Hui Zhang

The dried fruits of Ligustrum lucidum Ait. are well-established in East Asian medicine for hepatoprotection. Given this ethnopharmacological precedent and their close taxonomic kinship, we hypothesized that the fruit polysaccharide of its horticultural congener, Ligustrum × vicaryi L. (LVFP), may confer analogous hepatic benefits. We assessed LVFP in a murine model of acute liver injury (ALI) induced by lipopolysaccharide and D-galactosamine (LPS/D-GalN) to test this hypothesis. LVFP pretreatment significantly mitigated hepatic pathological damage, normalized serum aminotransferases (AST, ALT), and reversed lipid peroxidation (reduced MDA, elevated SOD). Simultaneously, LVFP reduced pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and corrected lipid metabolic abnormalities (CHO, TG). To decode these phenotypic rescues, network pharmacology and molecular docking nominated a 10-gene hub signature (featuring KDR (binding energy = −8.65 kcal/mol), AKT1, GSK3B, and IL2). we further found that this signature—particularly KDR and PKM—robustly discriminates ALI from controls (AUC = 1.00; AUPR = 0.848), supporting its disease relevance. Collectively, these findings support our initial hypothesis that LVFP exerts multi-dimensional hepatoprotection.

Purpose: Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid hepatocyte injury, excessive inflammation, and oxidative stress. Cornuside, an iridoid glycoside derived from Cornus officinalis Sieb. et Zucc, has been reported to exert anti-inflammatory and antioxidant activities, but its role in ALF remains unclear. This study aimed to evaluate the preventive and therapeutic effects of cornuside in a lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced mouse ALF model and to explore the underlying mechanisms. Methods: ALF was induced in mice by intraperitoneal injection of LPS and D-GalN. Cornuside was administered via tail vein injection either 3 h before or 1 h after LPS/D-GalN administration to assess its preventive and post-injury therapeutic effects, respectively. Serum and liver tissues were harvested 12 h after LPS/D-GalN challenge for the assessment of liver injury, hepatocyte apoptosis, intrahepatic immune cell activation, inflammatory cytokine production, oxidative stress, and ferroptosis-associated markers. Results: Cornuside administration after LPS/D-GalN challenge did not produce significant therapeutic protection against established ALF. In contrast, cornuside pretreatment markedly reduced serum alanine aminotransferase and aspartate aminotransferase levels, alleviated hepatic histopathological injury, and decreased hepatocyte apoptosis. Cornuside pretreatment also suppressed intrahepatic immune cell activation and reduced pro-inflammatory cytokine production. Moreover, cornuside attenuated oxidative stress, as indicated by reduced lipid peroxidation and enhanced antioxidant activity. Mechanistically, cornuside pretreatment modulated ferroptosis-associated signaling, including downregulation of ACSL4 and upregulation of xCT and Gpx4, suggesting that inhibition of ferroptosis may contribute to its hepatoprotective effects. Conclusion: Cornuside provided significant preventive protection against LPS/D-GalN-induced ALF. This protection may be associated with inhibition of inflammation, oxidative stress, and ferroptosis-related ACSL4/xCT/Gpx4 signaling, suggesting cornuside as a potential preventive candidate for ALF. The diagram illustrates the protective effects of cornuside against acute liver failure (ALF). Cornuside alleviates liver injury through three main mechanisms. First, it modulates immune and inflammatory responses by suppressing NKT cells, NK cells, activated T cells, and macrophages, while increasing the proportion of MDSCs. It also downregulates the expression of inflammatory cytokines, including IL-12/p40, IL-6, and TNF-α. Second, cornuside reduces oxidative stress by increasing GSH and SOD levels and decreasing MPO, LPO, MDA, and Fe levels. Third, cornuside inhibits ferroptosis by regulating the ACSL4/xCT/Gpx4 signaling pathway. Specifically, it decreases ACSL4 expression and increases xCT and Gpx4 expression, thereby suppressing ferroptosis and ultimately alleviating ALF.Cornuside aids acute liver failure by suppressing immunity, reducing oxidative stress and inhibiting ferroptosis.

Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an mRNA-binding protein implicated in tumorigenesis across multiple cancer types, but its functional role in oral squamous cell carcinoma (OSCC) remains incompletely understood. In this study, we combined bioinformatic analyses, validation in clinical specimens and cell lines, and functional experiments to investigate the role of IGF2BP2 in OSCC. IGF2BP2 was significantly elevated in OSCC and associated with poor overall survival. This upregulation was further validated in patient tissues and OSCC cell lines by quantitative real-time PCR, Western blot, and immunohistochemistry. IGF2BP2 knockdown markedly suppressed OSCC cell proliferation and migration in vitro and inhibited tumor growth in xenograft models in vivo. In parallel, IGF2BP2 depletion resulted in reduced phosphorylation of ERK and p38, supporting an association between IGF2BP2 and MAPK signaling activity in OSCC. In addition, immune-related pathway enrichment and immune infiltration analyses further suggested links between IGF2BP2 and the OSCC tumor immune microenvironment. Flow cytometric analysis of xenograft tumors revealed that IGF2BP2 knockdown altered macrophage-related immune features, including a reduced proportion of CD86⁺ M1-like tumor-associated macrophages. Collectively, these findings support an oncogenic role for IGF2BP2 in OSCC and suggest that IGF2BP2 is associated with MAPK signaling and macrophage-related immune features in OSCC.

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.

Hypercholesterolemia and carotid atherosclerosis contribute to the etiology of stroke. However, there has been a lack of appropriate comorbid animal models incorporating some of the ubiquitous characteristics that precede strokes. Curcumin is a natural active polyphenolic compound extracted from the rhizoma of Curcuma longa L. which possesses comprehensive bioactivities. The present study aimed to evaluate whether neurobehavioral deficits, neuroendocrine-immune dysregulations and cerebral microcirculation dysfunction, are part of the initial stages of cerebral ischemia in individuals suffering from carotid atherosclerosis resulting from a high cholesterol diet (HCD) and if they could be tested using a comorbid animal model. Furthermore, the utility of this model will be examined following the administration of curcumin. Adult wild-type SD rats were fed a regular diet or HCD and supplemented with either vehicle or curcumin for 4 weeks. Carotid injury was induced by an air-drying endothelial denudation method at the end of the second week. Plasma cholesterol, carotid pathomorphology, neurobehavioral tests, and neuroendocrine-immune parameters were measured. We found higher plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), intima and media (I/M) ratio, but lower high-density lipoprotein-cholesterol (HDL-C), spatial learning and memory capacity impairment, elevated NPY expression in the hypothalamus, increased plasma concentration of leptin, upregulated TNF-α, IL-1β, and CRP in the circulation as well as TNF-α and IL-1β in the cerebral cortex, plus enhanced ICAM-1, VCAM-1, and E-selectin in cerebral microvessels in HCD-fed model rats. All these alterations were ameliorated by curcumin. These results suggest that a comorbid rat model was effectively developed by HCD and carotid injury.

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.

Fulminant hepatitis (FH) is an acute clinical disease with a poor prognosis and high mortality rate. The purpose of this study was to determine the protective effect of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced explosive hepatitis and explore in vivo and in vitro mechanisms. Mice were pretreated with TAK-242 for 3 h prior to LPS (10 μg/kg)/D-GalN (250 mg/kg) administration. Compared to the LPS/D-GalN group, the TAK-242 pretreatment group showed significantly prolonged survival, reduced serum alanine aminotransferase and aspartate aminotransferase levels, relieved oxidative stress, and reduced inflammatory interleukin (IL)-6, IL-12, and tumor necrosis factor-α levels. In addition, TAK-242 increased the accumulation of myeloid-derived suppressor cells (MDSCs). Next, mice were treated with an anti-Gr-1 antibody to deplete MDSCs, and adoptive transfer experiments were performed. We found that TAK-242 protected against FH by regulating MDSCs. In the in vitro studies, TAK-242 regulated the accumulation of MDSCs and promoted the release of immunosuppressive inflammatory cytokines. In addition, TAK-242 inhibited protein expression of nuclear factor-κB and mitogen-activated protein kinases. In summary, TAK-242 had a hepatoprotective effect against LPS/D-GalN-induced explosive hepatitis in mice. Its protective effect may be involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs.