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Acute kidney injury (AKI) frequently emerges as a consequential non-neurological sequel to traumatic brain injury (TBI), significantly contributing to heightened mortality risks. The intricate interplay of oxidative stress in the pathophysiology of TBI underscores the centrality of the Keap1-Nrf2/HO-1 signaling pathway as a pivotal regulator in this context. This study endeavors to elucidate the involvement of the Keap1-Nrf2/HO-1 pathway in modulating oxidative stress in AKI subsequent to TBI and concurrently explore the therapeutic efficacy of dimethyl fumarate (DMF). A rat model of TBI was established via the Feeney free-fall method, incorporating interventions with varying concentrations of DMF. Assessment of renal function ensued through measurements of serum creatinine and neutrophil gelatinase-associated lipocalin. Morphological evaluation of renal pathology was conducted employing quantitative hematoxylin and eosin staining. The inflammatory response was scrutinized by quantifying interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α levels. Oxidative stress levels were discerned through quantification of malondialdehyde and superoxide dismutase. The apoptotic cascade was examined via the terminal deoxynucleotidyl transferase dUTP deletion labeling assay. Western blotting provided insights into the expression dynamics of proteins affiliated with the Keap1-Nrf2/HO-1 pathway and apoptosis. The findings revealed severe kidney injury, heightened oxidative stress, inflammation, and apoptosis in the traumatic brain injury model. Treatment with DMF effectively reversed these changes, alleviating oxidative stress by activating the Keap1-Nrf2/HO-1 signaling pathway, ultimately conferring protection against AKI. Activating Keap1-Nrf2/HO-1 signaling pathway may be a potential therapeutic strategy for attenuating oxidative stress-induced AKI after TBI.
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BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ± 2.07 mmol/l vs. 2.00 ± 1.80 mmol/l P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.
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Diabetes Mellitus Tipo 2 , Mortalidade Hospitalar , Hiperlactatemia , Hipoglicemiantes , Metformina , Humanos , Metformina/uso terapêutico , Metformina/efeitos adversos , Masculino , Feminino , Mortalidade Hospitalar/tendências , Estudos Retrospectivos , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Hiperlactatemia/epidemiologia , Hiperlactatemia/sangue , Hiperlactatemia/induzido quimicamente , Incidência , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Pessoa de Meia-Idade , Hipóxia/epidemiologia , Hipóxia/mortalidade , Hipóxia/sangue , Admissão do Paciente/tendências , Cardiopatias/epidemiologia , Cardiopatias/mortalidade , Cardiopatias/sangue , Idoso de 80 Anos ou mais , Fatores de RiscoRESUMO
BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.
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Doença do Armazenamento de Colesterol Éster , Heterozigoto , Linhagem , Esterol Esterase , Humanos , Masculino , Feminino , Doença do Armazenamento de Colesterol Éster/genética , Doença do Armazenamento de Colesterol Éster/diagnóstico , Esterol Esterase/genética , Adulto , Mutação , Genes Dominantes , Pessoa de Meia-Idade , Fenótipo , Adolescente , CriançaRESUMO
Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.
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Doença de Gaucher , Esplenopatias , Adulto , Humanos , Masculino , Doença de Gaucher/complicações , Doença de Gaucher/genética , Doença de Gaucher/cirurgia , Esplenectomia , Medula Óssea , Fenótipo , Esplenomegalia/genética , Mutação , Glucosilceramidase/genéticaRESUMO
PURPOSE: Previous studies have explored the role of immune cells on osteonecrosis. This Mendelian randomization (MR) study further assessed 731 immunocyte phenotypes on osteonecrosis, whether a causal relationship exists, and provides some evidence of causality. METHODS: The 731 immunocyte phenotypes and osteonecrosis data used in this study were obtained from their respective genome-wide association studies (GWAS). The authors used inverse variable weighting (IVW) as the primary analysis method. In addition, the authors simultaneously employed multiple analytical methods, including MR-Egger, weighted mode, simple mode, and weighted median, to strengthen the final results. Finally, sensitivity analyses were conducted to verify the stability and feasibility of the data. RESULTS: The results of the IVW method of MR analysis showed that 8 immunocyte phenotypes were positively associated with osteonecrosis [ P <0.05, odds ratio (OR) > 1]; 18 immunocyte phenotypes were negatively associated with osteonecrosis ( P <0.05, OR<1), none of which were heterogeneous or horizontally pleiotropic ( P > 0.05) or reverse causality. In addition to this, in reverse MR, osteonecrosis was positively associated with 10 additional immunocyte phenotypes ( P <0.05, OR > 1) and negatively associated with 14 immunocyte phenotypes ( P <0.05, OR<1). And none of them had heterogeneity and horizontal pleiotropy ( P > 0.05) or reverse causality. CONCLUSIONS: The authors demonstrated a complex causal relationship between multiple immune phenotypes and osteonecrosis through a comprehensive two-way, two-sample MR analysis, highlighting the complex pattern of interactions between the immune system and osteonecrosis.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteonecrose , Fenótipo , Humanos , Osteonecrose/genética , Osteonecrose/imunologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Bioadhesives have garnered widespread attention in the biomedical field, for wound healing and tissue sealing. However, challenges exist due to the inferior performance of bioadhesives, including weak adhesion, poor biocompatibility, or lack of biodegradability. In this work, we demonstrate the fabrication of hydrogel adhesive based on polypeptides composed of lysine and glutamic acid. The cation-π interaction between the ammonium cations and phenyl groups endows the hydrogel with strong cohesion, and the hydrophobicity of the phenyl group significantly enhances the interaction between polypeptides and the substrate interface, leading to excellent adhesive performance. The equivalent molar ratio of ammonium cations and the phenyl group is beneficial for the enhancement of adhesiveness. Furthermore, we discover that the polypeptides with an α-helix exhibit better adhesiveness than the polypeptides with a ß-sheet because the α-helical structure can increase the exposure of the side group on the polypeptide surface, which further strengthens the interaction between polypeptides and the substrate. Besides, this synthetic polypeptide adhesive can seal the tissue quickly and remain intact in water. This adhesive holds significant promise for application in wound healing and tissue sealing, and this study provides insight into the development of more peptide-based adhesives.
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Adesivos , Compostos de Amônio , Adesivos/química , Peptídeos/química , Hidrogéis/química , CátionsRESUMO
The low emission efficiency of clusteroluminogens restricts their practical applications in the fields of sensors and biological imaging. In this work, the clusteroluminescence of ordered/disordered polypeptides was observed, and the photoluminescence (PL) intensity of polypeptides can be modulated by the chirality of amino acid residues. Polyglutamates with different chiral compositions were synthesized, and the racemic polypeptides exhibited a significantly higher PL intensity than the enantiopure ones. This emission originates from the n-π* transition between CâO groups of polypeptides and is enhanced by clusterization of polypeptides. CD and Fourier transform infrared spectra demonstrated that the enantiopure and racemic polypeptides form α-helix and random coil structures, respectively. The disordered polypeptides can form more chain entanglements and interchain interactions because of their high flexibility, leading to more clusterizations and stronger PL intensity. The rigidity of ordered helical structures restrains the chain entanglements, and the formation of intrachain hydrogen bonds between amide groups of the backbone impairs the interchain interaction between polypeptides, resulting in lower PL intensity. The PL intensity of the polypeptides can also be manipulated by the addition of urea or trifluoroacetic acid. Our study not only elucidates the chirality/order-based structure-property relationship of clusteroluminescence in peptide-based polymers but also offers implications for the rational design of fluorescent peptides/proteins.
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Peptídeos , Proteínas , Estrutura Secundária de Proteína , Peptídeos/química , AminoácidosRESUMO
Propane (C3H8) is a widely used fuel gas. Metal-organic framework (MOF) physisorbents that are C3H8 selective offer the potential to significantly reduce the energy footprint for capturing C3H8 from natural gas, where C3H8 is typically present as a minor component. Here we report the C3H8 recovery performance of a previously unreported lonsdaleite, lon, topology MOF, a chiral metal-organic material, [Ni(S-IEDC)(bipy)(SCN)]n, CMOM-7. CMOM-7 was prepared from three low-cost precursors: Ni(SCN)2, S-indoline-2-carboxylic acid (S-IDECH), and 4,4'-bipyridine (bipy), and its structure was determined by single crystal X-ray crystallography. Pure gas adsorption isotherms revealed that CMOM-7 exhibited high C3H8 uptake (2.71 mmol g-1) at 0.05 bar, an indication of a higher affinity for C3H8 than both C2H6 and CH4. Dynamic column breakthrough experiments afforded high purity C3H8 capture from a gas mixture comprising C3H8/C2H6/CH4 (v/v/v = 5/10/85). Despite the dilute C3H8 stream, CMOM-7 registered a high dynamic uptake of C3H8 and a breakthrough time difference between C3H8 and C2H6 of 79.5 min g-1, superior to those of previous MOF physisorbents studied under the same flow rate. Analysis of crystallographic data and Grand Canonical Monte Carlo simulations provides insight into the two C3H8 binding sites in CMOM-7, both of which are driven by C-H···π and hydrogen bonding interactions.
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OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.
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Nefrite Lúpica , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Animais , Criança , Humanos , Camundongos , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine, and immune cells. Despite this, we and others have established tumor and stroma subtypes with prognostic significance. However, understanding of underlying signals driving distinct immune and stromal landscapes is still incomplete. Here we integrate 92 single cell RNA-seq samples from seven independent studies to build a reproducible PDAC atlas with a focus on tumor-TME interdependence. Patients with activated stroma are synonymous with higher myofibroblastic and immunogenic fibroblasts, and furthermore show increased M2-like macrophages and regulatory T-cells. Contrastingly, patients with 'normal' stroma show M1-like recruitment, elevated effector and exhausted T-cells. To aid interoperability of future studies, we provide a pretrained cell type classifier and an atlas of subtype-based signaling factors that we also validate in mouse data. Ultimately, this work leverages the heterogeneity among single-cell studies to create a comprehensive view of the orchestra of signaling interactions governing PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Microambiente Tumoral , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , FibroblastosRESUMO
The study was designed to determine whether urocortin 2 (Ucn2) gene transfer is as safe and effective as metformin in insulin-resistant mice. Four groups of insulin-resistant db/db mice and a nondiabetic group were studied: (1) metformin; (2) Ucn2 gene transfer; (3) metformin + Ucn2 gene transfer; (4) saline; and (5) nondiabetic mice. After completion of the 15-week protocol, glucose disposal was quantified, safety assessed, and gene expression documented. Ucn2 gene transfer was superior to metformin, providing reductions in fasting glucose and glycated hemoglobin and enhanced glucose tolerance. The combination of metformin + Ucn2 gene transfer provided no better glucose control than Ucn2 gene transfer alone and was not associated with hypoglycemia. Metformin alone, Ucn2 gene transfer alone, and metformin + Ucn2 gene transfer together reduced fatty infiltration of the liver. Serum alanine transaminase concentration was elevated in all db/db groups (vs. nondiabetic controls), but the metformin + Ucn2 gene transfer combined group had the lowest alanine transaminase levels. No group differences in fibrosis were detected. In a hepatoma cell line, activation of AMP kinase showed a rank order of combined metformin + Ucn2 peptide > Ucn2 peptide > metformin. We conclude (1) The combination of metformin + Ucn2 gene transfer does not result in hypoglycemia. (2) Ucn2 gene transfer alone provides superior glucose disposal versus metformin alone. (3) The combination of Ucn2 gene transfer and metformin is safe and has additive effects in reducing serum alanine transaminase concentration, activating AMP kinase activity, and increasing Ucn2 expression, but is no more efficacious than Ucn2 gene transfer alone in reducing hyperglycemia. These data indicate that Ucn2 gene transfer is more effective than metformin in the db/db model of insulin resistance and combined treatment with metformin + Ucn2 gene transfer appears to have favorable effects on liver function and Ucn2 expression.
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Hipoglicemia , Metformina , Camundongos , Animais , Glucose/metabolismo , Insulina/genética , Metformina/farmacologia , Urocortinas/genética , Urocortinas/farmacologia , Adenilato Quinase , Alanina TransaminaseRESUMO
OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.
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Infecções por Adenoviridae , Pneumonia Viral , Criança , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Infecções por Adenoviridae/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , AdenoviridaeRESUMO
BACKGROUND: The development of immune checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease. Unfortunately, ICIs are increasingly implicated in the development of autoimmune diseases. CASE SUMMARY: We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab, docetaxel, and cisplatin therapy who developed autoimmune polyendocrine syndrome type II (APS-2) including thyroiditis and type 1 diabetes mellitus and Crohn's disease (CD). He developed thirst, abdominal pain, and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab. Biochemistry confirmed APS-2 and thyrotoxicosis. He was commenced on an insulin infusion. However, his abdominal pain persisted. Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine. He was continued on insulin and mesalazine therapy. CONCLUSION: Immunotherapy can affect all kinds of organs. When clinical symptoms cannot be explained by a single disease, clinicians should consider the possibility of multisystem damage.
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The phase separation behavior of biomacromolecules plays a key role in the fields of biology and medicine. In this work, we gain a deep insight into how the primary and secondary structures govern and regulate the phase separation behavior of polypeptides. To this end, we synthesized a series of polypeptides with tailorable hydroxyl-containing side chains. The secondary structure of polypeptides can be modulated by the local chemical environment and content of side chains. Interestingly, these polypeptides with different helical contents exhibited upper critical solution temperature behavior with marked differences in the cloud point temperature (Tcp) and the width of hysteresis. The phase transition temperature is highly relevant to the content of secondary structure and interchain interactions of polypeptides. The aggregation/deaggregation and the transition of secondary structure are completely reversible during heating-cooling cycles. Much to our surprise, the recovery rate of the α-helical structure governs the width of hysteresis. This work establishes the structure-property relationship between the secondary structure and phase separation behavior of the polypeptide and delivers new insight into the rational design of peptide-based materials with tailor-made phase separation behavior.
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Ácido Glutâmico , Peptídeos , Peptídeos/química , Estrutura Secundária de Proteína , Temperatura , Temperatura de TransiçãoRESUMO
Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Methods:Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Results:Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. Conclusions:The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.
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BACKGROUND: Ovarian cancer (OV) is a severe and common gynecological disease. Ferroptosis can regulate the progression and invasion of tumors. The immune system is a decisive factor in cancer. The present study aimed to use gene expression data to establish an immunity and ferroptosis-related risk score model as a prognostic biomarker to predict clinical outcomes and the immune microenvironment of OV. METHODS: Common gene expression data were searched from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Immunity-related genes and ferroptosis-related genes were searched and downloaded from the ImmPort and FerrDb databases, followed by the analysis of the overall survival of patients with OV and the identification of genes. Subsequently, the status of the infiltration of immune cells and the association between immune checkpoints and risk score were assessed. RESULTS: A total of 10 prognostic genes (C5AR1, GZMB, IGF2R, ISG20, PPP3CA, STAT1, TRIM27, TSHR, RB1, and EGFR) were included in the immunity and ferroptosis-related risk score model. The high-risk group had a higher infiltration of immune cells. The risk score, an independent prognostic feature of OV was negatively associated with each immune checkpoint. The risk score may thus help to predict the response to immunotherapy. CONCLUSIONS: The immunity and ferroptosis-related risk score model is an independent prognostic factor for OV. The established risk score may help to predict the response of patients to immunotherapy.
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Ferroptose , Neoplasias Ovarianas , Humanos , Feminino , Ferroptose/genética , Neoplasias Ovarianas/genética , Imunoterapia , Microambiente Tumoral/genéticaRESUMO
C50 carotenoids, as unique bioactive molecules, have many biological properties, including antioxidant, anticancer, and antibacterial activity, and have a wide range of potential uses in the food, cosmetic, and biomedical industries. The majority of C50 carotenoids are produced by the sterile fermentation of halophilic archaea. This study aims to look at more cost-effective and manageable ways of producing C50 carotenoids. The basic medium, carbon source supplementation, and optimal culture conditions for Halorubrum sp. HRM-150 C50 carotenoids production by open fermentation were examined in this work. The results indicated that Halorubrum sp. HRM-150 grown in natural brine medium grew faster than artificial brine medium. The addition of glucose, sucrose, and lactose (10 g/L) enhanced both biomass and carotenoids productivity, with the highest level reaching 4.53 ± 0.32 µg/mL when glucose was added. According to the findings of orthogonal studies based on the OD600 and carotenoids productivity, the best conditions for open fermentation were salinity 20-25%, rotation speed 150-200 rpm, and pH 7.0-8.2. The up-scaled open fermentation was carried out in a 7 L medium under optimum culture conditions. At 96 h, the OD600 and carotenoids productivity were 9.86 ± 0.51 (dry weight 10.40 ± 1.27 g/L) and 7.31 ± 0.65 µg/mL (701.40 ± 21.51 µg/g dry weight, respectively). When amplified with both universal bacterial primer and archaeal primer in the open fermentation, Halorubrum remained the dominating species, indicating that contamination was kept within an acceptable level. To summarize, open fermentation of Halorubrum is a promising method for producing C50 carotenoids.
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Carotenoides , Halorubrum , Carotenoides/metabolismo , Halorubrum/química , Halorubrum/metabolismo , Fermentação , Sais , Meios de Cultura/químicaRESUMO
Histone deacetylase 6 (HDAC6) is the only member of the HDAC family that resides primarily in the cytoplasm with two catalytic domains and a ubiquitin-binding domain. HDAC6 is highly expressed in various solid tumors and participates in a wide range of biological activities, including hormone receptors, the p53 signaling pathway, and the kinase cascade signaling pathway due to its unique structural foundation and abundant substrate types. Additionally, HDAC6 can function as an oncogenic factor in solid tumors, boosting tumor cell proliferation, invasion and metastasis, drug resistance, stemness, and lowering tumor cell immunogenicity, so assisting in carcinogenesis. Pan-HDAC inhibitors for cancer prevention are associated with potential cardiotoxicity in clinical investigations. It's interesting that HDAC6 silencing didn't cause any significant harm to normal cells. Currently, the use of HDAC6 specific inhibitors, individually or in combination, is among the most promising therapies in solid tumors. This review's objective is to give a general overview of the structure, biological functions, and mechanism of HDAC6 in solid tumor cells and in the immunological milieu and discuss the preclinical and clinical trials of selective HDAC6 inhibitors. These endeavors highlight that targeting HDAC6 could effectively kill tumor cells and enhance patients' immunity during solid tumor therapy.
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Neoplasias , Humanos , Proliferação de Células , Desacetilase 6 de Histona/metabolismo , Desacetilase 6 de Histona/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
OBJECTIVE: To screen miRNAs that could simultaneously regulate osteo/odontogenic differentiation of multiple stem cells, including dental pulp stem cells (DPSCs), stem cells from the apical papilla (SCAPs) and periodontal ligament stem cells (PDLSCs). METHODS: Differentially expressed miRNAs analysis on three miRNA microarrays data of dental stem cells undergoing osteo/odontogenic differentiation (GSE138180, GSE154466 and GSE159508) was performed, and miR-146a-5p were identified by bioinformatic prediction, dual-luciferase reporter assay and quantitative real-time polymerase chain reaction (PCR). In addition, differentially expressed genes between miR-146a-5p overexpressed group and control group (GSE79341) were applied for KEGG pathways enrichment analysis. RESULTS: MiR-146a-5p expression increased in the osteo/odontogenic differentiation of DPSCs, SCAPs and PDLSCs. Tumour necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) was identified as the target gene of miR-146a-5p. Furthermore, miR-146a-5p could influence the NF-Kappa B signalling pathway. CONCLUSION: This study suggests that miR-146a-5p could promote differentiation in multiple dental stem cells through the NF-Kappa B signalling pathway by targeting TRAF6.
Assuntos
MicroRNAs , NF-kappa B , NF-kappa B/genética , Fator 6 Associado a Receptor de TNF/genética , Transdução de Sinais/genética , Diferenciação Celular/genética , Células-Tronco , MicroRNAs/genéticaRESUMO
Introduction: The function of the C6orf120 gene, which encodes an N-glycosylated protein, remains unknown. The study was performed to characterize the utility of the C6orf120 gene in carbon tetrachloride-induced acute liver injury and to elucidate the potential underlying mechanisms by establishing a C6orf120 gene-knockout (C6orf120-/-) rat model. Material and methods: C6orf120-/- and wild-type (WT) rats were intraperitoneally administered with CCl4 (1 : 1 v/v in olive oil, 2 µl/g). Rats were sacrificed 24 h after CCl4 administration. Liver tissues were collected for H&E, IHC, qRT-PCR, and Western blot analysis. Results: C6orf120 gene deficiency may be vulnerable to CCl4-induced acute liver injury in rats as indicated by the high levels of alanine aminotransferase (WT: 388.7 ±55.96 vs. C6orf120-/-: 915.9 ±118.8, p < 0.001) and greater degree of pathological damage. Quantitative reverse transcription polymerase chain reaction showed that the mRNA levels of inflammation-associated cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, in liver tissues were increased in C6orf120-/- rats compared with those in WT rats. Moreover, western blot showed that the protein expression of cytokines nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain containing 3 (NLRP3), caspase-1, IL-1ß, nuclear factor-κB, c-Jun N-terminal kinases, and Bax were increased in C6orf120-/- rats compared with those in WT rats. Conclusions: C6orf120-/- rats were susceptible to CCl4-induced liver injury, which may be related to NLRP3 inflammasome and JNK signaling pathway activation.