Changchun University of Chinese Medicine

Kaiyujiangzhuo formula (KYJZ) is an optimized herbal formulation derived from the classical prescription "Dahuang Huanglian Xiexin decoction," recorded in the ancient Chinese monograph Shang Han Lun. For many years, KYJZ has been used to treat glycolipid metabolic disorders in China, particularly in Jilin, Changchun, and Beijing, with significant therapeutic efficacy.

This study aimed to clarify the potential molecular mechanism underlying the therapeutic effect of KYJZ.

The chemical constituents of KYJZ and its absorbed components in the blood were identified using LC-MS/MS. A mouse model of glycolipid metabolic disorders was induced by feeding a high-fructose and high-fat diet (HFHFD) to evaluate the ameliorative effects of KYJZ. The mechanism of KYJZ was studied using multi-omics techniques, including transcriptomics, untargeted metabolomics, and 16S rRNA gene sequencing.

We identified that compounds represented by neomangiferin, aloe-emodin, and ginsenoside Re may be the active constituents through which KYJZ exerts its therapeutic effects. Furthermore, we demonstrated the effectiveness of KYJZ in treating HFHFD-induced glycolipid metabolic disorders. Specifically, KYJZ reduced fasting blood glucose levels, alleviated insulin resistance, enhanced insulin sensitivity, and improved lipid profiles. Mechanistically, KYJZ reduced the hepatic activity of ERK1/2, which reduced PPARγ phosphorylation at Ser273. In addition, our comprehensive metabolomics and intestinal microbiota analysis revealed that KYJZ rectified the homeostatic imbalance of liver and intestinal arginine metabolism induced by an HFHFD.

KYJZ exerted a beneficial effect against glycolipid metabolic disorders through a unique mechanism that inhibited hepatic PPARγ-Ser273 phosphorylation and regulated arginine metabolism homeostasis.

Viral replication in host cells commonly induces endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR) to regulate viral infection. However, the precise connection between virus-induced ER stress and the replication and pathogenesis of Newcastle disease virus (NDV) remains unclear. Here, we observed that NDV infection led to alterations in the structure of the endoplasmic reticulum in DF-1 cells and activated endoplasmic reticulum stress. Subsequent studies revealed that all three branches of the UPR were activated, including protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Treatment of DF-1 cells with endoplasmic reticulum stress inducers or inhibitors strongly inhibited or promoted viral replication. Specifically, activation of the PERK-eIF2α pathway hindered the proliferation of NDV. Furthermore, NDV infection activated the NF-κB pathway through the PERK-eIF2α axis, leading to the formation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes and the production of pro-inflammatory cytokines. Collectively, these data reveal how the UPR regulates the inflammatory response to inhibit NDV replication, which might guide the rational design of anti-NDV strategies.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a major clinical challenge due to escalating antibiotic resistance. This study aimed to evaluate the antivirulence activity of quercetin-3-O-glucuronide (Q3G) against MRSA and to elucidate its molecular targets and therapeutic efficacy in vitro and in vivo.

Enzymatic assays were conducted to determine the inhibitory effects of Q3G on sortase A (SrtA) and caseinolytic peptidase P (ClpP) in MRSA USA300. Virulence-associated phenotypes and gene expression were assessed in vitro. Target engagement was analyzed using structural approaches. Therapeutic efficacy was evaluated in Galleria mellonella and murine pneumonia and skin infection models.

Q3G inhibited SrtA and ClpP with IC₅₀ values of 10.64 and 7.11 µg/mL, respectively, without affecting bacterial growth. It markedly reduced adhesion, invasion, biofilm formation, toxin secretion including Hla and PVL, hemolytic activity, urease function, and virulence gene expression. Structural analysis confirmed direct binding to key residues of both targets. In vivo, 40 mg/kg Q3G significantly improved survival in wax borers and pneumonia mice, reduced skin lesion severity, and decreased bacterial burden by approximately 30%.

Q3G acts as a dual-target antivirulence agent that attenuates MRSA pathogenicity without bactericidal pressure, offering a growth-independent strategy with reduced potential for resistance development.