Physical activity trajectory during pregnancy and associations with maternal fatigue using a growth mixture modeling approach.

The purpose of this study was to investigate the associations of physical activity trajectories with maternal fatigue. Pregnant women provided objectively assessed physical activity data by Pregnancy Physical Activity Questionnaire four times. Fatigue scale-14 was used to assess fatigue during pregnancy. Growth mixture modelling characterized physical activity trajectories across pregnancy. The generalized estimating equations was used to analyze the relationship between different physical activity profiles and fatigue in pregnant women. A total of 626 pregnant women were included in analysis in a teaching hospital in Nantong city. Fatigue (total, mental and physical) was not different between two groups based on total energy expenditure of PA (constantly high vs. constantly low). The pregnant women in "constantly high household PA" group had the higher fatigue compared to "constantly low household PA" (P < 0.05) and "constantly medium household PA" (P < 0.05). The pregnant women in "constantly high sport PA" group had lower fatigue compared to "constantly low sport PA" (P < 0.05). Household PA and sport PA were still an independent influencing factor for fatigue after controlling for confounding variables. Specifically, we observed that higher household PA and lower sport PA were associated with higher fatigue during pregnancy.

Epigenetic repression of Cend1 by lysine-specific demethylase 1 is essential for murine heart development.

Epigenetic regulation of heart development remains incompletely understood. Here we show that LSD1, a histone demethylase, plays a crucial role in regulating cardiomyocyte proliferation during heart development. Cardiomyocyte-specific deletion of Lsd1 in mice inhibited cardiomyocyte proliferation, causing severe growth defect of embryonic and neonatal heart. In vivo RNA-seq and in vitro functional studies identified Cend1 as a target suppressed by LSD1. Lsd1 loss resulted in elevated Cend1 transcription associated with increased active histone mark H3K4me2 at Cend1 promoter. Cend1 knockdown relieved the cell-cycle arrest and proliferation defect caused by LSD1 inhibition in primary rat cardiomyocytes. Moreover, genetic deletion of Cend1 rescued cardiomyocyte proliferation defect and embryonic lethality in Lsd1 null embryos. Consistently, LSD1 promoted the cell cycle of cardiomyocytes derived from human-induced pluripotent stem cells by repressing CEND1. Together, these findings reveal an epigenetic regulatory mechanism involving the LSD1-CEND1 axis that controls cardiomyocyte proliferation essential for murine heart development.

Plasma Cell-Free DNA Is a Potential Biomarker for Diagnosis of Calcific Aortic Valve Disease.

INTRODUCTION: Calcific aortic valve disease (CAVD) is the third most common cardiovascular disease in aging populations. Despite a growing number of biomarkers having been shown to be associated with CAVD, a marker suitable for routine testing in clinical practice is still needed. Plasma cell-free DNA (cfDNA) has been suggested as a biomarker for diagnosis and prognosis in multiple diseases. In this study, we aimed to test whether cfDNA could be used as a biomarker for the diagnosis of CAVD. METHODS: Serum samples were collected from 137 diagnosed CAVD patients and 180 normal controls. The amount of cfDNA was quantified by amplifying a short fragment (ALU 115) and a long fragment (ALU 247) using quantitative real-time PCR. The cfDNA integrity (cfDI) was calculated as the ratio of ALU247 to ALU115. The association between CAVD and cfDI was evaluated using regression analysis. RESULTS: CAVD patients had increased ALU 115 fragments (median, 185.14 (416.42) versus 302.83 (665.41), p < 0.05) but a decreased value of cfDI (mean, 0.50 ± 0.25 vs. 0.41 ± 0.26, p < 0.01) in their serum when compared to controls. This difference was more dramatic in non-rheumatic CAVD patients (p < 0.001) versus rheumatic CAVD patients (no significant difference). Similarly, CAVD patients with bicuspid aortic valve (BAV) (p < 0.01) showed a greater difference than non-BAV CAVD patients (p < 0.05). Linear regression and logistic regression showed that cfDI was independently and significantly associated with the presence of CAVD (95% CI, 0.096 to 0.773, p < 0.05). The ROC assay revealed that cfDI combined with clinical characteristics had a better diagnostic value than cfDI alone (AUC = 0.6191, p < 0.001). CONCLUSION: cfDI may be a potential biomarker for diagnosis of CAVD.

Umbilical artery cord blood glucose predicted hypoglycemia in gestational diabetes mellitus and other at-risk newborns.

BACKGROUND: To explore the value of umbilical artery cord blood glucose (UACBG) in predicting hypoglycemia in gestational diabetes mellitus (GDM) and other at-risk newborns, and to provide a cut-off UACBG value for predicting hypoglycemia occurrence. METHODS: In this prospective study, we enrolled at-risk infants delivered vaginally, including neonates born to mothers with GDM, premature, macrosomic, and low birth weight. We separated the infants into GDM group and other at-risk group. All subjects underwent UACBG measurement during delivery. Neonatal peripheral blood glucose measurement was performed at 0.5 and 2 h after birth. The predictive performance of UACBG for neonatal hypoglycemia was assessed using receiver operating characteristic curve (ROC), area under curve (AUC), sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV). RESULTS: 916 newborns were included, with 538 in GDM group and 378 in other at-risk group. 85 neonates were diagnosed hypoglycemia within 2 h after birth, including 36 belonging to GDM group and 49 to other at-risk group. For hypoglycemia prediction within 2 h, the best cut-off of UACBG was 4.150 mmol/L, yielding an AUC of 0.688 (95% CI 0.625-0.751) and a NPV of 0.933. In detail, the AUC was 0.680 in GDM group (95% CI 0.589-0.771), with the optimal cut-off of 4.150 mmol/L and a NPV of 0.950. In other at-risk group, the AUC was 0.678(95% CI 0.586-0.771), the best threshold was 3.950 mmol/L and the NPV was 0.908. No significant differences were observed between GDM group and other at-risk group in AUC at 0.5 h, 2 h and within 2 h. CONCLUSIONS: UACBG has a high NPV for predicting neonatal hypoglycemia within 2 h after birth. It was implied that individuals with cord blood glucose levels above the threshold were at lower risk for hypoglycemia. UACBG monitoring provides evidence for subsequent classified management of hypoglycemia.

Short C-terminal Musashi-1 proteins regulate pluripotency states in embryonic stem cells.

The RNA-binding protein Musashi-1 (MSI1) regulates the proliferation and differentiation of adult stem cells. However, its role in embryonic stem cells (ESCs) and early embryonic development remains poorly understood. Here, we report the presence of short C-terminal MSI1 (MSI1-C) proteins in early mouse embryos and mouse ESCs, but not in human ESCs, under conventional culture conditions. In mouse embryos and mESCs, deletion of MSI1-C together with full-length MSI1 causes early embryonic developmental arrest and pluripotency dissolution. MSI1-C is induced upon naive induction and facilitates hESC naive pluripotency acquisition, elevating the pluripotency of primed hESCs toward a formative-like state. MSI1-C proteins are nuclear localized and bind to RNAs involved in DNA-damage repair (including MLH1, BRCA1, and MSH2), conferring on hESCs better survival in human-mouse interspecies cell competition and prolonged ability to form blastoids. This study identifies MSI1-C as an essential regulator in ESC pluripotency states and early embryonic development.

Outcomes of vertex-vertex vs. vertex-breech presentation in twin pregnancy after vaginal delivery in China.

OBJECTIVE: To compare the maternal and neonatal outcomes of twin pregnancies between vertex and nonvertex presentations of the second twin in vaginal delivery. METHODS: In this unicentric retrospective cohort study, we collected data from 213 cases of vaginal twin deliveries from January 2016 to July 2020. Participants were divided into the vertex-vertex presentation group (VV) and vertex-breech presentation group (VB). Data on maternal and neonatal outcomes were compared between groups. RESULTS: Among the 213 mothers and 426 infants (213 twin pairs), there were 140 women in the VV group and 73 women in the VB group (65.73% vs. 34.27%). Infants in the VB group had a higher incidence of admission to NICU (51.43% vs. 68.49%, p = 0.017), lower 1-min (11.43% vs. 28.77%, p < 0.001) and 5-minute Apgar scores (1.43% vs. 4.11%, p = 0.043) for the second twin. However, after the adjustment for sex of the twin, birth weight, chorionicity, and gestational age, the greater risk of admission to NICU and low 5-min Apgar score was no longer significantly different. CONCLUSION: VB twins are at no greater overall risk of a poor outcome due to breech presentation in the second twin. However, the presentation of the second fetus represents a risk factor for a low 1-min Apgar score. Obstetricians and midwives should consider appropriate interventions for second twins who present breech versus vertex.

ß-Catenin regulates endocardial cushion growth by suppressing p21.

Endocardial cushion formation is essential for heart valve development and heart chamber separation. Abnormal endocardial cushion formation often causes congenital heart defects. ß-Catenin is known to be essential for endocardial cushion formation; however, the underlying cellular and molecular mechanisms remain incompletely understood. Here, we show that endothelial-specific deletion of ß-catenin in mice resulted in formation of hypoplastic endocardial cushions due to reduced cell proliferation and impaired cell migration. By using a ß-catenin DM allele in which the transcriptional function of ß-catenin is selectively disrupted, we further reveal that ß-catenin regulated cell proliferation and migration through its transcriptional and non-transcriptional function, respectively. At the molecular level, loss of ß-catenin resulted in increased expression of cell cycle inhibitor p21 in cushion endocardial and mesenchymal cells in vivo. In vitro rescue experiments with HUVECs and pig aortic valve interstitial cells confirmed that ß-catenin promoted cell proliferation by suppressing p21. In addition, one savvy negative observation is that ß-catenin was dispensable for endocardial-to-mesenchymal fate change. Taken together, our findings demonstrate that ß-catenin is essential for cell proliferation and migration but dispensable for endocardial cells to gain mesenchymal fate during endocardial cushion formation. Mechanistically, ß-catenin promotes cell proliferation by suppressing p21. These findings inform the potential role of ß-catenin in the etiology of congenital heart defects.

Early ambulation and postoperative recovery of patients with lung cancer under thoracoscopic surgery-an observational study.

BACKGROUND: Enhanced recovery after surgery guidelines in China recommend early ambulation within 24 h after surgery. The aims of this audit were to investigate the early ambulation of patients with lung cancer under thoracoscopic surgery, and to explore the influence of different ambulation time on postoperative rehabilitation of patients. METHODS: Using observational study method, observe and record of 226 cases under the thoracoscope surgery early ambulation of patients with lung cancer. Data collected included postoperative bowel movements, chest tube extubation time, length of hospital stay, postoperative pain and the incidence of postoperative complications. RESULTS: The time of first ambulation was (34.18 ± 17.18) h, the duration was (8.26 ± 4.62) min, and the distance was (54.94 ± 46.06) m. The time of first postoperative defecation, the time of chest tube extubation and the length of hospital stay were significantly shortened in patients who ambulate within 24 h, and the pain score on the third day after surgery was decreased, and the incidence of postoperative complications was reduced, with statistical significance (P < 0.05). CONCLUSION: Early ambulation within 24 h after thoracoscopic surgery for lung cancer patients can promote the recovery of intestinal function, early removal of chest tube, shorten the length of hospital stay, relieve pain, reduce the incidence of complications, and facilitate the rapid recovery of patients.

Antinuclear antibody (ANA) status predicts immune-related adverse events in liver cancer patients undergoing anti-PD-1 therapy.

Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA- group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients.

Development of nurses' knowledge questionnaire of chest tube maintenance and management.

OBJECTIVE: The lack of chest tube maintenance and management knowledge in nurses can lead to serious adverse consequences. The purpose of this study was to develop a chest tube maintenance and management knowledge questionnaire for clinical nurses, and to verify its reliability and validity. METHODS: Based on literature review and expert consultation, a questionnaire on chest tube maintenance and management knowledge of clinical nurses was designed, and the reliability and validity of the questionnaire were tested in 60 clinical nurses. RESULTS: The initial questionnaire of chest tube maintenance and management knowledge for clinical nurses included 20 items, and three dimensions were finally determined by expert consultation method, including 15 items. The Cronbach's α coefficient of the questionnaire was 0.850, and the Cronbach's α coefficient of each dimension ranged from 0.704 to 0.743. Spearman-brown's split reliability was 0.756. The content validity (content validity index [CVI]) of each item of the questionnaire ranged from 0.833 to 1.000, and the total CVI was 0.978. CONCLUSIONS: The clinical nurses' knowledge questionnaire developed in this study has good reliability and validity, which can effectively and objectively evaluate clinical nurses' mastery of chest tube maintenance and management knowledge.

An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming.

Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo. Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming.

Evi5 is required for Xenopus limb and tail regeneration.

Amphibians such as salamanders and the African clawed frog Xenopus are great models for regeneration studies because they can fully regenerate their lost organs. While axolotl can regenerate damaged organs throughout its lifetime, Xenopus has a limited regeneration capacity after metamorphosis. The ecotropic viral integrative factor 5 (Evi5) is of great interest because its expression is highly upregulated in the limb blastema of axolotls, but remains unchanged in the fibroblastema of post-metamorphic frogs. Yet, its role in regeneration-competent contexts in Xenopus has not been fully analyzed. Here we show that Evi5 is upregulated in Xenopus tadpoles after limb and tail amputation, as in axolotls. Down-regulation of Evi5 with morpholino antisense oligos (Mo) impairs limb development and limb blastema formation in Xenopus tadpoles. Mechanistically, we show that Evi5 knockdown significantly reduces proliferation of limb blastema cells and causes apoptosis, blocking the formation of regeneration blastema. RNA-sequencing analysis reveals that in addition to reduced PDGFα and TGFß signaling pathways that are required for regeneration, evi5 Mo downregulates lysine demethylases Kdm6b and Kdm7a. And knockdown of Kdm6b or Kdm7a causes defective limb regeneration. Evi5 knockdown also impedes tail regeneration in Xenopus tadpoles and axolotl larvae, suggesting a conserved function of Evi5 in appendage regeneration. Thus, our results demonstrate that Evi5 plays a critical role in appendage regeneration in amphibians.

One-pot multi-step cascade protocols toward ß-indolyl sulfoximidoyl amides via intermolecular trapping of an α-indolylpalladium complex by CO.

Various ß-indolyl sulfoximidoyl amides were efficiently prepared from ortho-iodoanilines, propargyl bromides, 1 atm of CO, and substituted NH-sulfoximines, through a palladium-catalyzed indole annulation/carbonyl insertion/C-N bond formation cascade. Mostly good to high yields of the products were obtained through this multi-step, one-pot reaction protocol under very gentle reaction conditions. The obtained ß-indolyl sulfoximidoyl amides could be converted into biologically interesting sulfoximine analogues that contain a tryptamine moiety.

Effect of Musk Tongxin Dropping Pill on Myocardial Remodeling and Microcirculation Dysfunction in Diabetic Cardiomyopathy.

OBJECTIVE: To explore the effect of Musk Tongxin Dropping Pill (MTDP) on myocardial remodeling and microcirculation dysfunction in diabetic cardiomyopathy (DCM). METHODS: Forty male SD rats were randomly divided into control group (control group, n = 10), DCM model group (DCM group, n = 10), DCM model + pioglitazone group (DCM + PLZ group, n = 10), and DCM model + MTDP group (DCM + MTDP group, n = 10). An intraperitoneal single injection of 65 mg/kg streptozotocin (STZ) was used to establish rat model of DCM and the rats in control group were treated with the same dose of sodium citrate buffer solution. DCM + PLZ group was treated with 3 mg/kg/d PLZ by ig after modeling, DCM + MTDP group was treated with 22 mg/kg/d MTDP by ig, and DCM group was treated with 2 ml/kg/d sodium carboxymethyl cellulose (CMC-Na) by ig. The general condition of rats was continuously observed. After intervening for 3 weeks, the random blood glucose of rats was detected by tail vein, and the echocardiography examination was performed. Blood specimens were collected from the abdominal aorta, serum nitric oxide (NO) and endothelin-1 (ET-1) were detected to estimate endothelial function, and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1ß, malondialdehyde (MDA), and superoxide dismutase (SOD) were detected to observe the changes of inflammation and oxidative stress indexes. The heart mass index (HMI) was calculated through the ratio of heart mass (HM) to the corresponding body mass (BM). Myocardial pathological tissue staining was performed. RESULTS: Compared with control group, blood glucose in other three groups was higher. Left ventricular end systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) in DCM group showed a significant increase, while left ventricular ejection fraction (LVEF) and heart rate (HR) in this group displayed an obvious decrease (P < 0.01). BM and HM in DCM group exhibited a reduction, and HM/BM × 103 revealed an apparent increase (P < 0.01). The levels of serum NO and SOD were distinctly downregulated (P < 0.01), and the levels of ET-1, MDA, TNF-α, IL-1ß, and IL-6 were remarkably upregulated (P < 0.01). Compared with DCM group, a significant decrease was observed in LVSD and LVDD in DCM + MTDP group, while LVEF and HR obviously increased (P < 0.05). BM and HM indicated an apparent increase, but HM/BM ×103 reduced distinctly (P < 0.01). The levels of serum NO and SOD were markedly upregulated (P < 0.05), and the levels of ET-1, MDA, TNF-α, IL-1ß, and IL-6 were significantly downregulated (P < 0.05). HE staining showed that myocardial cells arranged neatly in the control group but not in the DCM group. The intercellular space between myocardial cells in DCM group increased, accompanied by damage of myocardial fibers and infiltration of inflammatory cells. Masson staining displayed an increase in interstitial collagen fibers in DCM group. Carstairs staining showed that microembolization occurred in the myocardium in DCM group, while in DCM + MTDP and DCM + PLZ groups the corresponding myocardial pathological changes were significantly improved. CONCLUSIONS: MTDP might show a positive effect on myocardial remodeling and microcirculation dysfunction in DCM rats.

Shexiang Tongxin dropping pill protects against sodium laurate-induced coronary microcirculatory dysfunction in rats.

OBJECTIVE: To investigate the protective effects of Shexiang Tongxin dropping pill (, STDP) in a rat model of coronary microcirculatory dysfunction (CMD). METHODS: Sprague-Dawley rats were allocated randomly into four groups: sham, CMD model, STDP, and nicorandil. After 4 weeks of treatment, CMD was induced by injection of sodium laurate (0.2 mL, 2 g/L) into the left ventricle while obstructing the ascending aorta. Rats in the sham group underwent an identical surgical procedure but were administered physiological (0.9% ) saline (0.2 mL). Twenty-four hours after surgery, blood samples were collected for biochemical analyses and enzyme-linked immunosorbent assays. Heart tissues were removed for histopathology staining; apoptosis and inflammatory cytokines were examined by Western blotting. RESULTS: The STDP group had a lower level of creatine kinase-myocardial band, lactate dehydrogenase, and cardiac troponin-I than that in the CMD model group. Infiltration of inflammatory cells, myocardial ischaemia, and microthrombosis were relieved in the STDP group compared with CMD model group. Levels of endothelin-1, nuclear factor-kappa B, tumour necrosis factor-α, interleukin-6, interleukin-1ß, malondialdehyde, B-cell lymphoma (Bcl)-2-associated X protein, and caspase-3 were lower, and levels of nitric oxide, Bcl-2, and superoxide dismutase were higher, in the STDP group in comparison with the CMD model group. CONCLUSION: STDP pretreatment improved the CMD induced by sodium laurate via anti-inflammatory, anti-apoptosis, and anti-oxidant mechanisms.

Resveratrol prevents TNF-α-induced VCAM-1 and ICAM-1 upregulation in endothelial progenitor cells via reduction of NF-κB activation.

OBJECTIVE: To assess the effects of resveratrol (RSV) on expression of adhesion molecules in endothelial progenitor cells (EPCs) following tumor necrosis factor-α (TNF-α) stimulation. METHODS: EPCs were treated with RSV and stimulated with TNF-α. A mononuclear cell (MNC) adhesion assay was used to assess the effects of RSV on TNF-α-induced MNC adhesion. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin expression levels and nuclear factor κB (NF-κB) activation were assessed by immunoblotting. RESULTS: MNC adhesion to TNF-α-treated EPCs and VCAM-1/ICAM-1/E-selectin levels in EPCs were increased following TNF-α stimulation and decreased following RSV treatment. TNF-α enhanced NF-κB inhibitor α (IκB-α) phosphorylation in the cytosol as well as nuclear NF-κB p65 levels, both of which were decreased by RSV. CONCLUSIONS: These findings provide new insights into RSV's anti-inflammatory and anti-atherosclerotic effects. RSV's mechanism of action might involve downregulation of VCAM-1, ICAM-1 and E-selectin by partial blockade of TNF-α-induced NF-κB activation and IκB-α phosphorylation in EPCs.

Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia.

Transarterial embolization/transarterial chemoembolization (TAE/TACE) is the acceptable palliative treatment for hepatocellular carcinoma (HCC), mainly through ischemic necrosis induced by arterial embolization. However, how HCC cells survive under such ischemic hypoxic condition remains unclear, which can be exploited to potentiate TAE/TACE treatment. We hypothesized that targeting mitophagy can increase HCC cell apoptosis during hypoxia. HCC cells were subjected to hypoxia and then mitophagy was quantified. The role of dynamin-related protein 1 (DRP1) in hypoxia-induced HCC mitophagy was determined. Moreover, the synergistic effect of hypoxia and DRP1 inhibitor on HCC apoptosis was assessed in vitro and in vivo. Clinical association between DRP1 expression and outcome for HCC patients was validated. HCC cells that survived hypoxia showed significantly increased DRP1-mediated mitochondrial fission and mitophagy compared with cells in normoxia. Hypoxia induced mitophagy in surviving HCC cells by enhancing DRP1 expression and its translocation into the mitochondria and excessive mitochondrial fission into fragments. Blocking the DRP1 heightened the possibility of hypoxic cytotoxicity to HCC cells due to impaired mitophagy and increased the mitochondrial apoptosis, which involved decreased in mitochondrial membrane potential and mitochondrial release of apoptosis-inducing factor and cytochrome c. Additionally, DRP1 inhibitor Mdivi-1 suppressed the in vivo growth of hypoxia-exposed HCC cells. High expression of DRP1 was significantly associated with shorter survival in HCC patients. In conclusion, our results demonstrate that blocking DRP1-mediated mitochondrial fission and mitophagy increases the incidence of mitochondrial apoptosis of HCC cells during hypoxia, suggesting the new approach of targeting mitophagy to potentiate TAE/TACE.

The Role of Xuefu Zhuyu Decoction in Prevention of Contrast-Induced Nephropathy after Percutaneous Coronary Intervention.

OBJECTIVE: This study aimed to investigate the effect of Xuefu Zhuyu decoction on preventing contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI). METHODS: A total of 256 patients undergoing selective PCI for coronary artery disease were consecutively enrolled and randomly divided into two groups: Group A (n = 126) and Group B (n = 130). Before and after PCI, all patients routinely received antiplatelet aggregation therapy, antilipidemic therapy, and hydration therapy. Besides routine therapy, patients in Group B received Xuefu Zhuyu decoction from 3 days before PCI to 3 days after PCI. Serum creatinine (Scr), estimated glomerular filtration rate (eGFR), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured, respectively, at baseline (72 h before PCI) and at 24, 48, and 72 h after PCI. RESULTS: Compared with Group A, Group B presented a lower fluctuation of SCr and eGFR (P < 0.01). The incidence of CIN was less in Group B. According to the definition, CIN occurred in 5 patients (2.0%) in the intervention group and 5 (4.0%) in the control group (P=0.167). In terms of oxidative stress, Group B had a lower MDA (P < 0.05), but a higher SOD (P < 0.05). CONCLUSIONS: Compared with the control group, Xuefu Zhuyu decoction intervention therapy increased the level of SOD and reduced MDA. The Xuefu Zhuyu decoction intervention group presented a higher level of eGFR at 24, 48, and 72 h after PCI in patients with coronary heart disease and a lower level of Scr. The results are propitious to prove that Xuefu Zhuyu decoction might play an antioxidative stress role in the prevention of CIN after PCI.

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis.

BACKGROUND: An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help. METHODS: The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis. RESULTS: Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P < 0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.22), P < 0.00001; current smoking: OR =2.51, 95% CI(1.39, 3.32), P = 0.0006). The proportion of underlying diseases such as hypertension, diabetes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (diabetes: OR=3.68, 95% CI (2.68, 5.03), P < 0.00001; hypertension: OR = 2.72, 95% CI (1.60,4.64), P = 0.0002; cardiovascular disease: OR = 5.19, 95% CI(3.25, 8.29), P < 0.00001; respiratory disease: OR = 5.15, 95% CI(2.51, 10.57), P < 0.00001). Clinical manifestations such as fever, shortness of breath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.82), P = 0.003;shortness of breath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P < 0.00001]. Laboratory examination such as aspartate amino transferase(AST) > 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > 28pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(LDH) > 245U/L, and D-dimer > 0.5mg/L predicted the deterioration of disease while white blood cells(WBC)<4 × 109/L meant a better clinical status[AST > 40U/L:OR=4.00, 95% CI (2.46, 6.52), P < 0.00001; Cr ≥ 133µmol/L: OR = 5.30, 95% CI (2.19, 12.83), P = 0.0002; hs-cTnI > 28 pg/mL: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; PCT > 0.5 ng/mL: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001;LDH > 245U/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; D-dimer > 0.5mg/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; WBC < 4 × 109/L: OR = 0.30, 95% CI (0.17, 0.51), P < 0.00001]. CONCLUSION: Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.

Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/ß-catenin positive feedback loop.

BACKGROUND: Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities. METHODS: HCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress. RESULTS: CM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on ß-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced ß-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/ß-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown. CONCLUSIONS: We identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/ß-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.