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- | Journal: The emerging roles of hydrogen sulfide in ferroptosis. (Pubmed Central) - Dec 12, 2024
Discovering more reliable and stable novel H2S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H2S, determining their safety, efficacy, and tolerance.
- | Journal: A fluorogenic ROS-triggered hydrogen sulfide donor for alleviating cerebral ischemia-reperfusion injury. (Pubmed Central) - Dec 11, 2024
This compound has demonstrated protective effects against cerebral ischemia-reperfusion (I/R) injury and contributes to the reconstruction of brain structure and function in a rat stroke model (tMCAO/R). As a ROS-responsive, self-reporting, and fluorescent H2S donor, HSDF-NH2 holds considerable promise for the treatment of ischemic diseases beyond stroke.
- | Journal: LIFU-unlocked endogenous H2S generation for enhancing atherosclerosis-specific gas-enzymatic therapy. (Pubmed Central) - Dec 7, 2024
Moreover, the high level of reactive oxygen species in the inflammatory microenvironment of the plaque was mitigated. Overall, LyP-1Lip@HS provides a specific and controlled treatment to prevent oxidative stress, inflammation and lipid metabolism disorders, making it a candidate for AS treatment.
- || Preclinical, Review, Journal: Hydrogen sulfide protects the endometrium in a rat model of type 1 diabetes via modulation of PPAR?/mTOR and Nrf-2/NF-?b pathways. (Pubmed Central) - Dec 3, 2024
NaHS administration reversed the previous conditions while PAG administration got them worse. We concluded that H2S prevented endometrial overgrowth in a rat model of type 1 diabetes through modulation of PPAR?/mTOR and Nrf-2/NF-?B pathways.
- | nitroprusside / Generic mfg.
Journal: CsLCD and CsDCD are involved in nitric oxide-enhanced salt tolerance in cucumber seedlings. (Pubmed Central) - Nov 29, 2024
The results showed that the H2S donor sodium hydrosulfide (NaHS) and the NO donor sodium nitroprusside (SNP) significantly promoted the growth of cucumber seedlings under salt stress...It was further found that SNP enhanced the salt tolerance of CsLCD/CsDCD overexpression lines, but it had no positive effect on the tolerance of CsLCD/CsDCD silencing lines. Therefore, NO might enhance salt tolerance in cucumber seedlings by upregulating the expression of H2S synthesis-related gene CsLCD/CsDCD.
- | doxorubicin hydrochloride / Generic mfg.
Journal: Sydnthiones are versatile bioorthogonal hydrogen sulfide donors. (Pubmed Central) - Nov 28, 2024
Furthermore, we explore the role of H2S, which is released from the sydnthione-DIBAC reaction, on doxorubicin-induced cytotoxicity. The results demonstrate that the viability of H9c2 cells can be significantly improved by pretreating with sydnthione 1b and DIBAC for 6?h prior to exposure to Dox.
- || Review, Journal: Hydrogen Sulfide and Gut Microbiota: Their Synergistic Role in Modulating Sirtuin Activity and Potential Therapeutic Implications for Neurodegenerative Diseases. (Pubmed Central) - Nov 27, 2024
Pharmacological interventions, including H2S donors and sirtuin-activating compounds (STACs), promise to improve these pathways synergistically, providing a novel therapeutic approach for neurodegenerative conditions. This suggests that maintaining gut microbiota diversity and promoting optimal H2S levels can have far-reaching effects on brain health.
- | Journal: The Role of Hydrogen Sulfide in iNOS and APP Localization and Expression in Neurons and Glial Cells Under Traumatic Effects: An Experimental Study with Bioinformatics Analysis and Biomodeling. (Pubmed Central) - Nov 27, 2024
Multiple sequence alignments revealed a high degree of identity among iNOS and APP amino acid residues in various vertebrate and invertebrate species. In the final stage of this study, biomodeling identified unique binding sites for H2S, hydrosulfide anion (HS-), and thiosulfate (S2O32-) with iNOS and APP.
- | Journal: Slow H2S-Releasing Donors and 3D Printable Arrays Cellular Models in Osteo-Differentiation of Mesenchymal Stem Cells for Personalized Therapies. (Pubmed Central) - Nov 27, 2024
This could optimize the BM array to mimic bone defects not only in terms of stiffness, but also in terms of shape. This culture system may enable a rapid screening of antioxidant and anti-inflammatory compounds, facilitating a more personalized approach to regenerative therapy.
- | GYY4137 / National University of Singapore
Preclinical, Journal: H2S-Eluting Hydrogels Promote In Vitro Angiogenesis and Augment In Vivo Ischemic Wound Revascularization. (Pubmed Central) - Nov 27, 2024
H2S donors NaHS and GYY4137 were incorporated into the photosensitive polymer hydrogel gelatin methacrylate and evaluated...A nearly two-fold increase in VEGF mRNA and a four-fold increase in VEGF protein expression were present in wounds from treated animals. Local-regional administration of H2S represents a novel potential therapeutic strategy to promote angiogenesis and improve wound healing after tissue injury or as a result of ischemic disease.
- | sirolimus / Generic mfg.
Preclinical, Journal: Hydrogen Sulfide Ameliorated Endothelial Dysfunction in hyperhomocysteinemia Rats: Mechanism of IRE1?/JNK pathway-mediated Autophagy. (Pubmed Central) - Nov 23, 2024
NaHS supplementation could improve the ACh-induced vasodilation, however it was eliminated by ER stress inducer Tunicamycin (TM) or autophagy inducer Rapamycin...In HUVECs, IRE1?-JNK induced autophagy was involved in HHcy-induced endothelial dysfunction, while NaHS stimulation decreased the protein expression in IRE1?/JNK-autophagy pathway with Hcy incubation. This study might suggest that endothelial dysfunction induced by HHcy might be correlate with IRE1?-JNK-autophagy axis pathway, which was suppressed by exogenous supplementation of H2S donor NaHS.
- || Preclinical, Retrospective data, Review, Journal: A meta-analysis of animal studies evaluating the effect of hydrogen sulfide on ischemic stroke: is the preclinical evidence sufficient to move forward? (Pubmed Central) - Nov 21, 2024
In conclusion, H2S significantly improves structural and functional outcomes in in vivo animal models of ischemic stroke. However, the level of evidence from preclinical studies is not sufficient to proceed to clinical trials due to the low external validity, high risk of bias, and variable design of existing animal studies.
- | Journal: An iridium(III) complex-based luminogenic probe for high-throughput screening of hydrogen sulfide donors in living cells. (Pubmed Central) - Nov 16, 2024
The results were further validated by a commercial assay. We anticipate this high-throughput platform could facilitate the discovery of H2S donors by discriminating the endogenous interfering fluorescence from biological systems.
- | Journal: Involvement of different K+ channel subtypes in hydrogen sulfide-induced vasorelaxation of human internal mammary artery. (Pubmed Central) - Nov 14, 2024
Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx.
- | Journal: Mitochondria-targeted hydrogen sulfide donor reduces atherogenesis by changing macrophage phenotypes and increasing UCP1 expression in vascular smooth muscle cells. (Pubmed Central) - Nov 13, 2024
Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation. Taken together, mitochondrial H2S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.
- | Journal: "One-Stone-Three-Birds" H2S-Photothermal Therapy for Enhanced Thrombolysis and Vascular Healing. (Pubmed Central) - Nov 13, 2024
It also provides sustained H2S release at thrombus sites, contributing to antiplatelet aggregation, reactive oxygen species clearance, and vascular healing. This approach opens up new possibilities for advanced thrombus treatment.
- | GYY4137 / National University of Singapore
Journal: GYY4137, as a slow-releasing H2S donor, ameliorates sodium deoxycholate-induced chronic intestinal barrier injury and gut microbiota dysbiosis. (Pubmed Central) - Nov 7, 2024
The above variations can be reversed with the administration of GYY4137. This study demonstrates that GYY4137 ameliorates sodium deoxycholate-induced chronic intestinal barrier injury by restricting the MLCK-P-MLC2 pathway while elevating the expression level of tight junction proteins, anti-apoptosis and maintaining the microbiome's homeostasis.
- | Journal: Hydrogen Sulfide Delivery System Based on Salting-Out Effect for Enhancing Synergistic Photothermal and Photodynamic Cancer Therapies. (Pubmed Central) - Oct 28, 2024
Elevated H2S levels promoted vasodilation, thereby enhancing the enhanced permeability and retention effect (EPR) of APZ NPs within solid tumors. This strategy effectively alleviated tumor hypoxia by disrupting the mitochondrial respiratory chain and mitigated tumor cell heat tolerance by inhibiting HSP expression.
- | Journal: Exogenous hydrogen sulfide increased Nicotiana tabacum L. resistance against drought by the improved photosynthesis and antioxidant system. (Pubmed Central) - Oct 27, 2024
Overall, our findings provide valuable insights into exogenous NaHS's role in enhancing tobacco drought tolerance. These results lay the foundation for further research utilizing H2S-based treatments to improve crop resilience to water deficit conditions.
- | GYY4137 / National University of Singapore
Journal: Miro2 sulfhydration by CBS/H2S promotes human trophoblast invasion and migration via regulating mitochondria dynamics. (Pubmed Central) - Oct 27, 2024
These results lay the foundation for further research utilizing H2S-based treatments to improve crop resilience to water deficit conditions. GYY4137 (H2S donor, 1?
- | Journal, Stroma: Mesenchymal stromal cells deliver H2S-enhanced Nrf2 via extracellular vesicles to mediate mitochondrial homeostasis for repairing hypoxia-ischemia brain damage. (Pubmed Central) - Oct 21, 2024
Moreover, Nrf2 knockdown in MSCs remarkably impaired H2S-EVs-mediated therapeutic effects on HI mice. In brief, the present study for the first time demonstrated that H2S-modified MSCs significantly accumulated higher Nrf2 in EVs via upregulating PARK7 expression, revealing the mechanism through which antioxidant protein Nrf2 delivered by H2S-EVs protect against mitochondrial dysfunction in HI brain damage.
- | Journal: Insufficient S-sulfhydration of Serum and Glucocorticoid-regulated Kinase 1 Participates in Hyperhomocysteinemia-induced Liver Injury. (Pubmed Central) - Oct 21, 2024
NaHS supplementation mitigates HHcy-induced liver injury by downregulating hepatic autophagy through the S-sulfhydration and activation of SGK1. This post-translational modification by H2S holds promise as a therapeutic approach for HHcy-induced liver injury.
- || Review, Journal: Emerging roles of hydrogen sulfide in colorectal cancer. (Pubmed Central) - Oct 19, 2024
In this review, we thoroughly analyzed the underlying mechanism of action of H2S in CRC from the following aspects: the synthesis and catabolism of H2S in CRC cells and its effect on cell signal transduction pathway; the inhibition effect of exogenous H2S donors with different concentrations on the growth of CRC cells and the underlying mechanism of H2S in garlic and other natural products. Furthermore, we elucidate the expression characteristics of H2S in CRC and construct a comprehensive H2S-related signaling pathway network, which has important basic and practical significance for promoting the clinical research of H2S-related drugs.
- | Preclinical, Journal, IO biomarker: Sodium Hydrosulfide Protects Rats from Hypobaric-Hypoxia-Induced Acute Lung Injury. (Pubmed Central) - Oct 16, 2024
Lastly, Western blot analysis was performed to detect Nrf2, HO-1, P-NF-?B, NF-?B, HIF-1?, Bcl-2, and Bax proteins in lung tissues. Results showed that H2S exhibited significant anti-hypoxic effects in various hypoxia models, effectively modulating blood gas and blood routine indicators in ALI rats, reducing pulmonary edema, improving lung tissue pathology, and alleviating oxidative stress, inflammatory responses, and apoptosis levels.
- | Journal: Regulating H2S release from self-assembled peptide H2S-donor conjugates using cysteine derivatives. (Pubmed Central) - Oct 15, 2024
CD spectroscopy studies monitoring changes in secondary structure over time during H2S release showed similar trends. This study sheds light on the driving forces behind self-assembling nanostructures and offers insights into tuning H2S release through thiol charge state modulation.
- | Journal: Exogenous hydrogen sulfide prevents necroptosis by inhibiting p38MAPK pathway activation in JEG-3 trophoblast cells: A role in preeclampsia. (Pubmed Central) - Oct 2, 2024
We proposed the putative role of necroptosis in early-onset PE, reflected by the blockage of caspase-8/3 and increased expression of RIPA1 and RIPA3 in PE placenta tissues. Furthermore, we demonstrated that exogenous H2S protected cytotrophoblasts against ceramide-induced necroptosis via the p38MAPK pathway.
- | Journal: Reduced Hydrogen Sulfide Bioavailability Contributes to Cardiometabolic Heart Failure with Preserved Ejection Fraction. (Pubmed Central) - Sep 30, 2024
These results suggest H2S dysregulation contributes to HFpEF and increasing H2S bioavailability may represent a novel therapeutic strategy for HFpEF. H2S deficiency is evident in both human HFpEF patients and two clinically relevant models.Reduced H2S production by CSE and increased metabolism by SQR impair H2S bioavailability in HFpEF.Pharmacological H2S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models.Targeting H2S dysregulation presents a novel therapeutic strategy for managing HFpEF.
- | Journal: Hydrogen Sulfide-Releasing Carbonic Anhydrase Inhibitors Effectively Suppress Cancer Cell Growth. (Pubmed Central) - Sep 29, 2024
This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser-CAI hybrids as effective and versatile tools in cancer treatment.
- | Journal: Dynamic Changes and Effects of HS, IGF-1, and GH in the Traumatic Brain Injury. (Pubmed Central) - Sep 26, 2024
Experiments in vitro and in vivo indicated that treatment with NaHS (HS donor), IGF-1, and MR-409 (GHRH agonist) showed protective effects after TBI. This study gives novel information on the functions of HS, IGF-1, and GH in TBI.
- | Journal: Hydrogen sulphide reduces renal ischemia-reperfusion injury by enhancing autophagy and reducing oxidative stress. (Pubmed Central) - Sep 24, 2024
These results indicate that exogenous H2S protects the kidney from IRI through enhancement of autophagy and reduction of oxidative stress. Novel H2S donors could be developed in the treatment of renal IRI.
- || Review, Journal: The functions of hydrogen sulfide on the urogenital system of both males and females: from inception to the present. (Pubmed Central) - Sep 24, 2024
Despite the limited clinical research, studies have demonstrated that applying H2S as an anti-oxidant source could ameliorate adverse effects of different conditions in the urogenital system. More clinical studies are required to confirm the role of this component in clinical settings.
- cisplatin / Generic mfg.
Hydrogen Sulfide Alleviates Cisplatin-Induced AKI by Targeting Pyroptosis (Exhibit Hall, Convention Center) - Sep 23, 2024 - Abstract #KIDNEYWEEK2024KIDNEY_WEEK_3642;
More clinical studies are required to confirm the role of this component in clinical settings. Funding: Government Support
- | GYY4137 / National University of Singapore
Journal: Slow Release of Hydrogen Sulfide in CA1 Hippocampal Neurons Rescues Long-Term Synaptic Plasticity and Associativity in an Amyloid-? Induced Model of Alzheimer's Disease. (Pubmed Central) - Sep 21, 2024
However, application of GYY4137 rescued these conditions in vitro. GYY4137, with its slow release of H2S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD.
- | Journal: Mitochondrial (Pubmed Central) - Sep 20, 2024
In addition, pharmacological disruption of mitochondrial electron transport chain activity, affected stomatal closure produced by flg22, indicating its participation in the stomatal immunity response. Our findings add evidence to the emerging realization that intracellular organelles play a decisive role in orchestrating stomatal signalling and immune responses and suggest that mitochondrial-derived H2S is an important player of the stomatal immunity signalling network.
- | Journal: NO- and H2S- releasing nanomaterials: A crosstalk signaling pathway in cancer. (Pubmed Central) - Sep 10, 2024
This review highlights recent progress in the design of NO and H2S-releasing nanomaterials for anticancer effects. It also explores the interactions between NO and H2S, which are crucial for developing combined therapies and nanomedicines with minimal side effects.
- || tadalafil / Generic mfg.
Clinical, Journal: Prospective, randomized, placebo-controlled, two-arm study to evaluate the efficacy of coadministration of garlic as a hydrogen sulfide donor and tadalafil in patients with erectile dysfunction not responding to tadalafil alone - A pilot study. (Pubmed Central) - Sep 9, 2024
It also explores the interactions between NO and H2S, which are crucial for developing combined therapies and nanomedicines with minimal side effects. Garlic (as an H2S donor) as adjunctive therapy was beneficial in our study participants responding poorly to tadalafil alone.
- | otenaproxesul (ATB-346) / Antibe
Journal: A hydrogen sulphide-releasing non-steroidal anti-inflammatory, ATB-346, significantly attenuates human myometrial contractions. (Pubmed Central) - Sep 4, 2024
ATB-346 exhibits potent tocolytic properties in human myometrium. These exciting results call for further exploration of ATB-346, with a view to repurposing this or similar drugs as novel therapies for delaying preterm labour.
- | Journal, Epigenetic controller: H2S donor SPRC ameliorates cardiac aging by suppression of JMJD3, a histone demethylase. (Pubmed Central) - Sep 1, 2024
SPRC can alleviate cardiac aging by up-regulating CSE and inhibiting endoplasmic reticulum stress pathways, which in turn suppressing JMJD3 expression. JMJD3 plays an essential role in cardiac aging regulation, while SPRC can suppress the expression of JMJD3 by up-regulating CSE, thus delaying cardiac aging, which suggests that SPRC may serve as an aging protective agent and pharmacological targeting of JMJD3 may also be a promising therapeutic approach in age-related heart diseases.
- | Journal: Identification and Validation of the miR/RAS/RUNX2 Autophagy Regulatory Network in AngII-Induced Hypertensive Nephropathy in MPC5 Cells Treated with Hydrogen Sulfide Donors. (Pubmed Central) - Aug 31, 2024
The miR/RAS/RUNX2 autophagy network driven by H2S donors was related to hypertensive nephropathy. H2S donors or miRNAs increased autophagic flux and reduced renal cell injury, which could be a potentially effective medical therapy.
- | Journal: Hydrogen sulphide alleviates root growth inhibition induced by phosphate starvation. (Pubmed Central) - Aug 23, 2024
Consistently, exogenous H2S significantly promoted SQD1 expression levels in roots of Col-0. Taken together, we demonstrate that DES1-mediated H2S participates in alleviating root growth inhibition by promoting the expression of SQD1 under Pi starvation.
- The impact of H2S on the intrinsic excitability of CA1 hippocampal cells (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_418;
Exploring how H2S specifically influences the intrinsic excitability of these neurons could uncover neuroprotective mechanisms beyond simple reactive oxygen species neutralization, delving into the regulation of ion channels and action potentials. This comprehensive approach offers crucial insights into understanding the role of H2S in neuronal health and its potential therapeutic implications.
- | sirolimus / Generic mfg.
Journal: Targeted H2S-Mediated Gas Therapy with pH-Sensitive Release Property for Myocardial Ischemia-Reperfusion Injury by Platelet Membrane. (Pubmed Central) - Aug 20, 2024
This comprehensive approach offers crucial insights into understanding the role of H2S in neuronal health and its potential therapeutic implications. In this study, a biomimetic functional poly(lactic-co-ethanolic acid) nanoparticle (RAPA/JK-1-PLGA@PM) was fabricated by loading rapamycin (RAPA; mTOR inhibitor) and JK-1 (H2S donor) and then coated with PM...Precise delivery and release of H2S attenuated inflammatory response and cardiac damage, promoted cardiac repair, and ameliorated cardiac function proven in MIRI mouse model in
- | Preclinical, Journal: Hydrogen sulfide upregulates hypoxia inducible factors and erythropoietin production in chronic kidney disease induced by 5/6 nephrectomized rats. (Pubmed Central) - Aug 19, 2024
In this study, regional hypoxia and oxidative stress in CKD, may cause the stabilization of the HIFs complexes, although erythropoietin synthesis was not increased due to destructive effects of CKD on the kidney tissues. Administration of NaHS caused up-regulating HIF-erythropoietin signaling pathway.
- | estradiol valerate / Generic mfg.
Preclinical, Journal: Exploring the Therapeutic Potential of Sodium Hydrosulfide in Alleviating Oxidative Stress and Ovarian Dysfunction in a Rat Model of Polycystic Ovary Syndrome. (Pubmed Central) - Aug 19, 2024
PCOS was induced by intramuscular injection of estradiol valerate to induce PCOS in the PCOS and PCOS+NaSH groups...This study showed that the decrease in the activity of H2S-producing enzymes and H2S levels may contribute to oxidative stress in PCOS. Therefore, administration of NaSH as a H2S donor can be considered as a potential therapeutic strategy for PCOS patients.
- || Review, Journal: Role of hydrogen sulfide in health and disease. (Pubmed Central) - Aug 19, 2024
Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options.
- || Review, Journal: Role of hydrogen sulfide in dermatological diseases. (Pubmed Central) - Aug 18, 2024
In addition, therapies based on H2S donors that release H2S are being developed to treat some of these conditions. In the review, we discuss recent advances in the function of H2S in normal skin, the role of altering H2S metabolism in dermatological diseases, and the therapeutic potential of diverse H2S donors for the treatment of dermatological diseases.
- | Journal: Pharmacology of hydrogen sulfide and its donors in cardiometabolic diseases. (Pubmed Central) - Aug 15, 2024
Endogenous H2S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H2S.
- | acetylcysteine solution / Generic mfg.
Journal: Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos. (Pubmed Central) - Aug 1, 2024
Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.
- || Review, Journal: Therapeutic Potential of Hydrogen Sulfide in Ischemia and Reperfusion Injury. (Pubmed Central) - Jul 31, 2024
H2S provides protection against I/R damage by alleviating inflammation and endoplasmic reticulum stress; inhibiting apoptosis, oxidative stress, and mitochondrial autophagy and dysfunction; and regulating microRNAs. Significant advancements in understanding the mechanisms by which H2S reduces I/R damage have led to the development and synthesis of H2S-releasing agents such as diallyl trisulfide-loaded mesoporous silica nanoparticles (DATS-MSN), AP39, zofenopril, and ATB-344, offering a new therapeutic avenue for I/R injury.
- GYY4137 / National University of Singapore
PATHWAY-SPECIFIC PERSULFIDATION OF PROTEINS AND GASEOUS MEDIATORS-SIGNALING CONTRIBUTE TO THE PATHOGENESIS AND PREVENTION OF BARRETT (Poster Stage 5) - Jul 18, 2024 - Abstract #UEGW2024UEGW_3261;
Decreased but stable biosynthesis of H2S reflects the adaptative resistance of the metaplastic cells to GERD. Restored H2S signaling counteracts BE development by interfering in oxidative balance and BE-associated IL-1?, PGE2 and mTOR pathways activation.