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Aim. To explore the expression levels of miR-210, miR-137, and miR-153 in patients with acute cerebral infarction. Material and Methods. 76 patients with acute cerebral infarction treated in our hospital from April 2016 to October 2017 were enrolled as the observation group. Another 64 normal patients were selected as the control group. The patients were divided into the death and survival groups based on 1-year mortality of patients. qRT-PCR was used to detect the expression of miR-210, miR-137, and miR-153 in the serum of each group. Receiver operating characteristic (ROC) curve was employed to analyze the diagnostic value and predictive value of miR-210, miR-137 and miR-153 death in patients. The correlation between miR-210, miR-137, and miR-153 in the serum of the observation group was analyzed by Pearson’s test. Results. Levels of miR-210 and miR-137 in the observation group were significantly lower than those in the control group, while levels of miR-153 in the observation group were significantly higher than those in the control group (all P < 0.05 ). The ROC curve of diagnosis of acute cerebral infarction showed that the area under curve of miR-210 was 0.836, that of miR-137 was 0.843, and that of miR-153 was 0.842. The 1-year survival rate was 71.05%. The 1-year survival of the low-expression group of miR-210 and miR-137 was significantly lower than that of the high-expression group, while the 1-year survival of the low-expression group of miR-153 was significantly higher than that of the high-expression group (all P < 0.05 ). The ROC curve for predicting death showed that the area under curve of miR-210 was 0.786, that of miR-137 was 0.824, and that of miR-153 was 0.858. Pearson’s correlation analysis showed that the expression of miR-210 was positively correlated with that of miR-137, while miR-137 was negatively correlated with that of miR-153 and miR-210 was negatively correlated with that of miR-153. Conclusion. miR-210, miR-137, and miR-153 have a certain value in the diagnosis and prediction of 1-year death of acute cerebral infarction and may be potential diagnostic and predictive indicators.

Background: Though imaging manifestations of COVID-19 and other types of viral pneumonia are similar, their clinical treatment methods differ. Accurate, non-invasive diagnostic methods using CT imaging can help develop an optimal therapeutic regimen for both conditions. Objectives: To compare the initial CT imaging features in COVID-19 with those in other types of viral pneumonia. Methods: Clinical and imaging data of 51 patients with COVID-19 and 69 with other types of viral pneumonia were retrospectively studied. All significant imaging features (Youden index >0.3) were included for constituting the combined criteria for COVID-19 diagnosis, composed of two or more imaging features with a parallel model. McNemar's chi-square test or Fisher's exact test was used to compare the validity indices (sensitivity and specificity) among various criteria. Results: Ground glass opacities (GGO) dominated density, peripheral distribution, unilateral lung, clear margin of lesion, rounded morphology, long axis parallel to the pleura, vascular thickening, and crazy-paving pattern were more common in COVID-19 (p Conclusion: The initial CT imaging features are helpful for the differential diagnosis of COVID-19 and other types of viral pneumonia.

The evidence regarding programmed cell death 1 (PD-1) inhibitors on pancreatic ductal adenocarcinoma (PDAC) with metastases remains controversial. This study aimed to assess the efficacy and safety of Nab-paclitaxel plus S1 (NPS) with or without Sintilimab, a PD-1 inhibitor, in patients with PDAC with only hepatic metastases (mPDAC). Untreated mPDAC patients who received NPS with (the combination group) or without Sintilimab (the NPS group) were retrospectively studied. Surgery was considered when the pancreatic tumor became resectable or borderline resectable on radiological examinations, and with complete metabolic response of liver metastases. Between October 2017 and February 2020, 32 patients were in the combination group and 34 patients in the NPS group. Successful salvage resection was achieved in 17 (25.8%) patients after tumor-downstaging (combination 12 vs. NPS 5, P = 0.03). The median overall survival (OS) was 16.8 months in the combination group and 10.0 months in the NPS group (P = 0.002). Remarkable OS benefit was observed in patients with decline in CA19-9 of ≥ 50% (16.0 vs. 6.5, P = 0.003), reduction in 18F-fluorodeoxyglucose uptake of primary tumor of ≥ 50% (16.5 vs. 10.0, P

The prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory due to limited effective treatment options. In this work, we investigated the therapeutic efficacy of Terbinafine for HCC and the underlying mechanism. The influence of Terbinafine on cell growth, 3D spheroid formation, clonogenic survival, and protein synthesis was investigated in human HCC cell lines. Co-immunoprecipitation, immunofluorescence, and other techniques were employed to explore how Terbinafine exerts its anticancer effect. Subcutaneous tumorigenicity assay, orthotopic and patient-derived xenograft (PDX) HCC models were used to evaluate the anticancer effect of Terbinafine monotherapy and the combinatorial treatment with Terbinafine and sorafenib against HCC. The anticancer activity of Terbinafine was Squalene epoxidase (SQLE)-independent. Instead, Terbinafine robustly suppressed the proliferation of HCC cells by inhibiting mTORC1 signaling via activation of AMPK. Terbinafine alone or in combination with sorafenib delayed tumor progression and markedly prolonged the survival of tumor-bearing mice. The synergy between Terbinafine and sorafenib was due to concomitant inhibition of mTORC1 and induction of severe persistent DNA double-strand breaks (DSBs), which led to the delayed proliferation and accelerated cell death. Terbinafine showed promising anticancer efficacy in preclinical models of HCC and may serve as a potential therapeutic strategy for HCC.

BACKGROUND: Erectile dysfunction (ED) shares common risk factors with cardiovascular disease (CVD), such as diabetes mellitus (DM) and dyslipidemia, but the relationship between the risk factors of CVD in biochemical markers and young men with ED age 20–40 years is not fully clarified. METHODS: A total of 289 ED outpatients (20–40 years old) were allocated under ED group, based on patients’ complaints and physical examinations. According to the frequency matching ratio of 1:4, 1,155 male individuals (20–40 years old) without ED were set as control group. All participants were tested for lipid profiles including total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), blood glucose (BG), homocysteine (HCY), liver function including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and renal function including uric acid (UA) and creatinine (CR). The study was designed to compare the two groups using an established binary logistic regression analysis model. The ED group was then subdivided into a younger ED group (20–30 years old) and an older ED group (31–40 years old) for further comparisons. RESULTS: After comparison, no obvious differences were found in medians of age, TC, TG, HDL, HCY, UA, and ALT in the two groups. Median LDL, BG, and CR were significantly higher and AST was much lower in the ED group (P

Background: Metabolic diseases pose considerable burden on the healthcare system worldwide, indicating the significance of prevention and treatment. In constitution theory of traditional Chinese medicine, phlegm-dampness constitution (PDC) is the common basis of metabolic diseases. In clinical practice, Huatan Qushi (HTQS) decoction targeting on PDC can effectively improve metabolic indicators. However, its underlying biochemical mechanism still remains unclear. Methods: Eight PDC participants received HTQS decoction for three months. Their blood was collected at baseline and 1 and 3 months after intervention started. Related biomedical indicators were detected. High-throughput sequencing and RT-qPCR were used for validation. Due to the missing data, repeated measures with missing values in mixed models were used. Results: After 3-month treatment, HDL-C level increased (P

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Metabolic reprogramming has been recognized as a core feature in HCC. In line with this idea, we verified that increased miR‐23a inhibited STAT5A expression and promoted glucose metabolism through activated AKT phosphorylation in HCC. This new signaling pathway may offer new treatment target for HCC patients., Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Here, we identified that increased miR‐23a expression in HCC tissues was associated with worse survival. More importantly, we found that STAT5A was a target of miR‐23a, whose levels significantly decreased in tumor tissues. Stable expression of STAT5A in Huh7 cells suppressed glucose metabolism and tumor growth. Finally, this study showed that increased miR‐23a negatively regulated STAT5A, which further activated AKT signaling to enable rapid metabolism for accelerated tumor growth in HCC. Taken together, our results demonstrated that the miR‐23a‐STAT5A‐AKT signaling pathway is critical to alter glucose metabolism in HCC and may offer new opportunities for effective therapy.

Purpose To investigate the genes of patients with sporadic endometrial cancer (EC) and suspected Lynch syndrome (LS)-related EC in the Chinese population. Identification of meaningful mutation sites can provide theoretical basis for molecular targeted therapy, aiming to improve the prognosis of patients with EC. Methods We recruited 388 patients with EC for mismatch repair (MMR) immunohistochemistry and MLH1 methylation analysis. Based on the results, they were divided into four groups: MMR without deletion group (sporadic EC group 1); MLH1P MSH2 and/or MSH6 deletion group (suspected LS group); and unclassified group (remainder cases). Patients from each group were randomly screened for whole-exome sequencing detection. Genome Analysis Toolkit, VarScant, MuTect, and CONTRA were used to detect the insertions/deletions, single nucleotide polymorphisms, and copy number variations. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction analysis was accomplished through the STRING database. Results The MMR immunohistochemistry results were positive (without MMR deletion) and negative in 299 patients and 89 patients, respectively. The 32, 10, 13, and 7 patients in the sporadic EC group 1, sporadic EC group 2, suspected LS group, and unclassified group were randomly selected for whole-exome sequencing, respectively. These three groups had a total of 86 common mutation sites, which were distributed on 26 genes. Among the top 30 common high-frequency mutation sites, 12, 5, 4, and 3 mutation sites were located on HNRNPCL1, PRAMEF1, HNRNPCL2, and CFAP74, respectively. Protein-protein interaction analysis showed that DFFB was associated with the most genes. There were some differences in the number of specific mutations in the families of different LS-related EC proband. Conclusion HNRNPCL1, PRAMEF1, CFAP74, and DFFB may be potential biomarkers for EC or LS-related EC.

Robotic pancreaticoduodenectomy (RPD) has gradually been accepted as it has overcome some of the limitations of laparoscopic surgery. Outcomes following RPD in elderly patients are still uncertain. This study aimed to evaluate the safety and feasibility of RPD in elderly patients.The demographics and perioperative outcomes of a consecutive series of patients who underwent RPD between January 2018 and September 2019, were retrospectively analyzed. Patients were divided into 2 groups: elderly patients (≥75 years) and younger patients (75 years).Of 431 patients who were included in this study, 77 were elderly patients and 354 were younger patients. Elderly patients had a significantly higher ASA score than younger patients (P 0.001). There were no significant differences in operative time, estimated blood loss and blood transfusion rate between groups (P 0.05). Elderly patients had significantly higher morbidity and longer postoperative hospital stay than younger patients (49.3% vs. 31.1%, P = 0.002; 22.8 vs. 13.3 days, P 0.001, respectively). However, the reoperation, 90-day readmission and mortality rates were comparable in the two groups (P 0.05). Multivariate analysis demonstrated that a higher ASA score was the only independent factor for postoperative morbidity (OR 2.02, 95% CI 1.06-3.88, P = 0.03), while old age was not (OR 0.81, 95% CI 0.36-1.81, P = 0.80).This study demonstrated that RDP was safe and feasible in elderly patients. Age should not be a contraindication to RPD. Elderly patients with careful patient selection should be considered for RPD.

Background: Endometriosis is a hormone- and organ-dependent disease with unclear pathogenesis. Danggui Shaoyao powder (DSP) has been used for the treatment of endometriosis for many years and has been proven to be effective, but its underlying molecular mechanisms remain unclear. In this study, we explored the molecular targets and pathways of DSP in the treatment of endometriosis mainly from the perspective of network pharmacology, and provided some novel ideas for managing this disease. Methods: In the present study, we focused on the underlying mechanisms between DPS and endometriosis, via oral bioavailability screening, drug similarity assessment, target identification, network analysis, drug relocation, and molecular docking using network pharmacology. Results: By bioinformatics, 54 active components of DSP were predicted from the 534 components provided by the TCMSP database. We then found 85 validated targets and 6059 predicted targets for herbal components, and 2241 targets for endometriosis. After mapping, there were 255 targets in common. After that, network analysis was performed to screen key networks and core targets. Ninety-nine indirect targets were collected from 14 direct ones. GO and KEGG analyses identified 63 enriched functions and 10 pathways (P

ObjectiveTo investigate the influencing factors of abnormal postpartum glucose tolerance and pregnancy recurrence in gestational diabetes mellitus (GDM) and to develop reasonable interventions to prevent postpartum glucose tolerance and recurrence of pregnancy. Methods. Retrospective analysis of clinical data of 238 GDM patients during pregnancy, including age, body mass index (BMI) before and after pregnancy, regular exercise during pregnancy, insulin use, family history of diabetes, fasting blood glucose (FPG) during pregnancy, oral glucose tolerance test (OGTT) 2 h time value, blood lipid index, and whether pregnant again. At the same time, the women were followed up by telephone or home visits to understand and guide the patient’s diet and exercise. The clinical characteristics of the two groups of patients were compared. According to the OGTT test, the recovery of glucose tolerance in pregnant women 6–8 weeks postpartum was divided into the normal postpartum glucose tolerance group and the abnormal group. Logistic multivariate analysis was used to find the influencing factors of postpartum glucose tolerance and recurrence of pregnancy. Results. Between 238 patients of followed-up, 150 pregnant women had abnormal postpartum glucose tolerance, accounting for 63.03%. There were 115 repregnants, of whom 37 (32.17%) had a recurrence of postpartum glucose tolerance. Pre and postpregnancy BMI, insulin use during pregnancy, family history of diabetes, FPG during pregnancy, OGTT 2 h values, and triglyceride (TG) were independent risk factors for abnormal postpartum diabetes and recurrence of pregnancy in GDM patients. Conclusions. Patients with GDM are at high risk of postpartum abnormal glucose tolerance and pregnancy recurrence, which may be influenced by the pregnant woman’s prepregnancy and postpartum BMI, insulin use during pregnancy, family history of diabetes, FPG, OGGT 2 h values during pregnancy, and TG levels. Therefore, health education for pregnant women should be strengthened in the clinic, with guidance on proper diet for weight control, increased exercise, and regular blood glucose screening and monitoring for those at risk.

Although soluble urokinase plasminogen activator receptor (suPAR), T helper (Th)-1 and Th17 cells are separately reported to be dysregulated and correlate with disease severity in several infection-mediated diseases, fewer studies report their interaction and clinical value in sepsis management. Thus, this study aimed to investigate the correlation of blood suPAR with Th1 and Th17 cell proportion, as well as their diagnostic and prognostic value in elderly sepsis patients. Totally, 223 elderly sepsis patients were recruited. Serum suPAR was detected by enzyme-linked immunosorbent assay. Besides, Th1 and Th17 cell proportion from CD4+ T cells were determined by flow cytometry. For sepsis severity evaluation, Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Sequential Organ Failure Assessment (SOFA) score were used. Moreover, survival profile within 28 days was documented. The mean value of suPAR, Th1 cell proportion and Th17 cell proportion was 27.5 ± 15.1 ng/mL, 15.3 ± 4.3% and 4.0 ± 2.3%, respectively. Furthermore, suPAR was positively correlated with Th1 cell proportion, Th17 cell proportion, IFN-γ, IL-17 and TNF-α. Meanwhile, suPAR was positively correlated with APACHE II score and SOFA score, so did Th17 cell proportion. Regarding their prognostic value, suPAR and Th17 cell proportion were superior to differ survivors from deaths than Th1 cell proportion. SuPAR positively correlates with Th1, Th17 cell proportion; and they correlate with increased disease severity and mortality risk in elderly sepsis patients.

Background: We aimed to explore the influencing factors of clinical adverse blood transfusion reactions, to provide theoretical basis and support for clinical safe blood transfusion, and to minimize the occurrence of adverse blood transfusion reactions. Methods: The method was to retrospectively analyze the report of adverse blood transfusion reports from 6 hospitals in Linyi area, Shandong, China to the blood station in Linyi City center from 2013 to 2020. We aimed to classify factors, analyze the occurrence of adverse transfusion reactions, and discuss the correlation between the occurrence of adverse transfusion reactions and the above factors. Results: Overall, 248 patients (77.98%) had a history of blood transfusion. The difference between this group and the group with no history was statistically significant (P

Background:Glutamate excitotoxicity caused by dysfunctional glutamate transporters plays an important role in the pathogenesis of Parkinson’s disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not fully elucidated. MicroRNAs have been reported to play key roles in regulating the translation of glutamate-transporter mRNA. Methods: We established model of PD 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice in vivo and 1-methyl-4-phenylpyridinium (MPP+) treated astrocyte in vitro. Stereotaxic injection of shRNA in mouse, and miRNA inhibitor/mimic, or antagonist/agonist treated the cell model, Behavioral experiments, glutamic acid uptake, transport activity of synaptosomes, underlying mechanisms and the impact on neuronal survival were assessed.Results We demonstrated that short-hairpin RNA-mediated knockdown of miR-30a-5p ameliorated motor deficits and pathological changes like astrogliosis and reactive microgliosis in a mouse model of PD. Western blotting and immunofluorescent labeling revealed that miR-30a-5p suppressed the expression and function of GLT-1 in MPTP-treated mice and specifically in astrocytes treated with (cell model of PD). Conclusion Both in vitro and in vivo, we found that miR-30a-5p knockdown promoted glutamate uptake and increased GLT-1 expression by hindering GLT-1 ubiquitination and subsequent degradation in a PKCα-dependent manner. Therefore, miR-30a-5p represents a potential therapeutic target for the treatment of PD.

BACKGROUND Late diagnosis and metastasis are leading causes of the high mortality of colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been reported to play a critical role in the development and progression of CRC. This study aimed to explore the clinical significance of 2 novel lncRNAs - RP11-296E3.2 and LEF1-AS1 - including their expression pattern, as well as diagnostic and prognostic values, for metastatic CRC patients. MATERIAL AND METHODS lncRNAs expression was examined in tissues (91 cases) and plasma (60 cases) from CRC patients by real-time quantitative PCR (qRT-PCR), and the correlations between its expression and clinicopathological features and diagnosis values in metastasis were analyzed. TCGA datasets were further used to analyze their utility in prediction of overall survival (OS) and disease-free survival (DFS). ATP-based tumor chemosensitivity assay (ATP-TCA) was used to evaluated tumor chemoresistance. RESULTS Compared with adjacent normal tissues, RP11-296E3.2 was significantly downregulated while LEF1-AS1 was significantly upregulated in cancer tissues (p=0.0143, p=0.0322, respectively). High levels of RP11-296E3.2 and LEF1-AS1 in tissues and plasma were correlated with tumor metastasis (p=0.0488, p=0.0252 in tissues, p=0.0331, p=0.1862 in plasma, respectively). Further analysis showed that RP11-296E3.2 sensitivity and specificity in diagnosis of CRC metastasis is better than CEA in plasma (0.690 and 0.621, and 0.621 and 0.500, respectively), and the OS of metastatic CRC patients with higher LEF1-AS1 expression levels in tissues was short (log-rank p

Nanosized drug delivery systems are promising tools in the field of nanomedicine applied to cancer. A novel temozolidomidehydroxyapatite (TMZ/HAp) sustained-release nanopreparation for implantation in glioblastoma multiforme (GBM) patients was designed, synthesized and characterized in this study. The structure, morphology, drug loading and in vitro delivery properties of the HAp particles and the novel polysuccinimide (PSI)-coated HAp(HAp-PSI) nanoparticles were evaluated using X-ray powder diffraction (XRD), Fourier Transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and high-performance liquid chromatography. The TMZ/HAp-PSI nanoparticles consist of a flower-like HAp core enclosed by a smooth PSI layer, which presents a spherical or nearly spherical form. The TMZ/HAp-PSI nanoparticles further strengthen the encapsulation efficiency to 93.0%. Compared with TMZ/HAp alone, both the TMZ/HAp-PSI nanoparticles and TMZ/HAp-PSI tablets can prolong the drug release time to more than 350 h and avoid an early burst drug release, suggesting a great potential for the brain or bone implantation drug delivery applications.

Glutamate, a primary excitatory neurotransmitter and an important intermediate in the cellular metabolism of the brain, has a widespread influence in the sleep-wake regulatory system. Glutamate transporters, including vesicular glutamate transporters and excitatory amino acid transporters, serve as the main force controlling the extracellular concentration of glutamate in the brain. These are likely to be critical tools needed for the brain to modulate the sleep-wake cycle and are likely innervated by the circadian rhythm system in a day-night variant pattern. Because in the initial stages, nearly all patients with neurodegenerative diseases have rhythmic sleep disorders that become aggravated with disease development and often exhibit glutamate uptake dysfunction, we examined whether the above glutamate transporters could be used as potential targets to help address circadian rhythm sleep disorders in patients with neurodegenerative diseases. Therefore, in this review, we sought to analyze the principles governing glutamate transmission and discuss whether the circadian rhythm regulatory properties of these processes endow glutamate transporters with unique functions in the sleep-wake shift of the brain. We attempt to provide a theoretical framework in this field for future studies, to help in the exploration of potential therapeutic targets to delay or prevent the development of neurodegenerative diseases.

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors worldwide. With unsatisfactory effects of traditional systematic chemotherapy for HCC owing to its drug resistance, novel therapeutic strategies based on nanomaterials for HCC treatments are promising solutions. To solve the challenges of nanoparticles (NPs)-based drug delivery systems for potential clinical applications, we designed water soluble amphiphilic oleic acid-NaYF4:Yb,Er/polydopamine Au nanoflower Janus NPs (OA-UCNPs/PDA-AuF JNPs) with discrete multi compartment nanostructures as dual-drug delivery systems (DDDSs). This unique nanostructure meets the requirements for containing hydrophobic hydroxycamptothecin/hydrophilic doxorubicin in divided spaces and releasing each drug from non-interfering channels under pH/near-infrared (NIR) dual-stimuli. The amphiphilic DDDSs were utilized to eradicate the tumor burden on a high-fidelity HCC model of a patient-derived xenograft (PDX), and represented an efficient strategy for defeating HCC using multi-modal imaging-guided dual-drug chemo-photothermal therapy in the second NIR window. In addition, the potential mechanisms of action for the DDDSs were evaluated.

This research aimed to evaluate the right ventricular segmentation ability of magnetic resonance imaging (MRI) images based on deep learning and evaluate the influence of curcumin (Cur) on the psychological state of patients with pulmonary hypertension (PH). The heart MRI images were detected based on the You Only Look Once (YOLO) algorithm, and then the MRI image right ventricle segmentation algorithm was established based on the convolutional neural network (CNN) algorithm. The segmentation effect of the right ventricle in cardiac MRI images was evaluated regarding intersection-over-union (IOU), Dice coefficient, accuracy, and Jaccard coefficient. 30 cases of PH patients were taken as the research object. According to different treatments, they were rolled into control group (conventional treatment) and Cur group (conventional treatment + Cur), with 15 cases in each group. Changes in the scores of the self-rating anxiety scale (SAS) and self-rating depression scale (SDS) of the two groups of patients before and after treatment were analyzed. It was found that the average IOU of the heart target detection frame of the MRI image and the true bounding box before correction was 0.7023, and the IOU after correction was 0.9016. The Loss of the MRI image processed by the CNN algorithm was 0.05, which was greatly smaller than those processed by other algorithms. The Dice coefficient, Jaccard coefficient, and accuracy of the MRI image processed by CNN were 0.89, 0.881, and 0.994, respectively. The MRI images of PH patients showed that the anterior wall of the right ventricle was notably thickened, and the main pulmonary artery was greatly widened. After treatment, the SAR and SDS scores of the two groups were lower than those before treatment ( P < 0.05 ), and the SAR and SDS scores of the curcumin group were lower than those of the control group ( P < 0.05 ). To sum up, the right ventricular segmentation ability of MRI images based on deep learning was improved, and Cur can remarkably alleviate the psychological state of PH patients, which provided a reference for the diagnosis and treatment for PH patients.

Multiple-drug resistance bacteria containing antimicrobial resistance genes (ARGs) are a concern for public health. Integrons are bacterial genetic elements that can capture, rearrange, and express mobile gene cassettes responsible for the spread of ARGs. Few studies link genotype and phenotype of swine-related ARGs in the context of mobile gene cassette arrays among commensal Escherichia coli (E. coli) in nonclinical livestock isolates from intensive farms. In the present study, a total of 264 isolates were obtained from 330 rectal swabs to determine the prevalence and characteristics of antibiotic-resistant gene being carried by commensal E. coli in the healthy swine from four intensive farms at Anhui, Hebei, Shanxi, and Shaanxi, in China. Antimicrobial resistance phenotypes of the recovered isolates were determined for 19 antimicrobials. The E. coli isolates were commonly nonsusceptible to doxycycline (75.8%), tetracycline (73.5%), sulfamethoxazole-trimethoprim (71.6%), amoxicillin (68.2%), sulfasalazine (67.1%), ampicillin (58.0%), florfenicol (56.1%), and streptomycin (53.0%), but all isolates were susceptible to imipenem (100%). Isolates [184 (69.7%)] exhibited multiple drug resistance with 11 patterns. Moreover, 197 isolates (74.6%) were detected carrying the integron-integrase gene (intI1) of class 1 integrons. A higher incidence of antimicrobial resistance was observed in the intI1-positive E. coli isolates than in the intI1-negative E. coli isolates. Furthermore, there were 17 kinds of gene cassette arrays in the 70 integrons as detected by sequencing amplicons of variable regions, with 66 isolates (94.3%) expressing their gene cassettes encoding for multiple drug resistance phenotypes for streptomycin, neomycin, gentamicin, kanamycin, amikacin, sulfamethoxazole-trimethoprim, sulfasalazine, and florfenicol. Notably, due to harboring multiple, hybrid, and recombination cassettes, complex cassette arrays were attributed to multiple drug resistance patterns than simple arrays. In conclusion, we demonstrated that the prevalence of multiple drug resistance and the incidence of class 1 integrons were 69.7 and 74.6% in commensal E. coli isolated from healthy swine, which were lower in frequency than that previously reported in China.

Radical antegrade modular pancreatosplenectomy (RAMPS) was first introduced in 2003. It has been accepted as an alternative technique for pancreatic cancer of the body and tail. However, robotic RAMPS is not yet popular because of its technical difficulty and lack of standardized technique. This study describes in detail the standard steps of robotic RAMPS using the flip-up approach with the benefit of a robotic view when treating pancreatic cancer of the body and tail. We took advantage of our single-center experience to provide a step-by-step technique of robotic RAMPS procedure using the da Vinci Si system. We divided the procedure into 11 key steps. The surgical steps are optimized to achieve margin-negative curative resection and sufficient regional lymphadenectomy. The artery-first approach is usually used to determine tumor resectability early before performing an irreversible operative step. We also determine the borders of surgical resection and divide the splenic artery after dividing the pancreatic neck and the splenic vein, which facilitates a complete lymphadenectomy around the celiac axis with a bottom-up view. Robotic RAMPS using the flip-up approach is safe and feasible in performing curative resection for well-selected pancreatic cancer of the body and tail. A randomized controlled trial comparing open and robotic RAMPS is needed in the future.

Highlights • YWHAB is a PCV2 ORF5-interacting host factor. • YWHAB expression is activated by PCV2 infection and ORF5 transfection. • YWHAB inhibits PCV2 replication. • YWHAB alleviates PCV2 infection induced ERS, autophagy, ROS production and apoptosis., Porcine circovirus type 2 (PCV2) infection causes porcine circovirus associated diseases (PCVAD) worldwide. Identification of host factors that interact with viral proteins is a fundamental step to understand the pathogenesis of PCV2. Our previous study reported that ORF5, a newly identified PCV2 viral protein supports PCV2 replication and interacts with multiple host factors. Here, we showed that a host factor YWHAB is an ORF5-interacting protein and plays essential roles during PCV2 infection. By using protein-protein interaction assays, we confirmed that YWHAB directly interacts with PCV2-ORF5 protein. We further showed that YWHAB expression was potently induced upon ORF5 overexpression and PCV2 infection. Remarkably, we found that the YWHAB strongly inhibited PCV2 replication, suggesting its role in defending PCV2 infection. By using the ectopic overexpression and gene knockdown approaches, we revealed that YWHAB inhibits PCV2-induced endoplasmic reticulum stress (ERS), autophagy, reactive oxygen species (ROS) production and apoptosis, suggesting its vital role in alleviating PCV2-induced cellular damage. Together, this study demonstrated that an ORF5-interacting host factor YWHAB affects PCV2 infection and PCV2-induced cellular response, which expands the current understanding of YWHAB biological function and might serves as a new therapeutic target to manage PCV2 infection-associated diseases.

Endometritis is characterized by severe inflammation and tissue damage. It is a common clinical disease that causes infertility due to infectious diseases of the reproductive system. MicroRNAs (miRNAs) are the current focus of research on the regulation of the inflammatory process and play a vital role in various inflammatory diseases. The highly conserved miR-505 regulates the mechanism of lipopolysaccharide (LPS) induced endometritis, but the extent to which pro-inflammatory genes are activated remains unclear. The results of this study showed that the expression of miR-505 was significantly down-regulated in mouse endometritis tissue and LPS-stimulated BEND cells. The study also showed that overexpression of miR-505 significantly suppressed the production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, and this effect was reversed by inhibiting the expression of miR-505. Moreover, miR-505 inhibited the expression of HMGB1 by targeting its 3'-UTR, thereby inhibiting the activation of HMGB1/NF-κB signalling. Taken together, the results of this study further confirmed that miR-505, as an anti-inflammatory agent, regulates the activation of the HMGB1/NF-κB signalling pathway through negative feedback.

A long-term of high concentration feeding in ruminants can bring huge economic profits, but it also impose ruminants into great threat of suffering subacute ruminal acidosis (SARA). SARA is a kind of disease which attenuate the health, feed intake and production of ruminants, and when ruminants suffer SARA, the concentration of lipopolysaccharide (LPS) increase largely. Glycyrrhizin is reported to have anti-inflammation effects, and the study was conducted to investigate effects of glycyrrhizin on LPS-induced goat ruminal epithelial cells (GRECs) to provide evidence for using glycyrrhizin as a treatment for SARA. Effects of LPS, and glycyrrhizin on cell viability of GRECs were investigated, respectively. Then GRECs were stimulated with LPS (50 mg/L) for 2 h, and glycyrrhizin were added at the concentration of 0, 50, 75, 100 and 125 mg/L for 24 h to investigate the expression of inflammatory cytokines (by Elisa kits), the mRNA expression of NF-κB and inflammatory cytokines (by qRT-PCR), the distribution of Zo-1 and Occludin (by immunofluorescence staining), the expression of Occludin (by Western blot analysis), and the morphology of GRECs. The results showed that: (1) Glycyrrhizin at the concentration of 50, 75, 100, and 125 mg/L had no cytotoxic effects on GRECs, and LPS at the concentration of 50 mg/L significantly decreased the cell viability of GRECs. (2) Glycyrrhizin attenuated the expression and relative mRNA expression of TNF-α, IL-1β, IL-6, IL-8 and IL-12 by a dose-dependent manner, and significantly attenuated the relative mRNA expression of NF-κB. (3) Immunofluorescence staining and Western blot analysis showed that the quantity of Zo-1 and Occludin, and the expression of Occludin all increased with the treatment of glycyrrhizin. (4) Glycyrrhizin attenuated LPS-induced autophagy and protected the structural integrity of GRECs. In conclusion, glycyrrhizin significantly inhibited the inflammatory response in LPS-stimulated GRECs, and it may be used as a potential agent for the treatment of SARA.

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by pathological dopaminergic (DA) neuronal death and α-synuclein aggregation. Glutamate excitotoxicity is a well-established pathogenesis of PD that involves dysfunctional expression of glutamate transporters. Glutamate transporter-1 (GLT-1) is mainly responsible for clearance of glutamate at synapses, including DA synapses. However, the role of GLT-1 in the aberrant synaptic transmission in PD remains elusive. In the present study, we generated small-interfering RNAs (siRNAs) to knockdown GLT-1 expression in primary astrocytes, and we report that siRNA knockdown of astrocytic GLT-1 decreased postsynaptic density-95 (PSD-95) expression in neuron-astrocyte cocultures in vitro. Using adeno-associated viruses (AAVs) targeting GLT-1 short-hairpin RNA (shRNA) sequences with a glial fibrillary acidic protein (GFAP) promoter, we abolished astrocytic GLT-1 expression in the substantia nigra pars compacta (SNpc) of mice. We found that GLT-1 deficiency in the SNpc induced parkinsonian phenotypes in terms of progressive motor deficits and nigral DA neuronal death in mice. We also found that there were reactive astrocytes and microglia in the SNpc upon GLT-1 knockdown. Furthermore, we used RNA sequencing to determine altered gene expression patterns upon GLT-1 knockdown in the SNpc, which revealed that disrupted calcium signaling pathways may be responsible for GLT-1 deficiency-mediated DA neuronal death in the SNpc. Taken together, our findings provide evidence for a novel role of GLT-1 in parkinsonian phenotypes in mice, which may contribute to further elucidation of the mechanisms of PD pathogenesis.

Objectives This study aimed to describe trends in antituberculosis drug prescribing for inpatients from 2011–2015 in a Chinese national tuberculosis (TB) hospital. Methods This retrospective study, performed in March 2016, reviewed the medical records of all inpatients from Beijing Chest Hospital diagnosed with TB between 2011–2015. Medication used for TB treatment during the inpatient period was recorded. Results A total of 11 465 inpatients were enrolled in the study. The most frequently prescribed drug for inpatients was isoniazid (71.2%; 8164/11 465), followed by ethambutol (67.5%; 7738/11 465), pyrazinamide (59.7%; 6839/11 465) and rifampicin (40.0%; 4589/11 465). In addition, amikacin (16.5%; 1889/11 465), levofloxacin (33.0%; 3789/11 465), para-aminosalicylic acid (12.4%; 1422/11 465) and clarithromycin (3.5%; 406/11 465) were the most common drugs used in the treatment of inpatients for Group II, III, IV and V drugs, respectively. A significant increasing trend in prescribing was found for rifampicin, pyrazinamide, capreomycin, moxifloxacin, prothionamide, para-aminosalicylic acid, cycloserine, clofazimine and linezolid, respectively, whilst there was a significant decreasing trend in the rate of prescribing of ethambutol, amikacin, levofloxacin, amoxicillin/clavulanic acid and clarithromycin during the 5-year study period (Ptrend Conclusions These data demonstrate that prescription of anti-TB drugs varied greatly across clinical diagnostic categories, treatment history and drug susceptibility profiles of TB patients. The World Health Organization (WHO)-endorsed standard regimen should be more extensively employed under conditions where drug susceptibility testing is unavailable in order to guide clinicians to formulate a suitable treatment regimen for TB patients.

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 μm. The encapsulation efficiency and drug loading yield of TDF‑PLGA‑MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF‑PLGA‑MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 μm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF‑PLGA‑MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy.

Graphical Abstract Unlabelled image, Tetramethylpyrazine (TMP) is a traditional Chinese herbal medicine with strong anti-inflammatory and cartilage protection activities, and thus a promising candidate for treating osteoarthritis. However, TMP is rapidly cleared from the joint cavity after intra-articular injection and requires multiple injections to maintain efficacy. The aim of this study was to encapsulate TMP into poly (lactic-co-glycolic acid) (PLGA) microspheres to enhance the TMP retention in the joint, reducing injection frequencies and decreasing dosage. TMP microspheres were prepared by emulsion/solvent evaporation method. The intra-articular retention of the drug was assessed by detecting the drug concentration distributed in the joint tissue at different time points. The therapeutic effect of TMP microspheres was evaluated by the swelling of knee joints and histologic analysis in papain-induced OA rat model. The prepared freeze-dried microspheres with a particle size of about 10 µm can effectively prolong the retention time of the drug in the articular cavity to 30 d, which is 4.7 times that of the TMP solution. Intra-articular injection of TMP microspheres efficiently relieved inflammatory symptoms, improved joint lesions and decreased the depletion of proteoglycan. In conclusion, intra-articular injection of TMP loaded microspheres was a promising therapeutic method in the treatment of OA.

Background/Aims: Based on the theory of constitution in Traditional Chinese Medicine (TCM), the Chinese Han population has been classified into nine constitutions. Of these, Yang deficiency constitution mainly exhibit cold intolerance while Yin deficiency constitution mainly exhibit heat intolerance. Some studies have been carried out to explore the modern genetic and biological basis of such constitution classification, but more remains to be done. MicroRNA (miRNA) serves as post-transcriptional regulators of gene expression and may play a role in the classification process. Here, we examined miRNA expression profile of saliva to further improve the comprehensiveness of constitution classification. Methods: Saliva was collected from Chinese Han individuals with Yang deficiency, Yin deficiency and Balanced constitutions (n=5 each), and miRNA expression profile was determined using the Human miRNA OneArray®v7. Based on 1.5 Fold change, means log2|Ratio|≥0.585 and P-value< 0.05, differentially expressed miRNA was screened. Target genes were predicted using DIANA-TarBasev7.0 and analysis of KEGG pathway was carried out using DIANA-mirPathv.3. Results: We found that 81 and 98 differentially expressed miRNAs were screened in Yang deficiency and Yin deficiency constitution, respectively. Among them, 16 miRNAs were identical and the others were unique. In addition, the target genes that are regulated by the unique miRNAs were significantly enriched in 27 and 20 signaling pathways in Yang deficiency and Yin deficiency constitution, respectively. Thyroid hormone signaling pathway is present in both constitutions. These unique miRNAs that regulated target genes of thyroid hormone signaling pathway may be associated with cold intolerance or heat intolerance. Conclusion: The results of our study show that Yang deficiency and Yin deficiency constitutions exhibit systematic differences in miRNA expression profile. Moreover, the distinct characteristics of TCM constitution may be explained, in part, by differentially expressed miRNAs.

Ethnopharmacological relevance Wu-Zi-Yan-Zong-Wan (WZYZW) is a classical traditonal Chinese herbal formula and a Chinese patent medicine used to treat male infertility. However, the chemical components of WZYZW and its mechanism are not yet fully clarified. Aim of the study The purpose of this study is to observe the effect and underlying mechanism of WZYZW on ameliorating blood-testis barrier (BTB) dysfunction in mice with spermatogenic dysfunction induced by administration of Tripterygium wilfordii Hook. f. multiglycosides (GTW). Materials and methods WZYZW was administered by gavage to mice with GTW-induced spermatogenic dysfunction (kidney essence deficiency pattern) for 40 days. Testis tissues were obtained for subsequent histopathological analysis. Biotin tracing was used to evaluate the permeability of Sertoli cell tight junctions. The levels of proinflammatory cytokines including interleukin (IL)-6, IL-17A, IL-1α and tumor necrosis factor (TNF)-α were analyzed by ELISA. The expression levels of proteins related to tight junction including ZO-1, JAM-A and occludin were analyzed by western blotting. The ultrastructures of tight junctions were observed by transmission electron microscopy. Results WZYZW ameliorated GTW-induced testicular spermatogenic dysfunction. Levels of IL-6, IL-17A, IL-1α, and TNF-α in the groups receiving low, medium, and high doses of WZYZW decreased in a dose-dependent manner. WZYZW impeded a biotin tracer from permeating the BTB, protecting its integrity in GTW-treated mice. In addition, our results showed no significant changes in the protein expressions of ZO-1, JAM-A, and occludin after WZYZW administration compared with the GTW group. Meanwhile, WZYZW exhibited a linear arrangement and restored the typical “sandwich” structure of BTB. No acute poisoning incidences were observed in all groups during the experiment. Conclusions Our findings demonstrate that WZYZW may ameliorate some GTW-induced BTB dysfunction, possibly by regulating proinflammatory cytokine levels. In vitro studies on the regulation of BTB permeability by WZYZW and its active components are further required.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects reproductive dysfunction and metabolism in women of childbearing age. An increasing number of studies have suggested that the bone morphogenetic protein 15 (BMP15) signalling pathway serves an important role in the pathogenesis of PCOS; however, the full mechanism remains unknown. The present study revealed that intrinsic follicular dysplasia may be associated with regulation disorders of ovarian granulosa cell apoptosis. Compared with the control group, body mass index, luteinising hormone and testosterone levels were significantly increased (P

Glutamate is an essential excitatory neurotransmitter that regulates brain functions, and its activity is tightly regulated by glutamate transporters. Excess glutamate in the synaptic cleft and dysfunction of excitatory amino acid transporters have been shown to be involved in development of Alzheimer's disease, but the precise regulatory mechanism is poorly understood. Using a D-[3H]-aspartic acid uptake assay, we found that Aβ1-42 oligomers impaired glutamate uptake in astrocytes and neurons. In astrocytes, this process was accompanied by reduced expression of GLT-1 and GLAST as detected by Western blot and immunocytofluorescence. However, mRNA levels of EAATs detected by qPCR in astrocytes and neurons were not altered, which suggests that this process is post-translational. Co-localization analysis using immunocytofluorescence showed that ubiquitylation of GLT-1 significantly increased. Therefore, we hypothesized that Aβ1-42 oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, Aβ1-42 oligomers enhanced secretion of IL-1β, TNF-α, and IL-6 into culture supernatant, which may be correlated with an inflammatory response and altered EAATs expression or function in Alzheimer's disease. These findings support the idea that dysregulation of the glutamatergic system may play a significant role in pathogenesis of Alzheimer's disease. Furthermore, enhancing expression or function of EAATs in astrocytes and neurons might be a new therapeutic approach in treatment of Alzheimer's disease.

Background As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment. Methods Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT. Results Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts. Conclusions Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1036-z) contains supplementary material, which is available to authorized users.

Parkinson's disease (PD) features the degeneration and death of dopamine neurons in the substantia nigra pars compacta and the formation of Lewy bodies that contain α-synuclein. Among the numerous PD etiologies, glutamate excitotoxicity is a research hot spot, and glutamate transporters play key roles in this theory. It has been shown that the expression of the glutamate transporter is regulated by microRNAs. In this study, we found that the levels of expression and function of glutamate transporter type 1 (GLT-1) were significantly reduced and miR-543-3p was upregulated during the development of PD. Furthermore, our results indicated that GLT-1 plays an important role in the pathomechanism of PD. We found that miR-543-3p can suppress the expression and function of GLT-1 in MPP+-treated astrocytes and MPTP-treated mice. Inhibition of miR-543-3p can rescue the expression and function of GLT-1 and relieve dyskinesia in the PD model, which suggests that inhibition of miR-543-3p could serve as a potential therapeutic target for PD.

Motivated by the "self-seeding" of the cancer cells, the EPR-independent nanoparticles (NPs)-based therapeutic strategy have been explored to prevent hepatocellular carcinoma metastasis in this paper, the mechanism of anti-metastasis of the NPs was also evaluated. We firstly have established an aggressive whole-body spreading orthotopic LM3 tumour model closing to actual cases of human patients and the synthesized Trojan Horse-like amphiphilic nanobowls have been engineered with dual drugs with completely different pharmacokinetic profiles for cancer cell-mediated anti-metastasis therapy. These Trojan Horse-like nanobowls can serve as dual-drug delivery depots for site-specific pH/NIR dual-stimuli drug release with effectively suppressed primary tumor growth and metastases. Furthermore, the multi-mode UCL/MR/CT imaging is competent for providing comprehensive and valuable information for evaluating and adjusting the treatment. The employ of cancer cell-mediated anti-metastasis therapeutic strategy delivering drugs into metastatic cells to defeat tumor metastases provides directions in the fields of anti-metastasis therapy.