Objective: This study aims to investigate the effect of astragaloside Ⅳ on adipose lipolysis and hepatic gluconeogenesis. Methods: High-fat diet (HFD) feeding induced adipose dysfunction with enhanced endogenous glucose production in mice. The effects of Astragaloside Ⅳ on lipolysis and hepatic glucose production were investigated. Results: HFD feeding induced cAMP accumulation through reducing PDE3B expression and activity in adipose tissue. As a result, HFD feeding increased adipose lipolysis in mice. Astragaloside Ⅳ enhanced Akt phosphorylation and promoted Akt binding to PDE3B to preserve PDE3B content, resultantly reducing adipose cAMP accumulation. Knockdown of Akt1/2 diminished the effect of astragaloside Ⅳ on PDE3B induction, indicative of the role of Akt in astragaloside Ⅳ action. As a result from blocking of cAMP/PKA signaling, astragaloside Ⅳ suppressed hormone-sensitive lipase (HSL) activation and inhibited inflammation-associated adipose lipolysis. Moreover, astragaloside Ⅳ reduced ectopic fat deposition in the liver and inhibited FoxO1 activation via regulation of Akt, resultantly restraining excess hepatic glucose production. Conclusion: We showed that preserving PDE3B content by Akt is a key regulation to prevent lipolysis. Astragaloside Ⅳ inhibited lipolysis by reducing cAMP accumulation via regulation of Akt/PDE3B, contributing to limiting hepatic lipid deposition and restraining excessive hepatic glucose production.

Colitis-associated cancer (CAC) is a malignant disease of the colon that is caused by recurrent episodes of chronic intestinal inflammation. Huangqi Baizhu decoction (HBD) is a classic prescription comprised of Radix Astragali and Rhizoma Atractylodis, which are usually used to treat digestive conditions, such as peptic ulcers, colitis, or colorectal carcinoma in clinics. HBD is well known for “tonifying qi and spleen” based on the theories of traditional Chinese medicine, and has the preponderant effect of alleviating chronic intestinal mucosa damage associated with disease. However, the underlying mechanism behind this is still unknown. In the current study, we employed the AOM/DSS mouse model to analyze the effects of HBD on the development of inflammation in colonic carcinoma. The in vivo study showed that HBD could significantly reduce the mortality of mice and control the incidence and size of colonic tumors by inhibiting the IL-6/STAT3 signaling pathway. In vitro, Astragaloside and Atractylenolide (CAA), the main components of HBD, inhibited the proliferation of HCT-116 cells as determined by an MTT assay. Furthermore, CAA notably suppressed the protein expression of IL-6R, STAT3, Survivin, and Cyclin D1 induced by IL-6 in HCT-116 and RAW264.7 cells. These results suggested that HBD exhibits anti-inflammatory and anti-proliferative effects, inhibiting the development of CAC in mice.

Breast cancer stem cells are an important cause of radiotherapy resistance in the clinical treatment of breast cancer patients. How to target breast cancer stem cells is the key to improving the efficacy of breast cancer radiotherapy. We proposed for the first time that curcumin combined with glucose nanogold particles (Glu‐GNPs) targeted breast cancer stem cells to reduce radiotherapy resistance, which can significantly enhance the apoptosis level of MCF‐7 and MDA‐MB‐231 breast cancer stem‐like cells (BCSCs) after radiotherapy and antiproliferation and colony‐forming. Under simulated hypoxic conditions, curcumin combined with Glu‐GNPs can significantly improve the ROS level of MCF‐7 and MDA‐MB‐231 mammospheres; reduce the expression of HIF‐1α and HSP90, thereby inhibiting the tumor cells’ own stress ability; promote the apoptosis of tumor stem cells; and enhance the sensitivity of radiotherapy. The current results indicate that the combination of curcumin and Glu‐GNPs has great potential to relieve tumor hypoxia and increase radiosensitivity on BCSCs, providing scientific research data for developing a novel radiosensitizer with high efficiency and low toxicity.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract in which mucosal healing is a crucial measure of therapeutic efficacy. Quercetin, a flavonoid prevalent in various foods and traditional Chinese medicines, exhibits notable pharmacological properties, including antioxidant and anti-inflammatory activities. Consequently, it warrants investigation to determine its potential therapeutic effects on UC. The objective of this study was to investigate the effects and underlying mechanisms of quercetin in a murine model of UC.Methods: A comprehensive approach integrating network predictions with transcriptomic analyses was employed to identify the potential targets and enriched pathways associated with quercetin in UC. Subsequently, the effects of quercetin on pathological morphology, inflammatory mediators, and mucosal barrier-associated proteins, as well as the identified potential targets and enriched pathways, were systematically investigated in a murine model of dextran sulfate sodium (DSS)-induced UC.Results: Network analyses identified CXCL8 and its receptors, CXCR1 and CXCR2, as primary target genes for therapeutic intervention in UC. Further validation through transcriptomic analysis and immunofluorescence staining demonstrated significant upregulation of the CXCL8-CXCR1/2 axis in the intestinal tissues of patients with UC. Experimental investigations in animal models have shown that quercetin markedly alleviates DSS-induced symptoms in mice. This effect includes the restoration of colonic crypt architecture, normalization of goblet cell structure and density, reduction of inflammatory cell infiltration, and decreased concentrations of inflammatory mediators. Quercetin enhanced the expression of tight junction (TJ) proteins, including ZO-1, MUC2 (Mucin 2), and occludin, thereby preserving the integrity of the intestinal mucosal barrier. Additionally, it significantly diminished the levels of IL-17A, NF-κB, CXCL8, CXCR1, and CXCR2 in the colonic tissues of mice with UC.Discussion: The ameliorative effects of quercetin on colon tissue damage in DSS-induced UC mice were significant, possibly due to its ability to inhibit the CXCL8-CXCR1/2 signaling axis. These findings provide a solid foundation for the clinical application and pharmaceutical advancement of quercetin.

Background: Interleukin (IL)-6/signal transducers and activators of transcription 3 (STAT3) signaling plays an important role in the development of colitis-associated colorectal cancer (CAC). The mechanism of CAC formation remains unclear, and the relationship between miRNAs and the IL-6/STAT3 signaling pathway in the development of CAC is not well understood. In this study, we investigated the relationship between miR-29a-5p and the IL-6/STAT3 signaling pathway in the development of CAC and alterations in 10-11 translocations (TETs) regulated by this network.Methods: miR-29a-5p was screened in a CAC mouse model by high-throughput microarray analysis and investigated in human colorectal cancer tissue samples and colon cell lines by quantitative reverse transcription polymerase chain reaction (Q-RTPCR). The expression of miR-29a and TETs was detected by Q-RTPCR, and the expression of STAT3/P-STAT3 and TET3 was detected via Western blot assay. The expression of TET1 and 5-hydroxymethylcytosine (5hmC) was detected through immunofluorescence.Results: Our results showed that miR-29a-5p was significantly upregulated and was accompanied by STAT3 activation in the colon tissues of CAC mouse and human colorectal cancer tissues, as compared with normal colon tissues. In contrast, the levels of TETs and 5hmC were decreased. In vitro, overexpression of miR-29a-5p in colonic cell lines (HCT-116 and IEC-6) and RAW264.7 cells increased STAT3 expression, but decreased that of TET3, TET1, and 5hmC. miR-29a-5p downregulation in HCT-116 and IEC-6 cell lines could rescue the expression of STAT3 and TET3. Notably, STAT3 activation induced by IL-6 upregulated miR-29a-5p expression and reduced TET expression in vitro, although STAT3 inhibitor treatment downregulated miR-29a-5p expression, which was induced by IL-6.Conclusions: Our studies showed that tumor development occurred with inflammation. The miR-29a-5p/STAT3 signaling axis could play an important role in the development of CAC, and the miR-29a-5p/STAT3 positive feedback loop may amplify the effects of inflammation, lead to decreased levels of TET and 5hmC, and eventually lead to the development of CAC.