In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model.

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

A correlational study between serum asymmetric dimethylarginine level and impaired glucose tolerance patients associated with obesity.

Asymmetric dimethylarginine (ADMA) plays a vital role in the regulation of insulin sensitivity and has been shown as a potential marker for various disease, including type 2 diabetes mellitus (DM2). However, the correlation between ADMA and impaired glucose tolerance (IGT) and obesity has not been studied. A total of 195 subjects were involved in our study. The characteristics of the subjects in the study cohort were measured and analyzed. We found that the serum ADMA and C-reactive protein levels were significantly increased in IGT and diabetic patients, whereas the levels of lipoprotein A and adiponectin were decreased, especially in diabetic patients with obesity. The serum ADMA level was positively correlated to a homeostatic model assessment for insulin resistance, and multivariate regression analysis further indicated that ADMA was an independent factor for DM patients with obesity. Our study expands the understanding of the complicated relationship between obesity, insulin resistance, IGT, and ADMA. In addition, we demonstrated that the serum ADMA level could serve as a diagnositic biomarker of the early signs for IGT patients with obesity.

Asymmetric dimethylarginine targets MAPK pathway to regulate insulin resistance in liver by activating inflammation factors.

Insulin resistance is associated with impaired glucose uptake and altered protein kinase B (Akt) signaling. Previous studies have suggested asymmetric dimethylarginine (ADMA) and inflammation are two distinguish factors that correlate with insulin resistance (IR). How ADMA and inflammation factors interact and synchronize in the regulation of IR in liver remain to be elucidated. In this study, we systematically investigated whether ADMA is involved in IR using primary hepatocytes, if yes, by via which molecular mechanism. Our results demonstrated that ADMA inhibits insulin sensitivity in a concentration-dependent manner by activating inflammation factors tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 in primary hepatocytes. Further analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathway act downstream of ADMA and inflammation factors, and inhibition of MAPK pathway rescued the IR. Furthermore, metformin effects has been found which could reverse ADMA-induced IR by suppressing MAPK signaling pathway. To our knowledge, we, for the first time, unveiled the complicated regulatory network and interactions among ADMA, inflammation, and MAPK signaling pathway, which advanced current research on the development and regulation of IR in liver. This study also certainly provided novel insights on comprehensive diagonistics roles of ADMA as a potential biomarker.

Systematic-analysis of mRNA expression profiles in skeletal muscle of patients with type II diabetes: The glucocorticoid was central in pathogenesis.

Since the past 30 years, the prevalence of diabetes has more than doubled, making it an urgent challenge globally. We carried out systematic analysis with the public data of mRNA expression profiles in skeletal muscle to study the pathogenesis, since insulin resistance in the skeletal muscle is an early feature. We utilized three GEO datasets, containing total 60 cases and 63 normal samples. After the background removal, R package QC was utilized to finish the preprocessing of datasets. We obtained a dataset containing 2481 genes and 123 samples after the preprocessing. Quantitative quality control measures were calculated to represent the quality of these datasets. MetaDE package provides functions for conducting different systematic analysis methods for differential expression analysis. The GO term enrichment was carried out using PANTHER. Protein-protein interactions, drug-gene interactions, and genetic association of the identified differentially expressed genes were analyzed using STRING v10.0 online tool, DGIdb, and the Genetic Association Database, respectively. The datasets had good performances on IQC and EQC, which suggested that the datasets had good internal and external quality. Totally 96 differentially expressed genes were detected using 0.01 as cutoff of AW. The enriched GO terms were mainly associated with the response to glucocorticoid. There were seven genes involving in the gluconeogenesis were differentially expressed, which might be the potential treatment target for this disease. The closely connected networks and potential targets of existed drugs suggested that some of the drugs might be applied to the treatment of diabetes as well.

The key genes underlying pathophysiology association between the type 2-diabetic and colorectal cancer.

Although diabetes mellitus (DM) is reported as an independent risk factor for colorectal cancer (CRC) in many researches, the underlying pathophysiology is still unclear. We investigated the differentially expressed genes (DEGs) for the diabetes and CRC to reveal the underlying pathophysiological association between the type 2-diabetic (T2D) and CRC. Gene expression profiles for T2D (GSE55650), CRC (GSE8671), and Metformin treated cell lines (GSE67342) were downloaded from GEO database. The DEGs between T2D samples and their control samples were identified with t-test and variance analysis. After cluster analysis and functional enrichment analysis, protein-protein interaction (PPI) network was constructed to find potential genes for diabetes and CRC in Metformin's treatment. Totally, we identified 583 overlapped genes, 169 common DEGs, and 414 independent DEGs between T2D and CRC samples. The common genes contained 89 up-regulated (DEGs1) and 80 down-regulated genes (DEGs3); and independent DEGs contained 270 down-regulated genes (DEGs4) in diabetes and 144 down-regulated genes (DEGs2) in CRC. In enrichment analysis, the Ribosome pathway was significantly enriched by the independent DEGs. The common genes were mainly enriched in some inflammatory related pathways. Two target genes of Metformin were significantly interacted with six hub genes (HADHB, NDUFS3, TAF1, MYC, HNFF4A, and MAX) with significant changes in expression values (P < 0.05, t-test). To summary, it is suggested that the six hub genes might play important roles in the process of Metformin treatment for diabetes and CRC. However, specific pathology remains to be further studied.

Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells.

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.