Smooth Muscle Proliferation Research Articles

Lower urinary tract symptoms in patients with small prostates: Smooth muscle proliferation and calcification might be causative factors.

The current study is designed to evaluate and compare the histological changes in the surgical samples of prostate taken from patients undergoing transurethral resection of prostate (TURP) for benign prostate hyperplasia (BPH) with different sizes. Prostate surgical tissue samples were obtained from BPH patients undergoing TURP after taking informed consent. Ultrasound measure of prostatic weight and prostate-specific antigen (PSA) levels were obtained from the patients along with other clinical and demographic details. Tissue samples were fixed, processed, sectioned and stained with hematoxylin and eosin and Masson's trichrome to look for histological features, specifically smooth muscle proliferation. Immunohistochemical expression of bone morphogenetic protein (BMP)-2 was recorded to assess the calcification potential. Fifty-nine surgical samples were obtained from the patients of age range 50-90 years and body mass index (BMI) 15.6-33.3kg/m2 . The range of ultrasound measures of prostate weight was 20-137 g with PSA ranged 1.03-93.3ng/mL. Patients with small-sized prostate had significant severe smooth muscle proliferation (P < .001). Prostate size/weight had significant positive association with BMI (P < 0.001, r=0.543) and negative association with BMP-2 (P < 0.001, r=-0.654). Samples with severe smooth muscle proliferation were with increased BMP-2 expression (P < .001) and higher levels of PSA levels (P=0.004). BMP-2 expression revealed positive significant association with PSA (P < .001, r=0.432). From this study we conclude that BPH patients with small-sized glands and high PSA levels have increased smooth muscle proliferation and calcification potential causing the symptoms of lower urinary tract symptoms in these patients.

Promotor Hypomethylation Mediated Upregulation of miR-23b-3p Targets PTEN to Promote Bronchial Epithelial-Mesenchymal Transition in Chronic Asthma.

Chronic asthma is characterized by airway inflammation and irreversible airway remodeling. Epithelial-mesenchymal transition (EMT) is a typical pathological change of airway remodeling. Our previous research demonstrated miR-23b inhibited airway smooth muscle proliferation while the function of miR-23b-3p has not been reported yet. Besides, miRNA is regulated by many factors, including DNA methylation. The function of miR-23b-3p and whether it is regulated by DNA methylation are worth exploring. Balb/c mice were given OVA sensitization to develop the asthmatic model. Expression of miR-23b-3p and EMT markers were measured by RT-qPCR, WB and immunohistochemistry (IHC). DNA methylation was detected by methylation-specific PCR (MSP) and the MassARRAY System. Asthmatic mice and TGF-β1-stimulated bronchial epithelial cells (BEAS-2B) showed EMT with increased miR-23b-3p. Overexpression of miR-23b-3p promoted EMT and migration, while inhibition of miR-23b-3p reversed these transitions. DNA methyltransferases were decreased in asthmatic mice. MSP and MassARRAY System detected the promotor of miR-23b showed DNA hypomethylation. DNA methyltransferase inhibitor 5’-AZA-CdZ increased the expression of miR-23b-3p. Meanwhile, PTEN was identified as a target gene of miR-23b-3p. Our results indicated that promotor hypomethylation mediated upregulation of miR-23b-3p targets PTEN to promote EMT in chronic asthma. miR-23b-3p and DNA methylation might be potential therapeutic targets for irreversible airway remodeling.

Potential of the TRPM7 channel as a novel therapeutic target for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an intractable vascular disease characterized by a progressive increase in pulmonary vascular resistance caused by pulmonary vascular remodeling, which ultimately leads to right-sided heart failure. PAH remains incurable, despite the development of PAH-targeted therapeutics centered on pulmonary artery relaxants. It is necessary to identify the target molecules that contribute to pulmonary artery remodeling. Transient receptor potential (TRP) channels have been suggested to modulate pulmonary artery remodeling. Our study focused on the transient receptor potential ion channel subfamily M, member 7, or the TRPM7 channel, which modulates endothelial-to-mesenchymal transition and smooth muscle proliferation in the pulmonary artery. In this review, we summarize the role and expression profile of TRPM7 channels in PAH progression and discuss TRPM7 channels as possible therapeutic targets. In addition, we discuss the therapeutic effect of a Chinese herbal medicine, Ophiocordyceps sinensis (OCS), on PAH progression, which partly involves TRPM7 inhibition.

Rapamycin and Paclitaxel Affect Human Aortic Smooth Muscle Cells-Derived Foam Cells Viability and Proliferation.

IntroductionDrug-eluting stents (DES) coated with rapamycin or paclitaxel as antiproliferative substances significantly reduced the incidence of clinical restenosis and had fewer side effects after percutaneous coronary intervention. However, DES coated with rapamycin or paclitaxel still cause restenosis due to abnormal tissue growth which remained a therapeutic problem, particularly in certain subgroups, possibly due to drug concentrations. This study examined the impact of different concentrations of rapamycin and paclitaxel on cytokine, cell viability and proliferation in human aortic smooth muscle cells (HASMC)-derived foam cells. MethodsThe foam cell model was established in vitro by incubating HASMC with 20 µg/mL oxidized low-density lipoprotein (ox-LDL) for 48 hours. Subsequently, foam cells were treated with different concentrations (0.01 µg/mL, 0.1 µg/mL, 0.5 µg/mL, 1 µg/mL, 5 µg/mL and 10 µg/mL) of rapamycin or paclitaxel for 48 hours, to measure cytokine, cell viability and proliferation by ELISA and MTT, respectively. Finally, viability and proliferation were measured by MTT after the foam cells were treated with 1 µg/mL rapamycin or paclitaxel combined with cytokine antibody for 48 hours. ResultsAfter incubation of HASMC with ox-LDL, the ratios of cholesterol ester and total cholesterol increased significantly (55.29%) (P<0.01). Lipid staining with Oil Red O showed many lipid vacuoles and red dye particles in the cells. Meanwhile, cell viability and proliferation significantly increased compared with the control. This indicated that HASMC had been transformed into foam cells (P<0.01) while rapamycin or paclitaxel concentrations ≥0.1 µg/mL can significantly decrease the foam cell proliferation (P<0.05 or P<0.01), and 1 µg/mL of rapamycin or paclitaxel appeared the most effective concentration. As for cytokines, rapamycin or paclitaxel concentrations ≥1 ug/mL could significantly increase the level of inflammatory cytokines IL-6 (P<0.05 or P<0.01), which was enhanced with the increase of drug concentration. However, rapamycin or paclitaxel concentrations ≥1 µg/mL could significantly reduce the levels of anti-inflammatory cytokines IL-35 and transforming growth factor beta (TGF-β) (P<0.05 or P<0.01), which decreased with the increase of drug concentration. In addition, rapamycin or paclitaxel combined with anti-IL-1β, anti-IL-6, anti- TNF-α or anti-IL-35 had no significant effect on foam cell proliferation compared to the drug alone. However, rapamycin or paclitaxel combined with anti-IL-10 or anti-TGF-β can significantly enhance foam cell proliferation (P<0.01). In addition, there was no difference in the effects of the same concentrations of rapamycin and paclitaxel on foam cells.ConclusionAlthough rapamycin or paclitaxel can reduce foam cell proliferation, too high or too low concentrations could decrease effectiveness. In particular, a high dose can induce foam cells to increase inflammatory cytokines secretion, reduce anti-inflammatory cytokines secretion, and thus affect the inhibiting proliferation. For rapamycin- and paclitaxel-eluting stents, this conclusion may explain the clinical observation of in-stent restenosis after percutaneous coronary intervention. DES coated with an appropriate concentration of rapamycin or paclitaxel may, at least to some extent, contribute significantly to reducing incidence of late in-stent restenosis.

PKCβ inhibitor blocked angiotensin II-induced vascular smooth muscle proliferation and oxidative stress

PKCβ inhibitor blocked angiotensin II-induced vascular smooth muscle proliferation and oxidative stress

PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/β-Catenin Pathway.

BackgroundFine-particulate matter ≤2.5 μm in diameter (PM2.5)-associated airway remodeling has recently been recognized as a central feature of COPD. Activation of the Wnt/β-catenin pathway is closely related to the occurrence of airway remodeling. Accordingly, the goal of this study was to determine whether the Wnt5a/β-Catenin pathway is involved in PM2.5-induced smooth muscle proliferation in vivo and in vitro, which promotes the development of airway remodeling in subjects with COPD.MethodsThe effect of Wnt5a on β-Catenin-mediated airway remodeling was assessed using an in vivo model of PM2.5-induced COPD and PM2.5-exposed human bronchial smooth muscle cells (HBSMCs) in vitro. Small animal spirometry was used to measure lung function in mice. H&E staining and immunohistochemistry were performed to inspect emphysema and airway remodeling indices. Real-time PCR was used to detect Wnt5a, β-Catenin, TGF-β1, CyclinD1 and c-myc mRNA expression. The CCK8 assay was performed to detect cellular activity. Western blotting was performed to assess PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and TenascinC protein expression. β-Catenin expression was detected using cellular immunofluorescence.ResultsExposure to PM2.5 led to emphysema, airway wall thickening, an increased smooth muscle layer thickness, decreased lung function and increased expression of the Wnt5a, β-Catenin, PDGFRβ and Tenascin C proteins in the mouse lung tissue. BOX5 (a Wnt5a antagonist) alleviated these PM2.5-induced outcomes in mice. Moreover, PM2.5 induced the expression of the Wnt5a, β-Catenin, TGF-β1, CyclinD1 and c-myc mRNAs in HBSMCs. BOX5 also inhibited the PM2.5-induced increases in PCNA, α-SMA, Wnt5a, β-Catenin, PDGFRβ and Tenascin C protein expression in HBSMCs.ConclusionOur findings suggest that PM2.5 exposure induces HBSMC proliferation, contributing to airway remodeling via the Wnt5a/β-Catenin signaling pathway in vivo and in vitro, which might be a target for COPD treatment.

Hypoxia-inducible factor-1α promotes proliferation of airway smooth muscle cells through miRNA-103-mediated signaling pathway under hypoxia.

The hypoxia-inducible factor-1α (HIF-1α) activated during asthma development plays a causative role in the abnormal proliferation of airway smooth muscle (ASM) cells and consequential airway remodeling. Although the underlying mechanisms of HIF-1α activity have not been fully revealed, HIF-1α-regulated miRNA signaling is considered important for disrupted differentiation and proliferation of local cells in various tissues under inflammation. We aimed to identify the key miRNA signaling involved in HIF-1α regulation of the proliferation of ASM cells. This study was based on primary ASM cells isolated from adult male rats. Three percent O2 and 21% O2 were set as hypoxic and normoxic condition for ASM cell treatment, respectively. Knockdown of HIF-1α was performed through transfection of pSUPER-shHIF-1α plasmid. Overexpression and knockdown of miRNA-103 were performed through transfection of miRNA-103 mimic or inhibitor, respectively. Levels of HIF-1α, PTEN, and PCNA were determined with Western blot and RT-qPCR. Hypoxia increased HIF-1α and miRNA-103 expression and proliferation in ASM cells. Knockdown of HIF-1α suppressed hypoxia-induced upregulation of proliferation and miRNA-103 expression in ASM cells. Knockdown of miRNA-103 displayed similar effects as knockdown of HIF-1α in ASM cells under hypoxia, while overexpression of miRNA-103 played the opposite role. Additionally, increased or decreased expression of PTEN was also detected when HIF-1α/miRNA-103 was knocked down under hypoxia or miRNA-103 was overexpressed under normoxia, respectively. Our results suggest that HIF-1α promotes the proliferation of ASM cells via upregulating miRNA-103 expression under hypoxia, and PTEN is involved in the miRNA-103-mediated signaling pathway.

Endovascular approach in the management of idiopathic myointimal hyperplasia of the inferior mesenteric vein

BackgroundIdiopathic myointimal hyperplasia of the mesenteric vein (IMHMV) is a rare, often undiagnosed pathology affecting the colon. Patients typically present with severe abdominal pain and inflammation caused by smooth muscle proliferation of the veins, leading to arterialization, stenosis, and potential occlusion. The etiology remains unclear, but it has been hypothesized that an arteriovenous connection may be associated with the pathology. This is the first reported case indicating such an association. This case additionally highlights the potential utility of endovascular treatment, as endovascular embolization is generally a less invasive alternative to surgical resection in the treatment of such vascular disorders.Case PresentationThis report describes a 24-year-old female patient with findings of colitis and an abnormal arteriovenous connection of the inferior mesenteric arterial and venous systems. Partial embolization of this arteriovenous connection temporarily improved the patient’s condition, but her symptoms ultimately returned due to the presence of multiple smaller feeder vessels not amenable to embolization, necessitating colonic resection for definitive treatment. Although prior reports have hypothesized that arterial pressurization of the veins may precipitate myointimal hyperplasia, to the authors’ knowledge, this is the first report of IMHMV with an associated abnormal arteriovenous connection.ConclusionsThis case illustrates the possibility of an association between an arteriovenous connection and IMHMV. This rare diagnosis should be considered in patients with a similar presentation of abdominal pain after common etiologies like IBD have been excluded.

Harnessing Therapeutic Potentials of Statins Using Nanofibrous Carriers.

Statins are a wide category of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor drugs extensively prescribed for hypercholesterolemia. In fact, many studies showed beneficial effects of these agents on a variety of related illnesses, which include increased atherosclerotic plaque stability, decreased proliferation of vascular smooth muscle, platelet aggregation, the dampening of vascular inflammation, and also anabolic effects on bone tissue. Therefore, these drugs are considered as pleiotropic agents having different clinical applications other than those for which they were initially developed. Controlled drug delivery is an efficient way of delivery in tissue engineering. Amongst different controlled release formulations, nanofibers are a novel, alternative, widely used agent because of their unique properties. These include their sustained release of drug, a high drug-loading capacity, flexible shapes with a high surface-to-volume ratio, and superior porosity. Electrospinning is an economic and a simple method employed to produce nanofibers. In this report, studies related to statin nanofiber applications have been reviewed and their results have been summarized. Four different applications of statin nanofibers have been reported, including bone generation, endothelial stenosis and thrombosis, peripheral nerve injury, and anti-inflammatory action. Studies carried out both in vitro and in vivo showed effectiveness of statins in bone healing, aneurysm, and the healing of sciatic nerve injury. In addition, statins showed apoptosis effects and anti-inflammatory effects, with dose-dependent reduction of IL-6 and dose-independent reduction of TNF-α. Despite these promising results, validation via clinical trials is yet to be performed. The scope of statins in their pleiotropic range of actions is still not completely explored, and studies are still needed to enlighten different useful aspects of such drugs.

A case of incidental pulmonary benign metastasizing leiomyoma

Benign metastasizing leiomyoma is exceedingly rare. Pulmonary benign metastasizing leiomyoma is defined as the metastasis of leiomyoma to the lung tissue. It has a benign histological character, but the presence of metastasis is contradictory. First reported in 1937, it is generally seen among women of young reproductive age and premenopausal women who have undergone uterine leiomyoma or hysterectomy, and the most common site of metastasis is the lung. The prognosis is generally very favorable, and it rarely undergoes a malignant transformation. However, various studies suggest that pulmonary and pleural leiomyoma may cause acute respiratory failure. Radiological findings have a wide spectrum ranging from primary malignant neoplasms to metastatic diseases. Benign metastasizing leiomyoma is usually incidentally found on chest x-rays, and it appears as nodules arising from the benign proliferation of smooth muscles. Here, we present a 46-year-old patient who had a hysterectomy 15 years ago due to uterine leiomyoma and was recently diagnosed with benign leiomyoma which metastasized to the lung. It should be kept in mind that benign leiomyomas with pulmonary metastasis may rarely undergo malignant transformation.

Gastric Adenomyoma: Salient Imitator

Abstract Introduction/Objective Gastric adenomyoma is a lesion characterized by proliferation of epithelium and smooth muscle in the stomach or small bowel. By ultrasound, gastric adenomyoma usually appears as a submucosal nodule with a cystic center. They can mimic many benign and malignant conditions and are an important differential diagnosis to consider in fine needle aspiration of submucosal upper gastrointestinal lesions. Methods/Case Report We present a 30-year-old male who presented with abdominal pain, dyspepsia, and heartburn. Esophagogastroduodenoscopy demonstrated a 10 mm well-circumscribed hypoechoic mass in the antral submucosa along the greater curvature of the stomach. Two years later, the lesion was 18.6 mm in greatest dimension and fine needle aspiration was performed. Cell block showed foci of benign gastric glands and bland smooth muscle tissue, positive for smooth muscle actin and desmin, and negative for CD34 and c-kit (CD117). Gastrointestinal stromal tumor was the main differential diagnosis and adenomyosis was not considered, thus, the biopsy was thought to represent normal gastric wall, and the glands were dismissed as contaminant from the aspiration. A subsequent ultrasound two years later again demonstrated the lesion, now 21.5 mm in greatest dimension, and definitive resection was performed. Histologic examination showed a segment of stomach with gastric antral-type mucosa and an underlying mass forming lesion consisting of scattered gastric type glands admixed with smooth muscle bundles, consistent with gastric adenomyoma. The glands were completely surrounded by smooth muscle and lamina propria. Our patient has been asyptomatic one year since resection of the gastric adenomyoma. Results (if a Case Study enter NA) NA Conclusion Gastric adenomyoma is an important differential of intramural spindle cell neoplasms of the gastrointestinal tract alongside many benign and malignant conditions. Consideration of gastric adenomyoma at the time of the original biopsy would have spared the patient uncertainty regarding their prognosis and allowed for definitive resection two years earlier.

CircSOD2: A Novel Regulator for Smooth Muscle Proliferation and Neointima Formation.

Vascular smooth muscle cell (SMC) proliferation contributes to neointima formation following vascular injury. Circular RNA-a novel type of noncoding RNA with closed-loop structure-exhibits cell- and tissue-specific expression patterns. However, the role of circular RNA in SMC proliferation and neointima formation is largely unknown. The objective of this study is to investigate the role and mechanism of circSOD2 in SMC proliferation and neointima formation. Approach and Results: Circular RNA profiling of human aortic SMCs revealed that PDGF (platelet-derived growth factor)-BB up- and downregulated numerous circular RNAs. Among them, circSOD2, derived from back-splicing event of SOD2 (superoxide dismutase 2), was significantly enriched. Knockdown of circSOD2 by short hairpin RNA blocked PDGF-BB-induced SMC proliferation. Inversely, circSOD2 ectopic expression promoted SMC proliferation. Mechanistically, circSOD2 acted as a sponge for miR-206, leading to upregulation of NOTCH3 (notch receptor 3) and NOTCH3 signaling, which regulates cyclin D1 and CDK (cyclin-dependent kinase) 4/6. In vivo studies showed that circSOD2 was induced in neointima SMCs in balloon-injured rat carotid arteries. Importantly, knockdown of circSOD2 attenuated injury-induced neointima formation along with decreased neointimal SMC proliferation. CircSOD2 is a novel regulator mediating SMC proliferation and neointima formation following vascular injury. Therefore, circSOD2 could be a potential therapeutic target for inhibiting the development of proliferative vascular diseases.

Exploring the mechanism of Danggui Buxue Decoction in regulating atherosclerotic disease network based on integrated pharmacological methods.

Objective: To explore the mechanism of Danggui Buxue Decoction (DGBXD) in regulating Atherosclerosis (AS) network based on integrated pharmacological methods.Methods: The active ingredients and targets of DGBXD are obtained from TCMSP database and ETCM. AS-related targets were collected from the Genecards and OMIM databases. The drug–disease protein interaction (PPI) networks were constructed by Cytoscape. Meanwhile, it was used to screen out densely interacting regions, namely clusters. Finally, Gene Ontology (GO) annotations are performed on the targets and genes in the cluster to obtain biological processes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations are performed on the targets of the PPI network to obtain signaling pathways.Results: A total of 212 known targets, 265 potential targets and 229 AS genes were obtained. The ‘DGBXD known-AS PPI network’ and ‘DGBXD-AS PPI Network’ were constructed and analyzed. DGBXD can regulate inflammation, platelet activation, endothelial cell apoptosis, oxidative stress, lipid metabolism, vascular smooth muscle proliferation, angiogenesis, TNF, HIF-1, FoxO signaling pathway, etc. The experimental data showed that compared with the model group, the expressions of ICAM-1, VCAM-1, and interleukin (IL)-1β protein and mRNA in the DGBXD group decreased (P<0.05). However, plasma IL-1β, TNF-α, and MCP-1 in the DGBXD group were not significantly different from the model group (P>0.05).Conclusion: The mechanism of DGBXD in the treatment of AS may be related to the improvement of extracellular matrix (ECM) deposition in the blood vessel wall and the anti-vascular local inflammatory response, which may provide a reference for the study of the mechanism of DGBXD.

S2967 Small Bowel Intussusception Due to Hamartomatous Polyp Related to Peutz-Jeghers Syndrome

Introduction: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant syndrome manifested by multiple hamartomatous polyps, predominantly present in the gastrointestinal tract, and mucocutaneous pigmentation changes. Cumulative lifetime risk of intussusception in patients with PJS has been reported to be as high as 69% with 80% of the cases presenting as an acute abdomen. The median size of polyps causing intussusception is 3.5 cm. We present a case of small bowel intussusception attributed to hamartomatous polyps. Case Description/Methods: A 39-year-old male with a history of PJS and prior small bowel resection due to obstruction, presented with abdominal pain and multiple episodes of hematochezia. His hemoglobin on arrival was 6.5 g/dL, however remained hemodynamically stable with blood transfusion. CT of the abdomen and pelvis with contrast revealed a new small bowel (SB) intussusception measuring 7 cm with the intussuscipiens measuring 3.7cm [Fig. A,B]. Since the patient remained clinically stable, an enteroscopy was performed to identify the site of intussusception with possible endoscopic reduction. Multiple large small bowel polyps were identified, the largest measuring 5 cm in the jejunum, 50 cm distal to the site of anastomosis and likely lead point of the intussusception [Fig C.]. A repeat enteroscopy was performed with piecemeal resection of the large jejunal polyp with hot snare and clip placement [Fig. D]. The patient’s hematochezia and abdominal pain resolved. He was discharged with planned staged resection of remaining large SB polyps and surveillance colonoscopy. Histology of the polyps showed proliferation of smooth muscle into the lamina propria in branching pattern and normal intestinal epithelium consistent with Peutz-Jeghers hamartomatous polyp [Figure E]. Discussion: Peutz-Jeghers syndrome is associated with increased risk of both gastrointestinal and non-gastrointestinal malignancy including, but not limited to, colon, pancreas, breast, lung, and ovarian cancer. Gastrointestinal complications are related to polyps and include anemia from bleeding, intussusception, obstruction and infarction. Timely recognition and treatment is important as the complications can be fatal. Fortunately with advancements in small bowel endoscopy, these complications can be prevented and managed by endoscopic surveillance and polypectomy, reducing the need for urgent surgical intervention.Figure 1.: A. Transverse view of small bowel intussusception B. Sagittal view of small bowel intussusception C. Endoscopic view of large pedunculated polyp D. Prior site of piecemeal resected polyp with subsequent placement of clips E. Histology slide of resected polyp confirming hamartomatous polyp.

Network Pharmacology-Based Exploration of the Mechanism of Guanxinning Tablet for the Treatment of Stable Coronary Artery Disease

Objective: Network pharmacology was utilized to explore the mechanism of Guanxinning (GXN) tablet for the treatment of stable coronary artery disease (SCAD). Materials and Methods: First, active ingredients and therapeutic targets were predicted by databases and gene chip. Then, we constructed the compound-target (C-T) network and target-disease (T-D) network to screen hub compounds and therapeutic targets based on contribution index (CI), degree, closeness, betweenness, and coreness in the networks. Enrichment analysis was performed on hub therapeutic targets, and finally, the verification of hub ingredients and hub therapeutic targets was performed through molecular docking. Results: With “oral bioavailability ≥30%, druglikeness ≥0.18, and half-life ≥4 h” as screening conditions, 58 active ingredients were obtained. Seven hundred and seventeen compound targets and 636 SCAD targets were retrieved using databases and gene chip, and the intersection of both (139 targets) was defined as therapeutic targets. According to CI, degree, betweenness, closeness, and coreness, 2 hub compounds and 13 hub therapeutic targets were chosen from the C-T network and T-D network, respectively. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that GXN treated SCAD from several aspects including inflammatory reaction, oxidative stress, nutritional metabolism, blood pressure regulation, ventricular remodeling, vascular smooth muscle proliferation, angiogenesis, and platelet aggregation. Tissue enrichment analysis revealed that the therapeutic targets were enriched in multiple organs and tissues. The excellent binding force between the hub compounds and hub therapeutic targets was verified by molecular docking. Conclusions: The treatment of SCAD by GXN has the characteristics of multiple ingredients, multiple targets, and multiple approaches. Consequently, it may theoretically treat SCAD from multiple angles and levels.

The Role and Molecular Mechanism of P2Y12 Receptors in the Pathogenesis of Atherosclerotic Cardiovascular Diseases

The P2Y receptor family is a class of G protein-coupled receptors activated primarily by adenosine triphosphate (ATP), adenosine diphosphate (ADP), uridine triphosphate (UTP) and uridine diphosphate (UDP). The P2Y12 receptor is expressed on platelets which mediates platelet aggregation and morphological changes. At the same time, during the process of vascular remodeling and atherosclerosis, ADP can also promote the migration and proliferation of vascular smooth muscle and endothelial cells through P2Y12 receptor activating. Furthermore, P2Y12 is involved in many signal transductions processes, such as intimal hyperplasia, monocyte infiltration and so on, which play an important role in immune inflammation and brain injury. In order to solve the diseases induced by P2Y12 receptor, inhibitors such as ticagrelor, clopidogrel were widely used for cardiovascular diseases. However, there were some problems, such as limited antithrombotic effect, remain unsolved. This article summarizes the role and molecular mechanism of P2Y12 receptors in the pathogenesis of cardiovascular-related diseases, providing in-depth expounding on the molecular mechanism of P2Y12 receptor inhibitors and contributing to the treatment of diseases based on P2Y12 receptors.

G protein-coupled receptor kinase 2 is essential to enable vasoconstrictor-mediated arterial smooth muscle proliferation

Hypertension is associated with increased production and circulation of vasoconstrictors, resulting in enhanced signalling through their cognate G protein-coupled receptors (GPCR). Prolonged vasoconstrictor GPCR signalling increases arterial contraction and stimulates signalling pathways that promote vascular smooth muscle cell (VSMC) proliferation, contributing to the development of atherosclerotic plaques, re-stenosis lesions and vascular remodelling. GPCR signalling through phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) promotes VSMC proliferation. In VSMC, G protein-coupled receptor kinase 2 (GRK2) is known to regulate numerous vasoconstrictor GPCRs and their downstream signalling pathways. As GRK2 is implicated in controlling various aspects of cellular growth, we examined whether GRK2 could affect VSMC proliferation. Using two indices of cell growth, we show that PI3K inhibition and depletion of GRK2 expression produced a similar ablation of pro-proliferative vasoconstrictor-stimulated VSMC growth. Furthermore, GRK2-knockdown ablated the sustained phase of endothelin-1 and angiotensin-II-stimulated Akt phosphorylation, whilst the peak (5 min) phase was unaffected. Conversely, the GRK2 inhibitor compound 101 did not affect vasoconstrictor-driven Akt phosphorylation. Vasoconstrictor-stimulated phosphorylation of the Akt substrates GSK3α and GSK3β was ablated following RNAi-mediated GRK2 depletion, or after PI3K inhibition. Moreover, GRK2 knockdown prevented endothelin-1 and angiotensin-II from increasing cyclin D1 expression.These data suggest GRK2 expression is essential to facilitate vasoconstrictor-driven VSMC proliferation through its ability to promote efficient prolonged PI3K-Akt signalling, and thus relieve the GSK3-mediated block on cell cycling. Considering VSMC GRK2 expression increases early in the development of hypertension, this highlights the potential for GRK2 to promote VSMC growth and exacerbate hypertensive pathophysiological vascular remodelling.

Treatment of In-Stent Stenosis Following Flow Diversion of Intracranial Aneurysms with Cilostazol and Clopidogrel

In-stent stenosis is a feared complication of flow diversion treatment for cerebral aneurysms. We present 2 cases of patients treated with pipeline flow diversion for unruptured cerebral aneurysms. Initial perioperative dual antiplatelet therapy (DAPT) consisted of standard aspirin plus clopidogrel. At 6-month follow-up cerebral angiography, the patients were noted to have developed significant in-stent stenosis (63% and 53%). The patients were treated with cilostazol and clopidogrel for at least 6 months. Subsequent angiography at 1-year post-treatment showed significant improvement of the in-stent stenosis from 63% to 34% and 53% to 21%. The role of cilostazol as treatment of intracranial in-stent stenosis has not been previously described. Cilostazol’s vasodilatory effect and suppression of vascular smooth muscle proliferation provides ideal benefits in this setting. Cilostazol plus clopidogrel may be a safe and effective alternative to standard DAPT for treatment of in-stent stenosis following flow diversion and warrants further consideration and investigation.

Role of Lipid Accumulation and Inflammation in Atherosclerosis: Focus on Molecular and Cellular Mechanisms.

Atherosclerosis is a chronic lipid-driven and maladaptive inflammatory disease of arterial intima. It is characterized by the dysfunction of lipid homeostasis and signaling pathways that control the inflammation. This article reviews the role of inflammation and lipid accumulation, especially low-density lipoprotein (LDL), in the pathogenesis of atherosclerosis, with more emphasis on cellular mechanisms. Furthermore, this review will briefly highlight the role of medicinal plants, long non-coding RNA (lncRNA), and microRNAs in the pathophysiology, treatment, and prevention of atherosclerosis. Lipid homeostasis at various levels, including receptor-mediated uptake, synthesis, storage, metabolism, efflux, and its impairments are important for the development of atherosclerosis. The major source of cholesterol and lipid accumulation in the arterial wall is proatherogenic modified low-density lipoprotein (mLDL). Modified lipoproteins, such as oxidized low-density lipoprotein (ox-LDL) and LDL binding with proteoglycans of the extracellular matrix in the intima of blood vessels, cause aggregation of lipoprotein particles, endothelial damage, leukocyte recruitment, foam cell formation, and inflammation. Inflammation is the key contributor to atherosclerosis and participates in all phases of atherosclerosis. Also, several studies have shown that microRNAs and lncRNAs have appeared as key regulators of several physiological and pathophysiological processes in atherosclerosis, including regulation of HDL biogenesis, cholesterol efflux, lipid metabolism, regulating of smooth muscle proliferation, and controlling of inflammation. Thus, both lipid homeostasis and the inflammatory immune response are closely linked, and their cellular and molecular pathways interact with each other.

Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA GUIDELINE PART I-Initial Work-up and Medical Management.

Benign prostatic hyperplasia (BPH) is a histologic diagnosis describing proliferation of smooth muscle and epithelial cells within the prostatic transition zone. The prevalence and severity of lower urinary tract symptoms (LUTS) in aging men are progressive and impact the health and welfare of society. This revised Guideline provides a useful reference on effective evidence-based management of male LUTS/BPH. See the accompanying algorithm for a summary of the procedures detailed in the Guideline (figures 1 and 2[Figure: see text][Figure: see text]). The Minnesota Evidence Review Team searched Ovid MEDLINE, Embase, Cochrane Library, and AHRQ databases to identify eligible English language studies published between January 2008 and April 2019, then updated through December 2020. Search terms included Medical Subject Headings (MeSH) and keywords for pharmacological therapies, drug classes, and terms related to LUTS or BPH. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, information is provided as Clinical Principles and Expert Opinions (table 1[Table: see text]). Nineteen guideline statements pertinent to evaluation, work-up, and medical management were developed. Appropriate levels of evidence and supporting text were created to direct both primary care and urologic providers towards streamlined and suitable practices. The work up and medical management of BPH requires attention to individual patient characteristics, while also respecting common principles. Clinicians should adhere to recommendations and familiarize themselves with standards of BPH management.