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1.
NPJ Syst Biol Appl ; 10(1): 22, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429306

RESUMO

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug's efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug's inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug's overall efficacy. The data and fit models suggest that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio , Canais de Cálcio
2.
J Pharmacol Sci ; 154(4): 256-263, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38485343

RESUMO

Platelet-activating factor (PAF) is expected to increase esophageal motility. However, to the best of our knowledge, this has not been examined. Thus, we investigated the contractile effects of PAF on guinea pig (GP) esophageal muscularis mucosae (EMM) and the extracellular Ca2+ influx pathways responsible. PAF (10-9-10-6 M) contracted EMM in a concentration-dependent manner. PAF (10-6 M)-induced contractions were almost completely suppressed by apafant (a PAF receptor antagonist, 3 × 10-5 M). In EMM strips, PAF receptor and PAF-synthesizing/degrading enzyme mRNAs were detected. PAF (10-6 M)-induced contractions were abolished by extracellular Ca2+ removal but were not affected by diltiazem [a voltage-dependent Ca2+ channel (VDCC) inhibitor, 10-5 M]. PAF (10-6 M)-induced contractions in the presence of diltiazem were significantly suppressed by LOE-908 [a receptor-operated Ca2+ channel (ROCC) inhibitor, 3 × 10-5 M], SKF-96365 [an ROCC and store-operated Ca2+ channel (SOCC) inhibitor, 3 × 10-5 M], and LOE-908 plus SKF-96365. Among the tested ROCC/SOCC-related mRNAs, Trpc3, Trpc6, and Trpv4/Orai1, Orai3, and Stim2 were abundantly expressed in EMM strips. These results indicate that PAF potently induces GP EMM contractions that are dependent on extracellular Ca2+ influx through ROCCs/SOCCs, and VDCCs are unlikely to be involved.


Assuntos
Diltiazem , Isoquinolinas , Fator de Ativação de Plaquetas , Cobaias , Animais , Diltiazem/farmacologia , Fator de Ativação de Plaquetas/farmacologia , Acetamidas , Canais de Cálcio/metabolismo , Mucosa/metabolismo , Cálcio/metabolismo
3.
Sci Rep ; 14(1): 6751, 2024 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514795

RESUMO

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.


Assuntos
Distrofia Muscular de Duchenne , Animais , Camundongos , Humanos , Distrofia Muscular de Duchenne/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Canais de Cálcio/metabolismo , Mitocôndrias/metabolismo , Necrose/metabolismo , Morte Celular , Cálcio/metabolismo
5.
Front Biosci (Landmark Ed) ; 29(2): 47, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38420828

RESUMO

BACKGROUND: The leaves of Origanum majorana (O. majorana) are traditionally renowned for treating diarrhea and gut spasms. This study was therefore planned to evaluate its methanolic extract. METHODS: Gas chromatography-mass spectrometry (GC-MS) was used to identify the phytochemicals, and Swiss albino mice were used for an in vivo antidiarrheal assay. Isolated rat ileum was used as an ex vivo assay model to study the possible antispasmodic effect and its mechanism(s). RESULTS: The GC-MS analysis of O. majorana detected the presence of 21 compounds, of which alpha-terpineol was a major constituent. In the antidiarrheal experiment, O. majorana showed a substantial inhibitory effect on diarrheal episodes in mice at an oral dosage of 200 mg/kg, resulting in 40% protection. Furthermore, an oral dosage of 400 mg/kg provided even greater protection, with 80% effectiveness. Similarly, loperamide showed 100% protection at oral doses of 10 mg/kg. O. majorana caused complete inhibition of carbachol (CCh, 1 µM) and high K+ (80 mM)-evoked spasms in isolated ileal tissues by expressing significantly higher potency (p < 0.05) against high K+ compared to CCh, similar to verapamil, a Ca++ antagonist. The verapamil-like predominant Ca++ ion inhibitory action of O. majorana was further confirmed in the ileal tissues that were made Ca++-free by incubating the tissues in a physiological salt solution having ethylenediaminetetraacetic acid (EDTA) as a chelating agent. The preincubation of O. majorana at increasing concentrations (0.3 and 1 mg/mL) shifted towards the right of the CaCl2-mediated concentration-response curves (CRCs) with suppression of the maximum contraction. Similarly, verapamil also caused non-specific suppression of Ca++ CRCs towards the right, as expected. CONCLUSIONS: Thus, this study conducted an analysis to determine the chemical constituents of the leaf extract of O. majorana and provided a detailed mechanistic basis for the medicinal use of O. majorana in hyperactive gut motility disorders.


Assuntos
Antidiarreicos , Origanum , Ratos , Camundongos , Animais , Antidiarreicos/farmacologia , Antidiarreicos/uso terapêutico , Antidiarreicos/química , Jejuno , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/química , Óleo de Rícino/farmacologia , Óleo de Rícino/uso terapêutico , Diarreia/tratamento farmacológico , Verapamil/farmacologia , Verapamil/uso terapêutico , Canais de Cálcio , Espasmo/tratamento farmacológico
6.
Cell Mol Biol (Noisy-le-grand) ; 70(1): 99-109, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38372107

RESUMO

This study aimed to explore the involvement of Transmembrane and coiled-coil domains 1 (TMCO1) in ovarian cancer progression and its regulatory mechanisms in cisplatin resistance. Using the GEPIA database, we analyzed TMCO1 expression in ovarian cancer and normal tissues. In a cohort of 99 ovarian cancer patients, immunohistochemistry and immunofluorescence were employed to assess TMCO1 expression in tumor and adjacent tissues, correlating findings with clinical and pathological characteristics. TMCO1 overexpression and knockout cell models were constructed, and their impact on non-cisplatin-resistant (SK-OV-3) and cisplatin-resistant (SK-OV-3-CDDP) ovarian cancer cells was investigated through cloning, wound healing, Fluo 4, and Transwell experiments. Knocking down CALR and VDAC1 was performed to examine their effects on TMCO1, cell proliferation, and malignant markers. Subcutaneous tumor models in nude mice elucidated the in vivo role of TMCO1 in tumor growth. Expression levels of CALR, VDAC1, angiogenesis indicators (CD34), and epithelial-mesenchymal transition (EMT) markers were evaluated. TMCO1 expression in ovarian cancer tissue significantly differed from normal tissue, correlating with survival rates. TMCO1 overexpression was associated with lymph node metastases, late FIGO stage, and larger tumors. TMCO1 promoted proliferation, calcium ion elevation, cytoskeletal remodeling, and metastasis in SK-OV-3 and SK-OV-3-CDDP cells, upregulating VDAC1, CALR, Vimentin, N-cadherin, ß-catenin, and downregulating E-cadherin. Silencing TMCO1 inhibited cell growth, proliferation, and angiogenesis in vivo, suppressing the expression of CALR, VDAC1, Vimentin, N-cadherin, and ß-catenin. Overall, this study highlighted TMCO1 as a crucial regulator in ovarian cancer progression, influencing VDAC1 through CALR and impacting diverse cellular processes, offering potential as a targeted therapeutic strategy for ovarian cancer.


Assuntos
Canais de Cálcio , Calreticulina , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , beta Catenina/metabolismo , Caderinas/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Transição Epitelial-Mesenquimal/genética , Camundongos Nus , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Vimentina/metabolismo , Calreticulina/genética , Calreticulina/metabolismo
7.
Mol Biol Rep ; 51(1): 248, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300413

RESUMO

Programmed cell death is a major life activity of both normal development and disease. Necroptosis is early recognized as a caspase-independent form of programmed cell death followed obviously inflammation. Apoptosis is a gradually recognized mode of cell death that is characterized by a special morphological changes and unique caspase-dependent biological process. Ferroptosis, pyroptosis and autophagy are recently identified non-apoptotic regulated cell death that each has its own characteristics. The transient receptor potential vanilloid 4 (TRPV4) is a kind of nonselective calcium-permeable cation channel, which is received more and more attention in biology studies. It is widely expressed in human tissues and mainly located on the membrane of cells. Several researchers have identified that the influx Ca2+ from TRPV4 acts as a key role in the loss of cells by apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy via mediating endoplasmic reticulum (ER) stress, oxidative stress and inflammation. This effect is bad for the normal function of organs on the one hand, on the other hand, it is benefit for anticancer activities. In this review, we will summarize the current discovery on the role and impact of TRPV4 in these programmed cell death pathological mechanisms to provide a new prospect of gene therapeutic target of related diseases.


Assuntos
Antineoplásicos , Canais de Cátion TRPV , Humanos , Canais de Cátion TRPV/genética , Apoptose , Morte Celular , Caspases , Canais de Cálcio , Inflamação
8.
Elife ; 132024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38334748

RESUMO

Two calcium-binding proteins, CaBP1 and CaBP2, cooperate to keep calcium channels in the hair cells of the inner ear open.


Assuntos
Cálcio , Células Ciliadas Auditivas , Cálcio/metabolismo , Células Ciliadas Auditivas/metabolismo , Canais de Cálcio/metabolismo , Cálcio da Dieta , Células Ciliadas Auditivas Internas/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo
9.
Sci Adv ; 10(7): eadk2317, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38354239

RESUMO

Lysosomal calcium (Ca2+) release is critical to cell signaling and is mediated by well-known lysosomal Ca2+ channels. Yet, how lysosomes refill their Ca2+ remains hitherto undescribed. Here, from an RNA interference screen in Caenorhabditis elegans, we identify an evolutionarily conserved gene, lci-1, that facilitates lysosomal Ca2+ entry in C. elegans and mammalian cells. We found that its human homolog TMEM165, previously designated as a Ca2+/H+ exchanger, imports Ca2+ pH dependently into lysosomes. Using two-ion mapping and electrophysiology, we show that TMEM165, hereafter referred to as human LCI, acts as a proton-activated, lysosomal Ca2+ importer. Defects in lysosomal Ca2+ channels cause several neurodegenerative diseases, and knowledge of lysosomal Ca2+ importers may provide previously unidentified avenues to explore the physiology of Ca2+ channels.


Assuntos
Cálcio , Proteínas de Transporte de Cátions , Animais , Humanos , Cálcio/metabolismo , Caenorhabditis elegans/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Transdução de Sinais , Lisossomos/metabolismo , Sinalização do Cálcio , Mamíferos/metabolismo , Antiporters/metabolismo , Proteínas de Transporte de Cátions/metabolismo
10.
Elife ; 122024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329474

RESUMO

Synaptic vesicles dock and fuse at the presynaptic active zone (AZ), the specialized site for transmitter release. AZ proteins play multiple roles such as recruitment of Ca2+ channels as well as synaptic vesicle docking, priming, and fusion. However, the precise role of each AZ protein type remains unknown. In order to dissect the role of RIM-BP2 at mammalian cortical synapses having low release probability, we applied direct electrophysiological recording and super-resolution imaging to hippocampal mossy fiber terminals of RIM-BP2 knockout (KO) mice. By using direct presynaptic recording, we found the reduced Ca2+ currents. The measurements of excitatory postsynaptic currents (EPSCs) and presynaptic capacitance suggested that the initial release probability was lowered because of the reduced Ca2+ influx and impaired fusion competence in RIM-BP2 KO. Nevertheless, larger Ca2+ influx restored release partially. Consistent with presynaptic recording, STED microscopy suggested less abundance of P/Q-type Ca2+ channels at AZs deficient in RIM-BP2. Our results suggest that the RIM-BP2 regulates both Ca2+ channel abundance and transmitter release at mossy fiber synapses.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Fibras Musgosas Hipocampais , Transmissão Sináptica , Animais , Camundongos , Transporte Biológico , Camundongos Knockout , Neurotransmissores , Sinapses , Peptídeos e Proteínas de Sinalização Intracelular/genética , Canais de Cálcio/metabolismo
11.
Neurology ; 102(1): e207992, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38175838

RESUMO

A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide was prescribed, which led to dose-responsive decrease in the frequency and intensity of eye movement episodes. After 6 months of episode freedom at 2 years of age, acetazolamide was discontinued without return of episodes. Neurodevelopmental assessments revealed continued typical development. This case is presented to describe the diagnostic formulation, etiologic evaluation, and symptomatic treatment of CACNA1A-related PTU with ataxia.


Assuntos
Transtornos da Motilidade Ocular , Estrabismo , Humanos , Lactente , Masculino , Acetazolamida/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/diagnóstico , Canais de Cálcio/genética , Movimentos Oculares , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/diagnóstico , Convulsões/tratamento farmacológico
12.
Biochem Biophys Res Commun ; 695: 149481, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38211534

RESUMO

Spinocerebellar ataxia type 6 (SCA6) is a polyglutamine (polyQ) disease, which is caused by the elongation of CAG repeats encoding polyQ in the CACNA1A gene. The CACNA1A gene encodes two proteins, namely, α1A (a subunit of the plasma membrane calcium channel), which is translated in its entire length, and α1ACT, which is translated from the second cistron, and both proteins have a polyQ tract. The α1A-polyQ and α1ACT-polyQ proteins with an elongated polyQ stretch have been reported to form aggregates in cells and induce neuronal cell death, but the subcellular localization of these proteins and their cytotoxic properties remain unclear. In this study, we first analyzed SCA6 model mice and found that α1A-polyQlong localized mainly to the Golgi apparatus, whereas a portion of α1ACT-polyQlong localized to the nucleus. Analysis using Neuro2a cells also showed similar subcellular localizations of these proteins, and a proportion of both proteins localized to the endoplasmic reticulum (ER). Cytotoxic studies demonstrated that both proteins induce both the ER stress response and apoptosis, indicating that they are able to induce ER stress-induced apoptosis.


Assuntos
Canais de Cálcio Tipo N , Ataxias Espinocerebelares , Animais , Camundongos , Canais de Cálcio/metabolismo , Canais de Cálcio Tipo N/metabolismo , Retículo Endoplasmático/metabolismo , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo
13.
Brain Res Bull ; 207: 110876, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215950

RESUMO

Numb is an evolutionarily conserved protein that regulates the differentiation of neuronal progenitor cells through unknown mechanisms. Numb has four alternative splice variants with different lengths of phosphotyrosine-binding (PTB) and proline-rich regions (PRR) domains. In this study, we demonstrated that Numb expression was increased in the primary cultures of rat cortical and hippocampal neurons over time in vitro, and Numb antisense inhibited neurite outgrowth. We verified that cells overexpressing short PTB (SPTB) or long PTB (LPTB) domains exhibited differentiation or proliferation, respectively. SPTB-mediated differentiation was related to the PRR domains, as cells expressing SPTB/LPRR had longer dendrites and more branched dendrites than cells expressing SPTB/SPRR. The differentiation of both cell types was completely blocked by the Ca2+ chelator. Western blot analysis revealed the increased total protein expression of voltage-gated calcium channel (VGCC) subunit α1C and α1D in cells expressing SPTB and LPTB Numb. The increased expression of the VGCC ß3 subunit was only observed in cells expressing SPTB Numb. Immunocytochemistry further showed that SPTB-mediated cell differentiation was associated with increased membrane expression of VGCC subunits α1C, α1D and ß3, which corresponded to the higher Ca2+ current (ICa) densities. Furthermore, we found that VGCC of cells transfected with SPTB/SPRR or SPTB/LPRR Numb isoforms exhibit steady-state inactivation (SSI) in both differentiated and undifferentiated phenotypes. A similar SSI of VGCC was observed in the differentiated cells transfected with SPTB/SPRR or SPTB/LPRR Numb isoforms, whereas a left shift SSI of VGCC in cells expressing SPTB/LPRR was detected in the undifferentiated cells. Collectively, these data indicate that SPTB domain is essential for neurite outgrowth involving in membrane expression of VGCC subunits, and LPRR plays a role in neuronal branching and the regulation of VGCC inactivation kinetics.


Assuntos
Proteínas de Membrana , Neurônios , Ratos , Animais , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Canais de Cálcio/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacologia , Crescimento Neuronal , Cálcio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
15.
Mol Metab ; 80: 101873, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199601

RESUMO

OBJECTIVE: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. METHODS: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. RESULTS: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. CONCLUSIONS: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.


Assuntos
Canais de Cálcio , Resistência à Insulina , Animais , Camundongos , Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Glucose/metabolismo , Resistência à Insulina/fisiologia , Lipídeos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
16.
Acta Biomater ; 176: 432-444, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38185232

RESUMO

The use of bone substitute materials is crucial for the healing of large bone defects. Immune response induced by bone substitute materials is essential in bone regeneration. Prior research has mainly concentrated on innate immune cells, such as macrophages. Existing research suggests that T lymphocytes, as adaptive immune cells, play an indispensable role in bone regeneration. However, the mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. This study demonstrates that CD4+ T cells are indispensable for ectopic osteogenesis by biphasic calcium phosphate (BCP). Subsequently, the recruitment of CD4+ T cells is closely associated with the activation of calcium channels in macrophages by BCP to release chemokines Ccl3 and Ccl17. Finally, these recruited CD4+ T cells are predominantly Tregs, which play a significant role in ectopic osteogenesis by BCP. These findings not only shed light on the immune-regenerative process after bone substitute material implantation but also establish a theoretical basis for developing bone substitute materials for promoting bone tissue regeneration. STATEMENT OF SIGNIFICANCE: Bone substitute material implantation is essential in the healing of large bone defects. Existing research suggests that T lymphocytes are instrumental in bone regeneration. However, the specific mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. In this study, we demonstrate that activation of calcium channels in macrophages by biphasic calcium phosphate (BCP) causes them to release the chemokines Ccl3 and Ccl17 to recruit CD4+ T cells, predominantly Tregs, which play a crucial role in ectopic osteogenesis by BCP. Our findings provide a theoretical foundation for developing bone substitute material for bone tissue regeneration.


Assuntos
Substitutos Ósseos , Substitutos Ósseos/farmacologia , Regeneração Óssea , Hidroxiapatitas/farmacologia , Canais de Cálcio , Quimiocinas , Osteogênese , Fosfatos de Cálcio/farmacologia
17.
Cell Biochem Funct ; 42(1): e3933, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38269518

RESUMO

Obesity is a complex disorder, and the incidence of obesity continues to rise at an alarming rate worldwide. In particular, the growing incidence of overweight and obesity in children is a major health concern. However, the underlying mechanisms of obesity remain unclear and the efficacy of several approaches for weight loss is limited. As an important calcium-permeable temperature-sensitive cation channel, transient receptor potential vanilloid (TRPV) ion channels directly participate in thermo-, mechano-, and chemosensory responses. Modulation of TRPV ion channel activity can alter the physiological function of the ion channel, leading to neurodegenerative diseases, chronic pain, cancer, and skin disorders. In recent years, increasing studies have demonstrated that TRPV ion channels are abundantly expressed in metabolic organs, including the liver, adipose tissue, skeletal muscle, pancreas, and central nervous system, which has been implicated in various metabolic diseases, including obesity and diabetes mellitus. In addition, as an important process for the pathophysiology of adipocyte metabolism, adipocyte differentiation plays a critical role in obesity. In this review, we focus on the role of TRPV ion channels in adipocyte differentiation to broaden the ideas for prevention and control strategies for obesity.


Assuntos
Antineoplásicos , Obesidade Pediátrica , Criança , Humanos , Diferenciação Celular , Adipócitos , Canais de Cálcio
18.
Cell Signal ; 116: 111043, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38211841

RESUMO

Calcium is a ubiquitous second messenger that is indispensable in regulating neurotransmission and memory formation. A precise intracellular calcium level is achieved through the concerted action of calcium channels, and calcium exerts its effect by binding to an array of calcium-binding proteins, including calmodulin (CAM), calcium-calmodulin complex-dependent protein kinase-II (CAMK-II), calbindin (CAL), and calcineurin (CAN). Calbindin orchestrates a plethora of signaling events that regulate synaptic transmission and depolarizing signals. Vitamin D, an endogenous fat-soluble metabolite, is synthesized in the skin upon exposure to ultraviolet B radiation. It modulates calcium signaling by increasing the expression of the calcium-sensing receptor (CaSR), stimulating phospholipase C activity, and regulating the expression of calcium channels such as TRPV6. Vitamin D also modulates the activity of calcium-binding proteins, including CAM and calbindin, and increases their expression. Calbindin, a high-affinity calcium-binding protein, is involved in calcium buffering and transport in neurons. It has been shown to inhibit apoptosis and caspase-3 activity stimulated by presenilin 1 and 2 in AD. Whereas CAM, another calcium-binding protein, is implicated in regulating neurotransmitter release and memory formation by phosphorylating CAN, CAMK-II, and other calcium-regulated proteins. CAMK-II and CAN regulate actin-induced spine shape changes, which are further modulated by CAM. Low levels of both calbindin and vitamin D are attributed to the pathology of Alzheimer's disease. Further research on vitamin D via calbindin-CAMK-II signaling may provide newer insights, revealing novel therapeutic targets and strategies for treatment.


Assuntos
Doença de Alzheimer , Vitamina D , Humanos , Sinalização do Cálcio , Calbindinas , Calmodulina , Cálcio , Proteínas de Ligação ao Cálcio , Canais de Cálcio , Calcineurina , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina
19.
J Clin Invest ; 134(1)2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38165034

RESUMO

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.


Assuntos
Infertilidade Masculina , Sêmen , Criança , Humanos , Masculino , Sêmen/fisiologia , Canais de Cálcio/genética , Motilidade dos Espermatozoides/fisiologia , Espermatozoides/fisiologia , Infertilidade Masculina/terapia , Infertilidade Masculina/genética , Fertilização In Vitro , Fertilização/fisiologia
20.
Sci Rep ; 14(1): 1479, 2024 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233493

RESUMO

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that alters neural activity and induces neural plasticity that outlasts the period of stimulation. This can modify corticospinal excitability or motor behaviours, suggesting that SMS may alter the intrinsic excitability of neurons. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity (changes in length and position from the soma) as a homeostatic mechanism to counteract chronic changes in neuronal activity. We investigated whether the chronic application of SMS (6 and 48 h, 0.5 T) induces structural AIS plasticity in postnatally derived primary cortical neurons. Following 6 h of SMS, we observed a shortening in mean AIS length compared to control, that persisted 24 h post stimulation. In contrast, 48 h of SMS induced an immediate distal shift that persisted 24 h post-stimulation. Pharmacological blockade of voltage gated L/T-type calcium channels during stimulation did not prevent SMS-induced AIS structural plasticity. Our findings provide the foundation to expand the use of chronic SMS as a non-invasive method to promote AIS plasticity.


Assuntos
Segmento Inicial do Axônio , Animais , Axônios/fisiologia , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Plasticidade Neuronal/fisiologia , Canais de Cálcio , Fenômenos Magnéticos , Mamíferos
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