Pharmacological activity and clinical progress of Triptolide and its derivatives LLDT-8, PG490-88Na, and Minnelide: a narrative review.

Triptolide, a compound isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. Due to its interesting structural features and diverse pharmacological activities, it has attracted great interest by the Society of Organic Chemistry and Pharmaceutical Chemistry. However, its clinical potential is greatly hampered by limited aqueous solubility and oral bioavailability, and multi-organ toxicity. In recent years, various derivatives of Triptolide have made varying degrees of progress in the treatment of inflammatory diseases, autoimmune diseases, and cancer. The most researched and potentially clinically valuable of them were (5R)-5-hydroxytriptolide (LLDT-8), PG490-88Na (F6008), and Minnelide. In this review, we provide an overview of the advancements made in triptolide and several of its derivatives' biological activity, mechanisms of action, and clinical development. We also summarized some prospects for the future development of triptolide and its derivatives. It is hoped to contribute to a better understanding of the progress in this field, make constructive suggestions for further studies of Triptolide, and provide a theoretical reference for the rational development of new drugs.

A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (E)-19-[(1'-benzoyloxy-1'-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.

Pancreatic cancer is a major cause of cancer-related deaths worldwide, with only 12% of patients surviving for five years after diagnosis. Individuals generally experience few symptoms of the disease in the early stages and are often diagnosed once the cancer has already spread to other parts of the body. By this point, options for treatment are limited. A molecule known as triptolide has been shown to kill breast, lung, pancreatic and other types of cancer cells. However, triptolide is toxic to humans and other animals, making it unsuitable for use in patients. One way to make drugs safer without compromising their beneficial effects is to modify their molecular structure. By formulating triptolide into an emulsion ­ a mixture of liquids allowing it to dissolve ­ Tian, Zhang et al. synthesized a new analogue called CK21. Experiments showed that CK21 inhibited the growth of human pancreatic cancer cells grown in a laboratory including cells grown in artificial organs similar to the pancreas, known as pancreatic tumor organoids. Furthermore, CK21 killed large tumors in mice pancreases with very few side effects, suggesting the structural modification of triptolide increased safety of the drug. To better understand how CK21 works, Tian, Zhang et al. examined the genes that were induced in the pancreatic tumor organoids at various time points after treatment with the drug. This revealed that CK21 switched off genes involved in the NF-κB cell signaling pathway, which regulates how cells grow and respond to stress. In turn, it triggered programmed cell death, killing the tumor cells in a controlled manner. The findings suggest that CK21 could be a promising candidate for treating pancreatic cancer. In the future, clinical trials will be required to establish whether CK21 is a safe and effective therapy for humans.

Pathophysiological Involvement of Mast Cells and the Lipid Mediators in Pulmonary Vascular Remodeling.

Mast cells are responsible for IgE-dependent allergic responses, but they also produce various bioactive mediators and contribute to the pathogenesis of various cardiovascular diseases, including pulmonary hypertension (PH). The importance of lipid mediators in the pathogenesis of PH has become evident in recent years, as exemplified by prostaglandin I2, the most central therapeutic target in pulmonary arterial hypertension. New bioactive lipids other than eicosanoids have also been identified that are associated with the pathogenesis of PH. However, it remains largely unknown how mast cell-derived lipid mediators are involved in pulmonary vascular remodeling. Recently, it has been demonstrated that mast cells produce epoxidized n-3 fatty acid (n-3 epoxides) in a degranulation-independent manner, and that n-3 epoxides produced by mast cells regulate the abnormal activation of pulmonary fibroblasts and suppress the progression of pulmonary vascular remodeling. This review summarizes the role of mast cells and bioactive lipids in the pathogenesis of PH. In addition, we introduce the pathophysiological role and therapeutic potential of n-3 epoxides, a mast cell-derived novel lipid mediator, in the pulmonary vascular remodeling in PH. Further knowledge of mast cells and lipid mediators is expected to lead to the development of innovative therapies targeting pulmonary vascular remodeling.

Triptolide Attenuates Muscular Inflammation and Oxidative Stress in a Delayed-Onset Muscle Soreness Animal Model.

Delayed-onset muscle soreness (DOMS) is associated with exercise-induced muscle damage and inflammation, which is mainly caused by prolonged eccentric exercise in humans. Triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, has been used for treating autoimmune and inflammatory diseases in clinical practice. However, whether triptolide attenuates acute muscle damage is still unclear. Here, we examined the effect of triptolide on carrageenan-induced DOMS in rats. Rats were injected with 3% of carrageenan into their muscles to induce acute left gastrocnemius muscular damage, and triptolide treatment attenuated carrageenan-induced acute muscular damage without affecting hepatic function. Triptolide can significantly decrease lipid hydroperoxide and nitric oxide (NO) levels, proinflammatory cytokine production, and the activation of nuclear factor (NF)-ĸB, as well as increase a reduced form of glutathione levels in carrageenan-treated rat muscles. At the enzyme levels, triptolide reduced the inducible nitric oxide synthase (iNOS) expression and muscular myeloperoxidase (MPO) activity in carrageenan-treated DOMS rats. In conclusion, we show that triptolide can attenuate muscular damage by inhibiting muscular oxidative stress and inflammation in a carrageenan-induced rat DOMS model.

Discovery of a novel water-soluble, rapid-release triptolide prodrug with improved drug-like properties and high efficacy in human acute myeloid leukemia.

In this work, a series of water-soluble triptolide prodrugs were synthesized, and their triptolide release rate, pharmacokinetic characteristics and anti-tumor effect were measured. We found that inserting glycolic acid as a linker between triptolide and the cyclic amino acid accelerated the release of triptolide from prodrugs into the plasma while preserving its safety. Among them, prodrug TP-P1 was significantly better than Minnelide (the only water-soluble triptolide prodrug in clinical trials) in terms of release rate in plasma and synthetic yield. In mouse models of human acute myeloid leukemia (AML), TP-P1 was effective in reducing xenograft tumors at dose levels as low as 25 µg/kg, and eliminating tumors at dose 100 µg/kg. Furthermore, TP-P1 could significantly enhance the efficacy of FLT3 inhibitors in the treatment of AML. These experimental results showed the potential of TP-P1 as water-soluble prodrugs of triptolide.

TP-CSO: A Triptolide Prodrug for Pancreatic Cancer Treatment.

Triptolide (TP) is a potential drug candidate for the treatment of cancer, but its use was hampered by its systemic toxicity and poor water solubility. Hence, a TP-CSO prodrug was synthesized by conjugating TP to chitosan oligosaccharide (CSO), and characterized by 1H NMR, FTIR, DSC and XRD analyses. The TP-CSO containing about 4 wt% of TP exhibited excellent water solubility (15 mg/mL) compared to TP (0.017 mg/mL). Compared with TP, the pharmacokinetics of the conjugate after oral administration showed a three-fold increase in the half-life in the blood circulation and a 3.2-fold increase in AUC (0-∞). The orally administered TP-CSO could more effectively inhibit tumor progression but with much lower systemic toxicity compared with TP, indicating significant potential for further clinical trials. In conclusion, CSO-based conjugate systems may be useful as a platform for the oral delivery of other sparingly soluble drugs.

Design, synthesis of novel triptolide-glucose conjugates targeting glucose Transporter-1 and their selective antitumor effect.

Six positional isomers of triptolide-glucose conjugates (TG1α, TG1ß, TG2, TG3, TG4 and TG6) were designed and synthesized. These conjugates exhibited better water solubility, and had selective cytotoxicity between tumor cells with high expression of glucose transport-1 (Glut-1) and non-tumor cells with low expression of Glut-1, in which TG2 formed by triptolide (TPL) and d-glucose C2-OH had the strongest cytotoxicity to tumor cells and lowest toxicity in non-tumor cells, therefore the highest relative therapeutic index, which was 5.7 times that of triptolide and consequent the most powerful selective antitumor activity in vitro. The cytotoxicity of TG2 was highly correlated with Glut-1 function. As a prodrug of triptolide, TG2 could promote RNA Pol II degradation and induce apoptosis as TPL does. TG2 had a stronger dose-dependent antitumor effect in vivo than TPL and no adverse reaction occurred when its tumor inhibition was higher than 90%, which was associated with its selective distribution in tumor tissues. TG2 could be used as a promising drug candidate for the treatment of solid tumors with high expression of Glut-1, which is worthy of further study.

Synthesis and characterization of epoxide impurities of abiraterone acetate.

Abiraterone acetate is an antiandrogen steroidal drug that is used to treat patients with metastatic prostate cancer. During the process development of abiraterone acetate, two process α and ß-epoxy abiraterone acetate related impurities (2 and 3) were observed along with the final API. In the present work we describe the synthesis of these two known impurities using abiraterone acetate in the presence of hydrogen peroxide and acetic acid as oxidizing agent. The structure of these impurities fully characterized by NMR, Mass, CHN and HPLC analysis.

Targeted therapy of rheumatoid arthritis via macrophage repolarization.

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

Triptolide Improves Renal Injury in Diabetic Nephropathy Rats through TGF-ß1/Smads Signal Pathway.

OBJECTIVE: To investigate the therapeutic effect and mechanism of Triptolide on renal injury in diabetic nephropathy rats. METHODS: A total of 15 male SD rats aged 8 weeks were randomly divided into five groups (3 rats in each group): control group, model group, Triptolide low-dose (Triptolide-L) group, Triptolide medium- dose (Triptolide-M) group, Triptolide high-dose (Triptolide-H) group. The rat models of diabetic nephropathy (DN) were established by a single intraperitoneal injection of STZ after being fed with high-fat and high-sugar diet for 4 weeks, and the fasting blood glucose (FBG) concentration of rats was detected. After 4 weeks, HE-staining was used to evaluate the renal pathological damage in rats; biochemical analysis was used to determine the blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC), triglyceride (TG); ELISA was used to measure the serum inflammatory factor levels; Western blot (WB) was used to detect the expression of TGF-ß1/Smads pathway proteins. RESULTS: In the four FBG tests (once a week), the FBG concentration in the model group was significantly higher than that in the control group, while Triptolide-treated rats were significantly lower than that in the model group. Rats in Model group showed obvious renal injury, and Triptolide significantly improved the renal injury in DN rats. Compared with the control group, the expression of BUN, SCr, TC, TG, inflammatory factors TNF-α, IL-6 and IL-1ß in the model group increased significantly. WB results showed that the expressions of TGF-ß1, Smad3, α -SMA and vimentin in the kidney significantly increased, while the Smad7 expression significantly decreased. Triptolide significantly reduced the levels of BUN, SCr, TC, TG and TNF-α, IL-6, IL-1ß in diabetic rats, decreased the expression of TGF-ß1, Smad3, α-SMA, vimentin, and increased the Smad7 expression. In different doses of Triptolide treatment group, its effect showed a significant concentration dependence. CONCLUSION: Triptolide alleviates renal injury in diabetic rats by inhibiting the TGF-ß1/Smads signaling pathway.

Engineering Exosomes Endowed with Targeted Delivery of Triptolide for Malignant Melanoma Therapy.

Malignant melanoma is considered the most aggressive skin carcinoma with invasive growth patterns. Triptolide (TPL) possesses various biological and pharmacological activities involved in cancer treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell apoptosis by binding to DR5 highly expressed on cancer cells. Exosomes are natural nanomaterials with low immunogenicity, nontoxicity, and excellent biocompatibility and have been extensively used as emerging delivery vectors for diverse therapeutic cargos. Herein, a delivery system based on TRAIL-engineered exosomes (TRAIL-Exo) for loading TPL for targeted therapy against malignant melanoma is proposed and systematically investigated. Our results showed that TRAIL-Exo/TPL could improve tumor targetability, enhance cellular uptake, inhibit proliferation, invasion, and migration, and induce apoptosis of A375 cells through activating the extrinsic TRAIL pathway and the intrinsic mitochondrial pathway in vitro. Moreover, intravenous injection of TRAIL-Exo/TPL significantly suppressed tumor progression and reduced the toxicity of TPL in the melanoma nude mouse model. Together, our research presents a novel strategy for high-efficiency exosome-based drug-delivery nanocarriers and provides an alternative dimension for developing a promising approach with synergistic therapeutic efficacy and targeting capacity for melanoma treatment.

Triptolide decreases rheumatoid arthritis fibroblast-like synoviocyte proliferation, invasion, inflammation and presents a therapeutic effect in collagen-induced arthritis rats via inactivating lncRNA RP11-83J16.1 mediated URI1 and ß-catenin signaling.

OBJECTIVE: Our previous study observed that long non-coding RNA (lncRNA) RP11-83J16.1 promoted rheumatoid arthritis (RA)-fibroblast-like synoviocyte (RA-FLS) proliferation, invasion and inflammation, which was downregulated by triptolide treatment. Therefore, the present study aimed to further investigate the mechanism and interaction between triptolide and lncRNA RP11-83J16.1 in RA treatment in vitro and in vivo. METHODS: RA-FLS was isolated and treated by different concentration of triptolide and lncRNA RP11-83J16.1 overexpression plasmid. Furthermore, collagen-induced arthritis (CIA) rat model was constructed followed by triptolide and lncRNA RP11-83J16.1 overexpression plasmid treatment. RESULTS: Triptolide inhibited RA-FLS viability and lncRNA RP11-83J16.1 expression in a dose-dependent manner. Afterward, triptolide treatment inhibited RA-FLS proliferation, invasion, levels of inflammatory markers (TNF-α, IL-1ß, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and ß-catenin signaling, but promoted apoptosis. However, lncRNA RP11-83J16.1 overexpression weakened the effects of triptolide on regulating RA-FLS cell behaviors, URI1 signaling and ß-catenin signaling. In CIA model, triptolide decreased arthritis score, hyperproliferation of synovial cells, inflammation infiltration of synovial tissue, inflammatory markers (TNF-α, IL-1ß, IL-6, MMP-3, and MMP-9), inactivated lncRNA RP11-83J16.1, URI1 and ß-catenin signaling, but increased cell apoptosis rate of synovial tissue. Nevertheless, lncRNA RP11-83J16.1 curtailed the treatment effect of triptolide in CIA model. CONCLUSION: Triptolide decreases RA-FLS proliferation, invasion, inflammation and presents a therapeutic effect in CIA model via inactivating lncRNA RP11-83J16.1 mediated URI1 and ß-catenin signaling.

Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives.

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.

Natural product triptolide induces GSDME-mediated pyroptosis in head and neck cancer through suppressing mitochondrial hexokinase-ΙΙ.

BACKGROUND: Pyroptosis is a lytic cell death form executed by gasdermins family proteins. Induction of tumor pyroptosis promotes anti-tumor immunity and is a potential cancer treatment strategy. Triptolide (TPL) is a natural product isolated from the traditional Chinese herb which possesses potent anti-tumor activity in human cancers. However, its role in pyroptosis remains to be elucidated. METHODS: Cell survival was measured by colony formation assay. Cell apoptosis was determined by Annexin V assay. Pyroptosis was evaluated by morphological features and release of interleukin 1ß and lactate dehydrogenase A (LDHA). Immunofluorescence staining was employed to measure subcellular localization of proteins. Tumorigenicity was assessed by a xenograft tumor model. Expression levels of mRNAs or proteins were determined by qPCR or western blot assay, respectively. RESULTS: Triptolide eliminates head and neck cancer cells through inducing gasdermin E (GSDME) mediated pyroptosis. Silencing GSDME attenuates the cytotoxicity of TPL against cancer cells. TPL treatment suppresses expression of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells, leading to activation of the BAD/BAX-caspase 3 cascade and cleavage of GSDME by active caspase 3. Silencing HK-II sensitizes cancer cells to TPL induced pyroptosis, whereas enforced expression of HK-II prevents TPL induced pyroptosis. Mechanistically, HK-II prevents mitochondrial translocation of BAD, BAX proteins and activation of caspase 3, thus attenuating cleavage of GSDME and pyroptosis upon TPL treatment. Furthermore, TPL treatment suppresses NRF2/SLC7A11 (also known as xCT) axis and induces reactive oxygen species (ROS) accumulation, regardless of the status of GSDME. Combination of TPL with erastin, an inhibitor of SLC7A11, exerts robust synergistic effect in suppression of tumor survival in vitro and in a nude mice model. CONCLUSIONS: This study not only provides a new paradigm of TPL in cancer therapy, but also highlights a crucial role of mitochondrial HK-II in linking glucose metabolism with pyroptosis.

Assessing the effectiveness of two intervention methods for stony coral tissue loss disease on Montastraea cavernosa.

Stony coral tissue loss disease (SCTLD) was first observed in Florida in 2014 and has since spread to multiple coral reefs across the wider Caribbean. The northern section of Florida's Coral Reef has been heavily impacted by this outbreak, with some reefs experiencing as much as a 60% loss of living coral tissue area. We experimentally assessed the effectiveness of two intervention treatments on SCTLD-affected Montastraea cavernosa colonies in situ. Colonies were tagged and divided into three treatment groups: (1) chlorinated epoxy, (2) amoxicillin combined with CoreRx/Ocean Alchemists Base 2B, and (3) untreated controls. The experimental colonies were monitored periodically over 11 months to assess treatment effectiveness by tracking lesion development and overall disease status. The Base 2B plus amoxicillin treatment had a 95% success rate at healing individual disease lesions but did not necessarily prevent treated colonies from developing new lesions over time. Chlorinated epoxy treatments were not significantly different from untreated control colonies, suggesting that chlorinated epoxy treatments are an ineffective intervention technique for SCTLD. The results of this experiment expand management options during coral disease outbreaks and contribute to overall knowledge regarding coral health and disease.

Triptolide inhibits JAK2/STAT3 signaling and induces lethal autophagy through ROS generation in cisplatin­resistant SKOV3/DDP ovarian cancer cells.

Advanced and recurrent ovarian cancer has a poor prognosis and is frequently resistant to numerous therapeutics; thus, safe and effective drugs are needed to combat this disease. Previous studies have demonstrated that triptolide (TPL) exhibits anticancer and sensitization effects against cisplatin (DDP)­resistant ovarian cancer both in vitro and in vivo by inducing apoptosis; however, the involvement of autophagy induced by TPL in resistant ovarian carcinoma remains unclear. In the present study, the results revealed that TPL induced autophagy to facilitate SKOV3/DDP ovarian cancer cell death. The xenograft experiment revealed that the autophagy inhibitor CQ significantly reduced TPL­mediated chemosensitization and tumor growth inhibition. Mechanically, TPL­induced autophagy in SKOV3/DDP cells was associated with the induction of ROS generation and inhibition of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription­3 (STAT3) pathway. The inhibitory effect of TPL on the JAK2/STAT3 pathway could be restored in the presence of the antioxidant NAC. Furthermore, it was further determined that TPL disrupted the interaction between Mcl­1 and Beclin1, which was prevented by the JAK2/STAT3 signaling activator IL­6. Overall, the present results revealed a novel molecular mechanism whereby TPL induced lethal autophagy through the ROS­JAK2/STAT3 signaling cascade in SKOV3/DDP cells. The present study has provided the groundwork for future application of TPL in the treatment of ovarian cancer.

Exploring a novel triptolide derivative possess anti-colitis effect via regulating T cell differentiation.

Inflammatory bowel disease (IBD) is generally characterized by chronic inflammatory disorders of the gastrointestinal tract that are known as ulcerative colitis (UC) or Crohn's disease (CD). Although the underlying mechanism of action of IBD is unclear and because of the lack of satisfactory treatment, increasing evidence has indicated that pro-inflammatory cytokines that activate JAK-STAT signaling pathway regulate the differentiation of naïve T cells towards T helper (Th)1 and Th17 cell subsets and contribute to the development of IBD. ZT01 is a newly obtained triptolide derivative with strong anti-inflammatory effects and low toxicity. In this study, we evaluated the effects of ZT01 on DSS-induced colitis and investigated the underlying mechanism of action involved. Mice with DSS-induced acute or chronic colitis were used to assess the efficacy of ZT01 treatment, and T cells were cultured to analyze the differentiation of Th1 and Th17 cell by flow cytometry. In addition, intestinal epithelial barrier function, macrophage polarization, activation of the JAK-STAT signaling pathway, and the expression of cytokines and transcription factors were measured to assess the possible mechanisms of ZT01. We found that ZT01 had an obviously beneficial effect on DSS-induced colitis by improving the symptoms of bloody diarrhea, weight loss, and a shortened colon, thereby preserving the epithelial barrier function in the mouse colon. Furthermore, ZT01 significantly inhibited T cell differentiation into Th1 and/or Th17 cell subsets and macrophage polarization towards into an inflammatory phenotype via regulating the JAK-STAT signaling pathway. Thus, our findings suggested that ZT01 might be a potential pharmaceutical candidate that deserves to be further investigated as a treatment for IBD patients.

The Anti-Tumor Mechanism and Target of Triptolide Based on Network Pharmacology and Molecular Docking.

BACKGROUND: According to the special physiological and pharmacological activities of natural compounds, many drugs with special therapeutic effects have been developed. The Triptolide (TP) is a natural anti-tumor drug with a world patent, but its target and mechanism are yet unknown. OBJECTIVE: The study aims to explore and predict the target and mechanism of TP on Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer (PC) and Colorectal Cancer (CC) through network pharmacology technology. METHODS: We screened the core targets of TP with NSCLC, PC and CC, respectively, and carried out network analysis, enrichment analysis and ligand-receptor docking to clarify its potential pharmacological mechanism. RESULTS: By screening the core genes between TP with NSCLC, PC and CC, respectively, it was found that PTGS2 was the common target gene in the three cancers. NSCLC, CCL2, IL6, HMOX1 and COL1A1 are the specific target genes, while MMP2, JUN, and CXCL8 are the specific target genes in PC. In CC, the specific target genes includeERBB2, VEGFA, STAT1 and MAPK8. In enrichment analysis, it was found that the NF- κB, toll-like receptors and IL-17 signaling pathway were mainly involved in TP for these cancers. The binding energy of TP to the core target is less than that of cyclophosphamide. CONCLUSION: This study preliminarily revealed that TP may prevent and treat cancers\ through multiple targets and pathways. The possible mechanisms of TP include regulating immune and inflammatory responses, promoting apoptosis and inhibiting tumor development. It shows that TP may have potential in treating kinds of tumors.

Triptolide improves neurobehavioral functions, inflammation, and oxidative stress in rats under deep hypothermic circulatory arrest.

This study investigated the neuroprotective effects of triptolide (TPL) in a rat model of cardiopulmonary bypass with deep hypothermia circulatory arrest (DHCA). Rats were randomly divided into six groups: control, sham, DHCA, and DHCA + TPL (100, 200, 300 µg/kg). Neurobehavioral functions were measured using the elevated plus-maze, Y-maze, and Morris water maze tests. Levels of inflammatory cytokines, oxidative stress indices, and brain neurotrophins were measured by ELISA. Microglial activation and cell death was measured by immunofluorescence staining and TUNEL assay, respectively. Finally, activation of the Nrf2 pathway and NF-κB were detected by western blot. The elevated plus-maze, Y-maze, and Morris water maze tests all showed that TPL mitigated anxiety-like behavior, working memory, spatial learning, and memory in DHCA rats. TPL inhibited inflammatory responses and oxidative stress, as well as increased brain neurotrophin levels in DHCA rats. Moreover, TPL attenuated microglia activation and cell death in DHCA rats. Finally, TPL activated the Nrf2 pathway and inhibited NF-κB activity in DHCA rats. These results demonstrated that TPL improved neurobehavioral functions, neuroinflammation, and oxidative stress in DHCA rats, which may be associated with the Nrf2 and NF-κB pathways.

Triptolide delivery: Nanotechnology-based carrier systems to enhance efficacy and limit toxicity.

Triptolide (TP) possesses a wide range of biological and pharmacological activities involved in the treatment of various diseases. However, widespread usages of TP raise the urgent issues of the severe toxicity, which hugely limits its further clinical application. The novel functional nanostructured delivery system, which is of great significance in enhancing the efficacy, reducing side effects and improving bioavailability, could improve the enrichment, penetration and controlled release of drugs in the lesion location. Over the past decades, considerable efforts have been dedicated to designing and developing a variety of TP delivery systems with the intention of alleviating the adverse toxicity effects and enhancing the bioavailability. In this review, we briefly summarized and discussed the recent functionalized nano-TP delivery systems for the momentous purpose of guiding further development of novel TP delivery systems and providing perspectives for future clinical applications.