Hemorrhagic stroke (HS) is a neurological disorder caused by the rupture of cerebral blood vessels, resulting in blood seeping into the brain parenchyma and causing varying degrees of neurological impairment, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Current treatment methods mainly include hematoma evacuation surgery and conservative treatment. However, these methods have limited efficacy in enhancing neurological function and prognosis. The current challenge in treating HS lies in inhibiting the occurrence and progression of secondary brain damage after bleeding, which is a key factor affecting the prognosis of HS patients. Studies have shown that medical gas therapy is gaining more attention and has demonstrated various levels of neuroprotective effects on central nervous system disorders, such as hyperbaric oxygen, hydrogen sulfide, nitric oxide, carbon monoxide, and other inhalable gas molecules. These medical gas molecules primarily improve brain tissue damage and neurological dysfunction by regulating inflammation, oxidative stress, apoptosis, and other processes. However, many of these medical gasses also possess neurotoxic properties. Therefore, the use of medical gases in HS deserves further exploration and research. In this review, we will elucidate the therapeutic effects and study the advances in medical gas molecules in HS.

The first cysteine (Cys) fluorescence sensing-driven flavonol, HIBC (3-hydroxy-2-(1-methyl-1H-indol-3-yl)-4H-benzo[g]chromen-4-one), has been developed as a single fluorescent probe (SFprobe) and a photoCORM. This compound is characterized by the simultaneous substitutions at both the A- and B-rings with naphthalene and indole, respectively. Notably, HIBC exhibits remarkable hypersensitivity to minor variations in water fractions (fw, vol% in acetonitrile) ranging from 0% to 15%, enabling in situ real-time visualization of lipid droplets (LDs) and the endoplasmic reticulum (ER) with high spatial resolution through distinct dual-colour fluorescence without any crosstalk. Under O2, HIBC facilitates the delivery of precisely controlled amounts of CO gas within a therapeutic and safe dosage range to living systems via visible light irradiation. This control is achieved by modulating either the intensity or the duration of the irradiated light or by adjusting the dosage of the photoCORM. Its fluorescence allows for in situ real-time imaging and tracking of intracellular distribution while monitoring CO delivery progress. HIBC is generated from the sensing reaction between the precursor IBCA (2-(1-methyl-1H-indol-3-yl)-4-oxo-4H-benzo[g]chromen-3-yl acrylate) and the Cys. In PBS buffer containing only 30% of DMSO, IBCA can rapidly detect and image both endogenous and exogenous Cys within just 250 seconds. It demonstrates high selectivity-particularly against homocysteine (Hcy) and glutathione (GSH)-and sensitivity, achieving detection limits as low as 87 nM in live HeLa cells and zebrafish across a wide linear concentration range of 0-10 μM (0-2 equiv.). Importantly, IBCA also targets LDs and ER while monitoring fluctuations in Cys levels during periods of ER stress. Both IBCA and HIBC, along with all photoreaction products, exhibit negligible toxicity while demonstrating good permeability in live HeLa cells and zebrafish. The HIBC we developed represents a pioneering instance of a flavonol driven by Cys fluorescence sensing that features simultaneous substitutions at both the A-and B-rings with naphthalene and indole moieties, respectively. Compared to the unsubstituted flavonol, these structural improvements not only lead to a substantial red shift of 88 nm in the absorption peak but also significantly enhance the overall performance. It serves not only as an exceptionally water hypersensitive SFprobe for simultaneous dual-colour fluorescence visualization of LDs and ER but also functions effectively as a photoCORM. This work not only provides a method for precise control over CO release but also facilitates the development of user-friendly molecular tools for further investigation into the roles played by LDs, ER, Cys and CO in biological processes, their interactions and relationships among them, along with their potential applications in clinical diagnosis.

Crush syndrome refers to the traumatic rhabdomyolysis leading to a spectrum of disorders culminating in acute kidney injury. The burden of crush syndrome is high, and mortality can be as high as 20%. The significant bulk of knowledge is from old articles. Over the last 10 years new research has occurred on diagnosis and treatment in animal models.

To overview of crush syndrome and discuss the newer advances related to the pathogenesis and management of a patient with crush syndrome.

The search of databases such as MEDLINE, Google Scholar, Web of Science, and EMBASE revealed 8226 articles. A thorough screening culminated in 83 crush syndrome articles included in this study.

Acute kidney injury in crush syndrome is currently thought to be due to iron retention. The management of crush syndrome has also been updated with antioxidants, and several gases are being used to treat crush syndrome. In the end, treatment of crush syndrome also includes mental, social, and physical rehabilitation for better outcomes.

The outcomes of crush syndrome have significantly improved with the introduction of newer treatment modalities, including antioxidants, hyperbaric oxygen therapy, and comprehensive mental, social, and physical rehabilitation.

Carbon monoxide (CO) is a novel anti-inflammatory molecule, but the effects of CO on SARS-CoV-2 spike RBD (S-RBD)-induced human bronchial epithelial cytokines release remains unclear. CO was delivered using CO-releasing molecule 3 (CORM-3). The effects of S-RBD, ATPγS and CO on cytokines secretion were determined by enzyme-linked immunosorbent assay (ELISA) in 16HBE14o-human bronchial epithelial cell line. The inhibitory effect of CO on S-RBD-induced ERK phosphorylation was assessed by Western blot analysis. The regulatory effect of CO on extracellular nucleotide-induced ion transport was quantified by short-circuit current (ISC). S-RBD evoked CCL5 and IL-6 release and this effect could be suppressed by CO. However, CO failed to inhibit ATP release induced by S-RBD while decreased ATP-induced CCL5 and IL-6 secretion as well as ion transport. Furthermore, CO significantly inhibited ERK phosphorylation induced by S-RBD. These findings suggest an anti-inflammatory role of CO during inflammation induced by S-RBD and extracellular nucleotide in human bronchiol epithelial cells.

The early stage of atherosclerosis (AS) is characterized by explosion of reactive oxygen species (ROS) in mitochondria and inflammatory reaction, and then abundant ROS further promote the progress of AS. As an endogenous signal biomolecule with antioxidant properties, carbon monoxide (CO) is enriched in mitochondria to combat oxidative stress, thereby significantly increasing during the pathogenesis of AS. However, there is currently no mitochondria-targeted near-infrared fluorescence probe for detecting CO in atherosclerosis. In this paper, we use a mitochondrion-targeting metal-free near-infrared fluorescence probe, AS-CO, for investigating AS via detecting and mapping the fluctuations of CO with enhanced sensitivity and selectivity. In addition, probe AS-CO can be positioned at mitochondria. It has also proven effective in detecting both internally and externally sourced CO in HUVEC cells. More importantly, using AS-CO, for the first time, we provided the visualization evidence of endogenous CO generation in the aorta of mice that induced AS by high-fat diet (HFD) and further investigated the protective effects of (-)-epicatechin gallate (ECG) against HFD-induced AS. The results demonstrated the feasibility of AS-CO for monitoring and evaluating personalized treatment of AS.

Endogenous carboxyhemoglobin (COHb) production is a byproduct of hemoglobin metabolism.

Blood carboxyhemoglobin concentrations are higher in cats with hemolytic anemia (HA).

Twenty cats with HA, 29 cats with non-HA, and 22 controls were prospectively followed.

Blood tests were performed upon admission. The Mann-Whitney and Kruskal-Wallis tests were used for comparisons. Receiver-operating characteristic (ROC) analyses tested COHb as a marker of HA or survival.

The HA group included 17 cats with immune-mediated HA and 3 with Heinz body (HB) anemia. In the non-HA group, leading diagnoses included kidney disease (n = 14), acute/chronic blood loss (n = 11) and pancytopenia (n = 3). Carboxyhemoglobin concentrations (median [IQR]) significantly differed between cats with HA (5.55% [1.9]) and cats with non-HA (1.9% [0.7]) or controls (1.9% [0.67]; p < 0.001 for both), but not between the last two groups (p = 0.6). Among 13 nonanemic stray cats with significant HB formation, the median (IQR) COHb concentration was 6.1% (1.2). The area under the ROC curve for COHb as a predictor of HA among all anemic cats was 0.996 (95% CI, 0.985-1), with an optimal cut-off point of 2.95% yielding a sensitivity/specificity of 95% (95% CI, 76%-99%) and 100% (95% CI, 88%-100%), respectively. Survival and COHb concentrations were not associated in either group.

COHb proved a useful ancillary test in cats with suspected HA. Nevertheless, endogenous COHb production occurs with the absorption of large hematomas, not studied herein, or during hemolysis irrespective of anemia. These caveats must be considered when applying the present findings to the clinical and research setting.

Small, gaseous molecules such as nitric oxide, carbon monoxide and hydrogen sulfide are produced as signalling molecules in mammalian cells. Here, we show that low concentrations of cyanide are generated endogenously in various mammalian tissues and cells. We detect cyanide in several cellular compartments of human cells and in various tissues and the blood of mice. Cyanide production is stimulated by glycine, occurs at the low pH of lysosomes and requires peroxidase activity. When generated at a specific rate, cyanide exerts stimulatory effects on mitochondrial bioenergetics, cell metabolism and cell proliferation, but impairs cellular bioenergetics at high concentrations. Cyanide can modify cysteine residues via protein S-cyanylation, which is detectable basally in cells and mice, and increases in response to glycine. Low-dose cyanide supplementation exhibits cytoprotective effects in hypoxia and reoxygenation models in vitro and in vivo. Conversely, pathologically elevated cyanide production in nonketotic hyperglycinaemia is detrimental to cells. Our findings indicate that cyanide should be considered part of the same group of endogenous mammalian regulatory gasotransmitters as nitric oxide, carbon monoxide and hydrogen sulfide.

Preeclampsia (PE) is a major cause of maternal mortality and morbidity, affecting 3-6% of pregnancies worldwide and ranking among the top six causes of maternal deaths in the U.S. PE typically develops after 20 weeks of gestation and is characterized by new-onset hypertension and/or end-organ dysfunction, with or without proteinuria. Current management strategies for PE emphasize early diagnosis, blood pressure control, and timely delivery. For prevention, low-dose aspirin (81 mg/day) is recommended for high-risk women between 12 and 28 weeks of gestation. Magnesium sulfate is also advised to prevent seizures in preeclamptic women at risk of eclampsia. Emerging management approaches include antiangiogenic therapies, hypoxia-inducible factor suppression, statins, and supplementation with CoQ10, nitric oxide, and hydrogen sulfide donors. Black women are at particularly high risk for PE, potentially due to higher rates of hypertension and cholesterol, compounded by healthcare disparities and possible genetic factors, such as the APOL1 gene. This review explores current and emerging strategies for managing PE and addresses the underlying causes of health disparities, offering potential solutions to improve outcomes.

To undertake a scoping review to identify methods and diagnostic levels used in determining unintentional, non-fire related carbon monoxide exposure.

Online databases and grey literature were searched from 1946 to 2023 identifying 80 papers where carbon monoxide levels were reported.

80 papers were included; 71 research studies and 9 clinical guidelines. Four methods were described: blood carboxyhaemoglobin (arterial or venous blood analysis), carbon monoxide oximetry (SpO2), expired carbon monoxide, and ambient carbon monoxide sampling. Blood analysis methods predominated (60.0% of the papers). Multiple methods of measurement were used in 26 (32.5%) of the papers. Diagnostic levels for carboxyhaemoglobin were described in 54 (67.5%) papers, ranging between 2% and 15%. 26 (32.5%) papers reported diagnostic levels that were adjusted for the smoking status of the patient.

Four methods were found for use in different settings. Variability in diagnostic thresholds impairs diagnostic accuracy. Agreement on standardised diagnostic levels is required to enable consistent diagnosis of unintentional, non-fire related carbon monoxide exposure.

The impact of islet neuronal nitric oxide synthase (nNOS) on glucose-stimulated insulin secretion (GSIS) is less understood. We investigated this issue by performing simultaneous measurements of the activity of nNOS versus inducible NOS (iNOS) in GSIS using isolated murine islets. Additionally, the significance of extracellular NO on GSIS was studied. Islets incubated at basal glucose showed modest nNOS but no iNOS activity. Glucose-induced concentration-response studies revealed an increase in both NOS activities in relation to secreted insulin. Culturing at high glucose increased both nNOS and iNOS activities inducing a marked decrease in GSIS in a following short-term incubation at high glucose. Culturing at half-maximal glucose showed strong iNOS expression revealed by fluorescence microscopy also in human islets. Experiments with nNOS-inhibitors revealed that GSIS was inversely related to nNOS activity, the effect of iNOS activity being negligible. The increased GSIS after blockade of nNOS was reversed by the intracellular NO-donor hydroxylamine. The enhancing effect on GSIS by nNOS inhibition was independent of membrane depolarization and most likely exerted in the pentose phosphate pathway (PPP). GSIS was markedly reduced, 50%, by glucose-6-phosphate dehydrogenase (G-6-PD) inhibition both in the absence and presence of nNOS inhibition. NO gas stimulated GSIS at low and inhibited at high NO concentrations. The stimulatory action was dependent on membrane thiol groups. In comparison, carbon monoxide (CO) exclusively potentiated GSIS. CO rather than NO stimulated islet cyclic GMP during GSIS. It is suggested that increased nNOS activity restrains GSIS, and that the alternative pathway along the PPP initially might involve as much as 50% of total GSIS. In the PPP, the acute insulin response is downregulated by a negative feedback effect executed by a marked upregulation of nNOS activity elicited from secreted insulin exciting insulin receptors at exocytotic sites of an nNOS-associated population of secretory granules.

Carbon monoxide (CO) is endogenously produced with a range of pharmacological activities. Sensitive and selective detection of CO is critical to studying its biology. Since the first report of a CO fluorescent probe in 2012, more than 100 papers on this topic have appeared. Noteworthy in such work is the widespread use of two commercially available ruthenium-carbonyl complexes (CORM-2 and CORM-3) as CO surrogates. Unfortunately, these two CORMs are chemically very reactive and preferentially release CO2 but not CO, unless in the presence of a nucleophile. As a result, there are "two tales" of the reported CO probes: those that detect CO and those that detect only the CORM used but not CO. In addition, because of their lack of reliable CO production and fast degradation in an aqueous solution, there is the question of what "detecting CORM-2 or CORM-3" really means in the context of CO research. Additionally, for applying fluorescent CO probes in detecting low levels (often nanomolar) of CO in vivo, fast reaction kinetics is a prerequisite for meaningful results. In this Perspective, we discuss in detail these issues with the understanding of the evolutionary nature of scientific discoveries and the aim of preventing further confusion.

The evidence on associations between ambient gaseous pollutants and conjunctivitis remains inconclusive, and limited research is available, particularly regarding children. Based on a case-crossover study conducted in ten Chinese cities from 2013 to 2023, we documented 418,027 outpatient visits for conjunctivitis in children. Of these visits, 256,525 were for boys and 161,502 for girls. A one standard deviation (SD) increase in daily concentrations of carbon monoxide (CO) was related to a 1.20 % rise in same-day outpatient visits for pediatric conjunctivitis (OR = 1.012, 95 % CI: 1.005, 1.018). Similar associations were found for nitrogen dioxide (NO2: 2.90 % increase; OR = 1.029, 95 % CI: 1.019, 1.040), sulfur dioxide (SO2: 1.70 % increase; OR = 1.017, 95 % CI: 1.007, 1.028), and ozone (O3: 1.30 % increase; OR = 1.013, 95 % CI: 1.006, 1.021). The positive associations remained significant in two-pollutant and mixed-effects models. Notably, we observed stronger associations in girls compared to boys, among children at 1-5 years of age compared to other age groups, and the relationships were more pronounced during the summer months. This study reveals a link between exposure to common gaseous air pollutants and increased risks of conjunctivitis in children, indicating the potential benefits of public health interventions.

Drug-induced liver injury (DILI) is a major hepatic dysfunction commonly caused by hepatotoxic drug overdose, resulting in a considerable number of fatalities worldwide. Recent studies have highlighted the regulatory and hepatoprotective effects of carbon monoxide (CO) during the liver injury process. However, precisely tracking the dynamic changes in the composition of CO in DILI is still a great challenge. In this work, leveraging the innovative "quencher-insertion" strategy, a unique endoplasmic reticulum (ER)-targetable lanthanide complex-based luminescence probe, ER-ANBTTA-Eu3+/Tb3+, has been developed for the selective and accurate monitoring of CO fluxes in live cells and laboratory animals. The new probe is composed of three covalently linked functional moieties: the terpyridine polyacid-Eu3+/Tb3+-mixed chelates as the long-lived luminophore, a p-toluenesulfonamide moiety as the ER-anchoring motif, and an allyloxy-nitrobenzyl ether moiety as the CO-specific recognition unit. Upon reaction with CO in the presence of Pd2+ ions, the Tsuji-Trost reaction leads to the cleavage of the allyloxy-nitrobenzyl group from the Eu3+/Tb3+-mixed chelates, which results in the restoration of Tb3+ emission at 538 nm and the attenuation of Eu3+ emission at 688 nm, leading to a dramatic increase of the I538/I688 ratio. In addition to the exceptional response sensitivity and selectivity toward CO, ER-ANBTTA-Eu3+/Tb3+ also exhibits the outstanding ER-locating capability, which allows the probe to be used for imaging of CO in the ER of live cells. Using this probe, combined with the time-gated luminescence imaging mode, the exogenous and endogenous CO in ER of live cells were monitored without the interference of background autofluorescence. Moreover, the upregulation of hepatic CO in DILI mice was successfully visualized. The results suggested the potential of ER-ANBTTA-Eu3+/Tb3+ for deeply exploring the functions of CO in DILI pathogenesis.

In the present study, we focus on dinuclear cobalt-based CO-RMs with the aim of elucidating their CO release mechanism, as well as to understand how structural changes targeted to modify the electronic properties of these compounds can modulate CO delivery. To this end, we specifically synthesized a set of phenyl-propargyl-based CO-RMs bearing -NO2, -H, and -OCH3 as para-substituents (R) with varying mesomeric influence (M) and different heteroatoms (X = NH, O, or S) linking the propargyl tail and the aromatic ring. The effects of R and X in modulating CO release were assessed by using several experimental and computational techniques to obtain a coherent picture and to shed light on the stability and release properties of Co-based CO-RMs.

Approximately two-thirds of the estimated one-billion metric tons of methane produced annually by methanogens is derived from the cleavage of acetate. Acetate is broken down by a Ni-Fe-S-containing A-cluster within the enzyme acetyl-CoA synthase (ACS) to carbon monoxide (CO) and a methyl group (CH3+). The methyl group ultimately forms the greenhouse gas methane, whereas CO is converted to the greenhouse gas carbon dioxide (CO2) by a Ni-Fe-S-containing C-cluster within the enzyme carbon monoxide dehydrogenase (CODH). Although structures have been solved of CODH/ACS from acetogens, which use these enzymes to make acetate from CO2, no structure of a CODH/ACS from a methanogen has been reported. In this work, we use cryo-electron microscopy to reveal the structure of a methanogenic CODH and CODH/ACS from Methanosarcina thermophila (MetCODH/ACS). We find that the N-terminal domain of acetogenic ACS, which is missing in all methanogens, is replaced by a domain of CODH. This CODH domain provides a channel for CO to travel between the two catalytic Ni-Fe-S clusters. It generates the binding surface for ACS and creates a remarkably similar CO alcove above the A-cluster using residues from CODH rather than ACS. Comparison of our MetCODH/ACS structure with our MetCODH structure reveals a molecular mechanism to restrict gas flow from the CO channel when ACS departs, preventing CO escape into the cell. Overall, these long-awaited structures of a methanogenic CODH/ACS reveal striking functional similarities to their acetogenic counterparts despite a substantial difference in domain organization.

As an important signaling molecule, carbon monoxide (CO) plays an important role in plant growth and development including affecting stomatal movement, stress response and root development. Thus, it is necessary to develop fluorescent probes that can be used to detect CO in live plant tissues and further enable a deep-understanding of its biological function, mechanism and metabolism. In this paper, a novel and sensitive fluorescent probe based on Cu2+ modulated polydihydroxyphenylalanine nanoparticles (PDOAs) has been developed for the detection of CO. The fluorescence of PDOAs can be effectively quenched by Cu2+ through the multi-coordination interaction. In the presence of CO, Cu2+ can be effectively reduced to Cu+, which resulted in the release of free PDOAs and the Cu2+-quenched bright green fluorescence was restored obviously. Through this ingenious strategy, the abiotic CO can be accurately detected and identified with high selectivity, rapid response time within 5 min and an ultralow detection limit of 72.4 nM. Due to the admirable biocompatibility, the nano-material based probe has been successfully applied for in vivo imaging CO in the root tip and leave tissues of lettuce. To the best of our knowledge, this is the first example of a fluorescent probe-based methodology for the sensitive tracking of CO in plant tissues.

Gases are essential for various applications relevant to human health, including in medicine, biomedical imaging, and pharmaceutical synthesis. However, gases are significantly more challenging to safely handle than liquids and solids. Herein, we review the use of porous materials, such as metal-organic frameworks (MOFs), zeolites, and silicas, to adsorb medicinally relevant gases and facilitate their handling as solids. Specific topics include the use of MOFs and zeolites to deliver H2S for therapeutic applications, 129Xe for magnetic resonance imaging, O2 for the treatment of cancer and hypoxia, and various gases for use in organic synthesis. This Perspective aims to bring together the organic, inorganic, medicinal, and materials chemistry communities to inspire the design of next-generation porous materials for the storage and delivery of medicinally relevant gases.

Luminescence imaging is a powerful and versatile technique for investigating cell physiology and pathology in living systems, making significant contributions to life science research and clinical diagnosis. In recent years, luminescent transition metal complexes have gained significant attention for diagnostic and therapeutic applications due to their unique photophysical and photochemical properties. In this Review, we provide a comprehensive overview of the recent development of luminescent transition metal complexes for bioimaging and biosensing applications, with a focus on transition metal centers with a d6, d8, and d10 electronic configuration. We elucidate the structure-property relationships of luminescent transition metal complexes, exploring how their structural characteristics can be manipulated to control their biological behavior such as cellular uptake, localization, biocompatibility, pharmacokinetics, and biodistribution. Furthermore, we introduce the various design strategies that leverage the interesting photophysical properties of luminescent transition metal complexes for a wide variety of biological applications, including autofluorescence-free imaging, multimodal imaging, organelle imaging, biological sensing, microenvironment monitoring, bioorthogonal labeling, bacterial imaging, and cell viability assessment. Finally, we provide insights into the challenges and perspectives of luminescent transition metal complexes for bioimaging and biosensing applications, as well as their use in disease diagnosis and treatment evaluation.

Because of endogenous signaling roles of carbon monoxide (CO) and its demonstrated pharmacological effects, there has been extensive interests in developing fluorescent CO probes. Palladium-mediated CO insertion has been successfully used for such applications. However, recent years have seen many publications of using uncatalyzed CO insertion into a hydrazone double bond as a way to sense CO. Such chemistry has no precedents otherwise. Further, the rigor of the CO-sensing work was largely based on using ruthenium-carbonyl complexes such as CORM-3 as CO surrogates, which have been reported to have extensive chemical reactivity and to release largely CO2 instead of CO unless in the presence of a strong nucleophile such as dithionite. For all of these, it is important to reassess the feasibility of such a CO-insertion reaction. By studying two of the reported "CO probes" using CO gas, this study finds no evidence of CO insertion into a hydrazone double bond. Further, the chemical reaction between CO gas and a series of eight hydrazone compounds was conducted, leading to the same conclusion. Such findings are consistent with the state-of-the-art knowledge of carbonylation chemistry and do not support uncatalyzed CO insertion as a mechanism for developing fluorescent CO probes.

Developing imaging tools that can report on the presence of disease-relevant analytes in multicellular organisms can provide insight into fundamental disease mechanisms as well as provide diagnostic tools for the clinic. Photoacoustic imaging (PAI) is a light-in, sound-out imaging technique that allows for high resolution, deep-tissue imaging with applications in pre-clinical and point-of-care settings. The continued development of near-infrared (NIR) absorbing small-molecule dyes promises to improve the capabilities of this emerging imaging modality. For example, new dye scaffolds bearing chemoselective functionalities are enabling the detection and quantification of disease-relevant analytes through activity-based sensing (ABS) approaches. Recently described strategies to engineer NIR absorbing xanthenes have enabled development of analyte-responsive PAI probes using this classic dye scaffold. Herein, we present current strategies for red-shifting the spectral properties of xanthenes via bridging heteroatom or auxochrome modifications. Additionally, we explore how these strategies, coupled with chemoselective spiroring-opening approaches, have been employed to create ABS probes for in vivo detection of hypochlorous acid, nitric oxide, copper (II), human NAD(P)H: quinone oxidoreductase isozyme 1, and carbon monoxide. Given the versatility of the xanthene scaffold, we anticipate continued growth and development of analyte-responsive PAI imaging probes based on this dye class.

Carbon monoxide (CO) is one of the signaling molecules that are ubiquitous in humans, which involves in the regulation of human physiology and pathology. In this work, the probe PEC was designed and synthesized based on BODIPY fluorophore that can selectively detect CO through reducing the nitro group to amino group, resulting in a "turn-on" fluorescence response with a simultaneous increase in the concentration of CO. The response is selective over a variety of relevant reactive free radicals, ions, and amino acid species. PEC has the advantages of good stability, good water solubility, and obvious changes in fluorescence signals. In addition, PEC can be used to detect and track endogenous CO in living cells.

Carbon monoxide, the "silent killer" gas, is increasingly recognised as an important signalling molecule in human physiology, which has beneficial biological properties. A particular way of achieving controlled CO administration is based on the use of biocompatible molecules that only release CO when triggered by internal or external factors. These approaches include the development of pharmacologically effective prodrugs known as CO releasing molecules (CORMs), which can supply biological systems with CO in well-regulated doses. An overview of transition metal-based CORMs with cytotoxic properties is here reported. The mechanisms at the basis of the biological activities of these molecules and their potential therapeutical applications with respect to their stability and CO releasing properties have been discussed. The activation of metal-based CORMs is determined by the type of metal and by the nature and features of the auxiliary ligands, which affect the metal core electronic density and therefore the prodrug resistance towards oxidation and CO release ability. A major role in regulating the cytotoxic properties of these CORMs is played by CO and/or CO-depleted species. However, several mysteries concerning the cytotoxicity of CORMs remain as intriguing questions for scientists.

Spinal Cord Injury (SCI) is a condition characterized by complete or incomplete motor and sensory impairment, as well as dysfunction of the autonomic nervous system, caused by factors such as trauma, tumors, or inflammation. Current treatment methods primarily include traditional approaches like spinal canal decompression and internal fixation surgery, steroid pulse therapy, as well as newer techniques such as stem cell transplantation and brain-spinal cord interfaces. However, the above methods have limited efficacy in promoting axonal and neuronal regeneration. The challenge in medical research today lies in promoting spinal cord neuron regeneration and regulating the disrupted microenvironment of the spinal cord. Studies have shown that gas molecular therapy is increasingly used in medical research, with gasotransmitters such as hydrogen sulfide, nitric oxide, carbon monoxide, oxygen, and hydrogen exhibiting neuroprotective effects in central nervous system diseases. The gas molecular protect against neuronal death and reshape the microenvironment of spinal cord injuries by regulating oxidative, inflammatory and apoptotic processes. At present, gas therapy mainly relies on inhalation for systemic administration, which cannot effectively enrich and release gas in the spinal cord injury area, making it difficult to achieve the expected effects. With the rapid development of nanotechnology, the use of nanocarriers to achieve targeted enrichment and precise control release of gas at Sites of injury has become one of the emerging research directions in SCI. It has shown promising therapeutic effects in preclinical studies and is expected to bring new hope and opportunities for the treatment of SCI. In this review, we will briefly outline the therapeutic effects and research progress of gasotransmitters and nanogas in the treatment of SCI.

Hydrogen sulfide (H2S) is not only a well-established toxic gas but also an important small molecule bioregulator in all kingdoms of life. In contemporary biology, H2S is often classified as a "gasotransmitter," meaning that it is an endogenously produced membrane permeable gas that carries out essential cellular processes. Fluorescent probes for H2S and related reactive sulfur species (RSS) detection provide an important cornerstone for investigating the multifaceted roles of these important small molecules in complex biological systems. A now common approach to develop such tools is to develop "activity-based probes" that couple a specific H2S-mediated chemical reaction to a fluorescent output. This Review covers the different types of such probes and also highlights the chemical mechanisms by which each probe type is activated by specific RSS. Common examples include reduction of oxidized nitrogen motifs, disulfide exchange, electrophilic reactions, metal precipitation, and metal coordination. In addition, we also outline complementary activity-based probes for imaging reductant-labile and sulfane sulfur species, including persulfides and polysulfides. For probes highlighted in this Review, we focus on small molecule systems with demonstrated compatibility in cellular systems or related applications. Building from breadth of reported activity-based strategies and application, we also highlight key unmet challenges and future opportunities for advancing activity-based probes for H2S and related RSS.

Carbon monoxide (CO) is notorious for its toxic effects but is also recognized as a gasotransmitter with considerable therapeutic potential. Due to the inherent challenges in its delivery, the utilization of organic CO photoreleasing molecules (photoCORMs) represents an interesting alternative to CO administration characterized by high spatial and temporal precision of release. This paper focused on the design, synthesis, and photophysical and photochemical studies of 20 3-hydroxyflavone (flavonol) and 3-hydroxyflavothione derivatives as photoCORMs. Newly synthesized compounds bearing various electron-donating and electron-withdrawing groups show bathochromically shifted absorption maxima and considerably enhanced CO release yields compared to the parent unsubstituted flavonol, exceeding 0.8 equiv of released CO in derivatives exhibiting excited states with a charge-transfer character. Until now, such outcomes have been limited to flavonol derivatives possessing a π-extended aromatic system. In addition, thione analogs of flavonols, 3-hydroxyflavothiones, show substantial bathochromic shifts of their absorption maxima and enhanced photosensitivity but provide lower yields of CO formation. Our study elucidates in detail the mechanism of CO photorelease from flavonols and flavothiones, utilizing steady-state and time-resolved spectroscopies and photoproduct analyses, with a particular emphasis on unraveling the structure-photoreactivity relationship and understanding competing side processes.

The role of carbon monoxide (CO) has evolved albeit controversial disputes on its toxicity. This biological gasotransmitter participates in the endogenous regulation of neurotransmitters and neuropeptides released in the nervous system. Exogenous CO gas inhalation at a lower concentration has been the subject of investigations, which have revealed its biological homeostatic mechanisms and protective effects against many pathological conditions. This therapeutic procedure of CO is, however, limited due to its immediate release, which favours haemoglobin at a high affinity with the subsequent generation of toxic carboxyhaemoglobin in tissues. In order to address this problem, carbon monoxide releasing molecule-2 (CORM-2) or also known as tricarbonyldichlororuthenium II dimer is developed to liberate a controlled amount of CO in the biological systems. In this review, we examine several potential mechanisms exerted by this therapeutic compound to produce the anti-nociceptive effect that has been demonstrated in previous studies. This review could shed light on the role of CORM-2 to reduce pain, especially in cases of chronic and neuropathic pain.

Carbon monoxide (CO) is a toxic gas that can be lethal in large doses and may also cause physiological damage in lower doses. Epidemiological studies suggest that CO in lower doses over time may impact on embryo development, in particular cardiac development, however other studies have not observed this association.

Here, we exposed chick embryos in ovo to CO at three different concentrations (3, 9, 18 ppm) plus air control (4 protocols in total) for the first 9 days of development, at which point we assessed egg and embryo weight, ankle length, developmental stage, heart weight, ventricular wall thickness, ventricular-septal thickness and atrial wall thickness.

We found that heart weight was reduced for the low and moderate exposures compared to air, that atrial wall and ventricular wall thickness was increased for the moderate and high exposures compared to air and that ventricular septal thickness was increased for low, moderate and high exposures compared to air. Ventricular wall thickness was also significantly positively correlated with absolute CO exposures across all protocols.

This intervention study thus suggests that CO even at very low levels may have a significant impact on cardiac development.

Precision drug delivery and multimodal synergistic therapy are crucial in treating diverse ailments, such as cancer, tissue damage, and degenerative diseases. Electrodes that emit electric pulses have proven effective in enhancing molecule release and permeability in drug delivery systems. Moreover, the physiological electrical microenvironment plays a vital role in regulating biological functions and triggering action potentials in neural and muscular tissues. Due to their unique noncentrosymmetric structures, many 2D materials exhibit outstanding piezoelectric performance, generating positive and negative charges under mechanical forces. This ability facilitates precise drug targeting and ensures high stimulus responsiveness, thereby controlling cellular destinies. Additionally, the abundant active sites within piezoelectric 2D materials facilitate efficient catalysis through piezochemical coupling, offering multimodal synergistic therapeutic strategies. However, the full potential of piezoelectric 2D nanomaterials in drug delivery system design remains underexplored due to research gaps. In this context, the current applications of piezoelectric 2D materials in disease management are summarized in this review, and the development of drug delivery systems influenced by these materials is forecast.

Photooxygenation of flavonoids leads to the release of carbon monoxide (CO). Our structure-photoreactivity study, employing several structurally different flavonoids, including their 13C-labeled analogs, revealed that CO can be produced via two completely orthogonal pathways, depending on their hydroxy group substitution pattern and the reaction conditions. While photooxygenation of the enol 3-OH group has previously been established as the CO liberation channel, we show that the catechol-type hydroxy groups of ring B can predominantly participate in photodecarbonylation.

Carbon monoxide (CO) not only causes damage to life and health as an environmental pollutant, but also undertakes many physiological functions in organisms. In particular, developing means that can be used for the determination of CO in organelles will provide insight into the vital role it plays. Studies have shown that mitochondrial respiration is closely related to CO concentrations, so it is critical to develop tools for CO detection in mitochondria. Here, we use a rhodamine derivative that can target mitochondria as fluorophores to construct a mitochondrial-labeled CO fluorescence probe (Rh-CO) with high sensitivity (detection limit: 9.4 nM), excellent water-solubility, and long emission (λem = 630 nm). Prominently, the probe has outstanding mitochondria-targeting capabilities. Moreover, we used transient glucose deprivation (TGD) and heme to stimulate endogenous CO production in living cells and zebrafish, respectively, and the probe exhibited excellent imaging capabilities. All in all, we expect this probe to contribute to a deeper understanding of the role played by CO in mitochondria.

Photoacoustic (PA) imaging is emerging as one of the important non-invasive imaging techniques in biomedical research. Small molecule- second near-infrared window (NIR-II) PA dyes combined with imaging data can provide comprehensive and in-depth in vivo physiological and pathological information. However, the NIR-II PA dyes usually exhibit "always-on" properties due to the lack of a readily optically tunable group, which hinders the further applications in vivo. Herein, a novel class of dyes GX have been designed and synthesized as an activatable NIR-II PA platform, in which the absorption/emission wavelength of GX-5 extends up to 1082/1360 nm. Importantly, the GX dyes have a strong tissue penetration depth and high-resolution for the mouse vasculature structures in NIR-II PA 3D imaging and high signal-to-noise ratio in NIR-II fluorescence (FL) imaging. Furthermore, to demonstrate the applicability of GX dyes, the first NIR-II PA probe GX-5-CO activated by carbon monoxide (CO) was engineered and employed to reveal the enhancement of the CO levels in the hypertensive mice by high-contrast NIR-II PA and FL imaging. We expect that many derivatives of GX dyes will be developed to afford versatile NIR-II PA platforms for designing a wide variety activatable NIR-II PA probes as biomedical tools.

Transcription factor EB (TFEB) is an important endogenous defensive protein that responds to ischemic stimuli. Acute ischemic stroke is a growing concern due to its high morbidity and mortality. Most survivors suffer from disabilities such as numbness or weakness in an arm or leg, facial droop, difficulty speaking or understanding speech, confusion, impaired balance or coordination, or loss of vision. Although TFEB plays a neuroprotective role, its potential effect on ischemic stroke remains unclear. This article describes the basic structure, regulation of transcriptional activity, and biological roles of TFEB relevant to ischemic stroke. Additionally, we explore the effects of TFEB on the various pathological processes underlying ischemic stroke and current therapeutic approaches. The information compiled here may inform clinical and basic studies on TFEB, which may be an effective therapeutic drug target for ischemic stroke.

Gasotransmitters are a group of short-lived gaseous signaling molecules displaying diverse biological functions depending upon their localized concentration. Nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) are three important examples of endogenously produced gasotransmitters that play a crucial role in human neurophysiology and pathogenesis. Alterations in their optimal physiological concentrations can lead to various severe pathophysiological consequences, including neurological disorders. Exogenous administration of gasotransmitters has emerged as a prominent therapeutic approach for treating such neurological diseases. However, their gaseous nature and short half-life limit their therapeutic delivery. Therefore, developing synthetic gasotransmitter-releasing strategies having control over the release and duration of these gaseous molecules has become imperative. However, the complex chemistry of synthesis and the challenges of specific quantified delivery of these gases, make their therapeutic application a challenging task. This review article provides a focused overview of emerging strategies for delivering gasotransmitters in a controlled and sustained manner to re-establish neurophysiological homeostasis.

Acute pancreatitis (AP) is a non-infectious pancreatic enzyme-induced disorder, a life-threatening inflammatory condition that can cause multi-organ dysfunction, characterized by high morbidity and mortality. Several therapies have been employed to target this disorder; however, few happen to be effectively employable even in the early phase. PFKFB3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) is a critical regulator of glycolysis and is upregulated under inflammatory, mitogenic, and hypoxia conditions. Essential information on the targeting of the inflammatory pathway will present the termination of the disorder and recovery. Herein we investigated the protective function of KAN0438757, a potent inhibitor of PFKFB3, and its mechanism of impeding AP induced in mice. KAN0438757 was confirmed to activate the Nrf2/HO-1 inflammatory signaling pathways in response to caerulein induced acute pancreatitis (CAE-AP) and fatty acid ethyl ester induced severe acute pancreatitis (FAEE-SAP). Additionally, KAN0438757 alleviated the inflammatory process in infiltrated macrophage via the Nrf2/HO-1 inflammatory signaling pathway and demonstrated a significant effect on the growth of mice with induced AP. And more importantly, KAN0438757 displayed negligible toxicity in vivo. Taken together our data suggest KAN0438757 directly suppresses the inflammatory role of PFKFB3 and induces a protective role via the Nrf2/HO-1 pathway, which could prove as an excellent therapeutic platform for SAP amelioration.

Nonalcoholic fatty liver disease (NAFLD) can progress to cirrhosis and liver cancer if left untreated. Therefore, it is of great importance to develop useful tools for the noninvasive and accurate diagnosis of NAFLD. Increased microenvironmental viscosity was considered as a biomarker of NAFLD, but the occurrence of increased viscosity in other liver diseases highly reduces the diagnosis accuracy of NAFLD by a single detection of viscosity. Hence, it is very necessary to seek a second biomarker of NAFLD. It has been innovatively proposed that the overexpressed heme oxygenase-1 enzyme in NAFLD would produce abnormally high concentrations of CO in hepatocytes and that CO could serve as a potential biomarker. In this work, we screened nine lactam Changsha dyes (HCO-1-HCO-9) with delicate structures to obtain near-infrared (NIR), metal-free, and "dual-locked" fluorescent probes for the simultaneous detection of CO and viscosity. Changsha dyes with a 2-pyridinyl hydrazone substituent could sense CO, and the 5-position substituents on the 2-pyridinyl moiety had a great electron effect on the reaction rate. The double bond in these dyes served as the sensing group for viscosity. Probe HCO-9 was utilized for precise diagnosis of NAFLD by simultaneous detection of CO and viscosity. Upon reacting with CO in a high-viscosity microenvironment, strong fluorescence at 745 nm of probe HCO-9 was turned on with NIR excitation at 700 nm. Probe HCO-9 was proven to be an effective tool for imaging CO and viscosity. Due to the advantages of NIR absorption and low toxicity, probe HCO-9 was successfully applied to image NAFLD in a mouse model.

Gas therapy has gained noteworthy attention in biomedical research, with the rise of gas-releasing molecules enhancing their therapeutic potential, especially when integrated into nano-based drug delivery systems. Herein, we present a lipid-coated gas delivery system to simultaneously shuttle two gas-releasing molecules carrying nitric oxide (NO) and carbon monoxide (CO), respectively. Upconversion nanoparticles (UCNPs) are designed to generate photons at 360 nm upon 808 nm of near-infrared (NIR) irradiation. These in situ-generated UV photons trigger simultaneous NO and CO release from S-nitrosoglutathione (GSNO) and the CO-releasing molecule (CORM), respectively, which are coloaded into lipid-coated UCNP/GSNO/CORM/FA nanoparticles (LUGCF). LUGCF with a GSNO/CORM mass ratio of 2:1 is determined to be optimal in terms of synergistically instigating apoptosis in HCT116 and CT26 colon cancer cells, where both NO/CO are released and subsequent production of ROS are detected. This CO/NO combination nanoplatform exhibits a very effective inhibition of colon tumor growth in vivo at relatively low doses upon a mild 808 nm irradiation. Overall, we effectively integrated two therapeutic gas-releasing molecules in one NIR-responsive nanosystem, presenting a promising therapeutic strategy for future biomedical applications in dual-gas cancer therapy.

Heme oxygenase-1 (HO-1) is an enzyme located at the endoplasmic reticulum, which is responsible for the degradation of cellular heme into ferrous iron, carbon monoxide and biliverdin-IXa. In addition to this main function, the enzyme is involved in many other homeostatic, toxic and cancer-related mechanisms. In this review, we first summarize the importance of HO-1 in physiology and pathophysiology with a focus on the digestive system. We then detail its structure and function, followed by a section on the regulatory mechanisms that control HO-1 expression and activity. Moreover, HO-2 as important further HO isoform is discussed, highlighting the similarities and differences with regard to HO-1. Subsequently, we describe the direct and indirect cytoprotective functions of HO-1 and its breakdown products carbon monoxide and biliverdin-IXa, but also highlight possible pro-inflammatory effects. Finally, we address the role of HO-1 in cancer with a particular focus on colorectal cancer. Here, relevant pathways and mechanisms are presented, through which HO-1 impacts tumor induction and tumor progression. These include oxidative stress and DNA damage, ferroptosis, cell cycle progression and apoptosis as well as migration, proliferation, and epithelial-mesenchymal transition.

Carbon monoxide (CO) poisoning is a significant public health issue and a considerable economic burden in developed countries. While the majority of non-fire-related CO poisonings are attributed to gas heating, there are several other less recognized sources that should be considered in the initial differential diagnosis.The patient in this case was a 21-year-old who experienced a brief episode of loss of consciousness and was subsequently admitted to the Emergency department. Upon evaluation, the patient was diagnosed with CO poisoning, which necessitated hyperbaric oxygen therapy to mitigate the effects of this toxic exposure.Despite exhibiting harmful symptoms initially, the patient stated in a phone interview two and a half years post-incident that they have not experienced any enduring effects such as cardiac arrhythmia or concentration deficits. While their understanding of the risks associated with waterpipe smoking has increased, it has not influenced any major changes in their waterpipe smoking habits.

Cisplatin-induced acute kidney injury (AKI) is an important factor that limits the clinical use of this drug for the treatment of malignancies. Oxidative stress and inflammation are considered to be the main causes of not only cisplatin-induced death of cancer cells but also cisplatin-induced AKI. Therefore, developing agents that exert antioxidant and anti-inflammatory effects without weakening the anti-tumor effects of cisplatin is highly desirable. Carbon monoxide (CO) has recently attracted interest due to its antioxidant, anti-inflammatory, and anti-tumor properties. Herein, we report that CO-loaded red blood cell (CO-RBC) exerts renoprotective effects on cisplatin-induced AKI. Cisplatin treatment was found to reduce cell viability in proximal tubular cells via oxidative stress and inflammation. Cisplatin-induced cytotoxicity, however, was suppressed by the CO-RBC treatment. The intraperitoneal administration of cisplatin caused an elevation in the blood urea nitrogen and serum creatinine levels. The administration of CO-RBC significantly suppressed these elevations. Furthermore, the administration of CO-RBC also reduced the deterioration of renal histology and tubular cell injury through its antioxidant and anti-inflammatory effects in cisplatin-induced AKI mice. Thus, our data suggest that CO-RBC has the potential to substantially prevent the onset of cisplatin-induced AKI, which, in turn, may improve the usefulness of cisplatin-based chemotherapy.

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are three endogenously produced gases with important functions in the vasculature, immune defense, and inflammation. It is increasingly apparent that, far from working in isolation, these three exert many effects by modulating each other's activity. Each gas is produced by three enzymes, which have some tissue specificities and can also be non-enzymatically produced by redox reactions of various substrates. Both NO and CO share similar properties, such as activating soluble guanylate cyclase (sGC) to increase cyclic guanosine monophosphate (cGMP) levels. At the same time, H2S both inhibits phosphodiesterase 5A (PDE5A), an enzyme that metabolizes sGC and exerts redox regulation on sGC. The role of NO, CO, and H2S in the setting of cancer has been quite perplexing, as there is evidence for both tumor-promoting and pro-inflammatory effects and anti-tumor and anti-inflammatory activities. Each gasotransmitter has been found to have dual effects on different aspects of cancer biology, including cancer cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and immunomodulation. These seemingly contradictory actions may relate to each gas having a dual effect dependent on its local flux. In this review, we discuss the major roles of NO, CO, and H2S in the context of cancer, with an effort to highlight the dual nature of each gas in different events occurring during cancer progression.

As one of the triumvirate of recognized gasotransmitter molecules, namely NO, H2S, and CO, the physiological effects of CO and its potential as a biomarker have been widely investigated, garnering particular attention due to its reported hypotensive, anti-inflammatory, and cytoprotective properties, making it a promising therapeutic agent. However, the development of CO molecular probes has remained relatively stagnant in comparison with the fluorescent probes for NO and H2S, owing to its inert molecular state under physiological conditions. In this review, starting from elucidating the definition and significance of CO as a gasotransmitter, the imperative for the advancement of CO probes, especially fluorescent probes, is expounded. Subsequently, the current state of development of CO probe methodologies is comprehensively reviewed, with an overview of the challenges and prospects in this burgeoning field of research.

Considering that carbon monoxide is both a vital gasotransmitter and an obnoxious gas, tremendous efforts have been dedicated toward its recognition through various methods. However, the fluorescent light-up approach through the exploration of optical markers remains one of the most convenient methods owing to its several advantages. Amongst the different approaches towards the development of CO responsive optically active molecular markers, the Tsuji-Trost reaction-based CO recognition strategy has remained one of the most significant areas of interest across researchers working in this field. However, there have been no attempts to exclusively summarize the commendable work done in this area yet. The current review, therefore, attempts to summarize the developments of various optical probes following this reaction strategy until the year 2022. This review provides detailed mechanistic insights into the Tsuji-Trost mediated CO detection strategy. Besides, discussions on the strategic development and employment of probes based on various allyl derivatives - allyl carbamate/carbonate/ethers - will provide a thorough understanding of the detection method. The significant advancements of the Tsuji-Trost reaction as an interesting strategy that is accepted and extensively explored for monitoring CO in various media including air, aqueous solutions and living systems have been elaborately discussed. Various potential applications and utilization of these developed fluorogenic probes for tracing CO in different living systems have been examined systematically. Moreover, monitoring of exogenous/endogenous CO levels, modulation of intracellular CO concentration under various induced conditions and bioimaging of CO in in vivo models have also been detailed here. Briefly, this review summarizes the current prospects of this detection method and the future directions in related fields.

Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H2S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H2S, and CO and the clinical scenarios where they are more promising.

Hydrogen selenide (H₂Se) is a possible bioregulator, potential gasotransmitter, and important precursor in biological organoselenium compound synthesis. Early tools for H₂Se research have benefitted from available mechanistic understanding of analogous small molecules developed for detecting or delivering H₂S. A now common approach for H₂S delivery is the use of small molecule thiocarbamates that can be engineered to release COS, which is quickly converted to H₂S by carbonic anhydrase. To expand our understanding of the chemical underpinnings that enable H₂Se delivery, we investigated whether selenocarbamates undergo similar chemistry to release carbonyl selenide (COSe). Using both light- and hydrolysis-activated systems, we demonstrate that unlike their lighter thiocarbamate congeners, selenocarbamates release H₂Se directly with concomitant isocyanate formation rather than by the intermediate release of COSe. This reaction mechanism for direct H₂Se release is further supported by computational investigations that identify a ΔΔG^‡ ∼ 25 kcal mol^-1 between the H₂Se and COSe release pathways in the absence of protic solvent. This work highlights fundamentally new approaches for H₂Se release from small molecules and advances the understanding of reactivity differences between reactive sulfur and selenium species.