Chronic hypoxia is the most common cause of secondary pulmonary hypertension, for which the mechanisms are still unclear. Recent studies implicated an important role for microRNAs (miRNAs) in ...hypoxia-mediated responses in various cellular processes, including cell apoptosis and proliferation. Therefore, we hypothesized that these regulatory molecules might be implicated in the etiology of hypoxic pulmonary hypertension. Here we show that miRNA-328, a posttranscriptional regulator, was drastically downregulated in the pulmonary artery (PA) after a hypoxic assault. PA rings, Western blot, quantitative real-time PCR, in situ hybridization, and luciferase assay were used to investigate the role of miRNA-328 in hypoxic pulmonary hypertension. We found that hypoxia produced a significant inhibition of miRNA-328 expression, which was involved in PA vasoconstriction and remodeling. Overexpressing miRNA-328 in the transgenic mice remarkably decreased the right ventricular systolic pressure and PA wall thickness under both normoxia and hypoxia. MiRNA-328 inhibited L-type calcium channel-α1C expression through a miRNA-328 binding site within the 3' untranslational region of L-type calcium channel-α1C. The L-type calcium channel-α1C inhibition attenuated the PA response to KCl. Furthermore, miRNA-328 suppressed the insulin growth factor 1 receptor, ultimately leading to apoptosis of pulmonary arterial smooth muscle cells. The posttranscriptional repression of L-type calcium channel-α1C and insulin growth factor 1 receptor was further confirmed by luciferase reporter assay. These results showed that miRNA-328, an important protecting factor, plays a significant role in PA constriction and remodeling by regulating multiple gene targets in hypoxic pulmonary hypertension.
Background: Tanshinone IIA inhibits the proliferation of pulmonary artery smooth muscle cells (PASMCs), but the potential mechanisms of its effects on PASMCs apoptosis remain unclear. Methods: Rat ...were subjected to hypoxia for 9 days with or without Tanshinone IIA treatment. PASMCs were exposed to the conditions of 2% O2 and 93% N2 for 24 h in vitro. Hematoxylin and eosin (HE) staining was used to evaluate vascular remodeling. The Cell viability was determined using cell fluorescence staining and MTT assays, and apoptosis was assessed using flow cytometry. Protein expression was quantified by Western blotting. Results: Our results showed that Tanshinone IIA treatment reduced pulmonary artery media thickening in hypoxic rats. Tanshinone IIA reduced PASMC viability in a dose-dependent manner. Additionally, Tanshinone IIA promoted PASMC apoptosis, lowered Hsp60 levels, and upregulated caspase-3 expressions under hypoxic conditions. This pro-apoptotic effect of Tanshinone IIA might be due to the reduction of the phosphorylation of JAK2/STAT3 signaling markers and the increase in the levels of the downstream target, Cx43 in PASMCs. Conclusion: These data suggest that Tanshinone IIA promotes PASMC apoptosis during hypoxia and reverses vascular remodeling. This effect is mediated by modulating the expression of Hsp60, caspase-3, and Cx43 via the JAK2/STAT3 signaling pathway. These results might provide a new therapeutic target to explore a novel strategy for hypoxia-induced vessel remodeling.
Previous studies revealed that consuming spicy food reduced mortality from CVD and lowered stroke risk. However, no studies reported the relationship between spicy food consumption, stroke types and ...dose–response. This study aimed to further explore the association between the frequency of spicy food intake and the risk of stroke in a large prospective cohort study. In this study, 50 174 participants aged 30–79 years were recruited. Spicy food consumption data were collected via a baseline survey questionnaire. Outcomes were incidence of any stroke, ischaemic stroke (IS) and haemorrhagic stroke (HS). Multivariable-adjusted Cox proportional hazard models estimated the association between the consumption of spicy food and incident stroke. Restricted cubic spline analysis was used to examine the dose–response relationship. During the median 10·7-year follow-up, 3967 strokes were recorded, including 3494 IS and 516 HS. Compared with those who never/rarely consumed spicy food, those who consumed spicy food monthly, 1–2 d/week and 3–5 d/week had hazard ratio (HR) of 0·914 (95 % CI 0·841, 0·995), 0·869 (95 % CI 0·758, 0·995) and 0·826 (95 % CI 0·714, 0·956) for overall stroke, respectively. For IS, the corresponding HR) were 0·909 (95 % CI 0·832, 0·994), 0·831 (95 % CI 0·718, 0·962) and 0·813 (95 % CI 0·696, 0·951), respectively. This protective effect showed a U-shaped dose–response relationship. For obese participants, consuming spicy food ≥ 3 d/week was negatively associated with the risk of IS. We found the consumption of spicy food was negatively associated with the risk of IS and had a U-shaped dose–response relationship with risk of IS. Individuals who consumed spicy food 3–5 d/week had a significantly lowest risk of IS.
•Hirsutine shows promise for a novel pharmacotherapy of thrombocytopenia.•The MEK/ERK/FOG-1/TAL-1 signaling pathway plays a vital role in the pathogenesis and treatment of thrombocytopenia.•Targeting ...MEK underlies the regulatory mechanism of hirsutine in megakaryocyte development and platelet production.
Thrombocytopenia (TP) remains a challenge in clinical hematology. TP may have serious consequences, such as recurrent skin and mucosal bleeding and increased risk of intracranial and internal organ hemorrhage. However, effective and safe therapeutic drugs for the long-term management of TP are still lacking.
This study aimed to identify more effective active compounds for TP therapy.
Liquid chromatography-mass spectrometry-nuclear magnetic resonance analysis was used to confirm the medicinal species and chemical structure of Hirsutine (HS). The proliferation of HS was examined by Cell Counting Kit (CCK-8) assay on cells lines. The effect of HS on megakaryocyte differentiation was analyzed by evaluating the expression of CD41, CD42b, and DNA ploidy via flow cytometry (FCM). The morphology of megakaryocytes and intermediate cells was observed using an optical microscope. K562 cells were then stained with Giemsa and benzidine. qRT-PCR was used to examine the mRNA expression of GATA-1, GATA-2, FOG-1, TAL-1, RUNX-1, NF-E2, and KLF-1 in K562 cells. Protein levels of the transcription factors were analyzed by western blotting. An MEK inhibitor was used to verify the relationship between the MEK/ERK signaling pathway and CD41/CD42b (FCM), FOG-1, and TAL-1. The Kunming thrombocytopenia mouse model was established by X-ray irradiation (4 Gy) and used to test HS activity and related hematopoietic organ index in vivo. Finally, computer simulations of molecular docking were used to predict the binding energies between HS-MEK and HS-ERK.
We preliminarily identified HS by screening a plant-sourced compound library for natural compounds with megakaryocytic differentiation and maturation (MKD/MKM)-promoting activity. We found that HS not only enhanced MKD/MKM of K562 and Meg01 cells, but also suppressed the decline of peripheral platelet levels in X-ray-induced myelosuppressive mice. In addition, HS promoted MKD via activation of MEK-ERK-FOG1/TAL1 signaling, which may be the key molecular mechanism of HS action in TP treatment. Molecular docking simulations further verified that HS targets the signaling protein MEK with high-affinity.
In this study, we report for the first time that hirsutine boosts MKD/MKM through the MEK/ERK/FOG1/TAL1 signaling pathway and thus represents a promising treatment option for TP.
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Despite the well-recognised health benefits of fresh fruit consumption, substantial uncertainties remain about its potential effects on incident diabetes and, among those with diabetes, on risks of ...death and major vascular complications.
Between June 2004 and July 2008, the nationwide China Kadoorie Biobank study recruited 0.5 million adults aged 30-79 (mean 51) y from ten diverse localities across China. During ~7 y of follow-up, 9,504 new diabetes cases were recorded among 482,591 participants without prevalent (previously diagnosed or screen-detected) diabetes at baseline, with an overall incidence rate of 2.8 per 1,000 person-years. Among 30,300 (5.9%) participants who had diabetes at baseline, 3,389 deaths occurred (overall mortality rate 16.5 per 1,000), along with 9,746 cases of macrovascular disease and 1,345 cases of microvascular disease. Cox regression yielded adjusted hazard ratios (HRs) associating each disease outcome with self-reported fresh fruit consumption, adjusting for potential confounders such as age, sex, region, socio-economic status, other lifestyle factors, body mass index, and family history of diabetes. Overall, 18.8% of participants reported consuming fresh fruit daily, and 6.4% never/rarely (non-consumers), with the proportion of non-consumers about three times higher in individuals with previously diagnosed diabetes (18.9%) than in those with screen-detected diabetes (6.7%) or no diabetes (6.0%). Among those without diabetes at baseline, higher fruit consumption was associated with significantly lower risk of developing diabetes (adjusted HR = 0.88 95% CI 0.83-0.93 for daily versus non-consumers, p < 0.001, corresponding to a 0.2% difference in 5-y absolute risk), with a clear dose-response relationship. Among those with baseline diabetes, higher fruit consumption was associated with lower risks of all-cause mortality (adjusted HR = 0.83 95% CI 0.74-0.93 per 100 g/d) and microvascular (0.72 0.61-0.87) and macrovascular (0.87 0.82-0.93) complications (p < 0.001), with similar HRs in individuals with previously diagnosed and screen-detected diabetes; estimated differences in 5-y absolute risk between daily and non-consumers were 1.9%, 1.1%, and 5.4%, respectively. The main limitation of this study was that, owing to its observational nature, we could not fully exclude the effects of residual confounding.
In this large epidemiological study in Chinese adults, higher fresh fruit consumption was associated with significantly lower risk of diabetes and, among diabetic individuals, lower risks of death and development of major vascular complications.
Worldwide 350 million people suffer from major depression, with the majority of cases occurring in low- and middle-income countries. We examined the patterns, correlates and care-seeking behaviour of ...adults suffering from major depressive episode (MDE) in China.
A nationwide study recruited 512 891 adults aged 30-79 years from 10 provinces across China during 2004-2008. The 12-month prevalence of MDE was assessed by the Modified Composite International Diagnostic Interview-short form. Logistic regression yielded adjusted odds ratios (ORs) of MDE associated with socio-economic, lifestyle and health-related factors and major stressful life events.
Overall, 0.7% of participants had MDE and a further 2.4% had major depressive symptoms. Stressful life events were strongly associated with MDE adjusted OR 14.7, 95% confidence interval (CI) 13.7-15.7, with a dose-response relationship with the number of such events experienced. Family conflict had the highest OR for MDE (18.9, 95% CI 16.8-21.2) among the 10 stressful life events. The risk of MDE was also positively associated with rural residency (OR 1.5, 95% CI 1.4-1.7), low income (OR 2.3, 95% CI 2.1-2.4), living alone (OR 2.6, 95% CI 2.3-3.0), smoking (OR 1.4, 95% CI 1.3-1.6) and certain other mental disorders (e.g. anxiety, phobia). Similar, albeit weaker, associations were observed with depressive symptoms. Among those with MDE, about 15% sought medical help or took psychiatric medication, 15% reported having suicidal ideation and 6% reported attempting suicide.
Among Chinese adults, the patterns and correlates of MDE were generally consistent with those observed in the West. The low rates of seeking professional help and treatment highlight the great gap in mental health services in China.
A20 is a zinc finger protein associated with hypoxia. As chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary artery, which are histological hallmarks of ...pulmonary artery hypertension, we intended to explore the role of A20 in angiogenesis of pulmonary artery endothelial cells (ECs). Here, we found a transient elevation of A20 expression in the lung tissues from hypoxic rats compared with normoxic controls. This rapid enhancement was mainly detected in the endothelium, and similar results were reproduced in vitro. During early hypoxia, genetic inhibition of A20 increased proliferation in pulmonary artery ECs, linking to advanced cell cycle progression as well as microtubule polymerization, and aggravated angiogenic effects including tube formation, cell migration and adhesion molecules expression. In addition, a negative feedback loop between nuclear factor‐kappa B and A20 was confirmed. Our findings provide evidence for an adaptive role of A20 against pulmonary artery ECs angiogenesis via nuclear factor‐kappa B activation.
Current experimental and epidemiological studies provide inconsistent evidence toward the association between tea consumption and cancer incidence. We investigated whether tea consumption was ...associated with the incidence of all cancers and six leading types of cancer (lung cancer, stomach cancer, colorectal cancer, liver cancer, female breast cancer and cervix uteri cancer) among 455,981 participants aged 30–79 years in the prospective cohort China Kadoorie Biobank. Tea consumption was assessed at baseline (2004–2008) with an interviewer-administered questionnaire. Cancer cases were identified by linkage to the national health insurance system. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In the present population, daily tea consumers were more likely to be current smokers and daily alcohol consumers. 22,652 incident cancers occurred during 10.1 years follow-up (5.04 cases/1000 person-years). When we restricted analyses to non-smokers and non-excessive alcohol consumers to minimize confounding, tea consumption was not associated with all cancers (daily consumers who added tea leaves > 4.0 g/day vs. less-than-weekly consumers: HR, 1.03; 95% CI, 0.93–1.13), lung cancer (HR, 1.08; CI, 0.84–1.40), colorectal cancer (HR, 1.08; CI, 0.81–1.45) and liver cancer (HR, 1.08; CI, 0.75–1.55), yet might be associated with increased risk of stomach cancer (HR, 1.46; CI, 1.07–1.99). In both less-than-daily and daily tea consumers, all cancer risk increased with the amount of tobacco smoked or alcohol consumed. Our findings suggest tea consumption may not provide preventive effect against cancer incidence.
•15-LO-1 activation is required for the survival in liver carcinoma cells.•The promotive effects of hypoxia on HCC cells are mediated by 15-LO-1/15-HETE.•The anti-apoptotic effects of 15-HETE are ...mediated by PI3K/Akt/Hsp90 in HCC cells.•15-HETE promoted the migration and invasion of HCC cells via PI3K/Akt/Hsp90.•15-HETE stimulates Akt interation with Hsp90 in HCC cells.
Hepatocellular carcinoma is a typical hypervascular tumor resulted from excessive growth of tumor cells. Previous studies have demonstrated that the lipoxygenase is considered as a potential therapeutic target and have important influence on human cancers. However, whether the 15-lipoxygenase-1 (15-LO-1)/15-hydroxyeicosatetraenoic acid (15-HETE) pathway participates in the development and progression of hepatocellular carcinoma has not been reported until now. To test the hypothesis that the 15-LO-1/15-HETE signaling regulates hepatocellular carcinoma cells growth and metastasis via the phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt)/heat shock protein 90 pathway, we performed these studies. Our results showed that hepatocellular carcinoma cell lines (HepG2 and SMMC7721) apoptosis and growth arrest occurred following blockade of the 15-LO pathway with a 15-LO-1 inhibitor or siRNA, and all the effects were reversed by exogenous 15-HETE. Meanwhile, 15-HETE strengthened the expression of phosphor-Akt and heat shock protein 90, and inhibited apoptosis induced by serum deprivation via promoting the interaction of Akt with heat shock protein 90. In addition, the invasion and migration of HepG2 enhanced by 15-HETE were both attenuated by the inhibitor of Akt or heat shock protein 90. These results indicate that the 15-LO-1/15-HETE pathway prevents hepatocellular carcinoma cells from apoptosis and promotes hepatocellular carcinoma progression via a specific intracellular signaling pathway centered by the interaction of Akt with heat shock protein 90, and suggest a new therapeutic target for hepatocellular carcinoma.
Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right ...heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.
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