Emerging Therapeutic Strategies for Attenuating Tubular EMT and Kidney Fibrosis by Targeting Wnt/β-Catenin Signaling

Epithelial-mesenchymal transition (EMT) is defined as a process in which differentiated epithelial cells undergo phenotypic transformation into myofibroblasts capable of producing extracellular matrix, and is generally regarded as an integral part of fibrogenesis after tissue injury. Although there is evidence that the complete EMT of tubular epithelial cells (TECs) is not a major contributor to interstitial myofibroblasts in kidney fibrosis, the partial EMT, a status that damaged TECs remain inside tubules, and co-express both epithelial and mesenchymal markers, has been demonstrated to be a crucial stage for intensifying fibrogenesis in the interstitium. The process of tubular EMT is governed by multiple intracellular pathways, among which Wnt/β-catenin signaling is considered to be essential mainly because it controls the transcriptome associated with EMT, making it a potential therapeutic target against kidney fibrosis. A growing body of data suggest that reducing the hyperactivity of Wnt/β-catenin by natural compounds, specific inhibitors, or manipulation of genes expression attenuates tubular EMT, and interstitial fibrogenesis in the TECs cultured under profibrotic environments and in animal models of kidney fibrosis. These emerging therapeutic strategies in basic researches may provide beneficial ideas for clinical prevention and treatment of chronic kidney disease.

Phytochemical Analysis Using UPLC-MS/MS Combined with Network Pharmacology Methods to Explore the Biomarkers for the Quality Control of Lingguizhugan Decoction

As a classic TCM prescription, LGZG has been widely used in clinical prevention and treatment of heart failure, nonalcoholic fatty liver, and hyperlipidemia. However, there are few studies on chemical components in recent years, and the basis of quality evaluation is not sufficient. This study was to find the active ingredients of the Lingguizhugan decoction using UPLC-MS/MS and network pharmacology. By comparing the retention time and MS dates of the reference and self-building database, the cleavage rules of chemical composition whose mass errors are less than 1 ppm(FL less than 3 ppm) are analyzed. On this basis, a network pharmacology method was used to find biomarkers for quantitative analysis. The results show that 149 compounds were preliminaries identified or inferred, including 63 flavonoids, 30 triterpenes, 22 phenylpropanoids, 13 organic acids, 6 lactones, 5 alkaloids, 4 anthraquinones, and 6 other compounds. According to the network pharmacology results, 20 chemical constituents were selected as the biomarkers, which were determined simultaneously for the first time, including poricoic acid A, poricoic acid B, glycyrrhizic acid, glycyrrhetinic acid, liquiritin, isoliquiritin, liquiritigenin, isoliquiritin apioside, cinnamic acid, caffeic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, isochlorogenic acid A, B, and C, atractylenolide I, II, and III, and coumarin. The methodological results show that the linearity, stability, precision, repeatability, and recovery of the method are satisfactory. Therefore, a comprehensive quality assessment system for LGZG was established on the basis of a systematic study of chemical substances and network pharmacology, which provided an important reference for the foundation of pharmacological action and its mechanics.

Characterization of Erysipelothrix rhusiopathiae Isolates from Diseased Pigs in 15 Chinese Provinces from 2012 to 2018

Erysipelothrix rhusiopathiae can cause erysipelas in animals and erysipeloid in humans. Since its recurrence in 2012, swine erysipelas has caused serious losses within the pig industry in China. The aim of this study was to perform multilocus sequence typing and understand the virulence and antimicrobial susceptibility of E. rhusiopathiae isolates in China. Multilocus sequence typing (MLST) of a total of 120 strains was performed, and as a result, three different sequence types were identified, of which ST48 was the main one. Five isolates of each MLST type were randomly selected to be used to challenge mice. ST48 was associated with a higher virulence. Antimicrobial susceptibility was tested using a microdilution technique and, to analyze the resistance mechanism, six strains were selected for genome sequencing. A comparison of the six genomes indicated the presence of a suspected macrolide resistance gene, namely, Erm(A)-like, in erythromycin-resistant strains, which increased the minimum inhibitory concentration (MIC) of erythromycin against E. coli C600 at least four-fold. In addition, three mutations (gyrA86T-I, gyrA90D-N, and parC81S-I) were observed in the quinolone resistance-determining regions (QRDRs) of gyrA and parC in quinolone-resistant strains. After the gyrA gene with the 86T-I mutation or the parC gene with the 81S-I mutation was transfected into E. coli C600, the MIC of enrofloxacin against this strain increased at least two-fold. Our findings provide a theoretical basis for developing antibacterial drugs and may contribute to the clinical prevention and control of E. rhusiopathiae.

The Self-Absorptive Trait of Dissociative Experience and Problematic Internet Use: A National Birth Cohort Study

Functional and excessive use of internet are hard to distinguish from each other, and internet use can affect adolescents’ development of self-identity. The aim of our study was to investigate the associated relationships between the risk and protective factors for internet use, including parental monitoring, the absorptive dissociative trait, having been bullied, exercise, self-perceived depressive mood, and happiness of 12-year-old adolescents. The Taiwan Birth Cohort Study dataset, which used a national household probability sampling method and included 17,694 12-year-old adolescents, was used for this study. Our results showed that 5.3% of adolescents reported spending more than five hours online during school days. Additionally, adolescents that spent more than five hours online during school days tended to have a higher absorptive trait, perceived less care from mothers, were more likely to have been bullied, and expressed a higher level of depressed mood, which led to a lower level of perceived happiness. Adolescents that spent more than five hours online during school days, compared to those that spent less than an hour online, were more likely to have been bullied, which effected their level of happiness, showing that they may be a group of higher concern. Therefore, spending more than five hours per day online maybe a clinical prevention indicator for problematic internet use.

A Meta-Analysis of the Risk Factors of Persistent Pulmonary Hypertension in Newborns

Objective: To determine the risk factors of persistent pulmonary hypertension of the newborn using a meta-analysis method and provide a reference for its clinical prevention and treatment.Methods: A meta-analysis was performed by searching the PubMed, Embase, Cochrane Library, China Biology Medicine Disc, Wanfang, and Chinese VIP journal databases, as well as the China National Knowledge Infrastructure.Results: A total of 22 references were included in the meta-analysis; the cumulative medical records comprised 7,937 cases, and 2,613,072 control cases were included. A total of 12 related risk factors were included (7 were associated with pregnant women and 5 were associated with newborns).Conclusion: Among the 12 associated risk factors included, the three most important and their combined odds ratio values and 95% CI were as follows: (1) pregnant women smoking, 4.85 (1.98–11.9) during pregnancy; (2) gestational weeks <37, 4.34 (1.64–11.5); (3) perinatal asphyxia, 3.9 (2.87–5.31).

Tunicamycin Induces Hepatic Stellate Cell Apoptosis Through Calpain-2/Ca2 +-Dependent Endoplasmic Reticulum Stress Pathway

It has been reported that calpain/caspase-mediated apoptosis induced by endoplasmic reticulum stress (ERS) in hepatic stellate cells (HSCs) by previous studies. At present, the activation of HSC is an important cause of liver fibrosis, and the induction of HSC apoptosis plays an irreplaceable role in reversing liver fibrosis. Therefore, it is of great significance to explore mechanisms of action that can induce HSC apoptosis for the reversal of hepatic fibrosis and the clinical prevention and treatment of hepatic-fibrosis-related diseases such as hepatitis, cirrhosis, and liver cancer. In the current study, we demonstrated that tunicamycin (a novel ERS inducer) can induce the apoptosis of HSCs and increase the concentration of intracellular Ca2+ and the expression of ERS protein GRP78, apoptosis protein caspase-12, and Bax, while it can decrease the antiapoptosis protein expression of Bcl-2. Our findings indicate that tunicamycin can induce HSCs apoptosis through calpain-2/Ca2+-dependent ERS pathway.

Murine Models Provide New Insights Into Pathogenesis of Chronic Graft-Versus-Host Disease in Humans

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for hematologic malignancies, but its success is complicated by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic types. Acute GVHD represents an acute alloimmune inflammatory response initiated by donor T cells that recognize recipient alloantigens. Chronic GVHD has a more complex pathophysiology involving donor-derived T cells that recognize recipient-specific antigens, donor-specific antigens, and antigens shared by the recipient and donor. Antibodies produced by donor B cells contribute to the pathogenesis of chronic GVHD but not acute GVHD. Acute GVHD can often be effectively controlled by treatment with corticosteroids or other immunosuppressant for a period of weeks, but successful control of chronic GVHD requires much longer treatment. Therefore, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HCT. Murine models of allo-HCT have made great contributions to our understanding pathogenesis of acute and chronic GVHD. In this review, we summarize new mechanistic findings from murine models of chronic GVHD, and we discuss the relevance of these insights to chronic GVHD pathogenesis in humans and their potential impact on clinical prevention and treatment.

Effect of Interleukin 17 and Epidermal Growth Factor 2 (FGF2) on the Biological Behavior of Endometrial Carcinoma Human Endometrial Cancer-1B Cells

The clinical prognosis of endometrial cancer is poor. We assessed the influence of IL-17 and FGF2 on HEC-1B cells to provide evidence for the clinical prevention and treatment. HEC-1B cells were assigned into control group, IL-17 group, FGF2 group, and IL-17+FGF2 group followed by analysis of cell viability, IL-17 and FGF2 protein and mRNA content by Western Blot and RT-PCR. Under co-culture, the cell viability, migration and invasion and FGF2 level in IL-17 group, FGF2 group, and IL-17+FGF2 group were found to be significantly higher than those in control Group (P <0.05), but the apoptosis rate was significantly lower than control group. The above changes were more significant in IL-17+ FGF2 group compared to other three groups (P < 0.05). IL-17 and FGF2 treatment in HEC-1B cells can significantly promote the viability, migration and invasion of malignant tumor cells with more significant changes in the IL-17+FGF2 intervention group, suggesting these two have a synergistic effect. In conclusion, IL-17 and FGF2 exerts synergistic effect on promoting endometrial cancer cell migration and invasion, indicating that they might be novel targets for the treatment of endometrial cancer.