Background: Postoperative cognitive dysfunction (POCD) is a common disorder after general anesthesia in elderly patients, the precise mechanisms of which remain unclear. Methods: We investigated the effect of isoflurane with or without dantrolene pretreatment on intracellular calcium concentration ([Ca²⁺]_i), reactive oxygen species (ROS) production, cellular lactate dehydrogenase (LDH) leak, calpain activity, and cognitive function using the Morris water maze test of young (3 months), middle-aged (12–13 months), and aged (24–25 months) C57BL6/J mice. Results: Aged cortical and hippocampal neurons showed chronically elevated [Ca²⁺]_i compared to young neurons. Furthermore, aged hippocampal neurons exhibited higher ROS production, increased LDH leak, and elevated calpain activity. Exposure to isoflurane exacerbated these markers in aged neurons, contributing to increased cognitive deficits in aged mice. Dantrolene pretreatment reduced [Ca²⁺]_i for all age groups and prevented or significantly mitigated the effects of isoflurane on [Ca²⁺]_i, ROS production, LDH leak, and calpain activity in aged neurons. Dantrolene also normalized or improved age-associated cognitive deficits and mitigated the cognitive deficits caused by isoflurane. Conclusions: These findings suggest that isoflurane-induced cytotoxicity and cognitive decline in aging are linked to disruptions in neuronal intracellular processes, highlighting the reduction of [Ca²⁺]_i as a potential therapeutic intervention.

Background/Objectives: Naringin, a major flavonoid found in citrus fruits, has garnered significant attention over the past two decades for its potential cardiovascular benefits. This systematic review evaluates the effects of naringin on endothelial function and myocardial performance, with particular emphasis on ischemia-reperfusion (I/R) injury, based on the literature published from January 2000 to June 2025. Methods: The review was conducted in accordance with PRISMA 2020 guidelines. A comprehensive search of PubMed, Scopus, EMBASE, and Web of Science databases was performed using key terms including “naringin”, “cardiovascular”, “endothelial function”, “atherosclerosis”, and “ischemia-reperfusion.” A total of 62 studies were included and categorized into three domains: cellular models, animal studies, and human trials. Risk of bias assessments were conducted for each study type using appropriate tools. Results: Naringin consistently exhibited antioxidant, anti-inflammatory, and vasoprotective effects across all study types. Mechanistic studies highlighted the modulation of key signaling pathways, including PI3K/Akt, NF-κB, Nrf2, the renin-angiotensin system (RAS), and enhancement of KATP channel expression, as well as its ability to inhibit apoptosis, autophagy, and ferroptosis. In animal models, naringin improved endothelium-dependent vasorelaxation, reduced infarct size, and preserved myocardial function. Although limited, human trials reported beneficial effects on lipid profiles, arterial stiffness, and adiponectin levels. Conclusions: Naringin demonstrates strong potential as a dietary adjunct for cardiovascular protection, especially in the context of ischemic injury and vascular dysfunction. Further well-designed clinical trials are needed to define optimal dosing strategies and improve its bioavailability in humans.

Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca²⁺ concentration ([Ca²⁺]_i) in their muscle cells. We have reported that the muscle dysregulation of [Ca²⁺]_i impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca²⁺]_i and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca²⁺]_i was recorded using a Ca²⁺-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca²⁺]_i and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca²⁺]_i using a Ca²⁺-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca²⁺]_i below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca²⁺]_i was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca²⁺]_i within a specific range (100–130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).

Type 2 diabetes mellitus (T2D) is a significant global public health problem that has seen a substantial increase in the number of affected individuals in recent decades. In a murine model of T2D (db/db), we found several abnormalities, including aberrant intracellular calcium concentration ([Ca²⁺]_i), decreased glucose transport, increased production of reactive oxygen species (ROS), elevated levels of pro-inflammatory interleukins and creatine phosphokinase (CK), and muscle weakness. Previously, we demonstrated that passive pulsatile shear stress, generated by sinusoidal (headward–forward) motion, using a motion platform that provides periodic acceleration of the whole body in the Z plane (pGz), induces the synthesis of nitric oxide (NO) mediated by constitutive nitric oxide synthase (eNOS and nNOS). We investigated the effect of pGz on db/db a rodent model of T2D. The treatment of db/db mice with pGz resulted in several beneficial effects. It reduced [Ca²⁺]_i overload; enhanced muscle glucose transport; and decreased ROS levels, interleukins, and CK. Furthermore, pGz treatment increased the expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), and neuronal nitric oxide synthase (nNOS); reduced inducible nitric oxide synthase (iNOS); and improved muscle strength. The cytoprotective effects of pGz appear to be mediated by NO, since pretreatment with L-NAME, a nonspecific NOS inhibitor, abolished the effects of pGz on [Ca²⁺]_i and ROS production. Our findings suggest that a non-pharmacological strategy such as pGz has therapeutic potential as an adjunct treatment to T2D.

Duchenne muscular dystrophy (DMD) is an inherited muscular disorder caused by mutations in the dystrophin gene. DMD patients have hypoxemic events due to sleep-disordered breathing. We reported an anomalous regulation of resting intracellular Ca²⁺ ([Ca²⁺]_i) in vascular smooth muscle cells (VSMCs) from a mouse (mdx) model of DMD. We investigated the effect of hypoxia on [Ca²⁺]_i in isolated and quiescent VSMCs from C57BL/10SnJ (WT) and C57BL/10ScSn-Dmd (mdx) male mice. [Ca²⁺]_i was measured using Ca²⁺-selective microelectrodes under normoxic conditions (95% air, 5% CO₂) and after hypoxia (glucose-free solution aerated with 95% N2-5% CO₂ for 30 min). [Ca²⁺]_i in mdx VSMCs was significantly elevated compared to WT under normoxia. Hypoxia-induced [Ca²⁺]_i overload, which was significantly greater in mdx than in WT VSMCs. A low Ca²⁺ solution caused a reduction in [Ca²⁺]_i and prevented [Ca²⁺]_i overload secondary to hypoxia. Nifedipine (10 µM), a Ca²⁺ channel blocker, did not modify resting [Ca²⁺]_i in VSMCs but partially prevented the hypoxia-induced elevation of [Ca²⁺]_i in both genotypes. SAR7334 (1 µM), an antagonist of TRPC3 and TRPC6, reduced the basal and [Ca²⁺]_i overload caused by hypoxia. Cell viability, assessed by tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, was significantly reduced in mdx compared to WT VSMCs. Pretreatment with SAR7341 increases cell viability in normoxic mdx (p < 0.001) and during hypoxia in WT and mdx VSMCs. These results provide evidence that the lack of dystrophin makes VSMCs more susceptible to hypoxia-induced [Ca²⁺]_i overload, which appears to be mediated by increased Ca²⁺ entry through L-type Ca²⁺ and TRPC channels.