RESUMO
Solute carrier family 26 member 4 (SLC26A4) is a member of the SLC26A transporter family and is expressed in various tissues, including the airway epithelium, kidney, thyroid, and tumors. It transports various ions, including bicarbonate, chloride, iodine, and oxalate. As a multiple-ion transporter, SLC26A4 is involved in the maintenance of hearing function, renal function, blood pressure, and hormone and pH regulation. In this review, we have summarized the various functions of SLC26A4 in multiple tissues and organs. Moreover, the relationships between SLC26A4 and other channels, such as cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and sodium chloride cotransporter, are highlighted. Although the modulation of SLC26A4 is critical for recovery from malfunctions of various organs, development of specific inducers or agonists of SLC26A4 remains challenging. This review contributes to providing a better understanding of the role of SLC26A4 and development of therapeutic approaches for the SLC26A4-associated hearing loss and SLC26A4-related dysfunction of various organs.
Assuntos
Transportadores de Sulfato , Humanos , Transportadores de Sulfato/metabolismo , Transportadores de Sulfato/genética , Animais , Rim/metabolismo , Antiportadores de Cloreto-Bicarbonato/metabolismo , Antiportadores de Cloreto-Bicarbonato/genética , Especificidade de Órgãos , Cloretos/metabolismo , Transporte de ÍonsRESUMO
Naturally derived essential oils and their active components are known to possess various properties, ranging from anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, and anti-cancer activities. Numerous types of essential oils and active components have been discovered, and their permissive roles have been addressed in various fields. In this comprehensive review, we focused on the roles of essential oils and active components in skin diseases and cancers as discovered over the past three decades. In particular, we opted to highlight the effectiveness of essential oils and their active components in developing strategies against various skin diseases and skin cancers and to describe the effects of the identified essential-oil-derived major components from physiological and pathological perspectives. Overall, this review provides a basis for the development of novel therapies for skin diseases and cancers, especially melanoma.
Assuntos
Óleos Voláteis , Neoplasias Cutâneas , Pele , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Óleos Voláteis/química , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Animais , Dermatopatias/tratamento farmacológicoRESUMO
Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin-proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca2+ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells.
Assuntos
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/metabolismo , Lisossomos/metabolismo , Corpos Multivesiculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Transdução de Sinais , Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
Poly L-lactic acid (PLLA) fillers stimulate collagen synthesis by activating various immune cells and fibroblasts. Piezo1, an ion channel, responds to mechanical stimuli, including changes in extracellular matrix stiffness, by mediating Ca2+ influx. Given that elevated intracellular Ca2+ levels trigger signaling pathways associated with fibroblast proliferation, Piezo1 is a pivotal regulator of collagen synthesis and tissue fibrosis. The aim of the present study was to investigate the impact of PLLA on dermal collagen synthesis by activating Piezo1 in both an H2O2-induced cellular senescence model in vitro and aged animal skin in vivo. PLLA elevated intracellular Ca2+ levels in senescent fibroblasts, which was attenuated by the Piezo1 inhibitor GsMTx4. Furthermore, PLLA treatment increased the expression of phosphorylated ERK1/2 to total ERK1/2 (pERK1/2/ERK1/2) and phosphorylated AKT to total AKT (pAKT/AKT), indicating enhanced pathway activation. This was accompanied by upregulation of cell cycle-regulating proteins (CDK4 and cyclin D1), promoting the proliferation of senescent fibroblasts. Additionally, PLLA promoted the expression of phosphorylated mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III in senescent fibroblasts, with GsMTx4 treatment mitigating these effects. In aged skin, PLLA treatment similarly upregulated the expression of pERK1/2/ERK1/2, pAKT/AKT, CDK4, cyclin D1, mTOR/S6K1/4EBP1, TGF-ß, and Collagen I/III. In summary, our findings suggest Piezo1's involvement in PLLA-induced collagen synthesis, mediated by heightened activation of cell proliferation signaling pathways such as pERK1/2/ERK1/2, pAKT/AKT, and phosphorylated mTOR/S6K1/4EBP1, underscoring the therapeutic potential of PLLA in tissue regeneration.
Assuntos
Colágeno , Fibroblastos , Poliésteres , Animais , Poliésteres/farmacologia , Poliésteres/química , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Colágeno/metabolismo , Colágeno/biossíntese , Canais Iônicos/metabolismo , Camundongos , Pele/metabolismo , Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cálcio/metabolismo , Transdução de Sinais/efeitos dos fármacos , HumanosRESUMO
New nurses must acquire accurate knowledge of medication administration, as it directly affects patient safety. This study aimed to develop a microlearning-based self-directed learning chatbot on medication administration for novice nurses. Furthermore, the study had the objective of evaluating the chatbot feasibility. The chatbot covered two main topics: medication administration processes and drug-specific management, along with 21 subtopics. Fifty-eight newly hired nurses on standby were asked to use the chatbot over a 2-week period. Moreover, we evaluated the chatbot's feasibility through a survey that gauged changes in their confidence in medication administration knowledge, intrinsic learning motivation, satisfaction with the chatbot's learning content, and usability. After using the chatbot, participants' confidence in medication administration knowledge significantly improved in all topics (P < .001) except "Understanding a concept of 5Right" (P = .077). Their intrinsic learning motivation, satisfaction with the learning content, and usability scored above 5 out of 7 in all subdomains, except for pressure/tension (mean, 2.12; median, 1.90). They scored highest on ease of learning (mean, 6.69; median, 7.00). A microlearning-based chatbot can help new nurses improve their knowledge of medication administration through self-directed learning.
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Carbonic anhydrase 12 is considered an oncogenic and acidic microenvironmental factor in cancer cells. To verify the role of histamine signalling as an anti-cancer signal, we determined the roles of CA12 and its associated bicarbonate transporters. In this study, histamine stimulation mediated mislocalization of CA12 in lung cancer cells. Histamine receptor activation-mediated CA12 endocytosis and pH were restored by CaMKII inhibition. CA12-associated AE2 expression was enhanced, whereas NBCn1 expression and its activity were reduced by histamine stimulation. Histamine receptor activation-mediated acidification was induced by internalised CA12 and NBCn1 and, at the same time by increased bicarbonate efflux through enhanced AE2 expression. Inhibition of protein trafficking by bafilomycin restored CA12 and AE2 localisation and diminished cellular acidosis. Thus, we verified that histamine stimulation induced an acidic scenario, which revealed trafficking of CA12 and its associated bicarbonate transporters in lung cancer cells and its dysregulated pH modulation may be involved in the histamine signalling-mediated anti-cancer process.
Assuntos
Anidrases Carbônicas , Neoplasias Pulmonares , Humanos , Histamina/farmacologia , Bicarbonatos/farmacologiaRESUMO
Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.
Assuntos
Artrite Reumatoide , Dexmedetomidina , Sinoviócitos , Humanos , Sinoviócitos/metabolismo , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Agonistas Adrenérgicos/farmacologia , Fibroblastos/metabolismo , Células Cultivadas , Proliferação de Células , Movimento CelularRESUMO
PyK2 is a member of the proline-rich tyrosine kinase and focal adhesion kinase families and is ubiquitously expressed. PyK2 is mainly activated by stimuli, such as activated Src kinases and intracellular acidic pH. The mechanism of PyK2 activation in cancer cells has been addressed extensively. The up-regulation of PyK2 through overexpression and enhanced phosphorylation is a key feature of tumorigenesis and cancer migration. In this review, we summarized the cancer milieu, including acidification and cancer-associated molecules, such as chemical reagents, interactive proteins, chemokine-related molecules, calcium channels/transporters, and oxidative molecules that affect the fate of PyK2. The inhibition of PyK2 leads to a beneficial strategy to attenuate cancer cell development, including metastasis. Thus, we highlighted the effect of PyK2 on various cancer cell types and the distribution of molecules that affect PyK2 activation. In particular, we underlined the relationship between PyK2 and cancer metastasis and its potential to treat cancer cells.
Assuntos
Quinase 2 de Adesão Focal , Neoplasias , Quinase 2 de Adesão Focal/metabolismo , Quinases da Família src/metabolismo , Fosforilação , Quinase 1 de Adesão Focal/metabolismoRESUMO
Lamins are nuclear envelope proteins involved in various cellular functions, such as DNA modulation, cellular differentiation, and development. In this study, we investigate the role of histamine in lung cancer biology. Since it is known that lamin-A/C is negatively regulated in lung cancer, we hypothesize that histamine signaling is related to nuclear lamin-A/C regulation and cancer progression. Our findings reveal that histamine stimulation enhances lamin-A/C expression in lung cancer cells. Lamin-A/C expression is dependent on histamine-mediated intracellular calcium signaling and subsequent calcium/calmodulin-dependent kinase II (Ca/CaMKII) activation. The nuclear protein nestin, which stabilizes lamin-A/C expression, is also modulated by Ca/CaMKII. However, histamine-mediated lamin-A/C expression is independent of Akt/focal adhesion kinase or autophagy signaling. Histamine stimulation attenuates lung cancer motility in the presence of enhanced lamin-A/C expression. In conclusion, we propose a regulatory mechanism that accounts for the modulation of lamin-A/C levels through the involvement of Ca/CaMKII in cancer cells and provides molecular evidence of histamine signaling in lamin-A/C biology.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Histamina , Lamina Tipo A , Neoplasias Pulmonares , Cálcio/metabolismo , Cálcio da Dieta , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Histamina/farmacologia , Humanos , Lamina Tipo A/metabolismo , Neoplasias Pulmonares/genética , FosforilaçãoRESUMO
Although cardiac tissue is considered a target of gravitational force (g-force), the mechanism of hypergravity on the ion modulation or identification of ion transporters is still unknown. Thus, we determine the effect of hypergravity on a physical force-sensitive cytokine, IL-6 and its related channel activity to investigate rat cardiac function changes in response to accelerated g-force. Serum IL-6 levels and intracellular calcium levels of the right atrium were moderately increased under hypergravity stimulation (4g). IL-6 was involved in the modulation of sodium-potassium-chloride cotransporter (Nkcc) activity. Surprisingly, the right atrium under 4g revealed significantly enhanced Nkcc1 activity. The use of IL-6 on the NKCC1-overexpressed or native NKCC-expressing cells also showed enhanced NKCC1 activity. Hypergravity conditions were also involved in the oxidative stress activated Trpm2 channel and revealed an enhanced expression of the Trpm2 channel under 4g in the rat right atrium. In conclusion, hypergravity revealed that moderate increases in serum IL-6 and enhanced Nkcc1 activity was modulated by IL-6. In addition, enhanced Trpm2 channel expression could be involved in the increased intracellular calcium levels of the right atrium under hypergravitational force. We therefore address that enhanced physical force-sensitive cytokine and oxidative stress by the gravitational force mediate activation of the cotransporter involved in possibilities of edema and calcium loading in cardiac tissue.
Assuntos
Cálcio/metabolismo , Átrios do Coração/metabolismo , Hipergravidade , Interleucina-6/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Canalopatias/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Insulin resistance, a key etiological factor in metabolic syndrome, is closely linked to ectopic lipid accumulation and increased intracellular Ca2+ concentrations in muscle and liver. However, the mechanism by which dysregulated intracellular Ca2+ homeostasis causes insulin resistance remains elusive. Here, we show that increased intracellular Ca2+ acts as a negative regulator of insulin signaling. Chronic intracellular Ca2+ overload in hepatocytes during obesity and hyperlipidemia attenuates the phosphorylation of protein kinase B (Akt) and its key downstream signaling molecules by inhibiting membrane localization of pleckstrin homology (PH) domains. Pharmacological approaches showed that elevated intracellular Ca2+ inhibits insulin-stimulated Akt phosphorylation and abrogates membrane localization of various PH domain proteins such as phospholipase Cδ and insulin receptor substrate 1, suggesting a common mechanism inhibiting the membrane targeting of PH domains. PH domain-lipid overlay assays confirmed that Ca2+ abolishes the binding of various PH domains to phosphoinositides (PIPs) with two adjacent phosphate groups, such as PI(3,4)P2, PI(4,5)P2, and PI(3,4,5)P3 Finally, thermodynamic analysis of the binding interaction showed that Ca2+-mediated inhibition of targeting PH domains to the membrane resulted from the tight binding of Ca2+ rather than PH domains to PIPs forming Ca2+-PIPs. Thus, Ca2+-PIPs prevent the recognition of PIPs by PH domains, potentially due to electrostatic repulsion between positively charged side chains in PH domains and the Ca2+-PIPs. Our findings provide a mechanistic link between intracellular Ca2+ dysregulation and Akt inactivation in insulin resistance.
Assuntos
Cálcio/metabolismo , Membrana Celular/metabolismo , Resistência à Insulina/fisiologia , Fosfatidilinositóis/metabolismo , Domínios de Homologia à Plecstrina/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Dieta Hiperlipídica , Intolerância à Glucose/patologia , Hiperinsulinismo/patologia , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Fosfolipase C delta/metabolismo , Fosforilação , Ligação ProteicaRESUMO
AIM AND OBJECTIVES: To explore the experiences of Korean nurses who had directly cared for patients with Middle East respiratory syndrome (MERS) and to derive the structure and meaning of these experiences. BACKGROUND: In 2015, the MERS epidemic struck Korea, and ill-prepared nurses had to care for patients with MERS. Nurses experienced conflict between their fear of the disease and their work and professional ethic. DESIGN: We employed a phenomenological qualitative approach. METHODS: Inductive, qualitative, in-depth interviews were performed with 17 nurses. The study process followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. RESULTS: The qualitative inductive content analysis generated seven theme clusters and 18 themes. The theme clusters were "Fear of Uncertainty," "Beyond Hesitation," "A Scene Like a Battlefield," "Chaotic Nursing Identity," "Buttresses for Sustainability," "Lingering Trauma" and "Expanded Horizon of Nursing." The final analysis revealed that the core theme was "Beyond the fear of uncertainty." CONCLUSIONS: This study contrives a more in-depth, holistic understanding by describing the experiences of nurses who directly cared for patients with MERS-the first large-scale infectious disease in Korea. Although nurses saw themselves as vital caregivers, they were frightened of the disease, had to work in a harsh environment, experienced various internal conflicts and had to deal with varying forms of uncertainty. RELEVANCE TO CLINICAL PRACTICE: This study sheds light on the nursing situation during crises involving serious infectious diseases; to combat these, more medical facilities are needed, and staff should be proactively guided on how to care for patients. It can serve as part of a good foundation for further study of medical staff during recurring epidemics.
Assuntos
Infecções por Coronavirus/enfermagem , Medo/psicologia , Recursos Humanos de Enfermagem Hospitalar/psicologia , Adulto , Surtos de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , República da Coreia , IncertezaRESUMO
The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved in the mechanism of bicarbonate movement and consist of complex of bicarbonate transport systems including bicarbonate transporters. This review focused on the convergent regulation of ion homeostasis through various ion transporters including bicarbonate transporters, their regulatory enzymes, such as carbonic anhydrases, pH regulatory role, and the expression pattern of ion transporters in non-secretory systems throughout the body. Understanding the correlation between these systems will be helpful in order to obtain new insights and design potential therapeutic strategies for the treatment of pH-related disorders. In this review, we have discussed the broad prospects and challenges that remain in elucidation of bicarbonate-transport-related biological and developmental systems.
Assuntos
Bicarbonatos/metabolismo , Anidrases Carbônicas/metabolismo , Bicarbonatos/química , Trato Gastrointestinal/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Sistema Imunitário/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Transporte de Íons , Músculo Liso Vascular/metabolismo , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Keratinocyte migration is initiated toward the wound skin barrier as a crucial process in wound healing. However, the migratory machinery used by keratinocytes is relatively unknown. Histamine signaling, including an increase in the Ca2+ signal, mediated the enhanced protein expression and chloride/bicarbonate exchange activity of anion exchanger AE2 in keratinocytes. In this study, we applied an agarose spot assay to induce a vectorial motion. The vectorial stimulation of the histamine-containing agarose spot enhanced the HaCaT keratinocyte migration, compared to non-directional stimulation. AE2 is associated with the vectorial movement of HaCaT keratinocytes. Enhanced expression of AE2 was mainly associated with an increase in Ca2+ and was abolished by the treatment with the Ca2+ chelating agent BAPTA-AM. These findings revealed that the directionality of Ca2+-exerted stimulation can play a prominent role in facilitating migration through the involvement of AE2 as a migratory machinery in HaCaT keratinocytes.
Assuntos
Sinalização do Cálcio , Queratinócitos/fisiologia , Cloreto de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/fisiologia , Antiportadores de Cloreto-Bicarbonato/antagonistas & inibidores , Antiportadores de Cloreto-Bicarbonato/genética , Antiportadores de Cloreto-Bicarbonato/metabolismo , Dissulfiram/farmacologia , Histamina/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Modelos Biológicos , Pele/lesões , Pele/patologia , Pele/fisiopatologia , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologiaRESUMO
The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption. Cytosolic calcium binds to calmodulin and subsequently activates calcineurin, leading to NFATc1 activation, a master transcription factor required for osteoclast differentiation. Targeting the various activation processes in osteoclastogenesis provides various therapeutic strategies for bone loss. Diverse compounds that modulate calcium signaling have been applied to regulate osteoclast differentiation and, subsequently, attenuate bone loss. Thus, in this review, we summarized the modulation of the NFATc1 pathway through various compounds that regulate calcium signaling and the calcium influx machinery. Furthermore, we addressed the involvement of transient receptor potential channels in osteoclastogenesis.
Assuntos
Sinalização do Cálcio , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/metabolismo , Osteogênese , Animais , Humanos , Fatores de Transcrição NFATC/genética , Osteoclastos/citologia , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
Diabetic heart dysfunctions during cardiac surgeries have revealed several clinical problems associated with ion imbalance. However, the mechanism of ion imbalance mediated by cardioplegia and a diabetic heart is largely unclear. We hypothesized that ion transporters might be regulated differently in the diabetic heart and that the differentially regulated ion transporters may involve in ion imbalance of the diabetic heart after cardioplegic arrest. In this study, we modified the Langendorff-free cardioplegia method and identified the involved ion transporters after cardioplegia-induced arrest between wild type and db/db heart. Enhanced expression of Na+-K+-2Cl- cotransporter 1 (NKCC1) was observed in the db/db heart compared to the wild type heart. Enhanced NKCC1 activity was observed in the left ventricle of db/db mice compared to that of wild type after cardioplegia-induced arrest. The expression and activity of Slc26a6, a dominant Cl-/HCO3 - exchanger in cardiac tissues, were enhanced in left ventricle strips of db/db mice compared to that of wild type. The Cl- transporting activity in left ventricle strips of db/db mice was dramatically increased as compared to that of wild type. Interestingly, expression of Slc26a6, as well as carbonic anhydrase IV as a supportive enzyme of Slc26a6, was increased in db/db cardiac strips compared to wild type cardiac strips. Thus, the enhanced Cl- transporting activity and expression by NKCC1 and Slc26a6 in db/db cardiac tissues after cardioplegia-induced arrest provide greater insight into enhanced acidosis and Cl- movement-mediated db/db heart dysfunction. Thus, we suggested that enhanced Cl- influx and HCO3 - efflux through NKCC1 and Slc26a6 offer more acidic circumstances in the diabetic heart after cardioplegic arrest. These transporters should be considered as potential therapeutic targets to develop the next generation of cardioplegia solution for protection against ischemia-reperfusion injury in diabetic hearts.
Assuntos
Antiporters/metabolismo , Parada Cardíaca Induzida/efeitos adversos , Parada Cardíaca/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Transportadores de Sulfato/metabolismo , Animais , Antiporters/genética , Coração , Parada Cardíaca/etiologia , Concentração de Íons de Hidrogênio , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membro 2 da Família 12 de Carreador de Soluto/genética , Transportadores de Sulfato/genéticaRESUMO
The highly aggressive fibroblast-like synoviocytes (FLSs) are inflammatory mediators involved in synovial joint destruction. Membrane channels and transporters are essential components of the cell migration apparatus and are involved in various cellular functions. Although evidence is emerging that cell migration is a physiological/pathological process, the mechanism of highly dynamic synoviocytes linked to the membrane channels and carbonic anhydrases (CAs) in inflamed joints is only partially understood. In this review, topics covered will give a brief overview of CAs and the membrane channels of synoviocytes. We have also systematically focused on the role of FLS channels and transporters under various conditions, including rheumatoid arthritis (RA), to understand the pathophysiology of the migration of synoviocytes as inflammatory mediators in joints.
Assuntos
Artrite Reumatoide/metabolismo , Anidrases Carbônicas/metabolismo , Mediadores da Inflamação/metabolismo , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Animais , HumanosRESUMO
Patients carrying the carbonic anhydrase12 E143K mutation showed the dry mouth phenotype. The mechanism underlying the modulation of aquaporin 5 and function in the salivary glands by carbonic anhydrase12 remains unknown. In this study, we identified the mislocalised aquaporin 5 in the salivary glands carrying the E143K. The intracellular pH of E143K cells was more acidic than that of the cells carrying wild type. To evaluate the role of carbonic anhydrase12 on the volume regulation of aquaporin 5, the submandibular gland cells were subjected to hypotonic stimuli. E143K enhanced the extent of swelling of cells on hypotonicity. Aquaporin 5 modulates water influx through ion transporters to prevent osmotic imbalance. These results suggest that the carbonic anhydrase12 E143K, including acidification or inflammation, mediates volume dysregulation by the loss of aquaporin 5. Thus, carbonic anhydrase12 may determine sensible effects on the cellular osmotic regulation by modulating aquaporin 5.
Assuntos
Aquaporina 5/metabolismo , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Mutação , Glândula Submandibular/enzimologia , Glândula Submandibular/metabolismo , Animais , Membrana Celular/enzimologia , Tamanho Celular , Estabilidade Enzimática , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Transporte de Íons , Proteínas de Membrana Transportadoras/metabolismo , Camundongos Endogâmicos C57BL , Concentração Osmolar , Glândula Submandibular/citologiaRESUMO
Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na+-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent.
Assuntos
Antineoplásicos/farmacologia , Anidrases Carbônicas/metabolismo , Movimento Celular/efeitos dos fármacos , Antiportadores de Cloreto-Bicarbonato/metabolismo , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Neoplasias/metabolismo , Neoplasias/patologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Humanos , Invasividade Neoplásica , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Although the standard treatment for the patients with recurrent and metastatic prostate cancer (CaP) is androgen deprivation therapy, castration-resistant prostate cancer (CRPC) eventually emerges. Our previous report indicated that bone morphogenetic protein 6 (BMP6) induced CRPC via tumour-infiltrating macrophages. In a separate line of study, we have observed that the WNT5A/BMP6 loop in CaP bone metastasis mediates resistance to androgen deprivation in tissue culture. Simultaneously, we have reported that BMP6 induced castration resistance in CaP cells via tumour-infiltrating macrophages. Therefore, our present study aims to investigate the mechanism of WNT5A and its interaction with macrophages on CRPC. METHODS: Doxycycline inducible WNT5A overexpression prostate cancer cell line was used for detailed mechanical study. RESULTS: WNT5A was associated with increased expression of chemokine ligand 2 (CCL2) in the human CaP cell line, LNCaP. Mechanistically, this induction of CCL2 by WNT5A is likely to be mediated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signalling pathway. Our in vivo experiments demonstrated that the overexpression of WNT5A in LNCaP cells promoted castration resistance. Conversely, this resistance was inhibited with the removal of macrophages via clodronate liposomes. When patient-derived CaP LuCaP xenografts were analysed, high levels of WNT5A were correlated with increased levels of CCL2 and BMP6. In addition, higher levels of CCL2 and BMP6 were more commonly observed in intra-femoral transplanted tumours as compared to subcutaneous-transplanted tumours in the patient-derived PCSD1 bone-niche model. CONCLUSIONS: These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.