International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H₂S Levels: H₂S Donors and H₂S Biosynthesis Inhibitors

Pharmacological Reviews, Journal Year: 2017, Volume and Issue: 69(4), P. 497 - 564

Published: Oct. 1, 2017

Over the last decade, hydrogen sulfide (H₂S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to previously characterized gasotransmitters nitric oxide carbon monoxide, H₂S is produced by various enzymatic reactions regulates a host of physiologic pathophysiological processes levels are decreased number conditions (e.g., diabetes mellitus, ischemia, aging) increased other states inflammation, critical illness, cancer). decades, multiple approaches have been identified for therapeutic exploitation H₂S, either based on donation or inhibition biosynthesis. can be achieved through inhalation gas and/or parenteral enteral administration so-called fast-releasing donors (salts such NaHS Na₂S) slow-releasing (GYY4137 being prototypical compound used hundreds studies vitro vivo). Recent work also identifies with regulated release profiles, including oxidant-triggered donors, pH-dependent esterase-activated organelle-targeted mitochondrial) compounds. There where existing, clinically approved drugs classes nonsteroidal anti-inflammatories) coupled H₂S-donating groups (the most advanced clinical trials ATB-346, derivative non-steroidal anti-inflammatory naproxen). For pharmacological synthesis, there now several small molecule compounds targeting each three H₂S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, 3-mercaptopyruvate sulfurtransferase. Although many these their limitations (potency, selectivity), molecules, especially combination genetic approaches, instrumental delineation biologic involving production. Moreover, some cell-permeable prodrugs CBS inhibitor aminooxyacetate, benserazide, potentially repurposable inhibitor) may serve starting points future translation. The present article overviews currently known biosynthesis inhibitors, delineates mode action, offers examples effects potential utility.

Language: Английский

---

The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 228, P. 107916 - 107916

Published: June 23, 2021

Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is standard of care to treat paracetamol intoxication, and included on World Health Organization's list essential medicines. Additionally, NAC increasingly became epitome an "antioxidant". Arguably, it most widely used "antioxidant" in experimental cell animal biology, well clinical studies. Most investigators use test with idea that prevents or attenuates oxidative stress. Conventionally, assumed acts (i) reductant disulfide bonds, (ii) scavenger reactive oxygen species and/or (iii) precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized explain effects majority settings situations. In cases mechanism action has remained unclear untested. this review, we discuss validity conventional assumptions scope newly discovered action, namely conversion into hydrogen sulfide sulfane sulfur species. The antioxidative cytoprotective activities per- polysulfides many have previously been ascribed NAC-derived glutathione.

Language: Английский

---

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

---

Hydrogen sulfide: An endogenous regulator of the immune system

Pharmacological Research, Journal Year: 2020, Volume and Issue: 161, P. 105119 - 105119

Published: Aug. 8, 2020

Hydrogen sulfide (H2S) is now recognized as an endogenous signaling gasotransmitter in mammals. It produced by mammalian cells and tissues various enzymes - predominantly cystathionine β-synthase (CBS), γ-lyase (CSE) 3-mercaptopyruvate sulfurtransferase (3-MST) but part of the H2S intestinal microbiota (colonic H2S-producing bacteria). Here we summarize available information on production functional role cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer mast basophils, eosinophils) adaptive (T B lymphocytes) under normal conditions it relates to development inflammatory immune diseases. Special attention paid physiological pathophysiological aspects oral cavity colon, where parenchymal are exposed a special "H2S environment" due bacterial production. has many cellular molecular targets. Immune "surrounded" "cloud" H2S, result exogenous from surrounding which, turn, importantly regulates their viability function. Downregulation producing diseases, or genetic defects biosynthetic enzyme systems either lead spontaneous autoimmune disease accelerate onset worsen severity immune-mediated diseases (e.g. rheumatoid arthritis asthma). Low, regulated amounts when therapeutically delivered small molecule donors, improve function protect them against dysfunction induced noxious stimuli reactive oxygen species oxidized LDL). These effects contribute maintenance functions, can stimulate antimicrobial defenses exert anti-inflammatory therapeutic

Language: Английский

---

Hydrogen sulfide signaling in mitochondria and disease

The FASEB Journal, Journal Year: 2019, Volume and Issue: 33(12), P. 13098 - 13125

Published: Oct. 24, 2019

Hydrogen sulfide can signal through 3 distinct mechanisms: 1) reduction and/or direct binding of metalloprotein heme centers, 2) serving as a potent antioxidant reactive oxygen species/reactive nitrogen species scavenging, or 3) post‐translational modification proteins by addition thiol (‐SH) group onto cysteine residues: process known persulfidation. Below toxic levels, hydrogen promotes mitochondrial biogenesis and function, thereby conferring protection against cellular stress. For these reasons, increases in sulfide‐producing enzymes have been implicated several human disease states. This review will first summarize our current understanding production metabolism, well its signaling mechanisms; second, this work detail the mechanisms mitochondria implications mitochondrial‐specific impacts pathologic conditions.—Murphy, B., Bhattacharya, R., Mukherjee, P. disease. FASEB J. 33, 13098–13125 (2019). www.fasebj.org

Language: Английский

---

The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer

Cells, Journal Year: 2019, Volume and Issue: 8(9), P. 1055 - 1055

Published: Sept. 8, 2019

The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance redox homeostasis and reductive biosynthesis in cells. also plays key roles cellular processes mediated by signaling. Insufficient G6PD activity predisposes cells to growth retardation demise. Severely lacking impairs embryonic development delays organismal growth. Altered associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, well diabetes hypertension. Aberrant activation leads enhanced cell proliferation adaptation many types cancers. present review aims update existing knowledge concerning emphasizes how modulates signaling affects survival demise, particularly diseases cancer. Exploiting a potential drug target against cancer discussed.

Language: Английский

---

Inhibitors of bacterial H ₂ S biogenesis targeting antibiotic resistance and tolerance

Science, Journal Year: 2021, Volume and Issue: 372(6547), P. 1169 - 1175

Published: June 10, 2021

Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine γ-lyase (CSE) as primary generator H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, discovered small molecules that inhibit CSE. These inhibitors potentiate bactericidal against both pathogens vitro mouse models infection. CSE also suppress tolerance, disrupting biofilm formation substantially reducing number persister bacteria survive antibiotic treatment. Our results establish a multifunctional factor drug target versatile enhancers.

Language: Английский

---

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

Biomolecules, Journal Year: 2020, Volume and Issue: 10(5), P. 697 - 697

Published: April 30, 2020

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in transsulfuration pathway, is an important mammalian health and disease. Its biochemical functions under physiological conditions include metabolism of homocysteine (a cytotoxic molecule cardiovascular risk factor) generation hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles vascular, nervous, immune system. CBS up-regulated several diseases, including Down syndrome many forms cancer; these conditions, preclinical data indicate that inhibition or inactivation exerts beneficial effects. This article overviews current information on expression, tissue distribution, roles, biochemistry CBS, followed by comprehensive overview direct indirect approaches to inhibit enzyme. Among small-molecule inhibitors, review highlights specificity selectivity problems related commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) provides their pharmacological actions various disease models.

Language: Английский

---

NBD-based synthetic probes for sensing small molecules and proteins: design, sensing mechanisms and biological applications

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(13), P. 7436 - 7495

Published: Jan. 1, 2021

Compounds with a nitrobenzoxadiazole (NBD) skeleton exhibit high reactivity toward biological nucleophilies accompanied by distinct colorimetric and fluorescent changes, environmental sensitivity, small size, all of which facilitate biomolecular sensing self-assembly.

Language: Английский

---

Sulfide regulation of cardiovascular function in health and disease

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 20(2), P. 109 - 125

Published: Aug. 5, 2022

Language: Английский

---