Hepatocellular carcinoma (HCC) is the most common primary liver malignant tumor, and the targeted therapy for HCC is very limited. Our previous study demonstrated that prodigiosin(PG), a secondary metabolite from Serratia marcescens found in the intestinal flora of cockroaches, inhibits the proliferation of HCC and increases the expression of CHOP, a marker protein for endoplasmic reticulum stress (ERS)-mediated apoptosis, in a dose-dependent manner. However, the mechanisms underlying the activity of PG in vivo and in vitro are unclear. This study explored the molecular mechanisms of PG-induced ERS against liver cancer in vitro and in vivo. The apoptosis of hepatocellular carcinoma cells induced by PG through endoplasmic reticulum stress was observed by flow cytometry, colony formation assay, cell viability assay, immunoblot analysis, and TUNEL assay. The localization of PG in cells was observed using laser confocal fluorescence microscopy. Flow cytometry was used to detect the intracellular Ca²⁺ concentration after PG treatment. We found that PG could promote apoptosis and inhibit the proliferation of HCC. It was localized in the endoplasmic reticulum of HepG2 cells, where it induces the release of Ca²⁺. PG also upregulated the expression of key unfolded response proteins, including PERK, IRE1α, Bip, and CHOP, and related apoptotic proteins, including caspase3, caspase9, and Bax, but down-regulated the expression of anti-apoptotic protein Bcl-2 in liver cancer. Alleviating ERS reversed the above phenomenon. PG had no obvious negative effects on the functioning of the liver, kidney, and other main organs in nude mice, but the growth of liver cancer cells was inhibited by inducing ERS in vivo. The findings of this study showed that PG promotes apoptosis of HCC by inducing ERS.

Background: Cerebral malaria (CM), a lethal neurological complication of Plasmodium falciparum , is characterized by blood–brain barrier (BBB) disruption. Although astrocytes constitute essential components of the BBB neurovascular unit, their immunoregulatory functions during CM pathogenesis remain elusive. Clinical evidence of altered copper homeostasis in patients with CM, coupled with known associations between copper dysregulation and astrocyte reactivity, prompted investigation of cuproptosis—a copper-dependent programmed cell death pathway—in the disease progression of CM. Methods: Using a P. berghei ANKA ( Pb A)-induced experimental CM (ECM) model in C57BL/6 mice, we evaluated pharmacological modulation with copper ionophore disulfiram (DSF) versus copper chelator tetrathiomolybdate (TTM). Parallel in vitro experiments assessed astrocytes stimulated by Pb A-infected red blood cells (iRBCs)/blood-stage soluble antigen ( Pb Ag) under DSF-CuCl ₂ or TTM-CuCl ₂ treatment. Results: ECM mice demonstrated significant cerebral copper accumulation with concomitant upregulation of cuproptosis markers (SLC31A1, FDX1, DLAT, and DLST) and downregulation of ATP7A copper transporter. DSF administration exacerbated ECM progression through amplified parasitemia, aggravated BBB permeability, cerebral edema, and neuroinflammatory responses, whereas TTM treatment counteracted these pathological manifestations. Immunohistochemical analysis revealed DSF-induced astrocyte reactivity (GFAP ⁺ /Serping1 ⁺ ) with colocalization of cuproptosis markers (GFAP ⁺ -SLC31A1 ⁺ /FDX1 ⁺ /DLAT ⁺ /DLST ⁺ ), contrasting with TTM-mediated suppression. In vitro, DSF-CuCl ₂ treatment augmented iRBC-stimulated astrocyte expression of reactivity markers (GFAP and Serping1), cuproptosis regulators (SLC31A1, FDX1, DLAT, and DLST), and proinflammatory mediators (CXCL10, tumor necrosis factor (TNF)-ɑ, interleukin (IL)-1β, and IL-6), but conversely reduced Pb Ag-stimulated cell viability. These effects were reversed by TTM-CuCl ₂ treatment. Conclusions: These findings establish that cuproptosis exacerbates ECM pathogenesis by promoting astrocyte reactivity, highlighting copper homeostasis modulation as a potential therapeutic strategy for CM. Graphical

Background: Hyperuricemia (HUA), a common metabolic disorder associated with gout, renal dysfunction, and systemic inflammation, necessitates safer and more comprehensive therapeutic approaches. Traditional Tibetan medicine has a rich history of treating HUA. This study aimed to identify novel anti-hyperuricemic herb derived from traditional Tibetan medicine. Methods: Traditional Tibetan medicine prescriptions for HUA were analyzed using data mining techniques, identifying T. chebula as a high-frequency herb. Its phytochemical composition was characterized by UPLC-QE-Orbitrap-MS. Hyperuricemic rat models were treated with T. chebula to assess its effects on serum uric acid (UA) levels, renal inflammation, intestinal barrier integrity, and gut microbiota composition. Molecular and histological analyses evaluated its impact on key biomarkers. Results: Through data mining, we identified T. chebula as a promising candidate for HUA treatment. T. chebula demonstrated dose-dependent inhibition of xanthine oxidase (XOD) in vitro and significantly reduced serum UA levels and XOD activity in vivo. It restored gut barrier function by upregulating tight junction proteins (ZO-1, Occludin, Claudin-1) and reduced pro-inflammatory cytokines (IL-6, TNF-α). T. chebula improved renal function, reducing serum creatinine (Cre) and blood urea nitrogen (BUN) levels. Gut microbiota analysis revealed a favorable shift in microbial composition, with reductions in harmful bacteria (eg, Clostridium spp.) and increases in beneficial bacteria (eg, Roseburia). These effects aligned with the modulation of the gut-kidney axis. Conclusion: This study highlights the multi-target therapeutic potential of T. chebula in HUA management. By regulating the gut-kidney axis, T. chebula alleviates systemic inflammation, enhances intestinal and renal health, and addresses critical aspects of HUA pathology. These findings underscore the value of integrating traditional medicine with modern scientific methodologies to develop innovative treatments.

Streptophenazines, a class of phenazine compounds with a variety of alkyl side chains and activity against methicillin-resistant Staphylococcus aureus (MRSA), are mainly derived from soil or marine microbial secondary metabolites. However, the discovered phenazine compounds still do not meet the needs of the development of anti-MRSA lead compounds. Here, we examined secondary metabolites of Streptomyces albovinaceus WA10-1-8 isolated from Periplaneta americana, for streptophenazines with anti-MRSA activity. In this study, a guidance method combining high-performance liquid chromatography-ultraviolet (HPLC-UV) with molecular networking analysis was used to isolate and identify a series of streptophenazines (A–T) from S. albovinaceus WA10-1-8. Among them, a new streptophenazine containing a dihydroxyalkyl chain structure named streptophenazine T was isolated and identified for the first time. The results of bioactivity assays showed that streptophenazine T had anti-MRSA activity with a minimum inhibitory concentration (MIC) of 150.23 µM, while the MICs of streptophenazine A, B, G, and F were 37.74-146.12 µM. This study was the first to report multiple streptophenazine compounds with anti-MRSA activity expressed by Streptomyces isolated from insect niches. These results provided a valuable reference for future exploration of new streptophenazine compounds with activity against drug-resistant bacteria.