Polychlorinated biphenyls exposure and type 2 diabetes: Molecular mechanism that causes insulin resistance and islet damage.

Polychlorinated biphenyls (PCBs) are typical persistent organic pollutants that have been associated with type 2 diabetes (T2DM) in cohort studies. This review aims to comprehensively assess the molecular mechanisms of PCBs-induced T2DM. Recent progress has been made in the research of PCBs in liver tissue, adipose tissue, and other tissues. By influencing the function of nuclear receptors, such as the aryl hydrocarbon receptor (AhR), pregnancy X receptor (PXR), and peroxisome proliferator activated receptor γ (PPARγ), as well as the inflammatory response, PCBs disrupt the balance of hepatic glucose and lipid metabolism. This is associated with insulin resistance (IR) in the target organ of insulin. Through androgen receptor (AR), estrogen receptor α/ß (ERα/ß), and pancreato-duodenal-homeobox gene-1 (PDX-1), PCBs affect the secretion of insulin and increase blood glucose. Thus, this review is a discussion on the relationship between PCBs exposure and the pathogenesis of T2DM. It is hoped to provide basic concepts for diabetes research and disease treatment.

PIK3CD correlates with prognosis, epithelial-mesenchymal transition and tumor immune infiltration in breast carcinoma.

BACKGROUND: Breast carcinoma (BRCA) is one of the most common, fatal, and aggressive cancers, with increasing morbidity that has a major impact on human health. PIK3CD appears to have important roles in the beginning and advancement of various forms of human cancer, according to mounting data. However,the particular role and mechanism of PIK3CD in BRCA remains not fully identified. METHODOLOGY: The Cancer Genome Atlas (TCGA, https://portal.gdc.cancer.gov/ ), Genotype-Tissue Expression (GTEx) data and the UCSC Xena browser ( https://xenabrowser.net ) data were used in this study's initial pan-cancer analysis of PIK3CD expression and prognosis. Circular RNAs (circRNAs) that regulated the expression of PIK3CD were subsequently found using a combination of in silico investigations of expression, correlation, and survival. Measurements of PIK3CD expression and an analysis of the in vitro function of PIK3CD in BRCA cells were performed using real-time RT-PCR, Western blotting and Transwell assays. RESULTS: In BRCA GLI2, RAB32, LAMB1, MGAT2, ITGA8, CHF, COL6A3 and PRRX1-miR-30b-5p axis was identified as the most likely upstream CircRNA-related route of PIK3CD. PIK3CD was correlated with the expression of EMT markers. The PIK3CD cDNA improved the capacity for invasion and migration. The expression of PIK3CD was linked to some of the m1A/m5C/m6A regulators. Additionally, it was discovered that the expression of PIK3CD was found to be highly connected to the expression of immunological checkpoints, immune cell biomarkers, and tumor immune cell invasion. CONCLUSIONS: Our findings reveal that PIK3CD expression is associated with prognosis, EMT, and tumor immune infiltration in BRCA patients.

Recent advances in pyroptosis, liver disease, and traditional Chinese medicine: A review.

In recent years, the incidence of liver disease has increased, becoming a major cause of death. Various liver diseases are intricately linked to pyroptosis, which is one of the most common forms of programmed cell death. As a powerful weapon in the fight against liver diseases, traditional Chinese medicine (TCM) can affect pyroptosis via a number of routes, including the classical, nucleotide oligomerization domain-like receptors protein 3/caspase-1/gasdermin D (GSDMD) pathway, the nonclassical lipopolysaccharide/caspase-11/GSDMD pathway, the ROS/caspase-3/gasdermin E pathway, the caspase-9/caspase-3/GSDMD pathway, and the Apaf-1/caspase-11/caspase-3 pathway. In this review, we provide an overview of pyroptosis, the interplay between pyroptosis and liver diseases, and the mechanisms through which TCM regulates pyroptosis in liver diseases. The information used in the text was collected and compiled from the databases of PubMed, Web of Science, Scopus, CNKI, and Wanfang Data up to June 2023. The search was not limited with regard to the language and country of the articles. Research and review articles were included, and papers with duplicate results or unrelated content were excluded. We examined the current understanding of the relationship between pyroptosis and liver diseases as well as the advances in TCM interventions to provide a resource for the identification of potential targets for TCM in the treatment of liver diseases.

KLF14/miR-1283/TFAP2C axis inhibits HER2-positive breast cancer progression via declining tumor cell proliferation.

MiR-1283 has been identified as a tumor suppressor in some malignancies. Whereas, the role of miR-1283 in HER2-positive (HER2+) breast cancer, particularly its role in regulating cell proliferation, one of the most significant features of tumor progression, is unclear. The related microRNA screened by the breast cancer sample GSE131599 dataset were detected in HER2+ breast cancer tissues and cell lines. Then, the obtained miR-1283 was overexpressed in SKBR3 and BT-474 cells followed by relevant functional assays concerning cell proliferation and apoptosis. The xenograft mouse model was induced and the effect of miR-1283 on tumor growth and cell proliferation was examined. The target of miR-1283 and the transcription factor regulating miR-1283 were predicted and identified. Finally, the influence of transcription factor KLF14 on cell proliferation and apoptosis was investigated. An integrated analysis confirmed that miR-1283 expression was significantly decreased in HER2+ breast cancer tissues. Also, by q-RT-PCR detection, miR-1283 expression was markedly reduced in HER2+ breast cancer tissues and cell lines. The miR-1283 overexpression prevented the proliferation and enhanced apoptosis of HER2+ breast cancer cells, as well as inhibited tumor growth. Mechanistically, miR-1283 inhibited TFAP2C expression by targeting the 3'-untranslated regions of TFAP2C messenger RNA, and the KLF14 enhanced miR-1283 level via binding to its promoter. The result subsequently confirmed the KLF14/miR-1283 signaling suppressed cell proliferation in HER2+ breast cancer. Our results suggested that the KLF14/miR-1283/TFAP2C axis inhibited HER2+ breast cancer progression, which might provide novel insight into mechanical exploration for this disease.

LncRNA HOTAIR promotes the proliferation and invasion/metastasis of breast cancer cells by targeting the miR-130a-3p/Suv39H1 axis.

Long noncoding RNAs (lncRNAs) are a group of transcripts, more than 200 bp in size and regulate cell proliferation, differentiation and apoptosis. LncRNA HOX Transcript Antisense Intergenic RNA (HOTAIR) promotes tumor progression and increases cancer susceptibility by regulating microRNA expression and function. HOTAIR regulates miR-130a-3p expression in hepatocellular carcinoma cells. Bioinformatics analysis revealed that Suv39H1 contained a putative binding site for miR-130a-3p. We speculate that LncRNA HOTAIR promotes the proliferation and invasion/metastasis of breast cancer (BC) cells by targeting the miR-130a-3p/Suv39H1 axis. High HOTAIR expression facilitated BC cell growth and metastasis. HOTAIR functioned as a ceRNA by sponging miR-130a-3p and subsequently promoted Suv39H1-mediated AKT/mTOR signaling. Suv39H1 restoration abolished the effects of HOTAIR knockdown on BC cell growth and metastasis. HOTAIR facilitated the Suv39H1-mediated AKT/mTOR pathway by acting as a molecular sponge of miR-130a-3p.Our results provide a better understanding of the interactions of HOTAIR and miR-103a-3p/Suv39H1 in BC and a potential prognostic biomarker and therapeutic target for BC.

Covalent Biosensing Polymer Chain Reaction Enabling Periphery Blood Testing to Predict Tumor Invasiveness with a Platelet Procancerous Protein.

Periphery blood testing is an attractive and relatively less invasive way of early cancer screening. In this work, based on the latest understanding of the pivotal role of platelets in promoting cancer invasion, a method for detecting a procancerous protein overexpressed both on platelets and in cancer cells is developed. As a kinase, the enzymatic activity, abundance, and self-phosphorylation of this protein are all important factors influencing its procancerous activity. To simultaneously determine these three important biochemical parameters, electrochemical control is called upon to connect or disconnect a polymer chain reaction (PCR) primer with a small-molecule synthetic probe, and with the target protein, in a target-specific manner. The resulting PCR signal amplification greatly improves the sensitivity of the design and also enables direct detection of the protein and its catalytic activity as well as its self-phosphorylation in clinical periphery blood samples from hepatocellular carcinoma (HCC) patients. This may point to future application of the proposed method in the early screening of HCC to assist its diagnosis and treatment.

Circular RNA circ-ERBB2 promotes HER2-positive breast cancer progression and metastasis via sponging miR-136-5p and miR-198.

BACKGROUND: Circular RNAs (circRNAs) are pivotal regulators of various human cancers and circ-ERBB2 is abnormally expressed in breast cancer cells. However, the role and mechanism of circ-ERBB2 in HER2-positive breast cancer are still unknown. METHODS: The circ-ERBB2 expressions in the tumor tissues of HER2-positive breast cancer patients were tested using quantitative real-time PCR. The circ-ERBB2 function was investigated by cell counting kit 8 assay, Transwell, flow cytometry and Western blot. Mechanistically, fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and dual-luciferase reporter gene assays were conducted to confirm the interaction between circ-ERBB2 and miR-136-5p or miR-198 in HER2-positive breast cancer cells. RESULTS: Circ-ERBB2 was elevated in the tumor tissues of HER2-positive breast cancer patients. Functionally, the interference with circ-ERBB2 repressed HER2-positive breast cancer cell proliferation, migration, invasion and accelerated cell apoptosis. Furthermore, the mechanistic analysis corroborated that circ-ERBB2 acted as a competing endogenous RNA for miR-136-5p or miR-198 to relieve the repressive influence of miR-136-5p or miR-198 on its target transcription factor activator protein 2C (TFAP2C). Meanwhile, in vivo assays further corroborated the oncogenic function of circ-ERBB2 in HER2-positive breast cancer. CONCLUSIONS: Circ-ERBB2 accelerated HER2-positive breast cancer progression through the circ-ERBB2/miR-136-5p/TFAP2C axis or the circ-ERBB2/miR-198/TFAP2C axis.

miR­125a­5p reverses epithelial­mesenchymal transition and restores drug sensitivity by negatively regulating TAFAZZIN signaling in breast cancer.

MicroRNA (miR)­125a­5p represses tafazzin phospholipid­lysophospholipid transacylases (TAFAZZIN) expression and inhibits the epithelial­mesenchymal transition (EMT) of ovarian cancer cells. EMT was found to have a crucial role in the acquisition of chemoresistance. Thus, the present study aimed to determine whether miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer. The expression of miR­125a­5p/TAFAZZIN and its association with chemotherapy response were determined in tissue samples from patients with breast cancer. Furthermore, the effects of miR­125a­5p on breast cancer cells were elucidated using cell proliferation and cell apoptosis assays. Then, the regulatory mechanism of miR­125a­5p in breast cancer was investigated by reverse transcription­quantitative PCR, western blotting, dual­luciferase reporter and RNA immunoprecipitation assays. The results demonstrated that miR­125a­5p inhibited the EMT of MCF­7/adriamycin (Adr) breast cancer cells, as well as decreased the proliferation and increased the apoptosis of breast cancer cells treated with Adr/docetaxel. In addition, miR­125a­5p downregulated the expression levels of TAFAZZIN, Transglutaminase 2, phosphorylated­AKT, N­cadherin, vimentin and proliferating cell nuclear antigen, and significantly increased those of E­cadherin, cleaved caspase-3 and Bax in MCF7/Adr cells. Similar results were obtained with small interfering RNA­TAFAZZIN. Moreover, TAFAZZIN was identified as a direct target of miR­125a­5p in MCF7/Adr breast cancer cells. In addition, increased miR­125a­5p expression was observed in breast tumors from patients exhibiting a chemotherapy response, and TAFAZZIN mRNA expression was elevated in patients with no chemotherapy response. Hence, miR­125a­5p expression was negatively correlated with TAFAZZIN mRNA expression in breast cancer tissues. All these data suggested that miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer and, therefore, has potential as a novel therapeutic target for this disease.

A single-interface photoelectrochemical sensor based on branched TiO2 nanorods@strontium titanate for the detection of two biomarkers.

In this study, a single-interface photoelectrochemical (PEC) sensor for detecting two antigens, alpha fetoprotein (AFP) and cancer antigen 153 (CA 153), was achieved based on the heterostructure of branched titanium dioxide nanorods (B-TiO2 NRs)@strontium titanate (SrTiO3) heterostructures. The B-TiO2 NRs@SrTiO3 heterostructure, prepared by a facile hydrothermal method with the feature of enhanced photogenerated charge carrier separation properties, was first employed as a photoactive substrate for anchored analyst. In order to achieve the goal of successfully detecting two biomarkers at a single interface, the two specific enzyme tags ß-galactosidase and acetylcholine esterase linked with a secondary detection antibody were utilized to catalytically hydrolyze p-aminophenyl galactopyranoside and acetylthiocholine to p-aminophenol and thiocholine, respectively. Based on the above enzyme-catalyzed reactions to produce sacrificial electron donors, the photocurrent signals generated from different analytes could be distinguished at a single interface. The results demonstrate that this single-interface PEC sensor not only provides a method for the early detection of AFP and CA 153 but also provides new insight into designing a novel PEC sensor for the detection of two biomarkers with high efficiency and a simple method of operation.

CyclinG1 Amplification Enhances Aurora Kinase Inhibitor-Induced Polyploid Resistance and Inhibition of Bcl-2 Pathway Reverses the Resistance.

BACKGROUND/AIMS: CyclinG1 (CycG1) is frequently overexpressed in solid tumors and overexpression of CycG1 promotes cell survival upon paclitaxel exposure by inducing polyploidy. Whether and how CycG1 regulates polyploidization caused by small molecular targeted inhibitors remains unclear. METHODS: Immunohistochemistry and immunoblotting were utilized to examine protein expression. Cell proliferation was measured by ATPlite assay, and cell cycle distribution and apoptosis were measured by flow cytometry and/or DNA fragmentation assays. RESULTS: Overexpression of CycG1 in breast cancer cells caused apoptosis-resistant polyploidy upon treatment with Aurora kinase inhibitor, ZM447439 (ZM). Addition of ABT-263, a small-molecule BH3 mimetic, to ZM, produced a synergistic loss of cell viability with greater sustained tumor growth inhibition in breast cancer cell lines. Decrease of Mcl-1 and increase of NOXA caused by ZM treatment, were responsible for the synergy. Furthermore, CycG1 was highly expressed in Triple-Negative-Breast-Cancer patients treated with paclitaxel and was paralleled by decreased cell survival. CONCLUSION: CycG1 is a crucial factor in ZM-induced polyploidy resistance, and ABT-263/ZM combination hold therapeutic utility in the CycG1-amplified subset of breast cancer and CycG1, thus, is a promising target in breast cancer.

Silencing of TGM2 reverses epithelial to mesenchymal transition and modulates the chemosensitivity of breast cancer to docetaxel.

Epithelial to mesenchymal transition (EMT) plays a critical role in drug resistance. The aim of the present study was to further elucidate its role by examining the effect of tissue transglutaminase (TG2) on EMT and drug resistance in breast cancer. An antisense lentiviral (LV) short hairpin (sh)RNA construct specific to the TG2 gene (TGM2) was designed, synthesized and stably transfected into MDA-MB-231 cells to silence TGM2 by RNA interference (RNAi). The transfected cells expressed low levels of TG2 and constituted the RNAi (TGM2-shRNA) group. A control (NC) group was also established by transfecting MDA-MB-231 cells with scrambled shRNA. The expression levels of TG2, E-cadherin, vimentin and B-cell lymphoma (Bcl)-2 in the cells were examined via western blotting. The transfected MDA-MB-231 cells were divided into four groups, two of which were treated with doxetaxel (TXT): NC, RNAi, TXT and RNAi + TXT groups,. Cell proliferation was analyzed by MTT assay and cell apoptosis was detected by flow cytometry. An in vivo assay was also conducted, in which MDA-MB-231 cells transfected with scrambled shRNA or TGM2-shRNA were subcutaneously implanted into nude mice. After 2 weeks, TXT or vehicle was intraperitoneally administered at a dose of 10 mg/kg on day 1 of every week and tumor growth was monitored. Following the silencing of TGM2 in the MDA-MB-231 cells, the cells showed changes in morphology, indicating that an increased expression of TG2 was associated with a mesenchymal morphology. Transfection of the cells with TGM2-shRNA affected the expression of TG2, E-cadherin, vimentin and Bcl-2. In the MTT assay, the proliferation of MDA-MB-231 cells was significantly inhibited in the RNAi group compared with the control group (P<0.05), and the inhibitory effect increased in a time-dependent manner. Following treatment with TXT for 48 h, apoptosis was significantly promoted in the RNAi + TXT group compared with that in the other groups (P<0.05). Measurement of the tumors in the nude mice indicated that the combination of RNAi and TXT brought about a stronger antitumor effect than either treatment alone. These results suggest that the downregulation of TG2 reversed EMT and modulated the chemosensitivity of breast cancer to TXT. TG2 may be an important predictive and prognostic factor for the treatment efficacy of chemotherapy in patients with breast cancer.