Asiaticoside ameliorates uterine injury induced by zearalenone in mice by reversing endometrial barrier disruption, oxidative stress and apoptosis.

Zearalenone (ZEA) is a mycotoxin produced by Fusarium fungi that has been shown to have adverse effects on human and animal health, particularly on the fertility of females. As a saponin derived from the medicinal plant Centella asiatica, asiaticoside (AS) has multiple bioactivities. This study aimed to investigate the protective effects of AS on ZEA-induced uterine injury and the underlying mechanism. In the present study, we demonstrated that AS could rescue ZEA-induced uterine histopathological damage and modulate the secretion of sex hormones, including progesterone (P4), luteinizing hormone (LH), and estradiol (E2), in ZEA-treated mice. Moreover, AS alleviated ZEA-induced damage to endometrial barrier function by upregulating the expression of tight junction proteins (ZO-1, occludin, and claudin-3). Further mechanistic investigations indicated that ZEA reduces the antioxidant capacity of uterine tissues, whereas AS improves the antioxidant capacity through activating the Nrf2 signaling pathway. Most notably, the protective effect of AS was blocked in Nrf2 gene knockout (Nrf2-/-) mice. Moreover, the p38/ERK MAPK pathway has been implicated in regulating ZEA toxicity and the beneficial effect of AS. Additionally, an Nrf2 inhibitor (ML385) weaken the suppressive effect of AS on the oxidative stress and MAPK pathway. AS also inhibits ZEA-induced apoptosis in uterine tissues via the PI3K/Akt signaling pathway. However, when the PI3K small molecule inhibitor LY294002 was co-administered, the ability of AS to suppress the expression of apoptosis-related proteins and inhibit ZEA-induced apoptosis decreased. Collectively, these findings reveal the involvement of multiple pathways and targets in the protective effect of AS against ZEA-induced uterine injury, providing a new perspective for the application of AS and the development of a ZEA antidote.

Role of Circular RNAs in the Pathogenesis of Malignant Melanoma.

Malignant melanoma is one of the most aggressive types of skin cancer. Thus, efficient diagnosis and treatment methods are crucial for advanced melanoma. Circular RNAs (circRNAs) have been regarded as a 'splicing noise' in the past decades. However, several circRNAs have been recently reported to be differentially expressed in melanoma, and the cell or tissue-specific expression makes these suitable candidate diagnostic or therapeutic biomarkers. In addition, emerging studies have confirmed that circular RNAs play pivotal roles in the proliferation, invasion, metastasis, and migration of malignant melanoma. However, specific pathogenic mechanisms between melanoma and circRNAs remain unclear. In the present study, it was summarized that circRNAs are associated with the pathogenesis of melanoma, including hsa_circ_0083444, hsa_circ_0005320, hsa_circ_0067531, hsa_circ_0084043, hsa_circ_0000082, hsa_circ_0016418, hsa_circ_0085533 and hsa_circ_0025039, hsa_circ_0001946, hsa_circ_0002770, hsa_circ_0079593, hsa_circ_0027247, hsa_circ_0017247, hsa_circ_0020710. These can provide potential diagnosis, treatment, and prognostication biomarkers for advanced melanoma in clinical applications.

A20 attenuates hypoxia-induced pulmonary arterial hypertension by inhibiting NF-κB activation and pulmonary artery smooth muscle cell proliferation.

PAH is a progressive disease characterized by uncontrolled proliferation of PASMCs. Zinc finger protein A20 is a negative feedback regulatory protein of NF-κB activity. The aim of this study was to evaluate zinc finger protein A20 can alleviate PAH in hypoxia exposed mice. C57BL/6 mice received a tail vein injection of adenovirus-mediated ad-A20 and ad-A20 shRNA were exposed to hypoxia. PASMCs isolated from rat pulmonary arteries were cultured in hypoxia, and were transfection of A20 adenovirus. Pulmonary hemodynamic parameters were measured by right heart catheterization. Pulmonary vascular morphological changes were analyzed by HE and α-SMA staining. The expression changes of A20, NF-κB and its downstream protein were detected. The expression of phospho-p65 was increased with the prolongation of hypoxia time. The expression of A20 in lung tissue of chronic hypoxia group decreased with the prolongation of hypoxia time. Adenovirus-mediated A20 (ad-A20) overexpression significantly attenuated the abnormally increased RVSP, RV/(LV + S) ratio, WT%, WA%, α-SMA and the pulmonary vessel muscularization. Ad-A20 treatment markedly attenuated the degradation of phospho-p65 and inhibited the induction of phospho-IκBα induced by hypoxia treatment. Furthermore, silencing A20 abolished the protection by anti-inflammatory activity and the inhibitory effect on cell proliferation. We showed that Zinc finger protein A20 can block NF-κB signaling pathway, alleviates the hypoxia-induced abnormal elevation of pulmonary arterial pressure, hyperproliferation of PASMCs and the pulmonary vascular remodeling.

Berberine attenuates hypoxia-induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor-ß signaling.

Hypoxia-induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia-induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia-induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α-smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR-II) and its downstream molecules P-smad1/5 and decreased the expression of transforming growth factor-ß (TGF-ß) and its downstream molecules P-smad2/3. Moreover, peroxisome proliferator-activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia-induced PAH in a mouse model may be achieved through altered BMPR-II and TGF-ß signaling.

A Pilot Study of the Use of Dexmedetomidine for the Control of Delirium by Reducing the Serum Concentrations of Brain-Derived Neurotrophic Factor, Neuron-Specific Enolase, and S100B in Polytrauma Patients.

BACKGROUND: Delirium is very common among patients with polytrauma, although no suitable means exist to feasibly reduce the incidence and duration of delirium in these patients. Recent reports have suggested that continuous intravenous (IV) infusions of dexmedetomidine, rather than benzodiazepine, be administered for sedation to reduce the duration of delirium in this population. However, serum neuron-specific enolase (NSE), S100 calcium binding protein B (S100B), and brain-derived neurotrophic factor (BDNF) levels have not yet been investigated in polytrauma patients who received sedation with dexmedetomidine rather than other conventional sedatives. The aim of this study was to assess the association of blood BDNF, NSE, and S100B with the occurrence of delirium among polytrauma patients who had been sedated with dexmedetomidine. MATERIALS AND METHODS: Consecutive patients were randomly assigned to 1 of 2 treatment study groups, namely the "dexmedetomidine group" or the "common group." This case-control study included 18 patients with delirium and 34 matched controls in a 63-bed general intensive care unit (ICU). Blood samples were collected from all patients upon ICU admission, on the day when delirium was diagnosed, and on days 3 and 5 following diagnosis. The serum levels of S100B, BDNF, and NSE were determined by enzyme-linked immunosorbent assay. The sedation levels and delirium were assessed using the Richmond Agitation and Sedation Scale and the Confusion Assessment Method for the ICU. RESULTS: The median BDNF, NSE, and S100B concentrations were significantly lower in the dexmedetomidine group than in the common group on the day when delirium was diagnosed and on the third day after delirium was diagnosed. The rate of delirium was significantly lower in the dexmedetomidine group than in the common group. There were clear differences in the BDNF, NSE, and S100B levels between the 2 groups on the fifth day after delirium was diagnosed. CONCLUSIONS: Our randomized controlled study suggests that the sedation of polytrauma patients with dexmedetomidine could help reduce the serum BDNF, S100B, and NSE levels, which appear to be associated with the occurrence of delirium in the dexmedetomidine group.

Hyaluronidase2 (Hyal2) modulates low shear stress-induced glycocalyx impairment via the LKB1/AMPK/NADPH oxidase-dependent pathway.

The endothelium glycocalyx layer (ECL), presents on the apical surface of endothelial cells, creates a barrier between circulating blood and the vessel wall. Low shear stress (LSS) may accelerate the degradation of the glycocalyx via hyaluronidase2 (Hyal2) and then alter the cell polarity. Yet the liver kinase B1 (LKB1) signaling pathway plays an important role in regulating cell polarity. However, the relationship between LKB1 and glycocalyx during LSS is not clear. In the current study, we demonstrate that LSS attenuates LKB1 and AMP-activated protein kinase activation as well as activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47phox ) and Hyal2 in the human umbilical vein endothelial cell (HUVEC). Pretreatment with 5-Aminoimidazole-4-carboxamide1-ß-D-ribofuranoside (AICAR), or diphenyleneiodonium (DPI chloride) and transfection with LKB1 overexpression vector and p47phox small interfering RNA downregulated LSS-induced Hyal2 activation. By coimmunoprecipitation, we discovered the existence of p47phox /Hyal2 complex. LSS induced the dissociation of p47phox /Hyal2 complex, which was inhibited by LKB1 overexpression and AICAR. Furthermore, knockdown of Hyal2 performed a positive feedback on LKB1 activity. In addition, we also show that LSS enhanced LKB1 translocation from the cytosol to the nucleus. Taken together, these data indicate that Hyal2 regulates LSS-induced injury of the glycocalyx via LKB1/AMPK/NADPH oxidase signaling cascades.

Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway.

Reactive oxygen species (ROS) contribute to many aspects of physiological and pathological cardiovascular processes. However, the underlying mechanism of ROS induction by low shear stress (LSS) remains unclear. Accumulating evidence has shown that the angiotensin II type 1 receptor (AT1R) is involved in inflammation, apoptosis, and ROS production. Our aim was to explore the role of AT1R in LSS-mediated ROS induction. We exposed human umbilical vein endothelial cells (HUVECs) to LSS (3 dyn/cm2 ) for different periods of time. Western blotting and immunofluorescence showed that LSS significantly induced AT1R expression in a time-dependent manner. Using immunohistochemistry, we also noted a similar increase in AT1R expression in the inner curvature of the aortic arch compared to the descending aorta in C57BL/6 mice. Additionally, HUVECs were cultured with a fluorescent probe, either DCFH, DHE or DAF, after being subjected to LSS. Cell chemiluminescence and flow cytometry results revealed that LSS stimulated ROS levels and suppressed nitric oxide (NO) generation in a time-dependent manner, which was reversed by the AT1R antagonist Losartan. We also found that Losartan markedly increased endothelial NO synthase (eNOS) phosphorylation at Ser(633,1177) and dephosphorylation at Thr(495), which involved AKT and ERK. Moreover, the ROS level was significantly reduced by endogenous and exogenous NO donors (L-arginine, SNP) and increased by the eNOS inhibitor L-NAME. Overall, we conclude that LSS induces ROS via AT1R/eNOS/NO.

Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro.

Excessive proliferation, migration, and antiapoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) underlies the development of pulmonary vascular remodeling. The innervation of the PA is predominantly sympathetic, and increased levels of circulating catecholamines have been detected in pulmonary arterial hypertension (PAH), suggesting that neurotransmitters released by sympathetic overactivation may play an essential role in PAH. However, the responsible mechanism remains unclear. Here, to investigate the effects of norepinephrine (NE) on PASMCs and the related mechanism, we used 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, the proliferating cell nuclear antigen and the cell counting kit-8 assay to evaluate the proliferation of PASMCs, Boyden chamber migration, and wound-healing assays to assess migration and western blot analysis to investigate protein expression. We demonstrated that the phosphorylation level of the protein phosphatase 2A (PP2A) catalytic subunit (Y307) was higher in PAH patients and PAH models than in controls, both in vivo and in vitro. In addition, NE induced the proliferation and migration of PASMCs, which was attenuated by berberine (BBR), a Chinese herbal medicine, and/or PP2A overexpression. PP2A inhibition worsened NE-induced PAH and could not be reversed by BBR. Thus, PP2A is critical in driving PAH, and BBR may alleviate PAH via PP2A signaling pathways, thereby offering a potential therapeutic option for PAH.

Inhibition of angiotension II type 1 receptor reduced human endothelial inflammation induced by low shear stress.

Low shear stress (LSS)-induced endothelial inflammation is the basis for the development of atherosclerosis. However, the mechanism underlying LSS-induced inflammation is not well understood. The angiotensin II type 1 receptor (AT1R), a component of the renin-angiotensin system, participates in atherosclerotic plaque progression. The aim of this study was to investigate the role of AT1R in LSS-induced endothelial activation. Using immunohistochemistry, we noted significant increases in AT1R, vascular endothelial adhesion cell-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) expression in the inner curvature of the aortic arch in C57BL/6 mice compared to the descending aorta in these mice. Moreover, western blotting revealed that these LSS-induced increases in AT1R, ICAM1 and VCAM1 expression were time dependent. However, the expression of these proteins was significantly abolished by treatment with the AT1R antagonist Losartan (1µM) or AT1R small interfering RNA (siRNA). AT1R inhibition significantly suppressed extracellular signal-regulated kinase 1/2 (ERK) upregulation, which also resulted in decreases in ICAM1 and VCAM1 protein expression. These findings demonstrate that LSS induces endothelial inflammation via AT1R/ERK signaling and that Losartan has beneficial effects on endothelial inflammation.

Eyelid sporotrichosis: Unique clinical findings in 72 patients.

Sporotrichosis on the eyelids is uncommon and has been rarely reported. As the largest series of 72 adults and children with eyelid sporotrichosis from Jilin ̀P̀̀rovince in China, this study provides useful information for the improved diagnosis and treatment of sporotrichosis.

The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome.

INTRODUCTION: Recent studies have revealed that lung inflammation mediated by CD4+ T cells may contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). The imbalance between CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and T helper (Th)17 cells has been found in a number of different inflammation and autoimmune diseases, while the role of the Th17/Treg balance in ARDS remains largely unknown. The aim of this study was to investigate the Th17/Treg pattern and its impact on disease severity and outcomes in patients with ARDS. METHODS: This prospective, observational study enrolled 79 patients who fulfilled the Berlin definition of ARDS and 26 age- and sex-matched healthy controls. Circulation Th17 and Treg cell frequencies were analyzed by flow cytometry, and the expressions of Th17- and Treg-related cytokines in serum were measured by enzyme-linked immunosorbent assay (ELISA). Acute Physiologic and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, and the Lung Injury Score were also calculated at enrollment. RESULTS: Within 24 hours after the onset of ARDS, the changes of peripheral circulating Th17 and Treg cell frequencies gradually increased from mild to severe ARDS. Th17/Treg ratio was positively correlated with APACHE II score, SOFA score, and Lung Injury Score, while negatively correlated with PaO2/FiO2. The areas under the receiver operating characteristic (AUC) curves of Th17/Treg ratio for predicting 28-day mortality in ARDS patients was higher than that of APACHE II score, SOFA score, Lung injury score, as well as PaO2/FiO2. Using a Th17/Treg ratio cutoff value of >0.79 to determine 28-day mortality, the sensitivity was 87.5% with 68.1% specificity. Multivariate logistic regression showed Th17/Treg ratio >0.79 (odds ratio = 8.68, P = 0.002) was the independent predictor for 28-day mortality in patients with ARDS. Finally, cumulative survival rates at 28-day follow-up also differed significantly between patients with Th17/Treg ratio >0.79 and ≤0.79 (P <0.001). CONCLUSIONS: The Th17/Treg imbalance favoring a Th17 shift represents a potential therapeutic target to alleviate lung injury and a novel risk indicator in patients with early ARDS.

[Severity analyese of acute pancreatitis based on etiology].

OBJECTIVE: To explore the relationship between etiology and severity of acute pancreatitis (AP). METHODS: A total of 486 AP patients, hospitalized at digestive, general surgery or critical care medicine departments from May 2012 to May 2014, were recruited retrospectively. And the data of clinical features, etiology and severity classification of AP according to the revised Atlanta criteria (2012) were collected. The relationships between different gender, age group, etiology and severity of disease were compared. RESULTS: The etiology distribution was as follows: gallstone (n = 296, 60.9%), hyperlipidemia (n = 93, 19.1%), alcohol (n = 48, 9.9%) and other causes (n = 49, 10.1%). And the severity was mild AP (MAP, n = 387, 79.6%), moderate-severe AP (MSAP, n = 53, 10.9%) and severe AP (SAP, n = 46, 9.5%). The proportion of females for gallstone AP was slightly higher than that of males (1.23: 1). However, for hyperlipidemic and alcoholic AP, the proportion of males was significantly higher than that of females (P = 0.00). The onset age of gallstone AP was generally over 40 years while hyperlipidemic and alcoholic AP tended to occur in patients aged under 60 years (P = 0.00). Among all age groups, the group of over 60 years had the highest MSAP incidence of 14% while <40-year-old group the highest incidence of SAP at 11.3%. And the >60-year-old group had the highest total incidence of MSAP and SAP at 22.2%. Compared with gallstone, alcohol and other causes, hyperlipidemic AP had a higher risk of MSAP and SAP (P = 0.028). CONCLUSION: Gallstone remains a leading cause of AP. Hyperlipidemic pancreatitis has shown a rising tendency in recent years and it often result in a more serious clinical process. And the clinicians should pay more attention to health education of patients.

[The effect of mild sedation on the prognosis and inflammatory markers in critical patients with mechanical ventilation].

OBJECTIVE: To compare the effect of slight and usual sedation on the prognosis and inflammatory marker levels in patients receiving mechanical ventilation in ICU. METHODS: We enrolled 78 critically ill adult patients who were undergoing mechanical ventilation and were expected to need ventilation for more than 48 h. The patients were prospectively and randomly assigned to receive: slight sedation (Richmond Agitation Sedation Score -1 to 0, n = 38 patients) or usual sedation (Richmond Agitation Sedation Score -3 to -2, n = 40 patients). Sedative dosages, duration of mechanical ventilation, length of ICU stay, complications (ventilator-associated pneumonia, tracheotomy) , adverse reactions (accidental extubation, reintubation, barotrauma) and levels of inflammatory markers on the day of sedation time for 48 h were recorded. RESULTS: When compared with the usual sedation group, duration of mechanical ventilation (d) ( 8 ± 5 vs 13 ± 8, P < 0.05) and length of ICU stay (d) ( 12 ± 10 vs 22 ± 9, P < 0.05) were significantly shorter in the slight sedation group. The total doses of midazolam (mg) , propofol (mg) and fentany (µg) were lower in the slight sedation group than those in the usual sedation group (275 ± 85 vs 575 ± 142, 4 562 ± 1 128 vs 7 434 ± 1 712 and 2 332 ± 1 458 vs 4 124 ± 2 743, P < 0.05) . Accidental extubation (5% vs 3%) , reintubation (5% vs 10%) and barotraumas (3% vs 8%) showed no differences between the 2 groups (P > 0.05). In the slight sedation group, the incidences of ventilator-associated pneumonia (26% vs 53%) and tracheotomy (18% vs 48%) were significantly decreased compared with those in the usual group. The levels of IL-1 (35 ± 12 vs 47 ± 18, P < 0.05) ng/L, IL-6 (49 ± 21 vs 62 ± 27, P < 0.05) ng/L, TNF-α ( 39 ± 16 vs 52 ± 25, P < 0.05) ng/L and CRP (95 ± 41 vs 125 ± 45, P < 0.05) mg/L were also lower in the slight sedation group than those in the conventional group. There were no differences in ICU mortality and 28 d-survival rate between the 2 groups. CONCLUSION: Slight sedation was shown to reduce the length of mechanical ventilation and ICU stay. It also decreased the levels of inflammatory markers while didn't increase the incidence of adverse reactions.

Evolution of catalyst design for controlled synthesis of chiral single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWCNTs) possess superb properties originating from their unique chiral structures. However, accurately controlling the structure of SWCNTs remains challenging due to the structural similarities of their chiral structures, which hinders their widespread application in various fields, particularly in electronics. In recent years, much effort has been devoted to preparing single chiral SWCNTs by adopting three constructive strategies, including growth condition control for structurally unstable liquid catalysts, employing stable solid catalyst design, and pre-synthesis of carbon seeds with a well-defined shape. This review comprehensively discusses the state-of-the-art developments in these approaches as well as their advantages and disadvantages. Moreover, insights into the key challenges and future directions are provided for acquiring chirally pure SWCNTs.

Low-Shear Stress Promotes Atherosclerosis via Inducing Endothelial Cell Pyroptosis Mediated by IKKε/STAT1/NLRP3 Pathway.

Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE-/- mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.

USP36-mediated PARP1 deubiquitination in doxorubicin-induced cardiomyopathy.

Doxorubicin (Dox) is a potent antineoplastic agent, but its use is curtailed by severe cardiotoxicity, known as Dox-induced cardiomyopathy (DIC). The molecular mechanism underlying this cardiotoxicity remains unclear. Our current study investigates the role of Ubiquitin-Specific Protease 36 (USP36), a nucleolar deubiquitinating enzyme (DUB), in the progression of DIC and its mechanism. We found increased USP36 expression in neonatal rat cardiomyocytes and H9C2 cells exposed to Dox. Silencing USP36 significantly mitigated Dox-induced oxidative stress injury and apoptosis in vitro. Mechanistically, USP36 upregulation positively correlated with Poly (ADP-ribose) polymerase 1 (PARP1) expression, and its knockdown led to a reduction in PARP1 levels. Further investigation revealed that USP36 could bind to and mediate the deubiquitination of PARP1, thereby increasing its protein stability in cardiomyocytes upon Dox exposure. Moreover, overexpression of wild-type (WT) USP36 plasmid, but not its catalytically inactive mutant (C131A), stabilized PARP1 in HEK293T cells. We also established a DIC model in mice and observed significant upregulation of USP36 in the heart. Cardiac knockdown of USP36 in mice using a type 9 recombinant adeno-associated virus (rAAV9)-shUSP36 significantly preserved cardiac function after Dox treatment and protected against Dox-induced structural changes within the myocardium. In conclusion, these findings suggest that Dox promotes DIC progression by activating USP36-mediated PARP1 deubiquitination. This novel USP36/PARP1 axis may play a significant regulatory role in the pathogenesis of DIC.

Stress transfer outpaces injection-induced aseismic slip and triggers seismicity.

As concerns rise over damaging earthquakes related to industrial activities such as hydraulic fracturing, geothermal energy extraction and wastewater disposal, it is essential to understand how subsurface fluid injection triggers seismicity even in distant regions where pore pressure diffusion cannot reach. Previous studies suggested long-range poroelastic stressing and aseismic slip as potential triggering mechanisms. In this study, we show that significant stress transfer far ahead of injection-induced aseismic slip can travel at much higher speeds and is a viable mechanism for distant earthquake triggering. It could also explain seismicity migration that is much faster than aseismic slip front propagation. We demonstrate the application of these concepts with seismicity triggered by hydraulic fracturing operations in Weiyuan shale gas field, China. The speed of stress transfer is dependent on the background stress level and injection rate, and can be almost an order of magnitude higher than that of the aseismic slip front.

[Causes and prognosis analysis of hyperdynamic left ventricular ejection fraction in intensive care unit patients with sepsis].

OBJECTIVE: To analyze the causes of hyperdynamic left ventricular ejection fraction (LVEF) in sepsis patients in the intensive care unit (ICU) and its impact on prognosis. METHODS: A retrospective cohort study was conducted. The clinical data of 273 sepsis patients admitted to the department of critical care medicine of the Affiliated People's Hospital of Jiangsu University from January 2018 to October 2021 were collected including gender, age, severity score, comorbidities, source of infection, vital signs, transthoracic echocardiographic (TTE) parameters, fluid intake and output, vasoactive drug dose, therapeutic measures and prognostic indicators. The patients were divided into normal LVEF group (LVEF 0.55-0.70), low LVEF group (LVEF < 0.55) and hyperdynamic LVEF group (LVEF > 0.70) according to the TTE examination results within 7 days of ICU admission. The clinical indicators among the three groups were compared and analyzed, and multivariate Logistic regression analysis was used to screen risk factors for the development of hyperdynamic LVEF in patients with sepsis. Spearman correlation analysis was used to determine the correlation between the mortality of different types of LVEF and clinical variables. RESULTS: Among 273 patients, 20 patients with severe valvular or cardiomyopathy at admission and those who did not completed cardiac ultrasound within 7 days of ICU admission were excluded. A total of 253 patients were finally enrolled, including 169 patients in the normal LVEF group, 40 patients in the low LVEF group, and 44 patients in the hyperdynamic LVEF group. There were statistically significant differences in age, sequential organ failure assessment (SOFA) score, central venous pressure (CVP), heart rate (HR), oxygenation index (PaO2/FiO2), blood lactate (Lac), urine output, vasoactive drug dose, ratio of hypertension, ischemic heart disease, chronic liver disease, cancer, invasive mechanical ventilation and renal replacement therapy (RRT), and incidence of septic shock among the different types of LVEF groups. TTE results analysis showed that the hyperdynamic LVEF group had higher stroke volume (SV) and cardiac index (CI) than those in the normal LVEF and low LVEF groups, lower systemic vascular resistance (SVR) than that in the normal LVEF and low LVEF groups, and an increased E/A ratio. The 90-day mortality in the hyperdynamic LVEF group was significantly higher than that in the normal LVEF and low LVEF groups [59.1% (26/44) vs. 24.9% (42/169), 32.5% (13/40), both P < 0.05]. Multivariate Logistic regression analysis showed that chronic liver disease [odds ratio (OR) = 1.712, 95% confidence interval (95%CI) was 0.912-3.234, P < 0.001], cancer (OR = 2.784, 95%CI was 1.296-6.151, P < 0.001), HR (OR = 1.026, 95%CI was 1.014-1.038, P < 0.001), vasoactive drug dose (OR = 1.133, 95%CI was 1.009-1.291, P < 0.001), and invasive mechanical ventilation (OR = 2.141, 95%CI was 1.285-3.651, P < 0.001) were independent factors for hyperdynamic LVEF in ICU sepsis patients. Correlation analysis showed that the mortality of hyperdynamic LVEF, normal LVEF and low LVEF patients was positively correlated with vasoactive drug dose (r value was 0.251, 0.361, 0.289, respectively, all P < 0.001). The mortality of the hyperdynamic LVEF patients was negatively correlated with SVR (r = -0.545, P < 0.001). CONCLUSIONS: Chronic liver disease, cancer, HR, vasoactive drugs dose, and invasive mechanical ventilation are independent risk factors for hyperdynamic LVEF in patients with sepsis. Hyperdynamic LVEF is positively associated with mortality in sepsis patients, which may be due to the the decrease of SVR caused by septic vascular paralysis.

Mechanism of progressive broad deformation from oceanic transform valley to off-transform faulting and rifting.

Oceanic transform faults (TFs) are commonly viewed as single, narrow strike-slip seismic faults that offset two mid-ocean ridge segments. However, broad zones of complex deformation are ubiquitous at TFs. Here, we propose a new conceptual model for the progressive deformation within broad zones at oceanic TFs through detailed morphological, seismic, and stress analyses. We argue that, under across-transform extension due to a change in plate motion, plate deformation occurs first along high-angle transtensional faults (TTFs) within the transform valleys. Off-transform normal faults (ONFs) form when across-transform deviatoric extensional stresses exceed the yield strength of the adjacent oceanic lithosphere. With further extension, these normal faults can develop into off-transform rift zones (ORZs), some of which can further develop into transform plate boundaries. We illustrate that such progressive complex deformation is an inherent feature of oceanic TFs. The new conceptual model provides a unifying theory to explain the observed broad deformation at global transform systems.

Berberine inhibits low shear stress-induced vascular endothelial inflammation via decreasing phosphorylation of Akt and IRF3.

BACKGROUND: Low shear stress (LSS) is closely related to vascular endothelial inflammation and the development of atherosclerosis. Berberine (BBR), a natural compound isolated from Coptis chinensis, has been reported to exert anti-inflammatory and antiatherosclerotic effects. However, the role of berberine in low shear stress-induced endothelial inflammation remains unclear. METHODS: The role of berberine in low shear stress-induced vascular endothelial inflammation was investigated in human umbilical vein endothelial cells (HUVECs) using a plate flow chamber in vitro and in mice with an established LSS model by partial ligation of the carotid artery in vivo. RESULTS: First, in vitro experiments demonstrated that BBR significantly decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the phosphorylation of Akt in HUVECs induced by low shear stress. Moreover, BBR significantly inhibited the low shear stress-mediated phosphorylation of IRF3 and its translocation to the nucleus. Notably, Akt overexpression markedly reversed the inhibitory effects of BBR on LSS-induced IRF3 activation and ICAM-1 expression. Moreover, in vivo experiments showed that BBR markedly decreased intimal ICAM-1 and IRF3 in the LSS areas of partially ligated carotid arteries in mice; however, EC-specific Akt overexpression mediated by adeno-associated viruses abolished the anti-inflammatory effect of BBR. CONCLUSION: Taken together, our findings suggest that BBR treatment attenuates LSS-induced vascular endothelial inflammation by decreasing the activation of the Akt/IRF3 signalling pathway.