Phlorizin, a novel caloric restriction mimetic, stimulates hypoxia and protects cardiomyocytes through activating autophagy via modulating the Hif-1α/Bnip3 axis in sepsis-induced myocardial dysfunction.

BACKGROUND: Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD. MATERIALS AND METHODS: In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 µM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes. RESULTS: In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes. CONCLUSION: We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis.

Case Report: Non-negligible Epstein-Barr virus-associated posttransplant lymphoproliferative disorders in a lung transplant recipient.

Background: Posttransplant lymphoproliferative disorders (PTLDs) are uncommon but serious complications in patients following solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is a risk factor for the development of PTLD, especially early-onset PTLD, in EBV-negative recipients. To date, however, there are no specific guidelines on the threshold of EBV-DNA load for therapeutic intervention, the source for measurement (e.g., blood, bronchoalveolar fluid), or the use of antiviral agents as prophylaxis for early PTLD prevention in EBV-mismatched patients. Methods: The present study describes a 56-year-old male lung transplant recipient diagnosed with EBV-associated PTLD. Results: This patient had a history of invasive fungal disease and Mucor and Aspergillus fumigatus infections in the early post-transplant period, necessitating antifungal therapy throughout the course of the disease. The patient was EBV-positive 15 days after transplantation, with lung CT showing multiple bilateral nodules of varying sizes beginning 98 days after transplantation. A lung biopsy showed PTLD, and next-generation sequencing (NGS) revealed EBV. This patient, however, did not receive any antiviral therapy for early PTLD prevention or any PTLD-related treatment. He died 204 days after lung transplantation. Conclusion: The present study describes a lung transplant recipient who developed EBV-associated PTLD, a non-negligible disease, after solid organ transplantation. Monitoring EBV-DNA load is important, as a sudden increase may be a sensitive indicator of PTLD. An earlier diagnosis may increase the likelihood of successful treatment.

Clinical research progress on drugs for non-alcoholic steatohepatitis treatment / 药学学报

Nonalcoholic steatohepatitis (NASH) is the leading chronic liver disease worldwide. NASH is commonly associated with metabolic risk factors, including obesity, hypertension, and diabetes. Hepatic glucose and lipid metabolism disorder, bile acid toxicity, oxidative stress, inflammation, fibrosis, intestinal dysbacteriosis, and susceptibility gene variation are involved in the pathogenesis of NASH. Drug development for NASH has been slow, this article focuses on the clinical research and development of several promising NASH drugs and their mechanisms, such as drugs targeting gut-liver axis, improving metabolism, inhibiting inflammation and fibrosis.

Clinical characteristics of 34 COVID-19 patients admitted to intensive care unit in Hangzhou, China.

OBJECTIVE: This study summarizes and compares clinical and laboratory characteristics of 34 patients admitted to the intensive care unit (ICU) for complications from coronavirus disease 2019 (COVID-19) at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China from Jan. 22 to Mar. 5, 2020. METHODS: A total of 34 patients were divided into two groups, including those who required noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) with additional extracorporeal membrane oxygenation (ECMO) in 11 patients. Clinical features of COVID-19 patients were described and the parameters of clinical characteristics between the two groups were compared. RESULTS: The rates of the acute cardiac and kidney complications were higher in IMV cases than those in NIV cases. Most patients had lymphocytopenia on admission, with lymphocyte levels dropping progressively on the following days, and the more severe lymphopenia developed in the IMV group. In both groups, T lymphocyte counts were below typical lower limit norms compared to B lymphocytes. On admission, both groups had higher than expected amounts of plasma interleukin-6 (IL-6), which over time declined more in NIV patients. The prothrombin time was increased and the levels of platelet, hemoglobin, blood urea nitrogen (BUN), D-dimer, lactate dehydrogenase (LDH), and IL-6 were higher in IMV cases compared with NIV cases during hospitalization. CONCLUSIONS: Data showed that the rates of complications, dynamics of lymphocytopenia, and changes in levels of platelet, hemoglobin, BUN, D-dimer, LDH and IL-6, and prothrombin time in these ICU patients were significantly different between IMV and NIV cases.

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.

OBJECTIVE: To study the clinical characteristics of patients in Zhejiang province, China, infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) responsible for coronavirus disease 2019 (covid-2019). DESIGN: Retrospective case series. SETTING: Seven hospitals in Zhejiang province, China. PARTICIPANTS: 62 patients admitted to hospital with laboratory confirmed SARS-Cov-2 infection. Data were collected from 10 January 2020 to 26 January 2020. MAIN OUTCOME MEASURES: Clinical data, collected using a standardised case report form, such as temperature, history of exposure, incubation period. If information was not clear, the working group in Hangzhou contacted the doctor responsible for treating the patient for clarification. RESULTS: Of the 62 patients studied (median age 41 years), only one was admitted to an intensive care unit, and no patients died during the study. According to research, none of the infected patients in Zhejiang province were ever exposed to the Huanan seafood market, the original source of the virus; all studied cases were infected by human to human transmission. The most common symptoms at onset of illness were fever in 48 (77%) patients, cough in 50 (81%), expectoration in 35 (56%), headache in 21 (34%), myalgia or fatigue in 32 (52%), diarrhoea in 3 (8%), and haemoptysis in 2 (3%). Only two patients (3%) developed shortness of breath on admission. The median time from exposure to onset of illness was 4 days (interquartile range 3-5 days), and from onset of symptoms to first hospital admission was 2 (1-4) days. CONCLUSION: As of early February 2020, compared with patients initially infected with SARS-Cov-2 in Wuhan, the symptoms of patients in Zhejiang province are relatively mild.

Effect of Gualou Xiebai Banxiatang on Expression of Gal-3 in Rats After Myocardial Infarction / 中国实验方剂学杂志

Objective:To observe the effect of Gualou Xiebai Banxiatang（GXBT） on cardiac function and myocardial fibrosis in rats after myocardial infarction. Method:The 36 male SD rats were randomly divided into blank group, sham group and surgical group, and 6 males in blank group and sham operation group. The model of phlegm obstruction in myocardial infarction of rats was replicated by ligation of left anterior descending coronary artery and high fat diet, and the successful rats were randomly divided into 3 groups: model group, GXBT group and acertil group. In the sham group, only the threading was not ligated. The blank group and the sham group and the model group were given 10 mL·kg-1·d-1 of normal saline, and 2.68 g·kg-1·d-1 of the GXBT group were given intragastric administration，and 0.36 mg·kg-1·d-1 was given intragastrically in acertil group. After 4 weeks of model, the heart function was detected by heart ultrasound to verify the success of the model. After 8 weeks, the heart function of the heart of the rat was detected by heart ultrasound again, and then the samples were sacrificed. The pathological changes of the myocardial cells of the rats were observed with hematoxylin-eosin(HE) staining， and the degree of myocardial fibrosis in the rats was observed by Masson staining. The changes of serum B-type natriuretic peptide (BNP) and galectin-3 (Gal-3) in rat serum were detected by enzyme-linked immunosorbent assay（ELISA） method, and the expression of Gal-3, Collagen Ⅰ (Col-Ⅰ) and Collagen Ⅲ (Col-Ⅲ) was detected by Western blot. Result:Compared with blank group and sham group, the left ventricular ejection fraction (EF) and short-axis shortening rate (FS) of model group were significantly decreased (P<0.01)， the infiltration of inflammatory cells, the increase of the myocardial collagen fibers, the contents of BNP and Gal-3 in the serum were increased (P<0.05). The expression of Gal-3,Col-Ⅰ and Col-Ⅲ in the myocardial tissue increased significantly (P<0.01). Compared with the model group, EF and FS of GXPD were significantly increased (P<0.05), the morphological structure of myocardial cells was improved, the collagen fiber was decreased. The expression of BNP and Gal-3 in serum decreased significantly (P<0.05), and the content of Gal-3, Col-Ⅰ and Col-Ⅲ in myocardial tissue was decreased (P<0.05). Conclusion:Gualou Xiebai Banxiatang can improve cardiac function, reduce myocardial fibrosis and slow down the process of heart failure after myocardial infarction in rats with myocardial infarction. Its mechanism may be related to the decrease of Gal-3 expression.

[The clinical application of remote critical care network].

OBJECTIVE: To discuss and evaluate whether a remote critical care program network can improve clinical and economic performance across multiple intensive care units (ICUs). METHODS: The consultative center composed of intensivists and physician extenders to provide remote consultations for the critical patients. Supporting software, including electronic data display and communication interface were available both in the ICU center and at the remote sites. Clinical and economic performance after 1 year application of the program was compared with the performance before the intervention. RESULTS: During January 2008 to July 2009, there had been 63 hospitals in Zhejiang Province joined the network. A total of 1 617 patients had received remote critical care consultations. One hundred and seventy-three remote teaching ward rounds and 72 lectures had been conducted on the network during this period. The before-and after-data comparison for 23 hospitals which had joined the network for longer than 1 year showed that, the program had decreased ICUs raw mortality by 11.6% (12.9% vs. 14.6%), and reduced transfer rate by 38.3% (2.9% vs. 4.7%), and ICUs bed occupancy rate increased by 6.1% (83.4% vs. 78.6%). CONCLUSION: The application of a remote critical care program was associated with improved clinical outcomes of critically ill patients and hospital financial performance.

Tumstatin185-191 increases the sensitivity to cisplatin in a cisplatin-resistant human lung adenocarcinoma cell line / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the effects and related mechanisms of Tumstatin 185-191 as a single agent or in combination with cisplatin on proliferation and apoptosis in a cisplatin-resistant human lung adenocarcinoma cell line A549-DDP cells.</p><p><b>METHODS</b>A549-DDP cells were treated with Tumstatin185-191 and cisplatin at varying concentrations. Cell viability was assessed by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 50% inhibiting concentration (IC(50)) values of the chemotherapeutic drugs were analyzed by MTT assay. Cell apoptosis was measured by flow cytometry. The activation of Akt and ERK was evaluated by Western blotting.</p><p><b>RESULTS</b>Tumstatin185-191 inhibited the proliferation of A549-DDP cells and its IC(50) value was 80.25 micromol/L. After cotreatment with 20 micromol/L Tum185-191, the IC(50) value of cisplatin in A549-DDP cells reduced from 77.16 micromol/L to 57.97 micromol/L, the reverse index was 1.33, while with 40 micromol/L Tumstatin185-191 the IC(50) was reduced from 77.16 to 26.40 micromol/L and the reverse index was 2.92. The early apoptosis rate was 19.5% +/- 1.1% in the cotreatment group, while 13.3% +/- 1.5% in cisplatin group and 10.2% +/- 2.0% in Tum185-191 group (F = 4.09, P < 0.05). The levels of phospho-Akt (p-Akt) and phospho-ERK (p-ERK) in the A549-DDP cells were remarkably lower after treatment with Tumstatin 185-191. The Tumstatin 185-191 treatment alone or in combination with cisplatin had a similar effect on the protein levels of p-Akt and p-ERK in A549-DDP cells.</p><p><b>CONCLUSION</b>Our data suggest that Tumstatin185-191 may promote apoptosis, downregulate proliferation and partly reverse the drug resistance of A549-DDP cells to cisplatin. The effects induced by Tum185-191 may be mediated through inactivation of the Akt and ERK pathways.</p>

Quantitative structure activity relationship models based on heuristic method and gene expression programming for the prediction of the pK(a) values of sulfa drugs / 药学学报

Quantitative structure-property relationships (QSPR) were developed to predict the pK(a) values of sulfa drugs via heuristic method (HM) and gene expression programming (GEP). The descriptors of 31 sulfa drugs were calculated by the software CODESSA, which can calculate constitutional, topological, geometrical, electrostatic, and quantum chemical descriptors. HM was also used for the preselection of 4 appropriate molecular descriptors. Linear and nonlinear QSPR models were developed based on the HM and GEP separately and two prediction models lead to a good correlation coefficient (R) of 0.90 and 0.95. The two QSPR models are tseful in predicting pK(a) during the discovery of new drugs and providing theory information for studying the new drugs.

Determination of tetrandrine and fangchinoline in Radix Stephaniae tetrandrae and its preparation by nonaqueous capillary chromatography / 中国中药杂志

<p><b>OBJECTIVE</b>To establish a new method for the determination of fangchinoline and tetrandrine in Stephania tetrandra and Fengtongan capsule by noanqueous capillary electrophoresis.</p><p><b>METHOD</b>Separation was carried out in an uncoated fused capillary (50 cm x 75 microm i.d.) with a running buffer containing 50 mmol x L(-1) ammonium acetate, 1.0% acetic acid and 20% acetonitrile in methanol. A separation voltage of 20 kV and a UV detector wavelength at 214 nm were adopted. Sample was introduced from the anode.</p><p><b>RESULT</b>The calibration ranges were 1.00, 500 mg x L(-1) for both analytes. Under the optimum conditions, the relative standard deviation (RSD, n = 6) for the migration time of each analyte were 0.09%, 1.9% (intra-day) and 0.63%, 1.9% (inter-day); The RSD for the peak area of each analyte were 0.45%, 5.9% (intra-day) and 2.3%, 5.6% (inter-day), respectively. The contents of the analytes were determined easily with average recoveries 102% for fangchinoline and 105% for tetrandrine in S. tetrandra and 94.6% for fangchinoline and 98.7% for tetrandrine in Fengtongan capsules, respectively.</p><p><b>CONCLUSION</b>The proposed method is simple, rapid, accurate and higher repeatable, and can be used to control of the quality of S. tetrandra and Fengtongan capsules.</p>