Anemarrhena asphodeloides Bunge total saponins ameliorate diabetic cardiomyopathy by modifying the PI3K/AKT/HIF-1α pathway to restore glycolytic metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Based on the theory of traditional Chinese medicine (TCM), diabetic cardiomyopathy (DCM) belongs to the category of "Xiaoke disease" according to the symptoms, and "stasis-heat" is the main pathogenesis of DCM. The Chinese medicine Anemarrhena asphodeloides Bunge (AAB), as a representative of heat-clearing and engendering fluid, is often used clinically in the treatment of DCM. Anemarrhena asphodeloides Bunge total saponins (RATS) are the main bioactive components of AAB, the modern pharmacologic effects of RATS are anti-inflammatory, hypoglycemic, and cardioprotective. However, the potential protective mechanisms of RATS against DCM remain largely undiscovered. AIM OF THE STUDY: The primary goal of this study was to explore the effect of RATS on DCM and its mechanism of action. MATERIALS AND METHODS: Streptozotocin and a high-fat diet were used to induce DCM in rats. UHPLC/Q-TOF-MS was used to determine the chemical components of RATS. The degenerative alterations and apoptotic cells in the heart were assessed by HE staining and TUNEL. Network pharmacology was used to anticipate the probable targets and important pathways of RATS. The alterations in metabolites and main metabolic pathways in heart tissue were discovered using 1 H-NMR metabolomics. Ultimately, immunohistochemistry was used to find critical pathway protein expression. RESULTS: First of all, UHPLC/Q-TOF-MS analysis showed that RATS contained 11 active ingredients. In animal experiments, we found that RATS lowered blood glucose and lipid levels in DCM rats, and alleviated cardiac pathological damage, and decreased cardiomyocyte apoptosis. Furthermore, the study found that RATS effectively reduced inflammatory factor release and the level of oxidative stress. Mechanistically, RATS downregulated the expression levels of PI3K, AKT, HIF-1α, LDHA, and GLUT4 proteins. Additionally, glycolysis was discovered to be a crucial pathway for RATS in the therapy of DCM. CONCLUSIONS: Our findings suggest that the protective effect of RATS on DCM may be attributed to the inhibition of the PI3K/AKT/HIF-1α pathway and the correction of glycolytic metabolism.

Integrative pharmacology reveals the mechanisms of Erzhi Pill, a traditional Chinese formulation, against diabetic cardiomyopathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi Pill (EZP) is a traditional Chinese prescription that has marked effects in treating type 2 diabetes mellitus and diabetic nephropathy. However, its underlying pharmacological mechanisms in the treatment of diabetic cardiomyopathy (DCM), remain to be elucidated. AIM OF THE STUDY: This study aimed to apply an integrative pharmacological strategy to systematically evaluate the pharmacological effects and molecular mechanisms of EZP, and provide a solid theoretical basis for the clinical application of EZP in the treatment of DCM. MATERIALS AND METHODS: In this study, the potential targets and key pathways of EZP were predicted and validated using network pharmacology and molecular docking, respectively. Changes in cardiac metabolites and major metabolic pathways in rat heart samples were examined using 1H-nuclear magnetic resonance (NMR) metabolomics. Finally, biochemical analysis was conducted to detect the protein expression levels of key pathways. RESULTS: We found that EZP decreased fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) levels, increased high-density lipoprotein (HDL) levels in the serum, and alleviated the morphological abnormalities of the heart tissue in diabetic rats. Furthermore, EZP effectively restored superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), caspase-3, caspase-8, and caspase-9 activity levels, as well as the levels of reactive oxygen species (ROS), malondialdehyde (MDA), B-cell lymphoma (Bcl)-2, and Bcl-2-associated X protein (Bax) in the heart tissue. Network pharmacology prediction results indicated that the mechanism of EZP in treating DCM was closely related to apoptosis, oxidative stress, and the HIF-1, PI3K-Akt, and FoxO signaling pathways. In addition, 1H-NMR metabolomics confirmed that EZP primarily regulated both energy metabolism and amino acid metabolism, including the tricarboxylic acid (TCA) cycle, ketone bodies metabolism, glutamine and glutamate metabolism, glycine metabolism, and purine metabolism. Finally, immunohistochemistry results indicated that EZP reduced the expression levels of p-AMPK, p-PI3K, p-Akt, and p-FoxO3a proteins, in the heart tissue of DCM rats. CONCLUSION: The results confirmed that the overall therapeutic effect of EZP in the DCM rat model is exerted via inhibition of oxidative stress and apoptosis, alongside the regulation of energy metabolism and amino acid metabolism, as well as the AMPK and PI3K/Akt/FoxO3a signaling pathways. This study provides an experimental basis for the use of EZP in DCM treatment.

Ferroptosis-Enhanced Cancer Immunity by a Ferrocene-Appended Iridium(III) Diphosphine Complex.

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy.

Phosphorescent metal complexes as theranostic anticancer agents: combining imaging and therapy in a single molecule.

Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(iii), ruthenium(ii) and rhenium(i) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.

Quantitative tracking of endoplasmic reticulum viscosity during ferroptosis by an iridium complex via TPPLM.

Herein, we report a neutral iridium complex, [Ir(4-(2-pyridinyl)benzaldehyde)2(acetylacetone)] (Ir-ER), with viscosity-responsive phosphorescent emission intensity and lifetime. Quantitative measurement by two-photon phosphorescent lifetime imaging shows that the viscosity of ER increases significantly in the process of erastin-induced ferroptosis. Our work provides an effective strategy for quantitative measurement of the micro-environmental alternations of subcellular organelles during a specific cell death process.

Serum metabonomic study of the effects of Huofeitong tablet on rats with COPD.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease. The Huofeitong tablet (HFTT), a Chinese compound medicine, exhibits an unambiguous therapeutic effect on COPD. However, the mechanism of its therapeutic effect on COPD is unclear. This study aimed to investigate the effect of HFTT on COPD and its mechanism. The changes in pulmonary function and the inflammatory factors in rats were determined via histopathology and bronchoalveolar lavage fluid. The mechanism of HFTT in COPD treatment was revealed using UPLC-Q-TOF-MS/MS and multivariate statistical analysis. Results showed that after HFTT treatment, the lung function began to recover, the lung tissue improved, and the TNF-α and IL-6 levels decreased, suggesting that HFTT had a therapeutic effect on COPD. In addition, 12 potential biomarkers, including malonate, urea-1-carboxylate, pyruvate, l-cysteate, glutathione, 2-deoxy-α-d-ribose1-phosphate, 3-fumarylpyruvate, 3-maleylpyruvate, 2-inosose, urate, allantoin, and inosine were screened. They associated with COPD development and concentrated in glutathione metabolism, glyoxylate and dicarboxylate metabolism, secondly concentrated in pyruvate metabolism, glycolysis/gluconeogenesis, pentose phosphate pathway, citrate cycle, glycine, serine and threonine metabolism, inositol phosphate, and purine metabolism. This study contributes to the development and application of HFTT in COPD treatment and provides a theoretical basis for COPD diagnosis, prevention, and treatment.

Circular RNA circ_0032821 contributes to oxaliplatin (OXA) resistance of gastric cancer cells by regulating SOX9 via miR-515-5p.

OBJECTIVES: Chemoresistance is one of the major obstacles for gastric cancer (GC) treatment. Exosome-mediated transfer of circular RNAs (circRNAs) is associated with the drug-resistance in GC. Circ_0032821 has been reported as an oncogene in GC. This study is designed to explore the function and mechanism of Exosomal circ_0032821 in oxaliplatin (OXA) resistance of GC. RESULTS: Circ_0032821 was highly expressed in OXA-resistant GC cells, and exosomes secreted by OXA-resistant GC cells. Moreover, circ_0032821-containing exosomes secreted by OXA-resistant GC cells could boost OXA resistance, proliferation, migration, and invasion in OXA-sensitive GC cells. The mechanical analysis discovered that circ_0032821 acted as a sponge of miR-515-5p to regulate SOX9 expression. Circ_0032821 silencing and OXA treatment repressed tumor growth in the GC mice model. CONCLUSIONS: Exosomal circ_0032821 boosted OXA resistance of GC cells partly by the miR-515-5p/SOX9 axis, hinting a promising therapeutic target for GC treatment.

Time series expression patterns reveal the molecular processes of pancreatic cancer progression.

PURPOSE: Pancreatic cancer is a fatal malignant tumor with no obvious characteristics in the early stage of onset and high metastatic ability which results in a low survival. Understanding the detailed process of pancreatic cancer contributes to new treatments to prolong patients' survival. METHODS: We carried out an in-depth analysis by modularization while seeking for critical genes in the pathogenesis of pancreatic cancer so as to identify the molecular mechanisms of the condition using differential analysis, co-expression module analysis, enrichment analysis, and network connectivity analysis. In light of the hypergeometric test, ncRNA (non-coding RNA) and transcription factors that regulate the module would be predicted. RESULTS: Conclusively, seven co-expression modules were obtained, in which CPA2 and A1BG were significantly differentially expressed in patients who had pancreatic cancer with active regulation in dysfunction modules. The modular genes significantly participated in second-messenger-mediated signaling as well as cellular calcium homeostasis and also controlled the interactions of neuroactive ligand-receptor. Besides, we identified ncRNA pivot including FENDRR and miR-92a-3p as well as transcription factors pivot including SPI1, STAT5A which significantly regulated the dysfunction module. CONCLUSION: This study can help reveal core dysfunction modules, potential regulatory factors, and driver genes for pancreatic cancer, enhancing the understanding of its pathogenesis and providing a reference for prediction with respect to the survival time of patients with this condition.

Cardioprotective effect exerted by Timosaponin Bâ ¡ through the regulation of endoplasmic stress-induced apoptosis.

BACKGROUND: Timosaponin BⅡ (TBⅡ), one of the primary bioactive compounds from Anemarrhena asphodeloides Bunge, possesses potential cardioprotective effects. However, the mechanism underlying TBⅡ-mediated cardioprotection, especially the involvement of endoplasmic reticulum stress, remains largely unknown. PURPOSE: This study was designed to evaluate the role of TBⅡ in myocardial injury protection and explore its possible mechanisms. METHODS: In vivo models of isoproterenol-induced myocardial injury and H2O2-induced cytotoxicty were established to investigate the effect of anti-myocardial injury of TBⅡ. The potential mechanisms were investigated in vitro and in vivo using multiple detection methods like electrocardiography, histo-pathological examination, JC-1 staining, TUNEL staining, ELISA technology, and western blot analysis. RESULTS: In vivo study revealed that TBⅡ improved electrocardiography and heart vacuolation, reduced myocyte apoptosis, and improved the antioxidant potential. In vitro investigation demonstrated that TBⅡ pretreatment inhibited ER stress-mediated apoptosis pathways. Further investigation of the underlying mechanisms revealed that TBⅡ prevented H2O2-induced H9c2 cardiomyocytes injury by the PI3K/Akt pathways, whereas the addition of LY294002, the pharmacologic antagonist of PI3K, attenuated TBⅡ-induced expression of apoptotic protein and cytoprotective effects. CONCLUSION: These results suggested that TBⅡ protects against myocardial injury in vitro and enhances cellular defense capacity by inhibiting ER stress-mediated apoptosis pathways in vivo by activating the PI3K/Akt pathways.

Cardioprotective effects of timosaponin B-II isolated from Anemarrhena rhizome in a zebrafish model.

Timosaponin B-II (TB-II; (25S)-26-(ß-D-glucopyranosyloxy)-3ß-[(2-O-ß-D-glucopyranosyl-ß-D-galactopyranosyl) oxy]-5ß-furostan-22-ol is extracted from Anemarrhena. Its anti-inflammation, anti-oxidation, and anti-asthma properties have been widely explored. However, its effect on the heart has not been reported. In this study, we used zebrafish as a research model to determine the effects of TB-II on the heart and its toxic and anti-inflammatory effects. To explore the cause of cardioprotective effects of TB-II, we used transgenic zebrafish with macrophages and neutrophils labeled with fluorescent protein. We found for the first time that TB-II had a protective effect on the zebrafish heart. It did not affect the survival and hatching rates of zebrafish embryos, indicating its low toxicity. Results showed that TB-II may have cardioprotective effects, which might be related to its anti-inflammatory effects.

Characterization of methylthioadenosin phosphorylase (MTAP) expression in colorectal cancer.

PURPOSE: Tumour seriously affects people's quality of life. Colorectal cancer is a refractory tumour in digestive tract tumors. In colorectal cancer, gene expression abnormalities is the main reason for its incidence, we mainly focus on the molecular mechanism of MTAP in the development of colorectal cancer. METHODS: The tumour tissue and its adjacent tissue samples of 50 patients with colorectal cancer were screened from July 2011 to February 2015, and the expression of MTAP was detected. Cell lines that overexpress MTAP and low expression of MTAP were constructed in colorectal cancer cell lines. The cell proliferation, invasion and migration was detected in the cells with different expression levels of MTAP. Immunohistochemistry was used to detect the expression of MTAP in liver metastasis and to investigate its clinical significance. And statistics of clinical significance. RESULTS: Q-PCR results showed that the expression of MTAP in colorectal cancer cell lines were significantly higher than that normal human colonic myofibroblasts cell line. Cell proliferation test results showed that cell proliferation was accelerated when MTAP was overexpression, cell invasion and migration were simultaneously accelerated. The expression of MTAP in primary liver was positively correlated with metastatic disease in patients with liver metastatic colorectal cancer via EMT. CONCLUSIONS: MTAP accelerates the growth and metastasis of colorectal cancer through EMT.

Shedding lights on the flexible-armed porphyrins: Human telomeric G4 DNA interaction and cell photocytotoxicity research.

DNA polymorphism exerts a fascination on a large scientific community. Without crystallographic structural data, clarification of the binding modes between G-quadruplex (G4) and ligand (complex) is a challenging job. In the present work, three porphyrin compounds with different flexible carbon chains (arms) were designed, synthesized and characterized. Their binding, folding and stabilizing abilities to human telomeric G4 DNA structures were comparatively researched. Positive charges at the end of the flexible carbon chains seem to be favorable for the DNA-porphyrin interactions, which were evidenced by the spectral results and further confirmed by the molecular docking calculations. Biological function analysis demonstrated that these porphyrins show no substantial inhibition to Hela, A549 and BEL 7402 cancer cell lines under dark while exhibit broad inhibition under visible light. This significantly enhanced photocytotoxicity relative to the dark control is an essential property of photochemotherapeutic agents. The feature of the flexible arms emerges as critical influencing factors in the cell photocytotoxicity. Moreover, an ROS-mediated mitochondrial dysfunction pathway was suggested for the cell apoptosis induced by these flexible-armed porphyrins. It is found that the porphyrins with positive charges located at the end of the flexible arms represent an exciting opportunity for photochemotherapeutic anti-cancer drug design.

TGF ß1 mediates epithelial mesenchymal transition via ß6 integrin signaling pathway in breast cancer.

BACKGROUND: To understand the function of ß6 integrin and elucidate its signaling pathways in TGF-ß-induced EMT in breast cancer. METHODS: The interactions between TGF-ß1 and ß6 integrin were measured by coimmunoprecipitation. The EMT responses, phospherlation of PI3K/Akt and COX-2 expression were determined by real-time PCR, transwell assay, and western blot after the blockage of ß6 integrin. RESULTS: TGF-ß1 and ß6 integrin could bind with each other. Blockage of ß6 integrin rescued TGF-ß1-induced EMT phenotype and reduced expression of COX-2 via dephosphorylation of PI3K/Akt. CONCLUSIONS: ß6 integrin plays a critical role in TGF-ß1-induced EMT and overexpression of COX-2 in breast cancer.