Endogenous Signaling Molecule Research Articles

Short-term plasticity in the spinal nociceptive system.

Somatosensory information is delivered to neuronal networks of the dorsal horn (DH) of the spinal cord by the axons of primary afferent neurons that encode the intensity of peripheral sensory stimuli under the form of a code based on the frequency of action potential firing. The efficient processing of these messages within the DH involves frequency-tuned synapses, a phenomenon linked to their ability to display activity-dependent forms of short-term plasticity (STP). By affecting differently excitatory and inhibitory synaptic transmissions, these STP properties allow a powerful gain control in DH neuronal networks that may be critical for the integration of nociceptive messages before they are forwarded to the brain, where they may be ultimately interpreted as pain. Moreover, these STPs can be finely modulated by endogenous signaling molecules, such as neurosteroids, adenosine, or GABA. The STP properties of DH inhibitory synapses might also, at least in part, participate in the pain-relieving effect of nonpharmacological analgesic procedures, such as transcutaneous electrical nerve stimulation, electroacupuncture, or spinal cord stimulation. The properties of target-specific STP at inhibitory DH synapses and their possible contribution to electrical stimulation-induced reduction of hyperalgesic and allodynic states in chronic pain will be reviewed and discussed.

Plant Elicitor Peptide (Pep) Signaling and Pathogen Defense in Tomato.

Endogenous signaling compounds are intermediaries in signaling pathways that plants use to respond to the perception of harmful and beneficial organisms. The plant elicitor peptides (Peps) of plants are important endogenous signaling molecules that induce elements of defense responses such as hormone production, increased expression of defensive genes, the activation of phosphorelays, and the induction of cell secondary messenger synthesis. The processes by which Peps confer resistance to pathogenic microorganisms have been extensively studied in Arabidopsis but are less known in crop plants. Tomato and many other solanaceous plants have an endogenous signaling polypeptide, systemin, that is involved in the defense against herbivorous insects and necrotrophic pathogens. This paper explores the similarity of the effects and chemical properties of Pep and systemin in tomato. Additionally, the relationship of the Pep receptor and systemin receptors is explored, and the identification of a second tomato Pep receptor in the literature is called into question. We suggest future directions for research on Pep signaling in solanaceous crops during interactions with microbes.

Multiple Ways of Nitric Oxide Production in Plants and Its Functional Activity under Abiotic Stress Conditions.

Nitric oxide (NO) is an endogenous signaling molecule that plays an important role in plant ontogenesis and responses to different stresses. The most widespread abiotic stress factors limiting significantly plant growth and crop yield are drought, salinity, hypo-, hyperthermia, and an excess of heavy metal (HM) ions. Data on the accumulation of endogenous NO under stress factors and on the alleviation of their negative effects under exogenous NO treatments indicate the perspectives of its practical application to improve stress resistance and plant productivity. This requires fundamental knowledge of the NO metabolism and the mechanisms of its biological action in plants. NO generation occurs in plants by two main alternative mechanisms: oxidative or reductive, in spontaneous or enzymatic reactions. NO participates in plant development by controlling the processes of seed germination, vegetative growth, morphogenesis, flower transition, fruit ripening, and senescence. Under stressful conditions, NO contributes to antioxidant protection, osmotic adjustment, normalization of water balance, regulation of cellular ion homeostasis, maintenance of photosynthetic reactions, and growth processes of plants. NO can exert regulative action by inducing posttranslational modifications (PTMs) of proteins changing the activity of different enzymes or transcriptional factors, modulating the expression of huge amounts of genes, including those related to stress tolerance. This review summarizes the current data concerning molecular mechanisms of NO production and its activity in plants during regulation of their life cycle and adaptation to drought, salinity, temperature stress, and HM ions.

Review on the Discovery of Novel Natural Herbicide Safeners.

The phytotoxicity of herbicides on crops is a major dilemma in agricultural production. Fortunately, the emergence of herbicide safeners is an excellent solution to this challenge, selectively enhancing the performance of herbicides in controlling weeds while reducing the phytotoxicity to crops. But owing to their potential toxicity, only a tiny proportion of safeners are commercially available. Natural products as safeners have been extensively explored, which are generally safe to mammals and cause little pollution to the environment. They are typically endogenous signal molecules or phytohormones, which are generally difficult to extract and synthesize, and exhibit relatively lower activity than commercial products. Therefore, it is necessary to adopt rational design approaches to modify the structure of natural safeners. This paper reviews the application, safener effects, structural characteristics, and modifications of natural safeners and provides insights on the discovery of natural products as potential safeners in the future.

Alleviating the Injuries of NaCl Exposure on Respiratory Activities, Leaf Stomatal and Antioxidant Defense of Silybum marianum L. Seedlings by Exogenous Nitric Oxide

Nitric oxide (NO) is recognized as an endogenous signaling molecule that plays an important role in the defence responses of medicinal plants to NaCl stress. In this study, we investigated the effects of sodium nitroprusside (SNP) as an NO donor at three concentrations (0, 100, and 200 µmol l−1) to alleviate the deleterious effects of salt stress (100 mM NaCl) on leaf gas exchange and biochemical characteristics of Silybum marianum L. seedlings. This study showed that salt stress significantly decreased relative water content (RWC), chlorophyll b content, endogenous NO concentration, maximum quantum yield (Fv/Fm), leaf gas exchange, stomatal size, K+/Na+ ratio, and plant dry weight, and increased malondialdehyde (MDA) content, hydrogen peroxide (H2O2) content, proline content, stomatal density, and enzyme activities. SNP treatment increased Fv/Fm, photosynthetic pigments, K+/Na+ ratio, and dry weights of the shoots and roots of NaCl-exposed plants. The exogenous application of NO increased the proline content under salinity stress more than under stress conditions without SNP application, so that the proline content increased from 32 to 47 µmol g−1. Application of 100 µM SNP also increased endogenous NO concentration (up to 43%) and consequently protected plants against salt stress-induced damage by improving enzyme activity and reducing the H2O2 generation rate (up to 14%) and MDA content (up to 50%) compared to plants treated with NaCl alone. Foliar application of NO to salt-stressed plants increased root and shoot respiration rates from 20 and 12%, respectively, under salinity stress to 57% under the application of SNP and stress conditions, and decreased stomatal conductance by up to 70%, resulting in improved RWC. Increased internal NO generation in plants induced by 100 µM SNP application has the potential to mitigate salinity injury in Silybum marianum L. plants.

Methyl jasmonate and selenium synergistically mitigative cadmium toxicity in hot pepper (Capsicum annuum L.) plants by improving antioxidase activities and reducing Cd accumulation.

Methyl jasmonate (MeJA) or selenium (Se)-mediated response to cadmium (Cd) stress in plant has been widely reported, but the combined effects both on plant growth in response to Cd stress and the underlying mechanisms remain obscure. Here, we showed the combined effects of MeJA (2.5μM) and Se (7μM) on hot pepper growth under Cd stress (CdCl2, 5μM). The results showed Cd suppressed the accumulation of total chlorophyll and carotenoid and reduced the photosynthesis, while it increased the content of endogenous signaling molecules, e.g. nitric oxide (NO) and hydrogen peroxide (H2O2), as well as Cd content in leaves. The combined application of MeJA and Se significantly decreased the malondialdehyde (MDA) accumulation and improved the activities of antioxidant enzymes (AOEs, e.g. SOD and CAT) and defense-related enzymes (DREs, POD and PAL). Additionally, the synergistic application of MeJA and Se also obviously improved photosynthesis in hot pepper plants under Cd stress compared with those treated with MeJA or Se respectively or not. Moreover, the treatment of MeJA associated with Se also effectively reduced the Cd accumulation in hot pepper leaves under Cd stress compared with the plants treated with MeJA or Se separately, which implied a potentially synergistic role of MeJA and Se in alleviating Cd toxicity in hot pepper plants. This study provides a theoretical reference for the further analysis of the molecular mechanism of MeJA and Se in jointly mediating the response to heavy metals in plants.

Sensing a CO-Releasing Molecule (CORM) Does Not Equate to Sensing CO: The Case of DPHP and CORM-3.

Carbon monoxide (CO) is an endogenous signaling molecule with demonstrated pharmacological effects. For studying CO biology, there is a need for sensitive and selective fluorescent probes for CO as research tools. In developing such probes, CO gas and/or commercially available metal-carbonyl-based "CO-releasing molecules" (CORMs) have been used as CO sources. However, new findings are steadily emerging that some of these commonly used CORMs do not release CO reliably in buffers commonly used for studying such CO probes and have very pronounced chemical reactivities of their own, which could lead to the erroneous identification of "CO probes" that merely detect the CORM used, not CO. This is especially true when the CO-sensing mechanism relies on chemistry that is not firmly established otherwise. Cu2+ can quench the fluorescence of an imine-based fluorophore, DPHP, presumably through complexation. The Cu2+-quenched fluorescence was restored through the addition of CORM-3, a Ru-based CORM. This approach was reported as a new "strategy for detecting carbon monoxide" with the proposed mechanism being dependent on CO reduction of Cu2+ to Cu1+ under near-physiological conditions ( Anal. Chem. 2022, 94, 11298-11306). The study only used CORM-3 as the source of CO. CORM-3 has been reported to have very pronounced redox reactivity and is known not to release CO in an aqueous solution unless in the presence of a strong nucleophile. To assess whether the fluorescent response of the DPHP-Cu(II) cocktail to CORM-3 was truly through detecting CO, we report experiments using both pure CO and CORM-3. We confirm the reported DPHP-Cu(II) response to CORM-3 but not pure CO gas. Further, we did not observe the stated selectivity of DPHP for CO over sulfide species. Along this line, we also found that a reducing agent such as ascorbate was able to induce the same fluorescent turn-on as CORM-3 did. As such, the DPHP-Cu(II) system is not a CO probe and cannot be used to study CO biology. Corollary to this finding, it is critical that future work in developing CO probes uses more than a chemically reactive "CO donor" as the CO source. Especially important will be to confirm the ability of the "CO probe" to detect CO using pure CO gas or another source of CO.

Integration of Phosphoproteomics and Transcriptome Studies Reveals ABA Signaling Pathways Regulate UV-B Tolerance in Rhododendron chrysanthum Leaves.

The influence of UV-B stress on the growth, development, and metabolism of alpine plants, such as the damage to DNA macromolecules, the decline in photosynthetic rate, and changes in growth, development, and morphology cannot be ignored. As an endogenous signal molecule, ABA demonstrates a wide range of responses to UV-B radiation, low temperature, drought, and other stresses. The typical effect of ABA on leaves is to reduce the loss of transpiration by closing the stomata, which helps plants resist abiotic and biological stress. The Changbai Mountains have a harsh environment, with low temperatures and thin air, so Rhododendron chrysanthum (R. chrysanthum) seedlings growing in the Changbai Mountains can be an important research object. In this study, a combination of physiological, phosphorylated proteomic, and transcriptomic approaches was used to investigate the molecular mechanisms by which abiotic stress leads to the phosphorylation of proteins in the ABA signaling pathway, and thereby mitigates UV-B radiation to R. chrysanthum. The experimental results show that a total of 12,289 differentially expressed genes and 109 differentially phosphorylated proteins were detected after UV-B stress in R. chrysanthum, mainly concentrated in plant hormone signaling pathways. Plants were treated with ABA prior to exposure to UV-B stress, and the results showed that ABA mitigated stomatal changes in plants, thus confirming the key role of endogenous ABA in plant adaptation to UV-B. We present a model that suggests a multifaceted R. chrysanthum response to UV-B stress, providing a theoretical basis for further elaboration of the mechanism of ABA signal transduction regulating stomata to resist UV-B radiation.

Synergistic antibacterial effect of multifunctional TiO2−X-based nanoplatform loading arginine and polydopamine for promoting infected wounds healing

The gas therapy of some endogenous signaling molecules to treat diseases has caused extensive research, among which NO gas has shown great potential in fighting infection with various pathogens, promoting wound healing, etc. Here, we propose a photothermal/photodynamic/NO synergistic antibacterial nanoplatform by loading L-arginine (LA) on mesoporous TiO2 and then encapsulating it with polydopamine. The obtained TiO2−x-LA@PDA nanocomposite possesses both the excellent photothermal effect and ROS generation ability of mesoporous TiO2, and the release of nitric oxide (NO) from L-arginine under near-infrared (NIR) light irradiation, while the sealing layer of PDA could induce NIR-triggered NO controlled release. In vitro antibacterial experiments confirmed that the synergistic effect of TiO2−x-LA@PDA nanocomposites has excellent antibacterial effects against Gram-negative and Gram-positive bacteria, while in vivo experiments showed that it has lower toxicity. It is worth noting that compared with the pure photothermal effect and ROS, the generated NO showed a better bactericidal effect, and NO had a better ability to promote wound healing. In conclusion, the developed TiO2−x-LA@PDA nanoplatform can be used as a nanoantibacterial agent, which can be further explored in the related biomedical field of photothermal activation of multimodal combined antibacterial therapy.

Antibacterial gas therapy: Strategies, advances, and prospects.

One of the challenges posed by current antibacterial therapy is that the expanded and massive use of antibiotics endows bacteria with the ability to resist almost all kinds of antibiotics. Therefore, developing alternative strategies for efficient antibacterial treatment is urgently needed. Antibacterial gas therapy has attracted much attention in the past decade. Nitric oxide (NO), carbon monoxide (CO), sulfur dioxide (SO2), hydrogen sulfide (H2S), and hydrogen (H2) are not only known as endogenous signaling molecules, but also play critical roles in many pathological processes. These gases are considered as attractive bactericidal agents because they are able to kill bacteria, disperse biofilms, and promote bacteria-infected wound healing while avoiding resistance. In this review, we discuss the bactericidal properties of these gases, as well as the recent advances of gas-involving systems in antibacterial, antibiofilm, and wound treatment applications. Moreover, we summarize various gas donors utilized in antibacterial treatment. We hope this review will shed new light on the future design and applications of advanced antibacterial gas therapy.

Abstract 152: Metabolism And Therapeutic Potential Of Lipidated Amino Acids In Nonalcoholic Steatohepatitis And Atherosclerosis

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the global population. Despite significant advances in our understanding of the underlying causes and considerable efforts in drug development, no pharmacological therapy currently exists for this disease. Accelerated atherosclerosis, independent of traditional risk factors, is the major cause of death in patients with NAFLD, particularly in those with the more severe nonalcoholic steatohepatitis (NASH). Thus, there is an urgent need to identify new pathways for simultaneous targeting of NASH and atherosclerosis. Imbalanced lipid metabolism and dysregulated amino acid metabolism are emerging as common features of both NASH and atherosclerosis, although their crosstalk has not received much attention. Lipidated amino acids or N-acyl amino acids (NAAs) have emerged as endogenous signaling molecules in which an amide bond links an amino acid to the acyl moiety of a long-chain fatty acid. Utilizing unbiased transcriptomics, we uncovered suppression of known NAA biosynthetic genes and upregulation of degradative genes in livers from humans and mice with NASH, concomitant with marked reduction of NAAs, as determined by metabolomics. Similar findings were noted in lipid loaded primary hepatocytes and hepatic cell lines. Hepatic NAAs, particularly N-oleoyl leucine (C18:1-Leu), inversely correlated with NASH and inflammatory indices. Importantly, C18:1-Leu administered to mice with established NASH reduced transaminases, steatohepatitis, hepatic macrophages and fibrosis. RNA-seq revealed induction of hepatic peroxisome proliferator-activated receptor α (PPARα)/fatty acid oxidation (FAO) and suppression of chemokine signaling pathways aligned with reduced liver and plasma C-C motif chemokine ligand 2 (CCL2). Luciferase and qPCR analyses showed that C18:1-Leu induces PPARα transcriptional activity, while stimulating FAO, as determined by Seahorse. In atherosclerotic mice, C18:1-Leu reduced lesional macrophages and atherosclerosis while lowering hepatic steatosis and CCL2. Our findings uncovered a newly identified metabolic pathway linking NASH and atherosclerosis and a novel potential therapy for the simultaneous treatment of these two prominent diseases.

CO-induced TTP improves efficacy through resetting tumor-associated macrophages toward M1 phenotype in combined CTLA-4 and PD-1 blockade immunotherapy

Abstract Combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 has improved the prognosis for many malignancies, but also occurred a high rate of immune-related adverse events (irAEs). The manifestation of these toxicities is an important limiting factor for the successful implementation of CICB, restraining its anti-tumor efficacy. Carbon monoxide (CO), a pivotal endogenous signaling molecule, is able to maintain cell and tissue homeostasis and could be used as a therapeutic regimen. In our previous reports, CO could be useful therapeutics for the regulation of various inflammatory diseases through the increase of tristetraprolin (TTP) that binds to the AU-rich elements in target mRNA. In this study, we observed that CO-induced TTP activation ameliorated colitis and hepatitis, and improved anti-tumor efficacy in CICB treatment. We found that the colitis and hepatitis in TTP deficient mice were further exacerbated by CICB treatment. Moreover, CO increases CICB efficacy through TAM to M1 polarization together with diminishes irAEs through TTP enhancement in several irAEs target organ. Thus, we suggest that CO might be efficiently decouples anti-tumor efficacy and toxicity of CICB through TTP enhancement.

Chronic exposure to nitric oxide sensitizes prostate cancer cells and improved ZnO/CisPt NPs cytotoxicity and selectivity

The co-therapy of common chemotherapeutics with nitric oxide (NO), an endogenous signaling molecule, is proposed as an alternative to sensitize cancer cells and enhance treatments’ efficacy. Herein, we have synthesized cisplatin-releasing zinc oxide nanoparticles (ZnO/CisPt NPs), which promoted a sustained and pH targeted release, able to release a higher amount of CisPt at tumor microenvironment conditions. This material was combined with a chronic NO treatment, at low concentration, in prostate cancer cells (PC3). NO treatment enhanced the S-NO concentration in PC3 cells, suggesting the nitrosylation or transnitrosylation processes enhancement, which are directly related to S-NO binding to proteins, function alterations and cancer cells death. Indeed, these mechanisms directly impacted the cytotoxic effect of ZnO/CisPt NPs, inducing a 30 % higher viability reduction of PC3 cells after NO treatment, along with a higher selectivity index when compared to normal human fibroblasts (FN1).

X‐Ray‐triggered Carbon Monoxide and Manganese Dioxide Generation based on Scintillating Nanoparticles for Cascade Cancer Radiosensitization

AbstractCarbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X‐ray‐triggered carbon monoxide (CO) and manganese dioxide (MnO2) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV‐responsive Mn2(CO)10 is not only indirectly activated to release CO by X‐ray but can also be degraded into MnO2. A high dose of CO can be used as a glycolytic inhibitor for tumor suppression; it will also sensitize tumor cells to radiotherapy. Meanwhile MnO2, as the photolytic byproduct of Mn2(CO)10, has both glutathione (GSH) depletion and Fenton‐like Mn2+ delivery properties to produce highly toxic hydroxyl radical (⋅OH) in tumors. Thus, this strategy can realize X‐ray‐activated CO release, GSH depletion, and ⋅OH generation for cascade cancer radiosensitization. Furthermore, X‐ray‐activated Mn2+ in vivo demonstrates an MRI contrast effect, making it a potential theranostic nanoplatform.

X-Ray-triggered Carbon Monoxide and Manganese Dioxide Generation based on Scintillating Nanoparticles for Cascade Cancer Radiosensitization.

Carbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X-ray-triggered carbon monoxide (CO) and manganese dioxide (MnO2 ) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV-responsive Mn2 (CO)10 is not only indirectly activated to release CO by X-ray but can also be degraded into MnO2 . A high dose of CO can be used as a glycolytic inhibitor for tumor suppression; it will also sensitize tumor cells to radiotherapy. Meanwhile MnO2 , as the photolytic byproduct of Mn2 (CO)10 , has both glutathione (GSH) depletion and Fenton-like Mn2+ delivery properties to produce highly toxic hydroxyl radical (⋅OH) in tumors. Thus, this strategy can realize X-ray-activated CO release, GSH depletion, and ⋅OH generation for cascade cancer radiosensitization. Furthermore, X-ray-activated Mn2+ in vivo demonstrates an MRI contrast effect, making it a potential theranostic nanoplatform.

Nitric oxide alleviates chilling injury in cucumber (Cucumis sativus L.) fruit by regulating membrane lipid and energy metabolism

ABSTRACT Chilling injury is the dominant factor for quality deterioration and marketability suffers of cucumber fruit during low-temperature storage. Nitric oxide (NO) is a kind of endogenous signaling molecule that significantly regulates the abiotic stress response. In the current investigation, the membrane lipid and energy metabolism were investigated after cucumber fruit was exposed to a sodium nitropruside (SNP) solution that acts as a NO donor before being kept at 4°C for 12 days. The results illustrated that SNP treatment reduced chilling injury and lightened the increase in membrane permeability under cold stress, maintaining a better quality. Subsequently, SNP regulated lipid metabolism by reducing the expression of genes encoding PLA, PLD, lipase, and LOX and decreasing the activities. Compared to the control, the SNP-treated fruit exhibited higher ATP and EC (energy charge) levels. Moreover, SNP-treated suppressed the decrease of H+-ATPase, Ca2+-ATPase, SDH, and CCO activity, which is involved in energy metabolism. The above results showed that exogenous nitric oxide might be an effective method to alleviate the chilling damage in postharvest cucumber fruit by modifying membrane lipids and energy metabolism.

C-H Functionalization of Heterocycles with Triplet Carbenes by means of an Unexpected 1,2-Alkyl Radical Migration.

The C-H functionalization of indole heterocycles constitutes a key strategy to leverage the synthesis of endogenous signaling molecules such as tryptamine or tryptophol. Herein, we report on the photocatalytic reaction of ethyl diazoacetate with indole, which shows an unusual solvent dependency. While C2-functionalization occurs under protic conditions, the use of aprotic solvents leads to a complete reversal of selectivity and exclusive C3-functionalization occurs. To rationalize for this unexpected reactivity switch, we have conducted detailed theoretical and experimental studies, which suggest the participation of a triplet carbene intermediate that undergoes initial C2-functionalization. A distinct cationic [1,2]-alkyl radical migration then leads to formation of C3-functionalized indole. We conclude with the application of this photocatalytic reaction to access oxidized tryptophol derivatives including gram-scale synthesis and derivatization reactions.

Cytochrome P450 and Other Drug-Metabolizing Enzymes As Therapeutic Targets.

Cytochrome P450 and other families of drug-metabolizing enzymes are commonly thought of and studied for their ability to metabolize xenobiotics and other foreign entities as they are eliminated from the body. Equally as important, however, is the homeostatic role that many of these enzymes play in maintaining the proper levels of endogenous signaling molecules such as lipids, steroids, and eicosanoids as well as their ability to modulate protein-protein interactions involved in downstream signaling cascades. Throughout the years, many of these endogenous ligands or protein partners of drug-metabolizing enzymes have been associated with a wide range of disease states from cancer to various cardiovascular, neurologic, or inflammatory diseases, prompting an interest in whether modulation of drug-metabolizing enzyme activity could have a subsequent pharmacological impact or lessening of disease severity. Beyond direct regulation of endogenous pathways, drug-metabolizing enzymes have also been proactively targeted for their ability to activate prodrugs with subsequent pharmacological activity or enhance the efficacy of a coadministered drug by inhibiting the metabolism of that drug through a rationally designed drug-drug interaction (i.e., ritonavir and human immunodeficiency virus antiretroviral therapy). The focus of this minireview will be to highlight research aimed at characterizing cytochrome P450 and other drug-metabolizing enzymes as therapeutic targets. Examples of successfully marketed drugs as well as early research efforts will be discussed. Finally, emerging areas of research utilizing typical drug-metabolizing enzymes to impact clinical outcomes will be discussed. SIGNIFICANCE STATEMENT: Although generally thought of for their drug-metabolizing capabilities, enzymes such as the cytochromes P450, glutathione S-transferases, soluble epoxide hydrolases, and others play a significant role in regulating key endogenous pathways, making them potential drug targets. This minireview will cover various efforts over the years to modulate drug-metabolizing enzyme activity toward pharmacological outcomes.

Current Status and Future Prospects of Hydrogen Sulfide Donor‐Based Delivery Systems

AbstractNowadays, hydrogen sulfide (H2S) is regarded as an endogenous gaseous signaling molecule in mammals. As a gas transmitter, it induces important biological effects in many physiological and pathological processes, and possesses great therapeutic potentials. However, this bioactive gas has concentration‐related toxicity, rapid evaporation, and high reactivity, making it inconvenient to use as a therapeutic agent. As an exogenous source of H2S, various H2S donors are developed to release H2S after triggering the response under specific conditions, so as to supplement the level of H2S in the body. Meanwhile, to enhance the therapeutic efficacy and reduce the possible toxicities of the H2S donors, various new materials or methods for H2S delivery are studied, realizing sustained/controlled release profiles as well as achieving triggered, long‐term, local or targeted delivery approaches for the gas. This review summarizes the representative H2S donors and the latest progress of hydrogen sulfide donor‐based delivery systems, and the applications of such delivery systems in a series of target diseases that are suitable and expected to be treated by H2S, in order to provide reference for the design of secure and efficient H2S donor drug delivery system. In addition, the future of this field is also prospected.

A cryptic natural variant allele of BYPASS2 suppresses the bypass1 mutant phenotype.

The Arabidopsis (Arabidopsis thaliana) BYPASS1 (BPS1) gene encodes a protein with no functionally characterized domains, and loss-of-function mutants (e.g. bps1-2 in Col-0) present a severe growth arrest phenotype that is evoked by a root-derived graft-transmissible small molecule that we call dalekin. The root-to-shoot nature of dalekin signaling suggests it could be an endogenous signaling molecule. Here, we report a natural variant screen that allowed us to identify enhancers and suppressors of the bps1-2 mutant phenotype (in Col-0). We identified a strong semi-dominant suppressor in the Apost-1 accession that largely restored shoot development in bps1 and yet continued to overproduce dalekin. Using bulked segregant analysis and allele-specific transgenic complementation, we showed that the suppressor is the Apost-1 allele of a BPS1 paralog, BYPASS2 (BPS2). BPS2 is one of four members of the BPS gene family in Arabidopsis, and phylogenetic analysis demonstrated that the BPS family is conserved in land plants and the four Arabidopsis paralogs are retained duplicates from whole genome duplications. The strong conservation of BPS1 and paralogous proteins throughout land plants, and the similar functions of paralogs in Arabidopsis, suggests that dalekin signaling might be retained across land plants.