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1.
J Adv Nurs ; 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39003658

RESUMO

AIM: To explore the transitional experiences of becoming housed from homelessness. DESIGN: A qualitative descriptive study. METHODS: Data were collected during 2017 and 2018 using a semi-structured interview method with 10 former homeless people who became housed at the time of the study. The grounded theory method was used to analyse qualitative data. RESULTS: 'Desire to keep a place to stretch out and lie down' was the basic social problem participants suffered during the transition from homeless to becoming housed. In addition, 'returning to the social world as a person living an ordinary life' was the basic social process that emerged as a core category. The process was divided into four phases: (1) being discarded from everyday life in the social world, (2) struggling to reconnect with society and (3) returning to the social world as a person living an ordinary life. CONCLUSION: The transition from homelessness to becoming housed is a significant experience for individuals that involves holistic changes. Community health nurses should consider their practical needs based on client views. IMPACT: What problem did the study address? This study explored the experiences of transitioning from homelessness to becoming housed among post-homeless individuals. What were the main findings? While moving from homelessness to becoming housed, homeless people experienced returning to the social world as a person living an ordinary life. They were also shown to go through the process of four stages. Where and on whom will the research have an impact? This study will contribute to suggesting a direction for self-reliance-based interventions among people who are homeless. Additionally, the findings will provide primary data to develop a program for social integration. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38961844

RESUMO

Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein like 7 (OSBPL7) modulates the expression and function of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Employing mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. While as expected the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7-deficiency related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7-deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study shed new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthen the role of OSBPL7 as a novel therapeutic target.

6.
Clin Lab ; 70(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38623660

RESUMO

BACKGROUND: Hereditary breast/ovarian cancer is associated with BRCA gene mutations. As large volumes of clinical data on BRCA variants are continuously updated, their clinical interpretation may change, leading to their reclassification. This study analyzed the class and proportion of the changed clinical interpretations of BRCA variants to validate the need for periodic reviews of these variants. METHODS: This retrospective study reinterpreted previously reported BRCA1 and BRCA2 exon variants according to the 2015 American College of Medical Genetics and Genomics guidelines and the clinical significance of the recent public genomic database. Reanalyzed results were obtained for patients tested for BRCA genetic mutation for 10 years and 4 months. RESULTS: We included data from 4,058 patients, with 595 having at least one pathogenic variant (P), likely pathogenic variant (LP), or variant of uncertain significance (VUS) at a detection rate of 14.66%. The numbers of exon and intron variants were 562 (87.81%) and 78 (12.19%), respectively. BRCA1 exhibited a significantly higher P/LP detection rate of 6.96% compared to that of BRCA2 at 6.89% (p < 0.001). Conversely, BRCA2 demonstrated a significantly higher VUS rate of 10.38% compared to that of BRCA1 at 5.08% (p < 0.001). Among BRCA1 mutations, substitutions were the most prevalent in P/LP and VUS. Among BRCA2 mutations, deletions were most prevalent in P/LP, and substitutions were most prevalent in VUS. Among the 131 patients with P/LP in BRCA1 exons, the clinical interpretation was reclassified in two cases (1.53%), one VUS and one benign/likely benign (B/LB), and 48 cases (48.00%) with VUS were reclassified; one to P/LP and 47 to B/LB. Among the 138 patients with P/LP in BRCA2 exons, the clinical interpretation was reclassified in six (4.35%), five to VUS, and one to B/LB, and all 74 with VUS were reclassified to B/LB. CONCLUSIONS: We determined the class and proportion of reclassified BRCA variants. In conclusion, reviews are required to provide clinical guidance, such as determining treatment direction and preventive measures in the future.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Estudos Retrospectivos , Predisposição Genética para Doença , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Mutação , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Testes Genéticos/métodos , Proteína BRCA1/genética , Proteína BRCA2/genética
7.
Hum Reprod ; 39(5): 1072-1077, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38514450

RESUMO

STUDY QUESTION: What are the characteristics of adolescents diagnosed with polycystic ovary syndrome (PCOS) based on the 2003 Rotterdam criteria, but who do not meet the diagnosis according to the international evidence-based guideline? SUMMARY ANSWER: Adolescents who had features of PCOS but did not meet the evidence-based guideline adolescent criteria exhibited unfavorable metabolic profiles compared to controls and shared considerable metabolic and hormonal features with adolescents who did meet the adolescent criteria. WHAT IS KNOWN ALREADY: The international evidence-based PCOS guideline recommended that ultrasound should not be used for the diagnosis of PCOS in girls with a gynecological age of <8 years. Thus far, few studies have evaluated the clinical characteristics of the girls diagnosed with PCOS based on the Rotterdam criteria but who do not meet the diagnosis according to the updated guideline. STUDY DESIGN, SIZE, DURATION: This is a retrospective study, and subjects attended for care from 2004 to 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Adolescent girls with PCOS diagnosed according to the 2003 Rotterdam criteria and healthy controls. All participants were between 2 and 8 years since menarche. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 315 girls diagnosed with PCOS according to the Rotterdam criteria, those with irregular menstruation (IM)/hyperandrogenism (HA)/polycystic ovary (PCO), IM/HA, HA/PCO, and IM/PCO phenotypes accounted for 206 (65.4%), 30 (9.5%), 12 (3.8%), and 67 (21.3%) participants, respectively. According to the evidence-based guideline, 79 girls (25.1%) with the HA/PCO or IM/PCO phenotypes were not diagnosed with PCOS, and aligned to the international guideline; they were designated as the 'at-risk' group. As expected, the girls meeting the evidence-based guideline adolescent criteria showed the worst metabolic profiles (degree of generalized or central obesity, frequency of insulin resistance, prediabetes or diabetes, and metabolic syndrome) and higher hirsutism scores than the at-risk group or controls. Approximately 90% of the at-risk group were not overweight or obese, which was similar to the controls. However, they showed worse metabolic profiles, with higher blood pressure, triglyceride, and insulin resistance parameters than controls; furthermore, these profiles were similar to those of the girls meeting the adolescent criteria. The at-risk group showed similarly elevated serum LH levels and LH/FSH ratio with the girls meeting adolescent criteria. LIMITATIONS, REASONS FOR CAUTION: We could not evaluate hormonal or ultrasound parameters in controls. WIDER IMPLICATIONS OF THE FINDINGS: Compared to the conventional Rotterdam criteria, the recent international evidence-based guideline-avoiding ultrasound in PCOS diagnosis in adolescents-still gives the opportunity to identify young girls at risk, aligned to the findings in this study. A practical approach to this adolescent population would involve establishing IM or HA (with ultrasound not indicated) and designating 'at-risk' PCOS status with regular check-ups for newly developed or worsening PCOS-related symptoms or metabolic abnormalities, with subsequent reassessment including ultrasound or anti-Müllerian hormone, once 8 years post-menarche. STUDY FUNDING/COMPETING INTEREST(S): No funding was received in support of this study. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Hiperandrogenismo , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/complicações , Feminino , Adolescente , Estudos Retrospectivos , Hiperandrogenismo/diagnóstico , Guias de Prática Clínica como Assunto , Criança , Ultrassonografia , Resistência à Insulina , Estudos de Casos e Controles
8.
Cancers (Basel) ; 16(5)2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38473292

RESUMO

Achieving textbook outcomes (TOs) improves the short-term and long-term performance of a hospital. Our objective was to assess TOs in the laparoscopic liver resection (LLR) of tumors in the PS (posterosuperior) section of the liver and identify the impact of the learning curve. We conducted a retrospective cohort study analyzing patients who underwent LLR for lesions located in the PS segments. Patients were divided into a TO and no-TO group. TOs were defined as negative margins, no transfusion, no readmission, no major complications, no 30-day mortality, and a length of stay ≤ 50th percentile. Patients' outcomes were assessed in two study periods before and after 2015. TOs were achieved in 47.6% (n = 117). In multivariable analysis, obesity (p = 0.001), shorter operation time (p < 0.001), less blood loss (p < 0.001), normal albumin (p = 0.003), and minor resection (p = 0.046) were significantly associated with achieving TOs. Although the 5-year recurrence-free survival rate (p = 0.096) was not significantly different, the 5-year overall survival rate was significantly greater in the TO group (p = 0.001). Body mass index > 25 kg/m2 (p = 0.020), age > 65 years (p = 0.049), and achievement of TOs (p = 0.024) were independently associated with survival. The proportion of patients who achieved a TO was higher after 2015 than before 2015 (52.3% vs. 36.1%; p = 0.022). TOs are important markers not only for assessing hospital and surgeon performance but also as predictors of overall survival. As the number of surgeons who achieve the learning curve increases, the number of patients with TOs will gradually increase with a subsequent improvement in overall survival.

9.
Nat Commun ; 15(1): 2564, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38519491

RESUMO

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.


Assuntos
Células Endoteliais , Células-Tronco Pluripotentes Induzidas , Humanos , Diferenciação Celular , Miócitos Cardíacos , Engenharia Tecidual/métodos
11.
PLoS One ; 19(2): e0291157, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38359002

RESUMO

OBJECTIVE: Uterine leiomyoma (UL), the most prevalent benign gynecologic tumor among reproductive-aged women, lacks sufficient research on the potential association between dietary intake and its occurrence in Korean women. Addressing this research gap, this study aims to evaluate the potential link between dietary intake and the prevalence of UL in Korean women. METHODS: In this cross-sectional study, a cohort of 672 women, aged 23 to 73, were enrolled, with 383 (57%) being premenopausal. Dietary intake was assessed using a validated food frequency questionnaire (FFQ), and UL presence was determined through ultrasonography. The analysis focused exclusively on items within ten categories, including vegetables/fruit, vegetables, fruits, red meat, processed meat, poultry, fish, dairy product, milk, and alcohol. Multiple logistic regression models were employed to explore the relationship between dietary intake and the prevalence of UL, calculating odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for confounding factors. RESULTS: Within the total cohort, 220 (32.7%) women were diagnosed with UL. High intakes of fish and poultry showed an association with higher UL prevalence. Odds ratios (95% CIs) for the upper quartiles compared to the lower quartiles were 1.68 (1.01-2.81; p trend = 0.05) for fish intake and 1.87 (1.11-3.17; p trend = 0.06) for poultry intake. Conversely, an inverse relationship emerged between dairy product intake and UL prevalence, with an odds ratio of 0.58 (95% CI 0.35-0.96; p trend = 0.05). Stratifying the analysis by menopausal status revealed a parallel pattern, with heightened UL prevalence with fish intake and reduced prevalence with dairy product intake. However, the link between poultry intake and UL prevalence was primarily observed among postmenopausal women. Among premenopausal women, elevated vegetable intake was linked to a decreased UL prevalence (OR 0.45, 95% CI 0.21-0.97 for top vs. bottom quartiles; p trend = 0.01). CONCLUSION: We found that high consumption of fish and poultry, coupled with low intake of dairy products, correlated with an elevated prevalence of UL. Furthermore, vegetable intake exhibited an inverse relationship with UL prevalence, particularly among premenopausal women.


Assuntos
Dieta , Leiomioma , Animais , Humanos , Feminino , Adulto , Fatores de Risco , Estudos Transversais , Prevalência , Estudos Retrospectivos , Inquéritos e Questionários , Frutas , Verduras , Ingestão de Alimentos , Leiomioma/epidemiologia , Leite , República da Coreia/epidemiologia
12.
Ann Lab Med ; 44(3): 279-288, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38205526

RESUMO

Background: The mechanism and medical treatment target for degenerative aortic valve disease, including aortic stenosis, is not well studied. In this study, we investigated the effect of clonal hematopoiesis of indeterminate potential (CHIP) on the development of aortic valve sclerosis (AVS), a calcified aortic valve without significant stenosis. Methods: Participants with AVS (valves ≥2 mm thick, high echogenicity, and a peak transaortic velocity of <2.5 m/sec) and an age- and sex-matched control group were enrolled. Twenty-four CHIP genes with common variants in cardiovascular disease were used to generate a next-generation sequencing panel. The primary endpoint was the CHIP detection rate between the AVS and control groups. Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for differences in baseline characteristics. Results: From April 2020 to April 2022, 187 participants (125 with AVS and 62 controls) were enrolled; the mean age was 72.6±8.5 yrs, and 54.5% were male. An average of 1.3 CHIP variants was observed. CHIP detection, defined by a variant allele frequency (VAF) of ≥0.5%, was similar between the groups. However, the AVS group had larger CHIP clones: 49 (39.2%) participants had a VAF of ≥1% (vs. 13 [21.0%] in the control group; P=0.020), and 25 (20.0%) had a VAF of ≥2% (vs. 4 [6.5%]; P=0.028). AVS is independently associated with a VAF of ≥1% (adjusted odds ratio: 2.44, 95% confidence interval: 1.11-5.36; P=0.027). This trend was concordant and clearer in the IPTW cohort. Conclusions: Participants with AVS more commonly had larger CHIP clones than age- and sex-matched controls. Further studies are warranted to identify causality between AVS and CHIP.


Assuntos
Estenose da Valva Aórtica , Calcinose , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Hematopoiese Clonal , Esclerose/patologia , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Calcinose/patologia
13.
Cancer Res Treat ; 56(1): 314-323, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37475138

RESUMO

PURPOSE: We designed and evaluated the clinical performance of a plasma circulating tumor DNA (ctDNA) panel of 112 genes in various subtypes of lymphoma. MATERIALS AND METHODS: Targeted deep sequencing with an error-corrected algorithm was performed in ctDNA from plasma samples that were collected before treatment in 42 lymphoma patients. Blood buffy coat was utilized as a germline control. We evaluated the targeted gene panel using mutation detection concordance on the plasma samples with matched tissue samples analyzed the mutation profiles of the ctDNA. RESULTS: Next-generation sequencing analysis using matched tissue samples was available for 18 of the 42 patients. At least one mutation was detected in the majority of matched tissue biopsy samples (88.9%) and plasma samples (83.3%). A considerable number of mutations (40.4%) that were detected in the tissue samples were also found in the matched plasma samples. Majority of patients (21/42) were diffuse large B cell lymphoma patients. The overall detection rate of ctDNA in patients was 85.7% (36/42). The frequently mutated genes included PIM1, TET2, BCL2, KMT2D, KLHL6, HIST1H1E, and IRF8. A cutoff concentration (4,506 pg/mL) of ctDNA provided 88.9% sensitivity and 82.1% specificity to predict ctDNA mutation detection. The ctDNA concentration correlated with elevated lactate dehydrogenase level and the disease stage. CONCLUSION: Our design panel can detect many actionable gene mutations, including those at low frequency. Therefore, liquid biopsy can be applied clinically in the evaluation of lymphoma patients, especially in aggressive lymphoma patients.


Assuntos
DNA Tumoral Circulante , Linfoma , Humanos , DNA Tumoral Circulante/genética , Biópsia Líquida , Mutação , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala
14.
Brief Bioinform ; 24(6)2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37889119

RESUMO

Microbial genome recovery from metagenomes can further explain microbial ecosystem structures, functions and dynamics. Thus, this study developed the Additional Clustering Refiner (ACR) to enhance high-purity prokaryotic and eukaryotic metagenome-assembled genome (MAGs) recovery. ACR refines low-quality MAGs by subjecting them to iterative k-means clustering predicated on contig abundance and increasing bin purity through validated universal marker genes. Synthetic and real-world metagenomic datasets, including short- and long-read sequences, evaluated ACR's effectiveness. The results demonstrated improved MAG purity and a significant increase in high- and medium-quality MAG recovery rates. In addition, ACR seamlessly integrates with various binning algorithms, augmenting their strengths without modifying core features. Furthermore, its multiple sequencing technology compatibilities expand its applicability. By efficiently recovering high-quality prokaryotic and eukaryotic genomes, ACR is a promising tool for deepening our understanding of microbial communities through genome-centric metagenomics.


Assuntos
Metagenoma , Microbiota , Eucariotos/genética , Microbiota/genética , Algoritmos , Metagenômica/métodos , Análise por Conglomerados
15.
Exp Mol Med ; 55(10): 2248-2259, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37779148

RESUMO

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Humanos , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Membro Posterior/irrigação sanguínea , Isquemia/terapia , Isquemia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Músculo Esquelético/metabolismo , Neovascularização Fisiológica
16.
ACS Appl Mater Interfaces ; 15(44): 50693-50707, 2023 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-37812574

RESUMO

The patch-based delivery system has been a promising therapeutic approach for treating various vascular diseases. However, conventional methods face several challenges, including labor-intensive and time-consuming processes associated with patch fabrication or factor incorporation, inadequate physical properties, and uncontrolled release of factors. These limitations restrict the potential applications in clinical settings. To overcome these issues, we propose a novel core-shell-shaped droplet patch system called an angiogenic patch (AP). Our system offers several distinct advantages over conventional patches. It enables a rapid and straightforward fabrication process utilizing only two biodegradable ingredients [alginate and ε-poly(l-lysine)], ensuring minimal toxicity. Moreover, the AP exhibits excellent physical integrity to match and withstand physiological mechanics and allows for customizable patch dimensions tailored to individual patients' pathological conditions. Notably, the AP enables facile loading of angiogenic cytokines during patch fabrication, allowing sustained release at a controlled rate through tunable network cross-linking. Subsequently, the AP, delivering a precisely formulated cocktail of angiogenic cytokines (VEGF, bFGF, EGF, and IGF), demonstrated significant effects on endothelial cell functions (migration and tubule formation) and survival under pathological conditions simulating ischemic injury. Likewise, in in vivo experiments using a mouse model of hindlimb ischemia, the AP encapsulating the angiogenic cocktail effectively restored blood flow following an ischemic insult, promoting muscle regeneration and preventing limb loss. With its simplicity and rapid processability, user-friendly applicability, physical tunability, and the ability to efficiently load and control the delivery of angiogenic factors, the AP holds great promise as a therapeutic means for treating patients with ischemic diseases.


Assuntos
Isquemia , Neovascularização Fisiológica , Animais , Humanos , Isquemia/tratamento farmacológico , Isquemia/patologia , Sistemas de Liberação de Medicamentos , Fenômenos Fisiológicos Cardiovasculares , Citocinas
17.
J Hazard Mater ; 457: 131761, 2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37290355

RESUMO

Concerns about antibiotic resistance genes (ARGs) released from wastewaters of livestock or fish farming into the natural environment are increasing, but studies on unculturable bacteria related to the dissemination of antibiotic resistance are limited. Here, we reconstructed 1100 metagenome-assembled genomes (MAGs) to assess the impact of microbial antibiotic resistome and mobilome in wastewaters discharged to Korean rivers. Our results indicate that ARGs harbored in the MAGs were disseminated from wastewater effluents into downstream rivers. Moreover, it was found that ARGs are more commonly co-localized with mobile genetic elements (MGEs) in agricultural wastewater than in river water. Among the effluent-derived phyla, uncultured members of the superphylum Patescibacteria possessed a high number of MGEs, along with co-localized ARGs. Our findings suggest that members of the Patesibacteria are a potential vector for propagating ARGs into the environmental community. Therefore, we propose that the dissemination of ARGs by uncultured bacteria should be further investigated in multiple environments.


Assuntos
Metagenômica , Águas Residuárias , Animais , Metagenômica/métodos , Água , Resistência Microbiana a Medicamentos/genética , Bactérias/genética , Antibacterianos/farmacologia , Genes Bacterianos , Rios/microbiologia
18.
Sci Rep ; 13(1): 9616, 2023 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-37316538

RESUMO

Decreased ATP Binding Cassette Transporter A1 (ABCA1) expression and caspase-4-mediated noncanonical inflammasome contribution have been described in podocytes in diabetic kidney disease (DKD). To investigate a link between these pathways, we evaluated pyroptosis-related mediators in human podocytes with stable knockdown of ABCA1 (siABCA1) and found that mRNA levels of IRF1, caspase-4, GSDMD, caspase-1 and IL1ß were significantly increased in siABCA1 compared to control podocytes and that protein levels of caspase-4, GSDMD and IL1ß were equally increased. IRF1 knockdown in siABCA1 podocytes prevented increases in caspase-4, GSDMD and IL1ß. Whereas TLR4 inhibition did not decrease mRNA levels of IRF1 and caspase-4, APE1 protein expression increased in siABCA1 podocytes and an APE1 redox inhibitor abrogated siABCA1-induced expression of IRF1 and caspase-4. RELA knockdown also offset the pyroptosis priming, but ChIP did not demonstrate increased binding of NFκB to IRF1 promoter in siABCA1 podocytes. Finally, the APE1/IRF1/Casp1 axis was investigated in vivo. APE1 IF staining and mRNA levels of IRF1 and caspase 11 were increased in glomeruli of BTBR ob/ob compared to wildtype. In conclusion, ABCA1 deficiency in podocytes caused APE1 accumulation, which reduces transcription factors to increase the expression of IRF1 and IRF1 target inflammasome-related genes, leading to pyroptosispriming.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Podócitos , Humanos , Nefropatias Diabéticas/genética , Inflamassomos , Piroptose , Caspase 1/genética , Caspases , Fator Regulador 1 de Interferon/genética , Transportador 1 de Cassete de Ligação de ATP/genética
19.
Elife ; 122023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37129368

RESUMO

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.


Assuntos
Diabetes Mellitus Tipo 2 , Nefrite Hereditária , Podócitos , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Camundongos , Animais , Podócitos/metabolismo , Nefrite Hereditária/tratamento farmacológico , Nefrite Hereditária/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Glucose/toxicidade , Glucose/metabolismo
20.
Am J Obstet Gynecol ; 229(1): 45.e1-45.e18, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37023913

RESUMO

BACKGROUND: Uterine leiomyomas are the most common benign tumors in women of childbearing age. Although there are several studies reporting the positive association of drinking alcohol with the incidence of uterine leiomyomas, studies targeting Korean women are lacking. OBJECTIVE: This study aimed to investigate the association between alcohol consumption and the risk of new-onset uterine leiomyomas in Korean women of early reproductive-age. STUDY DESIGN: This was a retrospective nationwide population-based cohort study using the Korean National Health Insurance Service database. Participants comprised 2,512,384 asymptomatic Korean women aged 20 to 39 years who underwent a national health examination from 2009 to 2012. The follow-up period was from the date of the first national health examination to the date of diagnosis of new-onset uterine leiomyomas or December 2018 if no uterine leiomyomas were detected. The diagnosis of uterine leiomyomas required 2 outpatient records within a year or 1 inpatient record of International Classification of Diseases, Tenth Revision (ICD-10) codes of uterine leiomyomas (D25) in the Korean National Health Insurance Service. Exclusion criteria were previously diagnosed uterine leiomyomas during the screening period (January 2002 to the date of first health examination) or uterine leiomyoma diagnosis within 1 year of baseline examination. The associations of alcohol consumption, amount drunk per drinking session, and sustained drinking over time with the risk of new-onset uterine leiomyomas were investigated. RESULTS: Approximately 6.1% of women aged 20 to 39 years were diagnosed with uterine leiomyomas after an average of 4.3 years. Alcohol consumption was associated with an increased incidence of new-onset uterine leiomyomas of 12% to 16% (hazard ratio, 1.12; 95% confidence interval, 1.11-1.14 for mild-to-moderate drinkers; hazard ratio, 1.16; 95% confidence interval, 1.12-1.20 for heavy drinkers). Drinking ≥1 days per week was associated with increased risk of uterine leiomyomas (hazard ratio, 1.11; 95% confidence interval, 1.10-1.12 for drinking 1 day per week; hazard ratio, 1.15; 95% confidence interval, 1.12-1.17 for drinking ≥3 days per week), and the association increased proportionately to the amount of alcohol consumed per drinking session (hazard ratio, 1.17; 95% confidence interval, 1.15-1.19 for ≥7 glasses per drinking session). Women who also reported alcohol consumption in the questionnaire administered 2 years later (sustained drinkers) exhibited a 20% increased risk of new-onset uterine leiomyomas (hazard ratio, 1.20; 95% confidence interval, 1.17-1.22) compared with women who answered that they did not drink alcohol at both times (sustained nondrinkers). In women who discontinued drinking, the risk was 3% (hazard ratio, 1.03; 95% confidence interval, 1.01-1.06), whereas in women who became drinkers, the risk was 14% (hazard ratio, 1.14; 95% confidence interval, 1.11-1.16). CONCLUSION: Having an alcohol drinking habit, the amount of alcohol consumed per drinking session, and sustained drinking over 2 years were significantly associated with the risk of new-onset uterine leiomyomas. Avoiding or discontinuing drinking could lower the risk of new-onset uterine leiomyomas in early reproductive-age women.


Assuntos
Consumo de Bebidas Alcoólicas , Leiomioma , Humanos , Feminino , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Leiomioma/epidemiologia , Etanol , República da Coreia/epidemiologia , Fatores de Risco
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