ETHNOPHARMACOLOGICAL RELEVANCE:Hypericum perforatum L. has been used for centuries in traditional medicine, with core therapeutic applications including alleviation of emotional, wound and burn healing and neurological disorders, and antiparasitic treatments. AIM OF THE STUDY:This review summarizes and interprets current knowledge on the traditional use, phytochemistry, pharmacology, quality control, safety, and herb-drug interactions of H. perforatum, with particular attention to the relationships between major constituents, proposed mechanisms, and clinical relevance. MATERIALS AND METHODS:Relevant literature on H. perforatum was identified through major scientific databases, including CNKI, Web of Science, and PubMed, together with complementary sources such as Flora of China, classical herbal literature, and academic dissertations. RESULTS:H. perforatum contains diverse bioactive constituents, notably PPAPs, naphthodianthrones, and flavonoids. The strongest clinical evidence supports its use in mild-to-moderate depression and menopausal symptoms, with efficacy comparable to SSRIs and superiority over placebo. Preliminary case reports also suggest potential benefits in diabetic complications, though these findings are limited. Beyond depression, most pharmacological activities, including neuroprotective, anticancer, antiviral, antimicrobial, wound healing, and metabolic effects, remain preclinical. Recent advances in nanoformulation strategies (e.g., nanostructured lipid carriers, plant-derived exosome-like nanovesicles) have enhanced the performance of key constituents such as hypericin and hyperforin in photodynamic therapy and antimicrobial applications. Quality control has evolved from single-marker assays to holistic approaches integrating non-targeted metabolomics, machine learning, and fingerprinting, addressing compositional variability and heavy metal contamination. However, heterogeneity in plant material, extraction procedures, constituent standardization, and experimental design still complicates data interpretation. Clinically relevant herb-drug interactions, especially those associated with CYP enzyme and P-gp induction, remain a major safety concern. CONCLUSION:This narrative review indicates that H. perforatum has established efficacy in depression and broader but uneven pharmacological potential elsewhere. Emerging formulation technologies and multi-component quality control offer promising ways to improve consistency and efficacy. Future progress requires better extract standardization, clearer constituent-mechanism links, higher-quality clinical trials (especially for non-psychiatric uses), and continued attention to safety and drug interactions.

Gut microbiota dysbiosis has been implicated in the pathogenesis of depression. Our previous studies identified loganin as a potential antidepressant agent; however, its oral bioavailability is low. Whether loganin alleviates depression via modulation of the gut microbiota remains unclear. Chronic unpredictable stress mice model was used to evaluate the antidepressant-like effects of loganin. To determine the role of gut microbiota, mice were treated with an antibiotic cocktail (ABX) to deplete microbiota. Fecal microbiota transplantation (FMT) from loganin-treated donors and Muribaculum intestinale (M. intestinale) were performed to assess microbial contributions. Loganin exerted antidepressant-like effects by modulating gut microbiota, as evidenced by reduced efficacy in ABX-treated mice and behavioral improvements in recipients of FMT from loganin-treated donors. Loganin modulated gut microbiota composition particularly increasing the abundance of Muribaculum, and increased short-chain fatty acids (SCFAs). M. intestinale alleviated depressive-like behaviors, prompted the butyrylation of RORγt, inhibited Th17 cells differentiation, and suppressed M1 microglia polarization. Importantly, overexpression of RORγt attenuated the behavioral benefits of M. intestinale. Loganin exerts antidepressant-like effects by enriching Muribaculum and SCFAs, thereby inhibiting Th17 cell differentiation and M1 microglia polarization. M. intestinale may represent a promising microbial-based therapeutic strategy for depression.

Three pairs of novel β-acid meroterpenoid enantiomers with an unprecedented 5/6/7/5 tetracyclic ring skeleton, (±)-humulunones A-C (1-3), were isolated from Humulus lupulus L. Their structures were elucidated by comprehensive spectroscopic data analysis, calculated NMR and electronic circular dichroism, and X-ray single-crystal diffraction. Compounds (+)-1, (-)-1, (+)-2, and (-)-2 exhibited significant anti-neuroinflammatory effects on LPS-induced BV2 cells. Furthermore, compound (-)-1 effectively ameliorated oxidative stress and inhibited NLRP3 inflammasome activation, demonstrating efficacy comparable to that of the classic inhibitor MCC950 in suppressing the expression of NLRP3, ASC, caspase-1, and downstream inflammatory factors. Molecular docking and a cellular thermal shift assay implied that (-)-1 exerted its anti-neuroinflammatory effect through potential interaction with the NLRP3 protein, which provided a fresh perspective for the drug development of neuroinflammatory-related diseases.

Five pairs of previously undescribed β-acid enantiomers, (±)-humulunes A-E (1-5), were isolated from Humulus lupulus L. These compounds feature an unusual 5/7/5 tricyclic ring skeleton bearing multiple stereocenters. Their structures were elucidated through comprehensive spectroscopic analysis, including calculated NMR and electronic circular dichroism (ECD), as well as single-crystal X-ray diffraction. Among them, compounds (+)-3, (-)-3, and (+)-4 exhibited significant anti-inflammatory activity in LPS-induced RAW 264.7 cells. Furthermore, compound (-)-3 was found to inhibit cell apoptosis and reactive oxygen species (ROS) production, modulate macrophage polarization, and suppress the TLR4/MyD88 signaling pathway. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay (CETSA) confirmed the direct and stable binding of (-)-3 to TLR4 protein, which may exert anti-inflammatory effects by blocking the activation of the TLR4/MyD88 signaling pathway, providing a reference for the development of anti-inflammatory therapeutics.

Alzheimer’s disease (AD) is the leading cause of dementia, yet current therapies provide limited clinical benefit. Neuroinflammation, as an early and sustained driver of AD, places the NLRP3 inflammasome at the center of pathological and therapeutic focus. In this review, we synthesize recent advances in the structure, assembly, and activation of the NLRP3 inflammasome, and evaluate its contribution to AD using evidence from human brain tissues, cerebrospinal fluid, and diverse AD animal models. Available data consistently support aberrant NLRP3 activation in AD brain, where it is closely associated with amyloid-β (Aβ) deposition, tau pathology, glial reactivity, and cognitive decline. We further discuss the cell-type-specific roles of microglia and astrocytes, highlighting microglia as the principal effector cells in inflammasome-associated pathology. Mechanistically, Aβ and tau converge on NLRP3 activation through interconnected pathways involving K+ efflux, lysosomal rupture, mitochondrial dysfunction, and impaired autophagy. Downstream IL-1β, IL-18, and gasdermin D amplify neuroinflammation and neuronal injury. We summarize emerging therapeutic strategies directly targeting its core components or downstream effectors, as well as anti-AD agents with indirect NLRP3 modulation including endogenous molecules, repurposed drugs, and natural products. Collectively, this review regards NLRP3 inflammasome as a critical inflammatory hub and a promising target for disease-modifying therapy in AD, and provide useful perspectives on AD pathogenesis and inform the development of more rational therapeutic strategies.

Isodon serra, a Chinese medicinal herb widely used in the Lingnan region, has extensive pharmacological activities. However, its chemical constituents remain to be studied. In this study, a variety of modern chromatographic separation techniques were used to isolate five compounds from 95% ethanol extract of the aboveground part of I. serra. Their planar structures were determined by ultraviolet spectroscopy(UV), infrared spectroscopy(IR), high resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), 1D and 2D nuclear magnetic resonance(1D NMR and 2D NMR), single-crystal X-ray diffraction(SC-XRD), and literature analysis. The compounds were identified as five 6,7-seco-ent-kaurane diterpenoids: isodon I(1), epi-nodosinol(2), carpalasionin(3), epi-nodosin(4), and enmein(5), among which compound 1 was a new one. The results of the pharmacological activity evaluation showed that compound 5 significantly inhibited nitric oxide(NO) release in RAW264.7 cells exposed to lipopolysaccharide(LPS).

Iridoids, a class of oxygenated monoterpene compounds with a methylcyclopentan-[c]-pyran skeletal, widely exist in plants and microorganisms. Iridoids are mainly classified into cyclopentane iridoids and secoiridoids. The unique structure makes it exhibit varieties of biological activities, such as neuroprotective, anti-tumor, anti-viral, anti-oxidant and anti-inflammatory effects. In order to take a deep dive into the structural properties of iridoid derivatives, as well as to facilitate the development of them, we recapitulate the modification strategies of representative iridoids and biological activities of iridoid derivatives, especially discuss their structure-activity relationship in this review. This article will provide the latest overview and offer insights for structural modification of iridoids in future.

Five new C20-diterpenoid alkaloids carmaloidlines A-E (1-5) and a known C20-diterpenoid alkaloid (6) were isolated from the lateral roots of Aconitum carmichaelii Debeaux. Their structures were determined through spectrometric analysis and quantum chemical calculations. Meanwhile, the plausible biosynthetic pathways of 1-6 were also discussed. Western blot results indicated that 2, 4, and 6 significantly inhibited caspase-1 maturation and IL-1β production on the NLRP3 signaling pathway at a concentration of 10 μM, among which 2 exhibited the greatest impact on NLRP3 inflammasome activation in a dose-dependent manner (5, 10 and 20 μM). Notably, the hot plate test in mice demonstrated that the analgesic efficacy of 2 was equivalent to that of morphine at the same dose (0.3 mg/kg), while also providing a longer pain latency period compared to morphine. Additionally, compound 2 effectively mitigated both mechanical allodynia and thermal hyperalgesia induced by the NLRP3 agonist nigericin at a dose of 0.03 mg/kg, exhibiting effects comparable to those of the NLRP3 inhibitor MCC950 (10 mg/kg). Molecular docking revealed that 2 could bind to the active site of MCC950 in NLRP3 protein, and 2 had the lower interaction energy. Cellular thermal shift assay (CETSA) further validated the binding of 2 to NLRP3. This could provide a scientific basis for developing NLRP3 activation inhibitors as novel analgesics.

Histidine triad nucleotide-binding protein 1 (HINT1) is related to depression. However, the underlying mechanisms and whether HINT1 is a therapeutic target for depression remain unclear. In this study, we report that loganin, an antidepressant candidate from our previous research, directly targets HINT1 to alleviate depressive-like behaviors. Overexpression of HINT1 in the hippocampus induces depressive-like behaviors. Mechanistically, HINT1 hinders sigma-1 receptor (Sigma-1R) binding to N-methyl-D-aspartate receptor (NMDAR), promotes  postsynaptic density protein (PSD95) binding to NMDAR, inhibits  brain derived neurotrophic factor (BDNF) signaling, and impairs synaptic plasticity. The interaction between HINT1 and NMDAR is disturbed by loganin. The antidepressant-like effects of loganin are reversed by HINT1 overexpression, Sigma-1R inhibitor and tropomyosin kinase receptor B (TrkB) inhibitor. These results not only indicate that HINT1 induces depression via impairing synaptic plasticity but also provide a candidate targeting HINT1 for depression therapy. Zhang et al. reported that a natural compound, loganin, improves synaptic plasticity and reduces depressive-like behaviors via its direct target HINT1. Mechanistically, overexpressed HINT1 hinders NMDAR/Sigma-1R interactions and increases NMDAR/PSD95 interactions, and HINT1/NMDAR interactions are disrupted by loganin treatment.

ETHNOPHARMACOLOGICAL RELEVANCE:Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse. AIM:In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy. METHODS:AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively. RESULTS:Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3BII. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527. CONCLUSION:Cornuside exerts therapeutic effects on LPS induced AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.

Achyranthes bidentata Blume (ABB; Chinese name: Huai Niuxi) and Cyathula officinalis K.C.Kuan (COK; Chinese name: Chuan Niuxi), two botanical drugs collectively termed “Niuxi” in traditional Chinese medicine (TCM), are widely used for rheumatoid arthritis (RA) management. This review comprehensively summarized the pharmacological mechanisms and therapeutic potential of the metabolites of ABB and COK on RA, while addressing limitations of current evidence. Of the 314 and 185 metabolites contained in ABB and COK, respectively, 22 metabolites (including Chikusetsusaponin V and chikusetsusaponin Ⅳa), showed multiple anti-RA activities. The mechanisms underlying the effects of ABB and COK with respect to the occurrence and development of RA (including inflammatory processes, immunoregulation, fibroblast-like synoviocytes, angiogenesis, oxidative stress, cartilage degradation, and bone destruction) were evaluated (Graphical Abstract). Numerous signaling pathways, such as the nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), are involved in RA. The metabolites contained in ABB and COK have significant medicinal value and potential in the treatment of RA, while in-depth mechanism studies and clinical research are warranted to support the clinical application of these metabolites.

The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), and dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.

Depression is a chronic mental disorder characterized by persistent low mood and loss of interest, often associated with dysregulation of neuroinflammatory pathways. Inhibition of NOD-like receptor protein 3 (NLRP3), a key mediator of neuroinflammation, is a promising strategy for alleviating depressive symptoms by modulating inflammatory responses in the brain. Seven polycyclic polyprenylated acylphloroglucinols (PPAPs), including six new hyperioxides A-F (1-6) and furohyperforin (7) were isolated from St. John's wort and characterized via spectroscopic analyses. Compounds 2 and 7 exhibited neuroprotective effects at 10 μM in corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, furohyperforin (7) was demonstrated potent antidepressant activity at 1.25 mg/kg in the forced swimming test (FST) of mice, which was equivalent to fluoxetine (10 mg/kg) and neurostan (78 mg/kg). Additionally, compound 7 was shown to reduce serum CORT levels in mice. Further studies highlighted its effects and potential mechanism through the NLRP3 inflammasome pathway and NLRP3 might be a protein target for the antidepressant effects of 7. Notably, this study provided the first evidence of furohyperforin (7)'s antidepressant properties in mice, highlighting its potential as a bioactive compound for antidepression.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and neuroinflammation play crucial roles in its progression. Our previous studies found that cornuside from Cornus officinalis Sieb.Et Zucc is an anti-AD candidate, however, its underlying mechanism remains unknown. In the present study, AD mice were established by intracerebroventricular injection of Aβ1−42 and treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated behavioral deficits, protected synaptic plasticity and relieved neuronal damage in Aβ1−42 induced mice. Importantly, cornuside decreased NLRP3 inflammasome activation, characterized by decreased levels of NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. Furthermore, cornuside promoted mitophagy accompanied by decreasing SQSTM1/p62 and promoting LC3B-I transforming into LC3B-II, via Pink1/Parkin signaling instead of FUNDC1 or BNIP3 pathways. In order to investigate the relationship between NLRP3 inflammasome and mitophagy in the neuroprotective mechanism of cornuside, we established an in-vitro model in BV2 cells exposed to LPS and Aβ1−42. And cornuside inhibited NLRP3 inflammasome activation and subsequent cytokine release, also protected neurons from damaging factors in microenvironment of conditional culture. Cornuside improved mitochondrial function by promoting oxidative phosphorylation and glycolysis, decreasing the production of ROS and mitochondrial membrane potential depolarization. Besides, mitophagy was also facilitated with increased colocalization of MitoTracker with LC3B and Parkin, and Pink1/Parkin, FUNDC1 and BNIP3 pathways were all involved in the mechanism of cornuside. By blocking the formation of autophagosomes by 3-MA, the protective effects on mitochondria, the inhibition on NLRP3 inflammasome as well as neuronal protection in conditional culture were eliminated. There is reason to believe that the promotion of mitophagy plays a key role in the NLRP3 inhibition of cornuside. In conclusion, cornuside re-establishes the mitophagy flux which eliminates damaged mitochondria and recovers mitochondrial function, both of them are in favor of inhibiting NLRP3 inflammasome activation, then alleviating neuronal and synaptic damage, and finally improving cognitive function.

Inflammation is known to exacerbate depressive symptoms. Loganin, a major iridoid glycoside derived from Cornus officinalis Sieb. et Zucc., exhibits antidepressant-like properties and anti-inflammatory effects; however, the mechanisms underlying these actions remain unclear. Given the involvement of the Sigma-1 receptor (Sigma-1R) in both depression and neuroinflammation, this study aimed to investigate whether loganin can ameliorate inflammation-related depression by modulating Sigma-1R. Experimental models of social isolation and lipopolysaccharide (LPS)-induced depressive-like behaviors were employed. The effects of loganin on behavioral outcomes, neurons, astrocytes, and microglia, oxidative stress levels, and the NLRP3 inflammasome were assessed. Molecular docking analysis and cellular thermal shift assay were conducted to evaluate the binding affinity of loganin to Sigma-1R. Additionally, the impact of a Sigma-1R inhibitor (BD1047) on loganin's effects was investigated. Loganin improved social isolation- and LPS-induced depressive-like behaviors. It also reduced astrocyte and microglia reactivity and decreased oxidative stress levels. Furthermore, loganin downregulated the expression of IRE1α, TXNIP, and the NLRP3 cascade. Molecular docking and cellular thermal shift assays confirmed strong binding of loganin to Sigma-1R. Loganin increased Sigma-1R expression in the hippocampus in response to LPS or social isolation. The antidepressant-like effects of loganin, as well as its inhibition of the NLRP3 inflammasome and oxidative stress, were reversed by BD1047. These findings suggest that loganin alleviates inflammation-associated depressive-like behaviors by inhibiting the NLRP3 inflammasome and oxidative stress via the Sigma-1R/IRE1α/TXNIP pathway, highlighting its potential as a therapeutic agent for inflammation-related depression.

A novel rearranged C20-diterpenoid alkaloid, carmiseconapline A (1), featuring a unique 10,20:11,12-di-seco-napelline skeleton with a fused 5/6/5/6/7 pentacyclic ring system, was isolated from Aconitum carmichaelii Debeaux. Compound 1 exhibited remarkable antidepressive activity, being twice as potent as fluoxetine (10 mg/kg) at 0.06 mg/kg in mice. Further mechanism studies showed that 1 effectively activated adenosine 5'-monophosphate-activated protein kinase (AMPK), protected HT22 cells from mitochondrial dysfunction, and inhibited apoptosis. These findings suggested 1 as a potential AMPK activator for antidepressant development.

Targeting NOD-like receptor protein 3 (NLRP3) holds promise as a novel strategy for treating depression. Chemical investigation of the lateral roots of Aconitum carmichaelii Debeaux (Fuzi) led to the isolation of five new diterpenoid alkaloids acarmalines A-E (1-5). Their structures were elucidated based on the spectroscopic analysis (1D, 2D NMR, HR-ESI-MS, and IR) and quantum chemical calculations. Their biosynthetic pathways were also discussed. Bioactivity studies demonstrated that 1, 2, 4 and 5 showed significant neuroprotective effects in LPS-stimulated BV2 cells. Notably, compound 1 revealed remarkable antidepressant effects in the tail suspension test (TST) of mice at a dose of 0.1 mg/kg, with efficacy comparable to the positive control fluoxetine (10 mg/kg). Furthermore, mechanistic studies indicated that 1 exhibited significant anti-neuroinflammatory effects through modulation of the NLRP3 pathway by western blot and immunofluorescence experiments. Finally, cellular thermal shift assay (CETSA) and molecular docking studies confirmed that 1 might acted as an inhibitor of NLRP3 activation. These findings provide a rationale for designing NLRP3 activation inhibitors as novel antidepressant agents.

A phytochemical investigation of flower buds of Wikstroemia Chamaedaphne Meissn. resulted in the isolation of 21 terpenoids (1-21), three lignans (22-24) and one aromatic compound (25). These compounds were elucidated using spectroscopic methods and comparing their data to those reported in the literature. Compounds 14, 18 and 22 were first isolated from the family Thymelaeaceae. Compounds 17, 19-21 and 25 were initially obtained from the genus Wikstroemia, while terpenoids 5, 15 and 16 have not been previously isolated from this species. In addition, distribution mapping of terpenoids was performed to explore their possible chemotaxonomic values among species of the family Thymelaeaceae, Euphorbiaceae, Lamiaceae, Rosaceae and Asteraceae.

Daphnane diterpenoids, as one of the representative types of diterpenoid compounds with rich structural diversity and significant biological activities, have an uncommon 5/7/6 tricyclic skeleton mainly found in species of Thymelaeaceae and Euphorbiaceae families. Due to the unique peculiarity of the framework and remarkable pharmacological activities, over the past three decades, novel structures have been continuously discovered and more structural subtypes have been derived. However, there is always a lack of a unified and convincing structural classification strategy for the summary of daphnane diterpenoids, which affects the in-depth and systematic research of pharmaceutical chemists and pharmacologists. In addition, the distinctive skeleton, continuous chiral centers, and prominent bioactivities of daphnane diterpenoids have attracted widespread interest among synthetic chemists. However, there are currently only a few reports of complete synthesis of compounds with low overall yields. Given the broad attention paid to daphnane diterpenoids in recent years, this review summarized the sources, structural classification, biological activities, and synthesis of around 300 natural daphnane diterpenoids discovered from 1993 to 2023, providing a reference for further discovery of novel structures, chemical and biological synthesis, and drug research.

Ethnopharmacological relevance: Cornus officinalis Sieb. et Zucc has significant neuroprotective activity and has been widely studied for its potential to improve cognitive function. Our team's previous research has found that loganin isolated from Cornus officinalis has an antidepressant effect. Depression is a mental disorder accompanied by dysfunction of Connexin43 (Cx43)-formed astrocytic gap junctions. However, the precise mechanisms of loganin involved remain uncertain. Aim of the study: We aimed to examine the mechanism by which loganin produces its antidepressant properties. Materials and methods: Using a chronic unpredictable stress (CUS) model of depression in rats, the study evaluated the behavioral responses to treatment with loganin, fluoxetine, and their combination. Biochemical analyses were conducted to measure the expression and phosphorylation status of Cx43, (3-catenin, GSK-3(3 in the brain. In vitro experiments were also performed how loganin protects the gap junctions in astrocytes that have been exposed to corticosterone. Results: After four weeks of loganin treatment, rats exposed to CUS showed a decrease in depressive-like behaviors. When combined with fluoxetine, the antidepressant-like effects were observed faster than with either treatment alone. Loganin significantly increased Cx43 expression in the prefrontal cortex and ventral hippo- campus, reversed Cx43 mimetic peptide Gap26-induced depressive-like behaviors, decreased Cx43 phosphorylation at Ser368, increased (3-catenin levels, and promoted GSK-3(3 phosphorylation at Ser9. In vitro, loganin prevented corticosterone-induced damage to gap junctions between astrocytes, an effect that was negated by XAV-939 ((3-catenin inhibitor). Conclusion: These results implied that loganin could exert antidepressant-like effects by improving the gap junctions of astrocytes in the prefrontal cortex and hippocampus, acting through the GSK-3(3/(3-catenin signaling pathway. The combination of loganin with fluoxetine may provide a faster onset of antidepressant action compared to either treatment alone, highlighting the potential of loganin as a natural adjunct therapy for depression.