Metformin raises hydrogen sulfide tissue concentrations in various mouse organs

Wiliński, Bogdan; Wiliński, Jerzy; Somogyi, E; Piotrowska, Joanna; Opoka, Włodzimierz

doi:10.1016/s1734-1140(13)71053-3

Cited by 55 publications

(47 citation statements)

References 36 publications

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“…These data indicate that reduced CSE expression in the proximal tubules is not only involved in renal scarring, but also directly contributes to ischemic injury in diabetic nephropathy by dysregulation of the tubulointerstitial microcirculation [21]. Interestingly, metformin, one of the most widely prescribed anti-diabetic drugs, has been found to increase H2S tissue concentrations in various mouse organs, including the kidney [91].…”

Section: H2s In the Onset And Progression Of Renal Diseasementioning

confidence: 86%

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

et al. 2015

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Section: H2s In the Onset And Progression Of Renal Diseasementioning

confidence: 86%

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

et al. 2015

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“…For instance, NaHS exerts insulin-sensitizing effects and alleviates insulin resistance (50). Moreover, metformin, the well-established AMPK activator and a favored first-line antidiabetes drug, increases H 2 S tissue concentrations in various organs (49). These published results as well as our finding (C-F) qPCR measurement of mRNA expression of M1 genes (iNOS, TNF-a, IL-1b, and IL-6) in the lateral septal complex area at 6 h after LPS injection.…”

Section: Discussionmentioning

confidence: 99%

CaMKKβ-Dependent Activation of AMP-Activated Protein Kinase Is Critical to Suppressive Effects of Hydrogen Sulfide on Neuroinflammation

Zhou

Cao

et al. 2014

Antioxidants & Redox Signaling

114

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Aims: The manner in which hydrogen sulfide (H 2 S) suppresses neuroinflammation is poorly understood. We investigated whether H 2 S polarized microglia to an anti-inflammatory (M2) phenotype by activating AMPactivated protein kinase (AMPK). Results: Three structurally unrelated H 2 S donors (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione [ADT-OH], (p-methoxyphenyl) morpholino-phosphinodithioic acid [GYY4137], and sodium hydrosulfide [NaHS]) enhanced AMPK activation in BV2 microglial cells in the presence and absence of lipopolysaccharide (LPS). The overexpression of the H 2 S synthase cystathionine bsynthase (CBS) in BV2 cells enhanced endogenous H 2 S production and AMPK activation regardless of LPS stimulation. On LPS stimulation, overexpression of both ADT-OH and CBS promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and elevated M2 signature gene expression. The promoting effects of ADT-OH on M2 polarization were attenuated by an AMPK inhibitor or AMPK knockdown. Liver kinase B1 (LKB1) and calmodulin-dependent protein kinase kinase b (CaMKKb) are upstream kinases that activate AMPK. ADT-OH activated AMPK in Hela cells lacking LKB1. In contrast, both the CaMKKb inhibitor and siRNA abolished ADT-OH activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKKb inhibitor and siRNA blunted ADT-OH suppression on M1 gene expression and enhancement of M2 gene expression in LPS-stimulated BV2 cells. Moreover, ADT-OH promoted M2 polarization of primary microglia in an AMPK activation-and CaMKKb-dependent manner. Finally, in an LPS-induced in vivo neuroinflammation model, both ADT-OH and NaHS enhanced AMPK activation in the brain area where microglia were overactivated on LPS stimulation. Furthermore, ADT-OH suppressed M1 and promoted M2 gene expression in this in vivo model. Innovation and Conclusion: CaMKKb-dependent AMPK activation is an unrecognized mechanism underlying H 2 S suppression on neuroinflammation.

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“…Although a recent in-vitro study points to a potentially adverse effect of H 2 S on hepatocyte glucose metabolism , the pathophysiological significance of an activated hepatic CBS/ CSE system in the onset and development of diabetes remains to be investigated. It is intriguing though that the insulin sensitizing agent metformin, which successfully reversed NAFLD in mice (Lin et al 2000), also increased liver H 2 S levels (Wilinski et al 2013). These findings raise the possibility that metformin could modulate H 2 S in NAFLD, and highlights the need to investigate whether this pharmacological agent targets the hepatic CBS/CSE system.…”

Section: Diabetesmentioning

confidence: 99%

The CBS/CSE system: a potential therapeutic target in NAFLD?

Siow

2015

Can. J. Physiol. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is a broad spectrum liver disorder diagnosed in patients without a history of alcohol abuse. NAFLD is growing at alarming rates worldwide. Its pathogenesis is complex and incompletely understood. The cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) system regulates homocysteine and cysteine metabolism and contributes to endogenous hydrogen sulfide (H2S) biosynthesis. This review summarizes our current understanding of the hepatic CBS/CSE system, and for the first time, positions this system as a potential therapeutic target in NAFLD. As will be discussed, the CBS/CSE system is highly expressed and active in the liver. Its dysregulation, presenting as alterations in circulating homocysteine and (or) H2S levels, has been reported in NAFLD patients and in NAFLD-associated co-morbidities such as obesity and type 2 diabetes. Intricate links between the CBS/CSE system and a number of metabolic and stress related molecular mediators have also emerged. Various dysfunctions in the hepatic CBS/CSE system have been reported in animal models representative of each NAFLD spectrum. It is anticipated that a newfound appreciation for the hepatic CBS/CSE system will emerge that will improve our understanding of NAFLD pathogenesis, and give rise to new prospective targets for management of this disorder.

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Metformin raises hydrogen sulfide tissue concentrations in various mouse organs

Abstract: Our experiment has shown that metformin administration is followed by H2S tissue concentrations increase in mouse brain, heart, kidney and liver.

Cited by 55 publications

References 36 publications

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

CaMKKβ-Dependent Activation of AMP-Activated Protein Kinase Is Critical to Suppressive Effects of Hydrogen Sulfide on Neuroinflammation

The CBS/CSE system: a potential therapeutic target in NAFLD?

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