Physiological roles of hydrogen sulfide in mammalian cells, tissues, and organs

Physiological Reviews, Journal Year: 2022, Volume and Issue: 103(1), P. 31 - 276

Published: April 18, 2022

Over the last two decades, hydrogen sulfide (H2S) has emerged as an endogenous regulator of a broad range physiological functions. H2S belongs to class molecules known gasotransmitters, which typically include nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized sources in various cells tissues: cystathionine γ-lyase (CSE), β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST). The present article reviews regulation these well pathways their enzymatic nonenzymatic degradation elimination. multiple interactions with other labile (e.g., NO) reactive oxygen species also outlined. Next, biological targets signaling outlined, special reference or oxidative posttranscriptional modification (persulfidation sulfhydration) proteins effect on channels intracellular second messenger pathways, gene transcription translation, cellular bioenergetics metabolism. pharmacological molecular tools currently available study physiology reviewed, including utility limitations. In subsequent sections, role functions is membrane potential, endo- exocytosis, cell organelles (endoplasmic reticulum, Golgi, mitochondria), movement, cycle, differentiation, aspects regulated death. roles types organ systems overviewed, red blood cells, immune central peripheral nervous (with focus neuronal transmission, learning, memory formation), vascular function (including angiogenesis its specialized cerebrovascular, renal, pulmonary beds) senses, vision, hearing, taste smell, pain-sensing. Finally, (lung, heart, liver, kidney, urogenital organs, reproductive system, bone cartilage, skeletal muscle, endocrine organs) presented, aging) but extending some common pathophysiological conditions. From data, wide array significant all emerges characteristic bell-shaped biphasic effects highlighted. addition, key aspects, debated areas, future research translational areas identified.

Language: Английский

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Implications of hydrogen sulfide in colorectal cancer: Mechanistic insights and diagnostic and therapeutic strategies

Redox Biology, Journal Year: 2023, Volume and Issue: 59, P. 102601 - 102601

Published: Jan. 7, 2023

Hydrogen sulfide (H2S) is an important signaling molecule in colorectal cancer (CRC). It produced the colon by catalytic synthesis of colonocytes' enzymatic systems and release intestinal microbes, oxidatively metabolized mitochondria. Both endogenous H2S colonic epithelial cells exogenous lumen contribute to onset progression CRC. The up-regulation synthetases thought be cause elevated levels CRC cells. Different diagnostic probes combination therapies, as well tumor treatment approaches through modulation, have been developed recent years become active area investigation for diagnosis In this review, we focus on specific mechanisms production oxidative metabolism function occurrence, progression, diagnosis, We also discuss present challenges provide insights into future research burgeoning field.

Language: Английский

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H₂S‐Activated Ion‐Interference Therapy: A Novel Tumor Targeted Therapy Based on Copper‐Overload‐Mediated Cuproptosis and Pyroptosis

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 33(38)

Published: June 6, 2023

Abstract Copper overload is a novel way to achieve copper‐ion‐interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it difficult reach since excess intracellular ions will be pumped out. Herein, achieved both raising cellular uptake reducing the efflux of using hydrogen sulfide (H 2 S)‐responsive hydroxyphosphate nanoparticles (Cu (PO 4 )(OH) NPs). After immersion in an H S‐enriched colon cancer microenvironment, Cu NPs can transform into with reduced size for higher entering, resulting improved Fenton activity as well ion dissociation. Reactive oxygen species generated reaction not only activate inflammasomes Caspase‐1 proteins, cause cleavage gasdermin D induce pyroptosis, but also affect mitochondrial function down‐regulate exporter ATP7A further reduce excretion. The combination endocytosis lower exportation leads maximized overload. Together efficient release, tricarboxylic acid cycle disrupted iron‐sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As pyroptosis cuproptosis ways death, this study provides realize effective tumor‐targeted based on S‐activated simple NPs.

Language: Английский

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Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease

Antioxidants, Journal Year: 2023, Volume and Issue: 12(3), P. 603 - 603

Published: March 1, 2023

3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well cytoplasm. 3-MST mediates reaction with dihydrolipoic acid and thioredoxin produce Hydrogen sulfide also produced through cystathionine beta-synthase gamma-lyase, along 3-MST, known alleviate a variety illnesses such cancer, heart disease, neurological conditions. The importance gamma-lyase biogenesis well-described, but documentation pathway limited. This account compiles current state knowledge about physiology pathology. Attempts at targeting for therapeutic benefit are discussed, highlighting potential target.

Language: Английский

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Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 209, P. 115444 - 115444

Published: Feb. 1, 2023

Language: Английский

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S-Adenosylmethionine: A Multifaceted Regulator in Cancer Pathogenesis and Therapy

Cancers, Journal Year: 2025, Volume and Issue: 17(3), P. 535 - 535

Published: Feb. 5, 2025

S-adenosylmethionine (SAMe) is a key methyl donor that plays critical role in variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression homeostasis. The involvement SAMe cancer pathogenesis multifaceted, through its multiple functions, it can influence tumor initiation, progression therapeutic resistance. In addition, the connection with polyamine synthesis oxidative stress management further underscores importance biology. Recent studies have highlighted potential biomarker diagnosis prognosis. Furthermore, implications are promising, evidence suggesting supplementation or modulation could improve efficacy existing treatments by restoring proper methylation patterns mitigating damage protect against induced chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate availability SAMe-independent regulatory effects, particularly methionine-dependent cancers colorectal lung cancer, presents promising approach. Additionally, exploring epitranscriptomic regulations, m6A modifications, their interaction non-coding RNAs enhance our understanding resistance mechanisms. Precision medicine approaches integrating patient subtyping combination therapies chemotherapeutics, decitabine doxorubicin, together SAMe, chemosensitivity modulate epigenomics, showing results may treatment outcomes. This review comprehensively examines various roles pathogenesis, diagnostic prognostic marker, emerging applications. While holds significant promise, challenges bioavailability, stratification context-dependent effects must be addressed before clinical implementation. better validation obtained into specific animal models would also help bridge gap between research practice.

Language: Английский

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Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter

Antioxidants, Journal Year: 2022, Volume and Issue: 11(9), P. 1788 - 1788

Published: Sept. 10, 2022

Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential a therapeutic agent for cardiovascular, inflammatory, infectious neuropathological diseases have undertaken. Here we review possible direct targets of H2S in mammals. directly interacts reactive oxygen/nitrogen species is involved redox signaling. also reacts hemeproteins modulates metal-containing complexes. Once being oxidized, can persulfidate proteins by adding -SSH to amino acid cysteine. These modifications significant impact cell structure many cellular functions, such tight junctions, autophagy, apoptosis, vesicle trafficking, signaling, epigenetics inflammasomes. Therefore, conclude that important physiological processes. Compounds donate systems be developed therapeutics different diseases.

Language: Английский

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H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(8)

Published: July 21, 2022

Cystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to biosynthesis cysteine and production hydrogen sulfide (H2S). Aberrant upregulation CBS overproduction H2S contribute pathophysiology several diseases including cancer Down syndrome. Therefore, pharmacological inhibition has emerged as prospective therapeutic approach. Here, we characterized binding inhibitory mechanism aminooxyacetic acid (AOAA), most commonly used inhibitor. We found that AOAA binds tighter than its respective substrates forms dead-end PLP-bound intermediate featuring an oxime bond. Surprisingly, serine, but not cysteine, replaced from formed aminoacrylate reaction intermediate, which allowed continuation catalytic cycle. Indeed, serine rescued essentially normalized enzymatic activity AOAA-inhibited CBS. Cellular studies confirmed decreased bioenergetics, while additional activity, mitochondrial function. The crystal structure AOAA-bound human showed lack bonding with residues G305 Y308, in serine-bound model. Thus, could be reactivated by serine. This difference may important cellular environment multiple pathophysiological conditions modulate CBS-inhibitory AOAA. In addition, our results demonstrate complexities using CBS-specific inhibitor biogenesis point urgent need develop potent, selective specific

Language: Английский

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Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors

Cancer Research, Journal Year: 2023, Volume and Issue: 83(9), P. 1426 - 1442

Published: March 2, 2023

Abstract Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine homocysteine. Demand for is increased during tumorigenesis generating glutathione to deal with oxidative stress. While cultured cells have been shown highly dependent on exogenous proliferation survival, how diverse tissues obtain use vivo has not characterized. We comprehensively interrogated metabolism normal murine cancers that arise them using stable isotope 13C1-serine 13C6-cystine tracing. De was highest liver pancreas absent lung tissue, while either inactive downregulated tumorigenesis. In contrast, downstream metabolites a universal feature of tumors. However, differences labeling were evident across tumor types. Thus, major contributor the tumors, differentially active Significance: Stable tracing characterizes its rewiring tumors genetically engineered mouse models liver, pancreas, cancers.

Language: Английский

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Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

Antioxidants, Journal Year: 2023, Volume and Issue: 12(8), P. 1520 - 1520

Published: July 29, 2023

A high level of homocysteine (Hcy) is associated with oxidative/ER stress, apoptosis, and impairment angiogenesis, whereas hydrogen sulfide (H2S) has been found to reverse this condition. Recent studies have shown that cancer cells need produce a endogenous H2S maintain cell proliferation, growth, viability, migration. However, any novel mechanism targets balance Hcy production yet be discovered or exploited. Cells require metabolism via the methionine cycle for nucleotide synthesis, methylation, reductive metabolism, pathway supports proliferative rate cells. Although favors their survival produces massive amount toxic somehow handle very well. Recently, research showed specific pathways important balancing antioxidative defense through in This review discusses relationship between antiapoptotic, antioxidative, anti-inflammatory, angiogenic effects different types. It also summarizes historical understanding targeting systems, other protective mechanisms role genesis, progression, metastasis cancer. defines nexus diet precision medicine delicate system explores possible future therapeutics could exploit balance.

Language: Английский

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