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H2S Induces a Suspended Animation-Like State in Mice
Abstract
Mammals normally maintain their core body temperature (CBT) despite changes in environmental temperature. Exceptions to this
norm include suspended animation–like states such as hibernation, torpor, and estivation. These states are all characterized
by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's CBT approaches that
of the environment. We report that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species,
the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended
animation-like states for medical applications.
... H 2 S is a substance produced endogenously by mammals and acts as a neuromodulator in the brain. Inhaling H 2 S can significantly reduce body temperature and metabolic rate (Blackstone et al., 2005). In 2005, researchers in Seattle found that exposing non-hibernating rodents to 80 ppm H 2 S resulted in normal CO 2 output and O 2 consumption of 10%, while the respiratory rate decreased from 120 to 10 breaths per minute, and body temperature decreased from 37°C to 15°C. ...
... This induced a decrease in metabolism and core hypothermia in rodents, leading to a type of hibernation state that is easily reversible and does not cause any harm to the animals. This indicates the possibility of H 2 S-induced hibernation in medical applications (Blackstone et al., 2005). H 2 S is a reversible inhibitor of brain cytochrome c oxidase. ...
Controlling intracranial pressure, nerve cell regeneration, and microenvironment regulation are the key issues in reducing mortality and disability in acute brain injury. There is currently a lack of effective treatment methods. Hibernation has the characteristics of low temperature, low metabolism, and hibernation rhythm, as well as protective effects on the nervous, cardiovascular, and motor systems. Artificial hibernation technology is a new technology that can effectively treat acute brain injury by altering the body’s metabolism, lowering the body’s core temperature, and allowing the body to enter a state similar to hibernation. This review introduces artificial hibernation technology, including mild hypothermia treatment technology, central nervous system regulation technology, and artificial hibernation-inducer technology. Upon summarizing the relevant research on artificial hibernation technology in acute brain injury, the research results show that artificial hibernation technology has neuroprotective, anti-inflammatory, and oxidative stress-resistance effects, indicating that it has therapeutic significance in acute brain injury. Furthermore, artificial hibernation technology can alleviate the damage of ischemic stroke, traumatic brain injury, cerebral hemorrhage, cerebral infarction, and other diseases, providing new strategies for treating acute brain injury. However, artificial hibernation technology is currently in its infancy and has some complications, such as electrolyte imbalance and coagulation disorders, which limit its use. Further research is needed for its clinical application.
... Despite several decades of research, it still has not been attained. The original concept proposed that hibernation is regulated by endogenous blood substances 7 and extensive efforts were devoted to searching for endogenous substances that induce a torpor-like state through systemically suppressing metabolism 8,9 . It is now believed that torpor is controlled libitum access to food and water. ...
... Despite several decades of research, it still has not been attained. The original concept proposed that hibernation is regulated by endogenous blood substances 7 and extensive efforts were devoted to searching for endogenous substances that induce a torpor-like state through systemically suppressing metabolism 8,9 . It is now believed that torpor is controlled Nature Metabolism Article https://doi.org/10.1038/s42255-023-00804-z ...
Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (>24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state.
... Historically, H2S was recognized as both a human and environmental toxin [39]. At high concentrations, it inhibits complex IV of the mitochondrial ETC, which suppresses cellular proliferation and metabolism while inducing apoptosis [40,41]. However, research on H2S over the past several years has shown that H2S is an important gaseous signaling molecule with biological usefulness and therapeutic potential [39,42]. ...
... In a more recent study by Meng et al. [56] involving donation after circulatory death (DCD) lung transplantation in male Sprague Dawley rats, the researchers either deflated the lungs or inflated the lungs with air containing gaseous H2S or air alone for two hours. During this period of warm ischemia, lungs inflated with H2S had a lower metabolic rate relative to the control lungs, which aligns with a previous study that showed H2S can induce a hypometabolic state in mice [41]. The left lungs were then harvested and stored in preservation solution at 4 °C for 3 h followed by syngeneic transplantation into recipient rats, where reperfusion occurred for 3 h [56]. ...
Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon’s enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.
... Results showed that 2-DG induced a fall in the core body temperature of hamsters to below 30°C, while MA had no effect [21]. Blackstone et al. [22] found that the average body temperature of mice could be lowered by up to 15°C after inhaling hydrogen sulfide gas. Additionally, repeated hypoxia can also cause severe hypothermia in mice which may have a protective effect on brain ischemia and hypoxia [4]. ...
Hibernation is a prolonged state of low metabolism that animals enter in response to extreme environmental conditions to enhance their survival in harsh environments. Recent studies have shown that non-hibernating species can also be induced to enter a hibernation-like state. 2-methyl-2-thiazoline (2MT), a potent analog of fox odor, can induce fear-related behavior in mice with low body temperature and low metabolism, and has specific organ-protective effects. A systematic understanding of 2MT-induced hibernation and its underlying mechanisms may aid in expanding its applications in medicine and other fields.
... This fall in metabolic activity was associated with bradypnea and consecutive hypothermia, with core temperature falling to levels close to ambient values. 21 Subsequent work has thus described and studied H 2 S-induced suspended animation-a hibernation-like state. Various other rodent models confirmed these observations: Inhaling gaseous H 2 S 22 and phosphomonoesters, α, β, and γ ATP levels (left) and mean ATP (right) in control-and NaHS-treated kidney. ...
Background
In rodents, hydrogen sulfide (H 2 S) reduces ischemia-reperfusion injury and improves renal graft function after transplantation. Here, we hypothesized that the benefits of H 2 S are conserved in pigs, a more clinically relevant model.
Methods
Adult porcine kidneys retrieved immediately or after 60 min of warm ischemia (WI) were exposed to 100 µM sodium hydrosulfide (NaHS) (1) during the hypothermic ex vivo perfusion only, (2) during WI only, and (3) during both WI and ex vivo perfusion. Kidney perfusion was evaluated with dynamic contrast-enhanced MRI. MRI spectroscopy was further employed to assess energy metabolites including ATP. Renal biopsies were collected at various time points for histopathological analysis.
Results
Perfusion for 4 h pig kidneys with Belzer MPS UW + NaHS resulted in similar renal perfusion and ATP levels than perfusion with UW alone. Similarly, no difference was observed when NaHS was administered in the renal artery before ischemia. After autotransplantation, no improvement in histologic lesions or cortical/medullary kidney perfusion was observed upon H 2 S administration. In addition, AMP and ATP levels were identical in both groups.
Conclusions
In conclusion, treatment of porcine kidney grafts using NaHS did not result in a significant reduction of ischemia-reperfusion injury or improvement of kidney metabolism. Future studies will need to define the benefits of H 2 S in human, possibly using other molecules as H 2 S donors.
... The remarkable response of mice to moderate H 2 S exposure has the hallmarks of inducing hibernation-like behavior, including low core body temperature and depressed cardiac and metabolic function 6,27,31 . A study using a synthetic model of cytochrome c oxidase ascribed the molecular basis of these changes to reversible sulfide coordination at ferrous heme a 3 (which was not certified by peer review) is the author/funder. ...
Hydrogen sulfide exposure in moderate doses can induce profound but reversible hypometabolism in mammals. At a cellular level, H 2 S inhibits the electron transport chain (ETC), augments aerobic glycolysis, and glutamine-dependent carbon utilization via reductive carboxylation; however, the durability of these changes is unknown. We report that despite its volatility, H 2 S preconditioning increases P 50(O2) , the O 2 pressure for half maximal cellular respiration, and has pleiotropic effects on oxidative metabolism that persist up to 24-48 h later. Notably, cyanide, another complex IV inhibitor, does not induce this type of metabolic memory. Sulfide-mediated prolonged fractional inhibition of complex IV by H 2 S is modulated by sulfide quinone oxidoreductase, which commits sulfide to oxidative catabolism. Since induced hypometabolism can be beneficial in disease settings that involve insufficient or interrupted blood flow, our study has important implications for attenuating reperfusion-induced ischemic injury, and/or prolonging shelf life of biologics like platelets.
... For example, lower doses of H 2 S are beneficial to mitochondria, whereas higher doses are harmful. One of the earliest recognized effects of H 2 S on energy metabolism involved induction of suspended animation in mice, which was caused by H 2 Smediated inhibition of complex IV of the ETC via binding the copper centre of cytochrome c oxidase (Blackstone et al., 2005;Hill et al., 1984;Modis et al., 2014;Nicholls et al., 2013). In addition to binding metal centres involving iron and copper, H 2 S is now known to signal prolifically via the posttranslational modification of proteins designated as sulfhydration, also known as persulfidation, wherein thiol groups on cysteine residues are converted to SSH groups, also known as persulfides (Filipovic, 2015;Mustafa et al., 2009;. ...
The gaseous neurotransmitter hydrogen sulfide (H2 S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signaling events. Unlike conventional neurotransmitters, H2 S cannot be stored in vesicles due to its gaseous nature. Instead, it is either locally synthesized or released from endogenous stores. Sulfhydration affords both specific and general neuroprotective effects and is critically diminished in several neurodegenerative disorders. Conversely, some forms of neurodegenerative disease are linked to excessive cellular H2 S. Here, we review the signaling roles of H2 S across the spectrum of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, Down syndrome, traumatic brain injury, the ataxias, and amyotrophic lateral sclerosis, as well as neurodegeneration generally associated with aging.
... Exactly how aerosols trigger memories, how they might work to improve or impair health, how inhaled toxins induce torpor without lasting damage (Blackstone et al., 2005) remain mysterious. More generally, how we might establish a science of identifying and assessing beneficial aerosols seems a worthy endeavor-and yet one more way to improve our understanding of what we have lost by being separated from the wild. ...
Humans have lived from equator to poles for millennia but are now increasingly intruding into the wild spaces of other species and steadily extruding ourselves from our own wild spaces, with a profound impact on: our relationship with the natural world; survival of other species; pollution; climate change; etc. We have yet to grasp how these changes directly impact our own health. The primary focus of this paper is on the beneficial influence of proximity to the natural environment. We summarize the evidence for associations between exposure to green space and blue space and improvements in health. In contrast, grey space - the urban landscape - largely presents hazards as well as reducing exposure to green and blue space and isolating us from the natural environment. We discuss various hypotheses that might explain why green, blue, and grey space affect health and focus particularly on the importance of the biodiversity hypothesis and the role of microbiota. We discuss possible mechanisms and exposure routes - air, soil, and water. We highlight the problem of exposure assessment, noting that many of our current tools are not fit for the purpose of understanding exposure to green and blue space, aerosols, soils, and water. We briefly discuss possible differences between indigenous perspectives on the nature of our relationship with the environment and the more dominant international-science view. Finally, we present research gaps and discuss future directions, particularly focusing on the ways in which we might - even in the absence of a full understanding of the mechanisms by which blue, green, and grey space affect our health - begin to implement policies to restore some balance to our environment of with the aim of reducing the large global burden of ill health.
... For safety reasons, however, the remaining caveats of ultrasoundinduced hypometabolism in mammals should not be neglected: how to jump-start metabolism and arouse from deep torpid states. Similar to previous attempts to induce torpor using hydrogen-sulfide infusion 13 , mice in cold environments with lower body temperatures did not recover spontaneously. While it is not clear whether body temperature would drop below fatal thresholds in large-bodied species such as humans, controlled feedback technologies, as exemplified by Yang et al., would be important to stabilize body temperatures at well-tolerated levels. ...
... Custom built gastight polypropylene chambers (i.e. Tupperware) large enough to temporarily house mice have been used to deliver a constant concentration of H 2 S mixed with air via tubing connected to cylinders [32,33]. Similarly, a custom chamber for culturing Caenorhabditis elegans has been described to study the effects of chronic exposure to 50 ppm H 2 S on thermotolerance, lifespan, and stress response [34][35][36]. ...
H2S is a redox-active signaling molecule that exerts an array of cellular and physiological effects. While intracellular H2S concentrations are estimated to be in the low nanomolar range, intestinal luminal concentrations can be significantly higher due to microbial metabolism. Studies assessing H2S effects are typically conducted with a bolus treatment with sulfide salts or slow releasing sulfide donors, are limited by the volatility of H2S, and by potential off-target effects of the donor molecules. To address these limitations, we describe the design and performance of a mammalian cell culture incubator for sustained exposure to 20-500 ppm H2S (corresponding to a dissolved sulfide concentrations of ∼4-120 μM in the cell culture medium). We report that colorectal adenocarcinoma HT29 cells tolerate prolonged exposure to H2S with no effect on cell viability after 24 h although ≥50 ppm H2S (∼10 μM) restricts cell proliferation. Even the lowest concentration of H2S used in this study (i.e. ∼4 μM) significantly enhanced glucose consumption and lactate production, revealing a much lower threshold for impacting cellular energy metabolism and activating aerobic glycolysis than has been previously appreciated from studies with bolus H2S treatment regimens.
... NO and CO can trigger states of suspended animation in Drosophila (Teodoro & O'Farrell 2003) and C. elegans (Nystul & Roth 2004), respectively. Mice enter a hypometabolic state when exposed to either low temperature or H 2 S, and retain the ability to recover from this hibernation-like condition (Blackstone et al. 2005;Blackstone & Roth 2007). All three gaseous messengers exhibit vasodilating, pro-angiogenic and cytoprotective properties that, in most heart disease models, are further backed by anti-inflammatory plus anti-apoptotic activities (Whiteman & Winyard 2011;Polhemus & Lefer 2014;Kimura 2014a;Shen et al. 2015;Magierowski et al. 2017). ...
... Initial studies on H 2 S predominantly revolved around its toxic effects in mammals [11][12][13], most notably with respect to mitochondrial bioenergetics [14,15]. Indeed, at high concentrations, H 2 S inhibits cytochrome c oxidase and uncouples oxidative phosphorylation, which decreases adenosine triphosphate( ATP) production [16,17]. ...
The gaseous signaling molecule hydrogen sulfide (H2S) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H2S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions. Although toxic and even fatal at very high concentrations, emerging evidence has also revealed a pronounced neuroprotective role for lower doses of endogenously generated or exogenously administered H2S. Unlike traditional neurotransmitters, H2S is a gas and, therefore, is unable to be stored in vesicles for targeted delivery. Instead, it exerts its physiologic effects through the persulfidation/sulfhydration of target proteins on reactive cysteine residues. Here, we review the latest discoveries on the neuroprotective roles of H2S in Alzheimer’s disease (AD) and traumatic brain injury, which is one the greatest risk factors for AD.
... H 2 S has protective and antioxidant effects on cells in the micromolar concentration range (Ali et al., 1990;Bucci et al., 2010;Minamishima et al., 2009;Predmore et al., 2012). However, high H 2 S exposure in the millimolar concentration range can enhance redox stress and produce cytotoxicity (Blackstone et al., 2005;Blackstone and Roth, 2007;. The fluorescence detection method has prompted many research teams to conduct intensive studies due to its immediate and sensitive detection characteristics and low cost (Wu et al., 2020). ...
Hydrogen sulfide (H2S) is an important environmental toxin with bi-directional biological effects on organisms. In natural waters, H2S complexes with heavy metal ions in an anaerobic environment influence heavy metals' bioavailability and induce phosphorus release and eutrophication in water columns. Traditional detection techniques, such as colorimetric, electrochemical, and chromatographic, cannot simultaneously detect H2S and pollution assessment of subtropical lakes. To address these technical defects, we developed small-molecule fluorescent probes to evaluate the pollution level in natural water bodies. This method relies on the combination of the probes' response signals to raw water and the water quality index, thereby enhancing the accuracy and reliability of water quality assessments. Furthermore, this novel material has a large Stokes shift. It can detect complex levels of H2S concentrations in natural water bodies by correlating the degree of contamination and fluorescence signals. The development of this visual research tool for detecting environmental H2S levels in natural water bodies is expected to have meaningful, practical applications.
... After the initial paper by Blackstone et al. [42], we and others investigated the hypometabolic capacity of H 2 S. H 2 S can induce a hypometabolic state when administered to small mammals, such as mice. H 2 S competes with O 2 for binding to cytochrome c oxidase (complex IV) of the electron transport chain in mitochondria. ...
Kidney extraction time has a detrimental effect on post-transplantation outcome. This study aims to improve the flush-out and potentially decrease ischemic injury by the addition of hydrogen sulphide (H2S) to the flush medium. Porcine kidneys (n = 22) were extracted during organ recovery surgery. Pigs underwent brain death induction or a sham operation, resulting in four groups: donation after brain death (DBD) control, DBD H2S, non-DBD control, and non-DBD H2S. Directly after the abdominal flush, kidneys were extracted and flushed with or without H2S and stored for 13 h via static cold storage (SCS) +/− H2S before reperfusion on normothermic machine perfusion. Pro-inflammatory cytokines IL-1b and IL-8 were significantly lower in H2S treated DBD kidneys during NMP (p = 0.03). The non-DBD kidneys show superiority in renal function (creatinine clearance and FENa) compared to the DBD control group (p = 0.03 and p = 0.004). No differences were seen in perfusion parameters, injury markers and histological appearance. We found an overall trend of better renal function in the non-DBD kidneys compared to the DBD kidneys. The addition of H2S during the flush out and SCS resulted in a reduction in pro-inflammatory cytokines without affecting renal function or injury markers.
... H 2 S can also improve the function of mitochondria under hypoxic conditions. Under normal conditions, H 2 S can reduce ATP production by inhibiting cytochrome c oxidase [60]. However, under conditions where oxygen concentrations are low (such as in I/R injuries), CSE can be translocated to mitochondria, where it produces H 2 S, which helps to preserve the generation of ATP [61]. ...
Endogenously produced hydrogen sulfide (H2S) is critical for cardiovascular homeostasis. Therapeutic strategies aimed at increasing H2S levels have proven cardioprotective in models of acute myocardial infarction (MI) and heart failure (HF). The present study was undertaken to investigate the effects of a novel H2S prodrug, SG-1002, on stress induced hypertrophic signaling in murine HL-1 cardiac muscle cells. Treatment of HL-1 cells with SG-1002 under serum starvation without or with H2O2 increased the levels of H2S, H2S producing enzyme, and cystathionine β-synthase (CBS), as well as antioxidant protein levels, such as super oxide dismutase1 (SOD1) and catalase, and additionally decreased oxidative stress. SG-1002 also decreased the expression of hypertrophic/HF protein markers such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), galectin-3, TIMP1, collagen type III, and TGF-β1 in stressed HL-1 cells. Treatment with SG-1002 caused a significant induction of cell viability and a marked reduction of cellular cytotoxicity in HL-1 cells under serum starvation incubated without or with H2O2. Experimental results of this study suggest that SG-1002 attenuates myocardial cellular oxidative damage and/or hypertrophic signaling via increasing H2S levels or H2S producing enzymes, CBS, and antioxidant proteins.
... However, despite such progress, there are still relatively little data on the role of gasotransmitters in hibernation. Blackstone et al. (2005) showed that H 2 S reduces metabolic rate and body temperature in mammals through specific reversible inhibition of complex IV of the electron transport chain. The authors concluded that in doses up to 80 ppm, H 2 S induces a suspended animation-like state in mice, similar to the induction of hibernation, torpor, or aestivation in hibernating animals. ...
The ultimate manifestations of life, birth, survival under various environmental pressures and death are based on bioenergetics. These manifestations of life were made possible by the remarkable "social" behaviour of biomolecules during billions of years of evolution: the evolution of life with oxygen. Oxygen was necessary for energy production and the evolutionary explosion of aerobic organisms. Nevertheless, reactive oxygen species, formed through oxidative metabolism, are dangerous - they can kill a cell and, on the other hand, play a plethora of fundamentally valuable roles. Therefore, the evolution of life depended on energy metabolism and redox-metabolic adaptations. The more extreme the conditions for survival are, the more sophisticated the adaptive responses of organisms become. Hibernation is a beautiful illustration of this principle. Hibernating animals use evolutionarily conserved molecular mechanisms to survive adverse environmental conditions, including reducing body temperature to ambient levels (often to near 0 °C) and severe metabolic depression. This long-built secret of life lies at the intersection of oxygen, metabolism, and bioenergetics, and hibernating organisms have learned to exploit all the underlying capacities of molecular pathways to survive. This is the story of integrated redox-metabolic orchestration in hibernation.
... Furthermore, often CKD is associated with diabetes mellitus and cardiovascular disease, which are other prevalent risk factors for death and adverse outcomes during a SARS-CoV-2 infection [5]. Finally, CKD is related to other conditions such as ageing, hypertension, and malnutrition [6][7][8][9], which usually affects CKD patients' survival and could affect the outcome during COVID-19. ...
COVID-19 remains a major world health problem, and its clinical manifestations can vary from an oligosymptomatic form to severe pulmonary infection, which can require invasive ventilation and is strictly related to death. Identifying risk factors for adverse outcomes is essential for performing adequate care and contrasting high mortality. Chronic kidney disease (CKD) is a widespread comorbidity and is a known risk factor for death during SARS-CoV-2 infection. The present study evaluates the death risk assessment during the COVID-19 pandemic in (CKD) patients, considering the baseline value of an estimated glomerular filtration rate (eGFR) and other possible risk factors. We retrospectively assessed the mortality risk in 150 patients with COVID-19 between 1 October and 31 December 2020. We evaluated eGFR, haemoglobin, albumin, uric acid, cholesterol, triglycerides, and significant risk factors, such as diabetes mellitus and cardiovascular disease in every patient. We had 53 deaths (35.3%) during the observational period, significantly related to age, eGFR, albumin, and baseline nephropathy. In the multivariable analysis, only baseline eGFR and age were independent predictors of death during SARS-CoV-2 infection, with an OR equal to 0.96 and 1.067, respectively. In conclusion, by our analysis, age, and the baseline eGFR were the only reliable predictors of death during COVID-19 in CKD patients.
... It is known to regulate myriad biological functions in vivo; oxidative stress, insulin signaling, and cell growth and death are all mediated by this species [7,8]. Energy available to the cell can also be affected by levels of H 2 S because it is involved in the inhibition of adenosine triphosphate (ATP) [9][10][11][12][13]. ...
Hydrogen sulfide (H2S) is an essential signaling gas within the cell, and its endogenous levels are correlated with various health diseases such as Alzheimer’s disease, diabetes, Down’s syndrome, and cardiovascular disease. Because it plays such diverse biological functions, being able to detect H2S quickly and accurately in vivo is an area of heightened scientific interest. Using probes that fluoresce in the near-infrared (NIR) region is an effective and convenient method of detecting H2S. This approach allows for compounds of high sensitivity and selectivity to be developed while minimizing cytotoxicity. Herein, we report a review on the synthesis, mechanisms, optical properties, and selected biomedical applications of H2S sensors.
Static cold storage of donor livers at 4°C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ failure. Hydrogen Sulfide (H 2 S) is an endogenously produced gas, previously demonstrated to reduce oxidative stress, reduce ATP depletion, and protect from ischemia and reperfusion injury. H 2 S is difficult to administer due to its rapid release curve, resulting in cellular death at high concentrations. AP39, a mitochondrially targeted, slow-release H 2 S donor, has been shown to reduce ischemia-reperfusion injury in hearts and kidneys. Thus, we investigated whether the addition of AP39 during 3-day static cold storage can improve liver graft viability. At the end of storage, livers underwent six hours of acellular normothermic machine perfusion, a model of transplantation. During simulated transplantation, livers stored with AP39 showed reduced resistance, reduced cellular damage (ALT and AST), and reduced apoptosis. Additionally, bile production and glucose, as well as energy charge were improved by the addition of AP39. These results indicate that AP39 supplementation improves liver viability during static cold storage.
Bacteria, omnipresent in our environment and coexisting within our body, exert dual beneficial and pathogenic influences. These microorganisms engage in intricate interactions with the human body, impacting both human health and disease. Simultaneously, certain organelles within our cells share an evolutionary relationship with bacteria, particularly mitochondria, best known for their energy production role and their dynamic interaction with each other and other organelles. In recent years, communication between bacteria and mitochondria has emerged as a new mechanism for regulating the host’s physiology and pathology. In this review, we delve into the dynamic communications between bacteria and host mitochondria, shedding light on their collaborative regulation of host immune response, metabolism, aging, and longevity. Additionally, we discuss bacterial interactions with other organelles, including chloroplasts, lysosomes, and the endoplasmic reticulum (ER).
The intriguing chemistry of chalcogen (S, Se)-containing ligands and their capability to bridge multiple metal centres have resulted in a plethora of reports on transition metal complexes featuring hydrosulfide (HS-) and polychalcogenides (En2-, E = S, Se). While a large number of such molecules are strictly organometallic complexes, examples of non-organometallic complexes featuring HS- and En2- with N-/O-donor ligands are relatively rare. The general synthetic procedure for the transition metal-hydrosulfido complexes involves the reaction of the corresponding metal salts with HS-/H2S and this is prone to generate sulfido bridged oligomers in the absence of sterically demanding ligands. On the other hand, the synthetic methods for the preparation of transition metal-polychalcogenido complexes include the reaction of the corresponding metal salts with En2- or the two electron oxidation of low-valent metals with elemental chalcogen, often at an elevated temperature and/or for a long time. Recently, we have developed new synthetic methods for the preparation of two new classes of binuclear transition metal complexes featuring either HS-, or Sn2- and Sen2- ligands. The new method for the synthesis of transition metal-hydrosulfido complexes involved transition metal-mediated hydrolysis of thiolates at room temperature (RT), while the method for the synthesis of transition metal-polychalcogenido complexes involved redox reaction of coordinated thiolates and exogenous elemental chalcogens at RT. An overview of the synthetic aspects, structural properties and intriguing reactivity of these two new classes of transition metal complexes is presented.
Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies such as static cold storage are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon’s enemy. This review discusses the pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.
Kidney transplantation has become the preferred treatment option for patients with end-stage renal disease. Although it is a superior alternative to long-term hemodialysis, optimal kidney preservation prior to transplantation remains a major challenge, as the gold standard of renal graft preservation by static cold storage tion in University of Wisconsin (UW) solution on ice at 4 °C contributes to graft injury and long-term post-transplantation complications. An emerging strategy which holds great therapeutic promise against cold renal graft injury and limiting long-term post-transplant complications is supplementation of the cold UW preservation solution with hydrogen sulfide (H2S), the third established member of the gasotransmitter family. This novel pharmacological strategy has been demonstrated experimentally, with compelling success at different preservation temperatures (hypothermic, normothermic and subnormothermic) and preservation techniques such as static cold storage and machine perfusion, suggesting the need for pharmacological modification of existing preservation solutions beyond cold storage to improve the quality of renal graft preservation. This chapter presents an overview of organ graft preservation strategies prior to transplantation, with particular emphasis on the kidney as the most commonly transplantable organ and highly vulnerable to transplantation-induced injury. The chapter also discusses H2S as the future of renal graft preservation for a better transplantation outcome. A section of the chapter also highlights important lessons that can be learned from how nature protects the organs of mammalian hibernators from the damaging effects of repetitive cycle of cold ischemia and reperfusion.
Hydrogen sulfide (H2S), a gas with a characteristic rotten-egg smell, gained historic notoriety for its toxicity and death at high concentrations especially among industrial workers. This is due to its ability to reversibly inhibit the activity of cytochrome c oxidase, a terminal enzyme of the mitochondrial electron transport chain. Recently, however, H2S has risen above its notorious public image and is now seen by researchers as an endogenously produced gaseous signaling molecule that plays an important role in cellular homeostasis and influences several physiological and pathological processes at low physiological and non-toxic concentrations. Its production is catalyzed by two cytosolic enzymes, cystathionine β-synthase and cystathionine γ-lyase, a mitochondrial enzyme, 3-mecaptopyruvate sulfurtransferase, and a peroxisomal enzyme, d-amino acid oxidase. Several recent experimental studies have demonstrated that at low micromolar concentrations, H2S plays a complex and essential role in normal renal function, and dysregulation of its production has been implicated in various renal pathologies. In addition, exogenous H2S administration has been reported to exhibit important therapeutic characteristics that target multiple molecular pathways in common renal pathologies in which reduced levels of renal and plasma H2S were observed. This chapter presents current understanding of H2S in the physiology of the renal system, and lays the foundation for discussion on H2S as a novel pharmacological agent to modify organ transplantation protocol, which are discussed in the subsequent chapters of this book.
Cold ischemia-reperfusion injury (IRI) is an inevitable and unresolved problem that is considered the transplant surgeon’s enemy. It poses a great challenge in solid organ transplantation (SOT), and represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays graft function. This complicates graft quality, post-transplant patient care and organ transplantation outcomes, and therefore undermines the success of SOT. This chapter presents recent advances in research regarding novel pharmacological strategies involving the use of different donor molecules of hydrogen sulfide (H2S), the third established member of the gasotransmitter family, against cold IRI in different experimental models of SOT (kidney, heart, lung, liver, pancreas and intestine). In addition, the author also discusses the molecular mechanisms underlying the effects of these H2S donor molecules in SOT, and suggestions for clinical translation. The findings in this chapter showed that storage of donor organs in H2S-supplemented preservation solution or administration of H2S to organ donor prior to organ procurement and to recipient at the start and during reperfusion is a novel, simple and cost-effective pharmacological approach to minimize cold IRI, limit post-transplant complications and improve transplantation outcomes. In conclusion, experimental evidence demonstrate that H2S donors can significantly mitigate cold IRI during SOT through inhibition of a complex cascade of interconnected cellular and molecular events involving microcirculatory disturbance and microvascular dysfunction, mitochondrial injury, inflammatory responses, cell damage and cell death, and other damaging molecular pathways while promoting protective pathways. Translating these promising findings from bench to bedside will lay the foundation for the use of H2S donor molecules in clinical SOT in the future.
Hydrogen sulfide exposure in moderate doses can induce profound but reversible hypometabolism in mammals. At a cellular level, H 2 S inhibits the electron transport chain (ETC), augments aerobic glycolysis, and glutamine-dependent carbon utilization via reductive carboxylation; however, the durability of these changes is unknown. We report that despite its volatility, H 2 S preconditioning increases P 50(O2) , the O 2 pressure for half-maximal cellular respiration, and has pleiotropic effects on oxidative metabolism that persist up to 24 to 48 h later. Notably, cyanide, another complex IV inhibitor, does not induce this type of metabolic memory. Sulfide-mediated prolonged fractional inhibition of complex IV by H 2 S is modulated by sulfide quinone oxidoreductase, which commits sulfide to oxidative catabolism. Since induced hypometabolism can be beneficial in disease settings that involve insufficient or interrupted blood flow, our study has important implications for attenuating reperfusion-induced ischemic injury and/or prolonging the shelf life of biologics like platelets.
More than 300 years ago, hydrogen sulfide (H2S; also known as dihydrogen sulfide or sulfane) was discovered and historically identified as a harmful gas molecule. More than 240 years later, H2S was reported to endogenously generate and stimulate plant physiological processes. Nowadays, interest in H2S surrounds its converted perception from that of a toxin to a signaling molecule with the admission that it plays a key role in seed germination, plant growth, plant development, and responses and adaptations to environmental stresses. The most important characteristic of the H2S signaling molecule is that it can be coded or initiated by environmental stimulation and maintain homeostasis under normal conditions. The initiation and homeostasis of H2S in plants are strictly controlled by metabolism, including anabolic and catabolic metabolism. Recently, the metabolism and homeostasis regulation of H2S in plants has gradually become clearer. This chapter is based on H2S research progress and discusses the anabolism, catabolism, and persulfidation (also called sulfhydration or sulfuration) of H2S and the regulation of calcium signaling in H2S metabolism. The aim is to further understand the metabolism of H2S in plants and lay a foundation for investigating H2S signaling in plant growth, development, and responses to environmental stimulation.
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.
26 Drugs that induce reversible slowing of metabolic and physiological processes 27 would have great value for organ preservation, especially for organs with high 28
Hydrogen sulfide (H2S), a gas with a characteristic rotten-egg smell, gained historic notoriety for its toxicity and death at high concentrations especially among industrial workers. This is due to its ability to reversibly inhibit the activity of cytochrome c oxidase, a terminal enzyme of the mitochondrial electron transport chain. Recently, however, H2S has risen above its notorious public image and is now seen by researchers as an endogenously produced gaseous signaling molecule that plays an important role in cellular homeostasis and influences several physiological and pathological processes at low physiological and nontoxic concentrations. Its production is catalyzed by two cytosolic enzymes, cystathionine β-synthase and cystathionine γ-lyase, a mitochondrial enzyme, 3-mercaptopyruvate sulfurtransferase, and a peroxisomal enzyme, d-amino acid oxidase. Several recent experimental studies have demonstrated that at low micromolar concentrations, H2S plays a complex and essential role in normal renal function, and dysregulation of its production has been implicated in various renal pathologies. In addition, exogenous H2S administration has been reported to exhibit important therapeutic characteristics that target multiple molecular pathways in common renal pathologies in which reduced levels of renal and plasma H2S were observed. Interestingly, whereas the distribution of all four H2S-producing enzymes is subcellular and tissue specific, they are abundantly expressed by endothelial cells, mesangial cells, and podocytes within the glomeruli, as well as in the brush border and cytoplasm of epithelial cells of the renal proximal tubules, distal tubules, and peritubular capillaries. This makes the kidney a rich source of endogenous H2S production. This chapter presents current understanding of H2S in renal physiology and lays the foundation for discussion on H2S as a new therapeutic target for common renal pathologies in the subsequent chapters.
Diabetic kidney disease (DKD) is a chronic renal pathology, which is currently the leading cause of end-stage renal disease. It accounts for 40% of morbidity and mortality among the diabetic population despite optimal management. Its clinical hallmark includes persistent hyperglycemia, hypercreatininemia, uremia, sustained albuminuria, renal hemodynamic changes, and elevated blood pressure. Histologically, DKD presents with excessive accumulation and deposition of extracellular matrix, leading to expansion of mesangial matrix, thickening of glomerular basement membrane, and tubulointerstitial fibrosis. At the molecular level, accumulating evidence suggests that hyperglycemia or high glucose mediates renal injury in DKD via multiple molecular mechanisms such as induction of oxidative stress, upregulation of renal transforming growth factor beta-1 expression, production of pro-inflammatory cytokines, activation of fibroblasts and renin-angiotensin-aldosterone system, and depletion of adenosine triphosphate. Moreover, existing therapies only retard the disease progression but do not prevent or reverse it. Therefore, novel modes of pharmacotherapeutic intervention are in demand to target additional disease mechanisms. A substantial body of experimental evidence demonstrates that hydrogen sulfide (H2S), a gas with a historic notorious label, has recently been established to possess important therapeutic properties that prevent and/or reverse DKD development and progression of DKD by targeting several important molecular pathways, and therefore could be considered a novel pharmacological agent for DKD treatment. The aim of this chapter is to discuss recent experimental findings on the molecular mechanisms underlying the pharmacotherapeutic effects of H2S against DKD development and progression, and its translation from bench to bedside, which could lay the foundation for its future clinical use. A section of the chapter also discusses focal segmental glomerulosclerosis as a mediator of DKD progression to end-stage renal disease, and H2S as a potential novel therapy.
Ischemia-reperfusion injury (IRI) is an unavoidable and unresolved problem that poses a great challenge in kidney transplantation. It represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays renal graft function. This complicates graft quality, posttransplant patient care, and kidney transplantation outcomes and therefore undermines the success of kidney transplantation. In this chapter, we present recent advances in research regarding novel pharmacological strategies involving the use of hydrogen sulfide (H2S), the third established member of the gasotransmitter family, against IRI in different experimental models of involving transplantation of kidney and other transplantable solid organs. Additionally, we also discuss the molecular mechanisms underlying the effects of H2S donor molecules in transplantation and suggestions for clinical translation. Our findings in this chapter showed that storage of renal graft and other solid organ grafts in H2S-supplemented preservation solution or administration of H2S to organ donor prior to organ procurement and to recipient at the start and during reperfusion is a novel, simple, and cost-effective pharmacological approach to minimize cold IRI, limit posttransplant complications, and improve transplantation outcomes. In conclusion, experimental evidence demonstrates that H2S can significantly mitigate IRI during transplantation through inhibition of a complex cascade of interconnected cellular and molecular events involving microcirculatory disturbance and microvascular dysfunction, mitochondrial injury, inflammatory responses, cell damage and cell death, and other damaging molecular pathways while promoting protective pathways. Translating these promising findings from bench to bedside will lay the foundation for the use of H2S in clinical organ transplantation in the future.
Chronic kidney disease (CKD) is a common global health challenge characterized by irreversible pathological processes that reduce kidney function and culminate in the development of end-stage renal disease. It is associated with increased morbidity and mortality in addition to increased caregiver burden and higher financial cost. A central player in CKD pathogenesis and progression is renal hypoxia. Renal hypoxia stimulates induction of oxidative and endoplasmic reticulum stress, inflammation, and tubulointerstitial fibrosis, which in turn promote cellular susceptibility and further aggravate hypoxia, thus forming a pathological vicious cycle in CKD progression. Although the importance of CKD is widely appreciated, including improvements in the quality of existing therapies such as dialysis and transplantation, new therapeutic options are limited, as there is still increased morbidity, mortality, and poor quality of life among CKD patients. Growing evidence indicates that hydrogen sulfide (H2S), a small gaseous signaling molecule with an obnoxious smell, accumulates in the renal medulla under hypoxic conditions and functions as an oxygen sensor that restores oxygen balance and increases medullary flow. Moreover, plasma H2S level has been recently reported to be markedly reduced in CKD patients and animal models. Also, H2S has been established to possess potent antioxidant, anti-inflammatory, and anti-fibrotic properties in several experimental models of kidney diseases, suggesting that its supplementation could protect against CKD and retard its progression. The purpose of this chapter is to discuss current clinical and experimental developments regarding CKD, its pathophysiology, and potential cellular and molecular mechanisms of protection by H2S in experimental models of CKD. A section of the chapter also discusses hyperhomocysteinemia and autosomal dominant polycystic kidney disease, which are forms of CKD, and H2S as an additional/alternative agent for pharmacological treatment or management of these conditions.
Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H2S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence shows that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This chapter discusses the biochemical and molecular pathways in the generation of STS from H2S, its clinical usefulness, and potential clinical applications in renovascular hypertension, renal ischemia-reperfusion injury, chronic kidney disease, and uremic pruritus, as well as the molecular mechanisms underlying these clinical applications and a future perspective in kidney transplantation.
Kidney transplantation is the treatment of choice for end-stage renal disease, during which renal grafts from deceased donors are routinely cold-stored to suppress metabolic demand, thereby limiting ischemic injury. However, prolonged cold storage followed by reperfusion induces extensive tissue damage termed cold ischemia-reperfusion injury (IRI) and puts the graft at risk of both early and late rejection. The underlying mechanism of IRI is not completely understood, and a reliable/suitable method to protect the renal graft against cold IRI is lacking. Hibernating animals constitute a natural model of coping with cold IRI, as they regularly alternate between 4 and 37 °C. Recently, endogenous hydrogen sulfide (H2S), a gas with a characteristic “rotten-egg” smell, has been implicated in organ protection in hibernation. In kidney transplantation, H2S also seems to confer cytoprotection by lowering metabolism and increasing preservation time while allowing cellular processes of preservation of homeostasis and tissue remodeling to take place, thus increasing renal graft survival. In this chapter, we first discuss mammalian hibernation as a natural model of cold organ preservation with reference to the kidney and highlight the involvement of H2S during hibernation. Next, we present recent developments on the protective effects and mechanisms of exogenous and endogenous H2S in preclinical models of transplant IRI and evaluate the potential of H2S therapy in organ preservation as a great promise for kidney transplant recipients in the future.
Detecting toxic gases, such as CH4, CO, and H2S, in everyday life holds great significance. This research article focuses on investigating the adsorption characteristics of CH4, CO, and H2S on MoTe2 and MoTe2 doped with Au and Ru using the density functional theory. The study examines various aspects, including adsorption energy, charge transfer, density of states, and charge density difference of the adsorption configuration. The findings demonstrate that the adsorption properties of Ru-doped MoTe2 exhibit a significant enhancement for all three gases, with CO displaying the highest adsorption performance. Through comparative analysis, it is evident that the adsorption affinity between MoTe2-Ru and the three gases is robust, thus indicating improved gas detection capabilities.
When histiocyte are ischemic for a certain time and blood supply is suddenly restored, the pathological condition of rapidly aggravated tissue damage is called ischemia reperfusion injury, which is mainly caused by a large amount of Ca2+ influx and oxygen free radicals attacking ischemic histiocyte. Ischemia reperfusion injury can increase the incidence rate and mortality of some diseases, such as acute myocardial infarction, ischemic stroke, acute renal injury, intestinal obstruction, hyperkalemia and multiple organ failure, and it also brings great challenges to surgery such as organ transplantation. However, the current treatment methods for ischemia-reperfusion are still very limited. Fortunately, increasing evidence suggests that reasonable concentrations of hydrogen sulfide may play a powerful organ protective role in ischemia-reperfusion injury, mainly through mechanisms such as anti apoptotic, antioxidant, stress reduction, regulation of autophagy, and inhibition of inflammation. Therefore, hydrogen sulfide has profound clinical conversion prospects in the treatment of I/R injury. This article systematically summarizes the generation and physiological effects of endogenous hydrogen sulfide, as well as its protective mechanisms in different systems such as the heart, brain, kidney, liver, retina, and testes. In addition, the clinical transformation prospects and current challenges of hydrogen sulfide in ischemia-reperfusion injury were discussed.
Hydrogen sulfide (H2S) is a toxic gas that is well-known for its acute health risks in occupational settings, but less is known about effects of chronic and low-level exposures. This critical review investigates toxicological and experimental studies, exposure sources, standards, and epidemiological studies pertaining to chronic exposure to H2S from both natural and anthropogenic sources. H2S releases, while poorly documented, appear to have increased in recent years from oil and gas and possibly other facilities. Chronic exposures below 10 ppm have long been associated with odor aversion, ocular, nasal, respiratory and neurological effects. However, exposure to much lower levels, below 0.03 ppm (30 ppb), has been associated with increased prevalence of neurological effects, and increments below 0.001 ppm (1 ppb) in H2S concentrations have been associated with ocular, nasal, and respiratory effects. Many of the studies in the epidemiological literature are limited by exposure measurement error, co-pollutant exposures and potential confounding, small sample size, and concerns of representativeness, and studies have yet to consider vulnerable populations. Long-term community-based studies are needed to confirm the low concentration findings and to refine exposure guidelines. Revised guidelines that incorporate both short- and long-term limits are needed to protect communities, especially sensitive populations living near H2S sources.
Reactive sulfur species (RSS), such as H2S, hydrogen polysulfide (H2Sn, n ≥ 2), and hydropersulfides (RSSnH, n ≥ 1), are known to mediate diverse signaling pathways and possess a plethora of exciting therapeutic opportunities. Historically, due to the rapid inter-conversion among those species in vivo, the biological differences of distinct sulfur species were often overlooked. These species were considered to enrich the global sulfur pool in almost an equal fashion. However, advancement in this field has revealed that sulfur species at different oxidation states result in different pharmacological effects including scavenging reactive oxygen species (ROS), activating ion channels, and exhibiting analgesic effects. Here, we summarize recent advances in studying the biological and pharmacological differences of distinct sulfur species; discuss this phenomenon from the view of chemical properties and sulfur signaling pathways; and lay out a roadmap to transforming such new knowledge into general principles in developing sulfur-based therapeutics.
Precise quantification of trace components in whole blood via fluorescence is of great significance. However, the applicability of current fluorescent probes in whole blood is largely hindered by the strong blood autofluorescence. Here, we proposed a blood autofluorescence‐suppressed sensing strategy to develop an activable fluorescent probe for quantification of trace analyte in whole blood. Based on inner filter effect, by screening fluorophores whose absorption overlapped with the emission of blood, a redshift BODIPY quencher with an absorption wavelength ranging from 600–700 nm was selected for its superior quenching efficiency and high brightness. Two 7‐nitrobenzo[c] [1,2,5] oxadiazole ether groups were introduced onto the BODIPY skeleton for quenching its fluorescence and the response of H 2 S, a gas signal molecule that can hardly be quantified because of its low concentration in whole blood. Such detection system shows a pretty low background signal and high signal‐to‐back ratio, the probe thus achieved the accurate quantification of endogenous H 2 S in 20‐fold dilution of whole blood samples, which is the first attempt of quantifying endogenous H 2 S in whole blood. Moreover, this autofluorescence‐suppressed sensing strategy could be expanded to other trace analytes detection in whole blood, which may accelerate the application of fluorescent probes in clinical blood test.
Precise quantification of trace components in whole blood via fluorescence is of great significance. However, the applicability of current fluorescent probes in whole blood is largely hindered by the strong blood autofluorescence. Here, we proposed a blood autofluorescence‐suppressed sensing strategy to develop an activable fluorescent probe for quantification of trace analyte in whole blood. Based on inner filter effect, by screening fluorophores whose absorption overlapped with the emission of blood, a redshift BODIPY quencher with an absorption wavelength ranging from 600–700 nm was selected for its superior quenching efficiency and high brightness. Two 7‐nitrobenzo[c] [1,2,5] oxadiazole ether groups were introduced onto the BODIPY skeleton for quenching its fluorescence and the response of H2S, a gas signal molecule that can hardly be quantified because of its low concentration in whole blood. Such detection system shows a pretty low background signal and high signal‐to‐back ratio, the probe thus achieved the accurate quantification of endogenous H2S in 20‐fold dilution of whole blood samples, which is the first attempt of quantifying endogenous H2S in whole blood. Moreover, this autofluorescence‐suppressed sensing strategy could be expanded to other trace analytes detection in whole blood, which may accelerate the application of fluorescent probes in clinical blood test.
After experiencing an acute ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) is a preferred method of restoring blood flow to the heart. While this reperfusion has long-term benefits, it can result in reperfusion injury in the short term, which involves the formation of reactive oxygen species (ROS) and neutrophil recruitment. FDY-5301 is a sodium iodide-based drug that acts as a catalyst in the conversion of hydrogen peroxide to water and oxygen. FDY-5301 is designed to be administered as an intravenous bolus following a STEMI, before reperfusion with PCI, to reduce the damage associated with reperfusion injury. Clinical trials have shown FDY-5301 administration to be safe, feasible, and fast-acting in its ability to increase plasma iodide concentration, and the results are favorable in demonstrating potential efficacy. FDY-5301 shows potential in its use to reduce the effects of reperfusion injury, and ongoing Phase 3 trials will allow for continued evaluation of its performance.
An injectable 'biostasis' drug that could slow organ injury by inducing a state of suspended animation through reversible slowing of metabolic processes would have great value for organ preservation and treatment of badly injured patients at the point-of-care. Using whole-organism screening of metabolism, mobility, and development in Xenopus, we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability, independently of its known delta opioid receptor modulating activity. Metabolic suppression was also achieved using SNC80 in cultured cells and microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Thermal proteome profiling revealed that SNC80 targets the NCX1/EEAT1 membrane transport system and chemical modulation of NCX1 induces biostasis in non-hibernating Xenopus tadpoles. Molecular induction of biostasis may offer a new therapeutic approach for organ preservation, trauma management, and enhancing patient survival in remote and low-resource locations.
Mammalian hibernators undergo a remarkable phenotypic switch that involves profound changes in physiology, morphology, and behavior in response to periods of unfavorable environmental conditions. The ability to hibernate is found throughout the class Mammalia and appears to involve differential expression of genes common to all mammals, rather than the induction of novel gene products unique to the hibernating state. The hibernation season is characterized by extended bouts of torpor, during which minimal body temperature (Tb) can fall as low as -2.9 degrees C and metabolism can be reduced to 1% of euthermic rates. Many global biochemical and physiological processes exploit low temperatures to lower reaction rates but retain the ability to resume full activity upon rewarming. Other critical functions must continue at physiologically relevant levels during torpor and be precisely regulated even at Tb values near 0 degrees C. Research using new tools of molecular and cellular biology is beginning to reveal how hibernators survive repeated cycles of torpor and arousal during the hibernation season. Comprehensive approaches that exploit advances in genomic and proteomic technologies are needed to further define the differentially expressed genes that distinguish the summer euthermic from winter hibernating states. Detailed understanding of hibernation from the molecular to organismal levels should enable the translation of this information to the development of a variety of hypothermic and hypometabolic strategies to improve outcomes for human and animal health.
Oxygen deprivation is a major cause of cellular damage and death. Here we demonstrate that Caenorhabditis elegans embryos, which can survive both in anoxia (<0.001 kPa O(2)) by entering into suspended animation and in mild hypoxia (0.25-1 kPa O(2)) through a hypoxia-inducible factor 1-mediated response, cannot survive in intermediate concentrations of oxygen, between 0.01 and 0.1 kPa O(2). Moreover, we show that carbon monoxide can protect C. elegans embryos against hypoxic damage in this sensitive range. Carbon monoxide can also rescue the hypoxia-sensitive mutant hif-1(ia04) from lethality in hypoxia. This work defines the oxygen tensions over which hypoxic damage occurs in C. elegans embryos and demonstrates that carbon monoxide can prevent this damage by inducing suspended animation.
For an understanding of the aberrant biology seen in mouse mutations and identification of more subtle phenotype variation,
there is a need for a full clinical and pathological characterization of the animals. Although there has been some use of
sophisticated techniques, the majority of behavioral and functional analyses in mice have been qualitative rather than quantitative
in nature. There is, however, no comprehensive routine screening and testing protocol designed to identify and characterize
phenotype variation or disorders associated with the mouse genome. We have developed the SHIRPA procedure to characterize
the phenotype of mice in three stages. The primary screen utilizes standard methods to provide a behavioral and functional
profile by observational assessment. The secondary screen involves a comprehensive behavioral assessment battery and pathological
analysis. These protocols provide the framework for a general phenotype assessment that is suitable for a wide range of applications,
including the characterization of spontaneous and induced mutants, the analysis of transgenic and gene-targeted phenotypes,
and the definition of variation between strains. The tertiary screening stage described is tailored to the assessment of existing
or potential models of neurological disease, as well as the assessment of phenotypic variability that may be the result of
unknown genetic influences. SHIRPA utilizes standardized protocols for behavioral and functional assessment that provide a
sensitive measure for quantifying phenotype expression in the mouse. These paradigms can be refined to test the function of
specific neural pathways, which will, in turn, contribute to a greater understanding of neurological disorders.
For many animals, the best defense against harsh environmental conditions is an escape to a hypometabolic or dormant state. Facultative metabolic rate depression is the common adaptive strategy of anaerobiosis, hibernation, and estivation, as well as a number of other arrested states. By reducing metabolic rate by a factor ranging from 5 to 100 fold or more, animals gain a comparable extension of survival time that can support months or even years of dormancy. The present review focuses on the molecular control mechanisms that regulate and coordinate cellular metabolism for the transition into dormancy. These include reversible control over the activity state of enzymes via protein phosphorylation or dephosphorylation reactions, pathway regulation via the association or dissociation of particle-bound enzyme complexes, and fructose-2,6-bisphosphate regulation of the use of carbohydrate reserves for biosynthetic purposes. These mechanisms, their interactions, and the regulatory signals (e.g., second messenger molecules, pH) that coordinate them form a common molecular basis for metabolic depression in anoxia-tolerant vertebrates (goldfish, turtles) and invertebrates (marine molluscs), hibernation in small mammals, and estivation in land snails and terrestrial toads.
The information available on the biological activity of hydrogen sulfide has been examined for present status of critical results pertaining to the toxicity of hydrogen sulfide. This review of the literature is intended as an evaluative report rather than an annotated bibliography of all the source material examined on hydrogen sulfide. The information was selected as it might relate to potential toxic effects of hydrogen sulfide to man and summarized, noting information gaps that may require further investigation. Several recommendations are listed for possible consideration for either toxicological research or additional short- and long-term tests. Two bibliographies have been provided to assist in locating references considered in this report: (1) literature examined but not cited and (2) reference citations. The majority of the references in the first bibliography were considered peripheral information and less appropriate for inclusion in this report.
Reducing body temperature of rodents has been found to improve their survival to ischaemia, hypoxia, chemical toxicants, and many other types of insults. Larger species, including humans, may also benefit from a lower body temperature when recovering from CNS ischaemia and other traumatic insults. Rodents subjected to these insults undergo a regulated hypothermic response (that is, decrease in set point temperature) characterised by preference for cooler ambient temperatures, peripheral vasodilatation, and reduced metabolic rate. However, forced hypothermia (that is, body temperature forced below set point) is the only method used in the study and treatment of human pathological insults. The therapeutic efficacy of the hypothermic treatment is likely to be influenced by the nature of the reduction in body temperature (that is, forced versus regulated). Homeostatic mechanisms counter forced reductions in body temperature resulting in physiological stress and decreased efficacy of the hypothermic treatment. On the other hand, regulated hypothermia would seem to be the best means of achieving a therapeutic benefit because thermal homeostatic systems mediate a controlled reduction in core temperature.
Continuous exposure to oxygen is essential for nearly all vertebrates. We found that embryos of the zebrafish Danio rerio can survive for 24 h in the absence of oxygen (anoxia, 0% O2). In anoxia, zebrafish entered a state of suspended animation where all microscopically observable movement ceased, including cell division, developmental progression, and motility. Animals that had developed a heartbeat before anoxic exposure showed no evidence of a heartbeat until return to terrestrial atmosphere (normoxia, 20.8% O2). In analyzing cell-cycle changes of rapidly dividing blastomeres exposed to anoxia, we found that no cells arrested in mitosis. This is in sharp contrast to similarly staged normoxic embryos that consistently contain more than 15% of cells in mitosis. Flow cytometry analysis revealed that blastomeres arrested during the S and G2 phases of the cell cycle. This work indicates that survival of oxygen deprivation in vertebrates involves the reduction of diverse processes, such as cardiac function and cell-cycle progression, thus allowing energy supply to be matched by energy demands.
Brains of hibernating mammals are protected against a variety of insults that are detrimental to humans and other nonhibernating species. Such protection is associated with a number of physiological adaptations including hypothermia, increased antioxidant defense, metabolic arrest, leukocytopenia, immunosuppression, and hypocoagulation. It is intriguing that similar manipulations provide considerable protection as experimental treatments for central nervous system injury. This review focuses on neuroprotective mechanisms employed during hibernation that may offer novel approaches in the treatment of stroke, traumatic brain injury, and neurodegenerative diseases in humans.
Katzaroff for helpful discussion and commentary J. Blackwood for instruction on the installation of telemetry devices and Byrne Specialty Gases for gas science consultations
- J We
- D Goldmark
- K Miller
- A J Chan