  
Underlying Mechanisms ◽  
Smooth Muscle Dysfunction

Abstract Erectile dysfunction (ED) is closely associated with smooth muscle dysfunction, but its underlying mechanisms remains incompletely understood. We here reported that the reduced expression of myosin phosphatase target subunit 1 (MYPT1), the main regulatory unit of myosin light chain phosphatase, was critical for the development of vasculogenic ED. Male MYPT1 knockout mice had reduced fertility and the penises displayed abolished erections as evidenced by reduced intracavernous pressure (ICP). The penile smooth muscles of the knockout mice displayed enhanced contractility and resistant relaxation. We further identified a natural compound lotusine that increased the MYPT1 expression by inhibiting SIAH1/2 E3 ligases-mediated protein degradation. This compound sufficiently restored the ICP and improved histological characters of the penile artery of Mypt1 haploinsufficiency mice. In diabetic ED mice (db/db), the decreased expression of MYPT1 was measured, and ICP was restored by lotusine treatment. We conclude that the reduction of MYPT1 is the major pathogenic factor of vasculogenic ED. The restoration of MYPT1 by lotusine improved the function of injured penile smooth muscles, and could be a novel strategy for ED therapy.

Aneurysmal Dilatation of Ductus Arteriosus and Pulmonary Artery in Association With ACTA2 Mutation

2020 ◽  
Vol 11 (4) ◽  
pp. 498-500
Author(s):  
Mohanageetha Ardhanari ◽  
Andrew Colin ◽  
Mustafa Tekin ◽  
Juan C. Infante ◽  
Sethuraman Swaminathan
Keyword(s):  
Genetic Variant ◽  
Ductus Arteriosus ◽  
Smooth Muscles ◽  
Arterial Disease ◽  
Muscle Dysfunction ◽  
Fetal Life ◽  
Rare Genetic Variant ◽  
Aneurysmal Dilatation ◽  
Characteristic Features ◽  
Smooth Muscle Dysfunction

Actin α2 (ACTA2) is a protein crucial for proper functioning of contractile apparatus in smooth muscles. A specific mutation resulting in substitution of arginine at position 179 by histidine (p.R179 H) in ACTA2 has been shown to be associated with multisystemic smooth muscle dysfunction syndrome. Characteristic features include aneurysmal arterial disease. Due to rarity of this disease, we report a nine-year-old girl with this rare genetic variant in whom cardiovascular manifestations were identified in fetal life and who needed neonatal cardiac surgical intervention.

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

scholarly journals Neurogenic Erectile Dysfunction. Where Do We Stand?

Medicines ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. 3
Author(s):  
Charalampos Thomas ◽  
Charalampos Konstantinidis
Keyword(s):  
Erectile Dysfunction ◽  
Large Cohort ◽  
Sexual Performance ◽  
Drug Induced ◽  
Underlying Mechanisms

Erectile Dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance, causing tremendous effects on both patients and their partners. The pathophysiology of ED remains a labyrinth. The underlying mechanisms of ED may be vasculogenic, neurogenic, anatomical, hormonal, drug-induced and/or psychogenic. Neurogenic ED consists of a large cohort of ED, accounting for about 10% to 19% of all cases. Its diversity does not allow an in-depth clarification of all the underlying mechanisms nor a “one size fits all” therapeutical approach. In this review, we focus on neurogenic causes of ED, trying to elucidate the mechanisms that lie beneath it and how we manage these patients.

scholarly journals Homeostatic and therapeutic roles of VIP in smooth muscle function: myo-neuroimmune interactions

2009 ◽  
Vol 297 (4) ◽  
pp. G716-G725 ◽  
Author(s):  
Xuan-Zheng Shi ◽  
Sushil K. Sarna
Keyword(s):  
Smooth Muscle ◽  
Inflammatory Response ◽  
Muscle Function ◽  
Contractile Response ◽  
Enteric Neurons ◽  
Muscle Dysfunction ◽  
Spontaneous Release ◽  
Circular Smooth Muscle ◽  
Smooth Muscle Function ◽  
Smooth Muscle Dysfunction

We tested the hypothesis that spontaneous release of vasoactive intestinal peptide (VIP) from enteric neurons maintains homeostasis in smooth muscle function in mild inflammatory insults and that infusion of exogenous VIP has therapeutic effects on colonic smooth muscle dysfunction in inflammation. In vitro experiments were performed on human colonic circular smooth muscle tissues and in vivo on rats. The incubation of human colonic circular smooth muscle strips with TNF-α suppressed their contractile response to ACh and the expression of the pore-forming α1C subunit of Cav1.2 channels. VIP reversed both effects by blocking the translocation of NF-κB to the nucleus and its binding to the κB recognition sites on hα1C1b promoter. The translocation of NF-κB was inhibited by blocking the degradation of IκBβ. Induction of inflammation by a subthreshold dose of 17 mg/kg trinitrobenzene sulfonic acid (TNBS) in rats moderately decreased muscularis externa concentration of VIP, and it had little effect on the contractile response of circular smooth muscle strips to ACh. The blockade of VIP and pituitary adenylate cyclase-activating peptide receptors 1/2 during mild inflammatory insult significantly worsened the suppression of contractility and the inflammatory response. The induction of more severe inflammation by 68 mg/kg TNBS induced marked suppression of colonic circular muscle contractility and decrease in serum VIP. Exogenous infusion of VIP by an osmotic pump reversed these effects. We conclude that the spontaneous release of VIP from the enteric motor neurons maintains homeostasis in smooth muscle function in mild inflammation by blocking the activation of NF-κB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.

scholarly journals Smooth muscle dysfunction occurs independently of impaired endothelium-dependent dilation in adults at risk of atherosclerosis

1998 ◽  
Vol 32 (1) ◽  
pp. 123-127 ◽  
Author(s):  
Mark R Adams ◽  
Jacqui Robinson ◽  
Robyn McCredie ◽  
J.Paul Seale ◽  
Keld E Sorensen ◽  
...  
Keyword(s):  
At Risk ◽  
Smooth Muscle ◽  
Muscle Dysfunction ◽  
Smooth Muscle Dysfunction

scholarly journals High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Aisling B. Mc Glacken-Byrne ◽  
David Prentice ◽  
Danial Roshandel ◽  
Michael R. Brown ◽  
Philip Tuch ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Case Report ◽  
High Resolution ◽  
Retinal Imaging ◽  
Muscle Dysfunction ◽  
Smooth Muscle Dysfunction

scholarly journals CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Yilan Yang ◽  
Jurui Luo ◽  
Xingxing Chen ◽  
Zhaozhi Yang ◽  
Xin Mei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Studies ◽  
Cell Cycle Progression ◽  
Combined Therapy ◽  
Small Sample ◽  
Combination Strategies ◽  
Novel Strategy ◽  
Underlying Mechanisms

Abstract Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

scholarly journals Dietary Fruit and Vegetable Supplementation Suppresses Diet-induced Atherosclerosis in LDL Receptor Knockout Mice (OR24-07-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Weimin Guo ◽  
Sharon Kim ◽  
Dayong Wu ◽  
Lijun Li ◽  
Michael Thomas ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Knockout Mice ◽  
Agricultural Research ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Plasma Lipid ◽  
Aortic Lesion ◽  
Freeze Dried ◽  
Underlying Mechanisms ◽  
Ldl Receptor Knockout Mice

Abstract Objectives Epidemiological studies have shown that consumption of fruits and vegetables (F&V) is inversely associated with incidence of cardiovascular disease (CVD). However, the evidence for causality and underlying mechanisms is lacking. Our objective was to determine if increased consumption of F&V could prevent atherosclerosis and its underlying mechanisms. Methods A unique blend of the most commonly consumed 24 F&V was freeze-dried into a powder and mixed into diets. Thirty six 4-week old male LDL receptor knockout mice were randomly assigned to one of 3 diet groups (12/group): low fat (LF, 10 kcal% fat), high-fat (27 kcal% fat) with 0% F&V (HF), and HF plus 15% F&V diet (HF + FV, equivalent to 8–9 servings for humans). After 20 weeks, mice were euthanized and blood, aorta, and liver tissue were collected. Aortic atherosclerotic lesion, hepatic steatosis, plasma lipid profile and pro-inflammatory cytokine levels were measured. Results No significant differences were found in body weight among the 3 groups. Mice fed HF diet had larger aortic atherosclerotic lesion and hepatic steatosis area than mice fed LF diet by 6.5 and 1.9 fold, respectively (p < 0.001). HF + FV group had 80% less aortic lesion and hepatic steatosis than HF group (p < 0.001). Mice fed HF diet had significantly higher plasma TG and LDL and lower HDL levels than mice fed LF diet, and this dyslipidemia was prevented by F&V supplementation. Further, HF + FV group had lower plasma TNFα levels compared to HF0 group (p < 0.05). Spearman correlation analysis showed that aortic atherosclerotic lesion and hepatic steatosis area were negatively correlated with plasma HDL (p < 0.001) and significantly and positively correlated with TNFα, and the ratios of LDL/HDL, TG/HDL, and non HDL/HDL. Conclusions Our results demonstrate a causal role of high intake of F&V in preventing HF-induced atherosclerosis and hepatic steatosis, which may be mediated through improved dyslipidemia and reduced inflammation. Funding Sources U.S. Department of Agriculture – Agricultural Research Service. Supporting Tables, Images and/or Graphs

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