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Renal Failure Dec 2023Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte...
Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated the mechanism of triptolide (TP) in podocyte injury in DN. DN mouse models were established by feeding with a high-fat diet and injecting with streptozocin and MPC5 podocyte injury models were induced by high-glucose (HG), followed by TP treatment. Fasting blood glucose and renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), blood urea nitrogen (BUN), and kidney/body weight ratio of mice were examined. H&E and TUNEL staining were performed for evaluating pathological changes and apoptosis in renal tissue. The podocyte markers, reactive oxygen species (ROS), oxidative stress (OS), serum inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, and pyroptosis were detected by Western blotting and corresponding kits. MPC5 cell viability and pyroptosis were evaluated by MTT and Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify the regulation of TP on Nrf2. TP improved renal function and histopathological injury of DN mice, alleviated podocytes injury, reduced OS and ROS by activating the Nrf2/heme oxygenase-1 (HO-1) pathway, and weakened pyroptosis by inhibiting the nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. experiments further verified the inhibition of TP on OS and pyroptosis by mediating the Nrf2/HO-1 and NLRP3 inflammasome pathways. Inhibition of Nrf2 reversed the protective effect of TP on MPC5 cells. Overall, TP alleviated podocyte injury in DN by inhibiting OS and pyroptosis Nrf2/ROS/NLRP3 axis.
Topics: Animals; Mice; Diabetes Mellitus; Diabetic Nephropathies; Heme Oxygenase-1; Inflammasomes; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Podocytes; Reactive Oxygen Species
PubMed: 36938748
DOI: 10.1080/0886022X.2023.2165103 -
Biomedicine & Pharmacotherapy =... Oct 2023Fibrotic extracellular matrix (ECM) remodeling characterized different types of pulmonary fibrosis, and its regulation could be a potential shared treatment strategy for...
BACKGROUND
Fibrotic extracellular matrix (ECM) remodeling characterized different types of pulmonary fibrosis, and its regulation could be a potential shared treatment strategy for pulmonary fibrosis.
PURPOSE
We aimed to investigate the effect of triptolide on pulmonary fibrosis through the inhibition of several important aspects of fibrotic ECM remodeling.
METHODS
Bleomycin-induced pulmonary fibrosis mice and TGF-β-induced primary lung fibroblasts were used. The effect of triptolide on pulmonary fibrosis was detected using histopathology, immunostaining, RT-qPCR, western blotting, ELISA, and protein activity assay.
RESULTS
Triptolide significantly alleviated bleomycin-induced pulmonary fibrosis in mice. It inhibited the expression of fibrotic genes α-SMA, collagen I, fibronectin, and vimentin and blocked the TGF-β-SMAD signaling pathway both in vivo and in vitro. In addition, triptolide regulated the expression and activity of MMPs during fibrosis. Interestingly, it suppressed the expression of lysyl oxidase, which was responsible for matrix cross-linking and elevated ECM stiffness. Furthermore, triptolide blocked the biomechanical stress transduction pathway integrin-β1-FAK-YAP signaling and attenuated the pro-fibrotic feedback of fibrotic ECM on fibroblasts via integrin inhibition.
CONCLUSION
These findings show that triptolide prevents the key linkages of fibrotic ECM remodeling, including deposition, degradation, cross-linking, and pro-fibrotic feedback and, therefore, has potential therapeutic value for pulmonary fibrosis.
Topics: Animals; Mice; Bleomycin; Extracellular Matrix; Integrins; Protein-Lysine 6-Oxidase; Pulmonary Fibrosis; Transforming Growth Factor beta; Matrix Metalloproteinases
PubMed: 37660647
DOI: 10.1016/j.biopha.2023.115394 -
Cancer Biology & Therapy Dec 2023Translocation of 14-3-3 protein epsilon (14-3-3ε) was found to be involved in Triptolide (Tp)-induced inhibition of colorectal cancer (CRC) cell proliferation. However,...
Translocation of 14-3-3 protein epsilon (14-3-3ε) was found to be involved in Triptolide (Tp)-induced inhibition of colorectal cancer (CRC) cell proliferation. However, the form of cell death induced by 14-3-3ε translocation and mechanisms underlying this effect remain unclear. This study employed label-free LC-MS/MS to identify 14-3-3ε-associated proteins in CRC cells treated with or without Tp. Our results confirmed that heterogeneous nuclear ribonucleoproteins C1/C2 (hnRNP C) were exported out of the nucleus by 14-3-3ε and degraded by ubiquitination. The nucleo-cytoplasmic shuttling of 14-3-3ε carrying hnRNP C mediated Tp-induced proliferation inhibition, cell cycle arrest and autophagic processes. These findings have broad implications for our understanding of 14-3-3ε function, provide an explanation for the mechanism of nucleo-cytoplasmic shuttling of hnRNP C and provide new insights into the complex regulation of autophagy.
Topics: Humans; Autophagy; Chromatography, Liquid; Cytoplasm; Heterogeneous-Nuclear Ribonucleoproteins; Tandem Mass Spectrometry; 14-3-3 Proteins; Heterogeneous-Nuclear Ribonucleoprotein Group C
PubMed: 37599448
DOI: 10.1080/15384047.2023.2246203 -
Molecular Cancer Dec 2023Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients...
Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study.
BACKGROUND
Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy.
METHODS
We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL.
RESULTS
Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia.
CONCLUSIONS
We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL.
TRIAL REGISTRATION
NCT05338931; Date: 2022-04-01.
Topics: Humans; Antibodies; Antigens, CD19; Epitopes; Immunotherapy, Adoptive; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell
PubMed: 38066564
DOI: 10.1186/s12943-023-01886-9 -
Journal of Nanobiotechnology Oct 2023Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not...
Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe and TA. Fe is reduced to Fe by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.
Topics: Humans; Pyroptosis; Ferroptosis; Metal-Organic Frameworks; Reactive Oxygen Species; Neoplasms; Melanoma; Immunotherapy; Lung Neoplasms; Cell Line, Tumor
PubMed: 37858186
DOI: 10.1186/s12951-023-02146-0 -
Nutrients Sep 2023It is hypothesized that garlic, , might protect against oxidative stress that causes damage to cells and tissues leading to the development of various health conditions...
It is hypothesized that garlic, , might protect against oxidative stress that causes damage to cells and tissues leading to the development of various health conditions including cancer. However, it is not known whether garlic's potential anticancer benefits differ by form of garlic consumed. This study aimed to quantify and compare the in vitro antioxidant and antiproliferative activity of several garlic forms in water and alcohol extracts including fresh garlic, fresh garlic set aside, heated garlic, heated garlic set aside, garlic powder, black garlic, two commercially available garlic supplements. Antioxidant activity of different garlic forms were measured using three assays: DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay, superoxide assay, and hydroxyl assay. In vitro effects of garlic extracts were investigated against the most common lung cancer subtypes: H520, H1975, and A549 cell lines using the sulforhodamine B (SRB) assay. Among free radical scavenging assays, Garlicin, a commercially available supplement, displayed high antioxidant activity in water and alcohol extracts (DPPH assay: 2.02 mg AAE (mg ascorbic acid equivalent)/g garlic and 3.53 mg AAE/g garlic, respectively; superoxide assay: 6.73 mg AAE/g garlic and 7.13 mg AAE/g garlic, respectively). In the hydroxyl assay, water extract of fresh garlic crushed and set aside for 10 min showed the highest antioxidant activity. Garlicin alcohol extract and fresh garlic water extracts strongly inhibited the proliferation of H1975, A549 and H520 cells. Other forms of garlic including garlic powder and black garlic exhibited low antioxidant and antiproliferative activity. Our results demonstrate that the preparation and processing methods of garlic may lead to different antioxidant benefits.
Topics: Antioxidants; Garlic; Superoxides; Powders; Plant Extracts; Water
PubMed: 37836382
DOI: 10.3390/nu15194099 -
International Immunopharmacology Nov 2023Hypoxic-ischemic encephalopathy (HIE) is a perinatal brain disease caused by hypoxia in neonates. It is one of the leading causes of neonatal death in the perinatal...
Hypoxic-ischemic encephalopathy (HIE) is a perinatal brain disease caused by hypoxia in neonates. It is one of the leading causes of neonatal death in the perinatal period, as well as disability beyond the neonatal period. Due to the lack of a unified and comprehensive treatment strategy for HIE, research into its pathogenesis is essential. Diallyl disulfide (DADS) is an allicin extract, with detoxifying, antibacterial, and cardiovascular disease protective effects. This study aimed to determine whether DADS can alleviate HIE induced brain damage in rats and oxygen-glucose deprivation (OGD)-induced pyroptosis in PC12 cells, as well as whether it can inhibit pyroptosis via the NLRP3/Caspase-1/IL-1β signaling pathway. In vivo, DADS significantly reduced the cerebral infarction volume, alleviated inflammatory reaction, reduced astrocyte activation, promoted tissue structure recovery, improved pyroptosis caused by HIE and improved the prognosis following HI injury. In vitro findings indicated that DADS increased cell activity, decreased LDH activity and reduced the expression of pyroptosis-related proteins, including IL-1β, IL-18, and certain inflammatory factors in PC12 cells caused by OGD. Mechanistically, DADS inhibited pyroptosis and protected against HIE via the NLRP3/Caspase-1/IL-1β pathway. The specific inhibitor of caspase-1, VX-765, inhibited caspase-1 activation, and IL-1β expression was determined. Additionally, the overexpression of NLRP3 reversed the protective effect of allicin against OGD-induced pyroptosis. In conclusion, these findings demonstrated that DADS inhibits the NLRP3/Caspase-1/IL-1β signaling pathway and decreases HI brain damage.
Topics: Pregnancy; Female; Rats; Animals; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Animals, Newborn; Caspase 1; Hypoxia-Ischemia, Brain; Oxygen; Brain; Signal Transduction; Inflammasomes
PubMed: 37844463
DOI: 10.1016/j.intimp.2023.111030 -
Cell Death & Disease Sep 2023Minimal change disease (MCD) is the common type of nephrotic syndrome (NS) in children. Currently, there is an urgent need to explore new treatments because of the...
Minimal change disease (MCD) is the common type of nephrotic syndrome (NS) in children. Currently, there is an urgent need to explore new treatments because of the significant side effects of long-term use of glucocorticoids and immunosuppressive drugs and the failure to reduce proteinuria in some patients. Angiopoietin-like protein 3 (Angptl3) is an essential target of NS, and anti-ANGPTL3-FLD monoclonal antibody (mAb) significantly reduces proteinuria in mice with adriamycin nephropathy (AN). However, some proteinuria is persistent. Minnelide, a water-soluble prodrug of triptolide, has been used for the treatment of glomerular disease. Therefore, the present study aimed to investigate whether minnelide combined with mAb could further protect mice with AN and the underlying mechanisms. 8-week-old C57BL/6 female mice were injected with 25 mg/kg of Adriamycin (ADR) by tail vein to establish the AN model. A dose of 200 μg/kg of minnelide or 20 mg/kg of mAb was administered intraperitoneally for the treatment. In vitro, the podocytes were treated with 0.4 μg/mL of ADR for 24 h to induce podocyte injury, and pretreatment with 10 ng/mL of triptolide for 30 min or 100 ng/mL of mAb for 1 h before ADR exposure was used to treat. The results showed that minnelide combined with mAb almost completely ameliorates proteinuria and restores the ultrastructure of the podocytes in mice with AN. In addition, minnelide combined with mAb restores the distribution of Nephrin, Podocin, and CD2AP and reduces the level of inflammatory factors in mice with AN. Mechanistically, minnelide combined with mAb could further alleviate apoptosis and promote autophagy in mice with AN by inhibiting the mTOR signaling pathway. In vitro, triptolide combined with mAb increases the expression of Nephrin, Podocin, and CD2AP, alleviates apoptosis, and promotes autophagy. Overall, minnelide combined with mAb completely protects the mice with AN by promoting autophagy and inhibiting apoptosis.
Topics: Female; Animals; Mice; Mice, Inbred C57BL; Antibodies, Monoclonal; Kidney Diseases; Proteinuria; Apoptosis; Autophagy; Doxorubicin
PubMed: 37689694
DOI: 10.1038/s41419-023-06124-0 -
European Review For Medical and... Nov 2023Triptolide, a compound isolated from a Chinese medicinal herb, has potent antitumor, immunosuppressive, and anti-inflammatory properties. Due to its interesting... (Review)
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.
Topics: Immunosuppressive Agents; Phenanthrenes; Epoxy Compounds
PubMed: 37975343
DOI: 10.26355/eurrev_202311_34294 -
Nutrients Jun 2023() is a plant belonging to the Cactaceae family that is abundant in tropical and subtropical regions worldwide. is consumed as a local delicacy and has no other... (Review)
Review
() is a plant belonging to the Cactaceae family that is abundant in tropical and subtropical regions worldwide. is consumed as a local delicacy and has no other current use. To understand the nutritional value of in human health and its application in the food, cosmetic, and drug industries, this review summarizes information on the chemical compounds (pure α-pyrone compounds, flavonoids, phenolic acids, polysaccharides, minerals, fatty acids, and betalains) and biological properties (anti-diabetic, anti-hyperglycemic, antihyperlipidemic, anti-atherosclerotic, anti-inflammatory, analgesic, antimicrobial, antifungal, antiviral, anti-spermatogenic, anticancer, antilarval, anti-angiogenic, and antioxidant) of extracts from each part of the plant (fruit juice, fruit peel, cladode, and seeds) (aqueous, ethanolic, and methanolic), and seed oil. In addition, data related to the recent applications of in various industries (e.g., edible coatings, food supplements, cosmetics, nanoparticles, and wastewater treatment) are provided.
Topics: Humans; Opuntia; Antioxidants; Plant Extracts; Flavonoids; Anti-Infective Agents; Fruit
PubMed: 37447287
DOI: 10.3390/nu15132962