Diabetic nephropathy (DN) is a prevalent complication and serious microvascular of diabetes mellitus. After previous studies, we found that phenylethanol glycosides (CPhGs) derived from Cistanche tubulosa (Schenk) Wight exerts antidiabetic and renoprotective effects. However, the effects of CPhGs on DN remain incompletely understood. The study aimed to examine the effects of CPhGs on DN in rats and explore the underlying mechanism involved. A DN rat model was established by streptozotocin (STZ) combined with a high-fat diet. Reagent kits were used to assess the extent to which CPhGs ameliorate hyperglycemia, insulin resistance (IR), renal dysfunction, kidney oxidative stress, and peripheral inflammation. Histology and immunohistochemical staining were used to detect the changes in renal tissue structure and the expression levels of α-smooth muscle actin (α-SMA) and collagen I. Furthermore, we analyzed the cecal contents of DN rats to investigate the effect of CPhGs on gut microbiota by using 16S rRNA sequencing and broad-spectrum metabolite profiling. The results showed that CPhGs demonstrated a range of advantageous outcomes in DN, encompassing the enhancement of kidney function and alleviation of hyperglycemia, IR, renal injury, oxidative stress, and peripheral inflammatory reactions. In addition, CPhGs regulated the abundance of the [Eubacterium]_coprostanoligenes_group, Oscillospiraceae_UCG-005, etc. to modulate the gut microbiota. CPhGs significantly upregulated the content of vitamin B6 and tyrosyl-tryptophan and downregulated histamine, L-methionine, etc. In summary, the therapeutic efficacy of CPhGs on DN rats may be achieved by modulating the gut microbiota and cecal metabolites to restore the metabolic disorders of vitamin B6, histidine, etc.

Oxaliplatin (OXA) is a first‑line chemotherapy agent for hepatocellular carcinoma (HCC); however, its application is hindered by low therapeutic sensitivity and severe adverse effects. Acteoside (ACT) has both antitumor and hepatoprotective properties. Therefore, the present study investigated the mechanisms underlying the synergistic and toxicity‑reducing effects of ACT as an adjuvant to OXA in HCC therapy. Liver cancer cell lines and a xenograft mouse model were treated with ACT and/or OXA. In vitro Cell Counting kit‑8, Transwell invasive assay, wound healing assay, cell cycle and apoptosis detection assays assessed cell viability, migration, invasion, cell cycle progression and apoptosis to evaluate the synergistic effects of the combination therapy. In vivo studies examined tumor growth, cell proliferation, survival time and blood biochemical indices. The effects of ACT on OXA‑induced toxicity were also evaluated. Transcriptomics and metabolomics analyses were integrated to elucidate the mechanisms by which ACT enhances OXA efficacy and mitigates its toxicities. The results revealed that ACT synergized with OXA to inhibit HCC progression both in vivo and in vitro. ACT significantly alleviated OXA‑induced toxicity, particularly neurotoxicity. Mechanistically, phosphatidylinositol signaling system‑associated genes/proteins exerted important roles in the anti‑HCC effects of ACT. Western blotting revealed that ACT‑induced upregulation of INPP4B inhibited the PI3K/AKT signaling pathway, which may underlie its ability to enhance the therapeutic efficacy of OXA and reduce its toxic effects. In conclusion, ACT enhanced efficacy and reduced the toxicity of OXA in the treatment of HCC, potentially via the regulation of INPP4B to inhibit the PI3K/AKT signaling pathway.

Objective: To elucidate the metabolic mechanisms by which acteoside (ACT) isolated from Cistanche tubulosa alleviates cancer-related fatigue (CRF) in a murine model of colon cancer with cachexia.Methods: BALB/c mice inoculated with C26 colon cancer cells were treated with paclitaxel (PTX, 10 mg/kg) and ACT (100 mg/kg) alone or in combination for 21 days. Fatigue-associated behaviors, tumor inhibition rate, and skeletal muscle morphology assessed by hematoxylin-eosin (H&E) staining and electron microscopy were evaluated. Finally, liquid chromatography-mass spectrometry (LC/MS) was employed to investigate alterations in the plasma metabolic profile of tumor-bearing mice with CRF in response to ACT treatment, and the affinity between metabolite-associated proteins and ACT was verified by Surface plasmon resonance (SPR) assay.Results: Our study demonstrated the presence of CRF in the colon cancer mouse model, with the severity of fatigue increasing alongside tumor growth. Administration of ACT ameliorated both tumor burden and PTX-induced muscle fatigue-like behavior. LC/MS analysis identified a panel of differentially regulated metabolites, including trans-aconitine, citric acid, 3-coumaric acid, ephedrine, thymine, cytosine, indole-3-acetic acid, and pantothenol-9. These metabolites were primarily enriched in pathways associated with valine biosynthesis, tyrosine metabolism, tryptophan metabolism, and biosynthesis of pyridine alkaloids. Furthermore, several key enzymes, including CYP3A4, CYP19A1, CYP2E1, TNF, BCL-2, RYR2, and ATP2A1, were identified as potential targets underlying the anti-CRF effects of ACT.Conclusion: This study suggests that ACT derived from C. tubulosa harbors protective properties against cancer-related fatigue mediated by tumor cells.