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Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel activated by heat, acidity and chemical ligands. While molecular dynamics simulations have shed some light on the cation permeation processes of TRPV1, the mechanisms in the native-state structure under near-physiological conditions remain unestablished. Therefore, the present study conducted molecular dynamics simulations of near-full-length human TRPV1 under a membrane potential of − 100 mV. During permeation events, sodium ions transiently interacted with three binding sites within the channel pore and moved toward the intracellular side. Potential of mean force analyses revealed that sodium ions in the selectivity filter reduced the energy barrier at the hydrophobic gate, facilitating permeation through cooperative interactions. Additionally, mutation of N677, a pre-gate binding site residue, reduced permeation events. Interaction analysis demonstrated that this residue plays an important role in efficient permeation by mediating moderately strong interactions with sodium ions through their coordinated water molecules. These findings highlight the importance of sodium ion accommodation at the selectivity filter and its interaction with N677 for ion permeation through TRPV1. Our data provide new insights into the gating and conduction mechanisms of TRPV1 under near-physiological conditions.

In vertebrates, the extracellular calcium-sensing receptor (CaSR) plays a key role in calcium homeostasis by sensing slight changes in extracellular Ca 2+ . CaSR is also expressed in mammals including rodent taste cells and is involved in sensing kokumi , a rich, savory quality that enhances the intensities of salty, sweet, and umami tastes. In this study, we focused on chicken CaSR (cCaSR) since calcium is an essential nutrient that is necessary for making eggshell and for the extremely rapid initial growth of bones. First we confirmed that cCaSR is expressed in taste cells. Next we cloned the c CaSR gene from kidney and transiently transfected human embryonic kidney 293 T (HEK293T) cells with the recombinant c CaSR , or empty vector and looked for the agonists and allosteric modulators (including kokumi substances) of cCaSR by Ca 2+ imaging. We found that cCaSR was activated by extracellular Ca 2+ and Mg 2+ in a dose dependent manner. Several L-amino acids and kokumi substances such as glutathione enhanced the response of cCaSR. In addition, NPS2143 as a negative allosteric modulator of human CaSR negatively modulated the response of cCaSR. These results suggest that cCaSR can sense extracellular Ca 2+ and Mg 2+ as well as positive and negative allosteric modulators. Taken together, the results imply that CaSR might be a multifunctional receptor for calcium, amino acids, and kokumi substances in chicken. The present finding that functional CaSR is expressed in the chicken oral tissues will allow us to further elucidate the physiological role of CaSR in the chickens' taste sense, and to create new feeds that will contribute to the poultry industry.

Background Early detection of cognitive decline is crucial for preventing progression to dementia. Although sensory impairments, such as olfactory and visual losses, have been identified as risk factors, the roles of gustatory and oral functions remain unclear. This study evaluated the association of taste perception and oral function, particularly oral diadochokinesis (ODK), with cognitive status in older dental outpatients. Methods A total of 58 outpatients aged ≥ 65 years were assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). Oral function was evaluated by measuring ODK, tongue pressure, occlusal force, and masticatory performance. Taste perception was assessed using the whole-mouth method across five basic tastes. Group comparisons were performed between cognitively normal and cognitively impaired participants. Receiver operating characteristic analysis and the Youden index were employed to identify optimal screening combinations. Multivariate logistic regression was used to assess the effects of age and sex. Results Cognitive decline (MoCA-J ≤ 25) was observed in 46.6% of the participants. The ODK performance for /ta/ and /ka/ as well as umami taste recognition, were significantly lower in the cognitively impaired group ( P  < 0.01). The combination of umami hypogeusia and reduced ODK /ka/ <5.7 repetitions/second had the highest diagnostic utility (Positive likelihood ratio, 2.30; specificity, 71.0%). Multivariate analysis confirmed that this combination was a significant predictor of cognitive decline (odds ratio, 4.727; P  = 0.013). Conclusion Umami hypogeusia and reduced ODK performance were significantly associated with cognitive impairment. This simple, noninvasive screening method may facilitate early detection of cognitive decline in routine dental care. Trial registration UMIN Clinical Trials Registry (UMIN-CTR), UMIN000057954. Registered retrospectively on 23 May 2025.

After menopause, a decline in ovarian function leads to various physical and psychological changes, potentially resulting in a range of pathological conditions, including abnormalities in energy metabolism. In recent years, environmental enrichment, which is characterized by positive and comfortable eustress, has been shown to improve various physiological and pathological conditions. This study investigated the effects of environmental factors on energy metabolism in a menopause model using an ovariectomized (OVX) mouse model. Wild-type female mice (8-week-old) were subjected to OVX or a sham operation and maintained under standard condition (SC), enriched environment (EE), or isolated (IS) condition for 4 weeks. OVX led to weight gain and disruption of circadian rhythms, along with changes in various metabolic parameters influenced by differences in housing environments; i.e., EE improved metabolic parameters, but IS deteriorated them. Physical activity and social interaction were factors that determined these differences. Menopause is usually a significant transitional period in a woman’s life, and changes in the social environment during this period can contribute to a diverse range of physical and psychological symptoms. Consequently, when implementing interventions to alleviate menopause-related pathological conditions, not only physical symptoms but also the social context should be carefully considered.

Little is known about the molecular mechanisms underlying drug-induced taste disorders, which can cause malnutrition and reduce quality of life. One of taste disorders is known adverse effects of bisphosphonates, which are administered as anti-osteoporotic drugs. Therefore, the present study evaluated the effects of risedronate (a bisphosphonate) on taste bud cells. Expression analyses revealed that farnesyl diphosphate synthase (FDPS, a key enzyme in the mevalonate pathway) was present in a subset of mouse taste bud and tongue epithelial cells, especially type III sour-sensitive taste cells. Other mevalonate pathway-associated molecules were also detected in mouse taste buds. Behavioral analyses revealed that mice administered risedronate exhibited a significantly enhanced aversion to HCl but not for other basic taste solutions, whereas the taste nerve responses were not affected by risedronate. Additionally, the taste buds of mice administered risedronate exhibited significantly lower mRNA expression of desmoglein-2 , an integral component of desmosomes. Taken together, these findings suggest that risedronate may interact directly with FDPS to inhibit the mevalonate pathway in taste bud and tongue epithelial cells, thereby affecting the expression of desmoglein-2 related with epithelial barrier function, which may lead to alterations in behavioral responses to HCl via somatosensory nerves.

Background/Objectives: Reducing the dietary intake of sugar and salt is considered a key strategy for preventing the onset and progression of lifestyle-related diseases. However, these dietary interventions often compromise the taste of foods, which can reduce patient satisfaction. To address this challenge, we focused on novel food-derived particles (NFPs; patent number P7383867) consisting of lipid, α-cyclodextrin, and xanthan gum formulated as an emulsion with excellent retention and diffusion properties. Methods: Here, we investigated the effects of NFPs on the taste responses of mice. Results: In two-bottle preference tests (n = 4–6), NFPs enhanced preferences for sweet and salty stimuli in behavioral tests (one-way ANOVA, p < 0.05) and increased the responses of the chorda tympani nerve (n = 6–8) to sweet and salty stimuli (two-way ANOVA, main treatment effect p < 0.05), but had no effect on the responses to sour, bitter, or umami stimuli. Conclusion: These findings suggest that NFPs may enhance peripheral taste responses to sweet and salty flavors, thereby helping maintain the palatability of foods with reduced sugar or salt content. Such modulation may have broad applications in improving the acceptability of therapeutic or restricted diets and supporting both disease management and prevention, including lifestyle-related diseases, kidney disease, and other conditions requiring dietary restriction and may offer translational relevance for human dietary interventions.

Drug-induced taste disorders are a serious problem in an aging society. This study investigated the mechanisms underlying taste disturbances induced by diclofenac, a non-steroidal anti-inflammatory drug that reduces pain and inflammation by inhibiting the synthesis of prostaglandins by cyclooxygenase enzymes (COX-1 and COX-2). RT-PCR analyses demonstrated the expression of genes encoding arachidonic acid pathway components such as COX-1, COX-2 and prostaglandin synthases in a subset of mouse taste bud cells. Double-staining immunohistochemistry revealed that COX-1 and cytosolic prostaglandin E synthase (cPGES) were co-expressed with taste receptor type-1 member-3 (T1R3), a sweet/umami receptor component, or gustducin, a bitter/sweet/umami-related G protein, in a subset of taste bud cells. Long-term administration of diclofenac reduced the expression of genes encoding COX-1, gustducin and cPGES in mouse taste buds and suppressed both the behavioral and taste nerve responses to sweet and umami taste stimuli but not to other tastants. Furthermore, diclofenac also suppressed the responses of both mouse and human sweet taste receptors (T1R2/T1R3, expressed in HEK293 cells) to sweet taste stimuli. These results suggest that diclofenac may suppress the activation of sweet and umami taste cells acutely via a direct action on T1R2/T1R3 and chronically via inhibition of the COX/prostaglandin synthase pathway inducing down-regulated expression of sweet/umami responsive components. This dual inhibition mechanism may underlie diclofenac-induced taste alterations in humans.

Taste disorders are common adverse effects of cancer chemotherapy that can reduce quality of life and impair nutritional status. However, the molecular mechanisms underlying chemotherapy-induced taste disorders remain largely unknown. Furthermore, there are no effective preventive measures for chemotherapy-induced taste disorders. We investigated the effects of a combination of three anticancer drugs (TPF: docetaxel, cisplatin and 5-fluorouracil) on the structure and function of mouse taste tissues and examined whether the drinking of ice-cold water after TPF administration would attenuate these effects. TPF administration significantly increased the number of cells expressing apoptotic and proliferative markers. Furthermore, TPF administration significantly reduced the number of cells expressing taste cell markers and the magnitudes of the responses of taste nerves to tastants. The above results suggest that anticancer drug-induced taste dysfunction may be due to a reduction in the number of taste cells expressing taste-related molecules. The suppressive effects of TPF on taste cell marker expression and taste perception were reduced by the drinking of ice-cold water. We speculate that oral cryotherapy with an ice cube might be useful for prophylaxis against anticancer drug-induced taste disorders in humans.

The sweet taste receptor plays an essential role as an energy sensor by detecting carbohydrates. However, the dynamic mechanisms of receptor activation remain unclear. Here, we describe the interactions between the transmembrane domain of the G protein-coupled sweet receptor subunit, TAS1R3, and allosteric modulators. Molecular dynamics simulations reproduced species-specific sensitivity to ligands. We found that a human-specific sweetener, cyclamate, interacted with the mouse receptor as a negative allosteric modulator. Agonist-induced allostery during receptor activation was found to destabilize the intracellular part of the receptor, which potentially interfaces with the Gα subunit, through ionic lock opening. A common human variant (R757C) of the TAS1R3 exhibited a reduced response to sweet taste, in support of our predictions. Furthermore, histidine residues in the binding site acted as pH-sensitive microswitches to modulate the sensitivity to saccharin. This study provides important insights that may facilitate the prediction of dynamic activation mechanisms for other G protein-coupled receptors. Molecular dynamics simulations and functional assays of the transmembrane domain of the sweet taste receptor subunit, TAS1R3 reveal mechanisms on the allostery of sweet receptor activation or inactivation and pH-dependent sensitivity to saccharin.

Background While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. Methods To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. Results The study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. Conclusions We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.