Search Results (23)

Ectopic olfactory receptors (ORs) are G protein-coupled chemosensors expressed outside the olfactory epithelium, where they may couple local chemical inputs to cell-specific signaling. The oral cavity is continuously exposed to food-derived compounds, microbial metabolites, volatile organic compounds, and inflammation-associated metabolites, yet the molecular roles of oral ORs remain incompletely defined. This review critically synthesizes current evidence for OR expression and signaling in oral tissues and associated cell populations, with emphasis on ligand–receptor–signaling relationships and disease relevance. Functional OR signaling has been demonstrated in mammalian taste cells, while emerging transcriptomic studies in oral mucosa and transcriptomic/localization studies in the periodontal ligament indicate OR-related programs during tissue-specific or repair-associated states. Candidate metabolic axes, including short-chain fatty acids and lactate linked to OR51E1/OR51E2/Olfr78-related pathways in non-oral models, provide testable mechanistic hypotheses for microbiome–host communication in periodontitis and oral cancer; however, direct causal validation in oral disease models remains limited. We propose an evidence-tiered framework integrating spatial expression mapping, metabolomics-guided deorphanization, receptor perturbation, and longitudinal oral-fluid profiling. Oral ORs should currently be regarded as candidate molecular modulators and components of multimodal biomarker strategies rather than validated standalone diagnostic or therapeutic targets. Full article

Medium- and long-chain fatty acids (MLFAs) are increasingly recognized not only as metabolic substrates but also as precursors of diverse bioactive metabolites generated through host and microbial transformations. Recent advances in analytical chemistry and microbiome research have revealed that gut microorganisms catalyze extensive modifications of dietary MLFAs—producing hydroxylated, conjugated, and keto-fatty acids with enhanced potency toward host receptors. These metabolites exhibit dual activity on classical metabolic receptors, including FFAR1/4 and PPARα/γ, as well as ectopically expressed chemosensory receptors such as olfactory receptors (ORs) and bitter taste receptors (TAS2Rs). This expanded receptor landscape establishes a previously unrecognized chemosensory–metabolic axis that integrates dietary signals, microbial metabolism, and host physiology. Microbial MLFA derivatives such as 10-hydroxyoctadecenoic acid and conjugated linoleic acid regulate incretin secretion, adipogenesis, macrophage polarization, and intestinal barrier function through coordinated activation of FFARs and PPARs. Concurrently, dicarboxylic acids such as azelaic acid activate Olfr544 to modulate lipolysis, ketogenesis, GLP-1 release, and feeding behavior. TAS2Rs also sense oxidized lipids, linking lipid metabolism to immune regulation and enteroendocrine signaling. Collectively, these pathways highlight the microbiome as a metabolic transducer that converts dietary lipids into signaling molecules influencing endocrine, immune, and gut–brain circuits. Understanding the mechanisms governing MLFA bioconversion and receptor engagement provides new opportunities for therapeutic and nutritional intervention. Targeting ORs and TAS2Rs, engineering probiotics to enhance beneficial FA-derived metabolites, and developing receptor-selective synthetic analogs represent promising strategies. Future progress will require integrative approaches combining physiology, biochemistry, metabolomics, and microbial genomics to elucidate receptor specificity and host variability. Full article

Background/Objectives: Asprosin is the endogenous ligand of the olfactory Olfr734 receptor linked to MASLD and glucose metabolism. Despite the involvement of asprosin in these processes, little has been published on the specific role of Olfr734 in liver function. The aim of this work is therefore to study the specific role of the olfactory Olfr734 receptor in MASLD and glucose metabolism. Methods: To achieve this objective, we performed a genetic inhibition specifically to inhibit Olfr734 in the livers of male mice. We then studied the progression of MASLD in DIO mice. In addition, we studied the glucose metabolism in hypoglycemia states and postprandial glucose production in standard diet-fed mice. Finally, analyses of liver biopsies from patients with obesity and with or without T2DM were conducted. Results: We found that hepatic Olfr734 levels vary according to changes in nutritional status and its knockdown effect in the liver is to increase the hepatic lipid content in DIO mice. Our results also showed that OLFR734 expression is involved in the adaptive response in terms of glucose production to nutrient availability. Finally, the hepatic human Olfr734 ortholog named OR4M1 has been observed to be at significantly higher levels in male patients with T2DM. Conclusions: This study increases understanding of the mechanisms by which the modulation of Olfr734 expression affects liver function. Full article

The flavor characteristics, perception, and molecular mechanisms of eight menthol isomers were investigated by sensory analysis combined with computational simulations. The sensory analysis results show significant differences in the odor profiles of the different menthol isomers. Among them, L-menthol shows a pleasant, sweet, and mint-like odor with a distinct freshness and no off-flavors, whereas the remaining seven isomers were interspersed with negative odors (musty, herbal, or earthy aromas). L-menthol and D-menthol had the lowest detection thresholds of 5.166 and 4.734 mg/L, respectively. The molecular docking results of the menthol isomers with olfactory receptors (Olfr874, OR8B8, and OR8B12) indicate that hydrogen bonding and hydrophobic interactions were the key binding forces. The binding energy ranged from −7.3 to −5.1 kcal/mol. Residues His-55 (Olfr874), Thr-56 (Olfr874), Leu-55 (OR8B8), Tyr-94 (OR8B8), Thr-57 (OR8B8), Phe-199 (OR8B12), and Ser-248 (OR8B12) with high frequencies particularly contributed to the recognition of menthol isomers. These findings contribute to a deeper understanding of the olfactory perception mechanism of menthol and provide data support for the development and precise application of minty odorants. Full article

Global pollution stems from the degradation of plastic waste, leading to the generation of microplastics (MPs). While environmental pollutants increase the risk of developing hypertension and kidney disease, the effects of MP exposure on these conditions in children remain unclear. Resveratrol, a phenolic compound known for its antihypertensive and renoprotective properties, has gained attention as a potential nutraceutical. This study investigates the effects of resveratrol on kidney disease and hypertension induced by MP exposure in a juvenile rat model. Three-week-old male Sprague–-Dawley (SD) rats were randomly allocated into four groups (n = 8 per group): a control group, a low-dose MP group (1 mg/L), a high-dose MP group (10 mg/L), and a high-dose MP group receiving resveratrol (50 mg/L). By 9 weeks of age, MP exposure resulted in elevated blood pressure and increased creatinine levels, both of which were mitigated by resveratrol treatment. The hypertension and kidney damage induced by high-dose MP exposure were linked to oxidative stress, which resveratrol effectively prevented. Additionally, resveratrol’s protective effects against hypertension and kidney damage were associated with increased acetic acid levels, reduced renal expression of Olfr78, and decreased expression of various components of the renin-angiotensin system (RAS). Low- and high-dose MP exposure, as well as resveratrol treatment, differentially influence gut microbiota composition. Our findings suggest that targeting oxidative stress, gut microbiota, and the RAS through resveratrol holds therapeutic potential for preventing kidney disease and hypertension associated with MP exposure. However, further research is needed to translate these results into clinical applications. Full article

Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation. Full article

Bisphenol A (BPA), a typical endocrine disruptor, is known to have various adverse effects on the male reproductive system. However, the toxic effects and mechanisms of low-dose BPA have not yet been fully explored. In this study, male Kunming mice were orally administered low-dose BPA (0.03, 0.3 and 3 mg/kg/d) for ten consecutive weeks. Pathological sections of testicular tissue showed no significant morphological differences after BPA exposure. An analysis of the functional parameters of sperm revealed that exposure to low-dose BPA significantly decreased sperm motility, chemotaxis, and the acrosome reaction. An in vitro BPA exposure model combined with an omics data analysis showed that the olfactory receptor-related pathway was significantly enriched after BPA treatment. Subsequent experiments verified the reduced mRNA level of a novel olfactory receptor gene, Olfr25, in vivo and in vitro exposure models. Meanwhile, exposure to low-dose BPA reduced the intracellular calcium ion concentration and the mRNA levels of pore-forming subunits of the CatSper channel in sperm. Importantly, the knockdown of Olfr25 inhibited calcium ion levels and CatSper subunit expression in GC-2 cells. Olfr25 overexpression attenuated the BPA-induced downregulation of CatSper subunit expression in GC-2 cells. These findings indicate that Olfr25 might participate in low-dose BPA-induced sperm dysfunction by affecting the CatSper-Ca²⁺ signaling pathway. This study reveals a new mechanism underlying the effects of low-dose BPA on sperm function and provides a reference for assessing the safety of low-dose BPA exposure. Full article

Polycyclic aromatic hydrocarbon (PAH) pollutants and microbiome products converge on the aryl hydrocarbon receptor (AhR) to redirect selective rapid adherence of isolated bone marrow (BM) cells. In young adult mice, Cyp1b1-deficiency and AhR activation by PAH, particularly when prolonged by Cyp1a1 deletion, produce matching gene stimulations in these BM cells. Vascular expression of Cyp1b1 lowers reactive oxygen species (ROS), suppressing NF-κB/RelA signaling. PAH and allelic selectivity support a non-canonical AhR participation, possibly through RelA. Genes stimulated by Cyp1b1 deficiency were further resolved according to the effects of Cyp1b1 and Cyp1a1 dual deletions (DKO). The adherent BM cells show a cluster of novel stimulations, including select developmental markers; multiple re-purposed olfactory receptors (OLFR); and α-Defensin, a microbial disruptor. Each one connects to an enhanced specific expression of the catalytic RNA Pol2 A subunit, among 12 different subunits. Mesenchymal progenitor BMS2 cells retain these features. Cyp1b1-deficiency removes lymphocytes from adherent assemblies as BM-derived mesenchymal stromal cells (BM-MSC) expand. Cyp1b1 effects were cell-type specific. In vivo, BM-MSC Cyp1b1 expression mediated PAH suppression of lymphocyte progenitors. In vitro, OP9-MSC sustained these progenitors, while Csf1 induced monocyte progenitor expansion to macrophages. Targeted Cyp1b1 deletion (Cdh5-Cre; Cyp1b1^fl/fl) established endothelium control of ROS that directs AhR-mediated suppression of B cell progenitors. Monocyte Cyp1b1 deletion (Lyz2-Cre; Cyp1b1^fl/fl) selectively attenuated M1 polarization of expanded macrophages, but did not enhance effects on basal M2 polarization. Thus, specific sources of Cyp1b1 link to AhR and to an OLFR network to provide BM inflammatory modulation via diverse microbiome products. Full article

Microglial activation often accompanies the plastic changes occurring in the brain of patients with neurodegenerative diseases. A_2A and A₃ adenosine receptors have been proposed as therapeutic targets to combat neurodegeneration. RNAseq was performed using samples isolated from lipopolysaccharide/interferon-γ activated microglia treated with SCH 58261, a selective A_2A receptor antagonist, and with both SCH 58261 and 2-Cl-IB-MECA, a selective A₃ receptor agonist. None of the treatments led to any clear microglial phenotype when gene expression for classical biomarkers of microglial polarization was assessed. However, many of the downregulated genes were directly or indirectly related to immune system-related events. Searching for genes whose expression was both significantly and synergistically affected when treated with the two adenosine receptor ligands, the AC122413.1 and Olfr56 were selected among those that were, respectively, upregulated and downregulated. We therefore propose that the products of these genes, olfactory receptor 56 and T-cell activation GTPase-activating protein 1, deserve attention as potential biomarkers of phenotypes that occur upon microglial activation. Full article

Olfaction is mediated via olfactory receptors (ORs) that are expressed on the cilia membrane of olfactory sensory neurons in the olfactory epithelium. The functional expression of most ORs requires the assistance of receptor-transporting proteins (RTPs). We examined the interactome of RTP1S and OR via proximity biotinylation. Deubiquitinating protein VCIP135, the F-actin-capping protein sub-unit alpha-2, and insulin-like growth factor 2 mRNA-binding protein 2 were biotinylated via AirID fused with OR, RTP1S-AirID biotinylated heat shock protein A6 (HSPA6), and double-stranded RNA-binding protein Staufen homolog 2 (STAU2). Co-expression of HSPA6 partially enhanced the surface expression of Olfr544. The surface expression of Olfr544 increased by 50–80%. This effect was also observed when RTP1S was co-expressed. Almost identical results were obtained from the co-expression of STAU2. The interactions of HSPA6 and STAU2 with RTP1S were examined using a NanoBit assay. The results show that the RTP1S N-terminus interacted with the C-terminal domain of HSP6A and the N-terminal domain of STAU2. In contrast, OR did not significantly interact with STAU2 and HSPA6. Thus, HSP6A and STAU2 appear to be involved in the process of OR traffic through interaction with RTP1S. Full article

The role of short-chain fatty acids (SCFAs) in the brain on the developmental programming of hypertension is poorly understood. The present study explored dysregulated tissue levels of SCFAs and expression of SCFA-sensing receptors in the hypothalamic paraventricular nucleus (PVN), a key forebrain region engaged in neural regulation of blood pressure of offspring to maternal high fructose diet (HFD) exposure. We further investigated the engagement of SCFA-sensing receptors in PVN in the beneficial effects of -biotics (prebiotic, probiotic, synbiotic, and postbiotic) on programmed hypertension. Maternal HFD during gestation and lactation significantly reduced circulating butyrate, along with decreased tissue level of butyrate and increased expression of SCFA-sensing receptors, GPR41 and olfr78, and tissue oxidative stress and neuroinflammation in PVN of HFD offspring that were rectified by oral supplement with -biotics. Gene silencing of GPR41 or olfr78 mRNA in PVN also protected adult HFD offspring from programmed hypertension and alleviated the induced oxidative stress and inflammation in PVN. In addition, oral supplement with postbiotic butyrate restored tissue butyrate levels, rectified expressions of GPR41 and olfr78 in PVN, and protected against programmed hypertension in adult HFD offspring. These data suggest that alterations in tissue butyrate level, expression of GPR41 and olfr78, and activation of SCFA-sensing receptor-dependent tissue oxidative stress and neuroinflammation in PVN could be novel mechanisms that underlie hypertension programmed by maternal HFD exposure in adult offspring. Furthermore, oral -biotics supplementation may exert beneficial effects on hypertension of developmental origin by targeting dysfunctional SCFA-sensing receptors in PVN to exert antioxidant and anti-inflammatory actions in the brain. Full article

Pluripotency maintenance and exit in embryonic stem cells is a focal topic in stem cell biology. However, the effects of screening under very stringent culture conditions (e.g., differentiation medium, no leukemia inhibitory factor, no chemical inhibitors such as PD0325901 and CHIR99021, and no feeder cells) and of prolonging culture for key factors that regulate pluripotency exit, have not yet been reported. Here, we used a genome-wide CRISPR library to perform such a screen in mouse embryonic stem cells. Naïve NANOG-GFP mESCs were first transfected with a mouse genome-wide CRISPR knockout library to obtain a mutant mESCs library, followed by screening for two months in a strict N2B27 differentiation medium. The clones that survived our stringent screening were analyzed to identify the inserted sgRNAs. In addition to identifying the enriched genes that were reported in previous studies (Socs3, Tsc1, Trp53, Nf2, Tcf7l1, Csnk1a1, and Dhx30), we found 17 unreported genes, among which Zfp771 and Olfr769 appeared to be involved in pluripotency exit. Furthermore, Zfp771 knockout ESCs showed a differentiation delay in embryonic chimera experiments, indicating Zfp771 played an important role in pluripotency exit. Our results show that stringent screening with the CRISPR library can reveal key regulators of pluripotency exit. Full article

Some short-chain fatty acids with a pungent or unpleasant odor are important components of human body odor. These malodors severely threaten human health. The antagonists of malodors would help to improve odor perception by affecting the interaction between odors and their receptors. However, the traditional odor detection and analysis methods, such as MOS, electrochemical, conductive polymer gas sensors, or chromatography-mass spectrometry are not suitable for screening the antagonists since they are unable to detect the ligand efficacy after odor-receptor binding. In this study, RT-PCR results showed that HL-1 cardiomyocytes endogenously express the olfactory receptor 558 (Olfr558) which can be activated by several malodorous short-chain fatty acids. Therefore, an in vitro HL-1 cardiomyocyte-based olfactory biosensor (HCBO-biosensor) was developed by combining cardiomyocytes and microelectrode array (MEA) chips for screening the potential antagonists of the Olfr558. Firstly, it showed that the biosensor specifically responded to ligands of Olfr558 through odor stimulation experiments. Then, an odor response model of HL-1 cardiomyocytes was constructed by a ligand of Olfr558 (isovaleric acid). The response feature of the in vitro HCBO-biosensor to individual odors and mixtures with a potential antagonist (citral or β-damascenone) were extracted and compared. Finally, the Olfr558-inhibited efficiency was indirectly detected by comparing the half-maximal inhibitory concentration of isovaleric acid. The results showed that β-damascenone greatly inhibited Olfr558 while citral showed no significant inhibitory effect. In conclusion, we built a novel screening method for the antagonists of Olfr558 based on HL-1 cardiomyocytes and the MEA chip which will assist odor-related companies to develop novel antagonists of Olfr558. Full article

Despite recent advances in pharma-nutritional management, chronic kidney disease (CKD) remains an increasingly prevalent disorder. Resveratrol, a pleiotropic phytochemical, has been found to reduce the risk for several chronic diseases. Considering the low bioavailability of resveratrol, we recently synthesized resveratrol butyrate ester (RBE) via the esterification of resveratrol with butyrate. The aim of this study was to examine the effectiveness of RBE as regards protection from hypertension and kidney damage and explore the underlying mechanisms using a young rat adenine-induced CKD model. Three-week-old male Sprague Dawley rats received regular or 0.5% adenine chow for three weeks. Three groups of adenine-fed CKD rats (N = 8/group) received resveratrol (50 mg/L), or a low dose (25 mg/L) or high dose (50 mg/L) of RBE in drinking water from week 6 to week 12. As compared with the controls, adenine-treated rats had markedly increased creatinine levels and blood pressure, which was associated with renal hypertrophy and decreased creatinine clearance. Treatment with resveratrol or a low or high dose of RBE, similarly protected adenine-fed rats against hypertension and kidney damage. CKD-induced hypertension is associated with an altered gut microbiota profile, dysregulated renal short chain fatty acid (SCFA) receptor expression, activation of the aryl hydrocarbon receptor (AhR) signaling pathway, and reduced nitric oxide bioavailability. We found gut microbiota compositions were shaped differentially by resveratrol and RBE treatment in adenine-treated CKD rats. The beneficial effect of high-dose RBE was associated with reduced renal expression of SCFA G protein-coupled receptor 41 (GPR41) and olfactory receptor 78 (Olfr78), antagonizing the AhR signaling pathway, and increased abundance of beneficial bacteria such as genera Akkermansia, Blautia, and Enterococcus. Our study provided the first evidence documenting RBE as a novel phytochemical supplement targeting the gut–kidney axis to protect against adenine-induced kidney damage and hypertension. Full article

(1) Background: Hormone-dependent events that occur throughout spermatogenesis during postnatal testis maturation are significant for adult male fertility. Any disturbances in the T/DHT ratio in male progeny born from females fertilized by finasteride-treated male rats (F0:Fin) can result in the impairment of testicular physiology. The goal of this work was to profile the testicular transcriptome in the male filial generation (F1:Fin) from paternal F0:Fin rats. (2) Methods: The subject material for the study were testis from immature and mature male rats born from females fertilized by finasteride-treated rats. Testicular tissues from the offspring were used in microarray analyses. (3) Results: The top 10 genes having the highest and lowest fold change values were mainly those that encoded odoriferous (Olfr: 31, 331, 365, 633, 774, 814, 890, 935, 1109, 1112, 1173, 1251, 1259, 1253, 1383) and vomeronasal (Vmn1r: 50, 103, 210, 211; Vmn2r: 3, 23, 99) receptors and RIKEN cDNA 5430402E10, also known as odorant-binding protein. (4) Conclusions: Finasteride treatment of male adult rats may cause changes in the testicular transcriptome of their male offspring, leading to a defective function of spermatozoa in response to odorant-like signals, which are recently more and more often noticed as significant players in male fertility. Full article