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1.
Toxicol Lett ; 323: 1-9, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31982503

RESUMO

Zearalenone (ZEA) is a prevalent non-steroidal estrogenic mycotoxin produced mainly by Fusarium contamination. Our previous study showed that ZEA induces the autophagy of Sertoli cells (SCs). However, the underlying mechanisms are still unknown. Several studies have indicated that the increasing level of cytoplasmic Ca2+ could induce autophagy through CaMKKß and AMPK pathways. Thus in order to investigate the potential mechanism underlying ZEA-induced autophagy, the activity of calmodulin-dependent kinase kinase ß(CaMKKß)and AMP-activated protein kinase (AMPK) signaling pathway in ZEA-infected TM4 cells was studied. In the present study, ZEA activated the CaMKKß and AMPK signaling pathways. The AMPK inhibitor and activator significantly inhibited and stimulated the effect of ZEA on AMPK, the transformation from LC3I to LC3II, and the distribution of LC3 dots. In addition, cytosolic calcium (Ca2+) was increased gradually with the concentration of ZEA. After treatment of ZEA-infected cells with 1, 2-bis (2-aminophenoxy) ethane-N, N, N', N'- tetraacetic acid- tetraac etoxymethyl ester (BAPTA-AM) and 2-aminoethyl diphenylborinate (2-APB), the intracellular concentration of Ca2+ reduced significantly. Also, the activities of CaMKKß and AMPK and subsequent autophagy decreased. Moreover, the antioxidant NAC significantly decreased activities of AMPK and autophagy -related protein. Therefore, it can be speculated that ROS- mediated ER-stress induced by ZEA activates AMPK via Ca2+-CaMKKß leading to autophagy in TM4 cells.


Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Autofagia/efeitos dos fármacos , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/fisiologia , Cálcio/fisiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Zearalenona/toxicidade , Animais , Células Cultivadas , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia
2.
Gene ; 722: 144101, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31479714

RESUMO

The catadromous species, eels, invariably exposed to variable Ca2+ concentrations circumstance i.e., lagoon or ocean. They need to maintain Ca2+ homeostasis by exchanging Ca2+ under different culture conditions. To understand the effects of environmental Ca2+ to fish, three types of genes coding for voltage-dependent L-type calcium channels (cacnb1, 2, 3) were cloned by screening an A. marmorata cDNA library. Tissue distribution analysis of Western blot showed that Cacnb1, 2, 3 had a significantly high expression in gill; while mRNA results showed the expressions of cacnb1 and cacnb3 were predominated in skin tissue but only cacnb2 was expressed in intestine. Serum osmolality and Ca2+ concentrations of A.marmorata were increased in a high calcium environment while reduced in a low calcium environment within 7 days; however, they were not significantly different among Ca2+ treatments after the eels were acclimated for 7 days. We also examined the influence of ambient Ca2+ levels on cacnbs expression of eels. With the increasing of exposure time, mRNA and protein expressions of cacnb1 were up-regulated in high level of Ca2+ (10 mM) and down-regulated in deficient Ca2+ (0 mM) compared to the control Ca2+ (2 mM). However, the opposite results were observed in cacnb2 and cacnb3. Notably, the cacnb2 expression was not significant different among Ca2+ treatments on day 7. Our study provided the insightful evidence that cacnbs play important roles in maintaining Ca2+ homeostasis of fish.


Assuntos
Anguilla/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/fisiologia , Aclimatação , Anguilla/sangue , Anguilla/genética , Animais , Cálcio/sangue , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/genética , Clonagem Molecular , Brânquias/metabolismo , Concentração Osmolar , RNA Mensageiro/metabolismo , Distribuição Tecidual
3.
Neuron ; 105(4): 630-644.e9, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31859031

RESUMO

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD+ depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD+ repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD+ dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets.


Assuntos
Cálcio/fisiologia , Homeostase/fisiologia , Neuroproteção/fisiologia , Niacinamida/metabolismo , Sirtuína 1/metabolismo , Ataxias Espinocerebelares/metabolismo , Animais , Linhagem Celular , Cerebelo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Transdução de Sinais/fisiologia , Sirtuína 1/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/prevenção & controle
4.
Adv Physiol Educ ; 43(4): 476-485, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553642

RESUMO

Lewis Victor Heilbrunn has been called the pioneer of Ca2+ as an intracellular regulator (Campbell AK. Cell Calcium 7: 287-296, 1986; Campbell AK. Intracellular Calcium, 2015). In 1947, he was the first to provide convincing evidence that Ca2+ triggered muscle contraction (Heilbrunn LV, Wiercinski FJ. J Cell Comp Physiol 29: 15-32, 1947). Yet his work was met mostly with silence and neglect. One wonders why. Heilbrunn was a general physiologist who believed in the uniformity of nature with regard to movement. He believed that ". . . the theory of what makes cells divide should not be very different from the theory of what makes muscle contract . . ." (Heilbrunn LV. The Dynamics of Living Protoplasm, 1956). He did not believe that one could understand how the living machine worked by investigating its parts. He believed that, to understand life, one must study the dynamics of living protoplasm. The origin and evolution of Heilbrunn's thought process regarding the role of Ca2+ as a physiological activator will be traced back to the 1920s. The ways in which he tested the Ca2+ hypothesis in sea urchin eggs in the 1920s and 1930s will be explored. This work shaped Heilbrunn's thinking about the role of Ca2+ in muscle contraction. Importantly, why he and his results were ignored for years will be examined. It turned out that being right was not enough. Bad luck and a stubborn belief in an outmoded scientific philosophy contributed to the neglect.


Assuntos
Cálcio , Pessoal de Laboratório Médico/história , Contração Muscular , Fisiologia/história , Cálcio/fisiologia , História do Século XIX , História do Século XX , Humanos , Masculino , Contração Muscular/fisiologia
6.
Dtsch Med Wochenschr ; 144(16): 1125-1132, 2019 08.
Artigo em Alemão | MEDLINE | ID: mdl-31416104

RESUMO

A finely balanced control system keeps the extracellular calcium concentration within narrow limits. Disorders of calcium metabolism are often based on altered parathormone levels. Symptoms are not always clear, sometimes they are even missing: the more it is important to know possible associated diseases. The author presents basics, current diagnostics and concrete therapy options. Central hormone for the regulation of the calcium balance is the parathyroid hormone. With decreasing calcium, PTH leads to an increase in extracellular free calcium concentration in three ways. The classic symptoms of pHPT (polyuria, polydipsia, "stone, leg, and stomach pain") are rare now, as the condition is diagnosed much earlier. Treatment of choice in all symptomatic patients with pHPT is surgery. FHH and pHPT are both characterized by hypercalcaemia and increased parathyroid hormone. The differential diagnosis of urinary calcium excretion, which is usually lower in FHH but normal or elevated in pHPT, is crucial. In primary hypoparathyroidism, parathyroid failure interferes with calcium homeostasis at a central location. Consequences are hypocalcaemia, hyperphosphatemia and lack of active vitamin D. Due to increased urinary calcium excretion, patients with ADH are at high risk for kidney stones, nephrocalcinosis and the development of renal insufficiency. Recently, rhPTH 1-84 has been available for the treatment of hypoparathyroidism. However, long-term data is still lacking to provide a safe indication, considering potential effects and side effects.


Assuntos
Distúrbios do Metabolismo do Cálcio , Cálcio na Dieta , Cálcio , Cálcio/metabolismo , Cálcio/fisiologia , Cálcio na Dieta/análise , Cálcio na Dieta/metabolismo , Humanos , Hipoparatireoidismo , Vitamina D
7.
Adv Exp Med Biol ; 1155: 429-442, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468420

RESUMO

Taurine is traditionally used to treat Down Syndrome (DS); however, the actual foundation for this treatment is not well understood. DS patients suffer from disturbance of the proteostasis network (PN) due to aberrant calcium signaling, which eventually causes endoplasmic reticulum stress (ERS). Taurine has been suggested to play a role in modulating calcium homeostasis and ERS. This study examined whether taurine affects DS symptoms using C. elegans - a DS model in which calcineurins, Ca2+/calmodulin-dependent protein phosphatase is mutated to null. The DS nematode model has short body length, slow growth, fertility defects, serotonin-resistant egg-laying defects, and faulty thermal sensing. This study focused on whether taurine may ameliorate the severity of DS at the whole-body level, including reduction in ERS. When treated with taurine, DS nematodes appeared to have lower levels of ERS and phenotypes closer to the wild type. DS nematodes also showed improved egg laying efficiency and thermal sensing index comparable to the wild type. Our findings offer a new perspective on the effectiveness of taurine in treating DS and designing therapeutic strategies to lower ERS and restore disrupted PN.


Assuntos
Caenorhabditis elegans/fisiologia , Cálcio/fisiologia , Síndrome de Down , Estresse do Retículo Endoplasmático , Taurina/farmacologia , Animais , Modelos Animais de Doenças , Homeostase , Humanos
8.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2452-2458, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359710

RESUMO

Exogenous calcium can enhance the resistance of certain plants to abiotic stress. Research have demonstrated that exogenous calcium could enhances the resistance of honeysuckle under salt stress by promoting the transmission of photosynthetic electrons.The aim of this study was to investigate the effects of exogenous calcium on the contents of Na~+,K~+,Ca~(2+),Mg~(2+)and the expression of photosynthetic related genes Cab and rbc L. In this study,we used ICP-OES to analysis ion contents and used qRT-PCR to analysis the expression patterns of Cab and rbc L. The results showed that CaCl_2 significantly enhanced the K~+-Na~+,Ca~(2+)-Na~+,Mg~(2+)-Na+ratio of honeysuckle treated with 50 and 100 mmol·L~(-1) NaCl. Meanwhile,Cab and rbc L were significantly up-regulated under short-term salt stress,and CaCl_2 promoted this trend. From the two gene expression patterns,rbc L rapidly up-regulated on the first day of stress and then decreased,and was more sensitive to environmental changes. In summary,exogenous calcium could alleviate salt stress and increase plant development by increasing intracellular K~+-Na~+,Ca~(2+)-Na~+,Mg~(2+)-Na+ratio,and the transient overexpression of Cab and rbc L.


Assuntos
Cálcio/fisiologia , Lonicera/fisiologia , Fotossíntese , Estresse Salino , Cátions/análise
9.
Adv Exp Med Biol ; 1124: 77-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183823

RESUMO

The peristaltic pressure waves in the renal pelvis that propel urine expressed by the kidney into the ureter towards the bladder have long been considered to be 'myogenic', being little affected by blockers of nerve conduction or autonomic neurotransmission, but sustained by the intrinsic release of prostaglandins and sensory neurotransmitters. In uni-papilla mammals, the funnel-shaped renal pelvis consists of a lumen-forming urothelium and a stromal layer enveloped by a plexus of 'typical' smooth muscle cells (TSMCs), in multi-papillae kidneys a number of minor and major calyces fuse into a large renal pelvis. Electron microscopic, electrophysiological and Ca2+ imaging studies have established that the pacemaker cells driving pyeloureteric peristalsis are likely to be morphologically distinct 'atypical' smooth muscle cells (ASMCs) that fire Ca2+ transients and spontaneous transient depolarizations (STDs) which trigger propagating nifedipine-sensitive action potentials and Ca2+ waves in the TSMC layer. In uni-calyceal kidneys, ASMCs predominately locate on the serosal surface of the proximal renal pelvis while in multi-papillae kidneys they locate within the sub-urothelial space. 'Fibroblast-like' interstitial cells (ICs) located in the sub-urothelial space or adventitia are a mixed population of cells, having regional and species-dependent expression of various Cl-, K+, Ca2+ and cationic channels. ICs display asynchronous Ca2+ transients that periodically synchronize into bursts that accelerate ASMC Ca2+ transient firing. This review presents current knowledge of the architecture of the proximal renal pelvis, the role Ca2+ plays in renal pelvis peristalsis and the mechanisms by which ICs may sustain/accelerate ASMC pacemaking.


Assuntos
Cálcio/fisiologia , Células Intersticiais de Cajal/fisiologia , Canais Iônicos/fisiologia , Pelve Renal/fisiologia , Contração Muscular , Peristaltismo , Animais , Ureter
10.
Adv Exp Med Biol ; 1124: 103-119, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183824

RESUMO

The ureter acts as a functional syncytium and is controlled by a propagating plateau-type action potential (AP) which gives rise to a wave of contraction (ureteral peristalsis) via a process called excitation-contraction (E-C)coupling. The second messenger Ca2+ activates Ca2+/calmodulin-dependent myosin light chain kinase-dependent phosphorylation of 20-kDa regulatory light chains of myosin which leads to ureteric contraction. Ca2+ entry from the extracellular space via voltage-gated L-type Ca2+ channels (VGCCs) provides the major source of activator Ca2+, responsible for generation of both the AP and a Ca2+ transient that appears as an intercellular Ca2+ wave. The AP, inward Ca2+ current, Ca2+ transient and twitch contraction are all fully blocked by the selective L-type Ca2+ channel blocker nifedipine. Ca2+ entry via VGCCs, coupled to activation of Ca2+-sensitive K+ (KCa) or Cl- (ClCa) channels, acts as a negative or positive feedback mechanism, respectively, to control excitability and the amplitude and duration of the plateau component of the AP, Ca2+ transient and twitch contraction. The ureter, isolated from the pelvis, is not spontaneously active. However, spontaneous activity can be initiated in the proximal and distal ureter by a variety of biological effectors such as neurotransmitters, paracrine, endocrine and inflammatory factors. Applied agonists depolarise ureteric smooth muscles cells to threshold of AP activation, initiating propagating intercellular AP-mediated Ca2+ waves to produce antegrade and/or retrograde ureteric peristalsis. Several mechanisms have been proposed to describe agonist-induced depolarization of ureteric smooth muscle, which include suppression of K+ channels, stimulation of ClCa current and activation of non-selective cation receptor/store operated channels.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Peristaltismo , Ureter/fisiologia , Cálcio/fisiologia , Humanos
11.
Adv Exp Med Biol ; 1124: 171-194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183827

RESUMO

The corpus cavernosum smooth muscle is important for both erection of the penis and for maintaining penile flaccidity. Most of the time, the smooth muscle cells are in a contracted state, which limits filling of the corpus sinuses with blood. Occasionally, however, they relax in a co-ordinated manner, allowing filling to occur. This results in an erection. When contractions of the corpus cavernosum are measured, it can be deduced that the muscle cells work together in a syncytium, for not only do they spontaneously contract in a co-ordinated manner, but they also synchronously relax. It is challenging to understand how they achieve this.In this review we will attempt to explain the activity of the corpus cavernosum, firstly by summarising current knowledge regarding the role of ion channels and how they influence tone, and secondly by presenting data on the intracellular Ca2+ signals that interact with the ion channels. We propose that spontaneous Ca2+ waves act as a primary event, driving transient depolarisation by activating Ca2+-activated Cl- channels. Depolarisation then facilitates Ca2+ influx via L-type voltage-dependent Ca2+ channels. We propose that the spontaneous Ca2+ oscillations depend on Ca2+ release from both ryanodine- and inositol trisphosphate (IP3)-sensitive stores and that modulation by signalling molecules is achieved mainly by interactions with the IP3-sensitive mechanism. This pacemaker mechanism is inhibited by nitric oxide (acting through cyclic GMP) and enhanced by noradrenaline. By understanding these mechanisms better, it might be possible to design new treatments for erectile dysfunction.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Músculo Liso/fisiologia , Pênis/fisiologia , Cálcio/fisiologia , Humanos , Masculino , Ereção Peniana
12.
Adv Exp Med Biol ; 1124: 195-215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183828

RESUMO

Spontaneous myogenic contractions have been shown to be significantly upregulated in prostate tissue collected from men with Benign Prostatic Hyperplasia (BPH), an extremely common disorder of the ageing male. Although originally thought likely to be involved in 'housekeeping' functions, mixing prostatic secretions to prevent stagnation, these spontaneous myogenic contractions provide a novel opportunity to understand and treat BPH. This treatment potential differs from previous models, which focused exclusively on attenuating nerve-mediated neurogenic contractions. Previous studies in the rodent prostate have provided an insight into the mechanisms underlying the regulation of myogenic contractions. 'Prostatic Interstitial Cells' (PICs) within the prostate appear to generate pacemaker potentials, which arise from the summation of number of spontaneous transient depolarisations triggered by the spontaneous release of Ca2+ from internal stores and the opening of Ca2+-activated Cl- channels. Pacemaker potentials then conduct into neighbouring smooth muscle cells to generate spontaneous slow waves. These slow waves trigger the firing of 'spike-like' action potentials, Ca2+ entry and contraction, which are not attenuated by blockers of neurotransmission. However, these spontaneous prostatic contractions can be modulated by the autonomic nervous system. Here, we discuss the mechanisms underlying rodent and human prostate myogenic contractions and the actions of existing and novel pharmacotherapies for the treatment of BPH. Understanding the generation of human prostatic smooth muscle tone will confirm the mechanism of action of existing drugs, inform the identification and effectiveness of new pharmacotherapies, as well as predict patient outcomes.


Assuntos
Sinalização do Cálcio , Células Intersticiais de Cajal/fisiologia , Canais Iônicos/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Animais , Cálcio/fisiologia , Humanos , Masculino , Hiperplasia Prostática
13.
Adv Exp Med Biol ; 1124: 233-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183830

RESUMO

We start by describing the functions of the uterus, its structure, both gross and fine, innervation and blood supply. It is interesting to note the diversity of the female's reproductive tract between species and to remember it when working with different animal models. Myocytes are the overwhelming cell type of the uterus (>95%) and our focus. Their function is to contract, and they have an intrinsic pacemaker and rhythmicity, which is modified by hormones, stretch, paracrine factors and the extracellular environment. We discuss evidence or not for pacemaker cells in the uterus. We also describe the sarcoplasmic reticulum (SR) in some detail, as it is relevant to calcium signalling and excitability. Ion channels, including store-operated ones, their contributions to excitability and action potentials, are covered. The main pathway to excitation is from depolarisation opening voltage-gated Ca2+ channels. Much of what happens downstream of excitability is common to other smooth muscles, with force depending upon the balance of myosin light kinase and phosphatase. Mechanisms of maintaining Ca2+ balance within the myocytes are discussed. Metabolism, and how it is intertwined with activity, blood flow and pH, is covered. Growth of the myometrium and changes in contractile proteins with pregnancy and parturition are also detailed. We finish with a description of uterine activity and why it is important, covering progression to labour as well as preterm and dysfunctional labours. We conclude by highlighting progress made and where further efforts are required.


Assuntos
Canais de Cálcio/fisiologia , Sinalização do Cálcio , Miométrio/fisiologia , Contração Uterina , Útero/fisiologia , Animais , Cálcio/fisiologia , Feminino , Gravidez , Retículo Sarcoplasmático/fisiologia
14.
Adv Exp Med Biol ; 1124: 313-328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183833

RESUMO

Veins exhibit spontaneous contractile activity, a phenomenon generally termed vasomotion. This is mediated by spontaneous rhythmical contractions of mural cells (i.e. smooth muscle cells (SMCs) or pericytes) in the wall of the vessel. Vasomotion occurs through interconnected oscillators within and between mural cells, entraining their cycles. Pharmacological studies indicate that a key oscillator underlying vasomotion is the rhythmical calcium ion (Ca2+) release-refill cycle of Ca2+ stores. This occurs through opening of inositol 1,4,5-trisphosphate receptor (IP3R)- and/or ryanodine receptor (RyR)-operated Ca2+ release channels in the sarcoplasmic/endoplasmic (SR/ER) reticulum and refilling by the SR/ER reticulum Ca2+ATPase (SERCA). Released Ca2+ from stores near the plasma membrane diffuse through the cytosol to open Ca2+-activated chloride (Cl-) channels, this generating inward current through an efflux of Cl-. The resultant depolarisation leads to the opening of voltage-dependent Ca2+ channels and possibly increased production of IP3, which through Ca2+-induced Ca2+ release (CICR) of IP3Rs and/or RyRs and IP3R-mediated Ca2+ release provide a means by which store oscillators entrain their activity. Intercellular entrainment normally involves current flow through gap junctions that interconnect mural cells and in many cases this is aided by additional connectivity through the endothelium. Once entrainment has occurred the substantial Ca2+ entry that results from the near-synchronous depolarisations leads to rhythmical contractions of the mural cells, this often leading to vessel constriction. The basis for venous/venular vasomotion has yet to be fully delineated but could improve both venous drainage and capillary/venular absorption of blood plasma-associated fluids.


Assuntos
Sinalização do Cálcio , Contração Muscular , Miócitos de Músculo Liso/fisiologia , Veias/fisiologia , Cálcio/fisiologia , Membrana Celular , Retículo Endoplasmático/fisiologia , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/fisiologia , Retículo Sarcoplasmático/fisiologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/fisiologia
15.
Adv Exp Med Biol ; 1124: 329-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183834

RESUMO

The microvasculature is composed of arterioles, capillaries and venules. Spontaneous arteriolar constrictions reduce effective vascular resistance to enhance tissue perfusion, while spontaneous venular constrictions facilitate the drainage of tissue metabolites by pumping blood. In the venules of visceral organs, mural cells, i.e. smooth muscle cells (SMCs) or pericytes, periodically generate spontaneous phasic constrictions, Ca2+ transients and transient depolarisations. These events arise from spontaneous Ca2+ release from the sarco-endoplasmic reticulum (SR/ER) and the subsequent opening of Ca2+-activated chloride channels (CaCCs). CaCC-dependent depolarisation further activates L-type voltage-dependent Ca2+ channels (LVDCCs) that play a critical role in maintaining the synchrony amongst mural cells. Mural cells in arterioles or capillaries are also capable of developing spontaneous activity. Non-contractile capillary pericytes generate spontaneous Ca2+ transients primarily relying on SR/ER Ca2+ release. Synchrony amongst capillary pericytes depends on gap junction-mediated spread of depolarisations resulting from the opening of either CaCCs or T-type VDCCs (TVDCCs) in a microvascular bed-dependent manner. The propagation of capillary Ca2+ transients into arterioles requires the opening of either L- or TVDCCs again depending on the microvascular bed. Since the blockade of gap junctions or CaCCs prevents spontaneous Ca2+ transients in arterioles and venules but not capillaries, capillary pericytes appear to play a primary role in generating spontaneous activity of the microvasculature unit. Pericytes in capillaries where the interchange of substances between tissues and the circulation takes place may provide the fundamental drive for upstream arterioles and downstream venules so that the microvasculature network functions as an integrated unit.


Assuntos
Sinalização do Cálcio , Canais Iônicos/fisiologia , Microvasos/fisiologia , Pericitos/fisiologia , Arteríolas/fisiologia , Cálcio/fisiologia , Humanos , Microvasos/citologia , Vênulas/fisiologia
16.
Curr Med Chem ; 26(36): 6572-6589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218950

RESUMO

Trypanosomatids are a group of flagellated unicellular eukaryotes, causing serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites including differentiation between stages, proliferation, osmoregulation, oxidative stress and quorum sensing. Interestingly, its signaling pathway is quite different from that of mammals, including structurally different adenylyl cyclases, the shortage of orthologous effector proteins and the absence of G-protein-coupled-receptors, among others. These characteristics make the proteins involved in these transduction pathways good candidates for therapeutic targets. However, the identification of new unknown druggable targets involves extensive research time and is economically very expensive, making difficult the transition from basic research to the clinical phase. Trypanosomatid PDEs have characteristic binding pockets that allow for a differential inhibition from their human orthologs. Modification in the approved drugs for human to convert them into trypanocidal treatments could lead to more effective therapies, shorter lab time and lower costs. In view of the fact that kinetoplastid PDEs are highly conserved with their mammalian counterparts, and since there are already numerous drugs on the market against human PDEs, the drug repositioning approach is highly promising. The development of new technologies, higher government and industrial involvement and more scientists committed to basic investigation, are the key to ultimately find an effective treatment and cure for the neglected tropical diseases.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/fisiologia , Cálcio/fisiologia , Doença de Chagas/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Leishmania donovani/enzimologia , Leishmania donovani/fisiologia , Proteínas Quinases/fisiologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/fisiologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Trypanosoma cruzi/fisiologia
17.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(2): 121-125, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31250601

RESUMO

OBJECTIVE: To investigate the effects of interval training on calcium transient and contractile function in ischemic ventricular myocytes of rats with myocardial infarction and their synchronization. METHODS: Twenty-four male sprague-dawley rats in three years old, were randomly divided into three groups (n=8): sham-operated group(S), sedentary MI group(MI) and MI with interval training group (ME). The MI model was established by ligation of the left anterior descending coronary artery. The rats in ME group started training 1 week after MI operation. The S model was established by threading only without ligation. ME model took one week adaptive training, 10 m/min and 30 min/d, then took subsequently 8-week aerobic interval training: 10 min×10 m/min, then reran the rats with 2 intensities 15 m/min×6 min and 25 m/min×4 min, 1 h/d, 5 d/week. After training 24 hours, the cardiomyocytes of all groups were isolated by using the Langendorff fusion system. The contractile function and calcium transient of single ventricular myocyte in myocardial infarction adult rats were detected by IonOptix. Calcium transients were measured as [Ca2+]i amplitude, departure velocity, ratio, TTB50%, TTP and TTP50%, return velocity and ratio amplitude. PTA, SL, ±dl/dtmax and SL shortening% were tested to evaluate contractility. RESULTS: Compared with S, the levels of [Ca2+]i amplitude, departure velocity, ratio amplitude and return velocity, SL shortening%, PTA and ±dl/dtmax of MI were decreased(P<0.01), the levels of TTP, TTP50% and TTB50% of MI were increased(P<0.01); Compared with MI, the levels of departure velocity, ratio amplitude, return velocity and [Ca2+]i amplitude of ME were increased(P<0.01), the levels of TTB50%, TTP and TTP50% of ME were decreased(P<0.01, P<0.05). The levels of SL shortening%, PTA and ±dl/dtmax of ME were increased(P<0.01, P<0.05). CONCLUSION: Interval training can improve calcium transient and contractile function of single ventricular myocyte in myocardial infarction adult rats.


Assuntos
Cálcio/fisiologia , Contração Miocárdica , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Condicionamento Físico Animal , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
18.
Poult Sci ; 98(11): 5582-5589, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31198961

RESUMO

Results from 3 experiments relating to the measurement of ileal calcium (Ca) digestibility in 4 different Ca sources for broiler chickens are presented herein. The first experiment was conducted to determine the effect of basal diet composition on the true Ca digestibility of limestone, meat and bone meal (MBM), monocalcium phosphate (MCP), and dicalcium phosphate (DCP). Eight experimental diets were developed based on 2 basal diets (corn-based or corn starch-based) with each of the 4 Ca sources. Two Ca-free diets representing both basal diets were used to determine the endogenous Ca losses. Each diet was randomly allotted to 6 replicate cages (6 birds per cage) and fed from 21 to 24 D post-hatch. Calcium digestibility of corn-based diet was higher (P < 0.05) than the corn starch-based purified diet. The average true Ca digestibility coefficients of limestone, MBM, MCP, and DCP were determined to be 0.51, 0.41, 0.43, and 0.32, respectively. The second experiment was conducted to examine the effect of indicator type on the apparent Ca digestibility of limestone. Two experimental diets with either titanium dioxide or acid insoluble ash (Celite) were developed. Each diet was randomly allotted to 6 replicate cages (8 birds per cage) and fed from 21 to 24 D post-hatch. Total tract Ca retention was also measured using the indicator ratios. Indicator type had no influence (P > 0.05) on the digestibility measurements. Ca retention determined using acid insoluble ash was higher (P < 0.05) compared to that determined using titanium dioxide. The third experiment was conducted to determine the effect of dietary adaptation length on apparent Ca digestibility of limestone. The experimental diet was offered from day 21 to 6 replicates (6 birds per cage) each for 24, 72, 120, or 168 h and the ileal digesta were collected. Calcium digestibility at 24 h was higher (P < 0.05), and increasing the adaptation length from 72 to 120 h had no effect (P > 0.05) on the digestibility.


Assuntos
Ração Animal/análise , Cálcio/fisiologia , Galinhas/fisiologia , Digestão/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Carbonato de Cálcio/metabolismo , Dieta/veterinária , Íleo/fisiologia , Masculino , Distribuição Aleatória
19.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31160362

RESUMO

Acid sphingomyelinase (ASM) is a lipid hydrolase that converts sphingomyelin to ceramide and that can be activated by various cellular stress mechanisms, including bacterial pathogens. Vesicle transportation or trafficking of ASM from the lysosomal compartment to the cell membrane is a prerequisite for its activation in response to bacterial infections; however, the effectors and mechanisms of ASM translocation and activation are poorly defined. Our recent work documented the key importance of ASM for Neisseria meningitidis uptake into human brain microvascular endothelial cells (HBMEC). We clearly identified OpcA to be one bacterial effector promoting ASM translocation and activity, though it became clear that additional bacterial components were involved, as up to 80% of ASM activity and ceramide generation was retained in cells infected with an opcA-deficient mutant. We hypothesized that N. meningitidis might use pilus components to promote the translocation of ASM into HBMEC. Indeed, we found that both live, piliated N. meningitidis and pilus-enriched fractions trigger transient ASM surface display, followed by the formation of ceramide-rich platforms (CRPs). By using indirect immunocytochemistry and direct stochastic optical reconstruction microscopy, we show that the overall number of CRPs with a size of ∼80 nm in the plasma membrane is significantly increased after exposure to pilus-enriched fractions. Infection with live bacteria as well as exposure to pilus-enriched fractions transiently increased cytosolic Ca2+ levels in HBMEC, and this was found to be important for ASM surface display mediated by lysosomal exocytosis, as depletion of cytosolic Ca2+ resulted in a significant decrease in ASM surface levels, ASM activity, and CRP formation.


Assuntos
Cálcio/fisiologia , Ceramidas/metabolismo , Fímbrias Bacterianas/fisiologia , Lisossomos/metabolismo , Neisseria meningitidis/fisiologia , Esfingomielina Fosfodiesterase/metabolismo , Células Cultivadas , Humanos
20.
BMC Neurosci ; 20(1): 27, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208328

RESUMO

BACKGROUND: The mosquito Aedes aegypti has a wide variety of sensory pathways that have supported its success as a species as well as a highly competent vector of numerous debilitating infectious pathogens. Investigations into mosquito sensory systems and their effects on behavior are valuable resources for the advancement of mosquito control strategies. Numerous studies have elucidated key aspects of mosquito sensory systems, however there remains critical gaps within the field. In particular, compared to that of the adult form, there has been a lack of studies directed towards the immature life stages. Additionally, although numerous studies have pinpointed specific sensory receptors as well as responding motor outputs, there has been a lack of studies able to monitor both concurrently. RESULTS: To begin filling aforementioned gaps, here we engineered Ae. aegypti to ubiquitously express a genetically encoded calcium indicator, GCaMP6s. Using this strain, combined with advanced microscopy, we simultaneously measured live stimulus-evoked calcium responses in both neuronal and muscle cells with a wide spatial range and resolution. CONCLUSIONS: By coupling in vivo live calcium imaging with behavioral assays we were able to gain functional insights into how stimulus-evoked neural and muscle activities are represented, modulated, and transformed in mosquito larvae enabling us to elucidate mosquito sensorimotor properties important for life-history-specific foraging strategies.


Assuntos
Aedes/genética , Cálcio/fisiologia , Estágios do Ciclo de Vida/fisiologia , Neurônios/fisiologia , Percepção Olfatória/fisiologia , Natação/fisiologia , Animais , Animais Geneticamente Modificados/fisiologia , Larva/fisiologia , Músculos/fisiologia , Optogenética
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