H2S protects from oxidative stress-driven ACE2 expression and cardiac aging

Barrow, Kalem; Wang, Yuehong; Yu, Ruihuan; Zhu, Jiechun; Yang, Guangdong

doi:10.1007/s11010-022-04386-4

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…Although the mechanism to generate the heme ferryl compound II and a thiyl radical, HS • , is diferent from the model proposed by Nicholls [57], the calculated energetic data indeed supported their hypothesis of the reaction between hem-eFe(IV)=O and the HS • to produce sulfheme. Furthermore, contrary to the classical peroxidative reaction of heme proteins with H 2 O 2 [60,61],the absence of the heme Cpd-I radical [Fe(IV)=O +• ] in sulfheme formation through reaction (1a) [53,59] supports the antioxidant role of hydrogen sulfde [18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 89%

“…Reduced H 2 S levels are also related to Parkinson's, Alzheimer's, and atherosclerosis [14,15]. Furthermore, H 2 S has been correlated with chronic diseases [16,17], infammation [18,19], oxidative stress [20][21][22][23][24][25], oral diseases [26], glaucoma [27], subarachnoid hemorrhage [28], infertile men [29], arterial oxygen saturation [30], and skin diseases [31].…”

Section: Introductionmentioning

confidence: 99%

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Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Rodriguez-Mackenzie,

Santos-Velazquez,

Arbelo-Lopez

et al. 2024

Journal of Chemistry

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The chemistry of hydrogen sulfide (H2S) has been directed towards physiologically relevant hemeproteins, including myoglobin, hemoglobin, and other similar proteins. Despite substantial efforts, there remains a need to elucidate the mechanism and identify the species involved in the reaction between oxy-hemeproteins and H2S. Here, we summarize both our experimental data and computational modeling results revealing the mechanisms by which sulfmyoglobin (sulfMb) and sulfhemoglobin (sulfHb) are formed. Our experimental data at pH 7.4 reveal differences in intensity between sulfMb and sulfHb chromophores in the 620 nm charge transfer region. This behavior could be attributed to the incomplete reaction of tetrameric oxy-Hb with H2S, where not all heme groups form sulfheme. The data also show that, for the reaction of oxy-myoglobin (oxy-Mb) and H2S, the 622 nm charge transfer band increases in intensity from a pH of 6.6 to 5.0. This increase is attributed to the presence of the heme pocket distal His64εδ, which is positively charged, resulting in an elevated yield of sulfMb formation compared to the mono-protonated tautomer, His64ε. Computational hybrid QM/MM methods support the conclusion, indicating that oxy-Mb His64εδ (pH 5.0) reacts with H2S in the triplet state, favored by −31.0 kcal/mol over the singlet His64ε (pH 6.6) species. The phenomenon is facilitated by a hydrogen bonding network within the heme pocket, between His64εδ, heme Fe(II)O2, and H2S. The results establish an energetically favored quantitative mechanism to produce sulfMb (−69.1 kcal/mol) from the reactions of oxy-Mb and H2S. Curiously, the mechanism between met-aquo Mb, H2O2, and H2S shows similar reaction pathways and leads to sulfheme formation (−135.3 kcal/mol). The energetic barrier towards intermediate Cpd-0 is the limiting step in sulfheme formation for both systems. ‬Both mechanisms show that the thiyl radical, HS•, is the species attacking the β-β double bond of heme pyrrole B, leading to the sulfheme structure.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Rodriguez-Mackenzie,

Santos-Velazquez,

Arbelo-Lopez

et al. 2024

Journal of Chemistry

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“…Cell viability assay. Cell viability was assessed using the MTT assay as described previously (34). In this assay, the living cells can convert MTT to purple formazan crystals.…”

Section: Methodsmentioning

confidence: 99%

“…After the cells were treated with dandelion root extracts (0.1 mg/ml), TS (0.01 µg/ml), LPS (0.5 µg/ml), TNFα (10 ng/ml) and/or CLI095 (10 µM) for 24 h at 37˚C, the cultured cells were collected for protein analysis by western blotting as described previously (34,35). Briefly, the cells were lysed with radioimmunoprecipitation assay buffer supplemented with a protease inhibitor cocktail (MilliporeSigma) for protein extraction.…”

Section: Detection Of Protein Expression Levels By Western Blottingmentioning

confidence: 99%

Dandelion root extracts and taraxasterol inhibit LPS‑induced colorectal cancer cell viability by blocking TLR4‑NFκB‑driven ACE2 and TMPRSS2 pathways

Yang,

Wang

2024

Exp Ther Med

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Colorectal cancer is the fourth leading cause of cancer-related death worldwide. Notably, abnormalities in intestinal bacteria may contribute to the initiation or progression of colorectal cancer. Lipopolysaccharide (LPS), a bacterial endotoxin, is elevated in patients with colorectal cancer. The present study investigated the protective effects of dandelion root extracts and taraxasterol (TS; a major pharmacologically active compound in dandelion root extracts) on LPS-induced colorectal cancer cell viability, as well as the underlying mechanisms. Cell viability was assessed by MTT assay, and protein and gene expression levels were determined by western blotting and quantitative PCR. It was revealed that LPS at a low dose (0.5 µg/ml) significantly promoted the viability of human colorectal cancer cells but did not affect normal colon epithelial cells. The addition of dandelion root extracts (0.1-1 mg/ml) or TS (0.05-1 µg/ml) was able to reverse the LPS-induced increase in colorectal cancer cell viability and colony formation. Mechanistically, dandelion root extracts or TS may inhibit the LPS-promoted toll-like receptor 4 (TLR4)/NFκB-p65 pathway and transcription levels of pro-inflammatory genes (TNFα, IL4 and IL6). Compared with normal colon epithelial cells, human colorectal cancer cells had higher expression levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which could be further enhanced by LPS treatment but this was reversed by co-incubation with dandelion root extracts or TS. In addition, suppression of the TLR4/NFκB-p65 pathway with CLI095 significantly reversed the stimulatory effect of LPS on the expression levels of ACE2 and TMPRSS2, whereas TNFα (10 ng/ml) markedly induced the expression levels of ACE2 and TMPRSS2. In conclusion, the present study suggested that dandelion root extracts and TS could be used as prevention strategies for reversing bacteria-driven colorectal cancer cell viability.

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“…Reduced H 2 S levels are also observed in Parkinson's, Alzheimer's, and atherosclerosis [17,18]. In addition, H 2 S has been correlated with chronic diseases [19][20][21], infammation [22][23][24], immune system regulation [25,26], cancer [27,28], oxidative stress [29][30][31][32][33][34], oral diseases [35], glaucoma [36], subarachnoid hemorrhage [37], infertility in men [38], arterial oxygen saturation [39], and skin diseases [40]. Furthermore, clinical studies have emphasized the potential of modulating H 2 S synthesis for therapeutic use [41][42][43].…”

Section: Introductionmentioning

confidence: 99%

Insights into Sulfhemoglobin Detection: UV-Vis and Fluorescence Spectroscopy Correlations

Santos-Velázquez,

López-Garriga

2023

Journal of Chemistry

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The mechanisms by which drugs and several sulfur chemicals induce sulfhemoglobin formation have not yet been elucidated. However, enzymes producing hydrogen sulfide in mammalian tissues and organs suggest sulfhemoglobin and sulfmyoglobin formation mechanisms are more complex than previously hypothesized. The process involves the interaction of H2S with hemoglobin or myoglobin in the presence of O2 or H2O2 to generate sulfhemoglobin or sulfmyoglobin, respectively. Structurally, the sulfheme product chromophore is a covalent heme modification. This modification involves the incorporation of one sulfur atom within carbon atoms to form a sulfur-carbons ring moiety across the β-β double bond of heme pyrrole B, which shows a characteristic optical band around 623 nm and 618 nm for sulfhemoglobin and sulfmyoglobin, respectively. The results show a linear correlation between the sulfHb electronic charge transfer transition at 623 nm and the emission wavelength of 460 nm upon Soret excitation at 420 nm. The data show no such linear relationship for oxy-Hb or met-aquo Hb. This new approach allows us to measure from 0.02% to 13.5% sulfhemoglobin in mixtures of met-aquo hemoglobin and oxy-hemoglobin. Although additional work is needed, the results suggest that simultaneously monitoring sulfHb electronic transition at 623 nm and emission wavelength at 460 nm upon Soret excitation at 420 nm is a powerful technique to determine the percentage of sulfhemoglobin in blood. The data and techniques presented indicate that fluorescence spectroscopy coupled with UV-vis spectroscopy provides a fast and accurate method for detecting sulfhemoglobin in the blood, facilitating the diagnosis of sulfhemoglobinemia in patients.

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H2S protects from oxidative stress-driven ACE2 expression and cardiac aging

Cited by 7 publications

References 46 publications

Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay

Dandelion root extracts and taraxasterol inhibit LPS‑induced colorectal cancer cell viability by blocking TLR4‑NFκB‑driven ACE2 and TMPRSS2 pathways

Insights into Sulfhemoglobin Detection: UV-Vis and Fluorescence Spectroscopy Correlations

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