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1.
Immunity ; 57(7): 1497-1513.e6, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38744293

RESUMO

RIPK1 is a multi-functional kinase that regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 acts in a kinase-dependent and kinase-independent manner to promote or suppress apoptosis and necroptosis, but the underlying mechanisms remain poorly understood. Here, we show that a mutation (R588E) disrupting the RIPK1 death domain (DD) caused perinatal lethality induced by ZBP1-mediated necroptosis. Additionally, these mice developed postnatal inflammatory pathology, which was mediated by necroptosis-independent TNFR1, TRADD, and TRIF signaling, partially requiring RIPK3. Our biochemical mechanistic studies revealed that ZBP1- and TRIF-mediated activation of RIPK3 required RIPK1 kinase activity in wild-type cells but not in Ripk1R588E/R588E cells, suggesting that DD-dependent oligomerization of RIPK1 and its interaction with FADD determine the mechanisms of RIPK3 activation by ZBP1 and TRIF. Collectively, these findings revealed a critical physiological role of DD-dependent RIPK1 signaling that is important for the regulation of tissue homeostasis and inflammation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular , Inflamação , Necroptose , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores , Transdução de Sinais , Animais , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos , Inflamação/metabolismo , Inflamação/imunologia , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteína de Domínio de Morte Associada a Fas/genética , Morte Celular , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Domínios Proteicos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Apoptose , Mutação , Proteína de Domínio de Morte Associada a Receptor de TNF
2.
Mol Cell ; 66(5): 698-710.e5, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506461

RESUMO

TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive cytokine production, cell survival, or cell death. TNFR1 stimulation causes activation of NF-κB, p38α, and its downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, and translation of target genes. Here we show that TNF-induced activation of MK2 results in global RIPK1 phosphorylation. MK2 directly phosphorylates RIPK1 at residue S321, which inhibits its ability to bind FADD/caspase-8 and induce RIPK1-kinase-dependent apoptosis and necroptosis. Consistently, a phospho-mimetic S321D RIPK1 mutation limits TNF-induced death. Mechanistically, we find that phosphorylation of S321 inhibits RIPK1 kinase activation. We further show that cytosolic RIPK1 contributes to complex-II-mediated cell death, independent of its recruitment to complex-I, suggesting that complex-II originates from both RIPK1 in complex-I and cytosolic RIPK1. Thus, MK2-mediated phosphorylation of RIPK1 serves as a checkpoint within the TNF signaling pathway that integrates cell survival and cytokine production.


Assuntos
Apoptose/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Caspase 8/metabolismo , Relação Dose-Resposta a Droga , Proteína de Domínio de Morte Associada a Fas/metabolismo , Células HT29 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Complexos Multiproteicos , NF-kappa B/metabolismo , Necrose , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais/efeitos dos fármacos , Transfecção
3.
Cell Mol Biol (Noisy-le-grand) ; 70(3): 22-28, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38650160

RESUMO

This study aimed to evaluate the physiological role of NAMPT associated with MDPC-23 odontoblast cell proliferation. Cell viability was measured using the (DAPI) staining, caspase activation analysis and immunoblotting were performed. Visfatin promoted MDPC-23 odontoblast cell growth in a dose-dependent manner. Furthermore, the up-regulation of Visfatin promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers in MDPC-23 cells. However, FK-866 cell growth in a dose-dependent manner induced nuclear condensation and fragmentation. FK-866-treated cells showed H&E staining and increased apoptosis compared to control cells. The expression of anti-apoptotic factors components of the mitochondria-dependent intrinsic apoptotic pathway significantly decreased following FK-866 treatment. The expression of pro-apoptotic increased upon FK-866 treatment. In addition, FK-866 activated caspase-3 and PARP to induce cell death. In addition, after treating FK-866 for 72 h, the 3/7 activity of MDPC-23 cells increased in a concentration-dependent manner, and the IHC results also confirmed that Caspase-3 increased in a concentration-dependent. Therefore, the presence or absence of NAMPT expression in dentin cells was closely related to cell proliferation and formation of extracellular substrates.


Assuntos
Apoptose , Proliferação de Células , Nicotinamida Fosforribosiltransferase , Odontoblastos , Nicotinamida Fosforribosiltransferase/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Odontoblastos/efeitos dos fármacos , Odontoblastos/citologia , Odontoblastos/metabolismo , Animais , Camundongos , Linhagem Celular , Citocinas/metabolismo , Caspase 3/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Acrilamidas/farmacologia , Odontogênese/efeitos dos fármacos
4.
Pflugers Arch ; 475(2): 267-275, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36278983

RESUMO

Mitochondria transplantation emerges as an effective therapeutic strategy for ischemic-related diseases but the roles in the donor hearts for transplant remain unidentified. Here, we investigated whether the preservation of the donor heart with human platelet-derived mitochondria (pl-MT) could improve mitochondrial and cardiac function. Incubation with pl-MT resulted in the internalization of pl-MT and the enhancement of ATP production in primary cardiomyocytes. In addition, incubation of rat hearts with pl-MT ex vivo for 9 h clearly demonstrated pl-MT transfusion into the myocardium. Mitochondria isolated from the hearts incubated with pl-MT showed increased mitochondrial membrane potential and greater ATP synthase activity and citrate synthase activity. Importantly, the production of reactive oxygen species from cardiac mitochondria was not different with and without pl-MT incubation. Functionally, the heartbeat and the volume of coronary circulation perfusate were significantly increased in the Langendorff perfusion system and the viability of cardiomyocytes was increased from pl-MT hearts.Taken together, these results suggest that incubation with Pl-MT improves mitochondrial activity and maintains the cardiac function of rat hearts with prolonged preservation time. The study provides the proof of principle for pl-MT application as an enhancer of the donor heart.


Assuntos
Transplante de Coração , Ratos , Animais , Humanos , Doadores de Tecidos , Miocárdio , Coração , Miócitos Cardíacos , Trifosfato de Adenosina
5.
Curr Issues Mol Biol ; 45(10): 8427-8443, 2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37886974

RESUMO

Focal cerebral ischemia (fCI) can result in brain injury and sensorimotor deficits. Brown algae are currently garnering scientific attention as potential therapeutic candidates for fCI. This study investigated the therapeutic effects of the hot water extract of Petalonia binghamiae (wPB), a brown alga, in in vitro and in vivo models of fCI. The neuroprotective efficacy of wPB was evaluated in an in vitro excitotoxicity model established using HT-22 cells challenged with glutamate. Afterward, C57/BL6 mice were administered wPB for 7 days (10 or 100 mg/kg, intragastric) and subjected to middle cerebral artery occlusion and reperfusion (MCAO/R) operation, which was used as an in vivo fCI model. wPB co-incubation significantly inhibited cell death, oxidative stress, and apoptosis, as well as stimulated the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, and the nuclear translocation of its upstream regulator, nuclear factor erythroid 2-related factor 2 (Nrf2) in HT-22 cells challenged with glutamate-induced excitotoxicity. Pretreatment with either dose of wPB significantly attenuated infarction volume, neuronal death, and sensorimotor deficits in an in vivo fCI model. Furthermore, the attenuation of oxidative stress and apoptosis in the ischemic lesion accompanied the wPB-associated protection. This study suggests that wPB can counteract fCI via an antioxidative effect, upregulating the Nrf2/HO-1 pathway.

6.
J Korean Med Sci ; 38(16): e127, 2023 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-37096310

RESUMO

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic has contributed to the change in the epidemiology of many infectious diseases. This study aimed to establish the pre-pandemic epidemiology of pediatric invasive bacterial infection (IBI). METHODS: A retrospective multicenter-based surveillance for pediatric IBIs has been maintained from 1996 to 2020 in Korea. IBIs caused by eight bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pyogenes, Listeria monocytogenes, and Salmonella species) in immunocompetent children > 3 months of age were collected at 29 centers. The annual trend in the proportion of IBIs by each pathogen was analyzed. RESULTS: A total of 2,195 episodes were identified during the 25-year period between 1996 and 2020. S. pneumoniae (42.4%), S. aureus (22.1%), and Salmonella species (21.0%) were common in children 3 to 59 months of age. In children ≥ 5 years of age, S. aureus (58.1%), followed by Salmonella species (14.8%) and S. pneumoniae (12.2%) were common. Excluding the year 2020, there was a trend toward a decrease in the relative proportions of S. pneumoniae (rs = -0.430, P = 0.036), H. influenzae (rs = -0.922, P < 0.001), while trend toward an increase in the relative proportion of S. aureus (rs = 0.850, P < 0.001), S. agalactiae (rs = 0.615, P = 0.001), and S. pyogenes (rs = 0.554, P = 0.005). CONCLUSION: In the proportion of IBIs over a 24-year period between 1996 and 2019, we observed a decreasing trend for S. pneumoniae and H. influenzae and an increasing trend for S. aureus, S. agalactiae, and S. pyogenes in children > 3 months of age. These findings can be used as the baseline data to navigate the trend in the epidemiology of pediatric IBI in the post COVID-19 era.


Assuntos
Infecções Bacterianas , COVID-19 , Meningites Bacterianas , Criança , Humanos , Lactente , Meningites Bacterianas/epidemiologia , Meningites Bacterianas/microbiologia , Staphylococcus aureus , Infecções Bacterianas/microbiologia , Bactérias , Streptococcus pneumoniae , Haemophilus influenzae , República da Coreia
7.
J Clin Nurs ; 32(15-16): 5328-5356, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36424691

RESUMO

AIMS AND OBJECTIVES: To determine the effectiveness of nurse-led interventions on medication adherence, medication knowledge and clinical outcomes in adults taking medication for metabolic syndrome. BACKGROUND: Despite the significance of interventions designed to improve medication adherence, a systematic review of nurse-led intervention studies for metabolic syndrome is lacking. DESIGN: A systematic review and meta-analysis of randomised controlled trials. METHODS: The study was conducted following the PRISMA guidelines checklist. PubMed, EMBASE, PsychINFO, CINAHL, Cochrane CENTRAL and other manual sources were searched in May 2021.The quality assessment was conducted using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Comprehensive Meta-Analysis 3.0 was used to calculate the pooled effect sizes with 95% confidence intervals. RESULTS: This review included 20 studies of nurse-led medication adherence interventions in 6017 adults at risk for metabolic syndrome. The pooled effect size using the random effects model indicated that nurse-led interventions had a significantly moderate impact on enhancing medication adherence and medication knowledge and improving selected clinical outcomes of available studies in nurse-led intervention groups compared with control groups. Duration of intervention (median 12 weeks), mode of delivery (group vs. individual) and using multiple strategies influenced outcomes of nurse-led medication adherence interventions. The results revealed that interventions of moderate- to high-quality studies were more likely to show significant improvements in medication adherence than those of low-quality studies. CONCLUSION: The meta-analyses showed that nurse-led interventions may enhance medication adherence and knowledge and improve clinical outcomes of this population. RELEVANCE TO CLINICAL PRACTICE: The findings may contribute to evidence-based information about nurse-led intervention and its selection of appropriate interventions for improving medication adherence in this population. PATIENT OR PUBLIC CONTRIBUTION: Patients or the public were not directly involved in this review.


Assuntos
Síndrome Metabólica , Humanos , Adulto , Síndrome Metabólica/tratamento farmacológico , Papel do Profissional de Enfermagem , Preparações Farmacêuticas , Adesão à Medicação
8.
Int J Mol Sci ; 24(16)2023 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-37629159

RESUMO

Long-term treatments for inflammatory skin diseases like atopic dermatitis or eczema can cause adverse effects. Super Protein Multifunction (SPM) was investigated as a potential treatment for managing skin inflammation by monitoring the expression of pro-inflammatory cytokines induced using LPS and poly(I:C)/TNFα in HaCaT keratinocytes and Hs27 fibroblasts as measured via RT-PCR. SPM solution was also assessed for its effect on cytokine release, measured using ELISA, in a UVB-irradiated 3D human skin model. To evaluate the efficiency of SPM, 20 patients with mild eczematous skin were randomized to receive SPM or vehicle twice a day for three weeks in a double-blind controlled trial. In vitro studies showed SPM inhibited inflammation-induced IL-1ß, IL-6, IL-33, IL-1α, TSLP, and TNFα expression or release. In the clinical study, the SPM group showed significant improvements in the IGA, PA, and DLQI scores compared to the vehicle group. Neither group showed significant differences in VAS (pruritus). Histological analysis showed reduced stratum corneum thickness and inflammatory cell infiltration. The results suggest that SPM may reduce inflammation in individuals with chronic eczematous skin.


Assuntos
Eczema , Fator de Necrose Tumoral alfa , Humanos , Fator de Necrose Tumoral alfa/genética , Pele , Inflamação , Prurido , Citocinas , Excipientes
9.
Int J Nurs Pract ; 29(6): e13199, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37667974

RESUMO

AIMS: The study aimed to develop and evaluate the effects of a self-determination theory-based, nurse-led, physical activity programme for postmenopausal women with rheumatoid arthritis. METHODS: Between December 2019 and April 2020, this randomized controlled trial recruited 62 postmenopausal women with rheumatoid arthritis from a university-affiliated hospital in South Korea. The intervention group participated in a self-determination theory-based, nurse-led, physical activity programme that consisted of Tai Chi-based physical activity, a supportive psychosocial strategy, and interactive counselling for 16 weeks, and the control group continued to undergo their usual care. RESULTS: There were statistically significant group-by-time interactions in physical activity and perceived sarcopenia, which favoured the intervention group. Additionally, the intervention group showed significant improvements in the perceived therapeutic efficacy of physical activity, grip strength, walking speed, disease activity score, and health-related quality of life. CONCLUSIONS: The programme developed in this study can be an effective and feasible approach for postmenopausal women with rheumatoid arthritis in improving physical activity, selected osteosarcopenic outcomes, and health-related quality of life. Further research is required to investigate the long-term effects of this theory-based programme for postmenopausal women in diverse settings.


Assuntos
Artrite Reumatoide , Qualidade de Vida , Humanos , Feminino , Pós-Menopausa , Exercício Físico , Artrite Reumatoide/terapia , Artrite Reumatoide/psicologia , República da Coreia
10.
Arch Psychiatr Nurs ; 43: 29-36, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37032012

RESUMO

This study examined the psychometric properties of the Barriers Self-Efficacy Scale-Physical Activity for Korean-speaking adults with osteoarthritis at risk for metabolic syndrome (N = 150). Factor analysis identified three dimensions of the Korean Barriers scale, explaining 65.9 % of the total variance. Confirmatory factor analysis indicated that the structural validity adequately fits the data. Construct validity confirmed significant associations between the amount of physical activity and psychological variables. The test-retest reliability was 0.87; the alpha was 0.90. The standardized response mean (0.497) indicated responsiveness to medium-magnitude change. The Korean Barriers scale can assess self-efficacy to engage in regular physical activity in clinical settings.


Assuntos
Exercício Físico , Autoeficácia , Adulto , Humanos , Psicometria , Reprodutibilidade dos Testes , República da Coreia , Inquéritos e Questionários
11.
Allergol Int ; 72(3): 466-476, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36586745

RESUMO

BACKGROUND: Platelets play a modulatory role in inflammatory response by secreting a vast array of granules and disintegrating into membrane-bound microparticles upon activation. The interplay between eosinophils and platelets is postulated to be implicated in the pathology of allergic airway inflammation. In this study, we investigated whether activated platelets can induce eosinophil extracellular trap (EET) formation, a cellular process by which activated eosinophils release net-like DNA fibers. METHODS: Platelets were stimulated with the calcium ionophore, A23187, and the platelet agonists, thrombin and adenosine diphosphate (ADP). Platelet cultures were fractionated into conditioned medium (CM) and pellet, which were then overlaid on eosinophils to examine EET formation. RESULTS: The CM and pellet from A23187-activated platelets stimulated eosinophils to generate EET, whereas those from thrombin- or ADP-activated platelets failed to induce such generation. The EET-inducing activity of the A23187-activated platelet culture was linearly proportional to the number of activated platelets. Interestingly, while EET formation induced by the direct stimulation of eosinophils with A23187 was NADPH oxidase (NOX)-dependent, EET formation induced by A23187-activated platelets was NOX-independent and significantly inhibited by necroptosis pathway inhibitors. CONCLUSIONS: Activated platelets and their products may induce EET formation, thereby potentiating their role in eosinophilic airway inflammation.


Assuntos
Plaquetas , Armadilhas Extracelulares , Humanos , Plaquetas/metabolismo , Trombina/farmacologia , Trombina/metabolismo , Ionóforos de Cálcio/metabolismo , Calcimicina/farmacologia , Calcimicina/metabolismo , Armadilhas Extracelulares/metabolismo , Inflamação/metabolismo , Difosfato de Adenosina/metabolismo , Cálcio/metabolismo
12.
Biochem Biophys Res Commun ; 601: 73-78, 2022 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-35231654

RESUMO

Although endocrine therapy with tamoxifen has improved survival in breast cancer patients, resistance to this therapy remains one of the major causes of breast cancer mortality. In the present study, we found that the expression level of YAP/TAZ in tamoxifen-resistant MCF7 (MCF7-TR) breast cancer cells was significantly increased compared with that in MCF7 cells. Knockdown of YAP/TAZ with siRNA sensitized MCF7-TR cells to tamoxifen. Furthermore, siRNA targeting PSAT1, a downstream effector of YAP/TAZ, enhanced sensitivity to tamoxifen in MCF7-TR cells. Additionally, mTORC1 activity and survivin expression were significantly decreased during cell death induced by combination treatment with YAP/TAZ or PSAT1 siRNA and tamoxifen. In conclusion, targeting the YAP/TAZ-PSAT1 axis could sensitize tamoxifen-resistant MCF7 breast cancer cells by modulating the mTORC1-survivin axis.


Assuntos
Neoplasias da Mama , Tamoxifeno , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Células MCF-7 , Alvo Mecanístico do Complexo 1 de Rapamicina , RNA Interferente Pequeno , Survivina/genética , Tamoxifeno/farmacologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Proteínas de Sinalização YAP/metabolismo
13.
Nat Chem Biol ; 16(8): 876-886, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32451509

RESUMO

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.


Assuntos
Alprostadil/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Prostaglandinas A/metabolismo , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Dopamina/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Ligação Proteica , Ratos , Transdução de Sinais , Transcrição Gênica
14.
Nature ; 540(7631): 124-128, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27819681

RESUMO

Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation through kinase-dependent and -independent functions. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3 and mixed lineage kinase like (MLKL)-dependent necroptosis. In addition, RIPK1 inhibits apoptosis and necroptosis through kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers. The mechanism by which RIPK1 counteracts RIPK3-MLKL-mediated necroptosis has remained unknown. Here we show that RIPK1 prevents skin inflammation by inhibiting activation of RIPK3-MLKL-dependent necroptosis mediated by Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM1). ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.


Assuntos
Apoptose , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Inflamação/metabolismo , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Glicoproteínas/deficiência , Inflamação/genética , Inflamação/patologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , Mutação , Fosforilação , Domínios Proteicos/genética , Proteínas Quinases/deficiência , Proteínas Quinases/metabolismo , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Pele/metabolismo , Pele/patologia
15.
Platelets ; 34(1): 2151996, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36529914

RESUMO

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing in vitro using a cell-based model. Wound repairs were assessed by 2D gap closure experiment in wound scratch assay using human dermal fibroblasts (hDFs). Results demonstrated that pl-MT were successfully internalized into hDFs. It increased cell proliferation and promoted the closure of wound gap. Importantly, pl-MT suppressed both intracellular and mitochondrial ROS production induced by hydrogen peroxide, cisplatin, and TGF-ß in hDFs. Taken together, these results suggest that pl-MT transfer might be used as a potential therapeutic strategy for wound repair.


What is the context? During the wound healing process, abnormal regulation of ROS and inflammation delays the healing process, resulting in chronic non-healing wounds.Mitochondria are key organelles responsible for the ROS generation. Mitochondrial dysfunction has been implicated in delayed wound repair.Mitochondria transfer, which utilizes intact mitochondria isolated from healthy cells to recover from disease, has been applied in various clinical studies, but additional evidence is needed to apply it to wound healing.What is new? In this study, we chose platelets as a cell source for mitochondrial transfer. We isolated the functional mitochondria from platelets and applied them to wound healing.What is the impact? This study provides evidence that platelet-derived mitochondria (pl-MT) improve the wound healing progress by increasing the viability of dermal fibroblasts and suppressing intracellular and mitochondrial ROS production.Platelets have also been demonstrated to be a suitable cell source for mitochondrial transfer.


Assuntos
Plaquetas , Cicatrização , Humanos , Plaquetas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fibroblastos , Mitocôndrias
16.
J Cardiovasc Nurs ; 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36103454

RESUMO

BACKGROUND: Although many studies have been conducted to examine predictors of quality of life (QoL), little information exists on the real-world application of Rector's conceptual model for QoL related to heart failure (HF). OBJECTIVES: In this study, we aimed to examine a hypothetical model of QoL based on Rector's conceptual model for QoL in relation to HF and the existing literature on patients with HF. METHODS: Using a cross-sectional survey, 165 patients with HF were recruited from an outpatient clinic in Korea. Data were collected based on Rector's model constructs, such as cardiac function, symptoms, functional limitation, depression, distress, and QoL. Left ventricular ejection fraction for cardiac function was measured using echocardiography. RESULTS: Functional limitation, depression, and distress, but not symptoms, had a direct effect on QoL (all Ps < .001). Cardiac function and symptoms directly affected functional limitation (ß = 0.186, P = .004, and ß = -0.488, P = < .001, respectively), whereas cardiac function, symptoms, and depression affected QoL through functional limitation and distress. CONCLUSIONS: These results confirm that the Rector's model is suitable for predicting QoL in patients with HF. These findings have potential to guide and inform intervention programs designed to alleviate symptoms in patients with HF, enhance their physical functioning, and moderate their psychological distress with the ultimate goal of improving their QoL.

17.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409225

RESUMO

Lysophosphatidylserine (LysoPS) is an amphipathic lysophospholipid that mediates a broad spectrum of inflammatory responses through a poorly characterized mechanism. Because LysoPS levels can rise in a variety of pathological conditions, we sought to investigate LysoPS's potential role in airway epithelial cells that actively participate in lung homeostasis. Here, we report a previously unappreciated function of LysoPS in production of a mucin component, MUC5AC, in the airway epithelial cells. LysoPS stimulated lung epithelial cells to produce MUC5AC via signaling pathways involving TACE, EGFR, and ERK. Specifically, LysoPS- dependent biphasic activation of ERK resulted in TGF-α secretion and strong EGFR phosphorylation leading to MUC5AC production. Collectively, LysoPS induces the expression of MUC5AC via a feedback loop composed of proligand synthesis and its proteolysis by TACE and following autocrine EGFR activation. To our surprise, we were not able to find a role of GPCRs and TLR2, known LyoPS receptors in LysoPS-induced MUC5AC production in airway epithelial cells, suggesting a potential receptor-independent action of LysoPS during inflammation. This study provides new insight into the potential function and mechanism of LysoPS as an emerging lipid mediator in airway inflammation.


Assuntos
Receptores ErbB , Sistema de Sinalização das MAP Quinases , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Humanos , Inflamação/metabolismo , Lisofosfolipídeos/metabolismo , Lisofosfolipídeos/farmacologia , Mucina-5AC/metabolismo , Mucosa Respiratória/metabolismo
18.
Int J Mol Sci ; 23(24)2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36555376

RESUMO

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.


Assuntos
Fibrose Pulmonar Idiopática , Mitocôndrias , Camundongos , Humanos , Animais , Mitocôndrias/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Fibroblastos/metabolismo
19.
Molecules ; 27(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36500343

RESUMO

Sargassum horneri (SH) is a seaweed that has several features that benefit health. In this study, we investigated the immune-enhancing effect of SH, focusing on the role of spleen-mediated immune functions. Chromatographic analysis of SH identified six types of monosaccharide contents, including mannose, rhamnose glucose, galactose xylose and fucose. SH increased cell proliferation of primary cultured naïve splenocytes treated with or without cyclophosphamide (CPA), an immunosuppression agent. SH also reversed the CPA-induced decrease in Th1 cytokines. In vivo investigation revealed that SH administration can increase the tissue weight of major immune organs, such as the spleen and thymus. A similar effect was observed in CPA-injected immunosuppressed BALB/c mice. SH treatment increased the weight of the spleen and thymus, blood immune cell count and Th1 cytokine expression. Additionally, the YAC-1-targeting activities of natural killer cells, which are important in innate immunity, were upregulated upon SH treatment. Overall, our study demonstrates the immune-enhancing effect of SH, suggesting its potential as a medicinal or therapeutic agent for pathologic conditions involving immunosuppression.


Assuntos
Sargassum , Camundongos , Animais , Sargassum/química , Camundongos Endogâmicos BALB C , Ciclofosfamida/farmacologia , Terapia de Imunossupressão , Citocinas/metabolismo
20.
Molecules ; 27(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35956750

RESUMO

7α,25-dihydroxycholesterol (7α,25-DHC) is an oxysterol synthesized from 25-hydroxycholesterol by cytochrome P450 family 7 subfamily B member 1 (CYP7B1) and is a monooxygenase (oxysterol-7α-hydroxylase) expressed under inflammatory conditions in various cell types. In this study, we verified that 7α,25-DHC-induced oxiapoptophagy is mediated by apoptosis, oxidative stress, and autophagy in L929 mouse fibroblasts. MTT assays and live/dead cell staining revealed that cytotoxicity was increased by 7α,25-DHC in L929 cells. Consequentially, cells with condensed chromatin and altered morphology were enhanced in L929 cells incubated with 7α,25-DHC for 48 h. Furthermore, apoptotic population was increased by 7α,25-DHC exposure through the cascade activation of caspase-9, caspase-3, and poly (ADP-ribose) polymerase in the intrinsic pathway of apoptosis in these cells. 7α,25-DHC upregulated reactive oxygen species (ROS) in L929 cells. Expression of autophagy biomarkers, including beclin-1 and LC3, was significantly increased by 7α,25-DHC treatment in L929 cells. 7α,25-DHC inhibits the phosphorylation of Akt associated with autophagy and increases p53 expression in L929 cells. In addition, inhibition of G-protein-coupled receptor 183 (GPR183), a receptor of 7α,25-DHC, using GPR183 specific antagonist NIBR189 suppressed 7α,25-DHC-induced apoptosis, ROS production, and autophagy in L929 cells. Collectively, GPR183 regulates 7α,25-DHC-induced oxiapoptophagy in L929 cells.


Assuntos
Oxisteróis , Receptores Acoplados a Proteínas G , Animais , Apoptose/genética , Apoptose/fisiologia , Autofagia/genética , Autofagia/fisiologia , Fibroblastos/metabolismo , Hidroxicolesteróis/metabolismo , Camundongos , Oxisteróis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
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