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This study aimed to investigate the link between the inhibitory effect of ginsenoside Rg3 on the ectopic endometrium growth and the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, a mechanism known to inhibit angiogenesis and induce ectopic endometrial cell apoptosis. A model of endometriosis was established by allotransplantation in rats. The rats were randomly divided into 5 groups: the ginsenoside Rg3 low-dose group (group A,5mg/kgBW/d of ginsenoside Rg3), the ginsenoside Rg3 high-dose group (group B, 10mg/kgBW/d of ginsenoside Rg3), the gestrinone group (group C, 0.5mg/kgBW/d of gestrinone), the control group (groupD, 10ml/kg BW/d of 0.5%CMC-Na) and the ovariectomized group (group E, 10ml/kgBW/d of 0.5%CMC-Na). Rats were executed after 21 days of continuous administration. The ectopic endometrium volume was measured and the inhibitory rate was calculated. The levels of serum estradiol (E2) and progesterone (P) were detected by Electro-Chemiluminescence Immunoassay (ECLI). The protein expressionof VEGF, VEGFR-2, p-Akt, and p-mTOR inthe ectopic endometrium wastested by immunohistochemistry(IHC) and Western Blotting. The mRNA expression levels of VEGF, VEGFR-2, Akt, and mTOR were tested by Real-Time Polymerase Chain Reaction (PCR). The apoptosis rate of the ectopic endometrial cells was detected by Terminal Deoxynucleotidyl Transferase-mediated Digoxigenin-dUTP Nick-End Labeling Assay(TUNEL). Tissue measurements revealed a dose-dependent inhibition effect of ginsenoside Rg3 on the growth of the ectopic endometrium in treated rats compared to controls. Immunohistochemical and Western Blotting assays confirmed that the expression of VEGF, p-Akt, and p-mTOR was down-regulated in ginsenoside Rg3 -treated lesions. Real-time PCR results also showed that the mRNA expression levels of VEGF, Akt, and mTOR in the ectopic endometrium were reduced. The present study demonstrates, for the first time, that ginsenoside Rg3 suppresses angiogenesis in developing endometrial lesions. The ginsenoside Rg3 inhibitory effect on the growth of the ectopic endometrium in EMs rats might occur through the blocking of the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway, thus halting angiogenesis and promoting the apoptosis of ectopic endometrial cells.

Hypertension is the most common cause of pathological left ventricular hypertrophy, a condition causally associated with debilitating heart failure and cardiovascular events in hypertensive patients. It is well recognized that the disease burden of hypertension-linked heart failure remains unabated with existing treatments. New therapies controlling hypertensive left ventricular hypertrophy are thus required to decelerate or prevent the development of heart failure. Our previous study has demonstrated that cinnamic acid, a naturally occurring monocarboxylic acid, mitigates transverse aortic constriction-induced pressure overload-mediated cardiac hypertrophy. However, whether cinnamic acid is effective at controlling hypertensive left ventricular hypertrophy remains unknown. Angiotensin II (ang II) plays a pivotal role in driving the pathogenesis of hypertensive left ventricular hypertrophy. The current work thus investigates the therapeutic potential and pharmacological mechanisms of cinnamic acid in the context of ang II-mediated hypertensive left ventricular hypertrophy. Ang II-infused mice and cardiomyocytes were analyzed by histological, immunohistochemical, cellular and molecular biological methods to delineate the impact of cinnamic acid on hypertensive left ventricular hypertrophy. The results showed that cinnamic acid lowered blood pressure and attenuated left ventricular hypertrophic and fibrotic alterations in the ang II-infused mice. Cinnamic acid counteracted hypertrophic responses, impairment of the mitochondrial function and overproduction of mitochondrial reactive oxygen species (ROS) in the cardiomyocytes exposed to ang II. At the molecular level, cinnamic acid mitigated ang II-induced activation of signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiomyocytes. Additionally, cinnamic acid blunted STAT3 and ERK1/2 activation as well as the hypertrophic responses in cardiomyocytes exposed to interleukin 6 (IL-6) as well. In summary, this is the first study demonstrating that cinnamic acid is effective at mitigating hypertensive left ventricular hypertrophy. Cinnamic acid antagonizes the vasopressor activity of ang II at the systemic level and the ligand-dependent pro-hypertrophic signaling of ang II in cardiomyocytes. Furthermore, our present study presents new evidence supporting that cinnamic acid lessens the activation of STAT3 and ERK1/2, which may in part contribute to its anti-hypertrophic actions in cardiomyocytes.

BackgroundGinsenoside Rb1 (Rb1) exerts pharmacological effects in attenuating the progression of atherosclerosis. However, whether the anti-atherosclerotic effects of Rb1 involve suppressing neutrophil extracellular traps (NETs)-induced endothelial activation and whether N6-methyadenosine (m6A) RNA modification is mechanistically implicated in this process remain unknown.MethodsHigh fat diet (HFD)-fed Apoe −/− mice were subjected to histological, immunohistological and molecular biological analyses. Moreover, NETs-induced endothelial activation and m6A RNA methylation were assessed in human aortic endothelial cells (HAECs).ResultsRb1 mitigated atherosclerotic lesions and endothelial activation in vivo . Rb1 diminished adhesion of neutrophils and monocytes to NETs-stimulated HAECs, offset NETs-upregulated endothelial expression of ICAM1 , VCAM1 , SELE and SELP , and counteracted NETs-induced endothelial barrier impairment in vitro . NETs exposure significantly decreased the level of m6A RNA methylation and increased the expression of demethylase fat mass and obesity-associated protein (FTO) in HAECs, whereas Rb1 treatment enhanced m6A RNA methylation and reduced FTO expression in the NETs-stimulated HAECs. Overexpression of FTO abrogated the protective effects of Rb1 against NETs-induced endothelial activation in HAECs. Furthermore, Fto overexpression in endothelial cells partially abolished Rb1-confered attenuation of atherosclerotic pathologies and the aortic expression of Vcam1 in HFD-fed Apoe −/− mice.ConclusionThe work here demonstrates that Rb1 mitigates atherosclerosis in part by suppressing NETs-induced endothelial activation. Mechanistically, the pharmacological effects of Rb1 in attenuating NETs-induced endothelial activation are in part mediated by modulating FTO-mediated m6A RNA demethylation in endothelial cells.

Under hyperglycemic conditions, impaired intestinal barrier integrity leads to heightened level of inflammation, playing important roles in driving diabetic complications. Emerging evidence supports the implications of neutrophil extracellular traps (NETs) in the pathogenesis of diabetes. However, whether NETs contribute to hyperglycemia-linked intestinal barrier impairment remains to be investigated. Moreover, baicalin, the major chemical component of Scutellaria baicalensis Georgi, is equipped with twofold intestinal protective and neutrophil suppressive activities. Yet, it is unclear if baicalin is effective at mitigating hyperglycemia-linked NETs-mediated intestinal barrier impairment. To directly address the mechanistic implications of NETs in hyperglycemia-linked intestinal epithelial barrier impairment, the impact of DNase I treatment or gene deficiency on intestinal epithelial integrity was first examined in the streptozotocin (STZ)-induced hyperglycemic mice . Next, the pharmacological impact of baicalin on NETs formation and intestinal epithelial barrier impairment was investigated in high glucose- and/or lipopolysaccharides (LPS)-stimulated neutrophils and in STZ-induced hyperglycemic mice , respectively. The experiments confirmed that high glucose and/or LPS induced NETs formation. NETs directly impaired the viability and tight junction of the intestinal epithelial cells. The histological and immunohistochemical examinations unveiled that along with impaired intestinal epithelial morphology, citrullinated histone H3 (H3Cit), a marker of NETs, and neutrophil specific Ly6G were readily detected in the intestinal epithelium in the hyperglycemic mice. Without affecting the presence of neutrophils, DNase I treatment or gene deficiency markedly mitigated intestinal NETs formation and improved the intestinal morphology in the hyperglycemic mice. Notably, baicalin suppressed NETs formation and inhibited histone H3 citrullination stimulated by high glucose, LPS or both . Furthermore, baicalin blunted NETs formation and partially preserved the integrity of the intestinal epithelium in the hyperglycemic mice . The current study sheds new light on the pathophysiological implications of NETs in intestinal epithelial barrier impairment under hyperglycemic conditions. Most importantly, the findings here demonstrate for the first time that baicalin directly inhibits NETs formation stimulated by high glucose and/or LPS, which may in part account for its pharmacological effects at protecting against hyperglycemia-linked intestinal epithelial barrier impairment.

Background Photoreceptor degeneration underpinned by oxidative stress-mediated mitochondrial dysfunction and cell death leads to progressive and irreversible vision impairment. Drug treatments that protect against photoreceptor degeneration are currently available in the clinical settings. It has been shown that hyperoside, a flavonol glycoside, protects against neuronal loss in part by suppressing oxidative stress and maintaining the functional integrity of mitochondria. However, whether hyperoside protects against photoreceptor degeneration remains unknown. Methods To address the pharmacological potentials of hyperoside against oxidative stress-mediated photoreceptor degeneration on molecular, cellular, structural and functional levels, multiple in vitro and in vivo methodologies were employed in the current study, including live-cell imaging, optical coherence tomography, electroretinography, histological/immunohistochemical examinations, transmission electron microscopy, RNA-sequencing and real-time qPCR. Results The in vitro results demonstrate that hyperoside suppresses oxidative stress-mediated photoreceptor cell death in part by mitigating mitochondrial dysfunction. The in vivo results reveal that hyperoside protects against photooxidative stress-induced photoreceptor morphological, functional and ultrastructural degeneration. Meanwhile, hyperoside treatment offsets the deleterious impact of photooxidative stress on multiple molecular pathways implicated in the pathogenesis of photoreceptor degeneration. Lastly, hyperoside attenuates photoreceptor degeneration-associated microglial inflammatory activation and reactive Müller cell gliosis. Conclusions All things considered, the present study demonstrates for the first time that hyperoside attenuates oxidative stress-induced photoreceptor mitochondrial dysfunction and cell death. The photoreceptor-intrinsic protective effects of hyperoside are corroborated by hyperoside-conferred protection against photooxidative stress-mediated photoreceptor degeneration and perturbation in retinal homeostasis, warranting further evaluation of hyperoside as a photoreceptor protective agent for the treatment of related photoreceptor degenerative diseases.

Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.

Obstructive sleep apnea (OSA) is much common and associated with worse clinical outcomes in patients with hypertrophic cardiomyopathy (HCM), however, the diagnosis of OSA in HCM is still insufficient. We aim to investigate the clinical predictors of OSA in a large series of patients with HCM. A total of 589 patients with HCM who underwent sleep evaluations were retrospectively enrolled. Data from clinical characteristics and polysomnography studies were recorded. OSA was present in 346 patients (58.7%). Patients who had OSA were older, more likely to be male and had more clinical comorbidities such as hypertension, atrial fibrillation and cardiac remodeling. Multivariate logistic analyses showed that male, age, body mass index, hypertension and left ventricular outflow tract obstruction were significant factors associated with OSA. The area under the ROC curve (AUC) was 0.78 (95% CI 0.74–0.82; P < 0.001). These factors were also able to identify moderate to severe OSA with an AUC of 0.77 (95% CI 0.73–0.81; P < 0.001). These findings suggest that identifying HCM patients with high risk for OSA is feasible using characteristics from clinical practices and clinicians should have no hesitate to conduct sleep test in these patients.

Background The impact of septal myectomy on the progression of ascending aortic (AAo) dilation in patients with obstructive hypertrophic cardiomyopathy (HOCM) remains uncertain. This study aimed to investigate the relationship between septal myectomy and AAo dilation in HOCM patients. Methods A total of 69 patients with HOCM were enrolled. All the participants underwent sequential cardiac magnetic resonance scans at a mean interval of 5.13 ± 2.04 years, with each scan being more than 3 years apart. Results At baseline, 17 patients with HOCM (25%) exhibited AAo dilation (Indexed AAo dimension > 19 mm/m²). Age (OR 1.10, 95%CI: 1.01–1.019, P  = 0.026) and female (OR 4.80, 95%CI: 1.05–21.93, P  = 0.043) were independently associated with AAo dilation. In patients who underwent myectomy, the AAo dimension at follow-up was similar to that at baseline (32.47 ± 4.70 mm vs. 32.81 ± 5.06 mm, P  = 0.197). Furthermore, the rate of AAo dilation was lower in patients with myectomy compared to those without myectomy (-0.06 ± 0.38 mm/year vs. 0.18 ± 0.43 mm/year, P  = 0.016). Additionally, moderate or severe mitral regurgitation was significantly associated with AAo dilation rate (B = 0.273, P  = 0.032). Conclusions Myectomy in patients with HOCM was associated with the absence of progression of AAo dilatation.

Atherosclerosis is the primary cause of cardiovascular diseases and stroke. The current study evaluated the interventional effects of a naturally occurring compound Notoginsenoside R1 (NR1) on atherosclerosis in ApoE-/- mice. The atherosclerotic lesion was significantly alleviated by NR1 treatment and this attenuation was marked by reduction in lipid deposition, fibrosis and oxidative stress. Increased serum levels of GSH and SOD and decreased level of MDH were observed in NR1-treated ApoE-/- mice. NR1 treatment also significantly decreased the levels of CHO, TG, ox-LDL and increased the level of HDL. Additionally, the levels of inflammatory cytokines including IL-2, IL-6, TNF-α and γ-IFN were markedly reduced in NR1-treated ApoE-/- mice. Furthermore, significantly increased aortic expression of miR-26a, miR-21, miR-126a, miR-132, miR-146 and miR-155 and decreased expression of miR-20a and miR-92a were observed in the vehicle-treated ApoE-/- mice. While NR1 treatment led to a significant reduction in the expression of miR-21, miR-26a, miR-126 and increased expression of miR-20a. Collectively, our results demonstrated for the first time the anti-atherosclerotic effects of NR1, which could be in part mediated through its multiple targeting effects on inflammation, oxidative stress, lipid metabolism and microRNA expression. These results therefore justify further evaluation of NR1 as a therapeutic agent treating atherosclerosis.

Background Myocardial bridging (MB) is common in patients with hypertrophic cardiomyopathy (HCM). There are sparse data on the impact of MB on myocardial fibrosis in HCM. This study was designed to evaluate the relationship between MB and myocardial fibrosis in patients with obstructive HCM. Methods In this cohort study, retrospective data were collected from a high-volume HCM center. Patients with obstructive HCM who underwent septal myectomy and preoperative cardiac magnetic resonance (CMR) were screened from 2011 to 2018. Results Finally, 492 patients were included in this study, with an average age of 45.7 years. Of these patients, 76 patients had MB. MB occurred mostly in the left anterior descending artery (73/76). The global extent of late gadolinium enhancement (LGE) was correlated with the degree of systolic compression ( r  = 0.33, p  = 0.003). Multivariable linear regression analysis revealed that the degree of systolic compression was an independent risk factor for LGE ( β  = 0.292, p  = 0.007). The LGE fraction of basal and mid anteroseptal segments in patients with severe MB (compression ratio ≥ 80%) was significantly greater than that in patients with mild to moderate MB (compression ratio < 80%). During a median follow-up of 28 (IQR: 15–52) months, 15 patients died. Kaplan–Meier analysis did not identify differences in all-cause death (log-rank p  = 0.63) or cardiovascular death (log-rank p  = 0.72) between patients undergoing MB-related surgery and those without MB. Conclusions MB with severe systolic compression was significantly associated with a high extent of fibrosis in patients with obstructive HCM. Concomitant myotomy or coronary artery bypass grafting might provide excellent survival similar to that of patients without MB. Identification of patients with severe MB and providing comprehensive management might help improve the prognosis of patients with HCM.