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Calcium overload is one of the early determinants of the core cellular events that contribute to the pathogenesis of acute kidney injury (AKI), which include oxidative stress, ATP depletion, calcium overload, and inflammatory response with self-amplifying and interactive feedback loops that ultimately lead to cellular injury and renal failure. Excluding adjuvant therapy, there are currently no approved pharmacotherapies for the treatment of AKI. Using an adipic dihydride linker, we modified the hyaluronic acid polymer chain with a potent antioxidant, bilirubin, to produce an amphiphilic conjugate. Subsequently, we developed a kidney-targeted and reactive oxygen species (ROS)-responsive drug delivery system based on the flash nanocomplexation method to deliver a well-known intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane- N , N , N ', N '-tetraacetic acid acetoxymethyl ester (BAPTA-AM, BA), with the goal of rescuing renal cell damage via rapidly scavenging of intracellularly overloaded Ca 2+ . In the ischemia-reperfusion (I/R) induced AKI rat model, a single dose of as-prepared formulation (BA 100 μg·kg -1 ) 6 h post-reperfusion significantly reduced renal function indicators by more than 60% within 12 h, significantly alleviated tissular pathological changes, ameliorated tissular oxidative damage, significantly inhibited apoptosis of renal tubular cells and the expression of renal tubular marker kidney injury molecule 1, etc., thus greatly reducing the risk of kidney failure. Mechanistically, the treatment with BA-loaded NPs significantly inhibited the activation of the ER stress cascade response (IRE1-TRAF2-JNK, ATF4-CHOP, and ATF6 axis) and regulated the downstream apoptosis-related pathway while also reducing the inflammatory response. The BA-loaded NPs hold great promise as a potential therapy for I/R injury-related diseases.

Among the complex mechanisms of AF pathogenesis, intracellular calcium overload and oxidative stress play a major role, both triggered by inflammatory processes. The additional basic event taking place in AF is atrial fibrotic remodeling, again triggered by oxidative stress, which is determined by connexins rearrangement and differentiation of fibroblasts into active collagensecreting myofibroblasts. RhoA/ROCK system is the final pathway of a wide spectrum of molecular effectors such as Angiotensin II, platelet-derived growth factor, connective tissue growth factor and transforming growth factor β, that overall determine calcium dysregulation and pro-fibrotic remodeling. Both in experimental and clinical studies, RhoA/ROCK activation has been linked to superoxide ion production, fibrotic remodeling and connexins rearrangement, with important consequences for AF pathogenesis. ROCK pathway inhibition may therefore be a therapeutic or preventive target for special AF subgroups of patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Primary cultures of bovine chromaffin cells are considered a good model to evaluate potential neuroprotective compounds for two major reasons: (i) they share many common features to neurons as they synthesize, store, and release neurotransmitters; they are excitable cells that express voltage-dependent calcium, potassium, and sodium channels; they express different neuronal receptor subtypes; and (ii) they can be easily cultured in high quantities from adult animals; as adult para-neurons, they can be used to reproduce different neurodegenerative-like cytotoxicity models. In this chapter, we describe protocols to mimic calcium overload (veratridine and thapsigargin) and oxidative stress (rotenone plus oligomycin-A and 6-hydroxydopamine) to evaluate potential neuroprotective compounds., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute myocardial infarction is an event of myocardial necrosis caused by unstable ischemic syndrome. Myocardial infarction (MI) occurs when blood stops flowing to the cardiac tissue or myocardium and the heart muscle gets damaged due to poor perfusion and reduced oxygen supply. Mitochondria can serve as the arbiter of cell fate in response to stress. Oxidative metabolism is the function of mitochondria within the cell. Cardiac cells being highly oxidative tissue generates about 90% of their energy through oxidative metabolism. In this review, we focused on the role of mitochondria in energy generation in myocytes as well as its consequences on heart cells causing cell damage. The role of mitochondrial dysfunction due to oxidative stress, production of reactive oxygen species, and anaerobic production of lactate as a failure of oxidative metabolism are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background We have previously shown that Elatoside C reduces cardiomyocyte apoptosis during ischaemia/reperfusion (I/R). Here, we investigated whether Elatoside C improves heart function in isolated rat hearts subjected to I/R and elucidated the potential mechanisms involved in Elatoside C-induced protection. Methods and results Isolated rat hearts were subjected to global ischaemia followed by reperfusion in the absence or presence of Elatoside C. We found that Elatoside C significantly attenuated cardiac dysfunction and depressed oxidative stress induced by I/R. Consistently, Elatoside C prevented I/R-induced mitochondrial dysfunction, which was evident by the inhibition of mitochondrial ROS production, mitochondrial permeability transition pore (mPTP) opening, cytochrome c release from the mitochondria and Bax translocation. Moreover, Elatoside C improved abnormal calcium handling during I/R, including increasing sarcoplasmic reticulum Ca2 + ATPase (SERCA2) activity, alleviating [Ca2 +]ER depletion, and reducing the expression levels of ER stress protein markers. All of these protective effects of Elatoside C were partially abolished by the PI3K/Akt inhibitor LY294002, ERK1/2 inhibitor PD98059, and JAK2/STAT3 inhibitor AG490. Further assessment in isolated cardiomyocytes showed that Elatoside C maintained the Ca2 + transients and cell shortening against I/R. Conclusions Elatoside C protects against cardiac injury during I/R by attenuating oxidative stress and [Ca2 +]i overload through the activation of both the reperfusion injury salvage kinase (RISK) pathway (including PI3K/Akt and ERK1/2) and the survivor activating factor enhancement (SAFE) pathway (including JAK2/STAT3) and, subsequently, inhibiting the opening of mPTPs. [ABSTRACT FROM AUTHOR]

Acanthopanax senticosus (Rupr. et Maxim.) Harms (AS), a traditional herbal medicine, has been widely used to treat ischemic heart disease. However, the underlying cellular mechanisms of its benefits to cardiac function remain unclear. The present study examined the effects of total flavones from AS (TFAS) on L-type Ca2+ channel currents (ICa-L) using the whole cell patch-clamp technique and on intracellular calcium ([Ca2+]i) handling and cell contractility in rat ventricular myocytes with the aid of a video-based edge-detection system. Exposure to TFAS resulted in a concentration- and voltage-dependent blockade of ICa-L, with the half-maximal inhibitory concentration (IC50) of 283.12 µg/mL and the maximal inhibitory effect of 36.49 ± 1.95%. Moreover, TFAS not only increased the maximum current in the current-voltage relationship but also shifted the activation and inactivation curves of ICa-L toward the hyperpolarizing direction. Meanwhile, TFAS significantly reduced amplitudes of myocyte shortening and [Ca2+]i with an increase in the time to 10% of the peak (Tp) and a decrease in the time to 10% of the baseline (Tr). Thus, the cardioprotective effects of TFAS may be attributed mainly to the attenuation of [Ca2+]i through the direct inhibition of ICa-L in rat ventricular myocytes and consequent negative effect on myocardial contractility. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Exposure to titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated to decrease learning and memory of animals. However, whether the impacts of these NPs on the recognition function are involved in hippocamal neuron damages is poorly understood. In this study, primary cultured hippocampal neurons from one-day-old fetal Sprague-Dawley rats were exposed to 5, 15, or 30 µg/mL TiO2 NPs for 24 h, we investigated cell viability, ultrastructure, and mitochondrial membrane potential (MMP), calcium homeostasis, oxidative stress, antioxidant capacity, apoptotic signaling pathway associated with the primary cultured hippocamal neuron apoptosis. Our findings showed that TiO2 NP treatment resulted in reduction of cell viability, promoted lactate dehydrogenase release, apoptosis, and increased neuron apoptotic rate in a dose-dependent manner. Furthermore, TiO2 NPs led to [Ca2+]i elevation, and MMP reduction, up-regulated protein expression of cytochrome c, Bax, caspase-3, glucose-regulated protein 78, C/EBP homologous protein and caspase-12, and down-regulated bcl-2 expression in the primary cultured hippocampal neurons. These findings suggested that hippocampal neuron apoptosis caused by TiO2 NPs may be associated with mitochondria-mediated signal pathway and endoplasmic reticulum-mediated signal pathway. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 1141-1149, 2015. [ABSTRACT FROM AUTHOR]

Objective To detect the dynamic expression level of inositol 1, 4, 5-trisphosphate receptor type I (IP3R1) in rat brain stem after diffuse axonal injury (DAI) by immunohistochemistry so as to explore its potential contribution to the secondary injury after DAI. Methods Twenty-five male adult Sprague-Dawley rats were divided into the injury group (n=25) and the control group (n=5). Before immunohistochemistry detection, Golgi silver staining was performed to ensure all rats in DAI group met the criteria of DAI. Then the level of IP3R1 expression was detected by immunohistochemistry at 3h, 12h, 24h and 72h after DAI, respectively. Results In the DAI group, a subset of axons exhibited bead-like structure, axonal retraction balls and swollen axons, and axonal axotomy was observed with Golgi silver staining. Immunohistochemical results showed mild expression of IP3R1 in the rat brain stem in the control group. After DAI the level of IP3R1 expression increased significantly. It began to increase at 3h after injury (PI), peaked at 24h PI, and then gradually decreased. At 72h PI, the expression in DAI group did not significantly differ from that in the control group. Conclusion Enhanced expression of IP3R1 may participate in the calcium overload and neuronal secondary injury in the early stage after DAI. [ABSTRACT FROM AUTHOR]

Objective To study the effect of excessive fluoride on calcium overload and apoptosis in cultured rat amelo-blasts in vitro. Methods Logarithmic-phase ameloblasts (HAT-7) were treated with 0, 0.4, 0.8, 1.6, 3.2, and 6.4 mmol-L-1 sodium fluoride (NaF) solution. Cell activities were detected by using a Cell Counting Kit 8 (CCK-8) assay after 48 h of treatment. The effect of fluoride on cell apoptosis was analyzed by using flow cytometry. Excessive fluoride-induced calcium concentration and calreticulin expression changes in ameloblasts were detected by using laser scanning confocal microscopy, Western blot analysis, and real-time quantitative polymerase chain reaction. Results NaF inhibited ameloblast activity at 1.6, 3.2, and 6.4 mmol-L-1 (dose-dependent) after 48 h of induction. The Ca2+ fluorescence intensity of HAT-7 cells incubated with 1.6 and 3.2 mmol*L-1 NaF was higher than that in the control group. The fluoride-induced early-stage apoptosis of ameloblasts after 48 h of induction and the early-stage apoptosis rate was positively correlated with fluoride concentration. Calreticulin mRNA expression in HAT-7 cells was higher than that in the control group after 48 h of incubation with 0.8, 1.2, and 1.6 mmol-L-1 NaF. Conclusion Excessive fluoride-induced calcium overload in ameloblasts and further caused endoplasmic reticulum stress-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Objective To demonstrate the protective effect and its mechanism of Panax notoginseng saponins (PNS) on severe acute pancreatitis (SAP) in rats of pancreatic acinar cell. Methods Thirty SD rats were randomly divided into three groups: sham operation group (group SO), severe acute pancreatitis group (group SAP), and PNS preconditioning group (group PNS). There were 10 rats in each group. Rat SAP model was induced by retrograde injection of 5% taurocholic acid sodium to pancreatic duct. Group SO was just treated with pancreas and duodenum turning after abdominal closure, not with taurocholic acid sodium injection. The rats in group PNS were given by intraperitoneal injection of 0.1 mL/100g PNS 50 mg/mL (xuesetong injection 0.1 mL/l0000g) once the models were established. And rats in the other two groups were given 0.9% physiological saline. Rats serum AMS were detected at 4 hours after modeling, and pancreatic pathological changes were observed to understand the pathogenesis of acute pancreatitis. The pancreatic tissue was obtained and the fluorescence intensity (FI) of acinar cells was observed by calcium fluorescent tracer Fluo-3-AM using fluorescence microscope observation. The average value of single acinar cell FI was analyzed and calculated quantitatively using flow cytometry, which could represent the concentration of calcium ion in cells. Results In groups PNS and SAP, rats serum AMS levels and pancreatic tissue pathology scores were significantly increased (< 0.05), and those in group SAP rats were significantly higher than in group PNS rats (< 0.05). The calcium ion concentrations showed that there were statistical differences in pancreas FI of intracellular [Ca2+]i among three groups. Compared with group SO, the pancreas FI of intracellular [Ca2+]I in rats of groups SAP and PNS were significantly increased (< 0.05) . And compared with group SAP, FI of [Ca2+]i in PNS group was significantly decreased (< 0.05). Conclusion The occurrence of SAP was related to cellular calcium overload, and the state of SAP became more serious with the higher degree of calcium overload. PNS could reduce the pancreatic intracellular calcium overload and the change of pancreatic tissue pathology. [ABSTRACT FROM AUTHOR]

Objective To investigate the possible role of canonical transient receptor potential channel 1 (TRPC1) after diffuse axonal injury (DAI) and discuss the mechanism of TRPC1 involved in calcium overload of neurons and myelin degeneration after DAI. Methods Rat models of DAI were established with the method of rotational acceleration of the brain. DAI intervention group was established by using SKF96365 intracerebroventricular injection. Intracellular calcium concentration was detected by Fura-2AM. The dynamic expressions of TRPC1 in the cortex were determined by Western blot and immunohistochemical staining. The results were compared with those in DMSO control group and normal group. The changes of neurons and myelin sheath were detected under electron microscope. The apoptosis of cortical neurons was detected by TUNEL. One-way ANOVA was used to compare within each group.Results The protein expressions of TRPC1 in the cortex increased after DAI and reached the peak at day 1 and then gradually decreased while intracellular calcium concentration also reached the peak at day 1. The structure of myelin sheath was destructed at the same time. After injection of TRPC1 blocker SKF96365, the protein expression of TRPC1 was inhibited and intracellular calcium concentration decreased. Meanwhile, the structure of myelin sheath was partially reserved and the scores of neurological functions in rats were improved. Conclusion TRPC1-induced calcium overload after DAI is the major cause of myelin degeneration and neuronal death. Suppressing the calcium influx induced by TRPC1 can protect the normal structure of myelin and improve neuronal apoptosis. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the role of intracellular calcium overload in the in vitro apoptosis of C6 glioma cells mediated by low level ultrasound and hematoporphyrin monomethyl ether (HMME) therapy. The frequency of ultrasound was optimized by the cell viability assay using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The apoptotic rate, reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) were determined by flow cytometry. Morphological changes were observed by the transmission electron microscope. Concentrations of intracellular Ca2+, [Ca2+]i were detected by a confocal microscopic laser scanning, and the release of cytochrome-c (cyt-c) was measured by western blotting. Results: The SDT-mediated apoptotic effect involved an overload of [Ca2+]i derived from the intra- and extracellular sources during the early progression of apoptotosis. The process was associated with an increased ROS production, a decreased MMP, and a release of cyt-c. In conclusion,the combined use of low level ultrasound and HMME improved the apoptotic rate of C6 glioma cells mediated by ultrasound alone. The [Ca2+]i overload involving activation of mitochondrial signaling played a pivotal role in the SDT-induced apoptosis. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) is the most recently discovered gasotransmitter molecule that activates multiple intracellular signaling pathways and exerts concentration-dependent antitumor effect by interfering with mitochondrial respiration and inhibiting cellular ATP generation. Inspired by the fact that H 2 S can also serve as a promoter for intracellular Ca 2+ influx, tumor-specific nanomodulators (I-CaS@PP) have been constructed by encapsulating calcium sulfide (CaS) and indocyanine green (ICG) into methoxy poly (ethylene glycol) -b- poly (lactide -co- glycolide) (PLGA-PEG). I-CaS@PP can achieve tumor-specific biodegradability with high biocompatibility and pH-responsive H 2 S release. The released H 2 S can effectively suppress the catalase (CAT) activity and synergize with released Ca 2+ to facilitate abnormal Ca 2+ retention in cells, thus leading to mitochondria destruction and amplification of oxidative stress. Mitochondrial dysfunction further contributes to blocking ATP synthesis and downregulating heat shock proteins (HSPs) expression, which is beneficial to overcome the heat endurance of tumor cells and strengthen ICG-induced photothermal performance. Such a H 2 S-boosted Ca 2+ -involved tumor-specific therapy exhibits highly effective tumor inhibition effect with almost complete elimination within 14-day treatment, indicating the great prospect of CaS-based nanomodulators as antitumor therapeutics., Competing Interests: The authors declare no conflict of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Tumor hypoxia and systemic toxicity seriously affect the efficacy of photodynamic therapy (PDT) and are considered as the "Achilles' heel" of PDT. Herein, to combat such limitations, an intelligent orthogonal emissions LDNP@SiO 2 -CaO 2 and folic acid-polyethylene glycol-Ce6 nanodrug is rationally designed and fabricated not only for relieving the hypoxic tumor microenvironment (TME) to enhance PDT efficacy, but also for determining the optimal triggering time through second near-infrared (NIR-II) fluorescence imaging. The designed nanodrug continuously releases a large amount of O 2 , H 2 O 2 , and Ca 2+ ions when exposed to the acidic TME. Meanwhile, under downshifting NIR-II bioimaging guidance, chlorine e6 (Ce6) consumes oxygen to produce 1 O 2 upon excitation of upconversion photon. Moreover, cytotoxic reactive oxygen species (ROS) and calcium overload can induce mitochondria injury and thus enhance the oxidative stress in tumor cells. As a result, the NIR-II bioimaging guided TME-responsive oxygen self-sufficient PDT nanosystem presents enhanced anti-tumor efficacy without obvious systemic toxicity. Thus, the fabricated nanodrug offers great potential for designing an accurate cancer theranostic system., (© 2022 Wiley-VCH GmbH.)

Patients with ischemic heart disease receiving reperfusion therapy still need to face left ventricular remodeling and heart failure after myocardial infarction. Reperfusion itself paradoxically leads to further cardiomyocyte death and systolic dysfunction. Ischemia/reperfusion (I/R) injury can eliminate the benefits of reperfusion therapy in patients and causes secondary myocardial injury. Mitochondrial dysfunction and structural disorder are the basic driving force of I/R injury. We summarized the basic relationship and potential mechanisms of mitochondrial injury in the development of I/R injury. Subsequently, this review summarized the natural products (NPs) that have been proven to targeting mitochondrial therapeutic effects during I/R injury in recent years and related cellular signal transduction pathways. We found that these NPs mainly protected the structural integrity of mitochondria and improve dysfunction, such as reducing mitochondrial division and fusion abnormalities, improving mitochondrial Ca2+ overload and inhibiting reactive oxygen species overproduction, thereby playing a role in protecting cardiomyocytes during I/R injury. This data would deepen the understanding of I/R-induced mitochondrial pathological process and suggested that NPs are expected to be transformed into potential therapies targeting mitochondria. [Display omitted] • Mitochondrial reactive oxygen species have emerged as an important mechanism of myocardial ischemia/reperfusion injury. • In ischemia/reperfusion-induced cardiac injury, natural products can target mitochondria to exert cardioprotection. • Natural products are potential therapies to protect mitochondria against ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a life-threatening disease, which is closely related to neuron damage during ischemia. Mitochondrial dysfunction is essentially involved in the pathophysiological process of ischemic stroke. Mitochondrial calcium overload contributes to the development of mitochondrial dysfunction. However, the underlying mechanisms of mitochondrial calcium overload are far from being fully revealed. In the present study, middle cerebral artery obstruction (MCAO) was performed in vivo and oxygen and glucose deprivation (OGD) in vitro. The results indicated that both MCAO and OGD induced significant mitochondrial dysfunction in vivo and in vitro. The mitochondria became fragmented under hypoxia conditions, accompanied with upregulation of the heat shock protein 75 kDa glucose-regulated protein (GRP75). Inhibition of GRP75 was able to effectively ameliorate mitochondrial calcium overload and preserve mitochondrial function, which may provide evidence for further translational studies of ischemic diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cu species are optimally impregnated along with Ca species in BG networks. • Cu-BG without drug induced Fenton-like reaction-assisted deadly free radicals. • Ca species in BG presented enhanced calcification for osteogenesis. • Biocompatible Cu-BG networks enhanced the (HIF)-1α expression. • Cu-BG networks showed synergistic cancer killing and bone regeneration abilities. Malignant osteosarcoma is one of the serious health concerns attributed to inferior prognosis and uncontrolled metastasis in clinics. Indeed, multifunctional therapeutics with precise tumor killing and subsequent regeneration of damaged tissue are of immense requirement in treating osteosarcoma. Herein, this study demonstrates the fabrication of versatile calcium/copper-impregnated bioactive glass (Ca-BG/Cu-BG) frameworks with orchestrated cancer inhibition and bone tissue calcification towards osteosarcoma therapy. Initially, the designed composites are systematically characterized to explore various morphological attributes and physicochemical properties. The optimal formulation of Cu-BG (10 mol%) presented orchestrated effects of an excellent pH-responsive anticancer effect through hydroxyl radical (·OH) generation and facilitated hydroxyapatite formation towards bone tissue calcification. Further , in vitro investigations demonstrated substantial biocompatibility in mouse embryo osteoblast precursor cell line (MC3T3-E1) and exceptional anti-tumor effects in human osteosarcoma cells (HOS) through improved cellular internalization efficacy and free radical generation, respectively. Finally, in vivo immunostaining and micro-computed tomography (μCT) images of osteosarcoma-bearing mice confirmed Fenton-like reaction-induced chemodynamic therapy (CDT), over-expressed hypoxia-inducible factor (HIF)-1α through p53 pathway, and formation of calcified nodules. In addition, hematological analyses of hematoxylin-eosin (HE) stained main organ sections presented biosafety elucidations. Together, the synergistic prospects of Cu2+ and Ca2+ species had substantially orchestrated towards regenerative medicine. [ABSTRACT FROM AUTHOR]

The present study investigated enhancement of apoptosis induction and the mechanisms underlying calcium overload on C6 glioma cells in vitro, stimulated by low-level ultrasound in combination with hematoporphyrin monomethyl ether (HMME). The optimum frequency of ultrasound was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The apoptotic rate, reactive oxygen species concentration and decreased mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Morphological changes were detected by a transmission electron microscope, and the concentration of intracellular Ca2+, [Ca2+]i, was detected by a confocal laser scanning microscope. In addition, the release of cytochrome c (cyt-c) was measured by western blot analysis. The results revealed that an increased apoptotic effect was induced by sonodynamic therapy (SDT), and this was found to correlate with the overloaded [Ca2+]i, derived from the intra- and extracellular sources in the early apoptotic process. The results also revealed an increased level of ROS production, a decreased MMP and an increased release of cyt-c. The present study indicated that low-level ultrasound in combination with HMME improved the apoptotic effect in C6 glioma cells. The overloaded [Ca2+]i was involved in the mechanism by which apoptosis was stimulated and enhanced by SDT. [ABSTRACT FROM AUTHOR]

This study examined the effect of cholic acid (CA) on cultured cardiac myocytes (CMs) from neonatal rats with an attempt to explore the possible mechanism of sudden fetal death in intrahepatic cholestasis of pregnancy (ICP). Inverted microscopy was performed to detect the impact of CA on the beating rates of rat CMs. MTT method was used to study the effect of CA on the viability of CMs. CMs cultured in vitro were incubated with 10 μmol/L Ca-sensitive fluorescence indicator fluo-3/AM. The fluorescence signals of free calcium induced by CA were measured under a laser scanning confocal microscope. The results showed that CA decreased the beating rates of the CMs in a dose-dependent manner. CA could suppress the activities of CMs in a time- and dose-dependent manner. CA increased the concentration of intracellular free calcium in a dose-dependent manner. Our study suggested that CA could inhibit the activity of CMs by causing calcium overload, thereby leading to the sudden fetal death in ICP. [ABSTRACT FROM AUTHOR]

High incidences of myocardial infarction associated with high morbidity and mortality, are a major concern and economic burden on industrialized nations. Persistent β-adrenergic receptor stimulation with isoproterenol leads to the development of oxidative stress, myocardial inflammation, thrombosis, platelet aggregation and calcium overload, which ultimately cause myocardial infarction. Therapeutic agents that are presently employed for the prevention and management of myocardial infarction are beta-blockers, antithrombotics, thrombolytics, statins, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, calcium channel blockers and nitrovasodilators. In spite of effective available interventions, the mortality rate of myocardial infarction is progressively increasing. Thus, there has been a regular need to develop effective therapies for the prevention and management of this insidious disease. In this review, the authors give an overview of the consequences of isoproterenol in the pathogenesis of cardiac disorders and various therapeutic possibilities to prevent these disorders. [ABSTRACT FROM PUBLISHER]

Reduced cardiac mortality and morbidity have long been observed in association with omega-3 long chain polyunsaturated fatty acids (LC-PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish consumption, without clear physiological explanation. This review seeks to identify mechanisms of action based on evidence: of physiological effects, active components and effective intakes. Fish oil pleiotropic effects reveal actions that are either intrinsic: effects on cardiac function dependent upon membrane incorporation; or extrinsic: indirect cardiac effects through vascular disease. Extrinsic actions require EPA + DHA doses >3 g/day. Intrinsic effects derive from usual dietary intakes, <1 g/day and include improved myocardial oxygen efficiency, heart rate, nutritional preconditioning against ischaemic injury, arrhythmias and heart failure. Myocardial Na and K currents are non-selectively modulated by omega-3 and omega-6 PUFA to stabilise cells in vitro, but not by fish oil-induced membrane change. In contrast, cellular Ca overload involved in ischaemic injury, arrhythmia and spontaneous pacemaker activity are modulated by both dietary fish oil and in vitro omega-3 LC-PUFA. A potential linking role of bioactive epoxy and hydroxy PUFA derivatives requires investigation. Omega-3 DHA predominates over EPA in population intake, is preferentially incorporated into myocardium and is selectively active in heart rate and arrhythmia modulation, but EPA predominates in clinical trials. Myocardial selectivity for DHA and independent intrinsic and extrinsic physiological mechanisms underpinning diverse clinical endpoints can explain some contradictory outcomes of clinical trials. Intrinsic modulation of intracellular Ca handling provides a unifying physiologically plausible basis for intrinsic fish oil actions and insight to nutritional optimisation of cardiac function. [ABSTRACT FROM AUTHOR]

Background: Numerous pathological processes that affect liver function in patients with liver failure have been identified. Among them, hyperammonia is one of the most common phenomena.The purpose of this study was to determine whether hyperammonia could induced specific liver injury. Methods: Hyperammonemic cells were established using NH4Cl. The cells were assessed by MTT, ELISA, and flow cytometric analyses. The expression levels of selected genes and proteins were confirmed by quantitative RT-PCR and western blot analyses. Results: The effects of 20 mM NH4Cl pretreatment on the cell proliferation and apoptosis of primary hepatocytes and other cells were performed by MTT assays and flow cytometric analyses. Significant increasing in cytotoxicity and apoptosis were only observed in hepatocytes. The cell damage was reduced after adding BAPTA-AM but unchanged after adding EGTA. The expression levels of caspase-3, cytochrome C, calmodulin, and inducible nitric oxide synthase were increased and that of bcl-2 was reduced. The Na+-K+-ATPase activities in hyperammonia liver cells was no signiaficant difference compaired with the control group, but was decreased in astrocytes. NH4Cl pretreatment of primary hepatocytes promoted the activation of mitochondrial permeability transition pores and the mitochondria swelled irregularly. Conclusions: Hyperammonia induces specific liver injury through an intrinsic Ca2+-independent apoptosis pathway. [ABSTRACT FROM AUTHOR]

Preventing the consequences of ischemia/reperfusion (I/R)-induced lesions in the clinic requires the administration of pharmacological agents prior to restoring coronary vascularization. The aim of this study was to evaluate the effects of ranolazine and propranolol when administered either alone or combined prior to I/R induction in a pig model. Thirty domestic pigs were randomly assigned to five groups of six animals including (i) sham animals; (ii) untreated animals with 45-min ischemia and 1-min reperfusion; animals administered intravenously with (iii) ranolazine, or (iv) propranolol, or (v) both combined, prior to 45-min ischemia and 1-min reperfusion. The heart rate (HR), duration of monophasic action potentials ( dMAP), and peak of the time derivative of left ventricular pressure (LV dP/dt max) were measured during ischemia and after 1 min of reperfusion. Structural and functional parameters of mitochondria were analyzed in tissue samples taken from the left ventricle ischemic area at the end of the experiment. I/R induced expected effects, namely accelerated HR, decreased dMAP and LV dP/dt max, and altered mitochondrial structural and functional parameters including decreased oxygen consumption, increased reactive oxygen species (ROS) production, and reduced calcium retention capacity resulting in the opening of mitochondrial permeability transition pores ( mPTP). Ranolazine and propranolol administered either alone or combined prior to I/R significantly decreased all of these deleterious consequences. The protective effects of ranolazine and propranolol are seemingly due to the prevention of calcium overload and resulting lesions in mitochondria. [ABSTRACT FROM AUTHOR]

Bisabololoxide A (BSBO), main constituents in German chamomile extract, is responsible for antipruritic effect. In previous study, the incubation with 30-100 μM BSBO for 24 h exerted cytotoxic and proapoptotic effects on rat thymocytes. To further characterize BSBO cytotoxicity, the effect on the cells suffering from calcium overload by calcium ionophore A23187 was examined. A23187 induced Ca2+-dependent cell death. Contrary to our expectation, 1-10 μM BSBO inhibited A23187-induced increase in cell lethality of rat thymocytes. BSBO attenuated A23187-induced increases in populations of shrunken living cells, phosphatidylserine-exposed living cells, and dead cells, without affecting the increase in intracellular Ca2+ concentration and the Ca2+-dependent hyperpolarization. The effect of BSBO on A23187-treated cells may be unique because the activation of Ca2+-dependent K+ channels is required for cell shrinkage, externalization of phosphatidylserine, and cell death in some cells. The cell death induced by A23187 was not inhibited by Z-VAD-FMK, a pan-inhibitor of caspases. Thus, the cell death may be a necrosis with some features observed during an early stage of apoptosis. These results suggest that BSBO at low micromolar concentrations is cytoprotective against calcium overload. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Background: Ginsenoside Rg1 (Rg1) is believed to be one of the main active principles in ginseng, a traditional Chinese medicine extensively used to enhance stamina and deal with fatigue as well as physical stress. It has been reported that Rg1 performs multiple biological activities, including neuroprotective activity. In this study, we investigated the efficacy of ginsenoside Rg1 on ischemia–reperfusion injury in cultured hippocampal cells and also probed its possible mechanisms. Methods: To establish a model of oxygen–glucose deprivation (OGD) and reperfusion, cultured hippocampal neurons were exposed to OGD for 2.5 hours, followed by a 24-hour reoxygenation. Cultured hippocampal neurons were randomly divided into control group, model group (vehicle), and ginsenoside Rg1 treatment groups (5μM, 20μM, 60μM). At 24 hours post-OGD, the intracellular free calcium concentration was detected using Furo-3/AM-loaded hippocampal neurons deprived of oxygen and glucose. Neuronal nitric oxide synthase (nNOS) activity was measured by chemical colorimetry. Cell apoptosis was evaluated by Hoechst staining, and the neuron viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: Excitotoxic neuronal injury of OGD was demonstrated by the increase of intracellular free calcium concentrations and elevated nNOS activity in the model group compared with the control group. The intracellular free calcium concentrations and the nNOS activity in the groups receiving intermediate and high dose of ginsenoside Rg1 were significantly lower than those of the control group (p < 0.05). In addition, intermediate and high dose of ginsenoside Rg1 administration could also attenuate the cell viability loss (p < 0.05) and cell apoptosis induced by OGD. Conclusion: Ginsenoside Rg1 has neuroprotective effect on ischemia–reperfusion injury in cultured hippocampal cells mediated by blocking calcium over-influx into neuronal cells and decreasing the nNOS activity after OGD exposure. We infer that ginsenoside Rg1 may serve as a potential therapeutic agent for cerebral ischemia injury. [Copyright &y& Elsevier]

The aim of the present study was to investigate the protective effects of emodin against calcium overload and endoplasmic reticulum (ER) stress in an acute pancreatitis model in vitro. AR42J rat pancreatic acinar cells treated with cerulein (10-7 M) and lipoplysaccharide (LPS; 10 mg/l) were used to mimic acute pancreatitis in vitro. The amylase activity in cellular lysates and culture media was detected by spectrophotometry. The level of cytosolic calcium was measured by laser confocal microscopy. Cell apoptosis and necrosis were examined by flow cytometry. Reverse transcription polymerase chain reaction was used to determine the mRNA expression of ER chaperone immunoglobulin binding protein (Bip) and downstream molecules, including protein kinase like ER kinase (PERK), activation transcription factor 6 (ATF6) and inositol-requiring protein 1 (IRE1). The results showed that emodin significantly reduced the expression and release of amylase, attenuated calcium overload and decreased the mRNA expression of Bip, PERK, ATF6 and IRE1 which was significantly elevated in AR42J cells treated with cerulein and LPS. Emodin also reduced cell apoptosis and necrosis. Therefore, the results of the present study indicate that emodin protects against AR42J cell injury caused by cerulein and LPS. These effects may be associated with reduced calcium overload and inhibited ER stress responses. [ABSTRACT FROM AUTHOR]

Taurine is an abundant β-amino acid that regulates several events that dramatically influence the development of ischemia-reperfusion injury. One of these events is the extrusion of taurine and Na from the cell via the taurine/Na symport. The loss of Na during the ischemia-reperfusion insult limits the amount of available Na for Na/Ca exchange, an important process in the development of Ca overload and the activation of the mitochondrial permeability transition, a key process in ischemia-reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger 'osmotic preconditioning,' a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia-reperfusion insult may increase the risk of ventricular remodeling and development of heart failure. [ABSTRACT FROM AUTHOR]

Iron is an essential element for various cellular metabolism. Cancer cells also have high requirement of iron in their proliferation, invasion, and metastasis processes. Alendronate (ALN), a kind of FDA-approved bisphosphonates with metal-chelating capability, is initially certified to selectively bind to intracellular Fe 3+ theoretically and experimentally in this study. Hence, CaALN iron nanochelator is rationally designed to kill cancer cells by synergism of Fe-depletion and calcium accumulation. In vitro experiments and RNA sequencing analysis indicate that CaALN nanomedicine inhibits the proliferation of cancer cells by depleting Fe, interfering with DNA replication, and triggering intracellular reactive oxygen species (ROS). Meanwhile, released Ca 2+ and ROS mutually promote and induce damage of cellular macromolecules, which leads to mitochondrial apoptosis of cancer cells. In an intraperitoneal disseminated mouse model with the human ovarian cancer cells SKOV3, CaALN nanoparticles selectively accumulate in tumor tissues and result in significant retardation of tumor growth and ascites formation. The mean survival time of SKOV3-bearing mice in treatment group is prolonged from 33 to 90 d. These results indicate that the alendronate-originated iron chelator can serve as an efficient strategy for the treatment of peritoneal carcinomatosis., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The anticancer mechanism of nanozymes is dominantly associated with the capacity for generation of reactive oxygen species (ROS) caused by the valence change of metal elements. However, very little research is focused on and has achieved the exploration and development of enzyme-mimicking activities of valence-invariable metal compounds. Herein, a distinct valence-invariable calcium fluoride (CaF 2 ) nanozyme with ultrasound (US)-enhanced peroxidase (POD)-mimicking activity is rationally designed and engineered for efficient calcium (Ca 2+ )-overload-enhanced catalytic tumor nanotherapy, which is the first paradigm of Ca-based nanozymes for catalytic cancer treatment. The release of exogenous Ca 2+ ions from CaF 2 nanocrystals and deleterious ROS generation derived from US-amplified POD-mimicking properties facilitate intracellular Ca 2+ accumulation and achieve Ca 2+ -overload-induced mitochondrial dysfunction through introducing exogenous Ca 2+ ions and regulating calcium-pumping channels of neoplastic cells. Especially, US as an exogenous energy input is capable of substantially amplifying POD-mimicking catalytic activities of CaF 2 nanozyme, ultimately achieving efficient anti-neoplastic outcome on both 4T1 breast tumor and H22 hepatic carcinoma animal models. Such a discovery of enzyme-like activity of valence-invariable metal compounds can broaden the cognition scope of nanozymes and effectively serves the field of catalytic and chemoreactive nanomedicine., (© 2022 Wiley-VCH GmbH.)

The efficiency of reactive oxygen species (ROS)-mediated cancer therapy is restrained by intrinsic characteristics in the tumor microenvironment (TME), such as overexpressed glutathione (GSH), hypoxia and limited efficiency of H 2 O 2 . In this work, intelligent copper-dropped calcium carbonate loading sonosensitizer Ce6 nanoparticles (Cu/CaCO 3 @Ce6, CCC NPs) are established to realize TME-responsive self-supply of oxygen and successively Ca 2+ -overloading-strengthened chemodynamic therapy/sonodynamic therapy (CDT/SDT). CCC NPs release Ca 2+ , Cu 2+ , and Ce6 in weakly acid and GSH-excessive TME. Released Cu 2+ can not only consume GSH and turn into Cu + via a redox reaction, but also provide CDT-creating hydroxyl radicals through the Fenton-like reaction. Under ultrasound irradiation, the intracellular oxidative stress is amplified profoundly relying on singlet oxygen outburst from SDT. Moreover, Ca 2+ influx aggravates the mitochondrial disruption, which further accelerates the oxidation level. The facile and feasible design of the Cu-dropped CaCO 3 -based nanoregulators will be further developed as a paradigm in ROS-contributed cancer therapy., (© 2022 Wiley-VCH GmbH.)

Background: Hypercalcemia induced by multiple myeloma (MM) affects the biological functions of excitable and non-excitable cells. However, red blood cells (RBCs) regulatory effect on calcium in hypercalcemia is still not fully understood., Methods: A total of 113 patients with MM osteolytic lesions were studied retrospectively. Flow cytometry and atomic absorption spectroscopy were used to detect calcium content. Immunofluorescence and Western blotting were used to investigate protein expression. GEO and miRNA databases were used to screen miRNAs. Exosomal miR-4261 migration was investigated by Transwell assay. Dual-luciferase assays confirmed the targeting relationship between miR-4261 and ATP2B4. An RBC oxidative stress model was constructed, and Omega-Agatoxin IVA was used to study the role of plasma membrane Ca 2+ -ATPase 4 (PMCA4) in RBCs., Results: The results showed that MM RBCs had calcium overload, and serum calcium levels increased as the number of RBCs decreased. The expression of PMCA4 in MM RBCs was significantly lower than in normal RBCs. The exosomal miR-4261 produced by MM cells could be transferred to RBCs to downregulate the expression of ATP2B4., Conclusions: Studies have confirmed that RBCs experience calcium overload in MM with osteolytic lesions, which is related to the downregulation of ATP2B4 by MM exosomal miR-4261., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bian, Zhang, Lin, Sun, Guo, Pan, Cui, Yao, Xu, Hao, Wang, Tong, Bu, Kong, Liu and Li.)