JNK and Jag1/Notch2 co-regulate CXCL16 to facilitate cypermethrin-induced kidney damage.

Cypermethrin (CYP), a widely-used composite pyrethroid pesticide, has underlying nephrotoxic effects. To elucidate potential roles of the MAPK pathway, the Jag/Notch pathway, and miRNAs in CYP-mediated kidney lesion, Sprague-Dawley rats and glomerular mesangial cells were used in this work. Results displayed that ß-CYP abnormally altered renal histomorphology and ultrastructures, induced renal DNA damage, and impaired renal functions, as evidenced by the increase in plasma levels of Cys-C and ß2-Mg. ß-CYP activated the JNK/c-Jun pathway by inducing ROS and oxidative stress. Meanwhile, ß-CYP changed the miRNA expression profile, miR-21-5p showing the most significant increase. Moreover, the Jag1/Notch2/Hes1 pathway was directly targeted by miR-21-5p, the mRNA and protein expression of Jag1, Notch2, and Hes1 being declined in vivo and in vitro. The chemokine CXCL16 was induced by ß-CYP, accompanied by the inflammatory factor production and inflammatory cell infiltration in kidneys. The specific JNK inhibitor, Jag1 overexpression, Hes1 overexpression, bidirectional Co-IP, ChIP, and CXCL16 silencing demonstrated that CXCL16 co-regulated by the JNK/c-Jun and Jag1/Notch2/Hes1 pathways elicited renal inflammation. Collectively, our findings indicate that ß-CYP is of nephrotoxicity and it not only directly changes renal histomorphology and ultrastructures, but induces CXCL16 to trigger renal inflammation via the JNK/c-Jun and Jag1/Notch2/Hes1 pathways, finally synergistically contributing to kidney damage.

Cypermethrin triggers YY1-mediated testosterone biosynthesis suppression.

Cypermethrin (CYP), an extensively-used broad-spectrum pyrethroid pesticide, is regarded as a potential environmental endocrine disruptor with the anti-androgenic characteristic. To explore underlying roles of non-coding RNAs and the Jak/Stat pathway in CYP-mediated testosterone biosynthesis suppression, SD rats and Leydig cells were employed in this work. Results displayed that ß-CYP decreased plasma testosterone levels and led to abnormal alterations of testicular histomorphology and ultrastructures. LncRNA XIST and miR-142-5p were co-localized in the cytoplasm of Leydig cells, but the expression of XIST was inhibited by ß-CYP while that of miR-142-5p was induced. Then overexpressed miR-142-5p dampened the Jak1/Stat1 pathway by directly targeting Jak1. Transcription factors NFκB and YY1 impeded by ß-CYP were positively regulated by the Jak1/Stat1 pathway. Bidirectional Co-IP and ChIP assays demonstrated that NFκB interacted with and modulated YY1 by directly binding to the promoter region of YY1. ChIP, qPCR, and YY1 knockdown/overexpression assays indicated that YY1 acted as a transcriptional activator to directly modulate steroidogenic StAR and 3ß-HSD in Leydig cells. Taken together, miR-142-5p sponged by lncRNA XIST directly targets the Jak1/Stat1 pathway, which regulates steroidogenic StAR and 3ß-HSD via NFκB and YY1, and ultimately dampens testosterone production in Leydig cells.

Polysaccharides derived from Balanophora polyandra significantly suppressed the proliferation of ovarian cancer cells through P53-mediated pathway.

Ovarian cancer (OC) is ranked the first among the cancers threatening women's health. It attracts tremendous attention of cancer researchers because of its extremely high mortality rate. Recent studies have indicated that traditional herbal medicines (THMs) can play a pivotal role in cancer prevention and treatment. THMs are gaining popularity as a source of anti-cancer agents. The plant of Balanophora polyandra, which has been used as a traditional herbal medicine, has been known for exhibiting potential haemostatic, analgesic, anti-inflammatory and anti-cancer properties. However, few studies on inhibitory effect of B. polyandra on OC have been performed. In the present study, we found that B. polyandra polysaccharides (BPP) induced cell cycle arrest at S phase, triggered apoptosis and inhibited migration and invasion of OC cells. Furthermore, we also found that there was a potential and close relationship between BPP and P53-mediated pathway. Overall, these findings suggest that BPP can be a potential therapeutic agent for the treatment of OC.

Apigenin improves testosterone synthesis by regulating endoplasmic reticulum stress.

Obesity is a growing epidemic among reproductive-age men, which can cause and exacerbate male infertility by means of associated comorbidities, endocrine abnormalities, and direct effects on the fidelity and throughput of spermatogenesis. A prominent consequence of male obesity is a reduction in testosterone levels. Natural products have shown tremendous potential anti-obesity effects in metabolic diseases. This study aimed to investigate the potential of apigenin (AP) to alleviate testicular dysfunction induced by a high-fat diet (HFD) and to investigate the underlying mechanisms, focusing on endoplasmic reticulum stress (ERS) and testosterone synthesis. A murine model of obesity was established using HFD-fed mice. The effects of AP on obesity, lipid metabolism, testicular dysfunction, and ERS were assessed through various physiological, histological, and molecular techniques. Administration of AP (10 mg/kg) ameliorated HFD-induced obesity and testicular dysfunction in a mouse model, as evidenced by decreased body weight, improved lipid profiles and testicular pathology, and restored protein levels related to testosterone. Furthermore, in vitro studies demonstrated that AP relieved ERS and recovered testosterone synthesis in murine Leydig cells (TM3) treated with free fatty acids (FFAs). It was also observed that AP rescued testosterone synthesis enzymes in TM3 cells, similar to that observed with the inhibitor of the PERK pathway (GSK2606414). In addition, ChIP, qPCR, and gene silencing showed that the C/EBP homologous protein (CHOP) bound directly to the promoter region of steroidogenic STAR and negatively modulated its expression. Collectively, AP has remarkable potential to alleviate HFD-induced obesity and testicular dysfunction. Its protective effects are attributable partly to mitigating ERS and restoring testosterone synthesis in Leydig cells.

Adverse effects of triclosan exposure on health and potential molecular mechanisms.

With the COVID-19 pandemic, the use of disinfectants has grown significantly around the world. Triclosan (TCS), namely 5-chloro-2-(2,4-dichlorophenoxy) phenol or 2,4,4'-trichloro-2'-hydroxydiphenyl ether, is a broad-spectrum, lipophilic, antibacterial agent that is extensively used in multifarious consumer products. Due to the widespread use and bioaccumulation, TCS is frequently detected in the environment and human biological samples. Accumulating evidence suggests that TCS is considered as a novel endocrine disruptor and may have potential unfavorable effects on human health, but studies on the toxic effect mediated by TCS exposure as well as its underlying mechanisms of action are relatively sparse. Therefore, in this review, we attempted to summarize the potential detrimental effects of TCS exposure on human reproductive health, liver function, intestinal homeostasis, kidney function, thyroid endocrine, and other tissue health, and further explore its mechanisms of action, thereby contributing to the better understanding of TCS characteristics and safety. Moreover, our work suggested the need to further investigate the biological effects of TCS exposure at the metabolic level in vivo.

Long Non-coding RNAs in Metabolic and Inflammatory Pathways in Obesity.

BACKGROUND: In recent decades, the incidence of obesity has been rising globally. Obesity can often cause various inflammatory reactions, resulting in several diseases that threaten public health. The purpose of this review is to explore the role of long non-coding RNAs in metabolic obesity and find new targets for the prevention and treatment of metabolic diseases. METHODS: We described the relationship between obesity and inflammation, reviewed several signaling pathways in metabolic inflammation, and summarized some of the long non-coding RNAs and their targets associated with metabolic inflammation. The related studies were retrieved through a systematic search of the PubMed database. RESULT: Metabolic stress during obesity can cause inflammation through several metabolic pathways. Many long non-coding RNAs can affect the progression of metabolic inflammation by affecting different pathways. CONCLUSION: Downregulation or antagonization of long non-coding RNAs in metabolic pathways may provide new ideas and therapeutic targets for the prevention and treatment of metabolic inflammation.

Pathophysiological Functions of the lncRNA TUG1.

BACKGROUND: Long non-coding RNAs (lncRNAs) with little or no coding capacity are associated with a plethora of cellular functions, participating in various biological processes. Cumulative study of lncRNA provides explanations to the physiological and pathological processes and new perspectives to the diagnosis, prevention, and treatment of some clinical diseases. Long non-coding RNA taurine-upregulated gene 1(TUG1) is one of the first identified lncRNAs associated with human disease, which actively involved in various physiological processes, including regulating genes at epigenetics, transcription, post-transcription, translation, and posttranslation. The aim of this review was to explore the molecular mechanism of TUG1 in various types of human diseases. METHODS: In this review, we summarized and analyzed the latest findings related to the physiologic and pathophysiological processes of TUG1 in human diseases. The related studies were retrieved and selected the last six years of research articles in PubMed with lncRNA and TUG1 as keywords. RESULTS: TUG1 is a valuable lncRNA that its dysregulated expression and regulating the biological processes were found in a variety of human diseases. TUG1 is found to exhibit aberrant expression in a variety of malignancies. Dysregulation of TUG1 has been shown to contribute to proliferation, migration, cell cycle changes, inhibited apoptosis, and drug resistance of cancer cells, which revealed an oncogenic role for this lncRNA, but some reports have shown downregulation of TUG1 in lung cancer samples compared with noncancerous samples. In addition, the molecular and biological functions of TUG1 in physiology and disease (relevant to endocrinology, metabolism, immunology, neurobiology) have also been highlighted. Finally, we discuss the limitations and tremendous diagnostic/therapeutic potential of TUG1 in cancer and other diseases. CONCLUSION: Long non-coding RNA-TUG1 likely served as useful disease biomarkers or therapy targets and effectively applied in different kinds of diseases, such as human cancer and cardiovascular diseases.

About three-fourths of mouse proteins unexpectedly appear at a low position of SDS-PAGE, often as additional isoforms, questioning whether all protein isoforms have been eliminated in gene-knockout cells or organisms.

Most genes in evolutionarily complex genomes are expressed to multiple protein isoforms, but there is not yet any simple high-throughput approach to identify these isoforms. Using an oversimplified top-down LC-MS/MS strategy, we detected, around the 26-kD position of SDS-PAGE, proteins produced from 782 genes in a Cdk4-/- mouse embryonic fibroblast cell line. Interestingly, only 213 (27.24%, about one-fourth) of these 782 genes have their proteins with a theoretical molecular mass (TMM) 10% smaller or larger than 26 kD, that is, between 23 and 29 kD, the range set as allowed variation in SDS-PAGE. These 213 proteins are considered as the wild type (WT). The remaining three-fourths includes proteins from 66 (9.44%) genes with a TMM smaller than 23 kD and proteins from 503 (64.32%, nearly two-thirds) genes with a TMM larger than 29 kD; these proteins are categorized into a larger-group or a smaller-group, respectively, for their appearance at a higher or lower position of SDS-PAGE. For instance, at this 26-kD position we detected proteins from the Rps27a, Snrpf, Hist1h4a, and Rps25 genes whose proteins' TMM is 8.6, 9.7, 11.4, and 13.7 kD, respectively, and detected proteins from the Plelc1 and Prkdc genes, whose largest isoform is 533.9 and 471.1 kD, respectively. We extrapolate that many of those proteins migrating unexpectedly in SDS-PAGE may be isoforms besides the WT protein. Moreover, we also detected a Cdk4 protein in this Cdk4-/- cell line, thus wondering whether some of other gene-knockout cells or organisms show similar incompleteness of the knockout.

Balanophora polyandra Griff. prevents dextran sulfate sodium-induced murine experimental colitis via the regulation of NF-κB and NLRP3 inflammasome.

Balanophora polyandra Griff. (B. polyandra) is a folk medicine used as an antipyretic, antidote, haemostatic, dressing and haematic tonic, for the treatment of gonorrhea, syphilis, wounds, and the bleeding of the alimentary tract by the local people in China. This study was designed to investigate the effects of B. polyandra on dextran sulfate sodium (DSS)-treated colitis mice in vivo and lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro. Mice were induced with B. polyandra total extract (BPE, 250 and 1000 mg kg-1) and B. polyandra polysaccharides (BPP, 100 and 400 mg kg-1) for 22 days and treated with 3.5% DSS in their drinking water for the last 7 days and the LPS-induced RAW264.7 macrophages were treated with BPE (100 µg ml-1) and BPP (100 µg ml-1). Mice treated with DSS developed severe mucosal colitis, with a marked distortion and crypt loss of colonic surface epithelium and a colonic shortening. B. polyandra significantly inhibited colonic shortening and reduced the severity of colitis in the colon and lowered the colonic inflammation score (p < 0.05) and decreased the expression of interleukin (IL)-1ß, tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), and anti-serum amyloid A3 (SAA3) as well as the pro-inflammatory chemokine C-X-C motif chemokine 10 (CXCL10). B. polyandra also significantly suppressed the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome and the nuclear factor kB (NF-κB). These results suggest that dietary intake of B. polyandra ameliorates colitis. Such activities of B. polyandra in humans remain to be investigated.

The Regulatory Roles of Long Non-Coding RNA in the Chemoresistance Process of Ovarian cancer.

BACKGROUND: Ovarian cancer is the most malignant tumor in gynecological tumors, with low five-year survival rate. The main reasons are diagnosis at advanced stages (the early symptoms are uncharacteristic, and most are diagnosedlate.), relapse, and resistance to existing chemotherapy drugs. METHODS: Search strategy was performed in the following steps. Firstly, LncRNA related to ovarian cancer was retrieved by using the LncRNA Disease database, and articles were searched by searching keywords: ovarian cancer, drug resistance, and LncRNA retrieved from the LncRNA Disease database. RESULTS/CONCLUSION: With the development of the study on drug resistance of ovarian cancer, the role of LncRNAs as sensitive biomarker and therapeutic target has emerged, providing a direction for precision medicine of ovarian cancer resistance.