The effects of Olmesartan/amlodipine administered in the Morning or At Night on nocturnal blood pressure reduction in Chinese patients with mild-moderate essential hypertension (OMAN Trial): study protocol for a prospective, multicenter, randomized, open-label clinical trial {1}.

INTRODUCTION: Hypertension increases the risk of cardiovascular disease. Uncontrolled nocturnal blood pressure is prevalent in patients taking antihypertensive medication, with an incidence rate of 30-60%. Although chronotherapy with antihypertensive agents may provide a new direction for effective control of nocturnal blood pressure, the clinical evidence base remains controversial. This research is presently underway to compare the effects of morning and bedtime administration of antihypertensive medication on nocturnal reduction and circadian rhythm of blood pressure in patients with hypertension. METHODS AND ANALYSIS: This study is being performed as a randomized, multicenter, open-label, parallel-group, clinical trial in which 720 participants are to undergo 24-h ambulatory blood pressure measurement (ABPM) and office blood pressure measurement (OBPM) at baseline before being randomly assigned to a morning (6-10 am) or a bedtime (6-10 pm) administration group. Each participant receives one 20/5-mg tablet of olmesartan/amlodipine (OA) daily for 4 weeks and is then followed up at 4-week intervals for a total of 12 weeks. During follow-up, the OA dosage is adjusted according to the ABPM and OBPM results. Patients with uncontrolled hypertension at the first follow-up visit will receive an increase in OA dosage to 1.5 tablets/day. For patients with blood pressure that is still uncontrolled after a further 4 weeks, the dosage of OA can be increased to 2 tablets/day. The primary objective is the reduction in mean nocturnal systolic blood pressure between baseline and week 12. The secondary objectives are the reduction in ambulatory blood pressure at weeks 4 and 12 and the blood pressure control rate at weeks 4, 8, and 12. DISCUSSION: Antihypertensive chronotherapy remains controversial. A superiority test hypothesis design has been adopted for this trial, in which all participants will be taking the same antihypertensive medication. We anticipate that our findings will determine if nocturnal blood pressure control in Chinese patients with essential hypertension varies according to whether antihypertensive medication is taken in the morning or at bedtime. This study may provide scientific evidence for the application of chronotherapy in clinical practice. TRIAL REGISTRATION: ChiCTR2200059719. Registered on 10 May 2022 ( http://www.chictr.org.cn/edit.aspx?pid=169782&htm=4 ) {2a,2b}.

Folic acid targets splenic extramedullary hemopoiesis to attenuate carbon black-induced coagulation-thrombosis potential.

Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.

Up-regulation of miR-297 mediates aluminum oxide nanoparticle-induced lung inflammation through activation of Notch pathway.

Exposure to Aluminum oxide nanoparticles (Al2O3 NPs) has been associated with pulmonary inflammation in recent years; however, the underlying mechanism that causes adverse effects remains unclear. In the present study, we characterized microRNA (miRNA) expression profiling in human bronchial epithelial (HBE) cells exposed to Al2O3 NPs by miRNA microarray. Among the differentially expressed miRNAs, miR-297, a homologous miRNA in Homo sapiens and Mus musculus, was significantly up-regulated following exposure to Al2O3 NPs, compared with that in control. On combined bioinformatic analysis, proteomics analysis, and mRNA microarray, NF-κB-activating protein (NKAP) was found to be a target gene of miR-297 and it was significantly down-regulated in Al2O3 NPs-exposed HBE cells and murine lungs, compared with that in control. Meanwhile, inflammatory cytokines, including IL-1ß and TNF-α, were significantly increased in bronchoalveolar lavage fluid (BALF) from mice exposed to Al2O3 NPs. Then we set up a mouse model with intranasal instillation of antagomiR-297 to further confirm that inhibition of miR-297 expression can rescue pulmonary inflammation via Notch pathway suppression. Collectively, our findings suggested that up-regulation of miR-297 expression was an upstream driver of Notch pathway activation, which might be the underlying mechanism involved in lung inflammation induced by exposure to Al2O3 NPs.

Suppression of PTPN6 exacerbates aluminum oxide nanoparticle-induced COPD-like lesions in mice through activation of STAT pathway.

BACKGROUND: Inhaled nanoparticles can deposit in the deep lung where they interact with pulmonary cells. Despite numerous studies on pulmonary nanotoxicity, detailed molecular mechanisms of specific nanomaterial-induced lung injury have yet to be identified. RESULTS: Using whole-body dynamic inhalation model, we studied the interactions between aluminum oxide nanoparticles (Al2O3 NPs) and the pulmonary system in vivo. We found that seven-day-exposure to Al2O3 NPs resulted in emphysema and small airway remodeling in murine lungs, accompanied by enhanced inflammation and apoptosis. Al2O3 NPs exposure led to suppression of PTPN6 and phosphorylation of STAT3, culminating in increased expression of the apoptotic marker PDCD4. Rescue of PTPN6 expression or application of a STAT3 inhibitor, effectively protected murine lungs from inflammation and apoptosis, as well as, in part, from the induction of chronic obstructive pulmonary disease (COPD)-like effects. CONCLUSION: In summary, our studies show that inhibition of PTPN6 plays a critical role in Al2O3 NPs-induced COPD-like lesions.

(-)-Epigallocatechin-3-gallate attenuates myocardial injury induced by ischemia/reperfusion in diabetic rats and in H9c2 cells under hyperglycemic conditions.

(-)-Epigallocatechin gallate (EGCG) exerts multiple beneficial effects on cardiovascular performance. In this study, we aimed to examine the effects of EGCG on diabetic cardiomyopathy during myocardial ischemia/reperfusion (I/R) injury. EGCG (100 mg/kg/day) was administered at week 6 for 2 weeks to diabetic rats following the induction of type 1 diabetes by streptozotocin (STZ). At the end of week 8, the animals were subjected to myocardial I/R injury. The EGCG-elicited structural and functional effects were analyzed. Additionally, EGCG (20 µM) was administered for 24 h to cultured cardiac H9c2 cells under hyperglycemic conditions (30 mM glucose) prior to hypoxia/reoxygenation (H/R) challenge, and its effects on oxidative stress were compared to H9c2 cells transfecteed with silent information regulator 1 (SIRT1) small interfering RNA (siRNA). In rats with STZ-induced diabetes, EGCG treatment ameliorated post-ischemic cardiac dysfunction, decreased the myocardial infarct size, apoptosis and cardiac fibrosis, and reduced the elevated lactate dehydrogenase (LDH) and malonaldehyde (MDA) levels, and attenuated oxidative stress. Furthermore, EGCG significantly reduced H/R injury in cardiac H9c2 cells exposed to high glucose as evidenced by reduced apoptotic cell death and oxidative stress. The protein expression levels of SIRT1 and manganese superoxide dismutase (MnSOD) were reduced in the diabetic rats and the H9c2 cells under hyperglycemic conditions, compared with the control rats following I/R injury and H9c2 cells under normal glucose conditions. EGCG pre-treatment significantly upregulated the levels of htese proteins in vitro and in vivo. However, treatment with EX527 and SIRT1 siRNA blocked the EGCG-mediated cardioprotective effects. Taken together, our data indicate that SIRT1 plays a critical role in the EGCG-mediated amelioration of I/R injury in diabetic rats, which suggests that EGCG may be a promising dietary supplement for the prevention of diabetic cardiomyopathy.

Integrative functional transcriptomic analyses implicate specific molecular pathways in pulmonary toxicity from exposure to aluminum oxide nanoparticles.

Gene expression profiling has developed rapidly in recent years and it can predict and define mechanisms underlying chemical toxicity. Here, RNA microarray and computational technology were used to show that aluminum oxide nanoparticles (Al2O3 NPs) were capable of triggering up-regulation of genes related to the cell cycle and cell death in a human A549 lung adenocarcinoma cell line. Gene expression levels were validated in Al2O3 NPs exposed A549 cells and mice lung tissues, most of which showed consistent trends in regulation. Gene-transcription factor network analysis coupled with cell- and animal-based assays demonstrated that the genes encoding PTPN6, RTN4, BAX and IER play a role in the biological responses induced by the nanoparticle exposure, which caused cell death and cell cycle arrest in the G2/S phase. Further, down-regulated PTPN6 expression demonstrated a core role in the network, thus expression level of PTPN6 was rescued by plasmid transfection, which showed ameliorative effects of A549 cells against cell death and cell cycle arrest. These results demonstrate the feasibility of using gene expression profiling to predict cellular responses induced by nanomaterials, which could be used to develop a comprehensive knowledge of nanotoxicity.

An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles.

BACKGROUND: Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable. METHODS: In the present study, RNA microarray coupled with metabolomics analysis were used to uncover mechanisms underlying cellular responses to Al2O3 NPs and imply the potential rescue. RESULTS: We found that Al2O3 NPs significantly triggered down-regulation of mitochondria-related genes located in complex I, IV and V, which were involved in oxidative phosphorylation and neural degeneration pathways, in human bronchial epithelial (HBE) cells. Subsequent cell- and animal- based assays confirmed that Al2O3 NPs caused mitochondria-dependent apoptosis and oxidative stress either in vitro or in vivo, which were consistent with the trends of gene regulation. To rescue the Al2O3 NPs induced mitochondria dysfunction, disruption of small molecular metabolites of HBE were profiled using metabolomics analysis, which facilitates identification of potential antagonizer or supplement against nanoparticle-involved damages. Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored the Al2O3 NPs modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced apoptosis and oxidative damages in both Al2O3 NPs treated HBE cells and animal lung tissues. CONCLUSION: Thus, our results demonstrate the potential mechanism of respiratory system damages induced by Al2O3 NPs. Meanwhile, based on the metabolomics profiling, application of acetyl-L-carnitine is suggested to ameliorate mitochondria dysfunction associated with Al2O3 NPs.

Sex-Dependent Depression-Like Behavior Induced by Respiratory Administration of Aluminum Oxide Nanoparticles.

Ultrafine aluminum oxide, which are abundant in ambient and involved occupational environments, are associated with neurobehavioral alterations. However, few studies have focused on the effect of sex differences following exposure to environmental Al2O3 ultrafine particles. In the present study, male and female mice were exposed to Al2O3 nanoparticles (NPs) through a respiratory route. Only the female mice showed depression-like behavior. Although no obvious pathological changes were observed in mice brain tissues, the neurotransmitter and voltage-gated ion channel related gene expression, as well as the small molecule metabolites in the cerebral cortex, were differentially modulated between male and female mice. Both mental disorder-involved gene expression levels and metabolomics analysis results strongly suggested that glutamate pathways were implicated in sex differentiation induced by Al2O3 NPs. Results demonstrated the potential mechanism of environmental ultrafine particle-induced depression-like behavior and the importance of sex dimorphism in the toxic research of environmental chemicals.

Shen-Fu injection preconditioning inhibits myocardial ischemia-reperfusion injury in diabetic rats: activation of eNOS via the PI3K/Akt pathway.

The aim of this paper is to investigate whether Shen-fu injection (SFI), a traditional Chinese medicine, could attenuate myocardial ischemia-reperfusion (MI/R) injury in diabetes. Streptozotocin-induced diabetic rats were randomly assigned to the Sham, I/R, SFI preconditioning, and SFI plus wortmannin (a phosphatidylinositol 3-kinase inhibitor) groups. After the treatment, hearts were subjected to 30 min of coronary artery occlusion and 2 h reperfusion except the Sham group. Myocardial infarct size and cardiomyocytes apoptosis were increased significantly in MI/R group as compared with the Sham group. SFI preconditioning significantly decreased infarct size, apoptosis, caspase-3 protein expression, MDA level in myocardial tissues, and plasma level of CK and LDH but increased p-Akt, p-eNOS, bcl-2 protein expression, and SOD activity compared to I/R group. Moreover, SFI-induced cardioprotection was abolished by wortmannin. We conclude that SFI preconditioning protects diabetic hearts from I/R injury via PI3K/Akt-dependent pathway.

Effect of Shenfu Injection (ginesenoside and aconite alkaloid) on the apoptosis of intestinal mucosal epithelial cells and its mechanism during ischemia-reperfusion in rats.

OBJECTIVE: To investigate the effect of Shenfu Injection (SF, ginesenoside and aconite alkaloid) on the apoptosis of intestinal mucosal epithelial cells during ischemia-reperfusion in rats and its potential mechanisms. METHODS: Ischemia-reperfusion model was established in rats. Twenty-four rats were divided into 3 groups with 8 rats in each, eg, ischemia-reperfusion (I/R) group, SF-treated group, and control group. In both SF and I/R groups, the superior mesenteric artery was closed with forceps for 1 hour and then reperfused for 2 hours. Either SF (3 ml/kg, SF group) or normal saline (I/R and control groups) was injected intravenously and continuously for 5 ml/kg with a micropump before the superior mesenteric artery was closed. The superior mesenteric artery was not closed for animals in control group. The expression of casapse-3 and Fas, and the level of TNF-alpha and pathological changes of the ileal mucosal tissue were assayed. RESULTS: (1) The number of apoptosis cells increased obviously in I/R group and was significantly higher than that in SF and control groups (P<0.05). (2) The expression of caspase-3, Fas, and TNF-alpha was significantly higher in I/R group than SF and control groups (P<0.01); however, there was not significant difference in the expression of capase-3 between control group and SF group. There was a positive correlation between the expression of caspase-3, Fas, and TNF-alpha, and the number of apoptosis cells. (3) Under light microscope, intestinal mucosal impairment was found milder in SF group than I/R group (P<0.05). CONCLUSIONS: SF can depress the apoptosis of intestinal mucosal epithelial cells during ischemia-reperfusion by restraining the expression of TNF-alpha, Fas, caspase-3, and accordingly alleviate the ischemia and reperfusion injury of intestinal mucosal epithelial cells.