Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, HS overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy.

Down syndrome (DS) is a genetic condition where the person is born with an extra chromosome 21. DS is associated with accelerated aging; people with DS are prone to age-related neurological conditions including an early-onset Alzheimer's disease. Using the Dp(17)3Yey/ + mice, which overexpresses a portion of mouse chromosome 17, which encodes for the transsulfuration enzyme cystathionine β-synthase (CBS), we investigated the functional role of the CBS/hydrogen sulfide (HS) pathway in the pathogenesis of neurobehavioral dysfunction in DS.

Sequential Accumulation of 'Driver' Pathway Mutations Induces the Upregulation of Hydrogen-Sulfide-Producing Enzymes in Human Colonic Epithelial Cell Organoids.

Recently, a CRISPR-Cas9 genome-editing system was developed with introduced sequential 'driver' mutations in the WNT, MAPK, TGF-β, TP53 and PI3K pathways into organoids derived from normal human intestinal epithelial cells. Prior studies have demonstrated that isogenic organoids harboring mutations in the tumor suppressor genes APC, SMAD4 and TP53, as well as the oncogene KRAS, assumed more proliferative and invasive properties in vitro and in vivo. A separate body of studies implicates the role of various hydrogen sulfide (HS)-producing enzymes in the pathogenesis of colon cancer.

Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response.

Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated state is associated with greater sensitivity to ferroptosis, a lipid peroxidation-reliant, iron-dependent form of cell death.

Epigallocatechin gallate is a potent inhibitor of cystathionine beta-synthase: Structure-activity relationship and mechanism of action.

Epigallocatechin gallate (EGCG) is the main bioactive component of green tea. Through screening of a small library of natural compounds, we discovered that EGCG inhibits cystathionine β-synthase (CBS), a major HS-generating enzyme. Here we characterize EGCG's mechanism of action in the context of CBS-derived HS production.

The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects.

Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling has become a key pathway for cellular regulation against oxidative stress and inflammation, and therefore an attractive therapeutic target. Several organosulfur compounds are reportedly activators of the Nrf2 pathway. Organosulfur compounds constitute an important class of therapeutic agents in medicinal chemistry due to their ability to participate in biosynthesis, metabolism, cellular functions, and protection of cells from oxidative damage.

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

Cystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to the biosynthesis of cysteine and production of hydrogen sulfide (HS). Aberrant upregulation of CBS and overproduction of HS contribute to pathophysiology of several diseases including cancer and Down syndrome. Therefore, pharmacological CBS inhibition has emerged as a prospective therapeutic approach.

Inhibition of the 3-mercaptopyruvate sulfurtransferase-hydrogen sulfide system promotes cellular lipid accumulation.

HS is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). HS plays multiple roles in the regulation of various metabolic processes, including insulin resistance. HS biosynthesis also occurs in adipocytes.

MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity.

Given the clinical, economic, and societal impact of obesity, unraveling the mechanisms of adipose tissue expansion remains of fundamental significance. We previously showed that white adipose tissue (WAT) levels of 3-mercaptopyruvate sulfurtransferase (MPST), a mitochondrial cysteine-catabolizing enzyme that yields pyruvate and sulfide species, are downregulated in obesity. Here, we report that Mpst deletion results in fat accumulation in mice fed a high-fat diet (HFD) through transcriptional and metabolic maladaptation.

Overproduction of hydrogen sulfide, generated by cystathionine β-synthase, disrupts brain wave patterns and contributes to neurobehavioral dysfunction in a rat model of down syndrome.

Using a novel rat model of Down syndrome (DS), the functional role of the cystathionine-β-synthase (CBS)/hydrogen sulfide (HS) pathway was investigated on the pathogenesis of brain wave pattern alterations and neurobehavioral dysfunction. Increased expression of CBS and subsequent overproduction of HS was observed in the brain of DS rats, with CBS primarily localizing to astrocytes and the vasculature. DS rats exhibited neurobehavioral defects, accompanied by a loss of gamma brain wave activity and a suppression of the expression of multiple pre- and postsynaptic proteins.

Human Cystathionine γ-Lyase Is Inhibited by -Nitrosation: A New Crosstalk Mechanism between NO and HS.

The 'gasotransmitters' hydrogen sulfide (HS), nitric oxide (NO), and carbon monoxide (CO) act as second messengers in human physiology, mediating signal transduction via interaction with or chemical modification of protein targets, thereby regulating processes such as neurotransmission, blood flow, immunomodulation, or energy metabolism. Due to their broad reactivity and potential toxicity, the biosynthesis and breakdown of HS, NO, and CO are tightly regulated. Growing evidence highlights the active role of gasotransmitters in their mutual cross-regulation.

The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter.

Cyanide is traditionally viewed as a cytotoxic agent, with its primary mode of action being the inhibition of mitochondrial Complex IV (cytochrome c oxidase). However, recent studies demonstrate that the effect of cyanide on Complex IV in various mammalian cells is biphasic: in lower concentrations (nanomolar to low micromolar) cyanide stimulates Complex IV activity, increases ATP production and accelerates cell proliferation, while at higher concentrations (high micromolar to low millimolar) it produces the previously known ('classic') toxic effects. The first part of the article describes the cytotoxic actions of cyanide in the context of environmental toxicology, and highlights pathophysiological conditions (e.

Physiological concentrations of cyanide stimulate mitochondrial Complex IV and enhance cellular bioenergetics.

In mammalian cells, cyanide is viewed as a cytotoxic agent, which exerts its effects through inhibition of mitochondrial Complex IV (Cytochrome C oxidase [CCOx]). However, the current report demonstrates that cyanide's effect on CCOx is biphasic; low (nanomolar to low-micromolar) concentrations stimulate CCOx activity, while higher (high-micromolar) concentrations produce the "classic" inhibitory effect. Low concentrations of cyanide stimulated mitochondrial electron transport and elevated intracellular adenosine triphosphate (ATP), resulting in the stimulation of cell proliferation.

Pharmacological induction of mesenchymal-epithelial transition via inhibition of H2S biosynthesis and consequent suppression of ACLY activity in colon cancer cells.

Hydrogen sulfide (HS) is an important endogenous gaseous transmitter mediator, which regulates a variety of cellular functions in autocrine and paracrine manner. The enzymes responsible for the biological generation of HS include cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). Increased expression of these enzymes and overproduction of HS has been implicated in essential processes of various cancer cells, including the stimulation of metabolism, maintenance of cell proliferation and cytoprotection.

The multifaceted roles of sulfane sulfur species in cancer-associated processes.

Sulfane sulfur species comprise a variety of biologically relevant hydrogen sulfide (HS)-derived species, including per- and poly-sulfidated low molecular weight compounds and proteins. A growing body of evidence suggests that HS, currently recognized as a key signaling molecule in human physiology and pathophysiology, plays an important role in cancer biology by modulating cell bioenergetics and contributing to metabolic reprogramming. This is accomplished through functional modulation of target proteins via HS binding to heme iron centers or HS-mediated reversible per- or poly-sulfidation of specific cysteine residues.

Mechanism of cystathionine-β-synthase inhibition by disulfiram: The role of bis(N,N-diethyldithiocarbamate)-copper(II).

Background: Hydrogen sulfide (HS) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) are the principal enzymes responsible for its biogenesis. A recent yeast screen suggested that disulfiram (a well-known inhibitor of aldehyde dehydrogenase and a clinically used drug in the treatment of alcoholism) may inhibit CBS in a cell-based environment.

Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition.

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (HS), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects.

Hydrogen Sulfide Metabolism and Signaling in the Tumor Microenvironment.

Hydrogen sulfide (HS), while historically perceived merely as a toxicant, has progressively emerged as a key regulator of numerous processes in mammalian physiology, exerting its signaling function essentially through interaction with and/or modification of proteins, targeting mainly cysteine residues and metal centers. As a gaseous signaling molecule that freely diffuses across aqueous and hydrophobic biological milieu, it has been designated the third 'gasotransmitter' in mammalian physiology. HS is synthesized and detoxified by specialized endogenous enzymes that operate under a tight regulation, ensuring homeostatic levels of this otherwise toxic molecule.

-Acetylcysteine Serves as Substrate of 3-Mercaptopyruvate Sulfurtransferase and Stimulates Sulfide Metabolism in Colon Cancer Cells.

Hydrogen sulfide (HS) is an endogenously produced signaling molecule. The enzymes 3-mercaptopyruvate sulfurtransferase (MST), partly localized in mitochondria, and the inner mitochondrial membrane-associated sulfide:quinone oxidoreductase (SQR), besides being respectively involved in the synthesis and catabolism of HS, generate sulfane sulfur species such as persulfides and polysulfides, currently recognized as mediating some of the HS biological effects. Reprogramming of HS metabolism was reported to support cellular proliferation and energy metabolism in cancer cells.

Hydrogen Sulfide Oxidation: Adaptive Changes in Mitochondria of SW480 Colorectal Cancer Cells upon Exposure to Hypoxia.

Hydrogen sulfide (HS), a known inhibitor of cytochrome oxidase (CcOX), plays a key signaling role in human (patho)physiology. HS is synthesized endogenously and mainly metabolized by a mitochondrial sulfide-oxidizing pathway including sulfide:quinone oxidoreductase (SQR), whereby HS-derived electrons are injected into the respiratory chain stimulating O consumption and ATP synthesis. Under hypoxic conditions, HS has higher stability and is synthesized at higher levels with protective effects for the cell.

Screening Pyridine Derivatives against Human Hydrogen Sulfide-synthesizing Enzymes by Orthogonal Methods.

Biosynthesis of hydrogen sulfide (HS), a key signalling molecule in human (patho)physiology, is mostly accomplished by the human enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MST). Several lines of evidence have shown a close correlation between increased HS production and human diseases, such as several cancer types and amyotrophic lateral sclerosis. Identifying compounds selectively and potently inhibiting the human HS-synthesizing enzymes may therefore prove beneficial for pharmacological applications.