Tomohiro Numata

Panax ginseng (PG) is a traditional herbal medicine widely used for the treatment of cardiovascular disorders in East Asia. Although PG has been reported to attenuate cardiomyocyte hypertrophy, the molecular mechanisms underlying its cardioprotective effects remain incompletely understood. In this study, we investigated whether modulation of the endothelin-1 (ET-1)–angiotensin II (AngII) signaling axis contributes to the anti-hypertrophic action of PG. Neonatal rat ventricular myocytes (NRVMs) were used to evaluate ET-1-induced hypertrophy, and pharmacological experiments using receptor antagonists were performed to examine the signaling pathways involved. Extracellular AngII levels were quantified by ELISA, intracellular Ca ²⁺ accumulation was assessed in AT _1A R-overexpressing NRVMs, and whole-cell patch-clamp recordings were performed in HEK293T cells co-expressing AT _1A R and TRPC6. PG significantly attenuated ET-1-induced cardiomyocyte hypertrophy without altering ET _A R or ET _B R expression. Pharmacological experiments with the ET _A R antagonist BQ-123 suggested that the anti-hypertrophic effect of PG could not be explained solely by direct inhibition of ET _A R signaling. PG markedly suppressed ET-1-induced extracellular AngII production, and interaction studies with losartan further implicated the AngII–AT _1A R pathway in the anti-hypertrophic action of PG. Moreover, PG inhibited AngII-induced intracellular Ca ²⁺ accumulation in AT _1A R-overexpressing NRVMs and attenuated AngII-evoked TRPC6-mediated membrane currents without affecting basal channel activity. These findings demonstrate that PG suppresses ET-1-induced cardiomyocyte hypertrophy by inhibiting both ET-1-induced AngII production and downstream AT _1A R-dependent signaling, identifying suppression of the AngII–AT _1A R signaling axis as a key mechanism underlying its cardioprotective effects.

Background: Mitochondrial dysfunction and oxidative stress are central to the development of cardiac hypertrophy and heart failure. Panax ginseng (PG), a principal herb used in Kampo medicine, has been reported to exert cardioprotective effects; however, its intracellular actions under endothelin-1 (ET-1)- and β-adrenergic stress remain incompletely defined.

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice (8–12 weeks old) respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H₂O₂)-induced Ca²⁺ influx characteristic of TRPM2; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling.

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. We compared how wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in the atria of WT mice, and measured ADP-ribose (ADPr)–evoked currents as well as hydrogen peroxide (H₂O₂)–induced Ca²⁺ influx characteristic for TRPM2 of WT atrial myocytes; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling.

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca²⁺ signaling, regulated by both endogenous Ca²⁺-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca²⁺-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca²⁺-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca²⁺ influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca²⁺-triggered secretomes modulate SC phenotypes and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca²⁺ channels—including transient receptor potential (TRP) channels and store-operated Ca²⁺ entry (SOCE; STIM/Orai)—in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca²⁺-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves.

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca²⁺ signaling, regulated by both endogenous Ca²⁺-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca²⁺-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca²⁺-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca²⁺ influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca²⁺-triggered secretomes modulate SC phenotype and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca²⁺ channels—including transient receptor potential (TRP) channels and store-operated Ca²⁺ entry (SOCE; STIM/Orai)—in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca²⁺-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves.

The Japanese Kampo medicine Boi‐ogi‐to (BOT) is known as an effective therapeutic agent for edema and nephrosis by promoting the excretion of excess body fluids. Despite its empirical effectiveness, scientific evidence supporting its effectiveness remains limited. In this study, we conducted a retrospective study of the effects of BOT administration on the blood test values of patients before and after taking the drug to attempt translational research between basic science and daily clinical practice by focusing on the molecular mechanism of action of BOT in vitro. We found that blood sodium and chloride levels are higher after taking BOT by analyzing the clinical test values before and after taking the drug from 28 patients attending Akita University Hospital. In this light, we measured the cell volume of human embryonic kidney HEK293T cells in vitro in order to investigate the possibility that BOT induces Cl ⁻ excretion and cell volume reduction. BOT showed concentration‐dependent cell volume reduction with an EC ₅₀ of 686 μg/mL. The volume reduction effect was suppressed by the Cl ⁻ channel inhibitors DIDS and DCPIB. Furthermore, patch‐clamp studies showed that BOT‐activated Cl ⁻ currents exhibit outward rectification and time‐dependent inactivation upon depolarization. These biophysical properties of BOT‐induced Cl ⁻ currents correspond to those of volume‐sensitive outward rectifier (VSOR) anion channels. The Cl ⁻ currents activated by the administration of BOT were inhibited by applying DIDS, DCPIB, and siRNA targeting the gene of LRRC8A, a core component of the VSOR channel, as well as in LRRC8‐deficient cells. Additionally, BOT‐induced Cl ⁻ currents were restored by coexpression of LRRC8A/C in LRRC8‐deficient cells. Also, BOT was found to translocate LRRC8A proteins to the plasma membrane. These results demonstrated that BOT activates LRRC8‐containing VSOR channels by delivering LRRC8A to the plasma membrane and induces Cl ⁻ release, thereby promoting water excretion.

Background/Objectives: The Sigma-1 receptor (Sigmar1), an intracellular chaperone protein, is ubiquitously expressed throughout the body, but its role in peripheral organs, such as the kidneys, remains unclear. Here, we investigated the protective effects and molecular mechanisms of SA4503, a selective Sigmar1 agonist, on Adriamycin (ADR)-induced renal glomerular injury. Methods: Using in vitro and in vivo models, we evaluated the effects of SA4503 on ADR-induced podocyte injury, including podocyte survival, albumin permeability, urinary albumin levels, and Sigmar1-nephrin interactions. NE-100, a Sigmar1 antagonist, was co-administered to validate the specificity of the effects of SA4503. Results: Sigmar1 was highly expressed in podocytes and mouse kidney tissues. SA4503 significantly reduced ADR-induced podocyte injury and urinary albumin leakage in mice. Mechanistically, SA4503 preserved Sigmar1-nephrin interactions, which were disrupted in ADR-treated kidneys. This protective effect was abolished by NE-100 co-treatment, confirming the Sigmar1-dependency of SA4503’s action. Conclusions: These findings demonstrate that the activation of Sigmar1 by SA4503 protects against ADR-induced podocyte injury and glomerular damage, likely by stabilizing Sigmar1-nephrin interactions. Therefore, Sigmar1 represents a promising therapeutic target for glomerular diseases such as nephrotic syndrome.

Tactile perception relies on mechanoreceptors and nerve fibers, including c-fibers, Aβ-fibers and Aδ-fibers. Schwann cells (SCs) play a crucial role in supporting nerve fibers, with non-myelinating SCs enwrapping c-fibers and myelinating SCs ensheathing Aβ and Aδ fibers. Recent research has unveiled new functions for cutaneous sensory SCs, highlighting the involvement of nociceptive SCs in pain perception and Meissner corpuscle SCs in tactile sensation. Furthermore, Piezo2, previously associated with Merkel cell tactile sensitivity, has been identified in SCs. The goal of this study was to investigate the channels implicated in SC mechanosensitivity and the release process of neurotrophic factor secretion. Immortalized IFRS1 SCs and human primary SCs generated two distinct subtypes of SCs: undifferentiated and differentiated SCs. Quantitative PCR was employed to evaluate the expression of differentiation markers and mechanosensitive channels, including TRP channels (TRPV4, TRPM7 and TRPA1) and Piezo channels (Piezo1 and Piezo2). To validate the functionality of specific mechanosensitive channels, Ca²⁺ imaging and electronic cell sizing experiments were conducted under hypotonic conditions, and inhibitors and siRNAs were used. Protein expression was assessed by Western blotting and immunostaining. Additionally, secretome analysis was performed to evaluate the release of neurotrophic factors in response to hypotonic stimulation, with BDNF, a representative trophic factor, quantified using ELISA. Induction of differentiation increased Piezo2 mRNA expression levels both in IFRS1 and in human primary SCs. Both cell types were responsive to hypotonic solutions, with differentiated SCs displaying a more pronounced response. Gd³⁺ and FM1-43 effectively inhibited hypotonicity-induced Ca²⁺ transients in differentiated SCs, implicating Piezo2 channels. Conversely, inhibitors of Piezo1 and TRPM7 (Dooku1 and NS8593, respectively) had no discernible impact. Moreover, Piezo2 in differentiated SCs appeared to participate in regulatory volume decreases (RVD) after cell swelling induced by hypotonic stimulation. A Piezo2 deficiency correlated with reduced RVD and prolonged cell swelling, leading to heightened release of the neurotrophic factor BDNF by upregulating the function of endogenously expressed Ca²⁺-permeable TRPV4. Our study unveils the mechanosensitivity of SCs and implicates Piezo2 channels in the release of neurotrophic factors from SCs. These results suggest that Piezo2 may contribute to RVD, thereby maintaining cellular homeostasis, and may also serve as a negative regulator of neurotrophic factor release. These findings underscore the need for further investigation into the role of Piezo2 in SC function and neurotrophic regulation.