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Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies.
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CRISPR-Cas systems function as adaptive immune mechanisms in bacteria and archaea and offer protection against phages and other mobile genetic elements. Among many types of CRISPR-Cas systems, Type I CRISPR-Cas systems are most abundant, with target interference depending on a multi-subunit, RNA-guided complex known as Cascade that recruits a transacting helicase nuclease, Cas3, to degrade the target. While structural studies on several other types of Cas3 have been conducted long ago, it was only recently that the structural study of Type I-C Cas3 in complex with Cascade was revealed, shedding light on how Cas3 achieve its activity in the Cascade complex. In the present study, we elucidated the first structure of standalone Type I-C Cas3 from Neisseria lactamica (NlaCas3). Structural analysis revealed that the histidine-aspartate (HD) nuclease active site of NlaCas3 was bound to two Fe2+ ions that inhibited its activity. Moreover, NlaCas3 could cleave both single-stranded and double-stranded DNA in the presence of Ni2+ or Co2+, showing the highest activity in the presence of both Ni2+ and Mg2+ ions. By comparing the structural studies of various Cas3 proteins, we determined that our NlaCas3 stays in an inactive conformation, allowing us to understand the structural changes associated with its activation and their implication.
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The family Convolvulaceae comprises approximately 50-60 genera with approximately 1600-1700 species, exhibiting a rich diversity of morphological characteristics and occupying a broad range of ecological habitats. High-throughput sequencing identified a tentative new virus in the family Geminiviridae infecting Calystegia sepium var. japonica in South Korea. The 2,706 nt long genome comprises six open reading frames (ORFs). The analysis of the nucleotide sequence of the genome and the putative amino acid sequences of ORFs indicated that the virus was closely related to the members of the family Geminiviridae. The genome organization of the virus was similar to that of members of the genus Topilevirus in terms of the number of ORFs and splicing signal. However, the virus, tentatively named bindweed mottle virus (BWMV), may not be assigned to current genera into the family Geminiviridae.
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Geminiviridae , Genoma Viral , Fases de Leitura Aberta , Filogenia , Doenças das Plantas , Genoma Viral/genética , Geminiviridae/genética , Geminiviridae/classificação , Geminiviridae/isolamento & purificação , República da Coreia , Doenças das Plantas/virologia , Sequenciamento Completo do Genoma , Sequência de Bases , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Microglia are primarily involved in inflammatory reactions and oxidative stress in the brain; as such reducing microglial activation has been proposed as a potential therapeutic strategy for neurodegenerative disorders. Herein, we investigated the anti-inflammatory and antioxidant activities of coniferaldehyde (CFA), a naturally occurring cinnamaldehyde derivative, on activated microglia to evaluate its therapeutic potential. CFA inhibited the production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6, in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. CFA also inhibited intracellular reactive oxygen species levels and oxidative stress markers such as 4-HNE and 8-OHdG. Detailed mechanistic studies showed that CFA exerted anti-inflammatory effects by inhibiting TAK1-mediated MAP kinase/NF-κB activation and upregulating AMPK signaling pathways. In addition, CFA exerted antioxidant effects by inhibiting the NADPH oxidase subunits and by increasing the expression of antioxidant enzymes such as HO-1, NQO1, and catalase by upregulating Nrf2 signaling. Finally, we confirmed the effects of CFA on the brains of the LPS-injected mice. CFA inhibited microglial activation and the expression of proinflammatory markers and increased Nrf2-driven antioxidant enzymes. Furthermore, CFA inhibited the production of 4-HNE and 8-OHdG in the brains of LPS-injected mice. As a result, CFA's significant anti-inflammatory and antioxidant properties may have therapeutic applications in neuroinflammatory disorders related with oxidative stress and microglial activation.
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Proteínas Quinases Ativadas por AMP , Anti-Inflamatórios , Antioxidantes , Lipopolissacarídeos , MAP Quinase Quinase Quinases , Microglia , Fator 2 Relacionado a NF-E2 , NF-kappa B , Transdução de Sinais , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Masculino , MAP Quinase Quinase Quinases/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Acroleína/análogos & derivados , Acroleína/farmacologia , Citocinas/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: This study investigated the impacts of exercise on irisin and fibroblast growth factor 21 (FGF-21) expression, as well as triiodothyronine (T3 ) and free fatty acid (FFA) levels in elderly women. METHODS: Thirty women aged 65 to 70 years (10 per group) were randomly assigned to aquatic exercise, land exercise, and control groups. The aquatic and land groups engaged in 3 exercise sessions per week (60 min/session) for 16 weeks. The intensity was progressively increased every 4 weeks. RESULTS: Irisin and FGF-21 levels significantly increased in the aquatic exercise group. In the posttest, the aquatic exercise group had the highest irisin levels. Significant findings were observed for irisin and FGF-21 for the main effect between aquatic and band exercise groups (p<0.05 for both), the main effect between measurement times (p<0.01 and p<0.001, respectively), and the interaction effect (p<0.05 and p<0.001, respectively). The irisin level was significantly higher in the aquatic than in the land group 30 minutes after the last session (p<0.05). In both exercise groups, T3 levels were significantly higher 30 minutes after the final session (p<0.05) than before the program. The FFA level was significantly higher in the aquatic exercise group than the others. In the aquatic group, FFA levels were significantly higher 30 minutes after both the first (p<0.01) and the last (p<0.001) session compared to pre-program values. CONCLUSION: Differences in exercise type and environment can promote fat metabolism by stimulating hormonal changes that induce brown fat activity and browning.
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BACKGROUND: The occurrence of type II endoleaks after endovascular repair of aortic aneurysm has gradually gained increasing attention. We present a case of a patient with an expanding aneurysm after thoracic endovascular aortic repair (TEVAR) for a type II endoleak, in which successful direct ligations of the intercostal artery were performed using a sac incision without cardiopulmonary bypass (CPB) or graft replacement. CASE PRESENTATION: A 62-year-old male patient, previously treated with TEVAR for a descending thoracic aortic aneurysm, presented with ongoing chest discomfort. Based on the diagnosis of a growing aneurysm and type II endoleak, the patient was prepared for CPB and aortic cross-clamping, as a precautions against the possibility of a type I endoleak. A longitudinal opening of the thoracic aortic aneurysm sac was performed following left thoracotomy. Visual confirmation identified the T5 level intercostal artery as the source of the endoleak, and after confirming the absence of a type I endoleak, multiple ligations were applied to the intercostal artery. Follow-up computed tomography confirmed the absence of endoleaks or sac growth. CONCLUSION: In a case involving TEVAR for a thoracic aortic aneurysm, open suture ligations were used to treat type II endoleaks without having to resort to CPB, resulting in successful outcomes.
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Aneurisma da Aorta Torácica , Endoleak , Procedimentos Endovasculares , Humanos , Masculino , Endoleak/cirurgia , Endoleak/etiologia , Pessoa de Meia-Idade , Aneurisma da Aorta Torácica/cirurgia , Procedimentos Endovasculares/métodos , Implante de Prótese Vascular/métodos , Implante de Prótese Vascular/efeitos adversos , Tomografia Computadorizada por Raios X , Aorta Torácica/cirurgia , Ligadura , Correção Endovascular de AneurismaRESUMO
BACKGROUND: Surgical treatment for Freiberg disease (also known as avascular necrosis of the metatarsal head) has not been completely defined. This retrospective study evaluated short-term outcomes after arthroscopic treatment of Freiberg disease. METHODS: From 2015 to 2019, 13 patients (15 feet) diagnosed as having Freiberg disease were enrolled for arthroscopic surgery. Feet were divided based on the Smillie classification system (two with stage I, eight with stage II, three with stage III, one with stage IV, and one with stage V). Arthroscopic interventions, including synovectomy, debridement, chondroplasty, microfracture, and loose body removal, were performed without considering the Smillie classification stage. Radiologic outcomes were evaluated by radiography (preoperatively and 3, 6, and 12 months postoperatively) and magnetic resonance imaging (preoperatively and 12 months postoperatively). Clinical outcomes were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) lesser metatarsophalangeal (MTP)-interphalangeal score and the visual analog scale (VAS) score. The MTP joint range of motion was measured using a goniometer preoperatively and postoperatively. RESULTS: Radiologic studies showed no evidence of osteonecrosis progression in postoperative 12-month radiographs of any patients. Postoperative 12-month magnetic resonance images showed reduction of bone marrow edema, irregularity of subchondral bone, and cartilage defects in all patients. Significant improvements in AOFAS and VAS scores occurred at all postoperative time points compared with preoperative scores (P = .001). The MTP joint range of motion also showed improvement at last follow-up (P = .001). CONCLUSIONS: Arthroscopic surgery for Freiberg disease showed excellent clinical outcomes, MTP joint range of motion, and short-term outcomes regardless of stage (Smillie classification) in radiologic evaluation.
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Artroscopia , Humanos , Feminino , Masculino , Artroscopia/métodos , Estudos Retrospectivos , Adulto , Resultado do Tratamento , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Articulação Metatarsofalângica/cirurgia , Articulação Metatarsofalângica/diagnóstico por imagem , Osteonecrose/cirurgia , Osteonecrose/diagnóstico por imagem , Adulto Jovem , Imageamento por Ressonância Magnética , Desbridamento/métodos , Metatarso/anormalidades , Osteocondrite/congênitoRESUMO
Given that the skin is the largest tissue in the human body, performing external barrier functions with innate and adaptive immunity and undergoing substantial changes during aging, it is under investigation as a major target of various bioactive molecules. In the present study, we examined the biological activity of the senolytic piperlongumine by analyzing alterations in mRNA expression of notable skin genes using transformed aneuploid immortal epidermal keratinocytes, HaCaT cells. We observed that piperlongumine increased the mRNA expression of genes playing critical roles in skin barrier function. In addition, piperlongumine increased expression enzymes involved in the synthesis of ceramide, a major component of intercellular lipids. Furthermore, we measured the protein levels of various cytokines secreted by epidermal keratinocytes and found changes in the release of GRO-αßγ, CCL5, and MCP1. Additionally, we observed that piperlongumine treatment modulated the expression of keratinocyte-specific aging markers and influenced telomerase activity. Based on these findings, piperlongumine could regulate the physiological activity of epidermal keratinocytes to induce beneficial effects in human skin by regulating important skin-related genes.
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Pre-eclampsia (PE) is a hypertensive disorder characterised by systemic vascular resistance and endothelial dysfunction. It is known to influence choroidal thickness (CT). No previous studies have explored the antepartum and postpartum changes in CT with respect to the protein-creatinine ratio (PCR), a measure of proteinuria that is a clinical hallmark of PE. This study evaluated the correlations between antepartum and postpartum CT and the PCR in patients with PE. In this retrospective study, sixty-six eyes (66 patients) were analysed. The patients were divided into two groups according to the median PCR value (2.36 mg/mg): low PCR group (< 2.36 mg/mg) and high PCR group (≥ 2.36 mg/mg). Ophthalmologic clinical data were collected and assessed. We observed higher antepartum CT and higher mean arterial pressure in high PCR group than in low PCR group. Moreover, postpartum CT decreased significantly in high PCR group. In the multivariate analysis, CT changes were correlated with antepartum CT and antepartum PCR after logarithm transformation. In conclusion, a greater decrease in CT was observed in high PCR group than in low PCR group. Further, the antepartum PCR showed a correlation with the extent of CT reduction.
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Corioide , Período Pós-Parto , Pré-Eclâmpsia , Proteinúria , Humanos , Feminino , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Adulto , Corioide/patologia , Corioide/diagnóstico por imagem , Estudos Retrospectivos , Creatinina/sangue , Creatinina/urinaRESUMO
A novel virus infecting Stellaria aquatica plants, tentatively named "Stellaria aquatica virus C" (StAVC), was identified in Gangwon-do Province, South Korea. Its monopartite genome consists of a single-stranded RNA of 15,024 nucleotides, and it shares 38.24 to 56.2% nucleotide sequence identity with known closterovirus genome sequences. Its genome contains nine hypothetical open reading frames. These encode the multifunctional protein RNA-dependent RNA polymerase (RdRp), hydrophobic protein (P7), heat shock protein 70 homolog (HSP70h), coat protein homolog (CPh), minor coat protein (CPm), and major coat protein (CP), along with proteins involved in suppressing RNA silencing. Phylogenetic analysis reveals that, based on its HSP70h amino acid sequence, StAVC is closely related to members of the genus Closterovirus within the family Closteroviridae. This is the first record of the full genome sequence of StAVC in South Korea.
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Closterovirus , Genoma Viral , Fases de Leitura Aberta , Filogenia , Doenças das Plantas , RNA Viral , Proteínas Virais , Genoma Viral/genética , República da Coreia , RNA Viral/genética , Doenças das Plantas/virologia , Closterovirus/genética , Closterovirus/isolamento & purificação , Closterovirus/classificação , Proteínas Virais/genética , Sequência de Aminoácidos , Sequência de BasesRESUMO
The greater the viscosity of the blood, the more difficult its flow becomes, leading to an increased incidence of diseases caused by blood circulation disorders. These diseases are commonly associated with the cardiovascular and cerebrovascular systems. High blood viscosity is a primary cause of circulatory system diseases. Studies have shown that accurately measuring blood viscosity and applying this data in clinical trials can help prevent circulatory system diseases. Viscosity data can vary depending on the measurement methods used, even when these methods are based on hydrodynamic principles. Despite using approved blood viscometers, the results often differ depending on the type of viscometer used, potentially causing confusion within the medical field. Informing the medical community about these differences and the level of error associated with each measurement method can help reduce this confusion. To our knowledge, the degree of difference in viscosity measurement results due to different measurement methods and the reasons for these differences have not yet been thoroughly explored. In this study, we selected three blood viscosity measurement methods registered with the Ministry of Food and Drug Safety of Korea to analyze the same canine blood. The viscosity measurements were carried out using each device and compared. The parallel plate and scanning capillary methods yielded similar viscosity values, while the cone plate method showed lower viscosity values. The viscosity of blood, as measured by the three viscometers, differed, indicating that more experimental data must be accumulated to evaluate the cause of these differences. In this paper, we identified several causes of inconsistency and suggested measures to avoid this confusion. However, confirming that the test results show systematic differences is expected to assist clinicians who diagnose and prescribe treatments based on blood viscosity results. The findings of this comparative study are anticipated to serve as a starting point for establishing guidelines or standards for blood viscosity measurement methods.
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BACKGROUND: This study aims to illuminate regional disparities and identify vulnerable areas in stroke care across Gyeonggi Province's hospital service areas. METHODS: Using data from the Korea National Cardio-cerebrovascular Disease Management Commission, we included 4,427 acute stroke patients admitted in 2018 to hospitals within Gyeonggi Province. Our evaluation focused on: 1) stroke care quality indicators, including rates of defect-free care, intravenous thrombolysis (IVT), endovascular thrombectomy (EVT), and acute reperfusion therapy (either IVT or EVT); 2) intra-regional treatment rates; and 3) one-year mortality across the province and its 12 hospital service areas. These were compared both with national averages and inter-regionally. Vulnerable areas were pinpointed by evaluating the number of quality indicators falling below the national average and through visual distribution mapping, categorizing each indicator into higher (ranks 1-4), middle (ranks 5-8), and lower (ranks 9-12) tiers. RESULTS: Despite fewer qualified stroke centers and specialists, Gyeonggi Province exhibited higher defect-free care rates (84.6 % vs. 80.7 %), intra-regional treatment rates (57.8 % vs. 51.0 %), and marginally lower one-year mortality (16.2 % vs. 17.3 %) compared to national averages. Notable regional disparities were observed; the highest-performing areas for defect-free care and acute reperfusion therapy exceeded the lowest by 1.4 and 3.3 times, respectively. Nine out of twelve areas fell below the national average for EVT rates, seven for IVT and reperfusion therapy rates, and five for intra-regional treatment rates. Pyeongtaek, with all stroke care quality indicators below the national average coupled with the highest one-year mortality, emerges as a critical area needing improvement in acute stroke care. CONCLUSION: This study not only exposes the regional disparities in stroke care within Gyeonggi Province's hospital service areas but also identifies areas most vulnerable. Consequently, a customized support strategy for these areas is imperative.
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Procedimentos Endovasculares , Disparidades em Assistência à Saúde , Indicadores de Qualidade em Assistência à Saúde , Acidente Vascular Cerebral , Terapia Trombolítica , Humanos , Acidente Vascular Cerebral/terapia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/diagnóstico , Indicadores de Qualidade em Assistência à Saúde/normas , Terapia Trombolítica/mortalidade , Terapia Trombolítica/normas , República da Coreia , Resultado do Tratamento , Procedimentos Endovasculares/mortalidade , Procedimentos Endovasculares/efeitos adversos , Masculino , Feminino , Idoso , Fatores de Tempo , Acessibilidade aos Serviços de Saúde , Trombectomia/mortalidade , Trombectomia/efeitos adversos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Área Programática de SaúdeRESUMO
Mtb12, a small protein secreted by Mycobacterium tuberculosis, is known to elicit immune responses in individuals infected with the pathogen. It serves as an antigen recognized by the host's immune system. Due to its immunogenic properties and pivotal role in tuberculosis (TB) pathogenesis, Mtb12 is considered a promising candidate for TB diagnosis and vaccine development. However, the structural and functional properties of Mtb12 are largely unexplored, representing a significant gap in our understanding of M. tuberculosis biology. In this study, we present the first structure of Mtb12, which features a unique tertiary configuration consisting of four beta strands and four alpha helices. Structural analysis reveals that Mtb12 has a surface adorned with a negatively charged pocket adjacent to a central cavity. The features of these structural elements and their potential effects on the function of Mtb12 warrant further exploration. These findings offer valuable insights for vaccine design and the development of diagnostic tools.
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Antígenos de Bactérias , Proteínas de Bactérias , Mycobacterium tuberculosis , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Modelos Moleculares , Peso Molecular , Sequência de Aminoácidos , Conformação Proteica , HumanosRESUMO
A novel auxetic structure applicable to airless tire spokes is designed based on the primitive-type triply periodic minimal surface (P-TPMS) to have higher stiffness through deformation under compressive force. For becoming higher stiffness by deformation, an unit cell of auxetic structure is proposed and its characteristics according to design parameters are studied. Based on the parametric study, a rotated primitive-type auxetic structure (RPAS) is designed, and the deformative behaviors of an airless tire with the RPAS spokes are compared with a generally used honeycomb spoke. Simulation and experiment results show that the designed RPAS tire exhibits more stable behavior through higher rigidity depending on the deformation state when compressed on flat ground and obstacles. This variable stiffness characteristic of RPAS tires can be advantageous for shock absorption and prevention of large local deformations. Also, the manufacturability of the designed auxetic structure is evaluated using real rubber-based additive manufacturing processes for practical application in the tire manufacturing industry.
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Dysregulated DNA methylation in cancer is critical in the transcription machinery associated with cancer progression. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, but no treatment targeting TNBC biomarkers has yet been developed. To identify specific DNA methylation patterns in TNBC, methyl-binding domain protein 2 (MBD) sequencing data were compared in TNBC and the three other major breast cancer subtypes. Integrated analysis of DNA methylation and gene expression identified a gene set showing a correlation between DNA methylation and gene expression. ATPase Na+/K+-transporting subunit alpha 1 (ATP1A1) was found to be specifically hypomethylated in the coding sequence (CDS) region and to show increased expression in TNBC. The Cancer Genome Atlas (TCGA) database also showed that hypomethylation and high expression of ATP1A1 were strongly associated with poor survival in patients with TNBC. Furthermore, ATP1A1 knockdown significantly reduced the viability and tumor-sphere formation of TNBC cells. These results suggest that the hypomethylation and overexpression of ATP1A1 could be a prognostic marker in TNBC and that the manipulation of ATP1A1 expression could be a therapeutic target in this disease.
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Background: Low compliance (LC) with lifestyle modification is a very common obstacle in obesity management. The purpose of the current study was to investigate the effectiveness of obesity management according to compliance with a lifestyle-modification program. Methods: The "Change 10 Habits" program was administered four times over 12 weeks. Eighty-seven participants were divided into LC and high compliance (HC) groups for analysis after intervention. Then, to assess the program's effectiveness based on compliance, we conducted t-tests and linear regression modeling. Results: In week 12, the scores of two dietary habits-specifically, "eat three meals regularly, adequate amount" and "do not eat after 9:00 PM"-were significantly higher in the HC group than in the LC group. Changes in leg and total body fat percentages were significantly improved in the HC group (-0.2%±0.3% vs. 0.9%±0.3%, P<0.05; -0.1%±0.3% vs. 1.1%±0.5%, P<0.05, respectively). The body mass index was also significantly lower in the HC group than in the LC group (26.7±1.8 kg/m2 vs. 27.7±2.1 kg/m2, P<0.05) at final follow-up. Finally, the systolic blood pressure, triglyceride, and very-low-density lipoprotein cholesterol values of the HC group also decreased significantly (from 117.9±12.2 to 114.3±15.0 mmHg, P<0.05; from 121.7±74.9 to 105.7±60.9 mg/dL, P<0.05; and from 24.3±15.0 to 21.1±12.2 mg/dL, P<0.05, respectively). Conclusion: HC with the study program effectively improved the dietary habits, body fat composition, blood pressure, and lipid profile of adults with mild obesity.
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Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.
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Fator 1 Associado a Receptor de TNF , Humanos , Fator 1 Associado a Receptor de TNF/metabolismo , Fator 1 Associado a Receptor de TNF/química , Fator 1 Associado a Receptor de TNF/genética , Animais , Ligação Proteica , Transdução de Sinais , Domínios Proteicos , Modelos MolecularesRESUMO
As a response to viral infections, bacteria have evolved the CRISPR-Cas system as an adaptive immune mechanism, enabling them to target and eliminate viral genetic material introduced during infection. However, viruses have also evolved mechanisms to counteract this bacterial defense, including anti-CRISPR proteins, which can inactivate the CRISPR-Cas adaptive immune system, thus aiding the viruses in their survival and replication within bacterial hosts. In this study, we establish the high-resolution crystal structure of the Type IE anti-CRISPR protein, AcrIE3. Our structural examination showed that AcrIE3 adopts a helical bundle fold comprising four α-helices, with a notably extended loop at the N-terminus. Additionally, surface analysis of AcrIE3 revealed the presence of three acidic regions, which potentially play a crucial role in the inhibitory function of this protein. The structural information we have elucidated for AcrIE3 will provide crucial insights into fully understanding its inhibitory mechanism. Furthermore, this information is anticipated to be important for the application of the AcrIE family in genetic editing, paving the way for advancements in gene editing technologies.
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Proteínas Associadas a CRISPR , Sistemas CRISPR-Cas , Modelos Moleculares , Sequência de Aminoácidos , Proteínas Associadas a CRISPR/química , Proteínas Associadas a CRISPR/metabolismo , Proteínas Associadas a CRISPR/genética , Cristalografia por Raios X , Conformação ProteicaRESUMO
Alcohol consumption, a pervasive societal issue, poses considerable health risks and socioeconomic consequences. Alcohol-induced hepatic disorders, such as fatty liver disease, alcoholic hepatitis, chronic hepatitis, liver fibrosis, and cirrhosis, underscore the need for comprehensive research. Existing challenges in mimicking chronic alcohol exposure in cellular systems, attributed to ethanol evaporation, necessitate innovative approaches. In this study, we developed a simple, reusable, and controllable device for examining the physiological reactions of hepatocytes to long-term alcohol exposure. Our approach involved a novel device designed to continuously release ethanol into the culture medium, maintaining a consistent ethanol concentration over several days. We evaluated device performance by examining gene expression patterns and cytokine secretion alterations during long-term exposure to ethanol. These patterns were correlated with those observed in patients with alcoholic hepatitis. Our results suggest that our ethanol-releasing device can be used as a valuable tool to study the mechanisms of chronic alcohol-mediated hepatic diseases at the cellular level. Our device offers a practical solution for studying chronic alcohol exposure, providing a reliable platform for cellular research. This innovative tool holds promise for advancing our understanding of the molecular processes involved in chronic alcohol-mediated hepatic diseases. Future research avenues should explore broader applications and potential implications for predicting and treating alcohol-related illnesses.
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Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer.