RESUMO
The prevalence of obesity has increased dramatically during the past decades, which has been a major health problem. Since 1975, the number of people with obesity worldwide has nearly tripled. An increasing number of studies find obesity as a driver of chronic kidney disease (CKD) progression, and the mechanisms are complex and include hemodynamic changes, inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS). Obesity-related kidney disease is characterized by glomerulomegaly, which is often accompanied by localized and segmental glomerulosclerosis lesions. In these patients, the early symptoms are atypical, with microproteinuria being the main clinical manifestation and nephrotic syndrome being rare. Weight loss and RAAS blockers have a protective effect on obesity-related CKD, but even so, a significant proportion of patients eventually progress to end-stage renal disease despite treatment. Thus, it is critical to comprehend the mechanisms underlying obesity-related CKD to create new tactics for slowing or stopping disease progression. In this review, we summarize current knowledge on the mechanisms of obesity-related kidney disease, its pathological changes, and future perspectives on its treatment.
Assuntos
Glomerulosclerose Segmentar e Focal , Nefropatias , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/complicações , Obesidade/complicações , Sistema Renina-Angiotensina/fisiologia , Glomerulosclerose Segmentar e Focal/complicações , Doença Crônica , Rim , Progressão da DoençaRESUMO
Type 2 diabetes mellitus (T2DM) is related to abnormal brain structure and function, increasing the risk of cognitive impairment and dementia. We systematically reviewed the published literature focusing on cerebral perfusion in patients with T2DM. Although no significant difference was found in global cerebral blood flow (CBF) between the T2DM group and the healthy control group, the regional cerebral perfusion in T2DM was significantly reduced in multiple locations, including the occipital lobe, domains involved in the default mode network and the cerebellum. The decline in regional CBF was associated with a wide range of cognitive disorders in T2DM, including learning, memory, attention, and executive processing, as well as visual function. In addition, diabetes-related biochemical indicators, such as glycated hemoglobin and insulin resistance, were negatively correlated with regional CBF. In general, these functional perfusion imaging studies indicate that decreased CBF in T2DM may be a potential cause of cognitive impairment.
Assuntos
Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Encéfalo , Circulação Cerebrovascular , Disfunção Cognitiva/etiologia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.
Assuntos
Doenças do Córtex Suprarrenal , Síndrome de Cushing , Criança , Adulto Jovem , Humanos , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/complicações , Adrenalectomia , Hormônio Adrenocorticotrópico , Mitotano , Resultado do Tratamento , Doenças do Córtex Suprarrenal/terapia , Doenças do Córtex Suprarrenal/etiologiaRESUMO
BACKGROUND: Antidiabetic medications (ADMs) may modify prostate cancer (PCa) risk in patients with diabetes mellitus (DM). Accordingly, the current study assessed the possible associations between ADMs and the risk of PCa in diabetics. METHODS: A systematic literature search (PubMed, Embase and Cochrane Library) identified studies evaluating the associations between ADMs and incidence of PCa. A meta-analysis followed PRISMA was performed using odds ratio (OR) with 95% confidence interval (CI) as effect measures. RESULTS: In total of 47 studies involving 3094,152 patients with diabetes were included. Results of meta-analysis of the observational studies suggested no significant association between metformin, thiazolidinediones, sulfonylureas, insulin or dipeptidyl peptidase-4 inhibitors administration and the risk of PCa (All p-values > 0.05). Separate analysis of randomized controlled trials (RCTs) revealed a significant reduction in PCa risk with thiazolidinediones (OR = 0.55, p = 0.04) or glucagon-like peptide-1 receptor agonists (GLP-1RA) administration (OR = 0.53, p = 0.006), whereas no significant association was found in SGLT2 inhibitors (p = 0.3). CONCLUSION: Thiazolidinediones or GLP-1RA administration may have benefits in PCa based on RCTs, however, further research is needed to confirm these findings.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Neoplasias da Próstata , Tiazolidinedionas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/epidemiologiaRESUMO
PURPOSE: Liquid biopsy refers to the detection and analysis of the components from biological fluids non-invasively, including circulating tumor cells, nucleic acids, and extracellular vesicles (EVs). It is necessary to review the clinical value of liquid biopsy assays in PC and explore its potential application. MATERIALS AND METHODS: We systematically reviewed of PubMed was performed to identify relevant literature on potential clinical applications of circulating tumor cells, circulating nucleic acids, and EVs in prostate cancer (PC). RESULTS: Liquid biopsy has emerged as a powerful tool to elucidate dynamic genomic, transcriptomic, and epigenomic tumor profiling in real-time. Here, the potential clinical applications of liquid biopsy include early detection, prognosis of survival, assessment of treatment response, and mechanisms of drug resistance in PC. CONCLUSIONS: Liquid biopsy provides great value in diagnosis, prognosis, and treatment response in PC. Characterization of liquid biopsy components provides benefits both to unravel underlying resistance mechanisms and to exploit novel clinically actionable targets in PC. In addition, we suggest that analysis of multiparametric liquid biopsies should be analyzed comprehensively, assisting in monitoring tumor characteristics in real-time, guiding therapeutic selection, and early therapeutic switching during disease progression.
Assuntos
Células Neoplásicas Circulantes , Neoplasias da Próstata , Biomarcadores Tumorais , Humanos , Biópsia Líquida , Masculino , Prognóstico , Neoplasias da Próstata/diagnósticoRESUMO
Mitochondria have an essential function in cell survival due to their role in bioenergetics, reactive oxygen species generation, calcium buffering, and other metabolic activities. Mitochondrial dysfunctions are commonly found in neurodegenerative diseases (NDs), and diabetes is a risk factor for NDs. However, the role of mitochondria in diabetic neurodegeneration is still unclear. In the present study, we review the latest evidence on the role of mitochondrial dysfunctions in the development of diabetes-related NDs and the underlying molecular mechanisms. Hypoglycemic agents, especially metformin, have been proven to have neuroprotective effects in the treatment of diabetes, in which mitochondria could act as one of the underlying mechanisms. Other hypoglycemic agents, including thiazolidinediones (TZDs), dipeptidyl peptidase 4 (DPP-4) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, have gained more attention because of their beneficial effects on NDs, presumably by improving mitochondrial function. Our review highlights the notion that mitochondria could be a promising therapeutic target in the treatment of NDs in patients with diabetes.
Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/complicações , Secreção de Insulina/fisiologia , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Encéfalo/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/prevenção & controleRESUMO
BACKGROUND: It is still unclear whether growth hormone (GH) replacement is able to improve cardiovascular parameters in adults with GH deficiency (AGHD) from the updated clinical trials reported to date. METHODS AND RESULTS: We systematically reviewed clinical trials of GH treatment on AGHD patients in recent decade, and evaluated the effects of GH on cardiovascular parameters assessed by echocardiography. 11 clinical trials were identified in 3 bibliographic databases. We conducted a combined analysis of effects on four aspects: General indicators: baseline heart rate (BHR), peak heart rate (PHR), systolic blood pressure (SBP), diastolic blood pressure (DBP); Cardiac structure: left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular interventricular septum (LVIS), left ventricular mass (LVM), left ventricular posterior wall (LVPW); Cardiovascular function: deceleration time of E wave (DT), E/A ratio (E/A), ejection fraction (EF), NT-BNP; Life quality: peak VO2, VE/VCO2 slope. Overall effect size was used to evaluate significance, and weighted mean difference after GH treatment was given to appreciate size of the effect. GH treatment was associated with a significant increase in BHR (3.03[2.00, 4.06]), LVIS (0.50[0.43, 0.57]), LVPW (0.50[0.43, 0.57]), and EF (2.12[1.34, 2.90]). Overall effect sizes were negative significant for DBP (- 1.19[- 2.33, - 0.05]), LVEDV (- 9.84[- 16.53, - 3.15]), NT-BNP (- 206.34[- 308.95, - 103.72]), and VE/VCO2 slope (- 2.31[- 2.92, - 1.71]). CONCLUSIONS: As assessed by echocardiography, GH administration may improve the general vital signs and life quality of AGHD patients, based on the positive effect on BHR and negative effects on DBP and VE/VCO2 slope. Also, GH treatment would influence the structure of heart with positive effects on LVIS, LVPW and negative effect on LVEDV, which together with the increase of EF and decrease of NT-BNP, then resulting in improving the systolic function of AGHD patients.
Assuntos
Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Adulto , Pressão Sanguínea/fisiologia , Ecocardiografia , Fatores de Risco de Doenças Cardíacas , Frequência Cardíaca/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/diagnóstico por imagem , Hipopituitarismo/fisiopatologia , Peptídeo Natriurético Encefálico/sangue , Tamanho do Órgão , Consumo de Oxigênio/fisiologia , Fragmentos de Peptídeos/sangue , Proteínas Recombinantes , Volume Sistólico/fisiologia , Remodelação Ventricular/fisiologia , Septo Interventricular/diagnóstico por imagem , Septo Interventricular/patologiaRESUMO
Fatty acid synthase (FASN) is vital for maintaining lipid homeostasis in prostate cancer (PCa) cells, which have an increased rate of de novo fatty acid (FA) synthesis. Mutations in the gene encoding the tumor suppressor speckle-type POZ protein (SPOP), which is a E3 ubiquitin ligase, are a critical feature of PCa. Here, we provide evidence that FASN is a substrate of SPOP and that interaction of these proteins induces FASN ubiquitination and proteasome-dependent degradation. We showed that SPOP mutants commonly found in PCa cannot bind to FASN. Moreover, a decrease in SPOP levels upregulated FASN expression and triggered lipid accumulation in PCa cells. These results demonstrate that FASN is a crucial mediator of SPOP-induced inhibition of PCa cell growth. Our data provide evidence that SPOP regulates lipid metabolism by decreasing FASN expression and FA synthesis, resulting in tumor suppression. Taken together, our study indicates that this pathway may be a new therapeutic target for treating PCa.
Assuntos
Ácido Graxo Sintase Tipo I/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Estabilidade Enzimática , Ácido Graxo Sintase Tipo I/biossíntese , Ácido Graxo Sintase Tipo I/genética , Células HEK293 , Humanos , Metabolismo dos Lipídeos , Masculino , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Repressoras/genética , Ubiquitinação , Regulação para CimaRESUMO
Werner syndrome (WS) is a rare, adult-onset progeroid syndrome. Classic WS is caused by WRN mutation and partial atypical WS (AWS) is caused by LMNA mutation. A 19-year-old female patient with irregular menstruation and hyperglycemia was admitted. Physical examination revealed characteristic faces of progeria, graying and thinning of the hair scalp, thinner and atrophic skin over the hands and feet, as well as lipoatrophy of the extremities, undeveloped breasts at Tanner stage 3, and short stature. The patient also suffered from severe insulin-resistant diabetes mellitus, hyperlipidemia, fatty liver, and polycystic ovarian morphology. Possible WS was considered and both WRN and LMNA genes were analyzed. A novel missense mutation p.L140Q (c.419T>A) in the LMNA gene was identified and confirmed the diagnosis of AWS. Her father was a carrier of the same mutation. We carried out therapy for lowering blood glucose and lipid and improving insulin resistance, et al. The fasting glucose, postprandial glucose and triglyceride level was improved after treatment for 9 days. Literature review of AWS was performed to identify characteristics of the disease. Diabetes mellitus is one of the clinical manifestations of WS and attention must give to the differential diagnosis. Gene analysis is critical in the diagnosis of WS. According to the literature, classic and atypical WS differ in incidence, pathogenic gene, and clinical manifestations. Characteristic dermatological pathology may be significantly more important for the initial identification of AWS. Early detection, appropriate treatments, and regular follow-up may improve prognosis and survival of WS patients.
Assuntos
Diabetes Mellitus/metabolismo , Hipogonadismo/fisiopatologia , Síndrome de Werner/fisiopatologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/genética , Feminino , Humanos , Hipogonadismo/etiologia , Hipogonadismo/genética , Hipogonadismo/metabolismo , Lamina Tipo A/genética , Síndrome de Werner/complicações , Síndrome de Werner/genética , Adulto JovemRESUMO
BACKGROUND: Our study was aimed at detecting the expression levels of miR-206 in prostate cancer (PCa) tissues and PCa cell lines, and exploring the potential functions of miR-206 by targeting chemokine ligand 11 (CXCL11). METHODS: RT-qPCR was applied to detect the expressions of miR-206 and CXCL11 in PCa tissues and in PCa cell lines. Expression of the CXCL11 protein was detected using Western blot. After manipulating the expression of miR-206 and CXCL11 in PC-3 and DU-145 cells, the changes of cell proliferation and cell cycle were observed through cell counting kit-8 (CCK-8) and flow cytometry. Wound healing and transwell assay were conducted for cell migration and invasion examination in vitro. The luciferase reporter assay was applied to validate the association between miR-206 and CXCL11. RESULTS: MiR-206 was significantly under-expressed in PCa tissues and in PCa cell lines. Up-regulation of miR-206 could inhibit proliferation, migration, invasion and induced G1/G0 arrest of PCa cells, and vice versa. MiR-206 bound to the 3'-UTR of CXCL11 and significantly repressed the luciferase activity. Overexpression of miR-206 decreased the expression level of CXCL11 significantly. CXCL11 mRNA and protein levels were significantly decreased in PCa cells. Downregulation of CXCL11 presented tumor-suppressing effects on PCa cells as miR-206 mimics did. And co-transfection miR-206 attenuated the tumor-promoting effects induced by CXCL11 overexpression. CONCLUSION: Our current finding demonstrated that miR-206 negatively regulated PCa cell proliferation and migration, and arrested cell cycle by targeting CXCL11 as a tumor suppressor in prostate cancer.
Assuntos
Quimiocina CXCL11/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Neoplasias da Próstata/genética , Animais , Ciclo Celular/genética , Movimento Celular/genética , Proliferação de Células/genética , Quimiocina CXCL11/biossíntese , Quimiocina CXCL11/metabolismo , Regulação para Baixo , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , TransfecçãoRESUMO
Gut hormones are known to play an important role in long-term weight loss maintenance after bariatric surgery. However, the interplay between gut hormones and diet-induced weight changes remains unclear. Our aims were to evaluate the alterations of gut hormones in diet-induced weight loss, weight maintenance, and weight regain periods. Available studies were searched on MEDLINE, EMASE, ClinicalTrials.gov, the Cochrane Library, and Web of science from inception to October 2016. After selection, 16 studies with 656 participants were included. Based on current evidence, we found significant alterations of gut hormones induced by different diets. In weight-loss diets, decreased fasting total PYY, GLP-1, CCK, GIP, PP, and amylin along with increased ghrelin levels were observed in most studies. After weight loss, the persistent decreases of fasting total PYY and GLP-1 levels as well as increased appetite were reported, suggesting the profound impact of altered gut hormones on later weight regain after dietary intervention. The differences between diet-induced changes in gut hormones and other treatments such as bariatric surgery and exercise are also discussed in this review. Although significant alterations of gut hormones were found during weight changes, huge heterogeneity exists in methods and populations. More large-scale studies with elaborate design addressing the gut hormone alterations in dietary weight regulation are required in the future.
Assuntos
Dieta Redutora , Hormônios Gastrointestinais/metabolismo , Redução de Peso , Dieta com Restrição de Carboidratos , Dieta Rica em Proteínas , Humanos , Garantia da Qualidade dos Cuidados de SaúdeRESUMO
BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed male cancer in the United States and is a hormone-driven disease. Androgens have been recognized as a major promoter of PCa development and progression. However, the mechanism of androgen action in PCa, especially in PCa cell invasion and metastasis remains largely unclear. SMAD ubiquitination regulatory factor-1 (SMURF1) is a C2-WW-HECT-domain E3 ubiquitin ligase that plays important roles in cancer cell metastasis. Whether there is a relationship between androgens and SMURF1 expression is not known. METHODS: The effect of androgens on the expression of SMURF1 in PCa cell lines was examined by Western blot analyses and reverse transcription-polymerase chain reaction (RT-PCR). Gene transfection was performed by electroporation to manipulate the expression levels of proteins studied. The binding of AR to the SMURF1 gene enhancer was determined by chromatin immunoprecipitation (ChIP) assay. Cell migration and invasion was measured by wound healing and Matrigel invasion assays, respectively. RESULTS: We found that expression of SMURF1 is upregulated by androgens in PCa cell lines and that this effect of androgens is mediated through the androgen receptor (AR). We further showed that androgens regulate SMURF1 expression at transcriptional level and provided evidence that AR transcriptionally activates SMURF1 by binding to its enhancer that contains a canonical half androgen responsive element (ARE). Finally, we demonstrated that SMURF1 is important for androgen-induced invasion of PCa cells. CONCLUSIONS: We demonstrate for the first time that SMURF1 is a bona fide target gene of the AR. Our findings also suggest a potential role of SMURF1 in PCa metastasis.
Assuntos
Nandrolona/análogos & derivados , Neoplasias da Próstata/patologia , Ubiquitina-Proteína Ligases/fisiologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Nandrolona/farmacologia , Invasividade Neoplásica , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/fisiologia , Transcrição Gênica , Ubiquitina-Proteína Ligases/genéticaRESUMO
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors with diverse clinical presentations. Alterations in energy expenditure state are commonly observed in patients with PPGL. However, the reported prevalence of hypermetabolism varies significantly and the underlying mechanisms and implications of this presentation have not been well elucidated. This review discusses and analyzes the factors that contribute to energy consumption. Elevated catecholamine levels in patients can significantly affect substance and energy metabolism. Additionally, changes in the activation of brown adipose tissue (BAT), inflammation, and the inherent energy demands of the tumor can contribute to increased resting energy expenditure (REE) and other energy metabolism indicators. The PPGL biomarker, chromogranin A (CgA), and its fragments also influence energy metabolism. Chronic hypermetabolic states may be detrimental to these patients, with surgical tumor removal remaining the primary therapeutic intervention. The high energy expenditure of PPGL has not received the attention it deserves, and an accurate assessment of energy metabolism is the cornerstone for an adequate understanding and treatment of the disease.
Assuntos
Neoplasias das Glândulas Suprarrenais , Metabolismo Energético , Paraganglioma , Feocromocitoma , Humanos , Metabolismo Energético/fisiologia , Feocromocitoma/metabolismo , Paraganglioma/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Catecolaminas/metabolismo , Tecido Adiposo Marrom/metabolismo , Cromogranina A/metabolismoRESUMO
Background: Numerous studies have demonstrated the influence of gut microbiota on the development of obesity. In this study, we utilized Mendelian randomization (MR) analysis to investigate the gut microbiota characteristics among different types of obese patients, aiming to elucidate the underlying mechanisms and provide novel insights for obesity treatment. Methods: Two-sample multivariable Mendelian randomization (MR) analysis was employed to assess causal relationships between gut microbiota and various obesity subtypes. Gut microbiota data were obtained from the international consortium MiBioGen, and data on obese individuals were sourced from the Finnish National Biobank FinnGen. Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables. Various analytical methods, including inverse variance weighted (IVW), MR-Egger regression, weighted median, MR-RAPS, and Lasso regression, were applied. Sensitivity analyses for quality control included MR-Egger intercept tests, Cochran's Q tests, and leave-one-out analyses and others. Results: Mendelian randomization studies revealed distinct gut microbiota profiles among European populations with different obesity subtypes. Following multivariable MR analysis, we found that Ruminococcaceae UCG010 [Odds Ratio (OR): 0.842, 95% confidence interval (CI): 0.766-0.926, Adjusted P value: 0.028] independently reduced the risk of obesity induced by excessive calorie intake, while Butyricimonas [OR: 4.252, 95% CI: 2.177-8.307, Adjusted P value: 0.002] independently increased the risk of medication-induced obesity. For localized adiposity, Pasteurellaceae [OR: 0.213, 95% CI: 0.115-0.395, Adjusted P value: <0.001] acted as a protective factor. In the case of extreme obesity with alveolar hypoventilation, lactobacillus [OR: 0.724, 95% CI: 0.609-0.860, Adjusted P value: 0.035] reduced the risk of its occurrence. Additionally, six gut microbiota may have potential roles in the onset of different types of obesity. Specifically, the Ruminococcus torques group may increase the risk of its occurrence. Desulfovibrio and Catenabacterium may serve as protective factors in the onset of Drug-induced obesity. Oxalobacteraceae, Actinomycetaceae, and Ruminiclostridium 9, on the other hand, could potentially increase the risk of Drug-induced obesity. No evidence of heterogeneity or horizontal pleiotropy among SNPs was found in the above studies (all P values for Q test and MR-Egger intercept > 0.05). Conclusion: Gut microbiota abundance is causally related to obesity, with distinct gut microbiota profiles observed among different obesity subtypes. Four bacterial species, including Ruminococcaceae UCG010, Butyricimonas, Pasteurellaceae and lactobacillus independently influence the development of various types of obesity. Probiotic and prebiotic supplementation may represent a novel approach in future obesity management.
Assuntos
Actinomycetaceae , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Obesidade/genética , Bacteroidetes , Clostridiales , Lactobacillus , Nonoxinol , Estudo de Associação Genômica AmplaRESUMO
Background: Graves' disease (GD) is the most common cause of hyperthyroidism, and its pathogenesis remains incompletely elucidated. Numerous studies have implicated the gut microbiota in the development of thyroid disorders. This study employs Mendelian randomization analysis to investigate the characteristics of gut microbiota in GD patients, aiming to offer novel insights into the etiology and treatment of Graves' disease. Methods: Two-sample Mendelian randomization (MR) analysis was employed to assess the causal relationship between Graves' disease and the gut microbiota composition. Gut microbiota data were sourced from the international consortium MiBioGen, while Graves' disease data were obtained from FINNGEN. Eligible single nucleotide polymorphisms (SNPs) were selected as instrumental variables. Multiple analysis methods, including inverse variance-weighted (IVW), MR-Egger regression, weighted median, weighted mode, and MR-RAPS, were utilized. Sensitivity analyses were conducted employing MR-Egger intercept test, Cochran's Q test, and leave-one-out analysis as quality control measures. Results: The Mendelian randomization study conducted in a European population revealed a decreased risk of Graves' disease associated with Bacteroidaceae (Odds ratio (OR) [95% confidence interval (CI)]: 0.89 [0.89 ~ 0.90], adjusted P value: <0.001), Bacteroides (OR: [95% CI]: 0.555 [0.437 ~ 0.706], adjusted P value: <0.001), and Veillonella (OR [95% CI]: 0.632 [0.492 ~ 0.811], adjusted P value: 0.016). No significant evidence of heterogeneity, or horizontal pleiotropy was detected. Furthermore, the preliminary MR analysis identified 13 bacterial species including Eubacterium brachy group and Family XIII AD3011 group, exhibiting significant associations with Graves' disease onset, suggesting potential causal effects. Conclusion: A causal relationship exists between gut microbiota and Graves' disease. Bacteroidaceae, Bacteroides, and Veillonella emerge as protective factors against Graves' disease development. Prospective probiotic supplementation may offer a novel avenue for adjunctive treatment in the management of Graves' disease in the future.
Assuntos
Bacteroidaceae , Doença de Graves , Humanos , Bacteroides/genética , Veillonella , Estudos Prospectivos , Doença de Graves/genética , Estudo de Associação Genômica AmplaRESUMO
The clinical characteristics of Cushing's syndrome (CS) vary with etiology, and few studies have investigated the risk factors affecting CS recurrence after surgery. This retrospective study involved 202 patients diagnosed with CS between December 2012 and December 2022. The patients were divided into three groups according to etiology: Cushing's disease (CD), adrenocortical adenoma (ACA), and ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). Of the patients with CS, 41.9% had hypokalemia and 15.0% had hypophosphatemia. The cortisol levels were negatively correlated with blood potassium, blood chlorine, and blood phosphorus. Moreover, 22.4% of patients had an abnormal heart structure, 11.2% had centripetal remodeling, 5.6% had centripetal hypertrophy, and 5.6% had centrifugal hypertrophy. The overall recurrence rate of CS caused by pituitary tumors and adrenal adenoma was 25.7%. The recurrence times were longer in the ACA group versus the CD group, in patients < 50 years of age versus in patients ≥ 50 years old group, and in patients with CD with tumors ≥ 1 cm versus tumors < 1 cm. Age, preoperative cortisol level, postoperative cortisol level, and absolute neutrophil value were closely related to postoperative recurrence, and etiology was an independent predictor of tumor recurrence in patients with CS. The results of this study showed that CS caused by different etiologies showed different clinical manifestations, blood electrolyte characteristics, and that CS could affect patient cardiac structure and function. Etiology is an independent predictor of tumor recurrence in patients with CS.
Assuntos
Adenoma Adrenocortical , Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Humanos , Pessoa de Meia-Idade , Síndrome de Cushing/cirurgia , Síndrome de Cushing/diagnóstico , Hidrocortisona , Estudos Retrospectivos , Recidiva Local de Neoplasia/complicações , Fatores de Risco , Hipersecreção Hipofisária de ACTH/cirurgia , Hipertrofia/complicaçõesRESUMO
Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.
Assuntos
Fenofibrato , Neoplasias da Próstata , Humanos , Masculino , Autofagia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Fenofibrato/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Estresse Oxidativo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismoRESUMO
Background and purpose: Observational studies have shown that sarcopenia and diabetic nephropathy (DN), are closely related; however, the causal relationship is unclear. This study aims to address this issue using a bidirectional Mendelian randomization (MR) study. Methodology: We data from genome-wide association studies including appendicular lean mass (n = 244,730), grip strength (right: n = 461,089, left: n = 461026), walking speed (n = 459,915), and DN (3283 cases and 181,704 controls) to conduct a bidirectional MR study. First, we conducted a Forward MR analysis to evaluate the causality of sarcopenia on the risk of DN from the genetic perspective with appendicular lean mass, grip strength, and walking speed as exposure and DN as the outcome. Then, DN as the exposure, we performed a Reverse MR analysis to determine whether DN impacted the appendicular lean mass, grip strength, and walking speed of the appendices. Finally, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and Leave-one-out analyses, were conducted to assess the MR analysis's accuracy further. Results: According to a forward MR analysis, a genetically predicted decrease in appendicular lean mass is associated with an increased risk of developing DN risk (inverse variance weighting[IVW]: odd ratio [OR] = 0.863, 95% confidence interval [CI] 0.767-0.971; P = 0.014). According to reverse MR results, grip strength decreased as DN progressed (IVW: right ß = 0.003, 95% CI: - 0.021 to - 0.009, P = 5.116e-06; left ß = 0.003, 95% CI: - 0.024 to - 0.012, P = 7.035e-09). However, the results of the other MR analyses were not statistically different. Conclusion: Notably, our findings suggest that the causal relationship between sarcopenia and DN cannot be generalized. According to analysis of the individual characteristic factors of sarcopenia, reducing in appendicular lean mass increases the risk of developing DN and DN is linked to reduced grip strength. But overall, there is no causal relationship between sarcopenia and DN, because the diagnosis of sarcopenia cannot be determined by one of these factors alone.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Sarcopenia , Humanos , Sarcopenia/complicações , Sarcopenia/genética , Sarcopenia/diagnóstico , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Nefropatias Diabéticas/genética , Força da MãoRESUMO
Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.
Assuntos
Metabolismo dos Lipídeos , Insuficiência Renal Crônica , Humanos , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Inflamação/metabolismo , LipídeosRESUMO
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis. The disease originates from the cortex of adrenal gland and lacks effective treatment. Efforts have been made to elucidate the pathogenesis of ACC, but the molecular mechanisms remain elusive. To identify key genes and pathways in ACC, the expression profiles of GSE12368, GSE90713 and GSE143383 were downloaded from the Gene Expression Omnibus (GEO) database. After screening differentially expressed genes (DEGs) in each microarray dataset on the basis of cut-off, we identified 206 DEGs, consisting of 72 up-regulated and 134 down-regulated genes in three datasets. Function enrichment analyses of DEGs were performed by DAVID online database and the results revealed that the DEGs were mainly enriched in cell cycle, cell cycle process, mitotic cell cycle, response to oxygen-containing compound, progesterone-mediated oocyte maturation, p53 signaling pathway. The STRING database was used to construct the protein-protein interaction (PPI) network, and modules analysis was performed using Cytoscape. Finally, we filtered out eight hub genes, including CDK1, CCNA2, CCNB1, TOP2A, MAD2L1, BIRC5, BUB1 and AURKA. Biological process analysis showed that these hub genes were significantly enriched in nuclear division, mitosis, M phase of mitotic cell cycle and cell cycle process. Violin plot, Kaplan-Meier curve and stage plot of these hub genes confirmed the reliability of the results. In conclusion, the results in this study provided reliable key genes and pathways for ACC, which will be useful for ACC mechanisms, diagnosis and candidate targeted treatment.