Corrigendum: ErHuang Formula Improves Renal Fibrosis in Diabetic Nephropathy Rats by Inhibiting CXCL6/JAK/STAT3 Signaling Pathway.

[This corrects the article DOI: 10.3389/fphar.2019.01596.].

The Cyr61 Is a Potential Target for Rotundifuran, a Natural Labdane-Type Diterpene from Vitex trifolia L., to Trigger Apoptosis of Cervical Cancer Cells.

Cervical cancer is a common female malignant tumor that seriously threatens human health. This study explored the anticervical cancer effects and potential mechanisms of Rotundifuran (RTF), a natural product isolated from Vitex trifolia L. In this study, we found that RTF can suppress the proliferation of cervical cancer cell lines, including HeLa and SiHa cells (with the IC50 less than 10 µM), via induction of apoptosis in vitro, and the antitumor effect of RTF is further confirmed on the HeLa cell-inoculated xenograft model. In addition, our results proved that the antitumor effects of RTF might be related with the reactive oxygen species- (ROS-) induced mitochondrial-dependent apoptosis through MAPK and PI3K/Akt signal pathways. Using proteomics analysis and the drug affinity responsive target stability- (DARTS-) combined mass spectrometry (DARTS-MS), Cyr61 was indicated as a potential target for RTF in cervical cancer cells. Our present study would be beneficial for the development of RTF as a candidate for treatment of cervical cancer in the future.

Using Differential Threshold Effects of Individual and Combined Periconceptional Methyl Donor Status on Maternal Genomic LINE-1 and Imprinted H19 DNA Methylation to Predict Birth Weight Variance in the Taiwan Pregnancy-Newborn Epigenetics (TPNE) Cohort Study.

BACKGROUND: Few studies have comprehensively examined the effect of methyl donor status on maternal DNA methylation and birth outcomes. OBJECTIVES: This study examined associations between periconceptional methyl donor status and genome-wide and specific imprinted gene methylation and fetal growth indices in the Taiwan Pregnancy-Newborn Epigenetics cohort. METHODS: Plasma folate, choline (free form), and betaine concentrations of the participants enrolled at 7-10 weeks of gestation were analyzed. DNA methylation at regulatory sequences of the imprinted H19 gene and genomic long interspersed nuclear element 1 (LINE-1) were measured in maternal lymphocytes using bisulfite/high-resolution melt polymerase chain reaction. Associations with birth weight (BW) were estimated through multiple regressions from 112 mother-newborn pairs. RESULTS: A nonlinear "L-shaped" relation and an inverse association between maternal plasma folate in T1 (mean ± SE: 17.6 ± 5.1 nmol/L) and lymphocytic LINE-1 methylation (ß: -0.49, P = 0.027) were characterized. After adjusting for LINE-1 methylation, individual maternal folate concentrations were positively associated with BW variance (ß = 0.24, P = 0.035), and the association was more pronounced in mothers with choline in T1 (mean ± SE: 5.4 ± 0.6 µmol/L; ß: 0.40, P = 0.039). Choline status of the mothers in T2 (mean ± SE: 7.2 ± 0.6 µmol/L) was inversely associated with LINE-1 methylation (ß: -0.43, P = 0.035), and a positive association was evident between T1 choline and H19 methylation (ß: 0.48, P = 0.011). After adjusting for epigenetic modification, maternal choline status predicted a positive association with BW (ß: 0.56, P = 0.005), but the effect was limited to mothers with high betaine concentrations in T3 (mean ± SE: 36.4 ± 8.8 µmol/L), depending on folate status. CONCLUSIONS: Our data highlight the differential threshold effects of periconceptional folate, choline, and betaine status on genomic LINE-1 and H19 DNA methylation and how their interplay has a long-term effect on BW variance.

Therapeutic effect of Dongbai-Tonglin-Fang, a Chinese herbal formula, on urinary tract infection in rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) has many obvious advantages in the treatment of chronic conditions such as urinary tract infection (UTI). Dongbai-Tonglin-Fang (DBTL), a Chinese herbal formula, has been used for the treatment of UTI for more than 40 years with proven efficacy. However, its mechanism of action is still unknown. AIM OF THE STUDY: The purpose of this study is to evaluate the therapeutic efficacy of DBTL and its mechanism of action in a rat UTI model. MATERIALS AND METHODS: E. coli solution induced UTI rat model was used to evaluate the therapeutic effect of DBTL on UTI. Biochemical indicators related to UTI were measured. The kidney tissue was stained with hematoxylin-eosin (HE) to observe pathological changes whilst the ear swelling, feet swelling, hot plate and body torsion tests were used to estimate the anti-inflammatory and analgesic effects of DBTL. RESULTS: After treatment with different doses of DBTL (1, 2, 4 g/kg), a decrease in weight of the kidney in the UTI rat model was observed. The contents of white blood cell, nitrite, urinary albumin, ketone body, bilirubin and occult blood in the urine were also reduced whilst an increase in the pH of urine was observed. HE staining showed that the pathological changes in the kidney tissue were alleviated. At the same time, ear swelling assay showed that the weight and the degree of swelling of the ear of the mice in DBTL groups were decreased remarkably. DBTL also reduced the degree of feet swelling of the rats caused by the adjuvant. Furthermore, with the DBTL treatment, the latency period of foot licking induced by thermal stimulation was increased while the number of twists was lessened. CONCLUSION: These results show that DBTL has an excellent therapeutic effect on UTI rats accompanying with anti-inflammation and analgesia. The data presented here lays the foundations for further investigations in the treatment of UTI.

CXCL6 Promotes Renal Interstitial Fibrosis in Diabetic Nephropathy by Activating JAK/STAT3 Signaling Pathway.

In this study the role of CXCL6 in diabetic nephropathy (DN) was investigated. It was found to be overexpression in DN patients and DN rat model. And the expression of fibrosis-related cytokines was consistent with the expression of CXCL6. High glucose significantly increased the proliferation of rat renal fibroblasts NRK-49F cell and the expression of CXCL6. Knockdown of CXCL6 ameliorated the pro-proliferation effect of high glucose and decreased the expression of fibrosis-related cytokines, while CXCL6 overexpression exhibited the opposite phenomenon. Gene set enrichment analysis, Western blot and ELISA showed that Janus kinase-signal transducer and activator of transcription (JAK-STAT) and CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION signaling pathways were correlative with CXCL6. This data indicates that CXCL6 may promote fibrosis-related factors to accelerate the development of DN renal interstitial fibrosis by activating JAK/STAT3 signaling pathway. CXCL6 is promising to be a potential novel therapeutic target and candidate biomarker for JAK/STAT3 signaling for the treatment of DN.

Phytochemistry, Pharmacological Activities, Toxicity and Clinical Application of Momordica cochinchinensis.

Momordica cochinchinensis (Lour.) Spreng (M. cochinchinensis) is a deciduous vine that grows in Southeast Asia. It is known as gac in Vietnam and as Red Melon in English. Gac is reputed to be extremely benificial for health and has been widely used as food and folk medicine in Southeast Asia. In China, the seed of M. cochinchinensis (Chinese name: Mu biezi) is used as traditional Chinese medicine (TCM) for the treatment of various diseases. More than 60 chemical constituents have been isolated from M. cochinchinensis. Modern pharmacological studies and clinical practice demonstrate that some chemical constituents of M. cochinchinensis possess wide pharmacological activities, such as anti-tumor, anti-oxidation, anti-inflammatory, etc. This paper reviews the phytochemistry, pharmacological activities, toxicity, and clinical application of M. cochinchinensis, aiming to bring new insights into further research and application of this ancient herb.

ErHuang Formula Improves Renal Fibrosis in Diabetic Nephropathy Rats by Inhibiting CXCL6/JAK/STAT3 Signaling Pathway.

Diabetic nephropathy (DN) is one of the main causes of renal fibrosis and is associated with high morbidity and mortality. Traditional Chinese Medicine (TCM) therapy has a long history of usage in a clinical setting and its usage is increasing. ErHuang Formula (EHF), a Chinese herbal compound, has been clinically used in treating DN for more than 30 years. However, its mechanism of action is still unknown. This study was conducted to evaluate the effect of EHF on renal fibrosis in a DN rat model and explore its underlying mechanism. The DN rat model was established by high-sugar-fat diet combined with a single intraperitoneal injection of streptozotocin (STZ), and EFH extract (4, 2, 1 g/kg d-1) was administered orally for 8 weeks. The biochemical parameters (blood glucose, weight, Scr, BUN, UA, U-Alb and UAE) were analyzed. The pathological changes in renal tissue were observed by histological staining with H&E and Masson. The effect of EHF on the proliferation of NRK-49F cells was examined by CCK-8 assay and the levels of several inflammation and fibrosis related cytokines (IL-6, TNF-α, TGF-ß1, Collagen I/III, MMP2/9) in serum and NRK-49F cell culture supernatants were detected by enzyme-linked immunoassay (ELISA). The mRNA levels of CXCL6, CXCR1, Collagen I/III, MMP2/9 in renal tissue were also measured by quantitative RT-PCR. Furthermore, the protein expression of PCNA, Collagen I/III, MMP2/9, CXCL6, CXCR1, p-STAT3, STAT3 in renal tissue and NRK-49F cells were determined by western blot. EHF improved the abnormal biochemical parameters and ameliorated the abnormal histology and fibrosis of renal tissue in a dose-dependent manner. EHF inhibited NRK-49F proliferation and decreased the expressions of inflammation and fibrosis related factors both in vitro and in vivo. Interestingly, the levels of Collagen I/III, PCNA, MMP2/9 and p-STAT3 were positively correlated with CXCL6. The amelioration of renal fibrosis in DN by EHF is related to CXCL6/JAK/STAT3 signal pathway, which is associated with inflammation and fibrosis of the tissue. These findings may have clinical implications for the treatment of DN.

ARHGAP9 suppresses the migration and invasion of hepatocellular carcinoma cells through up-regulating FOXJ2/E-cadherin.

Rho GTPase activating protein 9 (ARHGAP9), a member of RhoGAP family, has been identified as a RhoGAP for Cdc42 and Rac1. Here, we aimed to clarify the expression and functional role of ARHGAP9 in hepatocellular carcinoma (HCC). By analyzing TCGA (The Cancer Genome Atlas) LIHC (liver hepatocellular carcinoma) database, we found that ARHGAP9 expression was lower in HCC tissues than in normal liver tissues, and that patients with ARHGAP9 lower expression had a significant shorter overall survival time than those with ARHGAP9 higher expression. Cell counting kit-8 (CCK-8), transwell assays and in vivo experimental lung metastasis assay revealed that ARHGAP9 overexpression could inhibit HCC cell proliferation, migration and invasion, as well as HCC lung metastases. By next-generation RNA-sequencing, we identified that a transcription factor, Forkhead Box J2 (FOXJ2), was significantly induced by ARHGAP9 overexpression in HepG2 cells. Ectopic expression of FOXJ2 in HCC cell lines also exerted inhibitory effects on cell migration and invasion. Moreover, the inhibitory effects of ARHGAP9 on HCC cell migration and invasion was significantly attenuated by FOXJ2 knockdown. Luciferase reporter assay demonstrated that ARHGAP9 enhanced the transcription of E-cadherin (CDH1) via FOXJ2. Chromatin immunoprecipitation (ChIP) assay demonstrated that FOXJ2 modulated the transcription of E-cadherin (CDH1) by directly binding to its promoter. Furthermore, Pearson's correlation analysis indicated that the mRNA levels of ARHGAP9 in HCC tissues were positively correlated with the mRNA levels of FOXJ2 and CDH1. These data clearly show that ARHGAP9/FOXJ2 inhibit cell migration and invasion during HCC development via inducing the transcription of CDH1.

Medicinal Plants for the Treatment of Hair Loss and the Suggested Mechanisms.

Hair loss may not be recognized as a life-threatening disorder. However, it has a great harm to a person's self-respect, mental health, and entirety quality of life. Androgenic alopecia (AGA) is the most common type of hair loss, which affects a great number of both men and women. Alopecia can be treated with various hair loss strategies, including hair transplant, cosmetics and medication. Medical treatment shows the outstanding ability in improving hair growth. Plenty of drugs prevents alopecia by inhibiting the secretion of male hormone. But these medicines exhibit some undesirable side effects. Since hair loss requires a long-term treatment and minimizing adverse side effects is extremely urgent in drug development. Accordingly, new agents are obtained from natural products with less adverse effects. Traditional Chinese medicines exhibit unique advantages in hair loss treatment. This review generalizes and analyzes the recent progress of medicinal plants for the treatment of hair loss, suggested mechanisms and outlines a number of trials taken or underway to optimize the treatment.

Chinese Herbal Formulas and Renal Fibrosis: An Overview.

All forms of chronic kidney disease (CKD) eventually lead to renal fibrosis irrespective of its origin. It is generally characterized by an excessive accumulation and deposition of extracellular matrix (ECM) and to date, no ideal treatment has been established. Bian-Zheng-Lun-Zhi (syndrome differentiation and treatment), a classic feature of traditional Chinese Medicine (TCM), is a unique method used to diagnose and treat the pathology of a disease. Zheng (syndrome) is used to demonstrate the nature of a disease completely in an extensive and specific manner. Chinese herbal formulas are determined according to TCM theory and this review highlights these formulas and suggests a possible mechanism for their use in the treatment of renal fibrosis.

Dietary choline and folate relationships with serum hepatic inflammatory injury markers in Taiwanese adults.

BACKGROUND AND OBJECTIVES: The relationships of dietary choline and folate intake with hepatic function have yet to be established in the Taiwanese population. We investigated the associations of choline and folate intake with hepatic inflammatory injury in Taiwanese adults. METHODS AND STUDY DESIGN: Blood samples and data on dietary choline components and folate intake from 548 Taiwanese adults without pathological liver disease were collected. Dietary intake was derived using a semiquantitative food-frequency questionnaire. Serum liver injury markers of alanine transaminase, aspartate transaminase, and hepatitis viral infection were measured. RESULTS: Elevated serum hepatic injury markers (>40 U/L) were associated with low folate and free choline intake (p<0.05). Folate intake was the most significant dietary determinant of serum aspartate transaminase concentration (beta=-0.05, p=0.04), followed by free choline intake (beta=-0.249, p=0.055). Folate intake exceeding the median level (268 µg/d) was correlated with a reduced rate of hepatitis viral infection (p=0.032) and with normalized serum aspartate transaminase (odds ratio [OR]=0.998, 95% confidence interval [CI]=0.996-1, p=0.042) and alanine transaminase (OR=0.998, 95% CI=0.007-1, p=0.019). Total choline intake exceeding the median level (233 mg/d) was associated with normalized serum aspartate transaminase (OR=0.518, 95% CI=0.360-0.745, p=0.018). CONCLUSIONS: The newly established relationships of dietary intake of total choline and folate with normalized hepatic inflammatory markers can guide the development of dietary choline and folate intake recommendations for Taiwanese adults.