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OBJECTIVE: Interferon regulatory factor 1 (IRF1) is a transcriptional regulator conventionally associated with immunomodulation. Recent molecular analyses mapping DNA binding sites of IRF1 have suggested its potential function in DNA repair. However, the physiologic significance of this noncanonical function remains unexplored. Here, we investigated the role of IRF1 in osteoarthritis (OA), a condition marked by senescence and chronic joint inflammation. METHODS: OA progression was examined in wild-type and Irf1-/- mice using histologic assessments and microcomputed tomography analysis of whole-joint OA manifestations and behavioral assessments of joint pain. An integrated analysis of assay for transposase-accessible chromatin with sequencing and whole transcriptome data was conducted for the functional assessment of IRF1 in chondrocytes. The role of IRF1 in DNA repair and senescence was investigated by assaying γ-H2AX foci and senescence-associated beta-galactosidase activity. RESULTS: Our genome-wide investigation of IRF1 footprinting in chondrocytes revealed its primary occupancies in the promoters of DNA repair genes without noticeable footprint patterns in those of interferon-responsive genes. Chondrocytes lacking IRF1 accumulated irreversible DNA damage under oxidative stress, facilitating their entry into cellular senescence. IRF1 was down-regulated in the cartilage of human and mouse OA. Although IRF1 overexpression did not elicit an inflammatory response in joints or affect OA development, genetic deletion of Irf1 caused enhanced chondrocyte senescence and exacerbated post-traumatic OA in mice. CONCLUSION: IRF1 offers DNA damage surveillance in chondrocytes, protecting them from oxidative stress associated with OA risk factors. Our study provides a crucial and cautionary perspective that compromising IRF1 activity renders chondrocytes vulnerable to cellular senescence and promotes OA development.
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Cartilagem Articular , Condrócitos , Dano ao DNA , Fator Regulador 1 de Interferon , Camundongos Knockout , Osteoartrite , Animais , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Condrócitos/metabolismo , Cartilagem Articular/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Senescência Celular/genética , Reparo do DNA , Humanos , Progressão da DoençaRESUMO
Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1-HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.
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Neoplasias Ósseas , Condrossarcoma , Humanos , Animais , Camundongos , NAD/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Condrossarcoma/tratamento farmacológico , Condrossarcoma/genética , Condrossarcoma/patologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/uso terapêuticoRESUMO
An alcohol-induced blackout suggested to be related to a rapid increase in blood alcohol concentration and it is closely related to long-term memory creation. Blackout has been experienced by 35% of the general population and over 50% of university student population. In addition, it has been shown that blackout could be a precursor of injury risk. However, the rate of blackout and blackout related negative consequences in Korean university students have rarely been studied. Therefore, the objective of this study was to determine the blackout experience rate and its negative consequences among students from four universities in Korea. A survey was conducted among university students located in Pusan, Korea in 2013. Demographic and blackout related information were collected through self-report questionnaire, including blackout experience, age of first blackout, and negative consequences of blackout. Descriptive statistical analysis was performed for collected data. Of a total of 470 subjects (Male = 217, Female = 253) surveyed, 190 (40.4%) subjects had experienced a blackout at some points in their lives. The majority (86.3%) of them experienced the first blackout between 20-25 years old. Among those who had experienced a blackout, 57.0% reported that they could not remember how they went home at the end of the night, 8.1%, 7.6%, 3.1%, and 2.2% reported that they had bodily injuries, argument, physical or personal fight, and sexual-related incidences, respectively. This study shows that many Korean university students have experienced blackouts and related negative events. These results suggest that more systematic drinking control strategy is required for Korean university students.
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Protein kinase R (PKR) is an immune response protein that becomes activated by double-stranded RNAs (dsRNAs). PKR overactivation is associated with degenerative diseases with inflammation, including osteoarthritis (OA), but the dsRNA activator remains largely unknown. Here, we find that mitochondrial dsRNA (mt-dsRNA) expression and its cytosolic efflux are facilitated in chondrocytes under OA-eliciting conditions, leading to innate immune activation. Moreover, mt-dsRNAs are released to the extracellular space and activate Toll-like receptor 3 at the plasma membrane. Elevated levels of mt-dsRNAs in the synovial fluids and damaged cartilage of OA patients and in the cartilage of surgery-induced OA mice further support our data. Importantly, autophagy prevents PKR activation and protects chondrocytes from mitochondrial stress partly by removing cytosolic mtRNAs. Our study provides a comprehensive understanding of innate immune activation by mt-dsRNAs during stress responses that underlie the development of OA and suggests mt-dsRNAs as a potential target for chondroprotective intervention.
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Condrócitos , Osteoartrite , Animais , Inflamação/metabolismo , Camundongos , Mitocôndrias/metabolismo , RNA de Cadeia Dupla/metabolismoRESUMO
We investigated the effect of black sticky rice with giant embryo (BSRGE) extract known to contain high levels of gamma-aminobutyric acid (GABA) on alcohol cravings in social drinkers. A total of 41 subjects were divided into a BSRGE extract group (G group: n = 21) and a placebo group (P group: n = 20), and a randomized placebo-controlled experiment was performed for 12 weeks. The G group took the BSRGE extracts that contained 30 mg of GABA per day. (1) In the Pennsylvania Alcohol Craving Scale, there was a tendency for time and group interaction between the two groups (P = .087) on the total score. (2) In the Obsessive-Compulsive Drinking Scale (OCDS), there was a significance for time and group interaction between the G and P groups (P = .011) on the obsessive subscale. The total score of the OCDS showed significant time and group interactions between the G and P groups (P = .011). Our results showed that the extract of BSRGE containing a high level of GABA significantly reduced alcohol cravings in Korean social drinkers.
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Alcoolismo , Oryza , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Fissura , Humanos , Extratos Vegetais/uso terapêutico , República da Coreia , Ácido gama-AminobutíricoRESUMO
Objective: Capsaicin, the pungent analgesic substance of hot peppers which produces a burning sensation and pain is known to affect Substance P and central opioid activities. This experiment was designed to test the effect of capsaicin on alcohol consumption in C57BL/6 and DBA/2 mice. These two strains are known to differ in both their alcohol consumption and their endogenous opioid distribution and response to alcohol. It is hypothesized that this effect may be mediated by both increases Substance P and decreases beta-endorphin. Methods: After i.p. administration of 0.01 and 0.001 mg/kg of capsaicin with a vehicle or the vehicle alone as the control for eight days in C57BL/6 and DBA/2 mice on limited access alcohol model, Capsaicin's effects on 2-hour alcohol, 22-hours water, 24-hours food intake and body weight were studied. Results: In this study, as expected, C57BL/6 mice drank significantly more alcohol than DBA/2 mice under baseline conditions. Capsaicin at both doses tested significantly reduced baseline alcohol consumption in C57BL/6 but not DBA/2 mice. These effects were selective for alcohol as capsaicin did not disrupt food or water consumption. Conclusion: These results demonstrate that capsaicin differentially affects those mechanisms underlying alcohol consumption in two strains of mice known to differ in their preference for and consumption of alcohol. This effect is hypothesized to be related to differences in the response of the endogenous opioid system.
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Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.
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Anti-Inflamatórios/uso terapêutico , Osteoartrite/terapia , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Terapia Combinada/métodos , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Humanos , Terapia de Alvo Molecular , Osteoartrite/diagnóstico , Osteoartrite/etiologia , Osteoartrite/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The incidence of thyroid cancer has dramatically increased over the last few decades, and up to 60% of patients have multifocal tumors. However, the prognostic impact of multifocality in patients with papillary thyroid carcinoma (PTC) remains unestablished and controversial. We evaluate whether multifocality can predict the recurrence of PTC. A total of 1249 patients who underwent total thyroidectomy for PTC at the Ewha Medical Center between March 2012 and December 2019 were reviewed. In this study, multifocality was found in 487 patients (39.0%) and the mean follow-up period was 5.5 ± 2.7 years. Multifocality was associated with high-risk features for recurrence, including extrathyroidal extension, lymph node metastasis, and margin involvement. After adjustment of those clinicopathological features, 10-year disease-free survival was 93.3% in patients with multifocal tumors, whereas those with unifocal disease showed 97.6% (p = 0.011). Multivariate Cox regression analysis indicated that male sex (HR 2.185, 95% CI 1.047-4.559), tumor size (HR 1.806, 95% CI 1.337-2.441), N1b LN metastasis (HR 3.603, 95% CI 1.207-10.757), and multifocality (HR 1.986, 95% CI 1.015-3.888) were independent predictors of recurrence. In conclusion, multifocality increased the risk of recurrence in patients with PTC. Patients with multifocal PTCs may need judicious treatment and follow-up approaches.
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Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of the tendon matrix, which leads to tendon tear and rupture. The goal was to identify a rational molecular target whose blockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-related protein-3 (CTRP3) as a markedly up-regulated cytokine in human and rodent tendinopathy. Overexpression of CTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degenerating collagenous fibers in the mouse tendon, whereas CTRP3 knockdown suppressed the tendinopathy pathogenesis. Functional blockade of CTRP3 using a neutralizing antibody ameliorated overuse-induced tendinopathy of the Achilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormal differentiation of tendon stem/progenitor cells and ectopic chondrification as an effect linked to activation of Akt signaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeutic strategy for the treatment of tendinopathy.
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Transient gene expression is a suitable tool for the production of biopharmaceutical candidates in the early stage of development and provides a simple and rapid alternative to the generation of stable cell line. In this study, an efficient transient gene expression methodology using DC-Chol/DOPE cationic liposomes and pDNA in Chinese hamster ovary suspension cells was established through screening of diverse lipoplex formation conditions. We modulated properties of both the liposome formation and pDNA solution, together called complexation solutions. Protein expression and cellular cytotoxicity were evaluated following transfection over the cell cultivation period to select the optimal complexation solution. Changes in hydrodynamic size, polydispersity index, and ζ potential of the liposomes and lipoplexes were analyzed depending on the various pH ranges of the complexation solutions using dynamic light scattering. The transfer of lipoplexes to the cytosol and their conformation were traced using fluorescence analysis until the early period of transfection. As a result, up to 1785 mg/L and 191 mg/L of human Fc protein and immunoglobulin G (bevacizumab), respectively, were successfully produced using acidic liposome formation and alkaline pDNA solutions. We expect that this lipoplex formation in acidic and alkaline complexation solutions could be an effective methodology for a promising gene delivery strategy.
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Colesterol/análogos & derivados , Lipossomos/química , Fosfatidiletanolaminas/química , Plasmídeos/metabolismo , Transfecção/métodos , Animais , Bevacizumab/biossíntese , Bevacizumab/genética , Células CHO , Colesterol/química , Colesterol/metabolismo , Cricetulus , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Concentração de Íons de Hidrogênio , Fragmentos Fc das Imunoglobulinas/biossíntese , Fragmentos Fc das Imunoglobulinas/genética , Cinética , Lipossomos/metabolismo , Fosfatidiletanolaminas/metabolismo , Plasmídeos/química , Eletricidade Estática , TransgenesRESUMO
Importance: Multifocality is common in papillary thyroid carcinoma (PTC), but it is unclear whether multifocal tumors are associated with tumor recurrence or cancer-specific survival. Objective: To compare tumor recurrence rates in patients with multifocal vs unifocal PTCs. Data Sources: We searched PubMed, SCOPUS, Web of Science Core Collection, and Cochrane Database of Systematic Reviews for pertinent studies published in English from inception to June 30, 2020. Study Selection: The search strategy yielded 26 studies that compared tumor recurrence in patients with multifocal vs unifocal PTC. Data Extraction and Synthesis: Data was extracted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Characteristics of study populations and hazard ratio (HR) of multifocality were independently extracted by 2 investigators. Main Outcomes and Measures: The primary outcome was tumor recurrence and the secondary outcome was cancer-specific survival. Subgroup analysis of the primary outcome was based on primary tumor size, number of tumor foci, and patient age. Results: Among 26 studies with a total of 33â¯976 patients, recurrence rates were significantly higher in patients with multifocal PTC than in those with unifocal PTC (pooled HR, 1.81; 95% CI, 1.52-2.14). Cancer-specific survival was comparable between the groups (HR, 1.19; 95% CI, 0.85-1.68). In subgroup analyses, the HRs of multifocality for recurrence were associated with primary tumor size (HRs for PTC ≤1 cm and >1 cm were 1.81 and 1.90, respectively), number of tumor foci (HRs for 2 foci and ≥3 foci were 1.45 and 1.95, respectively), and patient age (HRs for pediatric and adult patients were 3.19 and 1.89, respectively). Conclusions and Relevance: This systematic review with meta-analysis found that multifocality was significantly associated with an increased risk of recurrence in patients with PTC, while cancer-specific survival showed no difference. Differences in tumor size, number of tumor foci, and patient age should be considered when interpreting the multifocality and the risk of recurrence.
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Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Humanos , Recidiva Local de Neoplasia , Prognóstico , Fatores de Risco , Análise de Sobrevida , Carga TumoralRESUMO
Liquid crystal polymer (LCP) composites filled with sepiolite and glass microcapsules were prepared by melt compounding. The composites were extruded using a twin-screw extruder and injection-molded. The objective of this study is to check a possibility of producing a polymeric composite with a low dielectric constant. Physical characteristics of the composites, such as morphological, rheological, mechanical, and electrical properties were analyzed. In particular, the glass microcapsule-reinforced LCP composites showed a significant improvement in lowering the dielectric constant due to its high air content. Additionally, sepiolite could act as an effective filler to improve the mechanical properties of the composites.
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Cellular senescence is a complex stress response implicated in aging. Autophagy can suppress senescence but is counterintuitively necessary for full senescence. Although its anti-senescence role is well described, to what extent autophagy contributes to senescence establishment and the underlying mechanisms is poorly understood. Here, we show that selective autophagy of multiple regulatory components coordinates the homeostatic state of senescence. We combined a proteomic analysis of autophagy components with protein stability profiling, identifying autophagy substrate proteins involved in several senescence-related processes. Selective autophagy of KEAP1 promoted redox homeostasis during senescence. Furthermore, selective autophagy limited translational machinery components to ameliorate senescence-associated proteotoxic stress. Lastly, selective autophagy of TNIP1 enhanced senescence-associated inflammation. These selective autophagy networks appear to operate in vivo senescence during human osteoarthritis. Our data highlight a caretaker role of autophagy in the stress support network of senescence through regulated protein stability and unravel the intertwined relationship between two important age-related processes.
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Autofagia , Senescência Celular , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Fator de Iniciação 3 em Eucariotos/metabolismo , Células HEK293 , Humanos , Inflamação/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Modelos Biológicos , Osteoartrite/metabolismo , Osteoartrite/patologia , Estresse Oxidativo , ProteostaseRESUMO
Twisted bilayer graphene (tBLG) has received substantial attention in various research fields due to its unconventional physical properties originating from Moiré superlattices. The electronic band structure in tBLG modified by interlayer interactions enables the emergence of low-energy van Hove singularities in the density of states, allowing the observation of intriguing features such as increased optical conductivity and photocurrent at visible or near-infrared wavelengths. Here, we show that the third-order optical nonlinearity can be considerably modified depending on the stacking angle in tBLG. The third-harmonic generation (THG) efficiency is found to significantly increase when the energy gap at the van Hove singularity matches the three-photon resonance of incident light. Further study on electrically tuneable optical nonlinearity reveals that the gate-controlled THG enhancement varies with the twist angle in tBLG, resulting in a THG enhanced up to 60 times compared to neutral monolayer graphene. Our results prove that the twist angle opens up a new way to control and increase the optical nonlinearity of tBLG, suggesting rotation-induced tuneable nonlinear optics in stacked two-dimensional material systems.
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Mixed-dimensional van der Waals heterostructures are scientifically important and practically useful because of their interesting exotic properties resulting from their novel hybrid structures. This study reports the composition- and phase-selective fabrication of low-dimensional molybdenum/tellurium (Mo/Te) compounds and the direct synthesis of mixed-dimensional in-plane 1D-2D Mo6 Te6 -MoTe2 heterostructures. The composition and phase of the Mo/Te compounds are controlled by changing the Te atomic flux that is adjusted by the Te temperature. Metallic 1D Mo6 Te6 wires with an intrinsic 1D structure with a diameter of 3-8 nm and length of 100-300 nm are synthesized to form wire networks under low Te flux conditions, whereas the semiconducting few-layer 2H MoTe2 films preferentially oriented along the <0001> direction are obtained under high Te flux. Under medium Te flux, the mixed-dimensional in-plane 1D-2D Mo6 Te6 -MoTe2 heterostructures are synthesized in which the semiconducting few-layer 2H MoTe2 circular domains are edge-contacted by the metallic 1D Mo6 Te6 wire networks. Furthermore, the present Te-flux-controlled method reveals that the 1D Mo6 Te6 networks change to few-layer MoTe2 films as the Te flux increases. The in-plane 1D-2D Mo6 Te6 -MoTe2 heterostructures synthesized by this method can be considered as advanced edge-contacted 2D semiconductors for high-performance 2D electronics.
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Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Condrossarcoma/tratamento farmacológico , Condrossarcoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Benzimidazóis/administração & dosagem , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Condrossarcoma/genética , Cisplatino/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Isocitrato Desidrogenase/genética , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phenol-soluble modulins (PSMs) are major determinants of Staphylococcus aureus virulence and their increased production in community-associated methicillin-resistant S. aureus (CA-MRSA) likely contributes to the enhanced virulence of MRSA strains. Here, we analyzed the differences in bacterial cell aggregation according to PSM presence in the specific human cerebrospinal fluid (CSF) environment. CSF samples from the intraventricular or lumbar intrathecal area of each patient and tryptic soy broth media were mixed at a 1:1 ratio, inoculated with WT and PSM-deleted mutants (Δpsm) of the CA-MRSA strain, USA300 LAC, and incubated overnight. Cell aggregation images were acquired after culture and image analysis was performed. The cell aggregation ratio in WT samples differed significantly between the two sampling sites (intraventricular: 0.2% vs. lumbar intrathecal: 6.7%, p < 0.001). The cell aggregation ratio in Δpsm samples also differed significantly between the two sampling sites (intraventricular: 0.0% vs. lumbar intrathecal: 1.2%, p < 0.001). Division of the study cases into two groups according to the aggregated area ratio (WT/Δpsm; group A: ratio of ≥ 2, group B: ratio of < 2) showed that the median aggregation ratio value differed significantly between groups A and B (5.5 and 0, respectively, p < 0.001). The differences in CSF distribution and PSM presence within the specific CSF environment are significant factors affecting bacterial cell aggregation.
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Toxinas Bacterianas/metabolismo , Staphylococcus aureus Resistente à Meticilina/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biofilmes/crescimento & desenvolvimento , Criança , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Solubilidade , Adulto JovemRESUMO
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.
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Cartilagem Articular/efeitos dos fármacos , Condrócitos/metabolismo , Matriz Extracelular/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais , Osteoartrite do Joelho/metabolismo , Poli ADP Ribosilação/efeitos dos fármacos , Fatores de Transcrição SOX9/efeitos dos fármacos , Tanquirases/antagonistas & inibidores , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/fisiologia , Simulação por Computador , Inibidores Enzimáticos , Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite do Joelho/genética , Poli ADP Ribosilação/fisiologia , Ratos , Regeneração/genética , Fatores de Transcrição SOX9/metabolismo , Tanquirases/genética , Tanquirases/metabolismoRESUMO
OBJECTIVE: Black sticky rice with giant embryo (BSRGE) contains high GABA content and affects alcohol-related indices among social drinkers, and alcohol intake and anxiety-related behavior of mice. However, it is unknown whether the intake of BSRGE affects GABAergic activity of brain directly. The purpose of this study is to elucidate the effect of oral administration of BSRGE on brain GABA concentrations compared with commercially available GABA compound and regular feeds. METHODS: Twenty-one male C57BL/6 mice were assigned to BSRGE, a regular feed (AIN-76) lacking GABA, and a regular feed containing GABA compound. After feeding freely for 48 h, the cortex and striatum were separated from the brain. An enzyme-linked immunosorbent assay was conducted to measure GABA and glutamate concentrations in mouse brain. RESULTS: The GABA concentration of the BSRGE group was higher than that of regular feed and GABA compound group (p<0.001). However, the GABA compound group showed no significant difference from the regular feed group (p=0.50). CONCLUSION: Intake of BSRGE containing high GABA content increased GABA concentrations in mouse brain compared with regular feed unlike GABA compound. The results of this study constitute an important basis for further investigations into the clinical applications of BSRGE.
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BACKGROUND: Excessive alcohol consumption is a major public health problem in East Asian countries. Alcohol use leads to a cascade of problems including increased chances of risky behavior and a wide range of negative health consequences, from alcoholic liver disease to upper gastric and liver cancer. These alcohol effects are known to be influenced by ethnic variability and genetics. METHODS: In this study, subjects were administered a single dose of alcohol (0.6 g/kg for men or 0.4 g/kg for women), and blood alcohol and acetaldehyde concentrations were measured eight times over 5 hours. To investigate genetically susceptible factors to alcohol metabolism, we selected single-nucleotide polymorphisms (SNP) of genes identified by prior genetic association studies for alcohol metabolism, alcohol consumption, alcohol dependence, and related traits, and performed genotyping on all subjects (n = 104). RESULTS: We identified variations in the ADH1A, SRPRB, and PGM1 genes, which are directly associated with blood alcohol or acetaldehyde concentrations. Namely, the T allele of SRPRB rs17376019 and the C allele of PGM1 rs4643 were associated with lower blood alcohol levels, while the ADH1 rs1229976 C allele group exhibited markedly higher blood acetaldehyde levels than those of the ADH1 rs1229976 T allele group. CONCLUSION: This study demonstrates that genetic variations in ADH1A, SRPRB, and PGM1 are associated with variations in blood alcohol and acetaldehyde concentration after alcohol intake.