ABSTRACT
Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of "reprogramming" and "interfering" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical "Trojan horse", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.
Subject(s)
Apoptosis , Gallium , Iron , Humans , Gallium/chemistry , Gallium/pharmacology , Apoptosis/drug effects , Iron/metabolism , Iron/chemistry , Animals , Mice , Cell Proliferation/drug effects , Receptors, Transferrin/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Sulfides/chemistry , Sulfides/pharmacology , Tumor Microenvironment/drug effects , Cell Line, Tumor , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/chemistry , Hydrogen Sulfide/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Paraptosis , Cation Transport ProteinsABSTRACT
Hydrogen sulfide (H2S) has emerged as a novel endogenous gas signaling molecule, joining the ranks of nitric oxide (NO) and carbon monoxide (CO). Recent research has highlighted its involvement in various physiological processes, such as promoting root organogenesis, regulating stomatal movement and photosynthesis, and enhancing plant growth, development, and stress resistance. Tobacco, a significant cash crop crucial for farmers' economic income, relies heavily on root development to affect leaf growth, disease resistance, chemical composition, and yield. Despite its importance, there remains a scarcity of studies investigating the role of H2S in promoting tobacco growth. This study exposed tobacco seedlings to different concentrations of NaHS (an exogenous H2S donor) - 0, 200, 400, 600, and 800 mg/L. Results indicated a positive correlation between NaHS concentration and root length, wet weight, root activity, and antioxidant enzymatic activities (CAT, SOD, and POD) in tobacco roots. Transcriptomic and metabolomic analyses revealed that treatment with 600 mg/L NaHS significantly effected 162 key genes, 44 key enzymes, and two metabolic pathways (brassinosteroid synthesis and aspartate biosynthesis) in tobacco seedlings. The addition of exogenous NaHS not only promoted tobacco root development but also potentially reduced pesticide usage, contributing to a more sustainable ecological environment. Overall, this study sheds light on the primary metabolic pathways involved in tobacco root response to NaHS, offering new genetic insights for future investigations into plant root development.
Subject(s)
Nicotiana , Plant Roots , Sulfides , Nicotiana/genetics , Nicotiana/drug effects , Nicotiana/physiology , Plant Roots/drug effects , Plant Roots/growth & development , Plant Roots/metabolism , Plant Roots/genetics , Sulfides/pharmacology , Transcriptome/drug effects , Metabolomics , Metabolic Networks and Pathways/drug effects , Seedlings/drug effects , Seedlings/growth & development , Seedlings/genetics , Seedlings/metabolism , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Gene Expression Profiling , Gene Expression Regulation, Plant/drug effectsABSTRACT
This Special Issue aims to gather new research on hydrogen sulfide (H2S)-releasing compounds (Figure 1) as cutting-edge pharmacological tools and to advance the understanding of the critical role that H2S plays in physiological and pathological processes [...].
Subject(s)
Hydrogen Sulfide , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/chemistry , Hydrogen Sulfide/pharmacology , Humans , AnimalsABSTRACT
Ischemia-reperfusion (I/R) injury, a prevalent pathological condition in medical practice, presents significant treatment challenges. Hydrogen sulfide (H2S), acknowledged as the third gas signaling molecule, profoundly impacts various physiological and pathophysiological processes. Extensive research has demonstrated that H2S can mitigate I/R damage across multiple organs and tissues. This review investigates the protective effects of H2S in preventing I/R damage in the heart, brain, liver, kidney, intestines, lungs, stomach, spinal cord, testes, eyes, and other tissues. H2S provides protection against I/R damage by alleviating inflammation and endoplasmic reticulum stress; inhibiting apoptosis, oxidative stress, and mitochondrial autophagy and dysfunction; and regulating microRNAs. Significant advancements in understanding the mechanisms by which H2S reduces I/R damage have led to the development and synthesis of H2S-releasing agents such as diallyl trisulfide-loaded mesoporous silica nanoparticles (DATS-MSN), AP39, zofenopril, and ATB-344, offering a new therapeutic avenue for I/R injury.
Subject(s)
Hydrogen Sulfide , Reperfusion Injury , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/therapeutic use , Hydrogen Sulfide/pharmacology , Humans , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Animals , Oxidative Stress/drug effects , Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effectsABSTRACT
Among the various drug discovery methods, a very promising modern approach consists in designing multi-target-directed ligands (MTDLs) able to modulate multiple targets of interest, including the pathways where hydrogen sulfide (H2S) is involved. By incorporating an H2S donor moiety into a native drug, researchers have been able to simultaneously target multiple therapeutic pathways, resulting in improved treatment outcomes. This review gives the reader some pills of successful multi-target H2S-donating molecules as worthwhile tools to combat the multifactorial nature of complex disorders, such as inflammatory-based diseases and cancer, as well as cardiovascular, metabolic, and neurodegenerative disorders.
Subject(s)
Hydrogen Sulfide , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Humans , Animals , Ligands , Drug Discovery/methods , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolismABSTRACT
In recent years, the impact of age-related diseases on human health has become increasingly severe, and developing effective drugs to deal with these diseases has become an urgent task. Considering the essential regulatory role of hydrogen sulfide (H2S) in these diseases, it is regarded as a promising target for treatment. H2S is a novel gaseous transmitter involved in many critical physiological activities, including anti-oxidation, anti-inflammation, and angiogenesis. H2S also regulates cell activities such as cell proliferation, migration, invasion, apoptosis, and autophagy. These regulatory effects of H2S contribute to relieving and treating age-related diseases. In this review, we mainly focus on the pathogenesis and treatment prospects of H2S in regulating age-related diseases.
Subject(s)
Aging , Hydrogen Sulfide , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Humans , Aging/metabolism , Animals , Autophagy/drug effects , Apoptosis/drug effects , Cell Proliferation/drug effectsABSTRACT
Spinal cord injury (SCI) causes irreversible cell loss and neurological dysfunctions. Presently, there is no an effective clinical treatment for SCI. It can be the only intervention measure by relieving the symptoms of patients such as pain and fever. Free radical-induced damage is one of the validated mechanisms in the complex secondary injury following primary SCI. Hydrogen sulfide (H2S) as an antioxidant can effectively scavenge free radicals, protect neurons, and improve SCI by inhibiting the p38MAPK/mTOR/NF-κB signaling pathway. In this report, we analyze the pathological mechanism of SCI, the role of free radical-mediated the p38MAPK/mTOR/NF-κB signaling pathway in SCI, and the role of H2S in scavenging free radicals and improving SCI.
Subject(s)
Free Radical Scavengers , Hydrogen Sulfide , NF-kappa B , Signal Transduction , Spinal Cord Injuries , TOR Serine-Threonine Kinases , p38 Mitogen-Activated Protein Kinases , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Hydrogen Sulfide/therapeutic use , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , NF-kappa B/metabolism , Animals , Free Radical Scavengers/therapeutic use , Free Radical Scavengers/pharmacology , Signal Transduction/drug effects , Rats , Mice , Free Radicals/metabolism , Antioxidants/therapeutic use , Antioxidants/pharmacology , Spinal Cord/drug effects , Spinal Cord/metabolism , HumansABSTRACT
Macrophage pyroptosis mediates vascular inflammation and atherosclerosis (AS). Hydrogen sulfide (H2S) exerts a protective role in preventing inflammation and AS. However, its molecular mechanisms of regulating the pyroptosis signaling pathway and inhibiting macrophage pyroptosis remain unexplored. The present study aimed to determine whether H2S mitigates macrophage pyroptosis by downregulating the pyroptosis signaling pathway and Ssulfhydrating caspase1 under the stimulation of oxidized lowdensity lipoprotein (oxLDL), a proatherosclerotic factor. Macrophages derived from THP1 monocytes were pretreated using exogenous H2S donors sodium hydrosulfide (NaHS) and D,Lpropargylglycine (PAG), a pharmacological inhibitor of endogenous H2Sproducing enzymes, alone or in combination. Subsequently, cells were stimulated with oxLDL or the desulfhydration reagent dithiothreitol (DTT) in the presence or absence of NaHS and/or PAG. Following treatment, the levels of H2S in THP1 derived macrophages were measured by a methylene blue colorimetric assay. The pyroptotic phenotype of THP1 cells was observed and evaluated by light microscopy, Hoechst 33342/propidium iodide fluorescent staining and lactate dehydrogenase (LDH) release assay. Caspase1 activity in THP1 cells was assayed by caspase1 activity assay kit. Immunofluorescence staining was used to assess the accumulation of active caspase1. Western blotting and ELISA were performed to determine the expression of pyroptosisspecific markers (NLRP3, procaspase1, caspase1, GSDMD and GSDMDN) in cells and the secretion of pyroptosisrelated cytokines [interleukin (IL)1ß and IL18] in the cellfree media, respectively. The Ssulfhydration of procaspase1 in cells was assessed using a biotin switch assay. oxLDL significantly induced macrophage pyroptosis by activating the pyroptosis signaling pathway. Inhibition of endogenous H2S synthesis by PAG augmented the propyroptotic effects of oxLDL. Conversely, exogenous H2S (NaHS) ameliorated oxLDLand oxLDL + PAGinduced macrophage pyroptosis by suppressing the activation of the pyroptosis signaling pathway. Mechanistically, oxLDL and the DTT increased caspase1 activity and downstream events (IL1ß and IL18 secretion) of the caspase1dependent pyroptosis pathway by reducing Ssulfhydration of procaspase1. Conversely, NaHS increased Ssulfhydration of procaspase1, reducing caspase1 activity and caspase1dependent macrophage pyroptosis. The present study demonstrated the molecular mechanism by which H2S ameliorates macrophage pyroptosis by suppressing the pyroptosis signaling pathway and Ssulfhydration of procaspase1, thereby suppressing the generation of active caspase-1 and activity of caspase-1.
Subject(s)
Caspase 1 , Hydrogen Sulfide , Lipoproteins, LDL , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphate-Binding Proteins , Pyroptosis , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Pyroptosis/drug effects , Humans , Caspase 1/metabolism , Macrophages/metabolism , Macrophages/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Lipoproteins, LDL/metabolism , Lipoproteins, LDL/pharmacology , Phosphate-Binding Proteins/metabolism , THP-1 Cells , Intracellular Signaling Peptides and Proteins/metabolism , Signal Transduction/drug effects , Gasdermins , Alkynes , Glycine/analogs & derivatives , SulfidesABSTRACT
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 (H2S) 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 H2S 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-ß-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.
Subject(s)
Autophagy , Mitochondrial Dynamics , Triple Negative Breast Neoplasms , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Mitochondrial Dynamics/drug effects , Humans , Animals , Autophagy/drug effects , Female , Cell Line, Tumor , Mice , Cell Movement/drug effects , Mice, Nude , Thiones/pharmacology , Xenograft Model Antitumor Assays , Mice, Inbred BALB C , Mitochondria/metabolism , Mitochondria/drug effects , Cell Proliferation/drug effects , Neoplasm Metastasis , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Dynamins/metabolism , Thiophenes/pharmacologyABSTRACT
Antimicrobial drug development faces challenges from bacterial resistance, biofilms, and excessive inflammation. Here, we design an intelligent nanoplatform utilizing mesoporous silica nanoparticles doped with copper ions for loading copper sulfide (DM/Cu2+-CuS). The mesoporous silica doped with tetrasulfide bonds responds to the biofilm microenvironment (BME), releasing Cu2+ions, CuS along with hydrogen sulfide (H2S) gas. The release of hydrogen sulfide within 72 h reached 793.5 µM, significantly higher than that observed with conventional small molecule donors. H2S induces macrophages polarization towards the M2 phenotype, reducing inflammation and synergistically accelerating endothelial cell proliferation and migration with Cu2+ions. In addition, H2S disrupts extracellular DNA within biofilms, synergistically photothermal enhanced peroxidase-like activity of CuS to effectively eradicate biofilms. Remarkably, DM-mediated consumption of endogenous glutathione enhances the anti-biofilm activity of H2S and improves oxygen species (ROS) destruction efficiency. The combination of photothermal therapy (PTT), chemodynamic therapy (CDT), and gas treatment achieves sterilization rates of 99.3 % and 99.6 % against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), respectively, in vitro under 808 nm laser irradiation. Additionally, in vivo experiments demonstrate a significant biosafety and antibacterial potential. In summary, the H2S donor developed in this study exhibits enhanced biocompatibility and controlled release properties. By integrating BME-responsive gas therapy with antibacterial ions, PTT and CDT, a synergistic multimodal strategy is proposed to offer new therapeutic approaches for wound healing. STATEMENT OF SIGNIFICANCE: The advanced DMOS/Cu2+-CuS (DMCC) multimodal therapeutic nanoplatform has been developed for the treatment of drug-resistant bacterial wound infections and has exhibited enhanced therapeutic efficacy through the synergistic effects of photothermal therapy, chemodynamic therapy, Cu2+ions, and H2S. The DMCC exhibited exceptional biocompatibility and could release CuS, Cu2+, and H2S in response to elevated concentrations of glutathione within the biofilm microenvironment. H2S effectively disrupted the biofilm structure. Meanwhile, peroxidase activity of CuS combined with GSH-mediated reduction of Cu2+ to Cu+ generated abundant hydroxyl radicals under acidic conditions, leading to efficient eradication of pathogenic bacteria. Furthermore, both H2S and Cu2+ could modulate M2 macrophages polarization and regulate immune microenvironment dynamics. These strategies collectively provided a novel approach for developing antibacterial nanomedical platforms.
Subject(s)
Anti-Bacterial Agents , Biofilms , Copper , Staphylococcus aureus , Wound Healing , Biofilms/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Wound Healing/drug effects , Animals , Mice , Staphylococcus aureus/drug effects , Copper/chemistry , Copper/pharmacology , Nanoparticles/chemistry , Escherichia coli/drug effects , Photothermal Therapy , Humans , Combined Modality Therapy , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/chemistry , Silicon Dioxide/chemistry , Silicon Dioxide/pharmacology , Cellular Microenvironment/drug effects , RAW 264.7 Cells , Macrophages/drug effects , Macrophages/metabolismABSTRACT
Asthma is a major noncommunicable disease, affecting both children and adults, and represents one of the major causes leading to high health care costs due to the need for chronic pharmacological treatments. The standard gold therapy of inflammation in asthmatic patients involves the use of glucocorticoids even if their chronic use is often related to serious adverse effects. Growing evidence suggests the biological relevance of hydrogen sulfide (H2S) in the pathogenesis of airway diseases. Hence, aiming to associate the beneficial effects of steroidal anti-inflammatory drugs (SAIDs) to H2S biological activity, we designed and synthesized novel multi-target molecules by chemically combining a group of glucocorticoids, usually employed in asthma treatment, with an isothiocyanate moiety, well-known for its H2S releasing properties. Firstly, the synthesized compounds have been screened for their H2S-releasing profile using an amperometric approach and for their in vitro effects on the degranulation process, using RBL-2H3 cell line. The physicochemical profile, in terms of solubility, chemical and enzymatic stability of the newly hybrid molecules, has been assessed at different physiological pH values and in esterase-rich medium (bovine serum albumin, BSA). The selected compound 5c, through both its corticosteroid and H2S releasing component, has been evaluated in vivo in experimental model of asthma. The compound 5c inhibited in vivo all asthma features with a significative effect on the restoration of pulmonary structure and reduction of lung inflammation.
Subject(s)
Asthma , Isothiocyanates , Asthma/drug therapy , Animals , Isothiocyanates/chemistry , Isothiocyanates/pharmacology , Isothiocyanates/chemical synthesis , Rats , Adrenal Cortex Hormones/pharmacology , Adrenal Cortex Hormones/chemistry , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/chemistry , Hydrogen Sulfide/pharmacology , Molecular Structure , Structure-Activity Relationship , Anti-Asthmatic Agents/pharmacology , Anti-Asthmatic Agents/chemistry , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/therapeutic use , Dose-Response Relationship, Drug , Humans , Male , Cell LineABSTRACT
Hydrogen sulfide (H2S) has been identified as a novel gasotransmitter and a substantial antioxidant that can activate various cellular targets to regulate physiological and pathological processes in mammals. However, under physiological conditions, it remains unclear whether it is involved in regulating cardiomyocyte (CM) proliferation during postnatal development in mice. This study mainly aimed to evaluate the role of H2S in postnatal CM proliferation and its regulating molecular mechanisms. We found that sodium hydrosulfide (NaHS, the most widely used H2S donor, 50-200 µM) increased neonatal mouse primary CM proliferation in a dose-dependent manner in vitro. Consistently, exogenous administration of H2S also promoted CM proliferation and increased the total number of CMs at postnatal 7 and 14 days in vivo. Moreover, we observed that the protein expression of SIRT1 was significantly upregulated after NaHS treatment. Inhibition of SIRT1 with EX-527 or si-SIRT1 decreased CM proliferation, while enhancement of the activation of SIRT1 with SRT1720 promoted CM proliferation. Meanwhile, pharmacological and genetic blocking of SIRT1 repressed the effect of NaHS on CM proliferation. Taken together, these results reveal that H2S plays a promotional role in proliferation of CMs in vivo and in vitro and SIRT1 is required for H2S-mediated CM proliferation, which indicates that H2S may be a potential modulator for heart development in postnatal time window.
Subject(s)
Cell Proliferation , Hydrogen Sulfide , Myocytes, Cardiac , Signal Transduction , Sirtuin 1 , Up-Regulation , Animals , Sirtuin 1/metabolism , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Cell Proliferation/drug effects , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Mice , Signal Transduction/drug effects , Animals, Newborn , Cells, Cultured , Mice, Inbred C57BL , SulfidesABSTRACT
Endogenous hydrogen sulfide (H2S) plays an important role in bone metabolism. However, the exact role of H2S in intestinal calcium and phosphorus absorption and its potential in preventing and treating primary osteoporosis remains unknown. Therefore, this study aimed to investigate the potential of H2S in promoting intestinal calcium and phosphorus absorption and alleviating primary osteoporosis. We measured the apparent absorptivity of calcium, femoral bone density, expression and sulfhydration of the duodenal endoplasmic reticulum protein of 57 kDa (ERp57), duodenal cystathionine γ-lyase (CSE) expression, and serum H2S content in adult and old CSE-knockout and wild-type mice. We also assessed intracellular reactive oxygen species (ROS) and Ca2+ content in CSE-overexpressing or knockout intestinal epithelial cell (IEC)-6 cells. In senile mice, CSE knockout decreased endogenous H2S, ERp57 sulfhydration, and intestinal calcium absorption and worsened osteoporosis, which were partially reversed by GYY4137, an H2S donor. CSE overexpression in IEC-6 cells increased ERp57 sulfhydration, protein kinase A and C activity, and intracellular Ca2+, whereas CSE knockout exerted the opposite effects. Furthermore, hydrogen peroxide (H2O2) stimulation had similar effects as in CSE knockout, which were reversed by pretreatment with sodium hydrosulfide before H2O2 stimulation and restored by DL-dithiothreitol. These findings suggest that H2S attenuates primary osteoporosis by preventing ROS-induced ERp57 damage in intestinal epithelial cells by enhancing ERp57 activity and promoting intestinal calcium absorption, thereby aiding in developing therapeutic interventions to prevent osteoporosis.
Subject(s)
Calcium , Hydrogen Sulfide , Osteoporosis , Protein Disulfide-Isomerases , Animals , Male , Mice , Calcium/metabolism , Cell Line , Cystathionine gamma-Lyase/metabolism , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Intestinal Absorption/drug effects , Mice, Inbred C57BL , Mice, Knockout , Osteoporosis/metabolism , Osteoporosis/prevention & control , Protein Disulfide-Isomerases/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Glioblastoma multiforme (GBM) is the most aggressive and lethal subtype of gliomas of the central nervous system. The efficacy of sonodynamic therapy (SDT) against GBM is significantly reduced by the expression of apoptosis-inhibitory proteins in GBM cells. In this study, an intelligent nanoplatform (denoted as Aza-BD@PC NPs) based on the aza-boron-dipyrromethene dye and phenyl chlorothionocarbonate-modified DSPE-PEG molecules is developed for synergistic ferroptosis-enabled gas therapy (GT) and SDT of GBM. Once internalized by GBM cells, Aza-BD@PC NPs showed effective cysteine (Cys) consumption and Cys-triggered hydrogen sulfide (H2S) release for ferroptosis-enabled GT, thereby disrupting homeostasis in the intracellular environment, affecting GBM cell metabolism, and inhibiting GBM cell proliferation. Additionally, the released Aza-BD generated abundant singlet oxygen (1O2) under ultrasound irradiation for favorable SDT. In vivo and in vitro evaluations demonstrated that the combined functions of Cys consumption, H2S production, and 1O2 production induced significant death of GBM cells and markedly inhibited tumor growth, with an impressive inhibition rate of up to 97.5%. Collectively, this study constructed a cascade nanoreactor with satisfactory Cys depletion performance, excellent H2S release capability, and prominent reactive oxygen species production ability under ultrasound irradiation for the synergistic ferroptosis-enabled GT and SDT of gliomas.
Subject(s)
Ferroptosis , Glioblastoma , Hydrogen Sulfide , Prodrugs , Ferroptosis/drug effects , Animals , Mice , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Prodrugs/pharmacology , Glioblastoma/therapy , Glioblastoma/metabolism , Glioblastoma/drug therapy , Humans , Cell Line, Tumor , Ultrasonic Therapy/methods , Disease Models, AnimalABSTRACT
In chronic liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblast-like cells and produce large amounts of extracellular matrix components, e.g. collagen type 1. Cellular senescence is characterized by irreversible cell-cycle arrest, arrested cell proliferation and the acquisition of the senescence-associated secretory phenotype (SASP) and reversal of HSCs activation. Previous studies reported that H2S prevents induction of senescence via its antioxidant activity. We hypothesized that inhibition of endogenous H2S production induces cellular senescence and reduces activation of HSCs. Rat HSCs were isolated and culture-activated for 7 days. After activation, HSCs treated with H2S slow-releasing donor GYY4137 and/or DL-propargylglycine (DL-PAG), an inhibitor of the H2S-producing enzyme cystathionine γ-lyase (CTH), as well as the PI3K inhibitor LY294002. In our result, CTH expression was significantly increased in fully activated HSCs compared to quiescent HSCs and was also observed in activated stellate cells in a in vivo model of cirrhosis. Inhibition of CTH reduced proliferation and expression of fibrotic markers Col1a1 and Acta2 in HSCs. Concomitantly, DL-PAG increased the cell-cycle arrest markers Cdkn1a (p21), p53 and the SASP marker Il6. Additionally, the number of ß-galactosidase positive senescent HSCs was increased. GYY4137 partially restored the proliferation of senescent HSCs and attenuated the DL-PAG-induced senescent phenotype. Inhibition of PI3K partially reversed the senescence phenotype of HSCs induced by DL-PAG. Inhibition of endogenous H2S production reduces HSCs activation via induction of cellular senescence in a PI3K-Akt dependent manner. Our results show that cell-specific inhibition of H2S could be a novel target for anti-fibrotic therapy via induced cell senescence.
Subject(s)
Alkynes , Cellular Senescence , Glycine , Hepatic Stellate Cells , Hydrogen Sulfide , Morpholines , Organothiophosphorus Compounds , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/drug effects , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Animals , Cellular Senescence/drug effects , Morpholines/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Alkynes/pharmacology , Organothiophosphorus Compounds/pharmacology , Rats , Male , Cystathionine gamma-Lyase/metabolism , Cell Proliferation/drug effects , Chromones/pharmacology , Collagen Type I/metabolism , Rats, Sprague-Dawley , Phosphatidylinositol 3-Kinases/metabolism , Cells, Cultured , Proto-Oncogene Proteins c-akt/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/metabolism , Signal Transduction/drug effects , Senescence-Associated Secretory Phenotype , Tumor Suppressor Protein p53/metabolismABSTRACT
AIMS: Our aim was to evaluate whether the hydrogen sulfide (H2S) donor, 4-carboxyphenyl-isothiocyanate (4-CPI), exerts cardioprotective effect in the two kidney- one clip (2K-1C) rats through oxidative stress and MMP-2 activity attenuation and compare it with the classical H2S donor, Sodium Hydrosulfide (NaHS). MATERIALS AND METHODS: Renovascular hypertension (two kidneys-one clip; 2K-1C) was surgically induced in male Wistar rats. After two weeks, normotensive (2K) and hypertensive rats were intraperitoneally treated with vehicle (0.6 % dimethyl sulfoxide), NaHS (0.24 mg/Kg/day) or with 4-CPI (0.24 mg/Kg/day), for more 4 weeks. Systolic blood pressure (SBP) was evaluated weekly by tail-cuff plethysmography. Heart function was assessed by using the Millar catheter. Cardiac hypertrophy and fibrosis were evaluated by hematoxylin and eosin, and Picrosirius Red staining, respectively. The H2S was analyzed using WSP-1 fluorimetry and the cardiac oxidative stress was measured by lucigenin chemiluminescence and Amplex Red. MMP-2 activity was measured by in-gel gelatin or in situ zymography assays. Nox1, gp91phox, MMP-2 and the phospho-p65 subunit (Serine 279) nuclear factor kappa B (NF-κB) levels were evaluated by Western blotting. KEY FINDINGS: 4-CPI reduced blood pressure in hypertensive rats, decreased cardiac remodeling and promoted cardioprotection through the enhancement of cardiac H2S levels. An attenuation of oxidative stress, with inactivation of the p65-NF-κB/MMP-2 axis was similarly observed after NaHS or 4-CPI treatment in 2K-1C hypertension. SIGNIFICANCE: H2S is a mediator that promotes cardioprotective effects and decreases blood pressure, and 4-CPI seems to be a good candidate to reverse the maladaptive remodeling and cardiac dysfunction in renovascular hypertension.
Subject(s)
Blood Pressure , Hydrogen Sulfide , Matrix Metalloproteinase 2 , NF-kappa B , Oxidative Stress , Animals , Male , Rats , Blood Pressure/drug effects , Cardiotonic Agents/pharmacology , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Hypertension/drug therapy , Hypertension/metabolism , Hypertension, Renovascular/drug therapy , Hypertension, Renovascular/metabolism , Hypertension, Renovascular/physiopathology , Isothiocyanates/pharmacology , Matrix Metalloproteinase 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Rats, Wistar , Sulfides/pharmacologyABSTRACT
KEY MESSAGE: Hydrogen sulfide improved cold resistance of tomato fruits by regulating energy metabolism and delaying cell wall degradation, thereby alleviating the damage of cold storage on fruits. Postharvest cold storage in tomato fruits extended shelf life but caused the appearance of chilling injury (CI), appeared by softness and spots on the surface of the fruits. These changes were linked closely with energy and cell wall metabolisms. Hydrogen sulfide (H2S), as the gaseous fresh-keeping regulator, was used in the present study to investigate the effects of H2S on energy and cell wall metabolisms in tomato fruits during cold storage. Fruits after harvest were fumigated with different concentrations (0, 0.5, 1, 1.5 mM) of sodium hydrosulfide (NaHS) solution as H2S honor for 24 h and stored at 4 °C for 25 days. The results showed that 1 and 1.5 mM NaHS solution fumigation promoted the accumulation of endogenous H2S, followed by the increase in L-cysteine desulfurase (LCD) and D-cysteine desulfurase (DCD) activities in fruits during cold storage. It was also found that 1 and 1.5 mM NaHS treatments improved H+-ATPase, Ca2+-ATPase, cytochrome C oxidase (CCO), and succinic dehydrogenase (SDH) activities. Moreover, the contents of cellulose and hemicellulose were increased by 1 and 1.5 mM NaHS, following down-regulated activities of cellulase (CL), pectin lyase (PL), α-mannosidase (α-man) and ß-Galactosidase (ß-Gal) and down-regulated expression of PL1, PL8, MAN4 and MAN7 genes. Thus, H2S alleviates CI led by cold storage in tomato fruits via regulating energy and cell wall metabolisms.
Subject(s)
Cell Wall , Cold Temperature , Energy Metabolism , Fruit , Hydrogen Sulfide , Solanum lycopersicum , Cell Wall/metabolism , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Solanum lycopersicum/genetics , Solanum lycopersicum/metabolism , Solanum lycopersicum/physiology , Fruit/metabolism , Fruit/genetics , Fruit/drug effects , Energy Metabolism/drug effects , Gene Expression Regulation, Plant/drug effects , Plant Proteins/metabolism , Plant Proteins/genetics , Food Storage/methods , Sulfides/pharmacology , Sulfides/metabolismABSTRACT
Spinal Cord Injury (SCI) is a condition characterized by complete or incomplete motor and sensory impairment, as well as dysfunction of the autonomic nervous system, caused by factors such as trauma, tumors, or inflammation. Current treatment methods primarily include traditional approaches like spinal canal decompression and internal fixation surgery, steroid pulse therapy, as well as newer techniques such as stem cell transplantation and brain-spinal cord interfaces. However, the above methods have limited efficacy in promoting axonal and neuronal regeneration. The challenge in medical research today lies in promoting spinal cord neuron regeneration and regulating the disrupted microenvironment of the spinal cord. Studies have shown that gas molecular therapy is increasingly used in medical research, with gasotransmitters such as hydrogen sulfide, nitric oxide, carbon monoxide, oxygen, and hydrogen exhibiting neuroprotective effects in central nervous system diseases. The gas molecular protect against neuronal death and reshape the microenvironment of spinal cord injuries by regulating oxidative, inflammatory and apoptotic processes. At present, gas therapy mainly relies on inhalation for systemic administration, which cannot effectively enrich and release gas in the spinal cord injury area, making it difficult to achieve the expected effects. With the rapid development of nanotechnology, the use of nanocarriers to achieve targeted enrichment and precise control release of gas at Sites of injury has become one of the emerging research directions in SCI. It has shown promising therapeutic effects in preclinical studies and is expected to bring new hope and opportunities for the treatment of SCI. In this review, we will briefly outline the therapeutic effects and research progress of gasotransmitters and nanogas in the treatment of SCI.
Subject(s)
Gasotransmitters , Spinal Cord Injuries , Spinal Cord Injuries/therapy , Humans , Animals , Gasotransmitters/therapeutic use , Gasotransmitters/metabolism , Nitric Oxide/metabolism , Neuroprotective Agents/therapeutic use , Neuroprotective Agents/pharmacology , Hydrogen Sulfide/therapeutic use , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/pharmacology , Carbon Monoxide/metabolism , Carbon Monoxide/therapeutic use , Oxygen/metabolism , Spinal Cord , Hydrogen/therapeutic use , Hydrogen/pharmacologyABSTRACT
Cryopreservation of sperm can cause oxidative stress and damage, leading to decreased different functional parameters and fertilization potential. In this study, we evaluated two types of H2S donors: NaHS, a fast-releasing donor, and GYY4137, a slow-releasing donor during cryopreservation of goat sperm. Initially, we determined that 1.5 and 3 µM NaHS, and 15 and 30 µM GYY4137 are optimal concentrations that improved different sperm functional parameters including motility, viability, membrane integrity, lipid peroxidation, and ROS production during incubation at 38.5 °C for 90 min. We subsequently evaluated the impact of the optimal concentration of NaHS and GYY4137 supplementation on various functional parameters following thawing during cryopreservation. Our data revealed that supplementation of extender improved different parameters including post-thaw sperm motility, viability, membrane integrity, and reduced DNA damage compared to the frozen-thawed control group. The supplementation also restored the redox state, decreased lipid peroxidation, and improved mitochondrial membrane potential in the thawed sperm. Finally, we found that supplementation of the extender with NaHS and GYY4137 enhanced IVF outcomes in terms of blastocyst rate and quality of blastocysts. Our results suggest that both donors can be applied for cryopreservation as antioxidants to improve sperm quality and IVF outcomes of frozen-thawed goat sperm.
Subject(s)
Cryopreservation , Fertilization in Vitro , Goats , Oxidative Stress , Semen Preservation , Sperm Motility , Spermatozoa , Male , Cryopreservation/methods , Animals , Oxidative Stress/drug effects , Fertilization in Vitro/methods , Spermatozoa/drug effects , Spermatozoa/metabolism , Sperm Motility/drug effects , Semen Preservation/methods , Organothiophosphorus Compounds/pharmacology , Lipid Peroxidation/drug effects , Hydrogen Sulfide/pharmacology , Hydrogen Sulfide/metabolism , Cryoprotective Agents/pharmacology , Cell Survival/drug effects , Female , Reactive Oxygen Species/metabolism , Membrane Potential, Mitochondrial/drug effects , Semen Analysis , Morpholines , SulfidesABSTRACT
BACKGROUND: Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle). METHODS: Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC). RESULTS: KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione ß-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion. CONCLUSIONS: These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.