Sato T, Isagawa T, Sugiura Y
… +23 more, Sawaki D, Nakagama Y, Kuchimaru T, Minatsuki S, Sato S, Ono K, Chuluun-Erdene A, Semba H, Ito M, Kawakami T, Tanaka R, Sakamoto M, Asagiri M, Harada H, Stockmann C, Yonezawa T, Hirota Y, Kido Y, Otsu K, Kohro T, Manabe I, Komuro I, Takeda N
J Pharmacol Sci
· 2026 Apr · PMID 41795960
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Full text
SGLT2 inhibitors are widely used to treat patients with chronic heart failure, and several studies have shown that the efficacy of SGLT2 inhibitors also extends to acute heart failure. However, the mechanisms remain unkn...SGLT2 inhibitors are widely used to treat patients with chronic heart failure, and several studies have shown that the efficacy of SGLT2 inhibitors also extends to acute heart failure. However, the mechanisms remain unknown. Here, using knockout mice and pharmacological approaches, we show that short-term SGLT2 inhibitor treatment activates hypoxia-inducible factor-1α (HIF-1α) signaling in cardiomyocytes, and further pharmacological studies raised the possibility that this effect is mediated by ketone body-derived succinate. One week of Dapagliflozin administration upregulated the expression of HIF-1α target genes, and the effect was abolished in cardiomyocyte-specific HIF-1α knockout mice. Metabolome analysis and enzyme-based assays revealed that, following one week of short-term Dapagliflozin treatment, ketone body levels in the heart increased, leading to an accumulation of succinate, which may act as a signaling metabolite that stabilizes HIF-1α. Administration of pimozide, which is a succinyl-CoA:3-ketoacid CoA transferase (SCOT) inhibitor that inhibits ketone body metabolism, abolished dapagliflozin-elicited activation of HIF-1α signaling. These results, although not conclusive, can be plausibly explained if short-term Dapagliflozin treatment activates HIF-1α signaling in cardiomyocytes via ketone body-derived succinate. Our study raises the possibility that HIF-1α plays a role in the effects of SGLT2 inhibitors and highlights HIF-1α as a speculative target for future studies.
BACKGROUND: Traumatic brain injury (TBI) ranks among the top contributors to neurological impairments worldwide, with Golgi stress implicated in neuronal injury. This study investigated the neuroprotective effects of fer...BACKGROUND: Traumatic brain injury (TBI) ranks among the top contributors to neurological impairments worldwide, with Golgi stress implicated in neuronal injury. This study investigated the neuroprotective effects of ferulic acid (FA) in TBI by regulating Golgi stress. METHODS: HT-22 and NSC34 cells were exposed to HO to induce a neuronal injury model. Protein expression were evaluated via Western blot and immunofluorescence. Cell viability and apoptosis were quantified using CCK-8 assay and TUNEL staining, respectively. The interactions between Src, SKP2, and Nrf2 were detected by Co-IP assay. RESULTS: FA treatment reduced LDH release, as well as repressed Golgi stress and apoptosis by HO-induced in HT-22 and NSC34 cells. Mechanistically, FA inhibited Src-mediated phosphorylation of SKP2 at Y131, preventing SKP2-mediated Nrf2 ubiquitination and degradation. Moreover, FA activated the antioxidative Nrf2/HO-1 pathway, alleviating HO-induced Golgi stress and neuronal injury. CONCLUSION: FA reduced neuronal Golgi stress in HO-treated neuronal cells by restoring the Nrf2/HO-1 signaling through inhibiting Src-mediated SKP2 phosphorylation. These findings indicate that FA is a potential neuroprotective agent.
Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavo...Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavonoid with neuroprotective and vascular benefits, has limited bioavailability due to poor water solubility. Although enzymatic glycosylation improves its solubility, it contains multiple compounds with differing numbers of sugar units and is not a single compound. To address this, EubioQuercetin®, a novel water-soluble rutin (wsRutin) formulation, was developed using L-arginine and ascorbic acid, without enzymatic processing. Here, we evaluated the neuroprotective effects of quercetin and isorhamnetin, the major metabolites of rutin, and compared the cognitive effects of rutin suspension and wsRutin solution in mice. Quercetin and isorhamnetin suppressed glutamate-, menadione- and HO-induced cell death and glutamate-induced reactive oxygen species production in HT22 mouse hippocampal cells. The oral administration of wsRutin solution significantly improved scopolamine- and MK-801-induced cognitive impairment in the novel object recognition test. wsRutin solution also enhanced the expression of brain-derived neurotrophic factor (BDNF)-related proteins in the hippocampus, including BDNF pro-peptide, p-TrkB, p-CREB, PKCα, NR1, HO-1 and NQO1. These findings suggest that wsRutin improves cognitive function via activating BDNF/TrkB signaling or antioxidant mechanism and may represent a preventive agent for dementia.
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling. This remodeling is primarily caused by abnormal proliferation of pulmonary arterial smoo...Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling. This remodeling is primarily caused by abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs), facilitated by perivascular inflammatory macrophages. Fingolimod, an immunosuppressive drug approved for multiple sclerosis, modulates sphingosine-1-phosphate (S1P) signaling. In the present study, the effects of fingolimod on the excessive proliferation of PASMCs from patients with idiopathic PAH (IPAH), the viability of human monocyte-derived macrophages, and pulmonary vascular remodeling and survival in monocrotaline (MCT)-induced PAH rats were examined. Fingolimod inhibited the abnormal proliferation of IPAH-PASMCs (IC = 3.8 μM) and reduced the viability of CD163-positive macrophages. S1P receptor 3, predominantly expressed in PASMCs, was upregulated in IPAH-PASMCs and in pulmonary arterial smooth muscle tissues from MCT-PAH rats. Administration of fingolimod (1 mg/kg/day) decreased perivascular accumulation of CD163-positive macrophages, lowered right ventricular systolic pressure, and attenuated pulmonary vascular remodeling in MCT-PAH rats. Kaplan-Meier survival analysis demonstrated that fingolimod prolonged survival. Collectively, these findings indicate that fingolimod ameliorates pulmonary vascular remodeling by inhibiting abnormal PASMC proliferation and CD163-positive macrophage viability, thereby improving survival in experimental PAH rats. Targeting the S1P signaling pathway with fingolimod may represent a promising repositioning strategy for PAH therapy.
Accurate assessment of animal behavior is limited by manual video observation. Here, we demonstrate that deep learning-based analysis of multi-site electromyograms enables classification of behavioral states. Electromyog...Accurate assessment of animal behavior is limited by manual video observation. Here, we demonstrate that deep learning-based analysis of multi-site electromyograms enables classification of behavioral states. Electromyograms were recorded from five muscles in the limbs and neck of mice alongside video monitoring to establish ground-truth labels (i.e., walking, grooming, rearing). A custom convolutional neural network was trained on electromyogram segments. Our model achieved robust classification accuracy, demonstrating the effective detection of behavioral patterns. Our electromyogram-based model provides an objective, automated, and scalable framework for behavioral classification, which can be seamlessly integrated with video monitoring workflows.
Ischemia-reperfusion (I/R) following reperfusion therapy for ischemic heart disease is a driver of adverse cardiac remodeling and eventual heart failure. We investigated the therapeutic potential of 2,5-dimethylelcelecox...Ischemia-reperfusion (I/R) following reperfusion therapy for ischemic heart disease is a driver of adverse cardiac remodeling and eventual heart failure. We investigated the therapeutic potential of 2,5-dimethylelcelecoxib (DM-C) to prevent cardiac remodeling in a mouse model of cardiac I/R injury. Male C57BL/6 mice were subjected to 30 min of left anterior descending coronary artery ligation followed by reperfusion. Immediately upon awakening, mice received a single oral administration of either vehicle or 150 mg/kg DM-C. This was followed by dietary administration of vehicle or 1000 ppm DM-C. Post-reperfusion administration of DM-C significantly attenuated cardiac remodeling, as demonstrated by improved left ventricular function and reduced cardiac fibrosis and hypertrophy. Mechanistically, DM-C transiently increased the accumulation of CD68-positive macrophages in the injured myocardium, potentially facilitating resolution of inflammation. DM-C also suppressed α-smooth muscle actin-expressing myofibroblast accumulation and downregulated extracellular matrix components. While DM-C treatment tended to mitigate I/R-induced mitochondrial structural destruction and dysfunction, it did not directly improve mitochondrial function in in vitro hypoxia-reoxygenation model. These findings suggest that DM-C suppresses post-I/R cardiac remodeling and dysfunction by modulating inflammatory and fibrotic responses and indirectly supporting mitochondrial integrity, underscoring its potential as a therapeutic agent for I/R injury-induced heart failure.
Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality and limited treatment options. Brain tissue injury featured by neuroinflammation and axonal damage plays a pivotal role in poor outcome....Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality and limited treatment options. Brain tissue injury featured by neuroinflammation and axonal damage plays a pivotal role in poor outcome. S-allyl-l-cysteine, a garlic-derived amino acid derivative, possesses antioxidant and anti-inflammatory properties and has been shown to afford neuroprotection in ischemic stroke models. In the present study, ICH was induced in male ICR mice by collagenase injection into the striatum. When S-allyl-l-cysteine (300 or 600 mg/kg) was administered intraperitoneally at 1 h before and 3, 27, and 51 h after ICH induction, the compound alleviated ICH-induced motor deficits as revealed by limb-placing and beam-walking tests in a dose-dependent manner. At 600 mg/kg, S-allyl-l-cysteine significantly suppressed hematoma-associated microglial/macrophage activation and neuronal loss, reduced axonal fragmentation in the internal capsule and decreased brain lesion volume, while having no effect on several other events such as astrocyte activation, nitrosative stress, or hemorrhage volume. S-allyl-l-cysteine also tended to inhibit neutrophil infiltration but did not alter expression of IL-6 and CXCL2 mRNAs. Overall, S-allyl-l-cysteine ameliorated prognosis of ICH, and the underlying mechanisms may involve suppression of microglial/macrophage activation and neuronal loss, attenuation of axonal injury, and reduction of brain lesion volume.
Owaki A, Kaseda S, Tanigawa S
… +17 more, Miike K, Sannomiya Y, Tsuhako H, Sato R, Mizumoto K, Horizono J, Kumabe R, Tokuyasu M, Fujiwara Y, Takeo T, Araki K, Davenport B, Lennon R, Shuto T, Nishinakamura R, Suico MA, Kai H
Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs...Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs filtration and triggers inflammation, fibrosis, and eventual kidney failure. Because disease progression is irreversible, identifying early molecular changes is essential for understanding disease onset. We performed glomerular single-cell RNA sequencing (scRNA-seq) in a Col4a5 G5X Alport mouse model at 5 weeks of age, prior to detectable proteinuria or GBM/podocyte abnormalities (pre-onset), and at 8 weeks, when mild proteinuria and structural defects emerged. Despite the early stage, scRNA-seq revealed widespread transcriptional alterations, most prominently in podocytes. Among genes upregulated at both time points, we identified Tumor Necrosis Factor Superfamily Member 15 (Tnfsf15), previously associated with kidney disease susceptibility but with unclear function. To determine its role in Alport syndrome, we generated Tnfsf15-deficient Alport mice. Tnfsf15 homozygous knockout mice exhibited increased proteinuria and exacerbated glomerular injury compared with Tnfsf15(+/+) Alport mice during early disease. These findings support a protective role for Tnfsf15 in the early stages of Alport syndrome, mitigating proteinuria and limiting glomerular injury.
Mirkatouli FB, Tao Y, Enkhbaatar U
… +15 more, Yamanaka R, Miura K, Yamasaki N, Ogata S, Hosomi N, Mori A, Yasuda T, Matsuda M, Sannomiya Y, Nabe T, Numata T, Sugiura K, Kitamura N, Gotoh M, Kaminuma O
Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17 cells are implicated in chronic AD, yet its efficacy against Th17-dependent pa...Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17 cells are implicated in chronic AD, yet its efficacy against Th17-dependent pathology remains unclear. We investigated the effects of tacrolimus using a murine model of Th17-mediated allergic skin inflammation. In CD4 T cells from DO11.10/Rag2 mice, which express ovalbumin (OVA)-specific T cell receptor, tacrolimus differentially suppressed stimulation-induced cytokine expression by Th2 cells. At similar concentrations, tacrolimus suppressed Il21, but not Il17a or Il22, expression in Th17 cells. Subcutaneous OVA challenge elicited ear thickening in BALB/c mice after adoptive transfer of Th2 or Th17 cells, with a stronger response in Th17-transferred mice, but less than OVA-immunized controls. Topical tacrolimus reduced Th17-mediated ear swelling, corroborated by histopathology. In Th2-transferred mice, tacrolimus tended to reduce early skin thickening (day 3) but did not affect late responses (day 7). In Th17-transferred mice, tacrolimus significantly reduced allergen-specific T-cell accumulation in OVA-injected skin and tended to reduce Il21 expression, whereas Th2-cell accumulation and cytokine expression were unaffected. Tacrolimus exerts stronger inhibitory effects on Th17- than Th2-driven responses in this model, suggesting that suppression of Th17 pathways may contribute to its therapeutic benefit in AD.
Hypertensive disorders of pregnancy (HDPs) are serious complications that pose significant risks to both maternal and fetal health. In HDP, placental circulatory impairment is generally attributed to defective differenti...Hypertensive disorders of pregnancy (HDPs) are serious complications that pose significant risks to both maternal and fetal health. In HDP, placental circulatory impairment is generally attributed to defective differentiation and invasion of the human extravillous trophoblasts (EVTs). Our previous RNA-seq analysis of placentas from early-onset HDP patients revealed decreased expression of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine biosynthesis. DHODH inhibition is hypothesized to induce mitochondrial dysfunction. In this study, we investigated whether DHODH inhibition affects mitochondrial homeostasis and invasive capacity in EVT cell line. Selective DHODH inhibitors resulted in decreased mitochondrial membrane potential, upregulation of mitochondrial degradation factors, and mitochondrial fragmentation. Inhibition of DHODH or mitochondrial complexes I, II, and IV led to impaired cell invasion, accompanied by an increase in SA-β-gal-positive senescent cells. Treatment with quercetin or riboflavin, enhancers of mitochondrial ATP functions, partially restored invasive capacity and reduced senescent cell accumulation under mitochondrial stress conditions. Thus, DHODH inhibition in EVTs induces cellular senescence and diminished capacity for invasion. Mitochondrial activators such as quercetin and riboflavin may hold therapeutic promise for ameliorating the pathology of HDPs.
Magnesium (Mg) is an essential cation critical for neuronal and cardiac homeostasis, principally by modulating N-methyl-d-aspartate (NMDA) receptor function. While magnesium deficiency (MgD) is known to impair memory and...Magnesium (Mg) is an essential cation critical for neuronal and cardiac homeostasis, principally by modulating N-methyl-d-aspartate (NMDA) receptor function. While magnesium deficiency (MgD) is known to impair memory and autonomic function, the systemic interplay remains poorly understood. As a preliminary step to investigating neural activity during memory tasks, this study investigated the effects of 3 weeks of MgD on neural activity patterns and cardiac function in rats. Simultaneous electrophysiological recordings from the dorsal hippocampus and medial prefrontal cortex, along with electrocardiogram and electromyogram (EMG) monitoring, revealed that MgD selectively altered neural oscillations without affecting cardiac function or sleep architecture. Notably, frequency-specific changes in local field potentials (LFPs) were most pronounced during quiet wakefulness under dark conditions. This excessive enhancement of gamma wave activity may contribute to memory impairment. This 3-week deficiency was characterized by altered neural excitability, which could lead to cognitive impairment and partial cardiac arrhythmia. Our findings demonstrate that spontaneous neural activity is altered even in the 3-week of MgD and support a model in which the deficiency progressively disrupts physiological regulation.
Appropriate processing of aversive information is essential for survival. We previously demonstrated that serotonin neurons in the median raphe nucleus (MRN) play a key role in such processing; however, MRN responses to...Appropriate processing of aversive information is essential for survival. We previously demonstrated that serotonin neurons in the median raphe nucleus (MRN) play a key role in such processing; however, MRN responses to predictive cues of aversive events remain unclear. Here, we found that the MRN serotonin neurons were activated by aversive air-puff stimuli but not by auditory cues predicting the air puff. Moreover, delayed activation of the ventral hippocampus-projecting MRN serotonin neurons, together with subsequent 5-HT receptor signaling, was required for aversion. These findings shed light on the roles of the hippocampus-projecting MRN serotonin neurons and elucidate their molecular mechanisms.
Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibito...Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ-induced PD-L1 mRNA and protein expression, as well as activation of PD-L1-related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8 T-cells, TNBC cells were more susceptible to T-cell-mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ-mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.
PURPOSE: Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in...PURPOSE: Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in hepatic ureagenesis for water conservation to the association between improvement of steatotic liver disease and the energy-consuming nature of hepatic ureagenesis. GENERAL METHODS: ob/ob mice fed a high-fat diet without carbohydrate restriction were administered luseogliflozin, an SGLT2 inhibitor, for eight weeks. FINDINGS: Luseogliflozin significantly decreased the liver weight, plasma aspartate aminotransferase and alanine aminotransferase levels, and fat content in mice with enhanced glycosuria (H-GlcV group). The ratio of urinary urea excretion decreased as a substitute for increased glucose excretion in the H-GlcV group. Luseogliflozin significantly increased liver urea content and tended to increase malate dehydrogenase (MDH)-1 activity. Liver MDH-1 activity was significantly positively correlated with liver urea content, suggesting that MDH-1-induced amino acid recruitment from the tricarboxylic acid cycle to the urea cycle may contribute to enhanced ureagenesis. In addition, liver weight was significantly negatively correlated with the liver urea content. CONCLUSIONS: Our data suggest that enhanced hepatic ureagenesis as a compensatory water conservation mechanism for glycosuria-induced fluid loss may be associated with amelioration of steatotic liver disease in SGLT2 inhibitor-treated ob/ob mice.
Ono A, Miyaoka T, Koan D
… +14 more, Jin Z, Chen L, Hayata-Takano A, Asano S, Yokoyama R, Ishimoto K, Hino N, Harada A, Nakazawa T, Hashimoto H, Waschek JA, Nakagawa S, Tanimoto K, Ago Y
Accumulating evidence suggests that microduplications of the VIPR2 gene are strongly associated with schizophrenia. VIPR2 encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of V...Accumulating evidence suggests that microduplications of the VIPR2 gene are strongly associated with schizophrenia. VIPR2 encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of VPAC2 overexpression with respect to schizophrenia remain unclear. Therefore, we aimed to determine the effects of human VPAC2 overexpression in neurons on cognition-related behaviors and prefrontal cortex dendritic morphology in mice. We crossed a Tau-Cre mouse line, which targets neuronal recombinase activity, with a newly generated double transgenic mouse line containing tetracycline-responsive element-human VPAC2-IRES-mCherry and ROSA:LNL:tTA. Immunohistochemical and Western blot analyses revealed that VPAC2 was overexpressed in neurons throughout the brain. Mice that overexpressed VPAC2 showed impaired performance in the novel object recognition test. Furthermore, VPAC2-overexpressing mice exhibited significant reductions in brain weight and the length, branch number, and complexity of arborization of prefrontal cortex pyramidal neuron dendrites. RNA sequencing analysis revealed that VPAC2 overexpression may affect signaling pathways involved in regulating stem cell pluripotency, cell cycle, and actin cytoskeleton. Quantitative PCR analysis also confirmed increased expression of the X-linked lymphocyte-regulated 3B gene, which regulates dendritic morphogenesis and spine assembly. These results suggest that VPAC2 overexpression in neurons has a detrimental effect on brain development, which leads to impaired neural circuitry and cognitive function.
Pericytes are perivascular cells that contribute to maintaining vascular integrity and central nervous system homeostasis. β-microglobulin (B2M) is a component of the major histocompatibility complex class I molecule; it...Pericytes are perivascular cells that contribute to maintaining vascular integrity and central nervous system homeostasis. β-microglobulin (B2M) is a component of the major histocompatibility complex class I molecule; it has recently been implicated in age-related and injury-associated inflammation. Here, we investigated the phenotypic and transcriptomic effects of B2M on mouse brain pericytes in vitro. B2M treatment increased Bromodeoxyuridine (BrdU) incorporation into the cultured pericytes as well as the number of Ki67-positive pericytes. Morphologically, B2M promoted pericyte extension. Toll-like receptor 4 (TLR4), one of the key molecules that regulates B2M function, was involved in the B2M-dependent pericyte proliferation. These findings were consistent with RNA-seq results showing differential expression of genes related to cell proliferation. These results suggest that B2M directly acts on pericytes and regulates part of their functional responses through TLR4 signaling.
Essential oils have long been recognized for their therapeutic potential, with growing interest in their molecular mechanisms of action in neurological health. Among emerging targets, polymodal Ca-permeable Transient Rec...Essential oils have long been recognized for their therapeutic potential, with growing interest in their molecular mechanisms of action in neurological health. Among emerging targets, polymodal Ca-permeable Transient Receptor Potential (TRP) cation channels have gained particular attention for their roles in neuronal signaling, synaptic plasticity, and modulation of cognitive, neurodegenerative, and psychological disorders. This review explores the ability of essential oil constituents to modulate TRP channels. The major channels to be discussed here include TRPV1, TRPM8, and TRPA1 and some other TRPVs and TRPMs. Some TRPC members have also been reviewed, albeit more briefly. Key bioactive compounds - including menthol, linalool, and eugenol - are highlighted for their ability to interact with TRP channels, while influencing neurophysiological pathways related to learning, memory, neuroinflammation, and emotional regulation. Preclinical evidence suggests these interactions may offer neuroprotective, anxiolytic, and antidepressant effects. However, challenges such as bioavailability, standardization, and safety remain barriers to clinical translation. This review underscores the therapeutic promise of essential oil constituents as modulators of TRP channels and outlines future directions for their integration into neurotherapeutic strategies.
Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as...Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are on the rise in super-aging societies. However, the mechanisms underlying the aggregation and propagation of prion-like proteins such as α-synuclein and Tau that contribute to the pathogenesis of neurodegeneration remain poorly understood. Although prion-like proteins are known to undergo liquid-liquid phase separation (LLPS) followed by a sol-gel transition in vitro, the key factors governing their phase transition remain to be elucidated in vivo. Most prion-like proteins are classified as RNA-binding proteins, and recent studies suggest that RNA plays a critical role in mediating both LLPS and the subsequent sol-gel transition of these proteins. In the review, we summarized our findings on RNA G-quadruplexes (rG4s) as a pathological key molecule in neurodegenerative disorders and introduce recent advances in RNA-induced phase transition of prion-like proteins.
Quantitative assessment of gait abnormality is essential for osteoarthritis (OA) model. We aimed to establish a low-cost, non-invasive and markerless gait analysis pipeline using machine learning. Rat OA model was induce...Quantitative assessment of gait abnormality is essential for osteoarthritis (OA) model. We aimed to establish a low-cost, non-invasive and markerless gait analysis pipeline using machine learning. Rat OA model was induced by intraarticular injection of monosodium iodoacetate, and walking behavior was recorded. Joint coordinates were analyzed using DeepLabCut, and hierarchical clustering based on our summarized features separated OA and healthy animals with high accuracy. Principal coordinates analysis demonstrated significant group separation while preserving intra-group variability. We developed a reproducible and non-biased method for gait analysis in OA rats, which can be applicable for pain and movement disorder models.
OBJECTIVE: This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle. METHODS: Female C57BL/6J mice...OBJECTIVE: This study aimed to investigate the acute and chronic effects of imeglimin, a novel antidiabetic agent, on peripheral circadian clocks in mice under a 12-h/12-h light/dark cycle. METHODS: Female C57BL/6J mice were administered imeglimin either as a single oral dose at Zeitgeber time (ZT) 0 or 12 (acute study) or via a 0.2 % admixture in chow for 4 weeks (chronic study). Clock gene mRNA expression in skeletal muscle and liver was analyzed by quantitative real-time PCR. RESULTS: Acute imeglimin administration at ZT 12 increased the peak mRNA expression of clock genes (Nr1d1 and Dbp in skeletal muscle; Per2 in liver), whereas dosing at ZT 0 decreased Nr1d1 and Dbp in both tissues. In the chronic study, imeglimin decreased the peak expression of Nr1d1 and Dbp in skeletal muscle, while liver rhythms remained unchanged. Nampt and Sirt1 expression was unaffected in either tissue. CONCLUSION: In this study, we demonstrated that imeglimin alters peripheral clock gene expression in healthy mice under both acute bolus administration and chronic mixed-feeding conditions. Further studies are warranted to clarify underlying mechanisms and their physiological relevance.