Review

Authors: Yang Yang, Huanan Wang, Mohammed Kouadir...

The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer's disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.

Topics: Animals; Calcium Signaling; Diterpenes, Kaurane; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Indenes; Inflammasomes; Lysosomes; Metals, Alkali; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Nitriles; Protein Processing, Post-Translational; Reactive Oxygen Species; Sulfonamides; Sulfones; Thiazolidines; Thiones; ortho-Aminobenzoates

PubMed: 30755589
DOI: 10.1038/s41419-019-1413-8

Authors: Xiaohan Gao, Yan Wang, Fang Lu...

Cachexia, characterized by loss of skeletal muscle mass and function, is estimated to inflict the majority of patients with oesophageal squamous cell carcinoma (ESCC) and associated with their poor prognosis. However, its underlying mechanisms remain elusive. Here, we developed an ESCC-induced cachexia mouse model using human xenograft ESCC cell lines and found that ESCC-derived extracellular vesicles (EVs) containing prolyl 4-hydroxylase subunit beta (P4HB) induced apoptosis of skeletal muscle cells. We further identified that P4HB promoted apoptotic response through activating ubiquitin-dependent proteolytic pathway and regulated the stability of phosphoglycerate dehydrogenase (PHGDH) and subsequent antiapoptotic protein Bcl-2. Additionally, we proved that the P4HB inhibitor, CCF642, not only rescued apoptosis of muscle cells in vitro, but also prevented body weight loss and muscle wasting in ESCC-induced cachexia mouse model. Overall, these findings demonstrate a novel pathway for ESCC-induced muscle wasting and advocate for the development of P4HB as a potential intervention target for cachexia in patients with ESCC.

Topics: Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Drug Delivery Systems; Esophageal Squamous Cell Carcinoma; Extracellular Vesicles; Humans; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscular Atrophy; Phosphoglycerate Dehydrogenase; Procollagen-Proline Dioxygenase; Protein Disulfide-Isomerases; Thiazolidines; Thiones

PubMed: 33732415
DOI: 10.1002/jev2.12060

Authors: Hua Jiang, Hongbin He, Yun Chen...

The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.

Topics: Adult; Animals; Cell Line, Tumor; Cryopyrin-Associated Periodic Syndromes; Diabetes Mellitus, Type 2; Disease Models, Animal; HEK293 Cells; Humans; Immunoblotting; Inflammasomes; Inflammation; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Molecular Structure; NLR Family, Pyrin Domain-Containing 3 Protein; Small Molecule Libraries; Thiazolidines; Thiones

PubMed: 29021150
DOI: 10.1084/jem.20171419

Authors: Masataka Kawamura, Catherine Parmentier, Samrat Ray...

We previously reported that normothermic ex vivo kidney  perfusion (NEVKP) is superior in terms of organ protection compared to static cold storage (SCS), which is still the standard method of organ preservation, but the mechanisms are incompletely understood. We used a large animal kidney autotransplant model to evaluate mitochondrial function during organ preservation and after kidney transplantation, utilizing live cells extracted from fresh kidney tissue. Male porcine kidneys stored under normothermic perfusion showed preserved mitochondrial function and higher ATP levels compared to kidneys stored at 4 °C (SCS). Mitochondrial respiration and ATP levels were further enhanced when AP39, a mitochondria-targeted hydrogen sulfide donor, was administered during warm perfusion. Correspondingly, the combination of NEVKP and AP39 was associated with decreased oxidative stress and inflammation, and with improved graft function after transplantation. In conclusion, our findings suggest that the organ-protective effects of normothermic perfusion are mediated by maintenance of mitochondrial function and enhanced by AP39 administration. Activation of mitochondrial function through the combination of AP39 and normothermic perfusion could represent a new therapeutic strategy for long-term renal preservation.

Topics: Animals; Kidney Transplantation; Mitochondria; Kidney; Organ Preservation; Male; Swine; Warm Ischemia; Perfusion; Hydrogen Sulfide; Adenosine Triphosphate; Oxidative Stress; Organophosphorus Compounds; Thiones

PubMed: 39278958
DOI: 10.1038/s41467-024-52140-9

Authors: Shihui Yu, Zhiting Cao, Fangfang Cai...

High basal autophagy and enhanced mitochondrial fission in triple-negative breast cancer (TNBC) cells support cell migration and promote plasticity of cancer cell metabolism. Here, we suggest a novel combination therapy approach for the treatment of TNBC that targets Drp1-mediated mitochondrial fission and autophagy pathways. Hydrogen sulfide (HS) mediates a myriad of biological processes, including autophagy and mitochondrial function. In this study, we demonstrated that 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), one of the most widely utilized sustained-release HS donors, effectively suppresses metastasis of TNBC cells in the absence of proliferation inhibition in vitro and in vivo. ADT-OH treatment ameliorated autophagy flux by suppressing autophagosome formation and induced mitochondrial elongation through decreasing expression of dynamin-related protein 1 (Drp1) and increasing expression of mitochondrial fusion protein (Mfn2). At the same time, ADT-OH downregulated mitophagy flux and inhibited mitochondrial function, eventually leading to the inhibition of migration and invasion in TNBC cells. In vivo, intraperitoneal administration of ADT-OH revealed a potent anti-metastatic activity in three different animal models, the MDA-MB-231 orthotopic xenograft model, the 4T1-Luci orthotopic model and the 4T1-Luci tail vein metastasis model. However, ADT-OH has an extremely low water solubility, which is a significant barrier to its effectiveness. Thus, we demonstrated that the solubility of ADT-OH in water can be improved significantly by absorption with hydroxypropyl-β-cyclodextrin (CD). Remarkably, the obtained CD-ADT-OH demonstrated superior anti-cancer effect to ADT-OH in vivo. Altogether, this study describes a novel regulator of mammalian mitochondrial fission and autophagy, with potential utility as an experimental therapeutic agent for metastatic TNBC.

Topics: Triple Negative Breast Neoplasms; Mitochondrial Dynamics; Humans; Animals; Autophagy; Female; Cell Line, Tumor; Mice; Cell Movement; Mice, Nude; Thiones; Xenograft Model Antitumor Assays; Mice, Inbred BALB C; Mitochondria; Cell Proliferation; Neoplasm Metastasis; Hydrogen Sulfide; Dynamins; Thiophenes

PubMed: 38942765
DOI: 10.1038/s41419-024-06829-w

Authors: Yunfei Luo, Shaohua Sun, Yuying Zhang...

PURPOSE

Oltipraz has various applications, including for treating cancer, liver fibrosis, and cirrhosis. However, its role in regulating metabolic processes, inflammation, oxidative stress, and insulin resistance in STZ-induced T2DM remains unclear. Hence, a comprehensive understanding of how oltipraz ameliorates diabetes, particularly inflammation and oxidative stress, is imperative.

METHODS

The negative control (NC), T2DM model (T2DM), and T2DM models treated with oltipraz (OLTI) and metformin (MET) were constructed. The RNA sequencing (RNA-Seq) was performed on the pancreatic tissues. H&E staining was conducted on the liver and pancreatic tissues. The intraperitoneal glucose tolerance test (IPGTT), blood glucose and lipids, inflammatory factors, and oxidative stress indexes were measured. qPCR and Western blotting examined the nuclear factor erythroid-derived 2-like 2 (Nrf2) hemoglobin-1 (HO-1) signaling pathway, cell apoptosis-related genes, and Reg3g levels. Immunofluorescence (IF) analysis of the pancreas was performed to measure insulin secretion.

RESULTS

A total of 256 DEGs were identified in OLTI_vs_T2DM, and they were mainly enriched in circadian rhythm, cAMP, AMPK, insulin, and MAPK signaling pathways. Moreover, Reg3g exhibits reduced expression in T2DM_vs_NC, and elevated expression in OLTI_vs_T2DM, yet remains unchanged in MET_vs_T2DM. OLTI reduced fasting blood glucose and alleviated T2DM-induced weight loss. It improved blood glucose and insulin resistance, decreased blood lipid metabolism, reduced inflammation and oxidative stress through the Nrf2/HO-1 signaling pathway, mitigated pancreatic and liver tissue injury, and enhanced pancreatic β-cell insulin secretion. OLTI exhibited anti-apoptosis effects in T2DM. Moreover, OLTI exhibits superior antioxidant activity than metformin.

CONCLUSION

In summary, OLTI improves blood glucose and insulin resistance, decreases blood lipid metabolism, reduces inflammation and apoptosis, suppresses oxidative stress through the Nrf2/HO-1 signaling pathway, mitigates pancreatic and liver tissue injury, and enhances pancreatic β-cell insulin secretion, thereby mitigating T2DM symptoms. Moreover, Reg3g could be an important target for OLTI treatment of T2DM.

Topics: NF-E2-Related Factor 2; Animals; Diabetes Mellitus, Type 2; Mice; Thiophenes; Male; Diabetes Mellitus, Experimental; Thiones; Glycolipids; Hypoglycemic Agents; Streptozocin; Mice, Inbred C57BL; Pyrazines; Oxidative Stress; Signal Transduction; Heme Oxygenase-1; Membrane Proteins

PubMed: 39654602
DOI: 10.2147/DDDT.S485729

Review

Authors: Shuai Wen, Changchang Cao, Jianwen Ge...

HS is an endogenous gas signaling molecule and its multiple biological effects have been demonstrated. The abnormal level of HS is closely related to the occurrence and development of many diseases, and HS donors has important pharmacological implications. In recent years, HS donors represented by ADTOH (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione) are often used to synthesize new 'conjugate' compounds that can release HS and parent drugs. These hybrids retain the pharmacological activity of the parent drugs and HS and have a synergistic effect. ADTOH and parent drug hybrids have become one of the important strategies for the development of HS donor conjugate drugs. This review summarizes molecular hybrids between ADTOH and clinical drugs to provide new ideas for the study of HS donor drug design.

Topics: Hydrogen Sulfide; Signal Transduction; Thiones; Drug Design

PubMed: 36615525
DOI: 10.3390/molecules28010331

Authors: Vilija Kederienė, Jolanta Rousseau, Marie Schuler...

The 1,3-oxazolidine-2-thiones (OZTs) are important chiral molecules, especially in asymmetric synthesis. These compounds serve as important active units in biologically active compounds. Herein, carbohydrate anchored OZTs were explored to develop a copper-catalyzed C-S bond formation with aryl iodides. Chemoselective -arylation was observed, with copper iodide and dimethylethylenediamine (DMEDA) as the best ligand in dioxane at 60-90 °C. The corresponding chiral oxazolines were obtained in reasonable to good yields under relatively mild reaction conditions. This approach is cheap, as using one of the cheapest transition metals, a simple protocol and various functional group tolerance make it a valuable strategy for getting -substituted furanose-fused OZT. The structures of the novel carbohydrates were confirmed by NMR spectroscopy and an HRMS analysis.

Topics: Catalysis; Copper; Iodides; Molecular Structure; Oxazoles; Thiones

PubMed: 36080364
DOI: 10.3390/molecules27175597

Review

Authors: Aashiq Hussain Bhat, Khalid Bashir Dar, Andleeb Khan...

Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn, and D609 might act as a potential chelator of Zn, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities.

Topics: Bridged-Ring Compounds; Norbornanes; Thiocarbamates; Thiones; Type C Phospholipases

PubMed: 35328726
DOI: 10.3390/ijms23063305

Authors: Ju-Hyun Ahn, Marlus da Silva Pedrosa, Lacey R Lopez...

Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.

Topics: Animals; Crohn Disease; Macrophages; Humans; Mice; Hypoxia-Inducible Factor 1, alpha Subunit; Escherichia coli; Fibrosis; Zinc; Disease Models, Animal; Mice, Inbred C57BL; Thiones; Intestines; Phenols; Thiazoles

PubMed: 39701098
DOI: 10.1016/j.chom.2024.11.012