Search Results (508)

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and is increasingly driven by cardiometabolic disease, including type 2 diabetes mellitus (T2DM), obesity, and insulin resistance. These conditions promote atrial electrical instability and a permissive substrate through mitochondrial dysfunction, oxidative stress, inflammation, calcium-handling abnormalities, and profibrotic signaling, culminating in atrial fibrosis and conduction heterogeneity. Metformin, the foundational glucose-lowering therapy for T2DM, exerts pleiotropic actions that intersect with these upstream pathways. Beyond glycemic control, metformin induces mild mitochondrial complex I modulation with reduction of reverse electron transfer-derived reactive oxygen species, activates adenosine monophosphate (AMP) activated protein kinase, and attenuates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated cytokine signaling; experimental data further suggest favorable effects on adiponectin–sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA) 2a-dependent calcium cycling, connexin expression, small-conductance Ca²⁺-activated K+ channel remodeling, lipid handling, and transforming growth factor-β (TGF)-β-associated fibrotic remodeling. Observational cohort studies have reported associations between metformin exposure and a modest reduction in incident AF, particularly with longer treatment duration and in higher-risk metabolic phenotypes; device-based surveillance cohorts support a preventive association for new-onset AF rather than reduction of established AF burden. Data after catheter ablation suggest improved freedom from recurrence in metformin-treated patients, whereas evidence in postoperative AF is largely neutral, likely reflecting distinct acute mechanisms. Collectively, metformin may be best conceptualized as a potential substrate-modifying, upstream therapy candidate; however, confounding, exposure misclassification, and heterogeneity in comparators limit causal inference, underscoring the need for prospective randomized trials with AF endpoints. In practice, integration with comprehensive risk-factor modification (blood pressure, weight, sleep apnea, and glycemic optimization) remains essential when considering AF prevention strategies. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Calcium leaching increases the hydraulic concrete material’s porosity and the diffusion coefficient, thereby jeopardizing engineering safety. Fly ash and silica fume are commonly used mineral admixtures in hydraulic concrete, and their effects on the material’s leaching characteristics, especially its microstructural and transport properties, require further investigation. In this study, calcium leaching tests were conducted on cement paste (CP), silica fume–cement paste (SF), and fly ash–cement paste (FA) using a 6 mol/L ammonium chloride solution to accelerate the leaching process. Subsequently, a series of quantitative and qualitative analyses was performed on the deteriorated specimens, including phenolphthalein indicator spraying, X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). Additionally, the diffusion coefficients of the material at different locations were calculated and analyzed. The results show that partially replacing cement with silica fume or fly ash increases the initial porosity, gel pore content, and initial diffusion coefficients. After 28 days of leaching, compared to the initial values, the porosity increases in the 0–4 mm layer from the leached surface were 83.6% for CP, 11.0% for SF, and 39.0% for FA. The diffusion coefficients increased by factors of 14.3 (CP), 6.1 (SF), and 13.6 (FA), indicating enhanced resistance to leaching. The primary reason for this is that the reactive silica in the admixtures undergoes a pozzolanic reaction with the calcium hydroxide generated by cement hydration, producing additional calcium silicate hydrate (C-S-H) gel, which reduces the capillary pores that would otherwise result from calcium hydroxide decomposition. Full article

Magnesium–rich environments are frequently encountered in cementitious systems, including the use of high–Mg raw materials in clinker production, cement–clay interfaces relevant to nuclear waste disposal, and exposure of cement–based materials to seawater, where progressive decalcification can substantially alter the structure and durability of calcium aluminosilicate hydrate (C–A–S–H) phases. In this study, density functional theory (DFT) calculations were employed to investigate the combined effects of interlayer and intralayer partial decalcification, Mg²⁺ substitution, and reinforcement with epoxy– and hydroxyl–functionalized reduced graphene oxide (rGO) on the structural stability and elastic properties of alkali charge–balanced C–A–S–H under dry and hydrated conditions. Adsorption–energy calculations reveal thermodynamically favorable interactions between functionalized rGO and silicate hydrate species in the presence of Mg²⁺, with hydroxyl/rGO promoting stronger interfacial stabilization and epoxy/rGO preserving greater graphene lattice integrity. The results demonstrate that Mg²⁺ substitution together with rGO intercalation generally enhances the mechanical response of partially decalcified structures through structural densification and interfacial cohesion. Relative to dry systems, hydration further improves elastic performance, increasing Young’s modulus and bulk modulus by 1–11% and 4–19%, respectively, for interlayer decalcified nanocomposites, while intralayer configurations exhibit stronger but model–dependent enhancements of up to ≈22% and ≈33%. Compared with untreated systems, rGO–treated nan–composites exhibit enhanced stiffness, with Young’s modulus and bulk modulus increasing by up to ≈22% and ≈15%, respectively. Overall, these findings provide atomistic insights into stabilization mechanisms in partially decalcified alkali charge–balanced C–A–S–H systems and identify Mg²⁺–rGO incorporation as a promising strategy for mitigating decalcification–induced degradation in durable low–carbon cementitious nanocomposites. Full article

To investigate the corrosion resistance and deterioration mechanism of cast-in situ concrete incorporating iron ore tailings aggregate (IOT), specimens with IOT replacement ratios of 0%, 30%, and 50% were exposed to distilled water, endogenous Cl⁻-SO₄²⁻ corrosion, exogenous Mg²⁺-SO₄²⁻ corrosion, and endogenous-exogenous coupled corrosion. The evolution of mass, size, compressive strength, and flexural strength was evaluated, while Nuclear Magnetic Resonance (NMR), Scanning Electron Microscope-Energy Dispersive Spectroscopy (SEM-EDS), X-ray Diffraction (XRD), and Thermogravimetric Analysis/Derivative Thermogravimetry (TG/DTG) were used to characterize pore structure and phase transformation. Results show that distilled water causes limited variation, whereas exogenous and coupled corrosion accelerate product accumulation, size expansion, pore coarsening, and strength degradation. Under exogenous Mg²⁺-SO₄²⁻ corrosion, the peak compressive strengths of specimens with 0%, 30%, and 50% IOT reach 43.30 MPa, 45.60 MPa, and 46.93 MPa, respectively, with the 50% IOT specimen showing an 8.38% increase compared with the specimen without IOT. TG/DTG results show that the Ca(OH)₂ related mass loss decreases from 5.42% under distilled water immersion to 4.37% under exogenous Mg²⁺-SO₄²⁻ corrosion, confirming calcium consumption during sulfate–magnesium attack. Microstructural characterization reveals that sulfate reaction, chloride binding, and Mg²⁺-induced decalcification jointly promote the formation of gypsum, ettringite, Friedel’s salt, magnesium silicate hydrate (M-S-H), and magnesium-associated corrosion products. Overall, 30% IOT provides better pore refinement and mechanical stability under endogenous and exogenous corrosion, whereas 50% IOT improves residual skeleton support under coupled corrosion. These findings provide guidance for durability design and sustainable utilization of IOT aggregate in cast-in situ concrete. Full article

Rice starch (RS) is widely consumed, but is usually rapidly digested, which may increase postprandial blood glucose levels. Therefore, regulating RS digestibility is important for development functional starch-based foods. In this study, sodium alginate (NaAlg) was incorporated into RS gels and subsequently crosslinked with Ca²⁺ to form a calcium alginate (CaAlg) network, and its effects on the physicochemical properties, digestion behavior, and physiological responses of RS gels were evaluated. Rheological measurement showed that the Ca²⁺-crosslinked alginate network increased the viscosity and viscoelastic moduli of RS gels. Low-field nuclear magnetic resonance analysis showed that the Ca²⁺-crosslinked alginate network reduced free water mobility. Structural characterization using Fourier-transform infrared spectroscopy, X-ray diffraction, and cold-field scanning electron microscopy shows that the Ca²⁺-crosslinked alginate network was associated with enhanced intermolecular interactions and a more continuous gel network, while all gelatinized samples exhibited predominantly amorphous structures. In vitro digestion experiments showed that the hydrolysis degree at 120 min decreased from 92.3% in RS to 85.6% in HCaAlg/RS. The rapidly digestible starch content significantly decreased from 72.4% to 68.4% (p < 0.05), while resistant starch significantly increased from 7.7% to 14.4% (p < 0.05). First-order kinetic fitting showed that C_∞ significantly decreased from 93.0% to 86.0%, and k significantly decreased from 0.027 to 0.013 min⁻¹ (p < 0.05). In vivo experiments showed that the Ca²⁺-crosslinked alginate/RS gels were associated with a lower postprandial glycemic response, with the incremental area under the curve significantly decreased from 747.2 to 591.7 mmol·min/L (p < 0.05), and the intestinal propulsion rate decreased from 89.6% to 75.3% (p < 0.05). These results suggest that Ca²⁺-crosslinked alginate network formation may modulate the structural properties, digestion behavior, and digestion-related physiological responses of RS gels, providing a basis for the development of starch-based functional foods with improved glycemic control. Full article

Associated with high morbidity and mortality, cisplatin-induced acute kidney injury (AKI) is a common clinical complication characterized by oxidative stress, inflammation, and mitochondria-associated signaling. Although multiple signaling pathways have been implicated in AKI progression, effective interventions targeting these complex mechanisms are still lacking. As a medicinal fungus with antioxidant and anti-inflammatory properties, Schizophyllum commune (SC) has shown potential biological activities; however, its renoprotective effects in cisplatin-induced AKI remain unclear. Therefore, this study aimed to investigate SC’s protective effects and underlying mechanisms in a cisplatin-induced AKI mouse model. SC treatment improved renal function and attenuated histopathological damage. It reduced oxidative stress and inflammatory responses, as evidenced by the modulation of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), and pro-inflammatory cytokines. Mechanistically, SC regulated multiple signaling pathways, including mitogen-activated protein kinase (MAPK), toll-like receptor 4/nuclear factor kappa B (TLR4/ NF-κB), PI3K/AKT, nuclear factor erythroid 2–related factor 2/heme oxygenase-1 (Nrf2/HO-1), and the calcium/calmodulin-dependent protein kinase kinase–AMP-activated protein kinase–sirtuin 1 (CaMKK–AMPK–Sirt1) axis. In addition, SC modulated apoptosis, autophagy, and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, suggesting improved mitochondrial homeostasis. These findings indicate that SC exerts renoprotective effects and may contribute to cisplatin-induced nephrotoxicity mitigation strategies. Full article

Although calcium overload dysregulation has been implicated in cellular senescence, its role in ionizing radiation (IR)-induced osteocyte senescence, a key pathogenic mechanism underlying radiotherapy-associated bone injury, remains poorly explored. This study investigated whether IR-induced osteocyte senescence is mediated through the Ca²⁺-NFATc1-ATF3 pathway. Exposure to 2 Gy X-rays impaired osteocyte homeostasis, manifesting as reduced viability and proliferation, G2/M phase arrest, and dendritic retraction. IR also induced persistent DNA damage response and senescence-associated phenotypes, including increased γ-H2AX foci, SA-β-gal activity, condensed punctate DAPI-dense nuclear foci, p16/p21 expression, and pro-inflammatory SASP profile. Intracellular Ca²⁺ levels surged within 6 h post-irradiation and remained elevated for at least 72 h in a dose-dependent manner. Pharmacological Ca²⁺ modulation with BAPTA-AM or verapamil attenuated IR-induced intracellular Ca²⁺ accumulation, G2/M arrest, SA-β-gal positivity, p21/p53 upregulation, and SASP secretion. Conditioned medium from irradiated osteocytes inhibited BMSC-mediated osteogenesis and enhanced BMM-driven osteoclastogenesis, whereas Ca²⁺ modulation partially mitigated these paracrine effects. Mechanistically, IR promoted NFATc1 nuclear translocation and ATF3 upregulation. Collectively, these findings support an important role for pathological intracellular Ca²⁺ elevation in IR-induced osteocyte senescence and suggest that the Ca²⁺-NFATc1-ATF3 axis may represent a potential therapeutic target for mitigating radiation-associated disruption of bone homeostasis. Full article

Mitochondrial dysfunction is not merely a byproduct of transformation but a driver of tumorigenesis, metastasis, and therapeutic resistance. Recent advancements in intercellular communication have identified Extracellular Vesicles (EVs) or exosomes as critical mediators that bridge the gap between the tumor and its microenvironment (TME). These EVs contain a complex repertoire of bioactive cargo, including proteins, lipids, and RNAs. Among the class of RNAs, small non-coding RNAs, microRNAs (miRNAs), are the most abundantly expressed bioactive compounds that are selectively packaged and delivered to recipient cells. EV-delivered miRNAs can target nuclear-encoded mitochondrial genes and have also been reported to localize to mitochondria (mitomiRs), where they function as post-transcriptional regulators of bioenergetic and mitochondrial dynamic adaptations that support tumor progression. This review explores the “EV-miRNA-Mitochondria Axis”, delineating the molecular mechanisms by which EV-carried miRNAs reprogram the “Mitochondrial Information Processing System” (MIPS) - a signaling network where mitochondria integrate metabolic cues (e.g., ROS, calcium flux) to dictate critical biological outcomes, such as immune regulation and cell survival. We summarized specific sorting machineries (e.g., hnRNPA2B1, Lupus La) that package oncogenic miRNAs into EVs and how these cargoes hijack mitochondrial function upon delivery. Specifically, we discussed how EV-miRNAs induce metabolic shifts, manipulate mitochondrial dynamics (fission/fusion), and inhibit the intrinsic apoptosis to drive cancer progression. Finally, we highlighted the dual utility of these EV-miRNAs as drivers of pathogenesis and promising non-invasive biomarkers for early diagnosis, prognostic and therapeutic monitoring. Full article

Sustainable phosphorus (P) management in agriculture requires a circular economy approach through the use of so-called bio-based fertilizers (BBFs). The properties of BBFs vary widely depending on raw materials and production processes. However, it is still unknown how these properties, and particularly the dominant P compounds determine not only the efficiency of BBFs in supplying P to crops, but also their effects on soil functioning and crop quality. This study aimed to evaluate the efficiency of a representative set of BBFs, and relate this efficiency to their composition and dominant P compounds. To this end, 14 BBFs were studied: four from water purification (struvite, vivianite, and sewage sludge with and without composting), four composts (municipal solid waste (MSW), vineyard residues, and two using olive husks), three vermicomposts (two homemade and one commercial), fish meal, digestate, and a commercial organic fertilizer. Phosphorus forms in BBFs were determined using ³¹P nuclear magnetic resonance spectroscopy (P-NMR). The BBFs were compared to a single superphosphate (SSP) in a pot experiment growing wheat in two different alkaline soils, one rich in iron (Fe) oxides and one rich in carbonates. The effects on critical elements in grain [magnesium, Fe, zinc (Zn), manganese, and copper] and enzyme activities related to soil functioning and P cycling were also assessed. The dominant P compound in the BBFs was orthophosphate (73.8–89.5% of the total P in the NaOH–EDTA extracts). The MSW had the highest polyphosphate content (4.1%), a complex inorganic P compound. The organic P content ranged from 9.2% (fish meal) to 25.5% (Moge). Sewage sludge and composted sludge contributed high levels of phosphonates (4.1 and 5.6% of extracted P). The most abundant organic P compound class was inositol hexakisphosphates (IHPs), and myo-IHP (phytate) was the dominant IHP stereoisomer (1.2–6.4%) followed by D-chiro-IHP and scyllo-IHP. Plant dry matter and grain yield with most BBFs were not significantly different from that of SSP in both soils, likely due to the high concentrations of phosphate in relatively soluble forms in most of the BBFs. Vivianite and sewage sludge resulted in significantly higher grain yield than SSP (43% and 40%, respectively) in the carbonate-rich soil, likely due to progressive phosphate dissolution, which decreased the precipitation rate of insoluble calcium (Ca) phosphates. The highest P recoveries were obtained with horse manure vermicompost (65% and 15% higher than SSP in the Fe oxide-rich and in the carbonate-rich soil, respectively), partially attributed to the decreased precipitation rate of insoluble Ca phosphates with the added organic matter. Some BBFs increased micronutrient concentrations in grains and most decreased the P-to-Zn ratio relative to SSP. Overall, phosphatase and β-glucosidase activities increased with carbon-rich BBFs. Most of the studied BBFs could effectively replace fertilizers from non-renewable sources, in some cases with better crop P recoveries. Furthermore, some BBFs could provide additional benefits to grain quality, in terms of micronutrient supply for humans, and soil functioning. Full article

Kujiol A is one of the kujigamberol-related compounds isolated from Kuji amber. We previously demonstrated that kujiol A exhibited multiple biological activities, including the inhibition of Ca²⁺ signal transduction. In the present study, we found that kujiol A prevented the transcription of interferon-γ (IFN-γ), interleukin (IL)-2, IL-4, and Fas ligand in T-box transcription factor Eomesodermin (Eomes)-transfected murine T cell lymphoma BW5147 cells stimulated with phorbol ester and ionomycin (a calcium ionophore). In the murine cytotoxic T cell line CTLL-2, kujiol A reduced ionomycin-induced increases in IFN-γ mRNA expression. Luciferase reporter assays revealed that kujiol A inhibited the transcriptional activities of nuclear factor of activated T cells (NFAT) and, to a lesser extent, nuclear factor κB in human embryonic kidney 293T cells. Kujiol A did not affect NFATc2 (also known as NFAT1) protein expression. However, a chromatin immunoprecipitation assay showed that kujiol A prevented the NFATc2 protein from interacting with the IFN-γ and IL-2 promoters in Eomes-transfected BW5147 cells. Collectively, these results demonstrate that kujiol A is a potent immunosuppressant that inhibits T cell cytokine expression by targeting the NFAT pathway. Full article

Preterm labor is a major cause of neonatal morbidity and mortality and is frequently driven by infection-associated inflammation that promotes premature uterine activation. In this study, we investigated the effects of adipose stem cell-derived extracellular vesicles (ASC-EVs) on macrophage-mediated inflammatory signaling in uterine smooth muscle cells (HUtSMCs). An in vitro model was established by treating HUtSMCs with conditioned media derived from LPS-stimulated RAW264.7 macrophages. Activation of signaling pathways was assessed by Western blotting and immunofluorescence, and functional responses were evaluated using calcium flux and collagen gel contraction assays. Conditioned media from LPS-stimulated macrophages induced robust activation of MAPK (ERK1/2 and JNK) and NF-κB signaling, accompanied by IκB degradation and nuclear translocation of phosphorylated p65, whereas ASC-EVs pretreatment significantly attenuated these responses and reduced the expression of pro-inflammatory cytokines, including IL-6, IL-8, and MCP-1. Furthermore, macrophage-conditioned media enhanced intracellular calcium flux and contractile activity in HUtSMCs, both of which were suppressed by ASC-EVs. Inhibition of TLR4 signaling in macrophages reduced the inflammatory potency of conditioned media, indicating a key upstream role of macrophage TLR4 activation. Collectively, these findings demonstrate that ASC-EVs suppress macrophage-mediated inflammatory activation and downstream contractile responses, suggesting their potential as a cell-free therapeutic strategy for preventing inflammation-associated preterm labor. Full article

Arrhythmogenic cardiomyopathy (ACM) is a genetic myocardial disorder marked by progressive cardiomyocyte loss, fibro-fatty replacement, ventricular arrhythmias, and risk of sudden cardiac death. Traditionally considered a structural and electrical disease driven by desmosomal dysfunction, emerging evidence redefines ACM as an inflammatory cardiomyopathy in which immune activation plays a central role. This review integrates genetic, molecular, experimental, and clinical data to highlight inflammation as a unifying feature of ACM. Desmosomal gene variants impair cell adhesion and also activate cardiomyocyte-intrinsic inflammatory pathways, including nuclear factor of kappa B (NFκB) and glycogen synthase kinase 3β (GSK3β) signaling, promoting cytokine release, immune cell recruitment, and fibrotic remodeling. Preclinical studies suggest inflammation precedes structural changes, indicating it may be an initiating event rather than a secondary response. Clinical and pathological findings support this model, with inflammatory infiltrates, circulating cytokines, and autoantibodies observed across disease stages. These processes often present as episodic “hot phases” resembling myocarditis, thus complicating diagnosis. The inflammatory landscape involves both innate and adaptive immunity, along with stromal and neuronal remodeling, contributing to arrhythmogenesis through gap junction disruption, calcium-handling abnormalities, and fibrosis. Environmental factors such as exercise, stress, and metabolic disturbances further modulate inflammatory pathways and disease expression. Therapeutically, this evolving perspective supports immunomodulatory approaches, including inhibition of NFκB, GSK3β, and cytokine signaling. Early clinical data on immunosuppressive and cytokine-directed therapies are promising, especially during active inflammatory phases, while gene-based strategies specifically address the underlying genetic defects. In conclusion, ACM should be recognized as an inflammatory cardiomyopathy shaped by interactions between genetic susceptibility and immune dysregulation. Integrating genetic and immunologic profiling may improve diagnosis, risk stratification, and treatment, ultimately leading to refined personalized therapeutic strategies. Full article

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

The Ca_v1.3 L-type calcium (Ca²⁺) channel plays a critical role in cardiac excitation-contraction coupling, regulating heart rate, contractility, and gene expression. The C-terminus of Ca_v1.3 has recently been shown to translocate to the nucleus and act as a transcriptional factor to modulate the function of Ca²⁺-activated K⁺ channels in atrial cardiomyocytes. However, the role of the Ca_v1.3-C-terminus in the regulation of transcription of its own Ca_v1.3 gene remains unknown. We evaluated the impact of the nuclear translocation of the Ca_v1.3-C-terminus on the transcription of the Ca_v1.3 gene and Ca_v1.3 promoter activity in vitro using cultured neonate rat ventricular myocytes (NRVMs), and mouse atrial cardiomyocytes (HL-1). Lentiviral infection of NRVMs demonstrated that the cleaved Ca_v1.3-C-terminus translocates to the nucleus where it acts as a trans-regulator. The C-terminus of Ca_v1.3 increased transcription of Ca_v1.3 in vitro in NRVMs and in vivo in mice ventricles. Additionally, MEF2 transcription factor binding sites within the Ca_v1.3 promoter may contribute to the regulatory effect of the Ca_v1.3-C-terminus. These data are the first to demonstrate unique upregulation of Ca_v1.3 transcription by its own mobile Ca_v1.3-C-terminus both in vitro and in vivo. These findings suggest that the Ca_v1.3-C-terminus has intrinsic properties as a trans-regulator of gene expression and may contribute to the modulation of cardiac function. Full article