Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

Liver cirrhosis affects the structures and physiological functions of the intestine. Our previous study revealed that liver injury inhibited 25-hydroxylation of vitamin D (25(OH)-VD). The aim of this study was to investigate the roles and mechanisms of vitamin D in liver cirrhosis-induced intestinal injury. The rat liver cirrhosis model was established through the administration of carbon tetrachloride (CCl4) for 8 weeks. Hematoxylin-eosin staining was performed to unveil the intestinal injury induced by liver cirrhosis. Enzyme-linked immunosorbent and reverse transcription PCR (RT-PCR) analysis were used to determine the levels of 25(OH)-VD, vitamin D receptor, Cytochrome P450 24A1 (CYP24A1), and α-defensin 5 (DEFA5) in rat and human serum of liver cirrhosis. Furthermore, liver cirrhosis rats were treated with low-dose (500 IU/kg) and high-dose (2,000 IU/kg) vitamin D intraperitoneally. The expression levels of TLR4/MyD88/NF-κB signaling pathway were evaluated by RT-PCR and Western blot. In conclusion, we determined the deficiency of vitamin D and down-regulation of DEFA5 and intestinal damage induced by liver cirrhosis. Moreover, vitamin D effectively inhibited liver cirrhosis-induced intestinal inflammation and oxidative stress through the TLR4/MyD88/NF-κB pathway. Vitamin D might be a promising therapeutic strategy for future treatment of liver-induced intestinal injury.

Metallothionein-2A Protects Cardiomyocytes from Hypoxia/reper-Fusion through Inhibiting p38.

The reperfusion of coronary artery blood supply is often accompanied by myocardial hypoxia/reperfusion (H/R) injury, and induced cardiomyocytes apoptosis. The activation of p38 can induce apoptosis, thereby aggravating the myocardial H/R injury. Metallothionein-2A (MT2A) has the functions of anti-apoptosis and protective effect through p38. However, it is not clear that MT2A may protect cardiomyocytes from H/R injury through p38 signaling pathway. Here, we constructed an H/R model for H9c2 cardiomyocytes to explore the protective effect of MT2A on cardiomyocytes apoptosis during the process of H/R through p38 signal pathway. The results revealed that both endogenously overexpressed MT2A and exogenously added MT2A can inhibit the active expression of p-p38 and cleaved caspase-3 under H/R. Based on our results, H/R induced cardiomyocytes apoptosis and activation of p38. And, MT2A can inhibit the active expression of caspase-3 and p38. We found that MT2A can protect cardiomyocytes apoptosis from H/R injury through p38 signaling pathway.

Treatment Effect of Qingfei Paidu Decoction Combined With Conventional Treatment on COVID-19 Patients and Other Respiratory Diseases: A Multi-Center Retrospective Case Series.

Background: Qingfei Paidu decoction (QFPDD) has been widely used in treating coronavirus disease 2019 (COVID-19) in China. However, studies on the treatment effect of COVID-19 patients and other respiratory diseases have not been well demonstrated. Our study aims to determine the treatment effect of QFPDD in combination with conventional treatment on COVID-19 patients and other respiratory diseases. Methods: This retrospective study recruited COVID-19 patients who were treated with QFPDD for at least two courses (6 days) from seven hospitals in five provinces from January 21 to March 18 2020. Demographic, epidemiological, clinical, laboratory, computed tomography characteristics, treatment, and outcome data were collected and analyzed. The improvements in clinical symptoms before and after QFPDD treatment were compared. Results: Eight COVID-19 patients were included in this study. Of them, six were males (75.0%). The median age of the patients was 66 (60-82) years. Four patients were classified as mild and moderate cases (50.0%); there were two severe cases (25.0%) and critical cases (25.0%). The most common symptom was cough (7 [87.5%]), followed by fever (6 [75.0%]), fatigue (4 [50.0%]), asthma (4 [50.0%]), and anorexia (3 [37.5%]). Abnormal findings included decrease in neutrophils (3 [37.5%]), lymphocytes (2 [25.0%]), alkaline phosphatase (3 [37.5%]), lactic dehydrogenase (4 [50.0%]), erythrocyte sedimentation rate (2 [25.0%]), and C-reactive protein (5 [83.3%]) at admission. After one course (3 days) of QFPDD, nasal obstruction and sore throat completely disappeared, and fever (5 [83.3%]), fatigue (2 [50.0%]), and cough (2 [28.6%]) were improved. After two courses (6 days), the fever disappeared completely in all patients, and the other symptoms showed a tendency to improve. In non-severe patients, 87.5% baseline symptoms completely disappeared. In severe patients, 61.1% of the baseline symptoms completely disappeared after patients were administered QFPDD for two courses. Of the abnormal indicators, 55.6% returned to normal levels. The median duration to complete fever recovery was 1.0 day. The median durations of viral shedding and hospitalization were 10.5 and 21.5 days, respectively. None of the patients worsened and died, and no serious adverse events occurred related to QFPDD during hospitalization. Conclusion: QFPDD combined with conventional treatment improved clinical symptoms in COVID-19 patients with other respiratory diseases, and no serious adverse reactions associated with QFPDD were observed. Larger sample studies confirm our findings in the future.

Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis.

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.

Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.

Association of common medical comorbidities with early renal damage in the Chinese tropics with essential hypertension.

BACKGROUND: Urine albumin/creatinine ratio (UACR) is an important marker of early renal damage (ERD) caused by hypertension. Recent studies showed that blood pressure was a significant inverse association with temperature and climate. The purposes of our study were sought to explore the association of common medical comorbidities with ERD, and find independent risk factors to ERD in Chinese tropics with essential hypertension. METHODS: From January 2018 to December 2019, we assessed UACR in a total of 599 hypertensive Chinese Hainan patients. We defined ERD as a UACR between 30 mg/g and 300 mg/g. We analysed differences between qualitative variables using the chi-squared (χ2) test. We calculated correlations between UACR and age, hypertension duration (HD), systolic blood pressure (SBP), and diastolic blood pressure (DBP) using the Spearman's rho test. To determine the odds ratio (OR), we evaluated binary logistic regression models. RESULTS: Among the 599 patients, 281 (46.9%) were found to have ERD. ERD and factors related to sex, body mass index (BMI), and SBP did not differ significantly (all, p>0.05). Our main findings showed that age, HD, and DBP were associated with ERD (p<0.01, respectively). Furthermore, age ≥ 65 years, HD ≥10 years, DBP ≥ 90 mmHg, SBP ≥ 160 mmHg, and diabetes differed significantly according to ERD status (p < 0.05, respectively). In multivariate analysis using stepwise regression, age (OR = 1.468), DBP (OR = 1.853), and diabetes (OR = 2.031) were significant independent predictors of ERD. The area under the receiver operating characteristic (ROC) curve was 0.677, and the sensitivity and specificity of the optimal cut-off value were 44.5 and 81.1%, respectively. CONCLUSIONS: Common medical comorbidities are associated with ERD; age, DBP, and diabetes are independent risk factors for ERD in patients with essential hypertension who live in the Chinese tropics. Early monitoring of the UACR, as well as control of blood glucose and DBP, can effectively delay ERD.

Clinical characteristics and treatment outcome of COVID-19 patients with stroke in China: A multicenter retrospective study.

OBJECTIVE: Previous studies mainly reported the clinical characteristics of novel coronavirus 2019 (COVID-19) infections, but the research on clinical characteristics and treatment outcomes of COVID-19 patients with stroke is still rare. METHODS: A multi-center retrospective study was conducted at 11 hospitals in 4 provinces of China, and COVID-19 patients with stroke were enrolled from February 24 to May 4, 2020. We analyzed epidemiological, demographic, and clinical characteristics of cases as well as the laboratory test results, treatment regimens and outcomes, and the clinical characteristics and therapeutic outcomes were compared between severe and nonsevere patients, and by age group, respectively. RESULTS: A total of 27 patients [mean age: 66.41 (SD 12.1) years] were enrolled. Among them, 9 (33.3%) were severe patients and 18 (66.7%) were nonsevere patients; 17 (63.0%) were female; 19 (70.4%) were aged 60 years and above. The most common symptoms were fever [19 (70.4%)], fatigue [12 (44.4%)] and cough [11 (40.7%)], respectively. Abnormal laboratory findings of COVID-19 patients with stroke included high levels of C-reactive protein [19 (73.1%)], D-dimer [14 (58.3%)], blood glucose [14 (53.8%)], fibrinogen [13 (50.0%)], and decreased lymphocytes [12 (44.4%)]. Comparing to nonsevere cases with stroke, severe patients with stroke were likely to be older, susceptible to receiving oxygen inhalation, and had more complications (p < 0.05). In addition, there were significant differences in lymphocytes, neutrophils, lactate dehydrogenase, C-reactive protein, creatine kinase between the severe cases and nonsevere cases (p < 0.05). The older patients had a decreased platelet count and elevated fibrinogen, compared with the younger (p < 0.05). All patients (100%) received antiviral treatment, 12 (44.4%) received antibiotics treatment, 26 (96.3%) received Traditional Chinese Medicine (Lung cleansing & detoxifying decoction), and oxygen inhalation was in 18 (66.7%). The median duration of hospitalization was 16 days. By May 4, 2020, a total of 26 (96.3%) patients were cured and discharged, and 1 (3.7%) patients died. CONCLUSION: COVID-19 patients with stroke had poor indicators of coagulation system, and severe and older patients might have a higher risk of complications and unfavorable coagulation system. However, the overall treatment outcome is favorable.

Association between early treatment with Qingfei Paidu decoction and favorable clinical outcomes in patients with COVID-19: A retrospective multicenter cohort study.

The coronavirus disease 2019 (COVID-19) epidemic has been almost controlled in China under a series of policies, including "early diagnosis and early treatment". This study aimed to explore the association between early treatment with Qingfei Paidu decoction (QFPDD) and favorable clinical outcomes. In this retrospective multicenter study, we included 782 patients (males, 56 %; median age 46) with confirmed COVID-19 from 54 hospitals in nine provinces of China, who were divided into four groups according to the treatment initiation time from the first date of onset of symptoms to the date of starting treatment with QFPDD. The primary outcome was time to recovery; days of viral shedding, duration of hospital stay, and course of the disease were also analyzed. Compared with treatment initiated after 3 weeks, early treatment with QFPDD after less than 1 week, 1-2 weeks, or 2-3 weeks had a higher likelihood of recovery, with adjusted hazard ratio (HR) (95 % confidence interval [CI]) of 3.81 (2.65-5.48), 2.63 (1.86-3.73), and 1.92 (1.34-2.75), respectively. The median course of the disease decreased from 34 days to 24 days, 21 days, and 18 days when treatment was administered early by a week (P < 0.0001). Treatment within a week was related to a decrease by 1-4 days in the median duration of hospital stay compared with late treatment (P<0.0001). In conclusion, early treatment with QFPDD may serve as an effective strategy in controlling the epidemic, as early treatment with QFPDD was associated with favorable outcomes, including faster recovery, shorter time to viral shedding, and a shorter duration of hospital stay. However, further multicenter, prospective studies with a larger sample size should be conducted to confirm the benefits of early treatment with QFPDD.

Several newly discovered Mo-enriched plants with a focus on Macleaya cordata.

Phytoremediation as an alternative strategy has been a widespread attention. The screening of enriched plants and hyperaccumulators is the key of the strategy. So this study examined the status of heavy metal pollution in molybdenum (Mo) mine soils, metal accumulation in plants growing on mine, and their tolerance strategies. The analysis of 14 soils and 27 plant samples in mining area showed that Mo, zinc (Zn), and cadmium (Cd) concentrations exceeded soil safety standards and their levels varied in 27 plant samples. Mo was the heavy pollution with an average total content of 256.1 mg/kg in soils. As Mo-enriched plants, Mo concentrations of Macleaya cordata (Willd.) R. Br. and Morus australis Poir. were 704.4 and 772.4 mg/kg, respectively. M. cordata was selected as the research material, due to its high biomass. Molybdenum significantly decreased the biomass and photosynthesis of M. cordata at high concentration (> 200 µmol/L), but its biomass and photosynthesis reached the maximum after 50 µmol/L Mo treatment, respectively. Analysis of the subcellular distribution and chemical speciation showed that Mo was distributed a certain way in the extracts and that this suggested that it may be present in cell wall and soluble fraction of roots (51.9-63.9%; 26.1-44.7%) or shoots (30.0-44.4%; 47.3-56.0%) and complexed to organic acid, pectate, oxalate, and protein. This might be responsible for the adaptation of M. cordata to Mo stress. Therefore, M. cordata could serve as a potential plant to utilize for the phytoremediation of Mo-contaminated soil.

Mammalian Metallothionein-2A and Oxidative Stress.

Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation. For many years, most studies evaluating the effects of MT2A have focused on reactive oxygen species (ROS), as second messengers that lead to oxidative stress injury of cells and tissues. Recent studies have highlighted that oxidative stress could activate mitogen-activated protein kinases (MAPKs), and MT2A, as a mediator of MAPKs, to regulate the pathogenesis of various diseases. However, the molecule mechanism of MT2A remains elusive. A deeper understanding of the functional, biochemical and molecular characteristics of MT2A would be identified, in order to bring new opportunities for oxidative stress therapy.

Interposed abdominal compression-cardiopulmonary resuscitation after cardiac surgery.

OBJECTIVES: The management of cardiac arrest after cardiac surgery differs from the management of cardiac arrest under other circumstances. In other studies, interposed abdominal compression-cardiopulmonary resuscitation (IAC-CPR) resulted in a better outcome compared with conventional CPR. The aim of the present study was to determine the feasibility, safety and efficacy of IAC-CPR compared with conventional CPR in patients with cardiac arrest after cardiac surgery. METHODS: Data on all cardiac surgical patients who suffered a sudden cardiac arrest during the first 24 h after surgery were collected prospectively. Cardiac arrest was defined as the cessation of cardiac mechanical activity with the absence of a palpable central pulse, apnoea and unresponsiveness, including ventricular fibrillation, asystole and pulseless electrical activity. Forty patients were randomized to either conventional CPR (n = 21) or IAC-CPR (n = 19). IAC-CPR was initially performed by compressing the abdomen midway between the xiphoid and the umbilicus during the relaxation phase of chest compression. If spontaneous circulation was not restored after 10-15 min, the surgical team would immediately proceed to resternotomy. The endpoints of the study were safety, return of spontaneous circulation (ROSC) >5 min, survival to hospital discharge and survival for 6 months. RESULTS: With IAC-CPR, there were more patients in terms of ROSC, survival to hospital discharge, survival for 6 months and fewer CPR-related injuries compared with patients who underwent conventional CPR. CONCLUSIONS: IAC-CPR is feasible and safe and may be advantageous in cases of cardiac arrest after cardiac surgery.

Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2.

AIMS: Cardiovascular diseases cause significant morbidity and mortality worldwide. Recently, our research team demonstrated that a multifunctional cytokine, pigment epithelium-derived factor (PEDF), plays a critical role in regulating myocardial infarction. However, few researchers have studied the molecular mechanisms by which PEDF and its receptors influence the pathophysiology of cardiovascular disease. We tested the hypothesis that PEDF affects cardiomyocyte apoptosis under hypoxic conditions and determined the role that its receptors phospholipase A2 (PLA2) and laminin receptor play in this process. MAIN METHODS: Cardiomyocytes were isolated from neonatal mice and treated with PEDF under normoxic and hypoxic conditions; then, apoptosis was assessed using Annexin V/PI staining and flow cytometry. Western blotting and immunofluorescence staining were used to detect PEDF receptor expression, and siRNA knockdown of PEDF receptors was performed to determine which receptor was involved in mediating cardiomyocyte apoptosis. KEY FINDINGS: Our results demonstrated that PEDF increased cardiomyocyte apoptosis during hypoxia via Fas and that PEDF receptors were expressed on cardiomyocyte cell membranes. Furthermore, siRNA experiments indicated that the PEDF receptor PLA2 was responsible for inducing cardiomyocyte apoptosis via the Fas pathway. SIGNIFICANCE: PEDF promoted Fas-induced cardiomyocyte apoptosis via its receptor PLA2.