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International Journal of Molecular... Apr 2024Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes...
Triptolide is a natural compound in herbal remedies with anti-inflammatory and anti-proliferative properties. We studied its effects on critical signaling processes within the cell, including Notch1 and STAT3 signaling. Our research showed that triptolide reduces cancer cell proliferation by decreasing the expression of downstream targets of these signals. The levels of each signal-related protein and mRNA were analyzed using Western blot and qPCR methods. Interestingly, inhibiting one signal with a single inhibitor alone did not significantly reduce cancer cell proliferation. Instead, MTT assays showed that the simultaneous inhibition of Notch1 and STAT3 signaling reduced cell proliferation. The effect of triptolide was similar to a combination treatment with inhibitors for both signals. When we conducted a study on the impact of triptolide on zebrafish larvae, we found that it inhibited muscle development and interfered with muscle cell proliferation, as evidenced by differences in the staining of myosin heavy chain and F-actin proteins in confocal fluorescence microscopy. Additionally, we noticed that inhibiting a single type of signaling did not lead to any significant muscle defects. This implies that triptolide obstructs multiple signals simultaneously, including Notch1 and STAT3, during muscle development. Chemotherapy is commonly used to treat cancer, but it may cause muscle loss due to drug-related adverse reactions or other complex mechanisms. Our study suggests that anticancer agents like triptolide, inhibiting essential signaling pathways including Notch1 and STAT3 signaling, may cause muscle atrophy through anti-proliferative activity.
Topics: Animals; Humans; Cell Line, Tumor; Cell Proliferation; Diterpenes; Epoxy Compounds; Phenanthrenes; Receptor, Notch1; Receptors, Notch; Signal Transduction; STAT3 Transcription Factor; Zebrafish; Zebrafish Proteins
PubMed: 38731894
DOI: 10.3390/ijms25094675 -
International Journal of Nanomedicine 2024Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent,...
BACKGROUND
Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy.
METHODS
In this study, we synthesized a pH/ROS dual-responsive mPEG--PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG--PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice.
RESULTS
The mPEG--PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity.
CONCLUSION
Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.
Topics: Animals; Humans; Chlorophyllides; Photochemotherapy; Reactive Oxygen Species; Hep G2 Cells; Liver Neoplasms; Porphyrins; Diterpenes; Hydrogen-Ion Concentration; Photosensitizing Agents; Mice, Nude; Apoptosis; Mice; Carcinoma, Hepatocellular; Epoxy Compounds; Nanoparticles; Xenograft Model Antitumor Assays; Antineoplastic Agents; Drug Liberation; Cell Proliferation; Polyethylene Glycols; Combined Modality Therapy; Phenanthrenes
PubMed: 38699684
DOI: 10.2147/IJN.S453199 -
Biomolecules Mar 2024Individuals who are overweight or obese are at increased risk of developing prediabetes and type 2 diabetes, yet the direct molecular mechanisms that connect diabetes to...
Individuals who are overweight or obese are at increased risk of developing prediabetes and type 2 diabetes, yet the direct molecular mechanisms that connect diabetes to obesity are not clear. Chronic, sustained inflammation is considered a strong risk factor in these interactions, directed in part by the short-lived gene expression programs encoding for cytokines and pro-inflammatory mediators. In this study, we show that triptolide administration in the C57BL/6 diet-induced obese mice at up to 10 μg/kg/day for 10 weeks attenuated the development of insulin resistance and diabetes, but not obesity, in these animals. Significant reductions in adipose tissue inflammation and improved insulin sensitivity were observed in the absence of changes in food intake, body weight, body composition, or energy expenditure. Analysis of the core cluster of biomarkers that drives pro-inflammatory responses in the metabolic tissues suggested TNF-α as a critical point that affected the co-development of inflammation and insulin resistance, but also pointed to the putatively protective roles of increased COX-2 and IL-17A signaling in the mediation of these pathophysiological states. Our results show that reduction of diet-induced inflammation confers partial protection against insulin resistance, but not obesity, and suggest the possibility of achieving overweight phenotypes that are accompanied by minimal insulin resistance if inflammation is controlled.
Topics: Animals; Insulin Resistance; Epoxy Compounds; Diterpenes; Phenanthrenes; Obesity; Mice; Mice, Inbred C57BL; Male; Inflammation; Adipose Tissue; Interleukin-17; Diet, High-Fat; Tumor Necrosis Factor-alpha; Diabetes Mellitus, Type 2; Cyclooxygenase 2; Energy Metabolism
PubMed: 38672413
DOI: 10.3390/biom14040395 -
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 Apr 2024Photothermal immunotherapy is regarded as the ideal cancer therapeutic modality to against malignant solid tumors; however, its therapeutic benefits are often modest and...
Photothermal immunotherapy is regarded as the ideal cancer therapeutic modality to against malignant solid tumors; however, its therapeutic benefits are often modest and require improvement. In this study, a thermoresponsive nanoparticle (BTN@LND) composed of a photothermal agent (PTA) and pyroptosis inducer (lonidamine) were developed to enhance immunotherapy applications. Specifically, our "two-step" donor engineering strategy produced the strong NIR-II-absorbing organic small-molecule PTA (BTN) that exhibited high NIR-II photothermal performance (ε = 1.51 × 10 M cm, η = 75.8%), and this facilitates the diagnosis and treatment of deep tumor tissue. Moreover, the fabricated thermally responsive lipid nanoplatform based on BTN efficiently delivered lonidamine to the tumor site and achieved spatiotemporal release triggered by the NIR-II photothermal effect. In vitro and in vivo experiments demonstrated that the NIR-II photothermal therapy (PTT)-mediated on-demand release of cargo effectively faciliated tumor cell pyroptosis, thereby intensifying the immunogenic cell death (ICD) process to promote antitumor immunotherapy. As a result, this intelligent component bearing photothermal and chemotherapy can maximally suppress the growth of tumors, thus providing a promising approach for pyroptosis/NIR-II PTT synergistic therapy against tumors.
Topics: Humans; Phototherapy; Pyroptosis; Nanoparticles; Neoplasms; Immunotherapy; Cell Line, Tumor; Indazoles
PubMed: 38600506
DOI: 10.1186/s12951-024-02424-5 -
Brain Research Bulletin Jun 2024To evaluate the potential efficacy of Triptolide (TP) on cerebral ischemia/reperfusion injury (CIRI) and to uncover the underlying mechanism through which TP regulates...
PURPOSE
To evaluate the potential efficacy of Triptolide (TP) on cerebral ischemia/reperfusion injury (CIRI) and to uncover the underlying mechanism through which TP regulates CIRI.
METHODS
We constructed a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate CIRI, and established a lipopolysaccharide (LPS)-stimulated BV-2 cell model to mimic the inflammatory state during CIRI. The neurological deficits score (NS) of mice were measured for assessment of neurologic functions. Both the severity of cerebral infarction and the apoptosis level in mouse brain tissues or cells were respectively evaluated using corresponding techniques. The expression levels of Ionized calcium binding adapter molecule 1 (IBA-1), Inductible Nitric Oxide Synthase (iNOS), Arginase 1 (Arg-1), Tumor necrosis factor-α (TNF-α), Interleukin 1β (IL-1β), Cysteine histoproteinase S (CTSS), Fractalkine, chemokine C-X3-C motif receptor 1 (CX3CR1), BCL-2-associated X protein (BAX), and antiapoptotic proteins (Bcl-2) were detected using immunofluorescence, qRT-PCR as well as Western blot, respectively.
RESULTS
Relative to the Sham group, treatment with TP attenuated the increased NS, infarct area and apoptosis levels observed in MCAO/R mice. Upregulated expression levels of IBA-1, iNOS, Arg-1, TNF-α and IL-1β were found in MCAO/R mice, while TP suppressed iNOS, TNF-α and IL-1β expression, and enhanced Arg-1 expression in both MCAO/R mice and LPS-stimulated BV-2 cells. Besides, TP inhibited the CTSS/Fractalkine/CX3CR1 pathway activation in both MCAO/R mice and LPS-induced BV-2 cells, while overexpression of CTSS reversed such effect. Co-culturing HT-22 cells with TP+LPS-treated BV-2 cells led to enhanced cell viability and decreased apoptosis levels. However, overexpression of CTSS further aggravated HT-22 cell injury.
CONCLUSION
TP inhibits not only microglia polarization towards the M1 phenotype by suppressing the CTSS/Fractalkine/CX3CR1 pathway activation, but also HT-22 apoptosis by crosstalk with BV-2 cells, thereby ameliorating CIRI. These findings reveal a novel mechanism of TP in improving CIRI, and offer potential implications for addressing the preventive and therapeutic strategies of CIRI.
Topics: Animals; Male; Mice; Apoptosis; Brain Ischemia; Chemokine CX3CL1; CX3C Chemokine Receptor 1; Disease Models, Animal; Diterpenes; Epoxy Compounds; Infarction, Middle Cerebral Artery; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Phenanthrenes; Reperfusion Injury; Signal Transduction
PubMed: 38574865
DOI: 10.1016/j.brainresbull.2024.110939 -
Acta Cirurgica Brasileira 2024XinJiaCongRongTuSiZiWan (XJCRTSZW) is a traditional Chinese medicine compound for invigorating the kidney, nourishing blood, and promoting blood circulation. This study...
PURPOSE
XinJiaCongRongTuSiZiWan (XJCRTSZW) is a traditional Chinese medicine compound for invigorating the kidney, nourishing blood, and promoting blood circulation. This study aimed to explore the effect of XJCRTSZW on triptolide (TP)-induced oxidative stress injury.
METHODS
Adult female Sprague-Dawley rats and human ovarian granulosa cell lines were treated with TP and XJCRTSZW. Hematoxylin and eosin staining, enzyme-linked immunosorbent assay, flow cytometry, CCK-8, JC-1 staining, transmission electron microscopy, reverse transcription-quantitative polymerase chain reaction, and Western blotting were performed in this study.
RESULTS
XJCRTSZW treatment observably ameliorated the TP-induced pathological symptoms. Furthermore, XJCRTSZW treatment observably enhanced the TP-induced reduction of estradiol, anti-Mullerian hormone, progesterone, superoxide dismutase, ATP content, mitochondrial membrane potential, p62, and Hsp60 mRNA, and protein levels in vivo and in vitro (p < 0.05). However, TP-induced elevation of follicle stimulating hormone and luteinizing hormone concentrations, malondialdehyde levels, reactive oxygen species levels, apoptosis rate, mitophagy, and the mRNA and protein expressions of LC3-II/LC3-I, PTEN-induced kinase 1 (PINK1), and Parkin were decreased (p < 0.05). In addition, XJCRTSZW treatment markedly increased cell viability in vitro (p < 0.05).
CONCLUSIONS
XJCRTSZW protects TP-induced rats from oxidative stress injury via the mitophagy-mediated PINK1/Parkin pathway.
Topics: Adult; Rats; Female; Humans; Animals; Mitophagy; Rats, Sprague-Dawley; Mitochondria; Oxidative Stress; Ubiquitin-Protein Ligases; Signal Transduction; Protein Kinases; RNA, Messenger; Diterpenes; Epoxy Compounds; Phenanthrenes
PubMed: 38511762
DOI: 10.1590/acb391424 -
BMC Complementary Medicine and Therapies Mar 2024Triptolide is a widely utilized natural anti-inflammatory drug in clinical practice. Aim of this study was to evaluate effects of triptolide on hPDLSCs osteogenesis in...
Triptolide mitigates the inhibition of osteogenesis induced by TNF-α in human periodontal ligament stem cells via the p-IκBα/NF-κB signaling pathway: an in-vitro study.
BACKGROUND
Triptolide is a widely utilized natural anti-inflammatory drug in clinical practice. Aim of this study was to evaluate effects of triptolide on hPDLSCs osteogenesis in an inflammatory setting and to investigate underlying mechanisms.
METHODS
Using the tissue block method to obtain hPDLSCs from extracted premolar or third molar. Flow cytometry, osteogenic and adipogenic induction were carried out in order to characterise the features of the cells acquired. hPDLSC proliferative activity was assessed by CCK-8 assay to determine the effect of TNF-α and/or triptolide. The impact of triptolide on the osteogenic differentiation of hPDLSCs was investigated by ALP staining and quantification. Osteogenesis-associated genes and proteins expression level were assessed through PCR and Western blotting assay. Finally, BAY-117,082 was used to study the NF-κB pathway.
RESULTS
In the group treated with TNF-α, there was an elevation in inflammation levels while osteogenic ability and the expression of both osteogenesis-associated genes and proteins decreased. In the group co-treated with TNF-α and triptolide, inflammation levels were reduced and osteogenic ability as well as the expression of both osteogenesis-associated genes and proteins were enhanced. At the end of the experiment, both triptolide and BAY-117,082 exerted similar inhibitory effects on the NF-κB pathway.
CONCLUSION
The osteogenic inhibition of hPDLSCs by TNF-α can be alleviated through triptolide, with the involvement of the p-IκBα/NF-κB pathway in this mechanism.
Topics: Humans; NF-kappa B; Tumor Necrosis Factor-alpha; Osteogenesis; NF-KappaB Inhibitor alpha; Periodontal Ligament; Signal Transduction; Stem Cells; Inflammation; Diterpenes; Epoxy Compounds; Phenanthrenes
PubMed: 38448925
DOI: 10.1186/s12906-024-04408-2 -
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 -
International Journal of Biological... 2024Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the...
Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the growth of colorectal cancer (CRC) cells have not been clarified. Herein, we show that DADS treatment impairs the activation of the pentose phosphate pathway (PPP) to decrease PRPP (5-phosphate ribose-1-pyrophosphate) production, enhancing DNA damage and cell apoptosis, and inhibiting the growth of CRC cells. Mechanistically, DADS treatment promoted POU2F1 K48-linked ubiquitination and degradation by attenuating the PI3K/AKT signaling to up-regulate TRIM21 expression in CRC cells. Evidently, TRIM21 interacted with POU2F1, and induced the K272 ubiquitination of POU2F1. The effects of DADS on the enhanced K272 ubiquitination of POU2F1, the PPP flux, PRPP production, DNA damage and cell apoptosis as well as the growth of CRC tumors were significantly mitigated by TRIM21 silencing or activating the PI3K signaling in CRC cells. Conversely, the effects of DADS were enhanced by TRIM21 over-expression or inhibiting the PI3K/AKT signaling in CRC cells. Collectively, our findings reveal a novel mechanism by which DADS suppresses the growth of CRC by promoting POU2F1 ubiquitination, and may aid in design of novel therapeutic intervention of CRC.
Topics: Humans; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Apoptosis; Allyl Compounds; Colorectal Neoplasms; DNA Damage; Octamer Transcription Factor-1; Disulfides; 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid
PubMed: 38385081
DOI: 10.7150/ijbs.91206