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Medicine Dec 2023This study aimed to validate the mechanism of triptolide in treating ankylosing spondylitis (AS) through network pharmacology, molecular docking, and in vitro...
OBJECTIVE
This study aimed to validate the mechanism of triptolide in treating ankylosing spondylitis (AS) through network pharmacology, molecular docking, and in vitro experiments.
METHODS
We gathered AS-related genes using databases including DrugBank, OMIM, GeneCards, TTD and DisGeNET. TCMSP database was used to collect Tripterygium wilfordii (TWHF)-related data. Additionally, the potential targets of TWHF in treating AS were predicted by consulting databases such as Venny, String, Cytoscape, and Cytohubba. Subsequently, a protein-protein interaction network was created and the gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed by metascape database. After selecting the most active ingredient of TWHF, molecular docking was performed to confirm the predicted results. Furthermore, we explore the potential mechanism of the most active ingredient of TWHF in the treatment of AS in vitro.
RESULT
By integrating the results of network pharmacological analysis, 62 genes were found to be strongly associated with AS, such as STAT3, TNF, MMP9, VEGFA, CXCL8, PTGS2, etc. Triptolide (TP) is one of the most active ingredients in TWHF. The enrichment analysis indicated that 292 biological processes and 132 signaling pathways were involved, with the T helper 17 cells cell differentiation pathway as the key pathway. TP was selected for molecular docking and in vitro experiments. The molecular docking results indicated that TP had excellent affinity with 6 key targets. Further, flow cytometry, cell counting assay, and ELISA demonstrated that the serum level of IL-17 was higher in AS patients compared to XXX, and 25 μg/mL TP was the optimal intervention concentration. RT-qPCR and Western blotting further verified that TP could inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway.
CONCLUSION
In conclusion, based on network pharmacology, molecular docking, and experimental verification in vitro, we proposed that the TP can inhibit the activation of RORγt and the JAK2/STAT3 signaling pathway and inhibit the differentiation of T helper 17 cells cells. The article provide a theoretical basis for further development and utilization of TWHF in AS management.
Topics: Humans; Nuclear Receptor Subfamily 1, Group F, Member 3; Tripterygium; Molecular Docking Simulation; Network Pharmacology; Spondylitis, Ankylosing; Drugs, Chinese Herbal
PubMed: 38115356
DOI: 10.1097/MD.0000000000036580 -
Canadian Respiratory Journal 2023Inhalation of nebulized TP has received little attention in the past. Here, we intend to investigate the effect of nebulized inhaled TP on airway inflammation in a mouse...
Inhalation of nebulized TP has received little attention in the past. Here, we intend to investigate the effect of nebulized inhaled TP on airway inflammation in a mouse model of asthma. 29 SPF BALB/c mice were divided into four groups: blank control (Blk, = 5), normal saline (NS, = 8), dexamethasone (Dex, = 8), and TP ( = 8). During the process of sensitization, mice in the three intervention groups were treated with nebulized NS, an injection of Dex, and nebulized triptolide, respectively. Then bronchoalveolar lavage fluid (BALF), peripheral blood, and lung tissue were collected. Relevant cytokines, transcriptional factors, and CD4+Th17+ T cell proportions were assessed and compared. IL-6, IL-17, IL-23, and TGF-1 demonstrated a significant difference between groups in the following order: Dex < TP < NS ( ≤ 0.001), while IL-10 changed in the opposite direction ( < 0.001). At the transcriptional level in lung tissue, the Ct value of IL-17 in the Dex group was significantly higher than in the NS and TP groups ( < 0.001). Meanwhile, it was higher in the TP group than in the NS group ( < 0.001). The Ct value of RORt demonstrated a significant difference among three groups in the following order: Dex > TP > NS ( < 0.001). An opposite trend of FoxP3 Ct value was revealed in the order: NS > TP > Dex. The proportion of CD4+Th17+ cells was 9.53 ± 2.74% in the NS group, 4.23 ± 2.26% in the Dex group, and 6.76 ± 2.99% in the TP group, which shows significant differences between the NS and Dex ( < 0.001) or NS and TP groups ( < 0.05). Inhalation of nebulized triptolide can play a role in suppressing airway inflammation with inflammatory cytokines and transcriptional factors reduced and CD4+Th17+ T cells dampened, also in a manner less than injected dexamethasone.
Topics: Animals; Mice; Interleukin-17; Asthma; Disease Models, Animal; Cytokines; Inflammation; Mice, Inbred BALB C; Dexamethasone
PubMed: 37645252
DOI: 10.1155/2023/2983092 -
JCI Insight Apr 2024Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by...
Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent antiinflammatory and antitumor activity in several preclinical models and has proven both safe and efficacious in clinical trials for advanced gastrointestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared with posttransplant cyclophosphamide (PTCy). Strikingly, we found Minnelide improved survival, weight loss, and clinical scores in an MHC-mismatched model of aHSCT. These benefits were also apparent in minor MHC-matched aHSCT and xenogeneic HSCT models. Minnelide was comparable to PTCy in terms of survival, GVHD clinical score, and colonic length. Notably, in addition to decreased donor T cell infiltration early after aHSCT, several regulatory cell populations, including Tregs, ILC2s, and myeloid-derived stem cells in the colon were increased, which together may account for Minnelide's GVHD suppression after aHSCT. Importantly, Minnelide's GVHD prevention was accompanied by preservation of graft-versus-tumor activity. As Minnelide possesses anti-acute myeloid leukemia (anti-AML) activity and is being applied in clinical trials, together with the present findings, we conclude that this compound might provide a new approach for patients with AML undergoing aHSCT.
Topics: Graft vs Host Disease; Animals; Mice; Hematopoietic Stem Cell Transplantation; Diterpenes; Epoxy Compounds; Phenanthrenes; Humans; Transplantation, Homologous; Female; Cyclophosphamide; Disease Models, Animal; Graft vs Leukemia Effect; Mice, Inbred C57BL; Male
PubMed: 38602775
DOI: 10.1172/jci.insight.165936 -
Journal of Nanobiotechnology Dec 2023Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has great promise in the treatment of cancer. However, there are many obstacles that...
Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has great promise in the treatment of cancer. However, there are many obstacles that can restrict the therapeutic efficacy of phototherapy. The hypoxic tumor microenvironment can restrict the production of reactive oxygen species (ROS) in PDT. As for PTT, the thermotolerance of cancer cells may lead to ineffective PTT. In this study, IR780 and glycolysis inhibitor lonidamine (LND)-encapsulated liposomes are prepared for photodynamic and photothermal therapy of hepatocellular carcinoma. IR780 can be used as a photosensitizer and photothermal agent for simultaneous PDT and PTT after being irradiated with 808 nm laser. LND can reduce the oxygen consumption of cancer cells by inhibiting glycolysis, which will relieve tumor hypoxia and produce more ROS for PDT. On the other hand, energy supply can be blocked by LND-induced glycolysis inhibition, which will inhibit the production of heat shock proteins (HSPs), reduce the thermotolerance of tumor cells, and finally enhance the therapeutic efficacy of PTT. The enhanced PTT is studied by measuring intracellular HSPs, ATP level, and mitochondrial membrane potential. The antitumor effect of IR780 and LND co-loaded liposomes is extensively investigated by in vitro and in vivo experiments. This research provides an innovative strategy to simultaneously enhance the therapeutic efficacy of PDT and PTT by inhibiting glycolysis, which is promising for future creative approaches to cancer phototherapy.
Topics: Humans; Carcinoma, Hepatocellular; Liposomes; Photothermal Therapy; Reactive Oxygen Species; Liver Neoplasms; Photochemotherapy; Phototherapy; Photosensitizing Agents; Neoplasms; Cell Line, Tumor; Nanoparticles; Tumor Microenvironment
PubMed: 38102658
DOI: 10.1186/s12951-023-02260-z -
Aging Oct 2023Epithelial ovarian cancer (EOC), the most predominant subtype of ovarian cancer (OC), involves poor prognosis and exhibits high aggression. Triptolide (TPL), like other...
Epithelial ovarian cancer (EOC), the most predominant subtype of ovarian cancer (OC), involves poor prognosis and exhibits high aggression. Triptolide (TPL), like other Chinese herbs, has historically played a significant role in modern medicine. The screening system based on Gli-dependent luciferase reporter activity assessed the effects of over 800 natural medicinal materials on hedgehog (Hh) signaling pathway activity and discovered that TPL had an excellent inhibitory effect on Hh signaling pathway activity. However, the significance and mechanism of TPL involvement in regulating the Hh pathway have not been well explored. Thus, this work aimed to understand better how TPL affects the Hh pathway activity, which, in turn, influences the biological behavior of EOC. Our findings observed that Smo agonist SAG-induced EOC cell proliferation, migration, and invasion were drastically reversed by TPL in a concentration-dependent pattern. Further evidence suggested that TPL promotes the degradation of Gli1 and Gli2 to inhibit the activity of the Hh signaling pathway by relying on Gli1 and Gli2 ubiquitination. Our studies also confirmed that TPL could significantly inhibit the tumor growth of EOC. Taken together, our results revealed that one of the antitumor mechanisms of TPL was the targeted inhibition of the Hh/Gli pathway.
Topics: Humans; Female; Hedgehog Proteins; Zinc Finger Protein GLI1; Signal Transduction; Ovarian Neoplasms; Cell Line, Tumor
PubMed: 37851362
DOI: 10.18632/aging.205110 -
Phytomedicine : International Journal... Jul 2024The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of...
BACKGROUND
The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of triptolide, has recently been evaluated in phase I and II clinical trials in patients with multiple cancers and has shown promise as an antileukemic agent. However, the molecular mechanism underlying minnelide's antileukemic activity remains unclear.
PURPOSE
To explore the molecular mechanisms by which minnelide exhibits antileukemic activity.
METHODS
AL cells, primary human leukemia cells, and a xenograft mouse model were treated with triptolide and minnelide. The molecular mechanism was elucidated using western blotting, immunoprecipitation, flow cytometry, GSEA and liquid chromatography-mass spectrometry analysis.
RESULTS
Minnelide was highly effective in inhibiting leukemogenesis and improving survival in two complementary AL mouse models. Triptolide, an active form of minnelide, causes cell cycle arrest in G1 phase and induces apoptosis in both human AL cell lines and primary AL cells. Mechanistically, we identified Ars2 as a new chemotherapeutic target of minnelide for AL treatment. We found that triptolide directly targeted Ars2, resulting in the downregulation of miR-190a-3p, which led to the disturbance of PTEN/Akt signaling and culminated in G1 cell cycle arrest and apoptosis.
CONCLUSIONS
Our findings demonstrate that targeting Ars2/miR-190a-3p signaling using minnelide could represent a novel chemotherapeutic strategy for AL treatment and support the evaluation of minnelide for the treatment of AL in clinical trials.
Topics: Phenanthrenes; Animals; Humans; Diterpenes; MicroRNAs; Epoxy Compounds; Cell Line, Tumor; Mice; Apoptosis; Xenograft Model Antitumor Assays; Leukemia; Organophosphates; Antineoplastic Agents, Phytogenic
PubMed: 38759317
DOI: 10.1016/j.phymed.2024.155724 -
Applied Biochemistry and Biotechnology Dec 2023Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children. The current major therapy is hormones for most steroid-sensitive...
Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children. The current major therapy is hormones for most steroid-sensitive patients. However, many patients have recurrent relapses of the disease and require long-term immunosuppression, leading to significant morbidity due to the side effects of the drugs. Therefore, better drugs need to be urgently explored to treat nephrotic syndrome while avoiding the side effects of drugs. Minnelide, a water-soluble prodrug of triptolide, has been proved to be effective in treating cancers in many clinical trials. This study aimed to investigate the therapeutic effect of minnelide in mice with adriamycin (ADR) nephropathy, its underlying protection mechanisms, and its reproductive toxicity. Minnelide was administered intraperitoneally to 6-8-week female mice with adriamycin nephropathy for 2 weeks, and the urine, blood, and kidney tissues were taken to analyze the therapeutic effect. In addition, we evaluated reproductive toxicity by measuring the levels of gonadal hormones and observing the histological changes in ovaries and testes. Primary mouse podocytes were exposed to puromycin (PAN) to damage the cytoskeleton and induce apoptosis, and then, triptolide was used to evaluate the therapeutic effect and underlying protection mechanisms in vitro. It was observed that minnelide dramatically alleviated proteinuria and apoptosis in mice with adriamycin nephropathy. In vitro, triptolide ameliorated puromycin-induced cytoskeletal rearrangement and apoptosis via reactive oxygen species-mediated mitochondrial pathway. In addition, minnelide caused no reproductive toxicity to male and female mice. The results suggested that minnelide might be a promising drug for nephrotic syndrome.
Topics: Humans; Child; Mice; Male; Female; Animals; Doxorubicin; Nephrotic Syndrome; Podocytes; Kidney Diseases; Proteinuria; Puromycin
PubMed: 37000351
DOI: 10.1007/s12010-023-04333-z -
The Oncologist Feb 2024Minnelide is a water-soluble prodrug of triptolide. Triptolide is an anticancer agent that targets cancer resistance through several mechanisms. Minnelide was evaluated...
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.
Topics: Humans; Antineoplastic Agents; Gastrointestinal Neoplasms; Neutropenia; Diterpenes; Epoxy Compounds; Phenanthrenes; Organophosphates
PubMed: 38169017
DOI: 10.1093/oncolo/oyad278 -
Aging Feb 2024Among aging adults, age-related macular degeneration (AMD), is a prevalent cause of blindness. Nevertheless, its progression may be halted by antioxidation in retinal...
Protective effects of triptolide against oxidative stress in retinal pigment epithelium cells via the PI3K/AKT/Nrf2 pathway: a network pharmacological method and experimental validation.
PURPOSE
Among aging adults, age-related macular degeneration (AMD), is a prevalent cause of blindness. Nevertheless, its progression may be halted by antioxidation in retinal pigment epithelium (RPE). The primary effective constituent of Tripterygium wilfordii Hook. F., triptolide (TP), has demonstrated anti-inflammatory, antiproliferative, and antioxidant properties. The mechanics of the protective effect of triptolide against the oxidative damage in retinal pigment epithelial (RPE) were assessed in this study.
METHODS
ARPE-19 cells were pretreated with TP, and then exposed to sodium iodate (SI). First, cell viability was assessed using CCK-8. Subsequently, we measured indicators for cell oxidation including reactive oxygen species (ROS), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). Then, we used network pharmacological analysis and molecular docking to explore the signaling pathway of TP. Last, we used western blot, ELISA, and immunofluorescence assays to clarify the potential mechanistic pathways.
RESULTS
The network pharmacology data suggested that TP may inhibit AMD by regulating the PI3K/Akt signaling pathway. Experimental results showed that the potential mechanism is that it regulates the PI3K/Akt pathway and promotes Nrf2 phosphorylation and activation, thereby raising the level of antioxidant factors (HO-1, NQO1) and reducing the generation of ROS, which inhibit oxidative damage.
CONCLUSION
Our findings suggested that the effect of TP on SI-exposed RPE cells principally relies on the regulation of oxidative stress through the PI3K/Akt/Nrf2 signaling pathway.
Topics: Humans; Reactive Oxygen Species; Proto-Oncogene Proteins c-akt; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Antioxidants; Retinal Pigment Epithelium; Molecular Docking Simulation; Network Pharmacology; Oxidative Stress; Macular Degeneration; Apoptosis; Diterpenes; Epoxy Compounds; Phenanthrenes
PubMed: 38393691
DOI: 10.18632/aging.205570 -
Journal of Orthopaedic Surgery and... Nov 2023Spinal cord ischemia-reperfusion injury (SCII) is a catastrophic event, which can cause paraplegia in severe cases. In the reperfusion stage, oxidative stress was...
BACKGROUND
Spinal cord ischemia-reperfusion injury (SCII) is a catastrophic event, which can cause paraplegia in severe cases. In the reperfusion stage, oxidative stress was up-regulated, which aggravated the injury and apoptosis of neurons. As the main active ingredient of garlic, diallyl trisulfide (DATS) displays strong antioxidant capacity. However, it is unknown whether DATS can protect the neurons of SCII.
MATERIALS AND METHODS
In this study, the descending aorta at the distal end of the left subclavian artery was ligated and perfused again after 14 min. Samples including blood and spinal cord (L2-L5) were taken 24 h later for morphological and biochemical examination.
RESULTS
After SCII, the rats showed motor dysfunction, increase apoptosis, malondialdehyde content, mitochondrial biogenesis and dynamic balance disorder. After the application of DATS, the adenosine monophosphate activated protein kinase (AMPK) was activated, the mitochondrial damage was improved, the oxidative stress was weakened, and the neuronal damage was recovered to some extent. However, the addition of compound C significantly weakened the protective effect of DATS.
CONCLUSION
Oxidative stress caused by mitochondrial damage was one of the important mechanisms of neuronal damage in SCII. DATS could activate AMPK, stabilize mitochondrial biogenesis and dynamic balance, and reduce neuronal damage caused by oxidative stress.
Topics: Rats; Animals; AMP-Activated Protein Kinases; Oxidative Stress; Reperfusion Injury; Antioxidants; Spinal Cord; Apoptosis; Mitochondria
PubMed: 37932742
DOI: 10.1186/s13018-023-04176-8