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Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-cat

Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta(INS-1)-cells.

Glucose-dependent insulinotropic polypeptide (GIP) acts as a glucose-dependent growth factor for beta-cells. Here we show that GIP and glucose also act synergistically as anti-apoptotic factors for beta-cells, using the well-differentiated beta-cell line, INS-1. Mitogenic and anti-apoptotic signaling of GIP were dependent upon pleiotropic activation of protein kinase A (PKA)/cAMP regulatory element binder (CREB), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase)/PKB signaling modules. The signaling modules activated by GIP were dependent on glucose metaboli

Native store-operated calcium channels are functionally expressed in mouse spinal cord dorsal horn neurons and regulate resting calcium homeostasis.

Store-operated calcium channels (SOCs) are calcium-selective cation channels that mediate calcium entry in many different cell types. Store-operated calcium entry (SOCE) is involved in various cellular functions. Increasing evidence suggests that impairment of SOCE is responsible for numerous disorders. A previous study demonstrated that YM-58483, a potent SOC inhibitor, strongly attenuates chronic pain by systemic or intrathecal injection and completely blocks the second phase of formalin-induced spontaneous nocifensive behaviour, suggesting a potential role of SOCs in central sensitization.

Mobilisation of intracellular calcium by P2Y2 receptors in cultured, non-transformed bovine ciliary epithelial cells.

PURPOSE: To examine extracellular ATP for its ability to mobilise intracellular calcium in bovine ciliary epithelial cells; to establish and characterise P2Y2 receptor-mediated signal transduction in this tissue. METHODS: Bovine ciliary epithelial cells were isolated and cultured until confluence. The cells were reseeded on sterile coverslips and grown to obtain monolayers, then loaded with fura-2. Fluorescence was measured by a computer-controlled spectrofluorimeter and values calculated for intracellular calcium concentration. ATP, its analogues and other drugs were tested for their ability

Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN).

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased react

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… Role of mitochondria in intracellular calcium signaling in primary and secondary sensory neurones of rats Cell Calcium 2002 32 121 130 10.1016/S0143-4160(02)00095-7 12208232 31. Chung M. The role of reactive oxygen species (ROS) in persistent pain Mol. …

Non-additive interactions between mitochondrial complex IV blockers and hypoxia in rat carotid body responses.

The metabolic hypothesis of carotid body chemoreceptor hypoxia transduction proposes an impairment of ATP production as the signal for activation. We hypothesized that mitochondrial complex IV blockers and hypoxia would act synergistically in exciting afferent nerve activity. Following a pre-treatment with low dosage sodium cyanide (10-20μM), the hypoxia-induced nerve response was significantly reduced along with hypoxia-induced catecholamine release. However, in isolated glomus cells, the intracellular calcium response was enhanced as initially predicted. This suggests a cyanide-mediated impa

The calcium-sensing receptor as a nutrient sensor.

Critical to cell fate in many cell types is the ability to sense and respond to acute changes in free ionized extracellular calcium concentration ([Ca(2+)](o)). Such tight control is mediated by the activation of a protein known as the extracellular-calcium-sensing receptor (CaR). CaR belongs to the 'family C' of G-protein-coupled receptors and was the first G-protein-coupled receptor to be identified to have an inorganic cation, calcium, as its ligand. While calcium is the physiological agonist of the receptor, several other polyvalent cations and polycations can also modulate CaR function as

Oscillatory behavior of control-systems of calcium homeostasis in chickens.

Computer simulation of calcium homeostasis in chicks predicted an oscillatory behavior of bone calcium flow and kidney 25-hydroxyvitamin D3-1-hydroxylase with a periodicity of 56 h and a 9 h phase difference between the two signals. In growing chickens subjected to a light: dark cycle of 22:2 h, and intravenously dosed with 45Ca, the temporal changes in plasma 45Ca could be described by an exponential decline with superimposed diurnal oscillations. The activity of the renal 25-hydroxyvitamin D3-1-hydroxylase in chicks subjected to a 12:12 h light: dark cycle ALSO followed diurnal oscillations,

Zinc oxide nanoparticles inhibit Ca2+-ATPase expression in human lens epithelial cells under UVB irradiation.

Epidemiological and experimental studies have revealed that lens epithelial cells exposed to ultraviolet B (UVB) light could be induced apoptosis, and lens epithelial cell apoptosis can initiate cataractogenesis. Posterior capsular opacification (PCO), the most frequent complication after cataract surgery, is induced by the proliferation, differentiation, migration of lens epithelial cells. Thus, inhibiting the proliferation of lens epithelial cells could reduce the occurrence of PCO. It is reported that zinc oxide (ZnO) nanoparticles have great potential for the application of biomedical fiel

Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development.

Calcium signaling plays a central role in the regulation of bone cells, although uncertainty remains with regard to the channels involved. In previous studies, we determined that the calcium channel Orai1 was required for the formation of multinucleated osteoclasts in vitro. To define the skeletal functions of calcium release-activated calcium currents, we compared the mice with targeted deletion of the calcium channel Orai1 to wild-type littermate controls, and examined differentiation and function of osteoblast and osteoclast precursors in vitro with and without Orai1 inhibition. Consistent …

Influence of calcium/calmodulin on budding of Ebola VLPs: implications for the involvement of the Ras/Raf/MEK/ERK pathway.

The VP40 matrix protein of Ebola virus is able to bud from mammalian cells as a virus-like particle (VLP). Interactions between L-domain motifs of VP40 and host proteins such as Tsg101 and Nedd4 serve to facilitate budding of VP40 VLPs. Since intracellular levels of calcium are known to influence localization and function of host proteins involved in virus budding, we sought to determine, whether alterations of calcium or calmodulin levels in cells would affect budding of VP40 VLPs. VP40 VLP release was assessed in cells treated with BAPTA/AM, a calcium ion chelator, or with ionomycin, a calci

Activatory effect of regucalcin on GTPase activity in rat liver plasma membranes.

The effect of regucalcin, a regulatory protein of Ca2+ signaling, on guanosine-5'-triphosphatase (GTPase) activity in isolated rat liver plasma membranes was investigated. GTPase activity was significantly increased by the addition of Ca2+ (25-100 microM) in the enzyme reaction mixture. Such an increase was not seen by other metals (Mg, Co, Zn, Cu, Ni and Mn) with 50 microM. The activatory effect of calcium (50 microM) was significantly decreased by calmodulin (2.5 and 5 microg/ml), indicating that it does not depend on calmodulin. The presence of regucalcin (0.1-0.5 microM) in the enzyme reac

[Influence of activator and inhibitors of Ca2+ channels on proliferative activity in Tetrahymena pyriformis infusoria].

It was determined that change in DNA content in macronuclei occurs in the T. pyriformis infusoria under the influence of an activator (caffeine) and inhibitors of Ca2+ channels (verapamil), NiCl2, and CdCl2. Caffeine (10 mM) stimulates DNA synthesis. Verapamil (5 microM), CdCl2 (125 microM), and NiCl2 (100 microM) decrease DNA content in macronuclei by 30 min after proliferative stimulation. By 4 h of incubation, there is, on average, 10% less DNA in macronuclei of Tetrahymena preprocessed with verapamil than in the control cells. The cells preprocessed with CdCl2 and NiCl2 differ from the con

BLA astrocytes are associated with withdrawal somatic signs during high-dose naloxone-precipitated morphine withdrawal revealed by 3D-AI behavioral analysis.

Relapse triggered by withdrawal memory is the important challenge in addiction therapy, with somatic withdrawal symptoms acting as its physi … A astrocytes were activated during morphine withdrawal conditioning. Inhibiting their intracellular calcium signaling reduced CPA scores. 3D-AI behavioral analysis showed a significantly locomotor suppression in withdrawal mice. Further, we identified two categories of behaviors: (1) jumping and standing, which were associated with the naloxone-induced withdrawal d …

[Effects of hydrogen sulfide (H2S) on cardiac hypertrophy and miRNA-133a-mediated Ca2+/calcineurin/NFATc4 signal pathway in rats].

OBJECTIVE: To investigate the effects of hydrogen sulfide (H2S) on the negatively regulation of cardiomyocyte hypertrophy and the relationship between the effect of H2S with miRNA-133a-mediated Ca2+/calcineurin/NFATc4 signal pathway. METHODS: Cardiomyocyte hypertrophy was induced by isoproterenol (ISO). The cell surface area was measured by image analysis system (Leica). The expression of brain natriuretic peptide(BNP), β-myosin heavy chain(β-MHC), cystathionase (CSE), miRNA-133a, calcineurin (CaN) were detected by qRT-PCR. The protein expressions of CaN、nuclear factors of activated T cells (

Arabidopsis CML38, a Calcium Sensor That Localizes to Ribonucleoprotein Complexes under Hypoxia Stress.

During waterlogging and the associated oxygen deprivation stress, plants respond by the induction of adaptive programs, including the redire … t CML38 is a core hypoxia response calcium sensor protein and suggest that it serves as a potential calcium signaling target within stress granules and other mRNPs that accumulate during flooding stress responses.

Neurotoxic effects of feline immunodeficiency virus, FIV-PPR.

FIV is a lentivirus of domestic cats that causes neurologic disorders which are remarkably similar to those found in HIV-1 infected people. Using feline neuron cultures, we investigated the potential of both FIV virus and FIV-Env protein to cause neuronal damage through the excitotoxicity mechanism. The neuron swelling and lactate dehydrogenase (LDH) release assays were used as measures of cellular damage. The effects of FIV Env protein on glutamate receptor mediated increases in intracellular calcium were also examined. We found that FIV virus and FIV-Env protein significantly increased LDH r

Inappropriate neutrophil activation in venous disease.

Neutrophil oxygen radical production was studied in 18 limbs with class 2 or 3 venous disease and compared with that of nine normal limbs. Neutrophils were isolated from arm and leg venous samples. Free radical production was determined using chemiluminescence after stimulation with the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) or the ester phorbol myristate acetate (PMA). The ratio of leg to arm luminescence was greater after FMLP stimulation in patients with venous disease (median 1.52 (95 per cent confidence interval (c.i.) 1.27-2.60)) than in controls (median 0.97 (9

Mechanisms of norepinephrine-induced Ca2+ responses in perivascular adipose tissue.

Structural changes in microcirculation are often considered the first signs of vascular damage due to hypertension. A key tissue type emerging as a regulator of vascular tone is perivascular adipose tissue (PVAT). PVAT is a complex collection of adipocytes, immune cells, nerves, collagen fibers, and capillaries that surround most blood vessels. Norepinephrine (NE) is an important catecholamine that has emerged as a key driver of PVAT anticontractile factors. The release of anticontractile factors such as nitric oxide (NO) and adiponectin counteract smooth muscle contraction and limit vasoconst

Confining thrombus morphospace through targeted inhibition of platelet mechanosensory signaling.

BACKGROUND: While current antiplatelets protect against thrombosis, their clinical utility is limited by an elevated risk of bleeding. OBJECTIVES: To understand how structure-function relations in the hemostatic system may be leveraged into improve risk/benefit ratios of antiplatelet therapies. METHODS: We developed a deep learning-based framework to track the activities of large numbers of platelets in vivo, enabling a detailed comparative assessment of the effects of therapeutic interventions on the evolving structural hierarchy of the hemostatic response. RESULTS: Unlike conventional ant