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关键词： Apoptosis   Drug-induced liver injury   HIF-1α   Mitochondria   Qinggan Lidan Capsule  

摘要： Acetaminophen-induced liver injury (AILI) is the leading cause of drug-induced liver injury (DILI) worldwide, posing significant clinical challenges. Qinggan Lidan Capsule (QGLDC), a traditional Chinese medicine formula used for jaundice and hepatobiliary disorders based on its heat-clearing and bile-promoting effects, has unexplored therapeutic potential against AILI, warranting investigation.

关键词： GLP-1 receptor   Hippocampus   PACAP   Rapid-acting antidepressant   Traditional Chinese medicine   Yueju pill  

摘要： Yueju pill (YJ), a classical Chinese medicine formula first documented in ‘Danxixinfa by Zhu Danxi for treating “six stagnations” (Liu Yu: qi, blood, phlegm, fire, dampness, and food), has been clinically prescribed for mood disorders characterized by qi stagnation and depression for centuries. Despite its historical application for relieving emotional constraint (Yujie) and treating depressive disorders, the rapid antidepressant mechanism and molecular targets of YJ remain incompletely elucidated.

关键词： Anmei Decoction   Mitophagy   Myocardial Injury   PI3K/Akt/mTOR/HIF-1   Sleep deprivation  

摘要： Sleep deprivation (SD) has become a major public health concern in modern society and is closely associated with an increased risk of myocardial injury. However, current therapeutic strategies are often limited by high costs and notable adverse effects. Anmei Decoction (AMD), a classical traditional Chinese medicine formula, has shown promising clinical efficacy in alleviating SD-induced myocardial injury, yet the underlying mechanisms of its cardioprotective effects remain to be fully elucidated.

关键词： IDO-1 inhibition   Immunotherapy   Lactate oxidase   Polyprodrug nanoreactor   Tumor-specific lactate depletion  

摘要： Although lactate oxidase (LOX)-based nanoplatforms have received considerable attention in modulating the immunosuppressive tumor microenvironment (TME), their clinical translation is hampered as most nanoenzymes rely on intratumoral injection to ensure tumor-specific lactate exhaustion and to avoid potential side effects. Here we report a LOX-loaded polyprodrug nanoreactor with tunable membrane permeability in response to the acidic tumor microenvironment for selective lactate exhaustion in tumors after intravenous administration. Additionally, LOX-catalyzed lactate oxidation can generate abundant H₂O₂ to promote the release of NLG919 from the polyprodrug nanoreactors, thus reprogramming the immunosuppressive TME via cooperative lactate depletion and NLG919-mediated indoleamine 2,3-dioxygenase 1 inhibition in tumors. As a result, the intelligent polyprodrug nanoreactors can elicit intense antitumor immunity after intravenous administration, especially in combination with PD-L1 checkpoint blockade, thereby realizing effective and long-lasting suppression of primary and metastatic tumors without the concern of systemic toxicity.

关键词： Gastric cancer   Tight junctions   Kruppel-like factor 4   Angiotensin II receptor type 1   Metastasis  

摘要： Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenograft models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on GC cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-sequencing (RNA-seq) data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of krüppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target.

关键词： HIF-1α signaling   Mitochondrial fission   Modified Erxian Decoction   Oxidative stress   Premature ovarian insufficiency  

摘要： Traditional herbal medicines have long been used to regulate female reproductive function. Erxian Decoction, a classical formula in traditional Chinese medicine, has is widely used to treat ovarian dysfunction and menopausal disorders. The Modified Erxian Decoction (MED) is clinically used to improve ovarian function; however, the pharmacological basis and active component interactions underlying its therapeutic effects remain unclear.

关键词： Energy metabolomics   Molecular docking   Shichangpu   Tenuifolin   Yuanzhi  

摘要： Alzheimer's disease (AD) presents a significant global therapeutic challenge. Growing evidence underscores the critical role of blood-brain barrier (BBB) disruption and cerebral energy metabolism dysfunction in driving AD pathogenesis, often forming a vicious cycle of “mitochondrial impairment–BBB damage–neuronal degeneration.” The classic herbal pair of Yuanzhi (YZ) and Shichangpu (SCP) has a long history of use in cognitive disorders within Traditional Chinese Medicine, yet an integrated understanding of how this herb pair systemically modulates key AD pathologies—particularly neurovascular unit integrity and bioenergetic homeostasis remains lacking.

关键词： Herpes simplex keratitis (HSK)   Herpes simplex virus type 1 (HSV-1)   Macrophage   Vaccine   saRNA  

摘要： Herpes simplex virus type 1 (HSV-1) infects over 1.5 million individuals annually, causing herpes simplex keratitis (HSK) with irreversible vision loss, as well as skin and mucosal infections. The virus establishes lifelong latency in the nervous system, rendering current therapies ineffective for eliminating latent reservoirs or preventing recurrence. To address this challenge, we developed a novel bivalent self-amplifying RNA (saRNA) vaccine, termed MTL-bivalent-IL12, which incorporates saRNAs encoding HSV-1 glycoproteins gD and gB, formulated within ganglioside GM3-engineered lipid nanoparticles (LNPs) for specific targeting of CD169⁺ macrophage, and is co-delivered with IL12 mRNA as an integrated adjuvant. In murine models of ocular and cutaneous HSV-1 challenge, prime-boost immunization with MTL-bivalent-IL12 elicited robust neutralizing antibodies and antigen-specific T-cell responses, resulting in a significant reduction in viral loads in trigeminal ganglia (TG) and dorsal root ganglia (DRG). Notably, subconjunctival administration preserved corneal integrity and effectively blocked neuroinvasion, whereas intramuscular immunization prevented epithelial shedding and skin lesion development, with both routes achieving 100% survival under high-dose challenge conditions. Critically, the developed macrophage-targeted LNP vaccine exhibited a favorable safety profile with no evidence of systemic toxicity. This integrated strategy confers robust cross-tissue protection against HSV-1 by enabling coordinated CD169⁺ macrophage-specific delivery, bivalent immunogen expression, and localized immune activation, positioning it as a promising translational platform for preemptive prophylaxis.

关键词： ACTH   Sphingosine 1-phosphate   Cortisol   Adrenal cortex   Bovine  

摘要： Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the synthesis of sphingosine-1 phosphate (S1P) in Gs-coupled receptors dependent manner, enabling S1P to mediate specific bioactivities of FSH and LH. Because adrenocorticotropic hormone (ACTH) also acts via a Gs-coupled receptor to regulate adrenal cortex function, we hypothesized that ACTH could induce S1P secretion in adrenocortical cells, which could then mediate the steroidogenic and number of viable cells effects associated with ACTH. Primary bovine adrenocortical cell cultures were treated with ACTH, and number of viable cells, as well as S1P and cortisol concentrations in the culture media were measured. The effects of exogenous cortisol on number of viable cells, S1P and phosphorylated SPHK1 concentrations were also determined. Results show that the addition of 0.001 μM and 0.1 μM ACTH to the culture medium increased the number of viable adrenocortical cells, and the concentration of cortisol in culture media, respectively. However, ACTH addition did not increase S1P concentrations. Interestingly, a negative correlation between S1P and cortisol concentrations in the culture medium was observed. Moreover, while addition of 0.1 ng/mL cortisol increased S1P and phosphorylated SPHK1 concentrations, increasing cortisol from 1 to 10 ng/mL did not affect phosphorylated SPHK1 but reduced S1P concentration. Thus, while our data suggest that ACTH does not promote S1P synthesis; by stimulating cortisol synthesis, ACTH could be involved in regulation of S1P levels in bovine adrenocortical cells.

关键词： 1,5-AG kinase   1,5-Anhydro-D-glucitol (1,5-AG)   1,5-Anhydro-D-glucitol-6-phosphate (1,5-AG6P)   Genomic enzymology   ROK  

摘要： 1,5-Anhydro-D-glucitol (1,5-AG), a 1-deoxy form of glucopyranose, is a major dietary-derived polyol in the human body and serves as a sensitive clinical marker for short-term glycemic control in diabetic patients. Its phosphorylated derivative, 1,5-anhydro-D-glucitol-6-phosphate (1,5-AG6P), is a non-canonical metabolite formed when glucose phosphorylating enzymes erroneously act on 1,5-AG. Accumulation of 1,5-AG6P is associated with neutrophil dysfunction. Recently, the Zhang group reported a gut bacterial pathway for 1,5-AG catabolism, in which the key enzyme is a glycyl radical enzyme (GRE) responsible for the ring-opening C–O cleavage of 1,5-AG6P. In this report, through a synergistic analysis of sequence similarity network (SSN) and genome neighborhood network (GNN) of this GRE homologs, we uncovered novel ATP-dependent 1,5-AG kinases belonging to the ROK family (PF00480). These enzymes exhibit higher catalytic efficiencies for 1,5-AG than for d-glucose, driven by both a smaller K_M and a larger k_cat. The substrate preference contrasts with that of other hexokinases and ADP-dependent glucokinases, which typically show a marked preference for d-glucose. This study expands the biocatalytic toolbox for the enzymatic synthesis of 1,5-AG6P, offering a more efficient and convenient approach, and reinforces the value of the “genomic enzymology” strategy applicable for enzyme function discovery.