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Shuotheriids are Jurassic mammaliaforms that possess pseudotribosphenic teeth in which a pseudotalonid is anterior to the trigonid in the lower molar, contrasting with the tribosphenic pattern of therian mammals (placentals, marsupials and kin) in which the talonid is posterior to the trigonid1-4. The origin of the pseudotribosphenic teeth remains unclear, obscuring our perception of shuotheriid affinities and the early evolution of mammaliaforms1,5-9. Here we report a new Jurassic shuotheriid represented by two skeletal specimens. Their complete pseudotribosphenic dentitions allow reidentification of dental structures using serial homology and the tooth occlusal relationship. Contrary to the conventional view1,2,6,10,11, our findings show that dental structures of shuotheriids can be homologized to those of docodontans and partly support homologous statements for some dental structures between docodontans and other mammaliaforms6,12. The phylogenetic analysis based on new evidence removes shuotheriids from the tribosphenic ausktribosphenids (including monotremes) and clusters them with docodontans to form a new clade, Docodontiformes, that is characterized by pseudotribosphenic features. In the phylogeny, docodontiforms and 'holotherians' (Kuehneotherium, monotremes and therians)13 evolve independently from a Morganucodon-like ancestor with triconodont molars by labio-lingual widening their posterior teeth for more efficient food processing. The pseudotribosphenic pattern passed a cusp semitriangulation stage9, whereas the tribosphenic pattern and its precursor went through a stage of cusp triangulation. The two different processes resulted in complex tooth structures and occlusal patterns that elucidate the earliest diversification of mammaliaforms.
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Evolução Biológica , Fósseis , Mamíferos , Dente , Animais , Eutérios/anatomia & histologia , Mamíferos/anatomia & histologia , Mamíferos/classificação , Mamíferos/fisiologia , Marsupiais/anatomia & histologia , Dente Molar/anatomia & histologia , Dente Molar/fisiologia , Filogenia , Dente/anatomia & histologia , Dente/fisiologia , MastigaçãoRESUMO
OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.
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Carcinoma Hepatocelular , Vírus da Hepatite B , Neoplasias Hepáticas , Integração Viral , Carcinoma Hepatocelular/virologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/patologia , Vírus da Hepatite B/genética , Humanos , Integração Viral/genética , Animais , Camundongos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Sequenciamento Completo do Genoma , Variações do Número de Cópias de DNA , IdosoRESUMO
Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.
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Química Farmacêutica , Animais , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteólise , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The objective of this study was to determine the role and regulatory mechanism of miR-380 in cholangiocarcinoma. METHODS: The TargetScan database and a dual-luciferase reporter assay system were used to determine if LIS1 was a target gene of miR-380. The Cell Counting Kit 8 assay, flow cytometry, and Transwell assay were used to detect the effects of miR-380 and LIS1 on the proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. Western blotting was used to determine the effect of miR-380 on MMP-2/p-AKT. Immunohistochemistry detected the regulatory effect of miR-380 on the expression of MMP-2/p-AKT/LIS1. RESULTS: Expression of miR-380 in cholangiocarcinoma was decreased but expression of LIS1 was increased. LIS1 was confirmed to be a target gene of miR-380. Transfection with miR-380 mimics inhibited the proliferation, S-phase arrest, and invasion of HCCC-9810/HuCCT1/QBC939 cells, and LIS1 reversed these inhibitory effects. miR-380 inhibitor promoted proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. si-LIS1 salvaged the promotive effect of miR-380 inhibitor. Overexpression of miR-380 inhibited expression of MMP-2/p-AKT/LIS1, but miR-380 inhibitor promoted their expression. CONCLUSION: An imbalance of miR-380 expression is closely related to cholangiocarcinoma, and overexpression of miR-380 inhibits the expression of MMP-2/p-AKT by directly targeting LIS1.
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Fabrication of robust isolated atom catalysts has been a research hotspot in the environment catalysis field for the removal of various contaminants, but there are still challenges in improving the reactivity and stability. Herein, through facile doping alkali metals in Pt catalyst on zirconia (Pt-Na/ZrO2), the atomically dispersed Ptδ+-O(OH)x- associated with alkali metal via oxygen bridge was successfully fabricated. This novel catalyst presented remarkably higher CO and hydrocarbon (HCs: C3H8, C7H8, C3H6, and CH4) oxidation activity than its counterpart (Pt/ZrO2). Systematically direct and solid evidence from experiments and density functional theory calculations demonstrated that the fabricated electron-rich Ptδ+-O(OH)x- related to Na species rather than the original Ptδ+-O(OH)x-, serving as the catalytically active species, can readily react with CO adsorbed on Ptδ+ to produce CO2 with significantly decreasing energy barrier in the rate-determining step from 1.97 to 0.93 eV. Additionally, owing to the strongly adsorbed and activated water by Na species, those fabricated single-site Ptδ+-O(OH)x- linked by Na species could be easily regenerated during the oxidation reaction, thus considerably boosting its oxidation reactivity and durability. Such facile construction of the alkali ion-linked active hydroxyl group was also realized by Li and K modification which could guide to the design of efficient catalysts for the removal of CO and HCs from industrial exhaust.
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Oxirredução , Zircônio , Catálise , Zircônio/química , Álcalis/química , Platina/químicaRESUMO
As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 µM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.
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Receptor do Peptídeo Semelhante ao Glucagon 1 , Tiofenos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Animais , Tiofenos/farmacologia , Tiofenos/química , Tiofenos/síntese química , Regulação Alostérica/efeitos dos fármacos , Camundongos , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Insulina/metabolismo , Fosfato de Sitagliptina/farmacologia , Fosfato de Sitagliptina/síntese química , Fosfato de Sitagliptina/químicaRESUMO
BACKGROUND: Relapse of infantile hemangiomas after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. OBJECTIVE: The objective of this study was to determine the optimal time to discontinue propranolol treatment for infantile hemangiomas. METHODS: A prospective study conducted at a tertiary referral center. RESULTS: Compared to withdrawal after 1-month maintenance treatment, withdrawal after 3-month maintenance, corresponding achieving maximum regression of infantile hemangiomas, was associated with a lower major relapse rate (P = .041). The relapse (P = .055) and adverse event rates (P = .154) between the 2 withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P = .396), major relapse (P = .963), and adverse event rates (P = .458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-month maintenance and age >13 months (area under the receiver operating characteristic curve = 0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-month maintenance (area under the receiver operating characteristic curve = 0.610). LIMITATIONS: The limitations of this study are nonrandomization and single-center design. CONCLUSIONS: The optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.
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Hemangioma Capilar , Hemangioma , Neoplasias Cutâneas , Humanos , Lactente , Propranolol/efeitos adversos , Antagonistas Adrenérgicos beta/efeitos adversos , Estudos Prospectivos , Hemangioma/tratamento farmacológico , Resultado do Tratamento , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/induzido quimicamente , Administração Oral , RecidivaRESUMO
A noise attenuation performance test was conducted on earmuffs using a recoilless weapon launch platform in a confined space, along with two acoustic test fixtures (ATFs). The overpressure at the ATF's effective tympanic membrane comprised direct sound at 185 dB sound pressure level (SPL) and reflected sound at 179 dB SPL. Wearing earmuffs reduced these peaks to 162 dB SPL and 169 dB SPL, respectively. The reflected sound from walls was defined as delayed sound. An analytical model for earmuff noise attenuation simulated their effectiveness. The simulation revealed that when the earmuffs attenuated delayed sound, the acoustic impedance of acoustic leakage and the acoustic impedance of the earmuff material decreased by 96% and 50%, respectively. The negative overpressure zone between direct and delayed sound decreased the earmuffs' fit against the ATF. Additionally, the enclosed volume between the earmuff and the ear canal decreased by 12%. After the installation of bandages on the earmuffs, the overpressure peak of delayed sound was reduced by 5 dB. Furthermore, the acoustic impedance of the earmuff's sound leakage path and the acoustic impedance of the earmuff material deformation path increased by 100% and 809%, respectively.
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Acústica , Dispositivos de Proteção das Orelhas , Pressão , Humanos , Desenho de Equipamento , Ruído , Som , Armas de Fogo , Adulto , Masculino , Fatores de Tempo , Modelos TeóricosRESUMO
As video platforms such as Douyin, also known as TikTok's Chinese version, continue to grow, there is an increasing interest in the study of green advertising videos to understand their audiovisual features and their impact on audience engagement. In this research, we specifically focus on green advertising within the automotive industry. Drawing on literature from sustainability, green advertising, and communication studies, we identified seven audiovisual aspects and three persuasive strategies pertinent to green automotive advertising videos. Utilizing a mixed-methods video analysis framework, we analyzed a dataset of 2,553 green automotive advertising videos on Douyin over three years from 15 June 2020 to 15 June 2023. These videos exhibited higher loudness, a faster pace, and longer durations compared to their non-green counterparts. We categorized three distinct types of green advertising videos on Douyin and established that specific audiovisual features and persuasive strategies are significantly correlated with audience engagement levels. This study not only delineates the audiovisual characteristics of green automotive advertising in China's digital space but also contributes to the broader discourse on sustainable marketing practices on social networks like TikTok. The findings extend image-centric research to video content and provide marketers with data-driven insights for crafting effective content creation strategies on Douyin.
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Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for protein synthesis. Recent studies have yielded new insights into their diverse physiological and pathological roles in health and disease. Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality globally. An increasing number of clinical studies have demonstrated that high levels of circulating BCAAs are associated with an increased risk of CVDs. Animal studies have provided preliminary evidence linking BCAA intake and metabolism with cardiovascular diseases. Despite these insights, the causal relationship between BCAA metabolism and CVD remains poorly established, and the underlying mechanisms remain incompletely understood. Here, we aim to provide an update on the current understanding of the roles of BCAAs and their metabolism in the development and progression of various CVDs. We also discuss the potential strategies targeting BCAA nutrition and metabolism for the prevention and treatment of CVDs.
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Aminoácidos de Cadeia Ramificada , Doenças Cardiovasculares , Animais , Aminoácidos de Cadeia Ramificada/metabolismo , Isoleucina/metabolismo , Leucina/metabolismo , Valina/metabolismoRESUMO
Background: Angiogenesis of the tumor microenvironment (TME) can promote the proliferation and metastases of colon cancer (CC). However, there is a lack of bioinformatics analysis to comprehensively clarify the molecular characteristics, immune interaction characteristics and predictive values of angiogenesis characteristics in CC patients. This study aimed to perform a comprehensive elucidation of the correlation between angiogenesis and CC for the purpose of improving the clinical management of CC. Methods: Angiogenesis-associated genes (AAGs) were evaluated in the population of CC patients from the Cancer Genome Atlas database and Gene Expression Omnibus dataset. The expression, prognostic role, and immune cell infiltration of AAGs were assessed first. And then we established the AAGs score to further explore the prognosis and treatment response of angiogenesis characteristics in individual patient. Results: Totally, we identified two different molecular subtypes of angiogenesis, and there was a significant difference in the background of genome, expression profiles, prognosis, and characteristics of TME between two subtypes. And the AAGs score was independently associated with over survival in CC patients, the prognostic value was significant and confirmed in the entire cohort. And we also constructed a nomogram based on the risk score and clinical parameters to maximize the predictive ability of the risk score. Additionally, the AAGs score was significantly correlated with the tumor mutation burden score, cancer stem cell score and drug sensitivity. Conclusions: Our study elucidated the role of angiogenesis characteristics in CC and the AAGs score could help clinicians plan for individual management with chemotherapy agents and promote the development of immunotherapy in CC. Prospective studies need to be conducted to further confirm our findings.
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Purpose: To compare the dietary inflammatory index (DII), triglyceride glucose index (TyG), waist triglyceride index (WTI), and body mass index (BMI) in predicting the survival of chronic kidney disease (CKD). Methodology: Inclusion of 23,099 participants from the NHANES database who met specific criteria. Baseline was established using quartiles of DII index. The relationship between DII index, WTI index, TyG index, and BMI index with mortality rate in CKD patients was evaluated using Kaplan-Meier curves. Univariate and multivariate COX regression risk models were used to study the relationship between DII index, WTI index, and TyG index with mortality risk in CKD patients. Stratification of eGFR by age and gender was conducted to investigate the association between DII index, WTI index, and TyG index with mortality risk in CKD patients. Restricted cubic spline analysis was used to study the correlation between DII index, WTI index, and TyG index with mortality risk in CKD patients. Results: The incidence of CKD increased with the increase of DII index, WTI index and TyG index. After multivariable adjustment, the fourth quartile of DII index, TyG index and WTI index showed the highest risk for CKD [DII: hazard ratio (HR) 1.36, 95% confidential interval (CI) (1.23-1.51); TyG: HR 1.21; 95% CI (1.07-1.37); WTI: HR 1.29; 95% CI (1.13-1.46)]. There was no difference in the risk of developing CKD between the obese group (BMI ≥24 kg/m2) and the normal weight group (P>0.05). Conclusion: This study has identified a significant association between elevated DII index, WTI index, and TyG index with the risk of CKD. Furthermore, the DII index demonstrated superior prognostic capability in predicting CKD compared to other indicators.
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Índice de Massa Corporal , Inflamação , Inquéritos Nutricionais , Insuficiência Renal Crônica , Triglicerídeos , Humanos , Masculino , Feminino , Insuficiência Renal Crônica/sangue , Pessoa de Meia-Idade , Triglicerídeos/sangue , Adulto , Inflamação/sangue , Estudos de Coortes , Glicemia/análise , Glicemia/metabolismo , Fatores de Risco , Dieta , Idoso , Circunferência da Cintura , PrognósticoRESUMO
The effects of calcium phosphate (CaP) materials on macrophage polarization state vary with their physicochemical properties. The study aims to elucidate the impact of phosphate ion-mediated energy metabolism on M2 macrophage polarization and the corresponding regulatory mechanism. The phosphate ions released from CaP ceramic as bioenergetic factor is identified; its concentration is closely associated with the polarized state. After being taken up by the sodium-dependent phosphate transporter 1, extracellular phosphate ions produce energy via oxidative phosphorylation by facilitating tricarboxylic acid flux, thereby contributing to M2 macrophage polarization. Further mechanistic analysis reveals that the elevation of the bioenergetic basis can drive macrophage M2 polarization via the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) axis. Another regulatory effect is that of the adenosine triphosphate (ATP), a signaling molecule. Intracellular ATP is released into the extracellular space and degraded to adenosine, which serves as a signaling molecule through the A2b adenosine receptor to activate the cyclic adenosine monophosphate (cAMP) pathway, thereby promoting M2 macrophage polarization. Overall, these findings may transform the existing knowledge on cell metabolism and energy homeostasis from bystanders to pivotal factors guiding M2 macrophage polarization and have implications for the future design of biomimetic CaP scaffolds.
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Fosfatos de Cálcio , Macrófagos , Fosfatos , Fosfatos/metabolismo , Macrófagos/metabolismo , Metabolismo Energético , Transdução de Sinais , Trifosfato de Adenosina/metabolismoRESUMO
Glutamine transporters are integral to the metabolism of glutamine in both healthy tissues and cancerous cells, playing a pivotal role in maintaining amino acid balance, synthesizing biomolecules, and regulating redox equilibrium. Their critical functions in cellular metabolism make them promising targets for oncological therapies. Recent years have witnessed substantial progress in the field of glutamine transporters, marked by breakthroughs in understanding of their protein structures and the discovery of novel inhibitors, prodrugs, and radiotracers. This review provides a comprehensive update on the latest advancements in modulators targeting the glutamine transporter, with special attention given to LAT1 and ASCT2. It also discusses innovative approaches in drug design aimed at these transporters.
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Aminoácidos , Glutamina , Glutamina/metabolismo , Proteínas de Membrana TransportadorasRESUMO
BACKGROUND: Interstitial lung disease (ILD) is the most widespread and fatal pulmonary complication of rheumatoid arthritis (RA). Existing knowledge on the prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is inconclusive. Therefore, we designed this review to address this gap. MATERIALS AND METHODS: To find relevant observational studies discussing the prevalence and/or risk factors of RA-ILD, EMBASE, Web of Science, PubMed, and the Cochrane Library were explored. The pooled odds ratios (ORs) / hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with a fixed/ random effects model. While subgroup analysis, meta-regression analysis and sensitivity analysis were carried out to determine the sources of heterogeneity, the I2 statistic was utilized to assess between-studies heterogeneity. Funnel plots and Egger's test were employed to assess publication bias. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, our review was conducted. RESULTS: A total of 56 studies with 11,851 RA-ILD patients were included in this meta-analysis. The pooled prevalence of RA-ILD was 18.7% (95% CI 15.8-21.6) with significant heterogeneity (I2 = 96.4%). The prevalence of RA-ILD was found to be more likely as a result of several identified factors, including male sex (ORs = 1.92 95% CI 1.70-2.16), older age (WMDs = 6.89, 95% CI 3.10-10.67), having a smoking history (ORs =1.91, 95% CI 1.48-2.47), pulmonary comorbidities predicted (HRs = 2.08, 95% CI 1.89-2.30), longer RA duration (ORs = 1.03, 95% CI 1.01-1.05), older age of RA onset (WMDs =4.46, 95% CI 0.63-8.29), positive RF (HRs = 1.15, 95%CI 0.75-1.77; ORs = 2.11, 95%CI 1.65-2.68), positive ACPA (ORs = 2.11, 95%CI 1.65-2.68), higher ESR (ORs = 1.008, 95%CI 1.002-1.014), moderate and high DAS28 (≥3.2) (ORs = 1.87, 95%CI 1.36-2.58), rheumatoid nodules (ORs = 1.87, 95% CI 1.18-2.98), LEF use (ORs = 1.42, 95%CI 1.08-1.87) and steroid use (HRs= 1.70, 1.13-2.55). The use of biological agents was a protective factor (HRs = 0.77, 95% CI 0.69-0.87). CONCLUSION(S): The pooled prevalence of RA-ILD in our study was approximately 18.7%. Furthermore, we identified 13 risk factors for RA-ILD, including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥3.2), rheumatoid nodules, LEF use and steroid use. Additionally, biological agents use was a protective factor.
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Artrite Reumatoide , Doenças Pulmonares Intersticiais , Nódulo Reumatoide , Humanos , Masculino , Nódulo Reumatoide/complicações , Prevalência , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Fatores de Risco , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Pulmonares Intersticiais/etiologia , EsteroidesRESUMO
In the face of escalating metabolic disease prevalence, largely driven by modern lifestyle factors, this study addresses the critical need for novel therapeutic approaches. We have identified the sodium-coupled citrate transporter (NaCT or SLC13A5) as a target for intervention. Utilizing rational drug design, we developed a new class of SLC13A5 inhibitors, anchored by the hydroxysuccinic acid scaffold, refining the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3's efficacy in reducing triglyceride levels in OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior pharmacokinetic properties and effectively lowered triglyceride and total cholesterol levels in diverse mouse models (PCN-stimulated and starvation-induced), without detectable toxicity. These findings not only spotlight LBA-3 as a promising candidate for hyperlipidemia treatment but also exemplify the potential of targeted molecular design in advancing metabolic disorder therapeutics.
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Hiperlipidemias , Humanos , Animais , Camundongos , Hiperlipidemias/tratamento farmacológico , Células Hep G2 , Relação Estrutura-Atividade , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Masculino , Hipolipemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/uso terapêutico , Hipolipemiantes/farmacocinética , Descoberta de Drogas , Camundongos Endogâmicos C57BL , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Desenho de FármacosRESUMO
Cushing's syndrome (CS) is a complex disorder characterized by the excessive secretion of cortisol, with Cushing's disease (CD), particularly associated with pituitary tumors, exhibiting heightened morbidity and mortality. Although transsphenoidal pituitary surgery (TSS) stands as the primary treatment for CD, there is a crucial need to optimize patient prognosis. Current medical therapy serves as an adjunctive measure due to its unsatisfactory efficacy and unpredictable side effects. In this comprehensive review, we delve into recent advances in understanding the pathogenesis of CS and explore therapeutic options by conducting a critical analysis of potential drug targets and candidates. Additionally, we provide an overview of the design strategy employed in previously reported candidates, along with a summary of structure-activity relationship (SAR) analyses and their biological efficacy. This review aims to contribute valuable insights to the evolving landscape of CS research, shedding light on potential avenues for therapeutic development.
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Síndrome de Cushing , Hipersecreção Hipofisária de ACTH , Humanos , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/etiologia , Hipersecreção Hipofisária de ACTH/complicações , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Desenvolvimento de Medicamentos , Hidrocortisona/uso terapêuticoRESUMO
Noble metal nanoparticle (NMP)-based composite substrates have garnered significant attention as a highly promising technique for surface-enhanced Raman scattering (SERS) in diverse scientific disciplines because their remarkable ability to amplify and functionalize Raman signals has positioned them as valuable tools for molecular detection. However, optimizing the size and distribution of NMPs has not received sufficient emphasis because of challenges associated with the precise control of deposition and the modulation of reducing rates during growth. In this research, we achieved the optimized size and spatial patterns of AgNWs on electrospun poly(vinylidene fluoride) (PVDF) nanofibers by utilizing a polydopamine (PDA) layer as a mild and controllable reduction mediator, by which the size and density of the AgNWs could be relatively precisely manipulated, achieving a dense distribution of effective "hot spots". On the other hand, harnessing the inherent piezoelectric properties of the electrospun PVDF nanofibers further boosted the LSPR effect during the SERS test, forming a flexible dual-enhancing composite SERS substrate with excellent sensitivity. In addition to addressing structural aspects, exploiting synergistic systems capable of transferring external energy or forces to enhance the SERS performances presents a compelling avenue to broaden the practical applications of SERS. The dual-enhanced substrate achieved an exceptional enhancement factor (EF) of 1.05 × 108 and a low detection limit (LOD) of 10-10 M during the SERS test. This study focuses on integrating NMPs with electrospun piezoelectric polymer nanofibers to develop a dual-enhancing SERS substrate with excellent sensitivity and practicality. The findings provide valuable insights into controllably depositing NMPs on electrospun polymer fibers and hold significant implications for the development of highly sensitive and practical SERS substrates across various applications.
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Polímeros de Fluorcarboneto , Nanopartículas Metálicas , Nanofibras , Polivinil , Nanofibras/química , Nanopartículas Metálicas/química , Prata/química , PolímerosRESUMO
Objective: To investigate the efficacy and safety of Shengjiang powder as a treatment for DKD. Methods: A comprehensive search was performed in eight databases from their inception to December 30, 2023, to identify relevant RCTs. The inclusion criteria were diagnosis of DKD and intervention including TCM that contained Shengjiang powder. Two researchers independently conducted literature screening and data extraction, utilizing the Rob2 tool and GRADE to assess the quality of the RCTs. Meta-analysis was carried out using RevMan 5.4.1 and Stata 15.0. Results: As a result of the search, 23 RCTs comprising 1,682 patients. The interventions resulted in significant reductions in all the assessed indicators: 24-h urinary protein, UAER, mALB, BUN, Scr, FBG, 2hPG, HbA1c, total cholesterol, and Triglycerides. Together the results showed that Shengjiang powder, in conjunction with conventional therapy, is an effective treatment of DKD. Subgroup analyses, considering duration, stage, blood glucose control levels, baseline blood glucose levels, and baseline Scr levels indicated that shorter duration treatment had a greater effect on UAER, 2hPG, and HbA1c. Additionally, Shengjiang powder was more effective in reducing 24-h urinary protein, Scr, and 2hPG in stage IV patients compared to corresponding values at other stages. However, with respect to FBG, the treatment was more effective in stage II/III. Shengjiang powder also, reduced Scr levels significantly in patients with higher baseline Scr and reduced urinary protein excretion with stricter blood glucose control. The interventions had additional lipid-regulating effects in cases with looser blood glucose control and led to a remarkable reduction in BUN and Scr levels in patients with FBG > 11.1 mmol/L. Conclusion: Shengjiang powder may supplement conventional therapy, thus benefiting DKD patients in terms of reducing urinary protein, stabilizing kidney function, and improving blood glucose and lipid metabolism. Considering the significant heterogeneity among studies and limited quality of some reports, our conclusions need to be further verified through analyses utilizing larger, multi-center samples of higher quality. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024490795.
Assuntos
Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Humanos , Glicemia/análise , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Medicina Tradicional Chinesa/métodos , Pós , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Repair of large cranial complex traumas in children is difficult. Notably, children have poorer underlying conditions than adults and are frailer under trauma. In addition, children have more limited treatment options, leading to the need to consider long-term functional and aesthetic outcomes. The present report describes the case of a 2-year-old child weighing 9 kg who experienced a skull fracture with encephalocele after a car accident and had a poor underlying condition. An artificial dura mater combined with bone cement was used to repair the skull, and then a free latissimus dorsi muscle flap (LDMF) combined with a split-thickness skin graft (STSG) was used to cover the wound, allowing the child to overcome the life-threatening situation as soon as possible with a satisfactory outcome. LDMF combined with STSG is an ideal option in repairing head wounds in children. Preoperative imaging and postoperative care also serve an important role in the success of the operation. When the situation is critical, multidisciplinary team treatment can guarantee the safety of the child.