Danlou Recipe promotes cholesterol efflux in macrophages RAW264.7 and reverses cholesterol transport in mice with hyperlipidemia induced by P407.

INTRODUCTION: Liver X Receptor (LXR) agonists could attenuate the development of atherosclerosis but bring excess lipid accumulation in the liver. Danlou Recipe was believed to be a benefit for improving the lipid profile. Thus, it is unclear whether Danlou Recipe could attenuate hyperlipidemia without excess lipid accumulated in the liver of mice. This study aimed to clarify if Danlou Recipe could alleviate the progression of hyperlipidemia in mice without extra lipids accumulated in the liver. METHODS: Male murine macrophage RAW264.7 cells and murine peritoneal macrophages were used for the in vitro experiments. Cellular cholesterol efflux was determined using the fluorescent cholesterol labeling method. Those genes involved in lipid metabolism were evaluated by qRT-PCR and western blotting respectively. In vivo, a mouse model of hyperlipidemia induced by P407 was used to figure out the effect of Danlou Recipe on reverse cholesterol transport (RCT) and hyperlipidemia. Ethanol extract of Danlou tablet (EEDL) was prepared by extracting the whole powder of Danlou Prescription from ethanol, and the chemical composition was analyzed by ultra-performance liquid chromatography (UPLC). RESULTS: EEDL inhibits the formation of RAW264.7 macrophage-derived foam cells, and promotes ABCA1/apoA1 conducted cholesterol efflux in RAW264.7 macrophages and mouse peritoneal macrophages. In the P407-induced hyperlipidemia mouse model, oral administration of EEDL can promote RCT in vivo and improve fatty liver induced by a high-fat diet. Consistent with the findings in vitro, EEDL promotes RCT by upregulating the LXR activities. CONCLUSION: Our results demonstrate that EEDL has the potential for targeting RCT/LXR in the treatment of lipid metabolism disorders to be developed as a safe and effective therapy.

CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Plasma exosomal miR-122 regulates the efficacy of metformin via AMPK in type 2 diabetes and hepatocellular carcinoma.

Metformin is a drug that has been applied in clinical use for many years for the treatment of type 2 diabetes mellitus (T2DM). It achieves its function through multiple targets and modulation of multiple signaling pathways. To date, the mechanism of the action of metformin is still not fully understood. Along with glycemic control, metformin has shown good inhibitory effects on the development of many tumors. Here, we elucidated that plasma exosomal microRNA-122-5p (miR-122) is closely related to the mechanism of metformin. MiR-122 regulates glycogen-glucose metabolism in hepatocytes or hepatocellular carcinoma cells (HCC) by inhibiting the phosphorylation of AMPK. Since miR-122 and metformin regulate glucose metabolism homeostasis through similar mechanisms, miR-122 can antagonize the effects of metformin. MiR-122 expression increases the sensitivity of hepatocytes or HCC to metformin. Conversely, decreased expression of miR-122 results in hepatocyte insensitivity to metformin. Therefore, significantly elevated levels of miR-122 in plasma exosomes of hepatocellular carcinoma patients could enhance their sensitivity to metformin. The results of the present study revealed a key regulatory role of plasma exosomal miR-122 on the molecular mechanism of metformin. The regulation of key molecules of related signaling pathways by miR-122 may lead to similar glycemic lowering and tumor suppression therapeutic effects as metformin. This provides new ideas for the development of new therapeutic strategies for hepatocellular carcinoma based on the mechanism of miR-122 and metformin.

Oral Supramolecular Adsorbent for Preventing Chemo-Induced Gastrointestinal Mucositis and Microbial Dysbiosis and for Enhancing Chemoimmunotherapy.

The addition of immune checkpoint blockade (ICB) to cytotoxic chemotherapy has emerged as the first-line treatment for multiple cancers. Paradoxically, cytotoxic chemotherapy may limit the therapeutic potential of ICB by significantly impairing the largest immune organ, the gastrointestinal (GI) tract, and driving gut microbial dysbiosis. Here, an orally administered polymeric adsorbent containing a supramolecular motif (named SPORA-SN9) is reported, which can selectively remove chemotherapeutics from the GI tract, thereby preventing chemotherapy-induced GI mucositis and microbial dysbiosis and providing better chemoimmunotherapy synergy. By theoretical design and experimental screening of the molecular recognition motifs, SPORA-SN9 exhibits superior complexation capacity for doxorubicin and irinotecan and high selectivity over a range of commonly used combinational medications. In mouse models of chemotherapy-induced GI mucositis, SPORA-SN9 protects the integrity of the GI tissues and the homeostasis of the gut microbiota. Finally, the addition of SPORA-SN9 enhances the efficacy of chemoimmunotherapy in tumor-bearing mice. SPORA-SN9 offers a translational approach for supramolecular chemistry to modulate complex biosystems by selectively removing target substrates from the GI tract.