RESUMO
Previous researches have reported that microcystin-LR (MC-LR) contributes to the progression of multiple types of carcinomas including colon cancer; however, the underlying molecular mechanisms remain unclear and require in-depth investigation. Here, the colon cell line DLD-1 was arranged for the analysis by the microRNA microarray which was associated with the cancer metastasis after MC-LR exposure. 31 human microRNAs were differentially expressed, including miR-221, which targeted 3'-UTR of PTEN mRNA and PTEN level was down-regulated by MC-LR treatment. Besides, MC-LR also induced the phosphorylation of STAT3, which can be reversed by adding miR-221 inhibitor and PTEN expression plasmid. Furthermore, miR-221 inhibitor, STAT3 siRNA and PTEN expression plasmid could reverse the effects of MC-LR induced migration with the accumulation of ß-catenin in nuclei. In conclusion, our study suggested that MC-LR promoted the progression of colon carcinoma, at least in part, by regulating the expression miR-221, PTEN and STAT3 phosphorylation, which offers a novel perspective to understand the connection between MC-LR and colon cancer.
Assuntos
Neoplasias do Colo/genética , Inibidores Enzimáticos/farmacologia , MicroRNAs/genética , Microcistinas/farmacologia , PTEN Fosfo-Hidrolase/genética , Fator de Transcrição STAT3/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo , Humanos , Toxinas Marinhas , MicroRNAs/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima , beta Catenina/metabolismoRESUMO
BACKGROUND: Major depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population. METHOD: We collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out. RESULTS: In the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249-3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999-1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471-4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204-1.718, P = 0.335; MR-Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021-15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD. LIMITATIONS: The results of this study may not be generalizable to non-European populations. CONCLUSION: MDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.
Assuntos
Doença de Alzheimer , Transtorno Depressivo Maior , Demência Frontotemporal , Humanos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/genética , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Estudo de Associação Genômica Ampla , Análise da Randomização MendelianaRESUMO
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, representing a significant public health problem with a poor prognosis. The development of efficient therapeutic strategies for HNSCC prevention and treatment is urgently needed. The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Dysfunction in components of this pathway, such as hyperactivity of PI3K, loss of PTEN function, and gain-of-function mutations in AKT, are well-known drivers of treatment resistance and disease progression in cancer. In this review, we discuss the major mutations and dysregulations in the PAM signaling pathway in HNSCC. We highlight the results of clinical trials involving inhibitors targeting the PAM signaling pathway as a strategy for treating HNSCC. Additionally, we examine the primary mechanisms of resistance to drugs targeting the PAM pathway and potential therapeutic strategies.
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Obesity has been recognized to be increasing globally and is designated a disease with adverse consequences requiring early detection and appropriate care. In addition to being related to metabolic syndrome disorders such as type 2 diabetes, hypertension, stroke, and premature coronary artery disease. Obesity is also etiologically linked to several cancers. The non-gastrointestinal cancers are breast, uterus, kidneys, ovaries, thyroid, meningioma, and thyroid. Gastrointestinal (GI) cancers are adenocarcinoma of the esophagus, liver, pancreas, gallbladder, and colorectal. The brighter side of the problem is that being overweight and obese and cigarette smoking are mostly preventable causes of cancers. Epidemiology and clinical studies have revealed that obesity is heterogeneous in clinical manifestations. In clinical practice, BMI is calculated by dividing a person's weight in kilograms by the square of the person's height in square meters (kg/m2). A BMI above 30 kg/m2 (defining obesity in many guidelines) is considered obesity. However, obesity is heterogeneous. There are subdivisions for obesity, and not all obesities are equally pathogenic. Adipose tissue, in particular, visceral adipose tissue (VAT), is endocrine and abdominal obesity (a surrogate for VAT) is evaluated by waist-hip measurements or just waist measures. Visceral Obesity, through several hormonal mechanisms, induces a low-grade chronic inflammatory state, insulin resistance, components of metabolic syndrome, and cancers. Metabolically obese, normal-weight (MONW) individuals in several Asian countries may have BMI below normal levels to diagnose obesity but suffer from many obesity-related complications. Conversely, some people have high BMI but are generally healthy with no features of metabolic syndrome. Many clinicians advise weight loss by dieting and exercise to metabolically healthy obese with large body habitus than to individuals with metabolic obesity but normal BMI. The GI cancers (esophagus, pancreas, gallbladder, liver, and colorectal) are individually discussed, emphasizing the incidence, possible pathogenesis, and preventive measures. From 2005 to 2014, most cancers associated with overweight and Obesity increased in the United States, while cancers related to other factors decreased. The standard recommendation is to offer or refer adults with a body mass index (BMI) of 30 or more to intensive, multicomponent behavioral interventions. However, the clinicians have to go beyond. They should critically evaluate BMI with due consideration for ethnicity, body habitus, and other factors that influence the type of obesity and obesity-related risks. In 2001, the Surgeon General's ``Call to Action to Prevent and Decrease Overweight and Obesity'' identified obesity as a critical public health priority for the United States. At government levels reducing obesity requires policy changes that improve the food and physical activity for all. However, implementing some policies with the most significant potential benefit to public health is politically tricky. The primary care physician, as well as subspecialists, should identify overweight and Obesity based on all the variable factors in the diagnosis. The medical community should address the prevention of overweight and Obesity as an essential part of medical care as much as vaccination in preventing infectious diseases at all levels- from childhood, to adolescence, and adults.
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Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Neoplasias Gastrointestinais , Síndrome Metabólica , Adulto , Feminino , Humanos , Estados Unidos , Criança , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Sobrepeso/complicações , Sobrepeso/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/etiologiaRESUMO
Background: COVID-19 is a respiratory illness caused by SARS-CoV-2. The most recent variant is Omicron (line B.1.1.529), which was first identified in South Africa in November 2021. The concern with this variant is the ineffectiveness of vaccines currently available. We aim to systematically evaluate the effectiveness of the currently available COVID-19 vaccines and boosters for the Omicron variant. Methods: We searched the PubMed, Embase, the Cochrane Library and Web of Science databases from inception to June 5th, 2022. Studies that examined the effectiveness of SARS-CoV-2 vaccines against the Omicron variant infection were included. Random-effects model was used to estimate the pooled vaccine effectiveness against the Omicron variant. Results: A total of 13 studies were included to evaluate the effectiveness of the vaccine against the Omicron variant, and 11 studies were included to compare the effectiveness between the two-dose and three-dose (booster) vaccinations. Full vaccination (two-dose with or without booster) showed a protective effect against the Omicron variant compared to no vaccination (OR = 0.62, 95% CI: 0.56-0.69), while the effectiveness decreased significantly over 6 months after the last dose. The two-dose vaccination plus booster provided better protection against the Omicron variant compared to the two-dose vaccination without booster (OR = 0.60, 95% CI: 0.52-0.68). Additional analysis was performed for the most commonly used vaccines in the United Staes: BNT162b2(Pfizer) (OR = 0.65, 95% CI: 0.52-0.82) and mRNA-1273(Moderna) (OR = 0.67, 95% CI: 0.58-0.88) vaccines in the US, which showed similar effectiveness compared to no vaccination. Conclusions: The full dose of SARS-CoV-2 vaccination effectively reduces infection from the SARS-CoV-2 Omicron variant; however, the effectiveness wanes over time. The booster vaccine provides additional protection against the Omicron variant.
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COVID-19 , Vacinas Virais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , SARS-CoV-2 , Eficácia de VacinasRESUMO
Dexmedetomidine (DEX) is a highly selective α2 receptor agonist that is routinely used in the clinic for sedation and anesthesia. Recently, an increasing number of studies have shown that DEX has a protective effect against brain injury caused by traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), cerebral ischemia and ischemia-reperfusion (I/R), suggesting its potential as a neuroprotective agent. Here, we summarized the neuroprotective effects of DEX in several models of neurological damage and examined its mechanism based on the current literature. Ultimately, we found that the neuroprotective effect of DEX mainly involved inhibition of inflammatory reactions, reduction of apoptosis and autophagy, and protection of the blood-brain barrier and enhancement of stable cell structures in five way. Therefore, DEX can provide a crucial advantage in neurological recovery for patients with brain injury. The purpose of this study was to further clarify the neuroprotective mechanisms of DEX therefore suggesting its potential in the clinical management of the neurological injuries.
RESUMO
Inflammation has recently been attributed to dysbiosis of the gut microbiome, which has been linked to proteinuria in chronic kidney disease. Since Adriamycin® (ADR) is widely used to induce proteinuria in mouse models, the aim of this study was to explore the potential effect of gut microbiome on this process. Both ADR resistant (C57BL/6) and susceptible (BALB/C) strains were part of the induced nephropathy with ADR injection. BALB/C mice significantly presented increased urinary albumin/creatinine ratio (UACR) with renal lesions in pathology, but C57BL/6 mice were absent from kidney damage. Species and genus level resolution analysis showed a shift in gut microbial profile between BALB/C and C57BL/6 mice. ADR further altered the stool microbiome in BALB/C mice, particularly with enrichment of Odoribacter and depletion of Turicibacter, Marvinbryantia and Rikenella. Moreover, the level of UACR in BALB/C mice was marked related to the abundance of Marvinbryantia, Odoribacter and Turicibacter in stool. Meanwhile, ADR remarkably increased the serum levels of interleukin (IL)-2 in BALB/C mice, but not in C57BL/6 mice. It is suggested that the favorably altered stools as shown in the microbiome might promote the inflammation and proteinuria in ADR-sensitive mice, which provides a new insight on the pathogenicity of chronic kidney disease.