Acta Pharmacologica Sinica最新文献

Immunotherapy targeting tumor-associated macrophages (TAMs) has emerged as a promising approach for treating glioma, driven by advances in drug discovery and development, including colony-stimulating factor 1 receptor (CSF1R) inhibitors. We previously developed a CSF1R inhibitor, C19, for TAM-targeting immunotherapy, which can reprogram TAMs and remodel the tumor immunosuppressive microenvironment. However, the application of CSF1R inhibitors in brain cancer is limited due to inefficient delivery across the blood-brain barrier (BBB). To address this limitation, we designed a brain-targeted liposomal delivery system (T12-Lipo) modified with the transferrin receptor-binding peptide T12. T12-Lipo can specifically bind to transferrin receptors, which are overexpressed in both the BBB and TAMs, thus enhancing the delivery efficiency of C19 across the BBB and to TAMs. This system promoted TAM repolarization toward an anti-tumor M1-like phenotype and thereby facilitated T-cell-mediated tumor killing. T12-Lipo improved the BBB permeability of C19, exhibiting significant therapeutic efficacy against glioma growth. The brain-targeted liposomal formulation of the CSF1R inhibitor C19 represents a promising and effective approach for glioma immunotherapy. T12 peptide-modified liposomes loaded with CSF1R inhibitor C19 can penetrate the BBB, promote M1 phenotypic differentiation of macrophages, effectively activate T-cell immunity, alleviate the tumor immunosuppressive microenvironment, and improve the therapeutic efficacy against glioma.

Addiction is a chronic relapsing disorder characterized by compulsive seeking and consumption of drugs, with this abnormal "Go" behavior resulting in significant negative consequences. Research has shown that the dorsal medial striatum (DMS) is associated with the pathophysiological mechanisms of addiction; however, drugs targeting the DMS to achieve therapeutic effects for addiction remain unavailable. Intracellular cAMP signaling, regulated by G protein-coupled receptors (GPCRs), critically modulates the excitability, plasticity and neurotransmission of GABAergic medium spiny neurons (MSNs). In this study we investigated how inhibition of PDE4 modulated cAMP levels with a specific focus on how these changes influenced the dopamine D1 receptor MSNs (D1-MSNs) and D2 receptor MSNs (D2-MSNs) in the DMS, thereby influencing abnormal "Go" behavior. We established alcohol-induced conditioned place preference (CPP) model and two-bottle choice drinking model in mice. PDE4 inhibitor rolipram (0.5 μg) were bilaterally microinjected into the DMS of mice 2 h prior to the combination of alcohol. The activation of D1-MSNs and D2-MSNs in the DMS was assayed using c-Fos immunofluorescence staining. We showed that rolipram microinjection significantly increased cAMP levels in MSNs of the DMS and restored the activation balance between D1-MSNs and D2-MSNs. This rebalancing of MSN activity attenuated abnormal "Go" behaviors including high-drinking behavior. We further identified the ERK signaling downstream of cAMP in D2-MSNs of the DMS, together with the PDE4 subtype PDE4B, as key mediators of the inhibitory effects of PDE4 inhibitors on high-drinking behavior. These results highlight a new strategy emphasizing the pivotal role of PDE4 as a key regulator of cAMP signaling in MSNs, maintaining the dynamic balance between D1-MSNs and D2-MSNs, and further identify D2-MSNs specific PDE4B/cAMP/ERK modulation as a promising target for addiction treatment.

Inflammatory bowel disease (IBD) comprises Crohn's disease and ulcerative colitis, and that is a major risk factor for colitis-associated colorectal cancer (CAC), a distinct and aggressive malignancy driven by chronic intestinal inflammation. Artemisinins, a group of sesquiterpene lactones derived from Artemisia annua, have emerged as promising therapeutic candidates for IBD due to their potent anti-inflammatory and anticancer properties. In this review, we summarize the current evidence that artemisinins exert diverse pharmacological actions including modulation of immune responses, reduction of oxidative stress, preservation of epithelial barrier function, and suppression of oncogenic signaling relevant to IBD and CAC. We also introduce the recent progress in formulation strategies designed to enhance the bioavailability, tissue specificity, and therapeutic efficacy of artemisinin-based agents. By bridging traditional medical philosophy with modern pharmacological insights, artemisinins represent a versatile platform for preventing and treating inflammation-driven colorectal cancer. This review offers a comprehensive overview of their translational potential in addressing the IBD-CAC continuum.

Immunotherapy has shown limited efficacy in hepatocellular carcinoma (HCC) due to the immunosuppressive tumor microenvironment (TME). Previous studies show that asiatic acid (AA), a naturally occurring pentacyclic triterpenoid, exhibits potent inhibitory effects on tumor cell proliferation. In this study we investigated the effects of AA on the TME and immunotherapy in HCC. Both subcutaneous and orthotopic HCC models were established in male mice. The mice were treated with AA (50 mg·kg⁻¹·d⁻¹, i.g) for two weeks. At the experimental endpoint, mice were euthanized, and tumor-infiltrating immune cell populations were analyzed using flow cytometry. We showed that AA treatment effectively converted "cold tumors" into "hot tumors" by promoting CD8⁺ T cell infiltration and activation in HCC. We demonstrated that AA non-covalently bound and inhibited histone deacetylase 8 (HDAC8), increasing H3K27 acetylation at the CXCL10 promoter to enhance its expression. This epigenetic reprogramming elevated CXCL10 expression and drove robust CD8⁺ T cell recruitment. HDAC8 overexpression abolished these effects, confirming the target specificity. Importantly, we demonstrated that AA synergized with anti-PD-L1 therapy while maintaining a favorable safety profile. This study identifies AA as a novel HDAC8 inhibitor that remodels the TME, offering a promising strategy to overcome immunotherapy resistance in HCC.

The incidence of digestive system diseases is increasing, with liver diseases, obesity, inflammatory bowel disease (IBD), and hepatoenteric cancers being prominent contributors to global morbidity and mortality. Targeting farnesoid X receptor (FXR) has emerged as a promising therapeutic strategy for various digestive disorders. FXR is a member of the nuclear receptor superfamily, is expressed primarily in the liver and small intestine, and is activated by bile acids (BAs). Beyond classical ligand-dependent activation, FXR activity is precisely modulated by epigenetic regulation and posttranslational modifications (PTMs), such as DNA methylation, histone methylation and acetylation, noncoding RNA regulation, phosphorylation, acetylation, SUMOylation, ubiquitination, O-glycosylation, methylation, sulfhydration, and poly(ADP-ribosyl)ation. Growing evidence reveals disease-associated alterations in FXR modification patterns, offering novel therapeutic perspectives for digestive pathologies. In this review, we comprehensively summarize the structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. The structure of FXR, its regulatory mechanisms through epigenetic modifications and PTMs, and its potential application in the treatment of digestive diseases. Upper: epigenetic regulation of FXR. Below: posttranslational modifications of FXR. OG O-glycosylation, P phosphorylation, SUMO SUMOylation, SSH sulfhydration, Ac acetylation, Me methylation, Ub ubiquitination.

Prolactin-releasing peptide (PrRP) is an endogenous ligand for the PrRPR, whose activation has been linked to anti-obesity effects. However, PrRP and its analogs also activate the neuropeptide FF receptor 2 (NPFF2R), which is associated with adverse cardiovascular effects. Understanding how PrRP-related peptides differentially engage these two distinct receptors is critical for developing safer, more selective therapeutics. In this study, we present cryo-EM structures of the PrRP analog GUB08248 bound to PrRPR-Gα_q and NPFF2R-Gα_i at resolutions of 2.45 Å and 2.85 Å, respectively. These structures reveal a conserved ligand recognition mode across both receptors, while highlighting distinct receptor-specific interactions. The NPFF2R-Gα_i complex further uncovers key features of receptor activation and G protein coupling. Together, our results offer structural insights that could guide structure-based drug design strategies favoring PrRPR selectivity, thereby advancing the therapeutic potential of the PrRP-PrRPR axis for obesity treatment.

Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI's lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg^-1·d^-1, i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα^-/-) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (-183/-165 bp) and CES2 (-1870/-1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI's lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.

While AlphaFold3 (AF3) extends AlphaFold2 (AF2) by predicting holo structures, it remains unclear whether its modeling process captures similar induced-fit mechanisms. In this study, we benchmarked the VS performance of ligand-induced AF3 holo structures on two datasets: a subset of DUD-E and VsNsBench designed to avoid sequence-level information leakage. On both datasets, AF3 holo structures demonstrated substantially improved enriching capability compared to AF3 apo, experimental apo, and AF2 structures. Compared to experimental holo structures, AF3 models demonstrated inferior performance on the DUD-E subset but performed slightly better on VsNsBench. Further analysis revealed that AF3's induced modeling critically depends on the bound ligand's affinity: high-affinity ligands produced conformations enabling excellent enrichment, while low-affinity or random ligands yielded poor performance. Moreover, direct VS using AF3 alone achieved satisfactory performance, but computational efficiency remains a major bottleneck for large-scale applications, even with single-round multiple sequence alignment (MSA) generation. In a DFG-motif kinase case study, AF3 successfully modeled inhibitor-specific conformations with a 75% success rate. These findings demonstrate that AF3 effectively incorporates induced-fit modeling, though improvement is needed, particularly for modeling multi-state conformational ensembles.

Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression, but their chronic use is associated with side effects and residual symptoms of depression. Both effects induced by SSRIs are mediated by serotonin receptor-dependent signaling pathways, yet the molecular mechanisms underlying these effects remain unclear. Here, we investigated the impact of chronic and acute activation of the 5-HT7 receptor (5-HT7R) using the selective agonist AGH-194 in male mice. Behavioral assessment revealed that chronic AGH-194 administration induced depressive-like effects in the novelty suppressed feeding test (NSFT), female urine sniffing test (FUST), and novel object location test (NOLT). After acute injection, depressive-like effects were observed only in NSFT. At the molecular level, AGH-194 administration activated matrix metalloproteinase 9 (MMP-9) through a 5-HT7R-Gαs signaling-dependent mechanism. Acute treatment induced transient activation, while chronic treatment led to prolonged enzymatic activity, accompanied by a reduction in the expression of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the hippocampus. At the cellular level, acute but not chronic AGH-194 treatment induced a shift toward more juvenile dendritic spine morphology in the CA1 and dentate gyrus (DG) regions of the hippocampus, along with an increase in dendritic spine density in DG. Electrophysiological recordings demonstrated that acute AGH-194 administration enhanced hippocampal excitability by increasing population spike amplitude in CA1. Chronic AGH-194 treatment further modulated short-term plasticity, increasing both population spike and extracellular field potential paired-pulse ratios (PS-PPR and EPSP-PPR) in CA1, while also enhancing the maximum EPSP slope amplitude. These findings provide novel evidence that chronic 5-HT7R activation can induce depressive-like behaviors in male mice, potentially through sustained MMP-9 activation and alterations in synaptic plasticity. Understanding the molecular and electrophysiological consequences of selective 5-HT7R stimulation may provide insights into receptor-specific mechanisms that could contribute to SSRI-induced side effects, thereby contributing to the development of improved antidepressant strategies.

Hypoxia-inducible factor 2-alpha (HIF-2α), a critical transcription factor, forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to drive the transcription of erythropoietin (EPO), a key regulator of erythropoiesis. Activation of this pathway plays a pivotal role in the treatment of anemia. By discovered structure-based virtual screening and pharmacological assays, we herein discovered an amide thiazole AT-1 that bound to HIF-2α with a K_D of 2.63 μM, and enhanced the stability of the HIF-2α-ARNT heterodimer. Molecular docking and site-directed mutagenesis analysis revealed the critical roles of His293 and Tyr307 in the binding of AT-1 to HIF-2α. Pharmacological studies showed that AT-1 (10, 20, 40 μM) dose-dependently enhanced both the transcription and secretion of EPO in 786-O and Hep3B cells. In zebrafish (Danio rerio), AT-1 (10 or 50 μM) exhibited favorable safety profiles and, when combined with the prolyl hydroxylase (PHD) inhibitor Molidustat (10 μM), effectively mitigated doxorubicin-induced anemia. In adenine-induced chronic kidney disease (CKD) mouse model, combined administration of AT-1 (50 mg·kg^-1·d^-1, i.p.) and Molidustat (10 mg·kg^-1·d^-1, i.p.) for 15 days produced stronger effects on increasing EPO levels and alleviating anemia than Molidustat alone, further supporting the therapeutic potential of AT-1 in CKD-related anemia.