Disturbance Of Ca2 Research Articles

Recoverability of zebrafish from decabromodiphenyl ether exposure: The persisted interference with extracellular matrix production and collagen synthesis and the enhancement of arrhythmias

As a widely used brominated flame retardant, the widespread presence of decabromodiphenyl ether (BDE-209) in the natural environment and the toxicity risks it poses are well established, but the recoverability of BDE-209-induced individual injuries remains unknown. Therefore, a 7-day depuration experiment following a 4-day exposure of zebrafish to BDE-209 was conducted to confirm the recoverability and its mode of action. Oxidative stress after depuration was significantly reduced compared with BDE-209 exposure as indicated by the decreased expression level of oxidative stress-related genes and the reduced MDA, Gpx, and GST in zebrafish, indicating a gradual recovery of antioxidant activity. However, BDE-209 inhibition of extracellular matrix (ECM) proteins worsened after depuration. Mechanistically, BDE-209 mediated ECM production and secretion by down-regulating integrin expression. Furthermore, BDE-209 inhibition of collagen synthesis worsened after depuration. Biochemical assays and histopathological observations revealed a same result in zebrafish. Mechanistically, lysine hydroxylation is inhibited thereby affecting collagen synthesis. Interestingly, zebrafish showed arrhythmia after depuration compared to BDE-209 exposure, and abnormal changes in ATPase levels indicated that disturbances in Ca2+ homeostasis contributed to arrhythmia. Collectively, BDE-209-induced interference with ECM production and collagen synthesis persisted after depuration, which will provide new insights for understanding the recovery patterns of individuals under BDE-209 stress.

The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases.

Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%-20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10-30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.

Cytotoxicity of Prymnesium parvum extracts and prymnesin analogs on epithelial fish gill cells RTgill-W1 and the human colon cell line HCEC-1CT.

Harmful algal blooms kill fish populations worldwide, as exemplified by the haptophyte microalga Prymnesiumparvum. The suspected causative agents are prymnesins, categorized as A-, B-, and C-types based on backbone carbon atoms. Impacts of P.parvum extracts and purified prymnesins were tested on the epithelial rainbow trout fish gill cell line RTgill-W1 and on the human colon epithelial cells HCEC-1CT. Cytotoxic potencies ranked A > C > B-type with concentrations spanning from low (A- and C-type) to middle (B-type) nM ranges. Although RTgill-W1 cells were about twofold more sensitive than HCEC-1CT, the cytotoxicity of prymnesins is not limited to fish gills. Both cell lines responded rapidly to prymnesins; with EC50 values for B-types in RTgill-W1 cells of 110 ± 11nM and 41.5 ± 0.6nM after incubations times of 3 and 24h. Results of fluorescence imaging and measured lytic effects suggest plasma membrane interactions. Postulating an osmotic imbalance as mechanisms of toxicity, incubations with prymnesins in media lacking either Cl-, Na+, or Ca2+ were performed. Cl- removal reduced morphometric rearrangements observed in RTgill-W1 and cytotoxicity in HCEC-1CT cells. Ca2+-free medium in RTgill-W1 cells exacerbated effects on the cell nuclei. Prymnesin composition of different P.parvum strains showed that analog composition within one type scarcely influenced the cytotoxic potential, while analog type potentially dictate potency. Overall, A-type prymnesins were the most potent ones in both cell lines followed by the C-types, and lastly B-types. Disturbance of Ca2+ and Cl- ionoregulation may be integral to prymnesin toxicity.

Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca2+/Calmodulin-Dependent Kinase II and Inositol-1,4,5-trisphosphate Signaling.

Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca2+ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca2+ transient (CaT) alternans-beat-to-beat alternations in CaT amplitude-served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca2+ current. Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP3 signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca2+ release and increased the degree of alternans. Inhibition of IP3 receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP3 signaling contribute to atrial arrhythmogenesis in HF.

Increased IP3R-3 degradation induced by acrylamide promoted Ca2+-dependent calpain activation and axon damage in rats

Occupational and environmental exposure to acrylamide (ACR) can cause selective peripheral and central nerve fiber degeneration. IP3R-3 is an important transmembrane Ca2+ channel on the endoplasmic reticulum (ER), previous studies have found that ACR could induce Ca2+-dependent calpain activation and axon injury, but the exact role of IP3R-3 in ACR neuropathy is still unclear. Here we show that ACR exposure (40 mg/kg) markedly increased the ubiquitination of IP3R-3 in rat spinal cords, and promoted the degradation of IP3R-3 through the ubiquitin-proteasome pathway. Furthermore, the normal structure of ER, especially the mitochondrial associated membranes (MAMs) component, was significantly impaired in ACR neuropathy, and the ER stress pathway was activated, which indicated that the aberrant increase of cytoplasmic Ca2+ could be attributed the destruction of IP3R-3. Further investigation demonstrated that the proteasome inhibitor MG-132 effectively rescued the IP3R-3 loss, attenuated the intracellular Ca2+ increase, and reduced the axon loss of Neuron 2a (N2a) cells following ACR exposure. Moreover, the calpain inhibitor ALLN also reduced the loss of IP3R-3 and axon injury in N2a cells, but did not alleviate the Ca2+ increase in cytosol, supporting that the abnormal ubiquitination of IP3R-3 was the upstream of the cellular Ca2+ rise and axon damage in ACR neuropathy. Taken together, our results suggested that the aberrant IP3R-3 degradation played an important role in the disturbance of Ca2+ homeostasis and the downstream axon loss in ACR neuropathy, thus providing a potential therapeutic target for ACR neurotoxicity.

TRP Channels as Emerging Therapeutic Targets in Neurological Disorders

Neurological disorders like Parkinson disease (PD), Alzheimer’s disease (AD), epilepsy, stroke, schizophrenia, depression, bipolar disorder, etc., are increasingly recognized as signifi cant causes of death and disability globally. All these neurological disorders have several similar causes, such as disturbance in Ca2+ homeostasis and misfolded proteins deposition in the brain through impairing the function of a no. of ion channels, including TRP channels. TRP channels superfamily consists of a broad collection of non-selective Ca2+ permeable channels that plays a crucial role in regulating intracellular Ca2+ homeostasis. These channels function as cellular sensors and are stimulated by a variety of physio-chemical stimulus, and endogenous and exogenous ligands. Numerous neuronal diseases are caused by disturbances in the activity of TRP channels, which are abundantly expressed in neuronal cells. When the activity of TRP channels is disturbed under pathological conditions, there is disruption of the homeostasis of neurons via oxidative stress, Ca2+ dyshomeostasis, and mitochondrial dysfunction. Therefore, these channels act as promising therapeutic candidates for pharmacological interventions in several neurological disorders. Thus within this review, we emphasize the function of TRP channels in neurological disorders and highlight the pharmacological modulators that target TRP channels

Insights into the role of intracellular calcium signaling in the neurobiology of neurodevelopmental disorders.

Calcium (Ca2+) comprises a critical ionic second messenger in the central nervous system that is under the control of a wide array of regulatory mechanisms, including organellar Ca2+ stores, membrane channels and pumps, and intracellular Ca2+-binding proteins. Not surprisingly, disturbances in Ca2+ homeostasis have been linked to neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. However, aberrations in Ca2+ homeostasis have also been implicated in neuropsychiatric disorders with a strong neurodevelopmental component including autism spectrum disorder (ASD) attention-deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). While plasma membrane Ca2+ channels and synaptic Ca2+-binding proteins have been extensively studied, increasing evidence suggests a prominent role for intracellular Ca2+ stores, such as the endoplasmic reticulum (ER), in aberrant neurodevelopment. In the context of the current mini-review, we discuss recent findings implicating critical intracellular Ca2+-handling regulators such as the sarco-ER Ca2+ ATPase 2 (SERCA2), ryanodine receptors (RyRs), inositol triphosphate receptors (IP3Rs), and parvalbumin (PVALB), in the emergence of ASD, SCZ, and ADHD.

Spironolactone as a Potential New Treatment to Prevent Arrhythmias in Arrhythmogenic Cardiomyopathy Cell Model

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic disease associated with ventricular arrhythmias in patients. The occurrence of these arrhythmias is due to direct electrophysiological remodeling of the cardiomyocytes, namely a reduction in the action potential duration (APD) and a disturbance of Ca2+ homeostasis. Interestingly, spironolactone (SP), a mineralocorticoid receptor antagonist, is known to block K+ channels and may reduce arrhythmias. Here, we assess the direct effect of SP and its metabolite canrenoic acid (CA) in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) of a patient bearing a missense mutation (c.394C>T) in the DSC2 gene coding for desmocollin 2 and for the amino acid replacement of arginine by cysteine at position 132 (R132C). SP and CA corrected the APD in the muted cells (vs. the control) in linking to a normalization of the hERG and KCNQ1 K+ channel currents. In addition, SP and CA had a direct cellular effect on Ca2+ homeostasis. They reduced the amplitude and aberrant Ca2+ events. In conclusion, we show the direct beneficial effects of SP on the AP and Ca2+ homeostasis of DSC2-specific hiPSC-CMs. These results provide a rationale for a new therapeutical approach to tackle mechanical and electrical burdens in patients suffering from ACM.

TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias.

Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear. In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4-/- mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4-/- mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner. The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.

Glyphosate exposure deteriorates oocyte meiotic maturation via induction of organelle dysfunctions in pigs

BackgroundRecently, defects in mammalian oocytes maturation induced by environmental pollution results in the decreasing animal reproduction. Animal exposed to glyphosate is largely unavoidable because glyphosate is one of the most widely used herbicide worldwide due to its high-efficiency and broad-spectrum effects, which causes glyphosate an environmental contaminant found in soil, water and food. During the last few years, the growing and wider use of glyphosate has raised great concerns about its effects of reproductive toxicity. In this study, using porcine models, we investigated effects of glyphosate on organelle functions during oocyte meiosis.ResultsThe results showed glyphosate exposure disrupted porcine oocyte maturation. Expression levels of cumulus expansion-related genes were interfered, further indicating the meiotic defects. The damaging effects were mediated by destruction of mitochondrial distribution and functions, which induced ROS accumulation and oxidative stress, also indicated by the decreased mRNA expression of related antioxidant enzyme genes. We also found an interference of endoplasmic reticulum (ER) distribution, disturbance of Ca2+ homeostasis, as well as fluctuation of ER stress, showing with the reduced ER stress-related mRNA or protein expression, which could indicate the dysfunction of ER for protein processing and signal transduction in glyphosate-exposed oocytes. Moreover, glyphosate exposure induced the disruption of lysosome function for autophagy, showing with the decrease of LAMP2 expression and autophagy-related genes mRNA expression. Additionally, our data showed the distribution of Golgi apparatus and the functions of ribosome were disturbed after glyphosate exposure, which might affect protein synthesis and transport.ConclusionsCollectively, our study showed that exposed to glyphosate could affect animal reproduction by compromising the quality of oocytes through its wide toxic effects on organelle functions.

Influence of preslaughter stress on poultry meat

In the present article the authors consider the importance of issue of the poultry meat quality. The increasing demand for poultry meat provides for the rapid growth of industrial stock of poultry, which contributes to appearance of meat with various defects in muscle tissue: PSE meat, that features low pH, pale color, soft and watery texture, and DFD meat — it is more dense and drier, of dark saturated color. Till now, the causes and mechanisms of appearance of those anomalies still haven’t been unambiguously formulated, however, a large number of publications prove the influence of the genetic characteristics of modern crosses of broilers and turkeys on disturbances in Ca2+ metabolism process in the sarcoplasm of muscle fibers. The uncontrolled release of calcium along with the high temperature of slaughtered poultry carcasses immediately after slaughter provokes an intense decrease in pH and launches denaturation processes in proteins. The numerous studies have shown deterioration in functional and technological properties of meat in stress-sensitive poultry, such as moisture-binding capacity and high acidity, which increases loss of meat juice during its storage and its weight during heat treatment. Recent publications have been devoted to development of a strategy for use of PSE poultry meat and search for efficient processing of PSE poultry meat, since the scientific community does not provide direct evidence on possibility of genetic adjustment of the poultry in order to exclude the occurrence of PSE quality of meat.

Chronic exposure to tralopyril induced abnormal growth and calcium regulation of turbot (Scophthalmus maximus)

Tralopyril is an emerging marine antifouling agent with limited data on its effects on fish growth and calcium regulation. To determine the changes induced by long-term exposure to tralopyril, multi-levels (such as molecular, biochemical, and individual levels) responses were measured in turbot at different concentrations (1 μg/L, 20 μg/L). The results showed that 1 μg/L mainly affected the immune response, while 20 μg/L affected the synthesis and metabolism of steroids and fat. However, different concentrations of tralopyril affected the synthesis, secretion and action of parathyroid hormone and growth hormone. The expression of GH/IGF axis gene and the level of growth hormone increased significantly, leading to abnormal growth. The energy tradeoff between immunity and growth at 1 μg/L tralopyril pressure may inhibit growth. The change of Ca2+ level was accompanied by the disturbance of PTH-related gene expression. The results of molecular docking showed that the disturbance of Ca2+ regulation might be attributed to the inhibition of vitamin D receptor by tralopyril, which affected the vitamin D signaling pathway. This study provides scientific data for the in-depth understanding and risk assessment of the toxicological effects of tralopyril and reveals the potential threat of tralopyril to environmental health.

Ero1α-dependent ERP44 dissociation from RYR2 contributes to cardiac arrhythmia

Oxidative stress in cardiac disease promotes pro-arrhythmic disturbances in Ca2+ homeostasis. This includes impaired luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ release channel the ryanodine receptor (RyR2), driving increased channel activity. However, exact mechanisms underlying the redox-mediated increase of RyR2 function in cardiac disease remain elusive. Using a rat model of hypertrophy induced by thoracic aorta banding (TAB), we tested whether oxidoreductase proteins that dynamically regulate the SR oxidative environment are involved in this process.

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia.

Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca2+ homeostasis, impairing luminal Ca2+ regulation of the sarcoplasmic reticulum (SR) Ca2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process. A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca2+ and reactive oxygen species imaging in isolated ventricular myocytes (VMs). The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of Ero1α (endoplasmic reticulum oxidoreductase 1 alpha). Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca2+ transient amplitude and SR Ca2+ content, and reduced proarrhythmic spontaneous Ca2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca2+-dependent ventricular tachyarrhythmias in TAB hearts challenged with isoproterenol. Experiments in TAB VMs and human embryonic kidney 293 cells expressing human RyR2 revealed that an Ero1α-mediated increase in SR Ca2+-channel activity involves dissociation of intraluminal protein ERp44 (endoplasmic reticulum protein 44) from the RyR2 complex. Site-directed mutagenesis and molecular dynamics simulations demonstrated a novel redox-sensitive association of ERp44 with RyR2 mediated by intraluminal cysteine 4806. ERp44-RyR2 association in TAB VMs was restored by Ero1α inhibition, but not by reducing agent dithiothreitol, as hypo-oxidation precludes formation of covalent bond between RyR2 and ERp44. A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca2+ release and Ca2+-dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.

The bacterium Pseudomonas protegens antagonizes the microalga Chlamydomonas reinhardtii using a blend of toxins.

The unicellular alga Chlamydomonas reinhardtii and the bacterium Pseudomonas protegens serve as a model to study the interactions between photosynthetic and heterotrophic microorganisms. P. protegens secretes the cyclic lipopeptide orfamide A that interferes with cytosolic Ca2+ homeostasis in C. reinhardtii resulting in deflagellation of the algal cells. Here, we studied the roles of additional secondary metabolites secreted by P. protegens using individual compounds and co-cultivation of algae with bacterial mutants. Rhizoxin S2, pyrrolnitrin, pyoluteorin, 2,4-diacetylphloroglucinol (DAPG) and orfamide A all induce changes in cell morphology and inhibit the growth of C. reinhardtii. Rhizoxin S2 exerts the strongest growth inhibition, and its action depends on the spatial structure of the environment (agar versus liquid culture). Algal motility is unaffected by rhizoxin S2 and is most potently inhibited by orfamide A (IC50 = 4.1μM). Pyrrolnitrin and pyoluteorin both interfere with algal cytosolic Ca2+ homeostasis and motility whereas high concentrations of DAPG immobilize C. reinhardtii without deflagellation or disturbance of Ca2+ homeostasis. Co-cultivation with a regulatory mutant of bacterial secondary metabolism (ΔgacA) promotes algal growth under spatially structured conditions. Our results reveal how a single soil bacterium uses an arsenal of secreted antialgal compounds with complementary and partially overlapping activities.

Pathological Mechanism of a Constitutively Active Form of Stromal Interaction Molecule 1 in Skeletal Muscle.

Stromal interaction molecule 1 (STIM1) is the main protein that, along with Orai1, mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. Abnormal SOCE due to mutations in STIM1 is one of the causes of human skeletal muscle diseases. STIM1-R304Q (a constitutively active form of STIM1) has been found in human patients with skeletal muscle phenotypes such as muscle weakness, myalgia, muscle stiffness, and contracture. However, the pathological mechanism(s) of STIM1-R304Q in skeletal muscle have not been well studied. To examine the pathological mechanism(s) of STIM1-R304Q in skeletal muscle, STIM1-R304Q was expressed in mouse primary skeletal myotubes, and the properties of the skeletal myotubes were examined using single-myotube Ca2+ imaging, transmission electron microscopy (TEM), and biochemical approaches. STIM1-R304Q did not interfere with the terminal differentiation of skeletal myoblasts to myotubes and retained the ability of STIM1 to attenuate dihydropyridine receptor (DHPR) activity. STIM1-R304Q induced hyper-SOCE (that exceeded the SOCE by wild-type STIM1) by affecting both the amplitude and the onset rate of SOCE. Unlike that by wild-type STIM1, hyper-SOCE by STIM1-R304Q contributed to a disturbance in Ca2+ distribution between the cytosol and the sarcoplasmic reticulum (SR) (high Ca2+ in the cytosol and low Ca2+ in the SR). Moreover, the hyper-SOCE and the high cytosolic Ca2+ level induced by STIM1-R304Q involve changes in mitochondrial shape. Therefore, a series of these cellular defects induced by STIM1-R304Q could induce deleterious skeletal muscle phenotypes in human patients carrying STIM1-R304Q.

Investigation of the effect of hyperthyroidism on endoplasmic reticulum stress and tran- sient receptor potential canonical 1 channel in the kidney

Background/aim Hyperthyroidism is associated with results in increased glomerular filtration rate as well as increased renin-angiotensin-aldosterone activation. The disturbance of Ca2+ homeostasis in the endoplasmic reticulum (ER) is associated with many diseases, including diabetic nephropathy and hyperthyroidism. Transient receptor potential canonical 1 (TRPC1) channel is the first cloned TRPC family protein. Although it is expressed in many places in the kidney, its function is uncertain. TRPC1 is involved in regulating Ca2+ homeostasis, and its upregulation increases ER Ca2+ level, activates the unfolded protein response, which leads to cellular damage in the kidney. This study investigated the role of TRPC1 in the kidneys of hyperthyroid rats in terms of ER stress markers that are glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), (protein kinase R (PKR)-like endoplasmic reticulum kinase) (PERK), Inositol-requiring enzyme 1 (IRE1).Materials and methods Twenty male rats were assigned into control and hyperthyroid groups (n = 10). Hyperthyroidism was induced by adding 12 mg/L thyroxine into the drinking water of rats for 4 weeks. The serum-free T3 and T4 (fT3, fT4), TSH, blood urea nitrogen (BUN), and creatinine levels were measured. The histochemical analysis of kidney sections for morphological changes and also immunohistochemical and western blot analysis of kidney sections were performed for GRP78, ATF6, PERK, IRE1, TRPC1 antibodies.Results TSH, BUN, and creatinine levels decreased while fT3 and fT4 levels increased in the hyperthyroid rat. The morphologic analysis resulted in the capillary basal membrane thickening in glomeruli and also western blot, and immunohistochemical results showed an increase in TRPC1, GRP78, and ATF6 in the hyperthyroid rat (p < 0.05).Conclusion In conclusion, in our study, we showed for the first time that the relationship between ER stress and TRPC1, and their increased expression caused renal damage in hyperthyroid rats.

Orai–vascular endothelial-cadherin signaling complex regulates high-glucose exposure-induced increased permeability of mouse aortic endothelial cells

IntroductionDiabetes-associated endothelial barrier function impairment might be linked to disturbances in Ca2+ homeostasis. To study the role and molecular mechanism of Orais–vascular endothelial (VE)-cadherin signaling complex and its downstream signaling...

Calmodulin and Its Binding Proteins in Parkinson's Disease.

Parkinson’s disease (PD) is a neurodegenerative disorder that manifests with rest tremor, muscle rigidity and movement disturbances. At the microscopic level it is characterized by formation of specific intraneuronal inclusions, called Lewy bodies (LBs), and by a progressive loss of dopaminergic neurons in the striatum and substantia nigra. All living cells, among them neurons, rely on Ca2+ as a universal carrier of extracellular and intracellular signals that can initiate and control various cellular processes. Disturbances in Ca2+ homeostasis and dysfunction of Ca2+ signaling pathways may have serious consequences on cells and even result in cell death. Dopaminergic neurons are particularly sensitive to any changes in intracellular Ca2+ level. The best known and studied Ca2+ sensor in eukaryotic cells is calmodulin. Calmodulin binds Ca2+ with high affinity and regulates the activity of a plethora of proteins. In the brain, calmodulin and its binding proteins play a crucial role in regulation of the activity of synaptic proteins and in the maintenance of neuronal plasticity. Thus, any changes in activity of these proteins might be linked to the development and progression of neurodegenerative disorders including PD. This review aims to summarize published results regarding the role of calmodulin and its binding proteins in pathology and pathogenesis of PD.

Influence of environmentally relevant concentrations of Zn, Cd and Ni and their binary mixtures on metal uptake, bioaccumulation and development in larvae of the purple sea urchin Strongylocentrotus purpuratus

Metal accumulation, disturbance of Ca2+ homeostasis, and occurrence of abnormalities are well-established consequences of single metal exposure during early development stages of sea urchins. However, the effects caused by low concentrations of metals and metal mixtures need to be better understood in marine invertebrates. Therefore, the present study investigated the effects of environmentally relevant concentrations of Zn (9 μg/L), Cd (30 μg/L) and Ni (5 μg/L) in single and binary exposures (Zn + Cd, Cd + Ni and Ni + Zn) to the early life stages of the purple sea urchin Strongylocentrotus purpuratus. Endpoints checked in all treatments after 48-h exposure were unidirectional metal influx rates, bioaccumulation, and Ca2+ influx rates. Additionally, the presence of abnormal larvae and developmental delay was evaluated at 24 h, 48 h and 72 h of exposure. Unidirectional influx rates of all three metals were significantly higher than control background rates in all single exposures and binary mixtures, and were generally not different between them. Net accumulation (body burden) of both Zn and Cd increased significantly as a result of their respective single exposures, while Ni accumulation decreased considerably. When Zn or Cd were presented in binary exposures with other metals, the net accumulations of Zn or Cd were reduced relative to single exposures to these metals, whereas this did not occur for Ni accumulation. Thus, bioaccumulation proved to be a better metric than influx rate measurements to analyze metal competition at a whole organism level at these low metal concentrations. Short-term Ca2+ influx also did not appear to be a sensitive metric, as the measured rates did not vary among all single and binary exposures, with the exception of a lower rate in Ni + Zn binary exposure. A critical aspect observed was the relationship between bioaccumulation versus influx measurements, which proved positive for Cd, but negative for Zn and Ni, demonstrating possible capacities for both Zn and Ni regulation by sea urchin larvae. Increases in larval abnormalities relative to controls occurred only after binary mixtures, starting at 48 h exposure and maintained until 72 h. However, delay of the sea urchin development by the presence of gastrula stage at 72 h exposure occurred in Zn and Ni single exposures and all metal mixtures, with very high abnormal development when Ni was present.