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BackgroundStaphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the conventional antibiotic efficacy. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With multi-targeting and immunomodulatory properties, traditional Chinese medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored.MethodsForty-one TCM monomers potentially regulating host apoptosis, a core mechanism of the host innate immune defense against intracellular pathogens, were screened to identify a compound that promotes the clearance of intracellular SA and methicillin-resistant SA (MRSA). The mechanism was investigated in infected macrophages using transcriptomics, proteomics, molecular dynamics simulations, and biochemical assays. The physiological function of the TCM monomer was examined in infected mice through lung pathology and multi-omics analysis, including transcriptomics, proteomics, metagenomics, and metabolomics.ResultsTriptolide was identified as a potent facilitator of host immunity-mediated intracellular clearance of SA and MRSA, without exerting direct bactericidal effects. Mechanistically, triptolide directly binds to the X-linked inhibitor of apoptosis protein (XIAP), disrupting its interaction with caspases to relieve their inhibition and thereby induce apoptosis. Furthermore, in murine infection models, triptolide treatment reduced bacterial loads, alleviated inflammation, and induced macrophage apoptosis in lungs, concurrently maintaining microbiota homeostasis and improving metabolic function.ConclusionThis study establishes a proof of concept for triptolide as a HDT candidate against SA and MRSA infections, which not only enhances host apoptosis-mediated pathogen clearance but also maintains host microbiota and metabolic homeostasis.

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.

Objective: To evaluate the efficacy of ultrasound-guided intra-articular injection of triptolide-loaded solid lipid nanoparticle (TP-SLN) for treatment of antigen-induced arthritis (AIA) in rabbits. Material and Methods: Knee joints of 33 New Zealand rabbits with AIA were injected intra-articularly with triptolide (TP: n = 7), TP-SLN (n = 7), betamethasone (BS: n = 7) and dimethyl sulfoxide (DMSO: n = 6). The remaining six rabbits were untreated as the control group. The injection therapy in intervention groups was initiated 1 week after the last immunization in order to avoid irreversible joint damage in the later induction. The ultrasonic scores of the joints were assessed based on synovitis, synovial blood flow and bone erosion. Meanwhile, the correlations of ultrasonic scores and pathological scores were determined. The efficacy and side effects of each group were determined by combining ultrasonic scores, pathological scores, behavior, appetite, weight, joint diameter, skin temperature and biochemical examination. Results: 1) Compared with the control group, the diameters of knee joints of the TP, TP-SLN and BS groups began to reduce 1 week after intra-articular injection ( p < 0.01). 2) With the exception of the DMSO group, the interventions were effective in treating synovitis compared with the control group, with TP-SLN and BS being the best. The ultrasonic and pathological scores in synovitis of the TP group were lower than that of model group (Z = -2.726 and -2.530, p < 0.05). The ultrasonic scores differed significantly between BS group and TP-SLN group (Z = −2.17 and -2.360, respectively, p < 0.05) and pathological scores (Z = −2.687 and −2.082, respectively, p < 0.05). 3) Compared with the control group, the TP, BS and TP-SLN were all effective in treating synovial blood flow and bone erosion and there were no significant differences of ultrasonic and pathological scores among them ( p > 0.05). The ultrasonic scores of synovial blood flow (Z = −3.033, −2.842, −3.277, p < 0.01) were lower than in the controls. The ultrasonic scores (Z = -2.948, -3.141, -3.210, p < 0.01) and pathological scores (Z = −2.216, −2.505, −2.505, p < 0.05) of bone erosion were also lower than in the model group.4) There were significant correlations between the ultrasonic and pathological scores of synovial inflammation and bone erosion (r = 0.832 and 0.859 respectively, p < 0.001). Conclusions: The therapeutic effect of TP-SLN on arthritis is better than that of TP, but there is no difference between BS and TP-SLN. Therefore, TP-SLN may be used as an alternative to BS in the treatment of rheumatoid arthritis in the future. The ultrasonic and pathological scores showed significant correlation in synovitis and bone erosion. Ultrasound can provide a useful assessment of synovitis in early arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease involving joints, with clinical manifestations of joint inflammation, bone damage and cartilage destruction, joint dysfunction and deformity, and extra-articular organ damage. As an important source of new drug molecules, natural medicines have many advantages, such as a wide range of biological effects and small toxic and side effects. They have become a hot spot for the vast number of researchers to study various diseases and develop therapeutic drugs. In recent years, the research of natural medicines in the treatment of RA has made remarkable achievements. These natural medicines mainly include flavonoids, polyphenols, alkaloids, glycosides and terpenes. Among them, resveratrol, icariin, epigallocatechin-3-gallate, ginsenoside, sinomenine, paeoniflorin, triptolide and paeoniflorin are star natural medicines for the treatment of RA. Its mechanism of treating RA mainly involves these aspects: anti-inflammation, anti-oxidation, immune regulation, pro-apoptosis, inhibition of angiogenesis, inhibition of osteoclastogenesis, inhibition of fibroblast-like synovial cell proliferation, migration and invasion. This review summarizes natural medicines with potential therapeutic effects on RA and briefly discusses their mechanisms of action against RA.

Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the ‘terpenoid induced autophagy’ phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.

Acute lung injury (ALI) associated with pulmonary edema is a severe clinical condition characterized by acute inflammation, disrupted lung barrier function, and high mortality. Current therapeutic strategies remain limited, highlighting the need for exploring novel agents and their underlying mechanisms. Triptolide (TP), an active component derived from Tripterygium wilfordii, has shown anti-inflammatory and tissue-protective properties 1 , 2 , but its specific role in alleviating ALI and the involvement of the lung-gut axis in metabolic regulation remain poorly understood. This study aims to investigate the therapeutic effects of TP on LPS-induced ALI, focusing on its impact on pulmonary edema and inflammatory injury. By analyzing the lung-gut axis using multi-omics approaches, we seek to clarify the metabolic network regulatory mechanisms through which TP exerts its effects. LPS-induced ALI model was established in Balb/c mice, with TP administered as the therapeutic intervention. Histopathological examination of lung tissues and detection of pro-inflammatory cytokines were performed to assess lung injury. Untargeted metabolomics via LC-MS/MS was used to identify differential metabolites in lung tissues and serum, while metagenomic sequencing analyzed changes in gut microbiota composition. Integrated multi-omics analysis was applied to explore associations between gut microbiota alterations, serum metabolites, and pulmonary bile acid levels. TP administration significantly reduced histopathological damage in lung tissues of ALI mice and decreased pro-inflammatory cytokine levels. Metabolomics profiling revealed distinct changes in key metabolites, including bile acids, amino acid derivatives, and energy metabolism intermediates, in both lung tissues and serum after TP treatment. Metagenomic analysis showed that TP restructured gut microbiota composition, with functional enrichment in glycolysis and thiamine metabolism pathways. Integrated analysis confirmed strong correlations between dynamic microbiota changes, serum metabolite profiles, and pulmonary bile acid levels, indicating a regulatory role of the lung-gut axis. This study demonstrates that TP alleviates pulmonary edema and inflammatory injury in ALI by modulating gut microbial ecology and function, which drives bile acid metabolic reprogramming and regulates metabolite interactions within the lung-gut axis. These findings provide novel insights into TP’s therapeutic mechanism and support its potential application in ALI treatment.

Triptolide, an abietane-type diterpenoid isolated from Tripterygium wilfordii Hook. F., has significant pharmacological activity. Research results show that triptolide has obvious inhibitory effects on many solid tumors. Therefore, triptolide has become one of the lead compounds candidates for being the next \"blockbuster\" drug, and multiple triptolide derivatives have entered clinical research. An increasing number of researchers have developed triptolide synthesis methods to meet the clinical need. To provide new ideas for researchers in different disciplines and connect different disciplines with researchers aiming to solve scientific problems more efficiently, this article reviews the research progress made with analyzes of triptolide pharmacological activity, biosynthetic pathways, and chemical synthesis pathways and reported in toxicological and clinical studies of derivatives over the past 20 years, which have laid the foundation for subsequent researchers to study triptolide in many ways.

Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant Hook F. These compounds exhibit similar pharmacological activities, including anti-cancer, anti-inflammation, anti-obesity, and anti-diabetic activities. Triptolide and celastrol also provide neuroprotection and prevent cardiovascular and metabolic diseases. However, toxicity restricts the further development of triptolide and celastrol. In this review, we comprehensively review therapeutic targets and mechanisms of action, and translational study of triptolide and celastrol. We systemically discuss the structure-activity-relationship of triptolide, celastrol, and their derivatives. Furthermore, we propose the use of structural derivatives, targeted therapy, and combination treatment as possible solutions to reduce toxicity and increase therapeutic window of these potent natural products from Hook F.

Background Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated in a phase I study in patients with advanced GI carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose (RP2D). Patients and Methods Patients with refractory GI carcinoma and with measurable disease on CT scan were eligible. The study used a 3 + 3 dose-escalation scheme. Due to neutropenia toxicity, 2 dosing schedules were evaluated to determine the RP2D for future studies. Response was assessed using RECIST 1.1 and Choi criteria. Minnelide and triptolide PK were evaluated. Patients who completed the first 28-day treatment cycle without DLTs continued treatment until disease progression or unacceptable toxicity. Results Forty-five patients were enrolled (23 pancreatic cancer, 10 colorectal, and the remaining 9 had other GI tumors); 42 patients received at least one dose of Minnelide. Grade ≥ 3 toxicities occurred in 69% of patients, most common neutropenia (38%). 2 patients with severe cerebellar toxicity who had a 2-fold higher triptolide concentration than other participants. ORR was 4%; the disease control rate (DCR) was 54% (15/28). Choi criteria demonstrated a decrease in average tumor density in 57% (16/28) patients. Conclusions This first-in-human, phase I clinical study identified a dose and schedule of Minnelide in patients with refractory GI cancers. The primary toxicity experienced was hematologic. Evidence of efficacy of Minnelide treatment in this group of patients was observed. The DCR ranged from ~2 to 6 months in 14/28 (50%) of evaluable patients. Studies in monotherapy and combination treatments are underway. In this phase I study, minnelide was evaluated in patients with advanced gastrointestinal carcinomas to establish the safety, pharmacodynamic, antitumor activity, and recommended phase II dose.