Acta Pharmacologica Sinica最新文献

Thymic egress is a crucial process for thymocyte maturation, strictly regulated by sphingosine-1-phosphate lyase (S1PL). Recently, cystathionine γ-lyase (CSE), one of the enzymes producing hydrogen sulfide (H₂S), has emerged as a vital immune process regulator. However, the molecular connection between CSE, H₂S and thymic egress remains largely unexplored. In this study, we investigated the regulatory function of CSE in the thymic egress of immune cells. We showed that genetic knockout of CSE or pharmacological inhibition by CSE enzyme inhibitor NSC4056 or D,L-propargylglycine (PAG) significantly enhanced the migration of mature lymphocytes and monocytes from the thymus to the peripheral blood, and this redistribution effect could be reversed by treatment with NaHS, an exogenous donor of H₂S. In addition, the CSE-generated H₂S significantly increased the levels of S1P in the peripheral blood, thymus and spleen of mice, suppressed the production of proinflammatory cytokines and rescued pathogen-induced sepsis in cells and in vivo. Notably, H₂S or polysulfide inhibited S1PL activity in cells and an in vitro purified enzyme assay. We found that this inhibition relied on a newly identified C²⁰³XC²⁰⁵ redox motif adjacent to the enzyme's active site, shedding light on the biochemical mechanism of S1PL regulation. In conclusion, this study uncovers a new function and mechanism for CSE-derived H₂S in thymic egress and provides a potential drug target for treating S1P-related immune diseases.

Poria cocos and its surface layer of Poria cocos (Schw.) Wolf (Polyporaceae), are used in traditional Chinese medicine for its diuretic and renoprotective effects. Phytochemical studies have shown that lanostane and 3,4-seco-lanostane tetracyclic triterpenoids are the main components of P. cocos and its surface layer. Accumulating evidence shows that triterpenoid components in P. cocos and its surface layer contribute to their renoprotective effect. The surface layer of P. cocos showed a stronger diuretic effect than P. cocos. The ethanol extract of the surface layer and its components improved acute kidney injury, acute kidney injury-to-chronic kidney disease transition and chronic kidney disease such as diabetic kidney disease, nephrotic syndrome and tubulointerstitial nephropathy, and protected against renal fibrosis. It has been elucidated that P. cocos and its surface layer exert a diuretic effect and improve kidney diseases through a variety of molecular mechanisms such as aberrant pathways TGF-β1/Smad, Wnt/β-catenin, IκB/NF-κB and Keap1/Nrf2 signaling as well as the activation of renin-angiotensin system, matrix metalloproteinases, aryl hydrocarbon receptor and endogenous metabolites. These studies further confirm the renoprotective effect of P. cocos and its surface layer and provide a beneficial basis to its clinical use in traditional medicine.

Astrocyte-derived IL-3 activates the corresponding receptor IL-3Rα in microglia. This cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer's disease in mice. In this study we investigated the role of IL-3/IL-3Rα cross-talk and its regulatory mechanisms in ischemic stroke. Ischemic stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery (MCA) for 60 min followed by reperfusion (I/R). Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation (OGD/Re) were used as in vitro models of brain ischemia. We showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3Rα protein levels, accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type microglia. Importantly, astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells, thereby mediating neuronal cell damage. By using metabolomics and multiple biochemical approaches, we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A, a rate-limiting enzyme for the mitochondrial β-oxidation, and increased levels of glycerophospholipids, the major components of cellular membranes, causing reduced accumulation of lipid droplets, thus reduced pro-inflammatory activation and necrosis, as well as increased phagocytosis of microglia. Notably, exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3Rα, improving microglial lipid metabolic levels via upregulation of CPT1A, restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation, ultimately contributing to brain recovery from I/R insult. Our results demonstrate that VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/microglia IL-3Rα cross-talk and drives pro-inflammatory activation, causing lipid metabolic reprogramming of microglia. These insights suggest VEGFR3 antagonism or restoring IL-3 levels as a potential therapeutic strategy for ischemic stroke.

Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.

Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR₃ antagonist tropisetron or by silencing 5-HTR_3a. The 5-HTR_2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR_2a or the 5-HTR_2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [²H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [²H]5-HT and MPP⁺ uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [²H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR_3a. The antagonistic effect of clozapine on islet 5-HTR_2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs.

Translational pharmacological research on traditional medicines lays the foundation for precisely understanding how the medicines function in the body to deliver therapeutic benefits. Borneolum syntheticum (Bingpian) is commonly used in Chinese herbal medicines for coronary heart disease, but its specific cardiovascular impact remains poorly understood. Isoborneol, a constituent of Bingpian, has been found to reduce lipid accumulation in macrophages in vitro, but its oral bioavailability is limited. This investigation aimed to evaluate anti-atherosclerotic effects of Bingpian, based on understanding its first-pass metabolism. Human subjects orally received an herbal medicine containing Bingpian and their plasma samples were analyzed to identify the major circulating compounds of Bingpian, with the metabolism that was also characterized in vitro and in mice. The identified compounds were evaluated for their ability to inhibit macrophage foam-cell formation induced by oxidized low-density lipoprotein. Furthermore, the anti-atherosclerotic effect of repeatedly dosed Bingpian was assessed in ApoE^-/- mice fed a high-fat diet. In human subjects, the major circulating compounds of Bingpian were metabolites, rather than their precursor constituents borneol and isoborneol. These constituents were efficiently absorbed in the intestinal tract but underwent significant first-pass metabolism, involving UGT2B7-mediated glucuronidation into borneol-2-O-glucuronide and isoborneol-2-O-glucuronide, respectively, and CYP2A6/2B6/3A-mediated oxidation both into camphor. Despite their poor membrane permeability, hepatic efflux of borneol-2-O-glucuronide and isoborneol-2-O-glucuronide into the systemic circulation was enhanced by MRP3/4. The circulating metabolites, particularly their combinations, markedly inhibited macrophage foam-cell formation induced by oxidized low-density lipoprotein in vitro. Sub-chronic administration of Bingpian (30 mg·kg^-1·d^-1, i.g.) for 12 weeks significantly decreased atherosclerotic lesion size and enhanced plaque stability in ApoE^-/- mice. Systemic exposure to Bingpian metabolites in mice closely resembles that in humans, suggesting that the pharmacodynamic effects of Bingpian in mice are likely applicable to humans. Overall, the cardiovascular benefits of Bingpian involve reducing atherosclerosis by inhibiting foam-cell formation through its metabolites. This investigation supports that oral Bingpian could be a druggable agent for reducing atherosclerosis.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

Inflammatory bowel diseases (IBDs) are chronic inflammatory conditions primarily affecting the gastrointestinal tract. Previous studies established the role of the NF-κB signaling pathway in the development of IBDs, suggesting that anti-inflammatory therapies might offer a viable treatment strategy. Tanshinone IIA and salviadione, both derived from Salviae Miltiorrhizae Radix et Rhizoma, possess anti-inflammatory and anti-oxidative activities. A series of new compounds were synthesized by hybridizing salviadione with tanshinone. Among these compounds, 15a showed beneficial effects in LPS-induced acute lung injury and diabetes-induced renal injury mouse models. The current study explored the therapeutic efficacy of 15a using both acute and chronic colitis models and elucidated the underlying mechanisms. DSS-induced colitis models were established in mice, where acute colitis was treated with compound 15a (5 or 10 mg·kg^-1·d^-1) for 8 days, while chronic colitis mice received compound 15a (5 or 10 mg·kg^-1·d^-1, i.g.) during 2.5% DSS administration. The 15a treatment significantly alleviated DSS-induced pathological and inflammatory damages in both acute and chronic colitis mouse models. In mouse intestinal epithelial cell line MODE-K, pretreatment with compound 15a (5 or 10 μM) significantly suppressed LPS + L18-MDP-induced inflammatory responses. The receptor-interacting serine/threonine kinase 2 (RIPK2) was identified as a direct binding target of compound 15a using microarrays and recombinant human proteins. Moreover, 15a could directly bind to and inhibit the phosphorylation of RIPK2, leading to the suppression of the NF-κB and MAPK signaling pathways. Furthermore, LEU153 and VAL32 were identified within the KD domain of RIPK2 as critical amino residues for the binding of 15a. Briefly, the current findings demonstrate that compound 15a holds promise as a therapeutic agent for managing acute and chronic colitis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers especially at advanced stage. In order to analyze the dynamics of potential prognostic biomarkers and further quantify their relationships with the overall survival (OS) of advanced PDAC patients, we herein developed a parametric time-to-event (TTE) model integrated with longitudinal submodels. Data from 104 patients receiving standard chemotherapies were retrospectively collected for model development, and other 54 patients were enrolled as external validation. The longitudinal submodels were developed with the time-course data of sum of longest diameters (SLD) of tumors, serum albumin (ALB) and body weight (BW) using nonlinear mixed effect models. The model-derived metrics including model parameters and individual predictions at different time points were further analyzed in the TTE model, together with other baseline information of patients. A linear growth-exponential shrinkage model was employed to describe the dynamics of SLD, while logistic models were used to fit the relationship of time prior to death with ALB and BW. The TTE model estimated the ALB and BW changes at the 9th week after chemotherapies as well as the baseline CA19-9 level that showed most significant impact on the OS, and the model-based simulations could provide individual survival rate predictions for patients with different prognostic factors. This study quantitatively demonstrates the importance of physical status and baseline disease for the OS of advanced PDAC patients, and highlights that timely nutrition support would be helpful to improve the prognosis.

Itch is an uncomfortable feeling that evokes a desire to scratch. This protective reflex can effectively eliminate parasites that invade the skin. When itchy skin becomes severe or lasts for more than six weeks, it has deleterious effects on both quality of life and productivity. Despite decades of research, the complete molecular and cellular coding of chronic itch remains elusive. This persistent condition often defies treatment, including with antihistamines, and poses a significant societal challenge. Obtaining pathophysiological insights into the generation of chronic itch is essential for understanding its mechanisms and the development of innovative anti-itch medications. In this review we provide a systematic overview of the recent advancement in itch research, alongside the progress made in drug discovery within this field. We have examined the diversity and complexity of the classification and mechanisms underlying the complex sensation of itch. We have also delved into recent advancements in the field of itch mechanism research and how these findings hold potential for the development of new itch treatment medications. But the treatment of clinical itch symptoms still faces significant challenges. Future research needs to continue to delve deeper, not only to discover more itch-related pathways but also to explore how to improve treatment efficacy through multitarget or combination therapy.