The overactivated BLT1 receptor is a key pathogenic driver and therapeutic target for acute lung injury and sepsis, yet no selective BLT1 inhibitors are available in the clinic. Using virtual screening, we identified the natural product hit compound BF-2 (IC50 = 255 nM), featuring a phloroglucinol-chromone scaffold, as a BLT1 inhibitor. Structural simplification and optimization of this scaffold led to a series of novel chromone derivatives. Among the derivatives, VI-8 showed potent BLT1 inhibition (IC50 = 8.7 nM), high selectivity over BLT2 (SI > 20), and strong binding affinity (Kd = 121 nM). Furthermore, in vivo evaluation showed that VI-8 (20 mg/kg, p.o.) conferred significant protection against acute lung injury and sepsis, with favorable oral bioavailability (F% = 85.3) and a good safety profile. This work provides a structural basis for developing novel selective BLT1 inhibitors and offers new insights for anti-inflammatory drug discovery.

Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Proanthocyanidin A1 (1) from peanut skin is a JAK2 activator to alleviate CIM, but the SAR and drug-like properties of Type-A proanthocyanidins remain unclear. Here, a series of Type-A proanthocyanidin derivatives (5-35) were designed, synthesized, and evaluated for JAK2 activation, leading to the identification of compound 32 as the most potent activator (EC50 = 64 nM). Target-binding assays demonstrated that 32 directly bound JAK2 and displayed preferential affinity for the JH2 pseudokinase domain over the JH1 catalytic domain, indicating a potential JH2-mediated activation mechanism. In primary BMHSCs, 32 activated the JAK2/STAT3 pathway and alleviated carboplatin-induced damage. Consistently, oral administration of 32 at 50 mg/kg activated JAK2/STAT3 signaling in vivo and promoted hematopoietic recovery in CIM mice, with favorable bioavailability and acceptable preliminary safety. These findings identify 32 as a promising orally available JAK2 activator for CIM treatment.

Two novel monoterpenoid quinoline alkaloids, tabernacatines A and B (1 and 2), and a new monoterpenoid indole alkaloid, tabernacatine C (3), along with three known alkaloids (4 - 6), were isolated from the twigs and leaves of Tabernaemontana divaricata. Their structures were elucidated based on UV, IR, HR-ESI-MS, NMR spectra analysis, X-ray diffraction, and ECD calculation methods. Compounds 1 - 6 were evaluated for their neuroprotective effects in glutamate-induced HT22 cells, and compounds 4-6 exhibited potent neuroprotective effects.

Six novel monoterpenoid indole alkaloid (MIA) heterodimers, hunterlanines A-F (1-6), were isolated from Hunteria zeylanica. Compounds 1 and 2 possess unprecedented carbon skeletons featuring cage-like 6/5/6/6/6/5/6 heptacyclic and 6/5/6/6/6/6 hexacyclic cores, respectively. Compounds 3 and 4 represent the first MIA-phenylpropanoid heterodimers characterized by an unusual C-C and N-C connectivity, forming two different 6/5/5/8/6 pentacyclic scaffolds. Compounds 5 and 6 exemplify novel heterodimers in which the MIA moiety was coupled with indole derivative or indole via C-C linkages. Their structures were established by spectroscopic analyses, X-ray crystallography, and quantum chemical calculations. Notably, compounds 1, 4, and 6 exhibited significant neuroprotective activity against l-glutamate-induced neural injury in HT-22 cells.

Background:Physician assessments of patient symptoms may not align with the patients' subjective experiences, potentially affecting disease management. The key drivers of patients with Crohn's disease (CD) regarding their physicians' engagement in treatment decision-making are unknown. Objective:This study aimed to compare cognitive differences between patients and gastroenterologists in the diagnostic and treatment processes of CD. Design:Retrospective multicenter study. Methods:This study was conducted at 39 inflammatory bowel disease (IBD) centers across China, ultimately recruiting 601 patients with CD and 181 gastroenterologists. Results:Regarding symptom focus, physicians were more concerned about abdominal pain, while patients, particularly inpatients, were more concerned about frequent medical visits. There were also significant differences in the treatment goals. Patients prioritized improving their quality of life, whereas physicians showed a hierarchical difference in their focus: resident and attending physicians emphasized mucosal healing, while deputy chief physicians and above placed greater importance on long-term remission (clinical, endoscopic, and histological). Regarding knowledge gaps about CD, physicians significantly overestimated patients' understanding of biologics (93.37% vs 71.55%, κ = 0.117), with inpatients showing slightly higher awareness than outpatients (73.96% vs 70.42%). Regarding follow-up compliance, the discrepancy was especially prominent: 46.96% of physicians recommended follow-up every ⩽2 months, while 61.73% of patients preferred follow-up every 6 months. The economic burden of CD revealed that 21.30% of patients were willing to spend over 50% of their household income on treatment, which far exceeded physicians' expectations (9.94%). Lastly, there was a significant divergence in decision-making models: 49.17% of physicians advocated for shared decision-making, but only 14.31% of patients agreed with this model (κ = 0.353). Conclusion:There are notable cognitive disparities between patients with CD and physicians in their approaches to disease management, particularly concerning follow-up frequency and treatment options. These differences underscore the need for targeted interventions to bridge the gap between patient and physician perspectives. Therefore, future research should focus on enhancing communication between doctors and patients and enabling them to play a more active role in health management and treatment decisions.

Nine undescribed hop bitter acids, humulupulones A-I (1-9), along with three known ones (10-12) were isolated from the pistillate flower of Humulus lupulus L. (hops). Structurally, compounds 1 and 2 possess an unprecedented nitrogen-containing skeleton in α-acids, and this is the first time that nitrogen has replaced oxygen at the same position, thereby forming a new skeleton consisting of a fused α-acid and a dimethyl-substituted pyridine. Compound 3 is a rare pyridine-2,4-dione derivative simultaneously incorporating prenyl and isopropyl moieties. Compounds 7-10 were separated into four pairs of enantiomers by chiral HPLC separation. Their structures were unambiguously established by comprehensive spectroscopic analysis, X-ray crystallography, and ECD calculations. Moreover, compounds 2, 4, and 7 exhibited significant anti-inflammatory activities in the CuSO4-induced zebrafish inflammation model. Compounds 4, 5, 7-10 and 12 possessed significant anti-dengue virus (DENV) activities at the viral adsorption and entry stages with IC50 values ranging from 0.29 μM to 70.09 μM, while compounds 7, 10, and 11 exerted anti-DENV activities at the viral replication stage with IC50 values of 71.47 ± 7.30, 19.36 ± 6.77, and 16.18 ± 3.49 μM, respectively.

Chemotherapy-induced myelosuppression (CIM) significantly impairs hematopoiesis. Trilaciclib (TC), originally developed for oncology application, is the only FDA-approved CDK4/6 inhibitor for CIM, which effectively protects bone marrow cells by inhibiting their proliferation. In this study, a series of TC derivatives were designed and synthesized as CDK4/6 inhibitors (CDK4/6i) for alleviating CIM. Among these, 42 displayed potent CDK4/6 inhibitory activity (IC50 = 11 nM), lower cytotoxicity (CC50 > 100 μM) and showed high selectivity among 86 kinases. Additionally, 42 possessed strong bone marrow penetration, favorable pharmacokinetic properties, excellent safety profiles, and superior efficacy in mitigating myelosuppression caused by 5-fluorouracil (5-FU) in vivo. In conclusion, as the first oral small-molecule CDK4/6 inhibitor optimized specifically for myelosuppression treatment, 42 expands the therapeutic applications of CDK4/6i, optimizes the mode of administration, and offers significant translational value and clinical potential.

Intestinal fibrosis is often observed in inflammatory bowel disease (IBD) and seriously affects intestinal health. Our previous study identified that triphenyl phosphate (TPhP), one kind of frequently used organophosphate flame retardants (OPFRs), induced IBD-like features in colon. Herein, we firstly observed extracellular matrix deposition in colon tissues, indicative of appearance of colonic fibrosis. Further studies showed that TPhP downregulated epithelial marker E-cadherin levels but upregulated alpha smooth muscle actin (α-SMA) in mouse colon tissues, and similar results were observed in cultured colon cells, indicating that fibrogenesis might be attributed to epithelial-mesenchymal transition (EMT). Further transcriptome and experimental data demonstrated that TPhP-induced EMT was closely associated with activated Wnt/β-catenin pathway. Moreover, FOXM1 facilitated the entrance of β-catenin into nucleus to regulate expression of Wnt target genes, promoting EMT initiation. Collectively, these findings demonstrated that TPhP induced colonic fibrosis in mice by activating EMT, and this work may provide new perspectives in exploring etiology of intestinal fibrosis and developing relevant treatment strategies.

Eleven undescribed piperidine alkaloids, arecachines A-J (1-11), were isolated from the peels of Areca catechu. Compounds 8-11 are featured as bis-piperidine alkaloids. Their structures were elucidated by analysis of UV, IR, HRESIMS, 1D and 2D NMR spectra. Compounds 1 - 4 , 6 , and 8-11 were evaluated for the monoamine oxidases (MAOs) inhibitory activity. Among them, compounds 3 , 4 , 6 , and 10 showed MAOA inhibitory activity with IC50 values of 7.85-55.96 mu M, while compounds 1 - 4 , 8 , 10 , and 11 showed MAOB inhibitory activity with IC50 values of 11.92-77.87 mu M.

Aim Dual-targeted therapy (DTT) may offer a promising approach for treating refractory inflammatory bowel disease (IBD). The aim of this case series was to evaluate the safety and clinical response of DTT in clinical practice.Methods We retrospectively analyzed data from refractory inflammatory bowel disease (IBD) patients receiving dual-target therapy (DTT) across several Chinese IBD centers. The treatment combinations included biologic agents (infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ), and ustekinumab (UST) and oral small molecule tofacitinib (TOF). We collected baseline characteristics, clinical and endoscopic activity indices, inflammatory markers (C-reactive protein and albumin), and adverse events to evaluate the clinical effectiveness, endoscopic response, biochemical remission, and safety profile of DTT.Results A total of 8 patients with ulcerative colitis (UC) and 10 with Crohn's disease (CD) underwent DTT at three tertiary hospitals in China. All corticosteroids initiated at baseline (six cases) were completely discontinued within 3 months. Clinical response rates were 88.23% (15/17), 91.67% (11/12), and 100% (7/7) at 3, 6, and 9 months, respectively. Endoscopic response was achieved in 88.89% (8/9) of patients who were evaluated at 9 months. Adverse events included ustekinumab-associated arthralgia and alopecia in one UC patient and tofacitinib-related allergic purpura in another, both of which were subsequently transitioned to monotherapy. Two CD patients developed infections (Clostridium difficile and bacterial intestinal infection) at 3 months, were treated with oral antibiotics, and successfully continued their original DTT regimens.Conclusion Our findings suggest that dual-target therapy demonstrates promising efficacy and an acceptable safety profile in refractory IBD patients. DTT may represent a valuable therapeutic option for patients who have not responded to conventional monotherapies.

Thrysaxinones A-F (1-6), six new phloroglucinol-terpenoid adducts (PTAs), were isolated from Thryptomene saxicola. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, X-ray crystallography, and quantum chemical calculations. Compounds 1-3 represent unprecedented PTAs with gorgonane- or oplopane-type sesquiterpenoid moieties. Notably, compound 1 features an unusual 11-oxa-tricyclo[6.2.1.04,9]undecane core. Compound 4 is a unique PTA with a new carbon skeleton formed by an acylphloroglucinol unit coupled with a bicyclogermacrene-type sesquiterpenoid moiety. The plausible biogenetic pathways for compounds 1-6 were proposed. Moreover, compounds 1, 2, 5, and 6 exhibited significant antibacterial activities against clinical methicillin-resistant Staphylococcus aureus (MRSA) strains. Compound 1, the most potent one, could rapidly and effectively eradicate bacteria by inducing hyperpolarization and disrupting cell membrane integrity.

Humulupones A-F (1-6), six new bitter acid derivatives with three types of new skeletons, were isolated from Humulus lupulus. Compounds 1-4 were four dimers with an unprecedented 6/6/6/6/6 pentacyclic skeleton featuring 6 stereogenic centers. Compounds 5 and 6 possessed an unreported 6/5/6 tricyclic ring system, with 5 consisting of spiro and bridged ring and 6 simultaneously incorporating bridged and fused ring systems. Their structures and absolute configurations were established by comprehensive spectroscopic analysis, DP4+ probability analyses, electronic circular dichroism, and X-ray diffraction analysis. Furthermore, compounds 1, 3, 4 and 6 showed anti-inflammatory effects in CuSO4-induced zebrafish inflammatory model, and compounds 1-4 showed remarkable antiviral activities against herpes simplex virus type-1.

Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ser/Thr-protein kinase that regulates neuronal protein synthesis homeostasis via an inhibitory phosphorylation of eEF2, has emerged as a promising therapeutic target for several diseases, including Alzheimer's disease (AD). In this study, we employed molecular docking with an in-house natural product library of 4270 compounds, containing 2177 novel compounds and 603 new structural frameworks, to identify eEF2K inhibitors. Following virtual screening, 25 natural products were selected for in-vitro evaluation of eEF2 phosphorylation inhibition as well as protein synthesis promotion. Our findings identified that compounds 17 and 23 potently suppress eEF2K activity, increase protein synthesis, and concurrently induce neuritogenesis. Molecular dynamics simulations suggest that 17 and 23 may stably bind to the eEF2K protein. Our findings highlighted 17 and 23 as new natural eEF2K inhibitors and promising candidates for promoting neural differentiation, providing potential therapeutic leads for the treatment of AD.

Four novel arecoline alkaloid atropisomers, arechuines A-D (1 - 4), were obtained from the peels of Areca catechu L. Their structures were elucidated by UV, IR, MS and NMR spectra. The absolute configurations of (+)/(-)-4 were determined by comparing the experimental and calculated ECD spectra. Compounds 1 - 4 were evaluated for their neuroprotective effects in glutamate-induced HT22 cell and 3 revealed potent neuroprotective effects at 10 μM. These are the first reported arecoline alkaloid atropisomers isolated from A. catechu.

L-type calcium channels (LTCCs), the largest subfamily of voltage-gated calcium channels (VGCCs), are the main channels for Ca2+ influx during extracellular excitation. LTCCs are widely present in excitable cells, especially cardiac and cardiovascular smooth muscle cells, and participate in various Ca2+-dependent processes. LTCCs have been considered as worthy drug target for cardiovascular, neurological and psychological diseases for decades. Natural products from Traditional Chinese medicine (TCM) have shown the potential as new drugs for the treatment of LTCCs related diseases. In this review, the basic structure, function of LTCCs, and the related human diseases caused by structural or functional abnormalities of LTCCs, and the natural LTCCs antagonist and their potential usages were summarized.

A mild copper-catalyzed asymmetric Kinugasa/Michael addition cascade process is developed. The reaction of α, β-unsaturated ester-tethered propiolamides with nitrones provides an efficient protocol for the construction of functionalized chiral 2,6-diazaspiro[3.4]octane-1,5-dione products in satisfactory yields and with high enantio- and diastereoselectivities.

Background and Purpose: Kaempferol-3-O-sophoroside (PCS-1) is the main component in Crocus sativus (Saffron), a herb with mood-enhancing properties. AMP-activated protein kinase (AMPK) is a potential therapeutic target for depression. This study explores the antidepressive-like properties of PCS-1 and its AMPK activation to confirm AMPK as a target for antidepression.Experimental Approach: Corticosterone (CORT)-induced PC12 cell injury served as an in vitro model to evaluate the neuroprotective effect of PCS-1. Neuro-2a cells and primary neurons were utilized to evaluate the synaptogenesis role of PCS-1. CORT-induced mouse depression model and chronic unpredictable mild stress (CUMS) model were used to assess the antidepressive-like properties of PCS-1 through behavioural tests, magnetic resonance imaging, and biochemical index measurements. Western blot and immunofluorescence assays were used to study the mechanisms of PCS-1. Cellular thermal shift assay was used to confirm the binding target.Key Results: PCS-1 (12.5-50 mu M) ameliorated CORT-induced PC12 cell damage, oxidative stress and inflammation. PCS-1 alone promoted an increase in synapses in Neuro-2a cells and primary neurons. Oral administration of PCS-1 (10 and 20 mg center dot kg(-1)) ameliorated weight loss, dyskinesia, and hippocampal volume reduction induced by CORT and CUMS. PCS-1 bound to AMPK to improve the expression of brain-derived neurotrophic factor (BDNF) and induce autophagy.Conclusion and Implications: PCS-1 binds to AMPK to promote BDNF production and autophagy enhancement, ultimately achieving antidepressant effects. This study provides support for the clinical application of saffron petals and provides further evidence for AMPK as a potential target for antidepression.

Eleven undescribed monoterpenoid bisindole alkaloids, alstomaphyines A-K (1-11), along with three known analogues were isolated from the leaves and stem bark of the Alstonia macrophylla. Compounds 1-3 were unprecedented dimerization alkaloids incorporating a macroline-type motif with an ajmaline-type motif via a C-C linkage. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and CD exciton chirality method. Compounds 1-3 displayed potential inhibitory bioactivity against AChE with IC50 values of 4.44 +/- 0.35, 3.59 +/- 0.18, and 3.71 +/- 0.23 mu M, respectively. Enzyme kinetic study revealed compounds 1-3 as mixed competitive AChE inhibitors. Besides, compounds 8 and 12-14 exhibited better cytotoxicity against human cancer cell line HT-29 than cisplatin. Flow cytometry data revealed that compounds 8, 13, and 14 significantly induced the HT-29 cells arrest in G0/G1 phase in a concentration-dependent manner.

Inflammatory bowel disease (IBD) is an inflammatory disease that occurs to the intestinal tract. Many patients with IBD often develop anemia and often receive oral iron supplementation. Many of them develop non-compliance with oral iron therapy, but the mechanisms are not well understood. We interrogated whether colonic epithelial iron overload impacts cell viability and disease severity. We observed increased expression of iron importers and iron accumulation in mature colonocytes in dextran sulfate sodium (DSS)-induced acute colitis and in humans with active colitis. Administration of hepcidin increased epithelial iron overload and aggravated colonic inflammation in DSS-treated mice and IL10-/- mice. Hepcidin-induced iron accumulation increased colonic epithelial death, which was prevented by treatment with Trolox, a vitamin E analog and a scavenger of lipid peroxides. By using cultured Caco-2 cells, we showed that iron and inflammatory cytokines (TNF-α and IL-1β) induced a synergistic increase in the number of necrotic cells. We then showed that the combined treatment by hepcidin and cytokines increased labile iron content and lipid peroxidation in Caco-2 cells. Moreover, liproxstatin-1, a ferroptosis inhibitor, and deferoxamine, an iron chelator, both abolished the hepcidin/cytokines induced death of Caco-2 cells, suggesting ferroptosis. We further elucidated that inflammatory cytokines promote lipid peroxidation and ferroptosis by inducing NOX1-dependent exhaustion of reduced glutathione (GSH). Collectively, our findings demonstrate that the inflammatory context predisposes colonic epithelial cells to iron overload mediated ferroptosis, exacerbating colonic inflammation.

Sixteen ceanothane-type triterpenoids, including four new compounds-hovendulcisic acids A-D (1-4) -were purified from the stems of Hovenia dulcis Thunb. The structures of 1-4 were confirmed by comprehensive means including ECD and quantum chemical calculations. Putative biosynthetic pathways of 1-16 were proposed, and 3, 5, and 15 exhibited antitumor activity on A549 and MDA-MB-231 cells.