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The structure of skin. The uppermost layer is the epidermis, the second layer is the dermis, and the deepest layer is the subcutaneous tissue hypodermis. The area indicated by the rectangle reveals that the epidermis is divided into five layers of cells.
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Together with nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is now recognized as a vital gaseous transmitter. The ubiquitous distributions of H2S-producing enzymes and potent chemical reactivities of H2S in biological systems make H2S unique in its ability to regulate cellular and organ functions in both health and disease. Act...
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... In mammalian organisms, H 2 S can be produced through the non-enzymatic and enzymatic pathways. The non-enzymatic process is mainly produced by the decomposition of the inorganic substances, which has a very small contribution to the production of H 2 S (Xiao et al., 2021). Cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) are the three important enzymes of the mammalian enzymatic pathway to produce H 2 S . ...
Endoplasmic reticulum (ER) is an important organelle for protein translation, folding and translocation, as well as the post-translational modification and assembly of newly synthesized secreted proteins. When the excessive accumulation of misfolded and/or unfolded proteins exceeds the processing capacity of ER, ER stress is triggered. The integrated intracellular signal cascade, namely the unfolded protein response, is induced to avoid ER stress. ER stress is involved in many pathological and physiological processes including myocardial diseases. For a long time, hydrogen sulfide (H 2 S) has been considered as a toxic gas with the smell of rotten eggs. However, more and more evidences indicate that H 2 S is an important gas signal molecule after nitric oxide and carbon monoxide, and regulates a variety of physiological and pathological processes in mammals. In recent years, increasing studies have focused on the regulatory effects of H 2 S on ER stress in myocardial diseases, however, the mechanism is not very clear. Therefore, this review focuses on the role of H 2 S regulation of ER stress in myocardial diseases, and deeply analyzes the relevant mechanisms so as to lay the foundation for the future researches.
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.
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.
The skin is the first protective barrier of the human body, and oxidative damage is one of the main mechanisms of skin injury. Effective antioxidant therapy plays an important role in skin healing. Therefore, exploring antioxidants and suitable drug delivery methods that can be used for skin injury repair is of great value in regulating skin repair and regeneration and promoting wound healing. Based on this, this paper presents a review of the progress of research on (1) antioxidants and (2) antioxidant carriers for skin repair in order to summarize the research results and provide reference for the subsequent development of new drug-carrier structures and new skin repair strategies.
Atopic dermatitis (AD) shows frequent recurrence. Staphylococcus aureus is the primary microbial component in AD and is associated with disease activity. However, traditional typing methods have failed to characterize virulent AD isolates at the clone level. We conducted a comprehensive genomic characterization of S. aureus strains isolated from the skin of AD patients and healthy donors, comparing the whole-genome sequences of the 261 isolates with anatomical and lesional (AD-A)/nonlesional (AD-NL)/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. Sequence type (ST) diversity was lost with worsening disease activity; ST188 was the most frequently detected ST in AD-A and had the strongest correlation with AD according to the culture rate and proportion with worsening disease activity. ST188 and ST20 isolates inhabited all skin conditions, with significantly higher proportions in AD skin than in healthy skin. ST8, ST15, and ST5 proportions were equivalent for all skin conditions; ST30 was detected only in healthy skin; and ST12 was detected only in AD skin. ST97 detected in AD-A and healthy skin was clearly branched into two subclades, designated ST97A and ST97H. A comparison of two genomes led to the discovery that only ST97A possessed the complete trp operon, enabling bacterial survival without exogenous tryptophan (Trp) on AD skin, where the Trp level was significantly reduced. Primary STs showing an AD skin inhabitation trend (ST188, ST97A, ST20, and ST12) were all trp operon positive. The predominant clones (ST188 and ST97) possessed almost no enterotoxin genes, no mecA gene, and few other antimicrobial resistance genes, different from the trend observed in Europe/North America. IMPORTANCE While Staphylococcus aureus is a member of the normal human skin flora, its strong association with the onset of atopic dermatitis (AD) has been suggested. However, previous studies failed to assign specific clones relevant to disease activities. Enterotoxins produced by S. aureus have been suggested to aggravate and exacerbate the inflammation of AD skin, but their role remains ambiguous. We conducted a nuanced comprehensive characterization of isolates from AD patients and healthy donors, comparing the whole-genome sequences of the isolates with anatomical and lesional/nonlesional/healthy sites, eruption types, clinical scores, virulence, and antimicrobial resistance gene repertoires in Japan. We demonstrate that specific clones are associated with disease severity and clinical manifestations, and the dominant clones are devoid of enterotoxin genes and antimicrobial resistance genes. These findings undermine the established notion of the pathophysiological function of S. aureus associated with AD and introduce a new concept of S. aureus colonization in AD.
Delayed wound healing is one of the major diabetes complications that occur in 25% of diabetic patients. Specific wound management and combination treatment are required to repair the wound, which still remains a challenge with few effective therapies available currently. In this work, a new H2S donor PRO-F, which is characterized by the capability to promote wound healing in diabetes, was designed. PRO-F can be activated by light without consuming endogenous substances and the accompanying fluorescent signal makes the real-time tracking of released H2S possible. PRO-F is able to deliver H2S in an intracellular environment with moderate release efficiency (50%), which presents cytoprotective effects against excessive reactive oxygen species (ROS) induced damage. Furthermore, the potential of PRO-F to enhance chronic wound healing was validated by employing diabetic models. This work provides new insights into the therapeutic role of H2S donors in complex wound conditions, which should advance the pathophysiological research associated with H2S.
Hydrogen sulfide (H2S) has been reported as an endogenous gasotransmitter that contributes to the modulation of a myriad of biological signalling pathways, which includes maintaining homeostasis in living organisms at physiological concentrations, controlling protein sulfhydration and persulfidation for signalling processes, mediating neurodegeneration, and regulating inflammation and innate immunity, etc. As a result, researchers are actively exploring effective approaches to evaluate the properties and the distribution of H2S in vivo. Furthermore, the regulation of the physiological conditions of H2S in vivo introduces the opportunity to further study the molecular mechanisms by which H2S regulates cellular functions. In recent years, many H2S-releasing compounds and biomaterials that can deliver H2S to various body systems have been developed to provide sustained and stable H2S delivery. Additionally, various designs of these H2S-releasing biomaterials have been proposed to aid in the normal conduction of physiological processes, such as cardioprotection and wound healing, by modulating different signalling pathways and cell functionalities. Using biomaterials as a platform to control the delivery of H2S introduces the opportunity to fine tune the physiological concentration of H2S in vivo, a key to many therapeutic applications. In this review, we highlight recent research works concerning the development and application of H2S-releasing biomaterials with a special emphasis to different release triggering conditions in in vivo studies. We believe that the further exploration of the molecular mechanisms underlying H2S donors and their function when incorporated with various biomaterials will potentially help us understand the pathophysiological mechanisms of different diseases and assist the development of H2S-based therapies.
Hydrogen sulfide (H2S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H2S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H2S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often contradictory. We herein examined two types of model hapten-induced inflammation models, colitis (an inflammatory bowel disease model of mucosal immunity) and contact dermatitis (a type IV allergic model of systemic immunity), in CTH-deficient (Cth–/–) and MPST-deficient (Mpst–/–) mice. Both mice exhibited no significant alteration from wild-type mice in trinitrobenzene sulfonic acid (Th1-type hapten)-induced colitis (a Crohn’s disease model) and oxazolone (Th1/Th2 mix-type; Th2 dominant)-induced colitis (an ulcerative colitis model). However, Cth–/– (not Mpst–/–) mice displayed more exacerbated phenotypes in trinitrochlorobenzene (TNCB; Th1-type)-induced contact dermatitis, but not oxazolone, at the delayed phase (24 h post-administration) of inflammation. CTH mRNA expression was upregulated in the TNCB-treated ears of both wild-type and Mpst–/– mice. Although mRNA expression of pro-inflammatory cytokines (IL-1β and IL-6) was upregulated in both early (2 h) and delayed phases of TNCB-triggered dermatitis in all genotypes, that of Th2 (IL-4) and Treg cytokines (IL-10) was upregulated only in Cth–/– mice, when that of Th1 cytokines (IFNγ and IL-2) was upregulated in wild-type and Mpst–/– mice at the delayed phase. These results suggest that (upregulated) CTH or H2S produced by it helps maintain Th1/Th2 balance to protect against contact dermatitis.
Hydrogen sulfide (H2S), known as the third gasotransmitter, exerts various physiological functions including cardiac protection, angiogenesis, anti-inflammatory, and anti-cancer capability. Given its promising therapeutic potential as well as severe perniciousness if improper use, the sustained and tunable H2S delivery systems are highly required for H2S-based gas therapy with enhanced bioactivity and reduced side effects. To this end, a series of stimuli-responsive compounds capable of releasing H2S (termed H2S donors) have been designed over the past two decades to mimic the endogenous generation of H2S and elucidate the biological functions. Further to improve the stability of H2S donors and achieve the targeted delivery, various delivery systems have been constructed. In this review, we focus on the recent advances of an emerging subset, biomolecular-based H2S delivery systems, which combine H2S donors with biomolecular vectors including polysaccharide, peptide, and protein. We demonstrated their basic structures, building strategies, and therapeutic applications respectively to unfold their inherent merits endued by biomolecules including biocompatibility, biodegradability as well as expansibility. The varied development potentials of biomolecular-based H2S delivery systems based on their specific properties are also discussed. At the end, brief future outlooks and upcoming challenges are presented as well.
