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The purpose of this study was to explore the inhibitory effect of andrographolide on the expression of key regulatory genes involved in the biofilm formation of Staphylococcus epidermidis (SE). Taking the film-producing strain Staphylococcus epidermidis SE1457 as the research object, the effect of andrographolide on the formation of Staphylococcus epidermidis biofilms was analyzed via crystal violet staining, and biofilm models of SE adhesion, aggregation and maturity were established in vitro. RT‒PCR was used to detect the effects of the expression of icaA-, atlE-, aap- and luxS-related genes of andrographolide on biofilm formation in SE. Congo red qualitative test to evaluate the ability of andrographolide to inhibit biofilm formation of Staphylococcus epidermidis. Compared with that of the control group, the light absorption value of the low- and high-concentration andrographolide groups was significantly lower, and the light absorption value of the high-concentration andrographolide group was significantly lower than that of the low-concentration andrographolide group. The levels of key genes involved in the adhesion, aggregation and maturation of icaA, atlE, aap and luxS in group C were greater than those in group B. The biofilm-forming ability of SE in group A was strong, and the colonies were obviously black. The colony in the direction of the arrow in group B was red, and the SE biofilm was inhibited. Most of the colonies in group C were red. SE biofilms were significantly inhibited. Andrographolide inhibits SE biofilm formation, and its mechanism may involve inhibition of the expression of the related genes icaA, atlE, aap and luxS., Competing Interests: Declarations. Ethics approval and consent to participate: Research ethics approval was received from the Second Hospital of Shandong University. Conflict of interest: The authors declare that there are no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates both oxidative stress and mitochondrial biogenesis. Our previous study reported the cardioprotection of calycosin against triptolide toxicity through promoting mitochondrial biogenesis by activating nuclear respiratory factor 1 (NRF1), a coregulatory effect contributed by Nrf2 was not fully elucidated. This work aimed at investigating the involvement of Nrf2 in mitochondrial protection and elucidating Nrf2/NRF1 signaling crosstalk on amplifying the detoxification of calycosin. Results indicated that calycosin inhibited cardiomyocytes apoptosis and F-actin depolymerization following triptolide exposure. Cardiac contraction was improved by calycosin through increasing both fractional shortening (FS%) and ejection fraction (EF%). This enhanced contractile capacity of heart was benefited from mitochondrial protection reflected by ultrastructure improvement, augment in mitochondrial mass and ATP production. NRF1 overexpression in cardiomyocytes increased mitochondrial mass and DNA copy number, whereas NRF1 knockdown mitigated calycosin-mediated enhancement in mitochondrial mass. For nuclear Nrf2, it was upregulated by calycosin in a way of disrupting Nrf2-Keap1 (Kelch-like ECH associated protein 1) interaction, followed by inhibiting ubiquitination and degradation. The involvement of Nrf2 in mitochondrial protection was validated by the results that both Nrf2 knockdown and Nrf2 inhibitor blocked the calycosin effects on mitochondrial biogenesis and respiration. In the case of calycosin treatment, its effect on NRF1 and Nrf2 upregulations were respectively blocked by PGCα/Nrf2 and NRF1 knockdown, indicative of the mutual regulation between Nrf2 and NRF1. Accordingly, calycosin activated Nrf2/NRF1 and the signaling crosstalk, leading to mitochondrial biogenesis amplification, which would become a novel mechanism of calycosin against triptolide-induced cardiotoxicity., Competing Interests: Declarations. Ethics approval: All procedures were performed in accordance with the guidelines of animal ethics and protocols of Shanxi university of Chinese medicine (AWE202403129). Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Oral ulcers have an impact on 25% of the global population including patients who are suffering from chemotherapy and radiotherapy treatments. Kaempferia galanga L. has been traditionally used for treatment of mouth sores and tongue blisters. However, the wound healing study of isopimarane diterpenes isolated from K. galanga is still limited., Objective: This study aims to evaluate the wound healing potential of 6β-acetoxysandaracopimaradiene-1α,9α-diol (KG 6 ), a compound isolated from Kaempferia galanga , by examining its biological activities. Additionally, we investigate the physicochemical and biological properties of (KG 6 ) in formulated mouth gels., Methods: The KG 6 mouth gels at 0.10%, 0.25% and 0.50% w/w were formulated using sodium carboxymethylcellulose as a gelling agent, and their physicochemical and biological stabilities were assessed through a heating-cooling acceleration test. The quantification of KG 6 contents in KG 6 mouth gels was determined using gas chromatography. Both KG 6 and KG 6 mouth gels were evaluated for their wound healing properties including cell proliferation, cell migration, and antioxidant activity (H 2 O 2 -induced oxidative stress) in human gingival fibroblast (HGF-1-ATCC CRL-2014) (HGF-1). In addition, the anti-inflammatory activity against nitric oxide (NO) production was investigated in macrophage cells (RAW 264.7)., Results: After KG 6 mouth gels were incubated under heating-cooling acceleration condition, the physicochemical properties of the KG 6 mouth gels remain stable across various parameters, including appearance, color, smell, texture, pH, viscosity, separation, and KG 6 content. The biological studies indicated that the KG 6 compound possessed good wound healing potential. The 0.50% KG 6 mouth gel exhibited marked anti-inflammatory effect by inhibiting NO production with an IC 50 of 557.7 µg/ml, comparable to that of Khaolaor mouth gel, a positive control. The 0.25% KG 6 mouth gel increased HGF-1 cell proliferation to 101.7-103.5%, whereas all formulations of KG 6 mouth gel enhanced HGF-1 cell migration to 94.7-98.9%, higher than Khaolaor mouth gel (73.5%). Moreover, 0.50% KG 6 mouth gel also showed a good antioxidant effect under H 2 O 2 -induced oxidative stress., Conclusion: This study substantiates the significant biological activities related to the wound healing property of 0.50% KG 6 mouth gel for treatment of aphthous ulcers and oral stomatitis from chemotherapy and radiotherapy treatments., Competing Interests: The authors declare that they have no competing interests., (© 2024 Iadnut et al.)

The growing awareness and need to protect public health, including food safety, require a thorough study of the mechanism of action of veterinary drugs in consumers to reduce their negative impact on humans. Inappropriate use of veterinary drugs in animal husbandry, such as tiamulin, leads to the appearance of residues in edible animal tissues. The use of natural substances of plant origin, extracted from hemp ( Cannabis sativa L.), such as cannabidiol (CBD), is one of the solutions to minimize the negative effects of tiamulin. This study aimed to determine the effect of CBD on the cytotoxicity of tiamulin in humans. The cytotoxic activity of tiamulin and the effect of its mixtures with CBD were tested after 72 h exposure to three human cell lines: SH-SY5Y, HepG2 and HEK-293. Cytotoxic concentrations (IC 50 ) of the tested drug and in combination with CBD were assessed using five biochemical endpoints: mitochondrial and lysosomal activity, proliferation, cell membrane integrity and effects on DNA synthesis. Oxidative stress, cell death and cellular morphology were also assessed. The nature of the interaction between the veterinary drug and CBD was assessed using the combination index. The long-term effect of tiamulin inhibited lysosomal (SH-SY5SY) and mitochondrial (HepG2) activity and DNA synthesis (HEK-293). IC 50 values for tiamulin ranged from 2.1 to >200 µg/mL (SH-SY5SY), 13.9 to 39.5 µg/mL (HepG2) and 8.5 to 76.9 µg/mL (HEK-293). IC 50 values for the drug/CBD mixtures were higher. Reduced levels of oxidative stress, apoptosis and changes in cell morphology were demonstrated after exposure to the mixtures. Interactions between the veterinary drug and CBD showed a concentration-dependent nature of tiamulin in cell culture, ranging from antagonistic (low concentrations) to synergistic effects at high drug concentrations. The increased risk to human health associated with the presence of the veterinary drug in food products and the protective nature of CBD use underline the importance of these studies in food toxicology and require further investigation.

Fibrosis is the terminal pathology of chronic illness in many organs, marked by excessive accumulation of extracellular matrix proteins. These changes influence organ function, ultimately resulting in organ failure. Although significant progress has been achieved in comprehending the molecular pathways responsible for fibrosis in the last decades, effective and approved clinical therapies for the condition are still lacking. Andrographolide is a diterpenoid isolated and purified mainly from the aboveground parts of the Andrographis paniculata plant, which possesses good effects of purging heat, detoxifying, antibacterial and anti-inflammatory. In-depth research has gradually confirmed the anticancer, antioxidant, antiviral and other effects of Andro so that it can play a preventive and therapeutic role in various diseases. Over the past few years, an increasing number of research findings have indicated that Andro exerts antifibrotic effects in various organs by acting on transforming growth factor-β/small mother against decapentaplegic protein, mitogen-activated protein kinases, nuclear factor-E2-related factor 2, nuclear factor kappa-B and other signalling molecules to inhibit inflammation, oxidative stress, epithelial-mesenchymal transition, fibroblast activation and collagen buildup. This review presents a compilation of findings regarding the antifibrotic impact of Andro in tissue and cell models in vitro and in vivo. Emphasis is placed on the potential therapeutic benefits of Andro in diseases related to organ fibrosis. Existing studies and cutting-edge technologies on Andro pharmacokinetics, toxicity and bioavailability are briefly discussed to provide evidence for accelerating its clinical conversion and adoption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Natural products (NPs) often act as sources of CNS-active agents and provide inspiration for the development of synthetic molecules that incorporate their best features. Vindeburnol (VIND; (±)-(3α,14β)-20,21-dinoreburnamenin-14-ol; developmental codes RU24722 or BC19), based on the core structure of eburnamine-vincamine alkaloids, has been extensively investigated for its biological activities. This molecule has demonstrated potential therapeutic properties in various in vivo models of CNS disorders such as multiple sclerosis, Alzheimer's disease, and depressive-like behavior. Although few clinical trials were conducted, further development of vindeburnol was abandoned. This review presents synthetic approaches to vindeburnol synthesis as well as the most complete discussion of its pharmacological effects. Studies involving vindeburnol in animal models of CNS disorders and a few human trials have been presented in separate sections. Special attention is placed on derivatives and analogs based on the vindeburnol scaffold. The interesting pharmacological profile of vindeburnol suggests that this NP-inspired compound may serve as a useful tool or structural basis for next-generation molecules in CNS drug design and discovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background/Objectives : Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in mediating anti-inflammatory and anticancer effects in the tumor microenvironment. Kaurenoic acid (KA), a diterpene compound isolated from Sphagneticola trilobata (L.) Pruski, has been demonstrated to exert anti-inflammatory, anticancer, and antihuman immunodeficiency virus effects. Methods : In this study, we identified KA as a novel activator of PPARγ with potent anti-inflammatory and antitumor effects both in vitro and in vivo. Given the potential of PPARγ regulators in overcoming radioresistance and chemoresistance in cancer therapies, we hypothesized that KA may enhance the efficacy of breast cancer radiotherapy. Results : In a lipopolysaccharide (LPS)-induced mouse inflammation model, KA treatment reduced the levels of pro-inflammatory cytokines, including COX-2, IL-6, IL-1β, and TNFα. In a xenograft mouse mode of breast cancer, KA treatment inhibited tumor growth. Specifically, KA treatment enhanced caspase-3 activity and cytotoxicity against MDA-MB-231 and MCF-7 breast cancer cells. When KA was co-treated with a caspase inhibitor, Z-VAD-FMK, caspase-dependent apoptosis was suppressed in these cells. KA was found to induce the generation of cytosolic calcium ions (Ca 2+ ) and reactive oxygen species (ROS), triggering endoplasmic reticulum (ER) stress via the PERK-ATF4-CHOP axis. Hence, the ER stressor thapsigargin (TG) synergized with KA treatment to enhance apoptosis in these cells, while the loss of the PERK or CHOP function inhibited this phenomenon. KA treatment was shown to induce oxidative stress via the NADPH oxidase 4 (NOX4) and stimulate ROS production. Specifically, NOX4 knockdown (KD) and antioxidant treatment (N-acetyl cysteine or diphenyleneiodonium) suppressed such ER stress-mediated apoptosis by inhibiting KA-enhanced caspase-3 activity, cytotoxicity, and intracellular ROS production in the treated cells. In radioresistant MDA-MB-231R and MCF-7R cells, KA combined with 2 Gy radiation overcame radioresistance by upregulating PPARγ and modulating epithelial-mesenchymal transition (EMT) markers, such as E-cadherin, N-cadherin, and vimentin. In PPARγ KD MDA-MB-231R and MCF-7R cells, this phenomenon was inhibited due to reduced PPARγ and NOX4 expression. Conclusions : In conclusion, these findings demonstrated KA as a novel PPARγ regulator with promising potential to enhance the efficacy of breast cancer radiotherapy.

Aberrant activation of the NLRP3 inflammasome contributes to the evolution of diverse inflammatory diseases. Inhibition of the NLRP3 inflammasome has been proven to be an effective treatment strategy for NLRP3-driven diseases. This study revealed that multiple natural diterpenes from Isodon plants can inhibit the NLRP3 inflammasome, among which Rosthornin B (Ros B) exhibited the best inhibitory effect, with an IC 50 of 0.39 μM. Further study revealed that Ros B directly interacts with NLRP3, thereby restraining NEK7-NLRP3 interaction and inhibiting NLRP3 inflammasome assembly and activation. Remarkably, Ros B had a significant therapeutic benefit in mouse models of NLRP3-driven septic shock, peritonitis, and colitis. Our study has identified a series of natural diterpenes that target the NLRP3 inflammasome. These natural diterpenes, especially those with low IC 50 values, may lead to the development of new drugs and potential clinical therapies for diseases driven by NLRP3 inflammasome activation., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Treating methicillin-resistant Staphylococcus aureus (MRSA) infection remains one of the most difficult challenges in clinical practice, primarily due to the resistance of MRSA to multiple antibiotics. Therefore, there is an urgent need to develop novel antibiotics with high efficacy and low cross-resistance rates. In this study, a series of novel pleuromutilin derivatives with coumarin structures were synthesized and subsequently assessed for their biological activities. Most of these derivatives showed potent antimicrobial activity against drug-resistant Gram-positive bacterial strains. Compound 14b displayed particularly rapid bactericidal effects, slow resistance development, and low cytotoxicity. Moreover, it decreased bacterial loads in the lung, liver, kidney, spleen, and heart and exhibited better antibacterial efficacy (ED 50 = 11.16 mg/kg) than tiamulin (ED 50 = 28.93 mg/kg) in a mouse model of systemic MRSA infection. Both in vitro and in vivo analyses suggest that compound 14b is a promising agent for the treatment of MRSA infections.

Covering: 2013 to 2023In an era where antimicrobial resistance severely threatens our ability to treat infections, the discovery of new drugs that belong to different chemical classes and/or bear original modes of action is urgently needed. In this case, diterpenoids comprise a productive field with a proven track record in providing new anti-infectives to tackle bacterial infections and malaria. This review highlights the potential of both naturally occurring and semi-synthetic bi- and tricyclic diterpenoids to become leads in search of new drugs to treat infections caused by bacteria, fungi, viruses and protozoan parasites. The literature from the last decade (2013-2023) is covered, focusing on naturally occurring and semi-synthetic bicyclic (labdanes and labdane-type) and tricyclic (all classes) diterpenoids, detailing their relevant biological activities in the context of infection, which are explained through structure-activity relationships.

Gastric cancer (GC) remains a significant global health challenge, particularly prevalent in East Asia. Despite advancements in various treatment modalities, the prognosis for patients, especially those in advanced stages, remains poor, highlighting the need for innovative therapeutic approaches. This review explores the promising potential of diterpenes, naturally occurring compounds with robust anticancer properties, derived from diverse sources such as plants, marine organisms, and fungi. Diterpenes have shown the ability to influence reactive oxygen species (ROS) generation, ferroptosis, and autophagy, positioning them as attractive candidates for novel cancer therapies. This review explores the mechanisms of action of diterpenes and their clinical implications for the treatment of GC. Additionally, it addresses the challenges in translating these compounds from preclinical studies to clinical applications, emphasizing the need for further research to enhance their therapeutic profiles and minimize potential side effects. The discussion underscores the importance of diterpenes in future anticancer strategies, particularly in the fight against gastric cancer.

Two new cembrane-derived tricyclic diterpenes belonging to the sarcophytin family, namely 4 a -hydroxy-chatancin ( 1 ) and sarcotoroid ( 2 ), together with two known related ones ( 3 and 4 ), were isolated from the soft coral Sarcophyton tortuosum collected off Ximao Island in the South China Sea. The structures of the new compounds were elucidated by extensive spectroscopic analysis, a quantum mechanical nuclear magnetic resonance (QM-NMR) method, a time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculation, X-ray diffraction analysis, and comparison with the reported data in the literature. A plausible biosynthetic pathway of compounds 1 - 4 was proposed, involving undergoing a transannular Diels-Alder cycloaddition. In the bioassay, the new compound 1 displayed significant inhibitory activities against the fish pathogens Streptococcus parauberis KSP28, oxytetracycline-resistant Streptococcus parauberis SPOF3K, and Photobacterium damselae FP2244, with MIC values of 9.1, 9.1, and 18.2 μg/mL, respectively. Furthermore, by conducting a luciferase reporter assay on rat liver Ac2F cells, compounds 1 , 3 , and 4 were evaluated for peroxisome proliferator-activated receptor (PPAR) transcriptional activity, and compound 3 showed selective PPAR-β agonist activity at a concentration of 10 μΜ.

The emergence of antibiotic resistance in pathogenic bacteria, including Salmonella gallinarum, poses a significant challenge to poultry health and food safety. In response, alternative strategies are urgently needed to mitigate bacterial infections without exacerbating antibiotic resistance. Phytoremediation, a sustainable and environmentally friendly approach, harnesses the natural detoxification capabilities of plants to remediate contaminants. This study explores the potential of combined phytoremediation using Andrographolide, derived from Andrographis paniculata, and Ajwain derived from Trachyspermum ammi as promising alternatives to antibiotics for treating Salmonella gallinarum infection in poultry. Andrographolide, known for its potent antimicrobial properties, exhibits inhibitory effects while Ajwain, rich in bioactive compounds, possesses antimicrobial and immunomodulatory properties. By leveraging their combined phytoremediation potential, Andrographolide and Ajwain offer a multifaceted approach to combat Salmonella gallinarum within the poultry environment. The study employed a rigorous experimental design, including in vitro assessments of antimicrobial susceptibility, cytotoxicity, and optimal concentration determination. Following this, in vivo experiments were conducted using a chicken model infected with Salmonella gallinarum. Results demonstrated that the selected combinations effectively reduced mortality rates, alleviated clinical symptoms, and mitigated gross pathological signs associated with Salmonella infection. Gene expression studies indicated a downregulation of proinflammatory cytokines, underscoring potential implications of a combined phytoremediation strategy as an innovative and sustainable solution to address Salmonella gallinarum infections in poultry production systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Ethnopharmacological Relevance: Glioblastoma (GB) is the most aggressive and prevalent glioma within the central nervous system. Despite considerable efforts, GB continues to exhibit a dismal 5-year survival rate (∼6%). This is largely attributed to unfavorable prognosis and lack of viable treatment options. Therefore, novel therapies centered around plant-derived compounds emerge as a compelling avenue to enhance patient survival and well-being. The South African species, Plectranthus hadiensis Schweinf. (P. hadiensis), a member of the Lamiaceae family, has a history of use in traditional medicine for treating a range of diseases, including respiratory, digestive, and liver disorders. This species exhibits diverse biological activities, such as anti-inflammatory and antitumoral properties, likely attributed to its rich composition of naturally occurring diterpenes, like the abietane diterpene, 7α-acetoxy-6β-hydroxyroyleanone (Roy). Roy has demonstrated promising antitumor effects in various cancer cell lines, making it a compelling candidate for further investigation into its mechanisms against GB., Aim of the Study: This study aims to investigate the antitumor activity and potential mechanism of Roy, a natural lead compound, in GB cells., Material and Methods: Roy was isolated from the acetonic extract of P. hadiensis and its antitumor mechanism was assessed in a panel of human GB cell lines (U87, A172, H4, U373, and U118) to mimic tumor heterogeneity. Briefly, the impact of Roy treatment on the metabolic activity of cells was evaluated by Alamar Blue® assay, while cell death, cell cycle regulation, mitochondrial membrane potential, and activated caspase-3 activity were evaluated by flow cytometry. Measurement of mRNA levels of target genes was performed by qPCR, while protein expression was assessed by Western blotting. Cell uptake and impact on mitochondrial morphology were evaluated by confocal microscopy., Results: Roy induced G 2 /M cell cycle arrest, mitochondrial fragmentation, and apoptosis by inhibiting the expression of anti-apoptotic proteins and increasing the levels of activated caspase-3. The concentrations of Roy needed to achieve significant inhibitory outcomes were notably lower (6-9 fold) than those of temozolomide (TMZ), the standard first-line treatment, for achieving comparable effects. In addition, at low concentrations (16 μM), Roy affected the metabolic activity of tumor cells while having no significant impact on non-tumoral cells (microglia and astrocytes)., Conclusion: Overall, Roy demonstrated a robust antitumor activity against GB cells offering a promising avenue for the development of novel chemotherapeutic approaches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. While triptolide (TPL) and curcumin (CUR) are known to have multiple beneficial effects on RA, the combined effect of TPL and CUR remains unexplored. This study aimed to investigate their synergistic effect on cell proliferation and apoptosis via the IL-17/NF-κB signaling pathway. The collagen-induced arthritis (CIA) rat model was established, showing severe joint and synovial damage compared to normal rats. Treatment with TPL and CUR reduced the severity of RA in the CIA rat model and alleviated serum inflammatory cytokines, such as rheumatoid factor, IL-17, TNF-α, IL-1β, and IL-6. The elevated levels of IL-17 and NF-κB in CIA rats were also inhibited, and the resistant apoptosis was aggravated by TPL and CUR. In vitro, the improvement of cell proliferation and induction of apoptosis were observed in LPS-stimulated MH7A cells treated with TPL and CUR, associated with the inhibition of the IL-17/NF-κB signaling pathway. Taken together, a synergistic effect of TPL and CUR on RA may involve relieving symptoms, improving excessive proliferation, inducing apoptosis resistance, and inhibiting the IL-17/NF-κB signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Modern pharmacological studies have demonstrated that although triptolide (TP) is effective against hepatocellular carcinoma, it has poor water solubility and more toxic side effects. In this study, we used triptolide (TP), a bioactive constituent in Tripterygium wilfordii Hook F, as a model drug to develop a novel nano-liposome drug delivery system for the treatment of liver tumours., Methods: We constructed a functionally-modified triptolide liposome (FA+TPP-TP-Lips) using the film-dispersion method and investigated its physicochemical properties, mitochondrial targeting of hepatic tumour cells, in vitro and in vivo anti-hepatic tumour activity and its mechanism., Results: The prepared FA+TPP-TP-Lips had a particle size of 99.28 ± 5.7 nm, a PDI of 0.20 ± 0.02, a zeta potential of 1.2 ± 0.08 mV, and an encapsulation rate of 74.37% ± 1.07%.FA+TPP-TP-Lips facilitates the cellular uptake of drug delivery systems and improves their targeted delivery to mitochondria. The results of cell efficacy showed that FA+TPP-TP-Lips significantly inhibited the growth of liver cancer cells, decreased mitochondrial membrane potential, and increased intracellular ROS, thus enhancing the highest apoptosis rate of liver cancer cells. The targeted liposomes (FA-TP-Lips, TPP-TP-Lips, and FA+TPP-TP-Lips) had some degree of inhibitory migration effect on Huh-7 cells relative to the unmodified TP-Lips. Studies on tumor-bearing mice demonstrated that FA+ TPP-TP-Lips effectively accumulated in tumor tissues and significantly inhibited the growth of subcutaneous tumors, achieving a tumor inhibition rate of 79.37%. FA+ TPP-TP-Lips demonstrated an enhanced anti-liver tumor effect and significantly mitigated the hepatotoxicity and systemic toxicity associated with TP., Conclusion: In summary, the results of this study can provide a feasible solution for improving the mitochondrial targeting of nano-liposomes, and lay a foundation for further developing a novel nano targeting preparation of triptolide for the treatment of hepatocellular carcinoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Zhou et al.)

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Promoting endogenous neurogenesis for brain repair is emerging as a promising strategy to mitigate the functional impairments associated with various neurological disorders characterized by neuronal death. Diterpenes featuring tigliane, ingenane, jatrophane and lathyrane skeletons, frequently found in Euphorbia plant species, are known protein kinase C (PKC) activators and exhibit a wide variety of pharmacological properties, including the stimulation of neurogenesis. Microbial transformation of these diterpenes represents a green and sustainable methodology that offers a hitherto little explored approach to obtaining novel derivatives and exploring structure-activity relationships. In the present study, we report the biotransformation of euphoboetirane A (4) and epoxyboetirane A (5), two lathyrane diterpenoids isolated from Euphorbia boetica, by Mucor circinelloides MC NRRL3631. Our findings revealed the production of nine biotransformation products (6-14), including jatrophane derivatives originated through an unprecedented rearrangement from the parent lathyranes. The chemical structures and absolute configurations of the new compounds were elucidated through comprehensive analysis using NMR and ECD spectroscopy, as well as MS. The study evaluated how principal metabolites and their derivatives affect TGFα and NRG1 release, as well as their potential to promote proliferation or differentiation in cultures of NSC isolated from the SVZ of adult mice. In order to shed some light on the mechanisms underlying the ability of 12 as a neurogenic compound, the interactions of selected compounds with PKC δ-C1B were analyzed through molecular docking and molecular dynamics. Based on these, it clearly appears that the ability of compound 12 to form both acceptor and donor hydrogen bonds with certain amino acid residues in the enzyme pocket leads to a higher affinity compound-PKC complex, which correlates with the observed biological activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Epoxytiglianes are a novel class of diterpene esters. The prototype epoxytigliane, EBC-46 (tigilanol tiglate), is a potent anti-cancer agent in clinical development for local treatment of a range of human and animal tumors. EBC-46 also consistently promotes wound re-epithelialization at the treatment sites, mediated via activation of classical protein kinase C (PKC) isoforms. We have previously shown that epoxytiglianes stimulate proliferative and wound repopulation responses in immortalized human skin keratinocytes (HaCaTs) in vitro, abrogated by pan-PKC inhibitor, bisindolylmaleimide-1. In this study, we further investigate the specific PKC isoforms responsible for inducing such wound healing responses, following HaCaT treatment with 1.51 nM-15.1 µM EBC-46 or analogue, EBC-211. Classical PKC inhibition by GӦ6976 (1 μM), significantly attenuated epoxytigliane induced, HaCaT proliferation and wound repopulation at all epoxytigliane concentrations. PKC-βI/-βII isoform inhibition by enzastaurin (1 μM), significantly inhibited HaCaT proliferation and wound repopulation responses induced by both epoxytiglianes, especially at 1.51-151 nM. PKC-α inhibitor, Ro 31-8220 mesylate (10 nM), exerted lesser inhibitory effects on HaCaT responses. Epoxytigliane changes in key keratin (KRT17) and cell cycle (cyclin B1, CDKN1A) protein levels were partly attenuated by GӦ6976 and enzastaurin. GӦ6976 also inhibited increases in matrix metalloproteinase (MMP-1, MMP-7, MMP-10) activities. Phospho-PKC (p-PKC) studies confirmed that epoxytiglianes transiently activated classical PKC isoforms (p-PKCα, p-PKC-βI/-βII, p-PKCγ) in a dose- and time-dependent manner. By identifying how epoxytiglianes stimulate classical PKCs to facilitate keratinocyte healing responses and re-epithelialization, these findings support further epoxytigliane development as topical therapeutics for clinical situations involving impaired re-epithelialization, such as non-healing wounds in skin., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was conducted with financial support from QBiotics Group. P.R. and V.G. are employees and possess ownership interests in QBiotics Group. R.M., R.S., R.L.M., P.R., V.G., G.M.B. and QBiotics Group have filed patents on the work disclosed within this manuscript. E.L.W., J.D., J.P.J. and V.K. have no conflict of interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nine previously unreported lathyrane diterpenoids named euphorantesters A-I, along with 16 known analogues, have been separated from the tubers of Euphorbia antiquorum. Their structures were established by means of spectroscopic analyses, time-dependent density functional theory based electronic circular dichroism calculation and single crystal X-ray crystallography. Their reversal ability against P-glycoprotein-mediated multidrug resistance (MDR) in MCF-7/ADR cell line was then evaluated, and 15 ones exhibited moderate MDR reversal activity with reversal fold falling in the range of 1.12-13.15. The most active euphorantester B could effectively increase the sensitivity of MCF-7/ADR cell to adriamycin comparably to the reference drug verapamil., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Two previously undescribed natural cyathane diterpenoids Me-dentifragilin A ( 1 ) and Epi-neocyathin O ( 2 ), and three known cyathane diterpenoids 3 - 5 , cyathin O, neocyathin P, and cyathin I, were isolated from the rice medium of the Cyathus striatus CBPFE A06. Their structures were established by NMR spectra, and HR-ESI-MS. Compounds 1 - 5 displayed encouraging neurotrophic activity in PC-12 cells at doses of 5 µM. Meanwhile, 1 - 5 significantly inhibited LPS-induced NO generation in BV2 cells with the IC 50 values ranging from 2.44 ± 0.16 to 4.33 ± 0.32 μM. Western blot analysis showed that 2 and 4 inhibited the expression of genes involved in nitric oxide (NO) production. Molecular docking revealed that five residues of inducible NO synthase (iNOS) are key residues affecting the interaction of 2 and 4 with iNOS. This study enriches the structural diversity of cyathane diterpenes and adds to the evidence that cyathane diterpenes prevent and treat neurodegenerative diseases.

Background: Leukemia is one of the most lethal cancers worldwide and represents the sixth-leading cause of cancer deaths. The results of leukemia treatment have not been as positive as desired, and recurrence is common., Purpose: Thus, there is an urgent requirement for the development of new therapeutic drugs. Salvia multicaulis (Bardakosh) is a widespread species that contains multiple phytochemical components with anti-cancer activities., Methods: We isolated and characterized the major diterpene candesalvone B methyl ester from S. multicaulis and investigated its action as a cytotoxic agent towards sensitive and drug-resistant leukemia cells by the resazurin reduction assay. Additionally, the targeted genes and the affected molecular mechanisms attributed to the potent cytotoxic activities were discovered by transcriptome-wide mRNA expression profiling. The targets predicted to be regulated by candesalvone B methyl ester in each cell line were confirmed by qRT-PCR, molecular docking, microscale thermophoresis, and western blotting. Moreover, cell cycle distribution and apoptosis were analyzed by flow cytometry., Results: Candesalvone B methyl ester was cytotoxic with IC 50 values of 20.95 ± 0.15 µM against CCRF-CEM cells and 4.13 ± 0.10 µM against multidrug-resistant CEM/ADR5000 leukemia cells. The pathway enrichment analysis disclosed that candesalvone B methyl ester could regulate the heat-shock response signaling pathway via targeting heat shock factor 1 (HSF1) in CCRF-CEM cells and ELOVL fatty acid elongase 5 (ELOVL5) controls the fatty acid metabolism pathway in CEM/ADR5000 cells. Microscale thermophoresis showed the binding of candesalvone B methyl ester with HSF1 and ELOVL5, confirming the results of molecular docking analysis. Down-regulation of both HSF1 and ELOVL5 by candesalvone B methyl ester as detected by both western blotting and RT-qPCR was related to the reversal of drug resistance in the leukemia cells. Furthermore, candesalvone B methyl ester increased the arrest in the sub-G1 phase of the cell cycle in a dose-dependent manner from 1.3 % to 32.3 % with concomitant induction of apoptosis up to 29.0 % in CCRF-CEM leukemic cells upon inhibition of HSF1., Conclusion: Candesalvone B methyl ester isolated from S. multicaulis exerted cytotoxicity by affecting apoptosis, cell division, and modulation of expression levels of genes contributing to the heat stress signaling and fatty acid metabolism pathways that could relieve drug resistance of leukemia cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Both human beings and animals around the globe are vulnerable to the transmission of infectious diseases carried by mosquitoes. They have the ability to transmit a diverse array of pathogenic agents, such as viruses and parasites, while feeding on blood. The objective of this research is to investigate andrographolide isolation, characterization, and structure elucidation from Andrographis paniculata. Furthermore, it aims to evaluate the activity of andrographolide against the immature stages of Aedes aegypti and Culex quinquefasciatus. The fractions obtained from A. paniculata extracts underwent further purification and analysis to identify the most active ones. To confirm the structure of andrographolide, spectroscopic methods including IR, 1 H-NMR, 13 C-NMR, and GC-MS were used. Biological assays were conducted to assess its ovicidal, larvicidal, and pupicidal activities. Importantly, andrographolide demonstrated moderate ovicidal activity, resulting in mortality rates of 36% and 32% in Ae. aegypti and Cx. quinquefasciatus eggs, respectively, at a concentration of 2 ppm. Additionally, it exhibited strong larvicidal and pupicidal efficacy, with LC 50 values of 2.02 ppm and 3.19 ppm against Ae. aegypti larvae and pupae, and 2.14 ppm and 2.73 ppm against Cx. quinquefasciatus larvae and pupae. These findings highlight the potential of andrographolide as a powerful natural compound in mosquito control efforts. Furthermore, this study underscores the importance of natural products as viable alternatives to synthetic insecticides in managing vector-borne diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tripterygium hypoglaucum (Lévl.) Hutch rhizome (THH) is mainly used in the clinical setting for the treatment of autoimmune diseases such as rheumatoid arthritis. In total, four active compounds were isolated from THH methanol extract （THH-MeOH）and identified. The HPLC results showed that the proportions of the active ingredients in THH-MeOH (i.e., celastrol, triptolide, and 3-O-acetyloleanolic acid) were 0.79 ‰, 0.46 ‰, and 0.76 ‰, respectively. THH-MeOH attenuated the M5-induced hyperproliferation of HaCaT cells, decreased the mRNA expression levels of inflammatory cytokines, and inhibited the phosphorylation of IκBα, NF-κB p65, MAPK, and STAT3/JAK2. Furthermore, THH-MeOH significantly reduced PASI scores in mice; reduced the level of Ki67 expression in skin tissues; decreased the expression of inflammatory cytokines in the skin lesions and serum; and ameliorated the IMQ-induced imbalance in the RORγt/Foxp3 ratio. The extract can attenuate psoriasis-like lesions by inhibiting cellular hyperproliferation, ameliorating inflammatory reactions, and modulating immune responses. Our work provides a theoretical basis to support the use of THH for treating psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Acute lung injury (ALI) remains a devastating clinical condition with limited therapeutic options. While Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2) has emerged as a critical mediator in ALI pathogenesis, effective SHP2-targeting therapeutics remain largely elusive. Baliospermum solanifolium (Burm.) is a traditional medicine used to treat various diseases such as asthma, edema, bronchitis, jaundice, and constipation. Baliosperoid A (BA), a diterpenoid compound derived from Baliospermum solanifolium's roots, exhibits potent NO inhibitory activity in RAW264.7 cells. However, its anti-inflammatory activity and potential targets have never been reported. Here, we report BA acts as a selective SHP2 inhibitor with remarkable therapeutic potential against ALI. Through comprehensive molecular and functional analyses, we demonstrate that BA directly binds to and inhibits SHP2 phosphatase activity with high specificity (IC 50  = 1.638 ± 0.324 μM). Mechanistically, BA orchestrates a dual-action therapeutic effect by simultaneously suppressing inflammatory cascades through SHP2-mediated MAPK and NF-κB pathway inhibition while activating the Nrf2-dependent antioxidant response. In preclinical models of ALI and sepsis, BA treatment significantly improved survival rates, preserved lung architecture, and prevented multi-organ dysfunction. Notably, BA demonstrated superior efficacy to the existing SHP2 inhibitor SHP099, particularly in sepsis survival outcomes (90 % vs 50 % survival at 24 h). Our findings not only identify BA as a promising therapeutic candidate for ALI but also establish a novel paradigm for targeting SHP2 in inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Age-related dysfunction of salivary glands (SGs) leading to xerostomia or dry mouth is typically associated with increased dental caries and difficulties in mastication, deglutition or speech. Inflammaging-induced hyposalivation plays a significant role in aged SGs; however, the mechanisms by which ageing shapes the inflammatory microenvironment of SGs remain unclear. Here, we show that reduced salivary secretion flow rate in aged human and mice SGs is associated with impaired autophagy and increased M1 polarization of macrophages. Our study reveals the crucial roles of SIRT6 in regulating macrophage autophagy and polarization through the PI3K/AKT/mTOR pathway, as demonstrated by generating two conditional knock out mice. Furthermore, triptolide (TP) effectively rejuvenates macrophage autophagy and polarization via targeting this pathway. We also design a local delivery of TP-loaded apoptotic extracellular vesicles (ApoEVs) to improve age-related SGs dysfunction therapeutically. Collectively, our findings uncover a previously unknown link between SIRT6-regulated autophagy and macrophage polarization in age-mediated hyposalivation, while our locally therapeutic strategy exhibits potential preventive effects for age-related hyposalivation., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Phytochemical study on the methanol extract of the stems of Tinospora crispa (L.) Hook.f. & Thomson led to the isolation of thirteen compounds including three undescribed cis-clerodane-type furanoditerpenoids (1-3) and ten known ones (4-13). Their chemical structures were determined by IR, HR-ESI-MS, 1D-, and 2D-NMR spectra. Compounds 2-4, 6 and 8 inhibited moderately NO production in LPS activated RAW 264.7 cells with the IC 50 values of 83.5, 57.6, 75.3, 78.1, and 74.7 μM, respectively., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

One new lathyrane-type diterpenoid, euphlathin A ( 1 ), and 11 known analogues ( 2-12 ), were isolated from the fruits of Euphorbia lathyris . Their structures were elucidated by spectroscopic data. The absolute configurations of 1 were established by single-crystal X-ray crystallography. All diterpenoids ( 1-12 ) were evaluated for antiproliferative activity against the human hypertrophic scar (HTS) cells. Compound 1 exhibited significantly against HTS cells growth with an IC 50 value of 6.33 μM. Morphological features of apoptosis were evaluated in 1 -treated HTS cells. Wound healing assays indicated that 1 significantly inhibited the migration of HTS at 24 h and 48 h. Compound 1 effectively induced apoptosis of HTS, which was associated with G 2 /M or S phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 1 significantly induced HTS cell apoptosis in a dose-dependent manner. Overall, euphlathin A ( 1 ) has the potential to be a therapeutic agent for the treatment of hyperplastic scar therapy.

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Beside early detection, early diagnosis, and early surgery, it is urgent to try new strategies for the treatment of HCC. Triptolide (TPL) has been employed to treat HCC. However, its clinical applications were restricted by the narrow therapeutic window, severe toxicity, and poor water-solubility. In this study, we developed cancer cell membrane-camouflaged biomimetic PLGA nanoparticles loading TPL (TPL@mPLGA) with the homologous targeting property for the treatment of HCC. The TPL@mPLGA was successfully prepared with particle size of 195.5 ± 7.5 nm and zeta potential at -21.5 ± 0.2 mV with good stability. The drug loading (DL) of TPL@mPLGA was 2.94%. After Huh-7 cell membrane coating, the natural Huh-7 cell membrane proteins were found to be retained on TPL@mPLGA, thus endowing the TPL@mPLGA with enhanced accumulation at tumor site, and better anti-tumor activity in vitro and in vivo when compared with TPL or TPL@PLGA. The TPL@mPLGA showed enhanced anti-tumor effects and reduced toxicity of TPL, which could be adopted for the treatment of HCC.

Objective: This study aims to explore the effects of Triptolide (TP) on the differentiation of Th17 cells in ankylosing spondylitis (AS)., Methods: Peripheral blood mononuclear cells (PBMCs) collected from 10 patients with active AS patients were exposed to TP, GSK-J4 or vehicle. T lymphocyte subsets were analyzed using flow cytometry. ELISA was used to assess the level of IL-17. Western blot analysis and quantitative RT-PCR were used to measure the mRNA and protein levels of RORγt, JMJD3, EZH2, JAK2 and STAT3 in the JAK2/STAT3 signaling pathway., Results: We observed a tendency toward a greater percentage of IL-17-positive CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with active AS than in those from healthy controls. Triptolide (TP) and GSK-J4 significantly reduced IL-17 expression. In cultured PBMCs from patients with active AS, 24 h of treatment with TP or GSK-J4 decreased the expression of RORγt ( p  < 0.05), JAK2 and STAT3 (JAK2: p  < 0.05; STAT3: p  < 0.05). Furthermore, both triptolide and GSK-J4 increased the level of histone 3 with Lys 27 trimethylation (H3K27me3) in patient-derived PBMCs. H3K27me3 enrichment was detected at the promoters of the RORc, STAT3 and IL-17 genes. Consistent with this finding, triptolide upregulated the EZH2 gene and downregulated the JMJD3 gene., Conclusion: Triptolide inhibits Th17 cell differentiation via H3K27me3 upregulation and orchestrates changes in histone-modifying enzymes, including JMJD3 and EZH2. These findings support the clinical efficacy of triptolide for AS and may provide clues for identifying molecular targets for the development of novel treatments.

Background: Triptolide (TP) has been confirmed to possess many beneficial functions including anti-inflammation and immunosuppression., Objective: The present study aimed to explore the potential involvement of IL-2/IL-2R pathway in the immunosuppressive activities of TP., Methods: Cultured CTLL-2 cells were utilized to evaluate the potential benefits of TP. Then cell viability was determined by CCK-8 assay, IFN-γ level by ELISA assay, Annexin V-FITC/PI double-staining and CD25 expression by flow cytometry, and protein expression by western blotting. Additionally, rhIL-2-driven lymphocytes following ConA activation were investigated. The interactions of TP with IL-2 and IL-2Rα were investigated by binding assays and molecular dynamics simulations., Results: TP treatment attenuated IFN-γ level and cell viability in both rhIL-2-induced CTLL-2 cells and rhIL-2-driven splenic lymphocytes. TP treatment increased cellular apoptosis/necrosis and cleaved PARP-1 level, while suppressed c-Myc level in rhIL-2-induced CTLL-2 cells. Additionally, TP treatment reduced CD25 expression on CTLL-2 cell surface. Notably, the phosphorylation protein levels in IL-2R signaling pathways were inhibited by TP exposure prior to rhIL-2 stimulation. SPR and BLI assays verified TP that directly bound to rhIL-2 and rmIL-2Rα, respectively. Molecular simulations suggested that TP bound at the interface of IL-2 and IL-2Rα near the hydrophobic patch composed of F62, L92 on IL-2 and L23, I46, V139 on IL-2Rα, resulting in decreased binding free energy between IL-2 and IL-2Rα., Conclusions: These findings collectively emphasized that TP interfered IL-2/IL-2Rα interactions, down-regulated IL-2Rα expression, and inhibited IL-2R signaling pathways activation, thereby leading to the immune cells being desensitized to rhIL-2 and exhibiting immunosuppressive properties.

Propolis is a natural product widely used in folk medicine. Among its various applications, its antiparasitic properties stand out. Due to its great biodiversity, Brazil is a major producer of several types of propolis. This study proposes to evaluate the leishmanicidal properties of the hydroalcoholic extract of propolis collected in the southern region of Brazil (Brown propolis - HEBP) and its main isolated compounds: abietic acid (1), 13-epi-cupressic acid (2), 13-epi-torulosol (3), dehydroabietic acid (4), cis -communic acid (5) and ent -agatic acid (6). In general, the diterpenes did not show activity against the promastigotes of Leishmania ( Leishmania ) amazonensis at the evaluated concentrations. However, the HEBP was very active with an inhibition concentration of 50% at 8.32 µg/mL. Moreover, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) assays showed morphological and structural alterations in promastigote forms of L . ( L. ) amazonensis when incubated with HEBP.

Aim: The tumor microenvironment in pancreatic cancer, characterized by abundant desmoplastic stroma, has been implicated in the failure of chemotherapy. Therefore, developing therapeutic strategies targeting tumor and stromal cells is essential. Triptolide, a natural compound derived from the plant Tripterygium wilfordii, has shown antitumor activity in various cancers, including pancreatic cancer. However, its effects on pancreatic cancer cells and the microenvironment remain unclear. This study aimed to explore the effect of triptolide on tumor cells and the tumor microenvironment in pancreatic cancer., Methods: Cell Counting Kit-8, colony formation, apoptosis, and cell cycle assays were performed to determine the effect of triptolide on tumor cells. Additionally, co-culture assays were performed to explore the effects of the compound on cancer-associated fibroblasts (CAFs) in vitro. Orthotopic xenograft and subcutaneous tumor models were used to explore the antitumor and antistromal activation effects of triptolide in vivo. RNA sequencing was performed to identify the pathways involved in these processes in pancreatic cancer cells., Results: Triptolide inhibited the proliferation of pancreatic cancer cells and attenuated stromal activation in vitro and in vivo. Furthermore, it suppressed autophagy and induced apoptosis in pancreatic cancer cells by inhibiting the secretion of CXCL1. Extracellular matrix formation in CAFs was disrupted by suppressing the paracrine secretion of TGF-β from tumor cells., Conclusion: These findings indicate that triptolide plays a dual antitumor role against tumor cells and CAFs, thus providing new insights into treating pancreatic cancer in the future., (Copyright © 2025 Journal of Cancer Research and Therapeutics.)

The metabolites from the endophytic fungus Talaromyces malicola hosted in the gastrointestinal tract of the arthropods Armadillidium vulgare were investigated, and six undescribed fusicoccane diterpenoids, talarmalnoids A-F (1-6), along with three known analogs were isolated. Talarmalnoid C (3) was an unprecedented fusicoccane diterpenoid with two sugar units, i.e., 6-O-methyl-α-d-glucose and α-d-glucose. Talarmalnoids D and E (4 and 5) were fusicoccane-type diterpenoids with unusual seven-membered rings attached at the C-3' and C-4' positions. Their structures and absolute configurations were identified by NMR, HRESIMS analyses, X-ray single crystal diffraction, GC-MS, ECD analyses, 13 C NMR calculations, and DP4+ probability analyses. Bioassay results showed that talarmalnoid B (2) exhibited significant inhibitory activities against the LPS-inducted production of NO in RAW 264.7 cells, with IC 50 value of 0.83 μM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids ( 1 - 8 ), including a new one with a rarely occurring α,β-unsaturated diketone C-ring, were isolated from O. aristatus . Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives ( 9-15 ). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1β, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.

Background: Cerebral ischemia (CI), a cerebrovascular disorder, is a major contributor to disability and mortality. Marine-derived compounds are an important source of new neuroprotective drug candidates. Xenicane-type diterpenes from brown algae of the genus Dictyota have exhibited potential neuroprotective effects against CI injury, attributed to their antioxidant properties. However, whether there are other underlying neuroprotective mechanisms of xenicane diterpenes against CI is still ambiguous., Purpose: This study aims to elucidate the neuroprotective efficacy and mechanism of 4-hydroxydictyolactone (HDTL) in the treatment of CI., Methods: The LPS-induced BV2 cell model was used for anti-neuroinflammatory activity assay. Tandem Mass Tag (TMT)-based quantitative proteomics was employed to identify underlying mechanisms. The OGD/R-induced SH-SY5Y cell model and a MCAO mice model were used to assess the neuroprotective effect of HDTL against CI in vitro and in vivo., Results: HDTL reduced inflammation in LPS-stimulated BV2 cells by inhibiting the IKK/IκB/NF-κB pathway and by enhancing AMPK phosphorylation. Additionally, in SH-SY5Y cells treated with OGD/R, HDTL facilitated autophagy and reduced apoptosis. The neuroprotective properties of HDTL were abrogated in AMPK- silenced SH-SY5Y cells. In MCAO mice, HDTL ameliorated CI injury as evidenced by decreases in neurological deficit scores and cerebral infarction. HDTL also promoted autophagy and reduced apoptosis in vivo through both the AMPK/mTOR and IKK/IκB/NF-κB pathways., Conclusion: HDTL exhibits neuroprotective effects through regulating the AMPK/mTOR and IKK/IκB/NF-κB pathways. These findings suggest that HDTL is a promising therapeutic candidate for CI treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In this study, four franchetine-type diterpenoid alkaloids (1-4) were isolated from Aconitum sinoaxillare, and fourteen diverse franchetine analogs (5-18) were synthesized. Compounds 1, 2, 7 and 16 exhibited stronger inhibitory effects on NO production when compared to celecoxib. Among them, compound 1 had the best inhibitory effect on iNOS and COX-2 inflammatory proteins. The in vitro studies displayed that the anti-inflammatory effect of the most active compound 1 was ascribed to the inhibition of the TLR4-MyD88/NF-κB/MAPKs signalling pathway. Consequently, this led to a inhibition in the expression of inflammatory factors or mediators including NO, ROS, TNF-α, IL-6, IL-1β, iNOS, and COX-2. Additionally, compound 1 had low toxicity (LD 50  > 20 mg/kg) in mice, and it had notable analgesic effects on acetic acid-induced visceral pain (ED 50  = 2.15 ± 0.07 mg/kg). Moreover, compound 1 exhibited a distinct reduction in the Na V 1.7 and Na V 1.8 channel currents during both resting and half-inactivated states at 50 μM. The present study enriches the pharmacological activities of franchetine derivatives and provides valuable insights for the development of novel anti-inflammatory and analgesic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Glioblastoma (GBM) recurrence leads to high mortality, which remains a major concern in clinical therapy. Herein, an injectable triptolide (TP)-preloaded hydrogel (TP@DNH) accompanied by a postoperative injection strategy is developed to prevent the recurrence of GBM. With a potential inhibitor of the NRF2/SLC7A11/GPX4 axis, it is demonstrated that TP can deactivate glutathione peroxidase 4 (GPX4) from the source of glutathione (GSH) biosynthesis, thereby activating ferroptosis in GBM cells by blocking the neutralization of intracellular lipid peroxide (LPO). Based on acid-sensitive Fe 3+ /tannic acid (TA) metal-phenolic networks (MPNs), the TP@DNH hydrogel can induce the effective generation of reactive oxygen species (ROS) through Fe 3+ /TA-mediated Fenton reaction and achieve controllable release of TP in resected GBM cavity. Due to ROS generation and GPX4 deactivation, postoperative injection of TP@DNH can achieve high-level ferroptosis through dual-pathway LPO accumulation, remarkably suppressing the growth of recurrent GBM and prolonging the overall survival in orthotopic GBM relapse mouse model. This work provides an alternative paradigm for regulating ferroptosis in the postoperative treatment of GBM., (© 2024 Wiley‐VCH GmbH.)

Fourteen undescribed diterpenoids, including eleven lathyrane diterpenoids wallathyanes A-K (1-11) and three ent-isopimarane diterpenoids wallisopiranes A-C (12-14), together with fourteen known analogues 15-28, were obtained from the whole plant of Euphorbia wallichii. Their chemical structures were elucidated by spectroscopic data analysis, experimental electronic circular dichroism measurements, and X-ray crystallography. Bioactivity screening indicated that compound 2 exhibited an inhibitory effect on NO generation in LPS-stimulated RAW264.7 macrophage cells with an IC 50 value of 4.76 ± 1.08 μM. The network pharmacology and molecular docking studies also revealed that compound 2 can bind with the potential targets GRB, AKT1, MAPK1, MAPK14, HSP90AA1, PIK3R1, PIK3CB, PRKACA, SRC, CASP3, RXRA, PTPNA11, ZAP70, and PRKC of inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The management of non-small cell lung cancer (NSCLC) often includes the use of radiotherapy, with individual outcomes being impacted by the tumor's response to this treatment modality. Cephalomannine (CPM), a taxane diterpenoid found in Taxus spp, has been found to have anti-tumor activity. This study was aim to the explore the role and mechanism by which CPM affects radiotherapy resistance in NSCLC., Methods: H460 cells were pretreated with different doses of CPM. H460 cells were transfected with β-catenin overexpression plasmids. The cell viability, colony-forming ability, migration ability, and sphere-forming ability and apoptosis of the cells were measured by using CCK-8, colony-forming, transwell, and sphere-forming assay and flow cytometry. Western blot assay was employed to detect the expression of β-catenin and BMP2., Results: The cell viability, proliferation, migration and sphere-forming ability of cells in the radiotherapy-resistant (RR) group were significantly higher than those in the radiotherapy-sensitivity (RS) group. Conversely, the apoptosis rate of cells in the RR group was lower than that in the RS group. However, after CPM pretreatment of RR group cells, the above phenomena were reversed in a CPM dose-dependent manner. Subsequently, pretreatment with CPM resulted in a decrease in the expression levels of β-catenin and BMP2 in the RR group. In addition, overexpression of β-catenin mitigated the inhibitory effects of CPM on radiotherapy-resistant NSCLC cells., Conclusion: CPM has the potential to decrease radiotherapy resistance in NSCLC cells by inhibiting the β-catenin-BMP2 signaling pathway, promoting apoptosis, and ultimately impeding cell growth., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Two new indole-diterpenoids, penpaxilloids F and G (1 and 2), along with 11 known analogues (3-13), were isolated from the marine fungus Penicillium sp. ZYX-Z-718. The structures of the new compounds were identified by extensive spectroscopic analyses including HR-ESI-MS, UV, and NMR, as well as theoretical NMR chemical shifts and ECD calculations. Compounds 6 and 10 showed antibacterial activity against Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, and MRSA with MIC values ranging from 16.0-32.0 μg/mL., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The phytochemical investigation of the leaves and the roots of Suregada procera afforded the new ent-abietane diterpenoid sureproceriolide A (1) along with the known secondary metabolites 8,14β:11,12α-diepoxy-13(15)-abietane-16,12-olid (2), jolkinolide A (3), jolkinolide E (4), ent-pimara-8(14),15-dien-19-oic acid (5), sitosterol (6), oleana-9(11):12-dien-3β-ol (7), and oleic acid (8). Their structures were elucidated by NMR spectroscopic and mass spectrometric analyses, and the structure of jolkinolide A (3) was confirmed by single-crystal X-ray diffraction analysis. Sureproceriolide A (1) showed modest activity against the Gram-positive bacterium Staphylococcus lugdunensis (MIC = 31.44 μM), and sitosterol (6) against the Gram-negative bacterium Porphyromonas gingivalis (IC 50  = 45.37 μM). Jolkinolide A (3) and E (4) as well as sitosterol (6) inhibited the release of NOS (IMR-90 cells), TNF-α (HaCaT cells) and NF-κB (HaCaT cells), with IC 50 values of 0.43, 3.21, and 10.32 μM, respectively. Compound 6 showed antitumoral activity against SK-MEL-28 (IC 50  = 20.66 μM) and CCD-13Lu (IC 50  = 24.70 μM) cell lines, with no cytotoxic effect against the prostate cells PrEC (CC 50  > 300 μM)., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2024. Published by Elsevier B.V.)

Background: Marine diterpenes represent a promising reservoir for identifying potential anti-rheumatoid arthritis (RA) candidates. Praelolide is a gorgonian-derived briarane-type diterpenoid with antioxidative and anti-osteoclastogenetic properties., Objective: This study aims to evaluate the therapeutic efficacy of praelolide against RA and investigate its underlying mechanisms both in vivo and in vitro., Method: Collagen-induced arthritis (CIA) mice and human RA fibroblast-like synoviocyte MH7A cells were employed for bioassays. The VisuGait system was utilized to assess gait dysfunction resulting from joint pain. Histopathological changes in ankle and synovial tissues were evaluated using micro-computed tomography, hematoxylin and eosin staining, Safranin-O/Fast Green staining, tartrate resistant acid phosphatase staining, and immunohistochemistry. Fluorescence spectroscopy, circular dichroism, and surface plasmon resonance were employed to investigate interactions between praelolide and catalase. The production of inflammatory cytokines and expression levels of proteins were assessed using ELISA and Western blotting, respectively., Result: Praelolide significantly reduced paw swelling and arthritis scores, improved gait deficits, and restored synovial histopathological alterations and bone erosion in CIA mice. In vivo and in vitro, praelolide effectively decreased the expression and production of inflammatory cytokines such as interleukin (IL)-1β and IL-6. Additionally, praelolide inhibited osteoclastogenesis on bone surface of the ankle joints and in a tumor necrosis factor-α (TNF-α)-induced MH7A/bone marrow-derived macrophages (BMMs) co-culture system, and it strongly suppressed reactive oxygen species (ROS) production. Mechanistically, praelolide modulated catalase through non-covalent interactions, inducing conformational alterations that enhanced catalase activity and stability against time- and temperature-induced degradation. Further investigation revealed that praelolide significantly upregulated the expression of Nrf2, subsequently activating downstream antioxidant enzymes., Conclusion: Praelolide markedly alleviated synovial inflammation and bone destruction in CIA mice by enhancing catalase activity and activating the Nrf2 pathway to reduce disease-related ROS accumulation, highlighting praelolide as a promising candidate for multitarget treatment of RA., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with this manuscript submitted., (Copyright © 2024. Published by Elsevier GmbH.)

A natural product isolated from Brazilian plant species Baccharis retusa (Asteraceae), 15β-senecioyloxi-ent-kaurenoic acid (1), demonstrated activity against trypomastigotes of the parasite Trypanosoma cruzi but it was inactive against intracellular forms. In the present work, compound 1a, a methyl ester derivative of 1, exhibited activity against intracellular amastigotes (EC 50  = 11.8 μM), similar to that determined by the standard drug benznidazol (EC 50  = 16.2 μM) and no toxicity against NCTC cells (CC 50  > 200 μM). Based on this selectivity, compound 1a was incorporated into Langmuir monolayers of three lipids, DPPC, DPPE, and DPPS, to characterize the interaction of the compound with each lipid as model for cell membranes. For that, we used tensiometry, surface potential measurements, and infrared spectroscopy. Our results showed that incorporating the drug into DPPC monolayers significantly altered the physicochemical properties, resulting in more condensed monolayers. In contrast, the incorporation of the drug into DPPE and DPPS monolayers led to their expansion. The effects on DPPC were more pronounced than on the other lipids, inducing a viscoelastic monolayer with lower alignment of the alkyl chains, as observed through surface potential measurements and infrared spectroscopy. These changes indicate a more cohesive DPPC monolayer upon drug incorporation, forming domains in a strip shape. We believe these results contribute to understanding the interaction between 1a and lipid interfaces, especially those involved in biological interactions with amastigotes of parasite T. cruzi., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a often heterogeneous condition in urology. Accumulating evidence suggests that the autoimmune response against prostate antigens is related to CP/CPPS. The gut microbiota may be a possible cause of a number of autoimmune diseases. Eriocalyxin B (EriB) is used as an anti-inflammatory treatment for autoimmune disorders. The underlying mechanism of fecal metabolome involved in CP/CPPS treatment by EriB remains unclear., Methods: The experimental autoimmune prostatitis (EAP) mouse model was generated by subcutaneous immunization. Macrophages, inflammatory cytokines, intestinal microbiota, and fecal metabolome of the mice were analyzed. The alteration of the fecal metabolome was investigated in detail in EriB-treated EAP mice and confirmed by in vitro experiments., Results: EriB ameliorated significantly decreased prostate inflammation in EAP mice and promoted macrophage phenotype polarizing from M1 to M2. The gut microbiome was altered, and intestinal barrier damage was improved by EriB treatment. Furthermore, the enrichment of vitamin digestion and absorption pathways in the fecal metabolome revealed that vitamin D 3 was altered by EriB. In vitro experiments confirmed that macrophage polarization from M1 to M2 was promoted by vitamin D 3 . Finally, fecal transplantation from EriB-treated mice markedly reduced inflammatory indicators and the macrophage M1/M2 ratio in pseudogerm-free EAP mice. In our study, the immune state of macrophage regulated by gut microbiota-mediated vitamin D3 alteration was first time revealed in EAP treatment., Conclusions: EriB ameliorated in mice with EAP, the gut microbiota mediates vitamin D 3 alterations to modulate macrophage phenotype polarizing from M1 to M2., Competing Interests: Declaration of competing interest We declare that there no conflicts of interest in relation to the manuscript titled “Eriocalyxin B ameliorated experimental autoimmune prostatitis via modulation of macrophage polarization through gut microbiota-mediated vitamin D3 alteration” submitted to “Phytomedicine”. we confirm that the results and interpretations reported in the manuscript are original and have not been plagiarized., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Delphinium forrestii var. viride is a plant of the genus Delphinium in the family Ranunculaceae. The chemical composition of the 95% ethanol extract of the whole herb of D. forrestii var. viride was investigated. 7 previously undescribed C 19 -type diterpenoid alkaloids along with 5 known ones were isolated from D. forrestii var. viride. Based on chemical evidence and spectral data analysis (UV, optical rotation data, 1D/2D-NMR and HR-ESI-MS), the structures of new compounds were elucidated. All compounds were also tested for anti-inflammatory effects. Our work has enriched the chemical diversity of D. forrestii var. viride and the Delphinium genus, providing valuable information for further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)