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Miniaturized and portable on-chip spectrometers have been widely explored to facilitate many applications including chemical analysis, environmental monitoring, medical diagnostics, and astronomical observations. However, the optical spectra of micro-spectrometers are mostly within the visible range. Here, we develop high-performance short-wave infrared (SWIR) micro-spectrometers through the integration of wafer-scale uniform lead sulfide (PbS) thin films with an on-chip Fabry-Perot filter array. The optoelectronic performance of PbS-based detectors could be markedly improved through the optimization of chemical bath deposition (CBD) conditions. The high-sensitivity PbS detectors based on the Fabry-Perot filter array demonstrate chemical analysis application.
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Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
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The intestinal epithelium is an important gatekeeper of the human body by forming a barrier for the luminal content of the intestine. The barrier function is regulated by a complex crosstalk between different cell types, including cells from the enteric nervous system (ENS). ENS is considered to influence gastrointestinal processes and functions, but its direct effect on epithelial barrier function remains to be confirmed. To investigate the effect of nerve cells on the gut barrier function, an in vitro co-culture system was established in which T84 intestinal epithelial cells and SH-SY5Y nerve cells were seeded in ratios of 29:1 and 14:1. When the epithelial barrier was disrupted with the calcium ionophores A23187, we found that nerve cells exert a protective effect on A23187-induced disruption and that this protective effect is nerve cell concentration-dependent. This was demonstrated by rescuing effects on transepithelial electrical resistance (TEER) and upregulation of tight junction (TJ) protein expression. Furthermore, we studied whether similar rescuing effects could be achieved with the human milk oligosaccharides (hMOs) 2'-fucosyllactose (2'-FL) and 3-fucosyllactose (3-FL). Our results illustrate that in the presence of nerve cells 2'-FL and 3-FL do not have any additional rescuing effects, but that these hMOs can substitute the rescuing effects of nerve cells in the absence of nerve cells. Meanwhile, 2'-FL and 3-FL show different regulation effects on TJ expression. These findings provide valuable insights into potential therapeutic strategies for maintaining intestinal barrier integrity.
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In sodium-ion pouch batteries based on hard carbon, an additional source of active sodium significantly enhances the battery's initial coulombic efficiency and compensates for the loss of active sodium ions during cycling. This study investigates the interaction between metallic sodium with carbon materials and develops a composite powder material of sodium-rich lithium-aluminum using a multi-alloy grafting strategy, to replenish the initial loss of active sodium in the hard carbon materials. To enhance the stability and utilization of this highly active sodium source, a novel slurry system based on polyethylene oxide (PEO) as a binder and dimethyl carbonate (DMC) as a solvent is introduced. Furthermore, this study designs a hard carbon composite electrode structure with a stable layer and sacrificial layer (NPH), which not only accommodates current battery processing environments but also demonstrates excellent potential in practical applications. Ultimately, the soft-packed sodium-ion battery consists of NPH electrodes with composite sodium ferric pyrophosphate (NFPP) and demonstrates excellent initial coulombic efficiency (91%) and ultra-high energy density (205 Wh kg-1). These results indicate significant technological and application implications for future energy storage.
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OBJECTIVES: The type of ligamentous tear and the degree of knee laxity have important guiding significance for the diagnosis and management of anterior cruciate ligament (ACL) tears. Instrumental measurement is necessary for ACL tears since physical examination and magnetic resonance imaging (MRI) cannot provide an objective and quantitative assessment of knee laxity. This study aimed to compare the application of a novel knee arthrometer and simultaneous stress radiography in differentiating between complete and partial acute ACL tears, and further assess the correlation between the two measurements. METHODS: A total of 106 patients with complete acute ACL tears and 52 patients with partial acute ACL tears were included in the study. Preoperative arthrometry and simultaneous stress radiography were performed using the Ligs arthrometer at 90, 120, and 150 N to assess side-to-side difference (SSD) in anterior knee laxity. The optimal threshold was determined using the receiver operating characteristic (ROC) curve. The area under the ROC curve (AUC) was used to assess the diagnostic value of the measurement. Pearson's correlation coefficient was used to assess the correlation between the two measurements. RESULTS: The optimal differential SSD thresholds in the Ligs arthrometer were 2.7 mm at 90 N, 3.8 mm at 120 N, and 4.6 mm at 150 N. Similarly, the optimal differential SSD thresholds in simultaneous stress radiography were 3.8 mm at 90 N, 5.1 mm at 120 N, and 5.6 mm at 150 N. The AUC analysis revealed that the Ligs arthrometer was fairly informative at 90 N (AUC = 0.851), 120 N (AUC = 0.878), and 150 N (AUC = 0.884), and simultaneous stress radiography was highly informative at 90 N (AUC = 0.910), 120 N (AUC = 0.925), and 150 N (AUC = 0.948). Moreover, the AUC of the combined measurements was 0.914 at 90 N, 0.931 at 120 N, and 0.951 at 150 N. A significantly strong correlation was found between the two measurements at 90 N (r = 0.743, p < 0.001), 120 N (r = 0.802, p < 0.001), and 150 N (r = 0.823, p < 0.001). CONCLUSIONS: The Ligs arthrometer and simultaneous stress radiography proved to be valid diagnostic tools to differentiate between complete and partial acute ACL tears, with a strong correlation between the two measurements in SSD values. Compared with single instrumental measurement, the combination of the two measurements can further improve the diagnostic value in this regard.
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BACKGROUND: Microvascular infiltration (MVI) before liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is associated with postoperative tumor recurrence and survival. MVI is mainly assessed by pathological analysis of tissue samples, which is invasive and heterogeneous. PET/computed tomography (PET/CT) with 18F-labeled fluorodeoxyglucose (18F-FDG) as a tracer has been widely used in the examination of malignant tumors. This study investigated the association between 18F-FDG PET/CT metabolic parameters and MVI before LT in HCC patients. METHODS: About 124 HCC patients who had 18F-FDG PET/CT examination before LT were included. The patients' clinicopathological features and 18F-FDG PET/CT metabolic parameters were recorded. Correlations between clinicopathological features, 18F-FDG PET/CT metabolic parameters, and MVI were analyzed. ROC curve was used to determine the optimal diagnostic cutoff value, area under the curve (AUC), sensitivity, and specificity for predictors of MVI. RESULT: In total 72 (58.06%) patients were detected with MVI among the 124 HCC patients. Univariate analysis showed that tumor size (P = 0.001), T stage (P < 0.001), maximum standardized uptake value (SUVmax) (P < 0.001), minimum standardized uptake value (SUVmin) (P = 0.031), mean standardized uptake value (SUVmean) (P = 0.001), peak standardized uptake value (SUVpeak) (P = 0.001), tumor-to-liver ratio (SUVratio) (P = 0.010), total lesion glycolysis (TLG) (P = 0.006), metabolic tumor volume (MTV) (P = 0.011) and MVI were significantly different. Multivariate logistic regression showed that tumor size (P = 0.018), T stage (P = 0.017), TLG (P = 0.023), and MTV (P = 0.015) were independent predictors of MVI. In the receiver operating characteristic curve, TLG predicted MVI with an AUC value of 0.645. MTV predicted MVI with an AUC value of 0.635. Patients with tumor size ≥5 cm, T3-4, TLG > 400.67, and MTV > 80.58 had a higher incidence of MVI. CONCLUSION: 18F-FDG PET/CT metabolic parameters correlate with MVI and may be used as a noninvasive technique to predict MVI before LT in HCC patients.
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Non-thermal plasma has been an emerging technology for water treatment for decades. In this study, we have designed and fabricated a bubbling plasma batch reactor using an atmospheric pressure dielectric barrier discharge with a hydrophobic porous membrane. The reactor performance is assessed for purifying synthetic contaminated water samples containing chemical contaminant sulfamethoxazole (SMX), a widely used antibiotic, and biological contaminant E. coli K12. The SMX decontamination tests indicate that the degradation process is not first-order and the reaction rate dwindle with increasing initial concentration. The yield at 50% removal achieves its highest value of 8.12 g/kWh for 50 mg/L SMX sample. For inactivation of E. coli K12 tests, the inactivation process is also not first-order, and the pathogen is completely inactivated for 102 CFU/mL and 104 CFU/mL cases after 10 min and 45 min of plasma treatment, respectively. For the 108 CFU/mL sample, a 5-log reduction is achieved after 60 min of treatment. The developed plasma reactor can achieve fast deployment in point of use, low cost for manufacturing, and simple for maintenance. Moreover, it can be used for in-situ water purification in future long duration crewed space missions as well as tackling with water pollution issues on our planet.
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High-entropy materials (HEMs) have recently emerged as a prominent research focus in materials science, gaining considerable attention because of their complex composition and exceptional properties. These materials typically comprise five or more elements mixed approximately in equal atomic ratios. The resultant high-entropy effects, lattice distortions, slow diffusion, and cocktail effects contribute to their unique physical, chemical, and optical properties. This study reviews the electrical, magnetic, and optical properties of HEMs and explores their potential applications. Additionally, it discusses the theoretical calculation methods and preparation techniques for HEMs, thereby offering insights and prospects for their future development.
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BACKGROUND: Acute lumbar sprain (ALS) is common musculoskeletal disorder characterized by severe low back pain and activity limitation, which significantly impacts the patient's work and life. Immediate relief of pain and restoration of mobility in a short period of time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of this combined treatment for ALS within 10 minutes. METHODS: This is a single-center, prospective, randomized clinical trial. 128 eligible patients with ALS will be randomly allocated in a 1:1 ratio to either the auricular acupuncture (AA) group or the sham auricular acupuncture (SAA) group. All patients will receive a single 10-minute treatment. The primary outcome will be the change in pain intensity after 10 minutes of treatment. The secondary outcomes include changes in pain intensity at other time points (2, 5 minutes), changes in lumbar range of motion (ROM) at different time points, blinded assessment, treatment effect expectancy scale evaluation, and treatment satisfaction scale evaluation. All participants will be included in the analysis according to the intention-to-treat principle. DISCUSSION: This is the first randomized controlled trial to assess the immediate efficacy of AA combined with active exercise for ALS. The findings of this study are expected to provide a simple and rapid treatment for ALS in clinical. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400083740. Registered 30 April 2024.
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Acupuntura Auricular , Terapia por Exercício , Humanos , Adulto , Masculino , Feminino , Acupuntura Auricular/métodos , Pessoa de Meia-Idade , Terapia por Exercício/métodos , Dor Lombar/terapia , Resultado do Tratamento , Entorses e Distensões/terapia , Estudos Prospectivos , Região Lombossacral , Amplitude de Movimento Articular , Adulto Jovem , Adolescente , Terapia Combinada , Vértebras Lombares/fisiopatologia , Medição da DorRESUMO
Non-Hodgkin lymphoma (NHL) limited to the larynx is very rare. The authors present the clinical diagnosis and treatment of four patients with laryngeal NHL. Case 1 was diagnosed with glottic, subglottic, and tracheal mucosa-associated lymphoid tissue (MALT) lymphoma, and was treated with radiotherapy and chemotherapy after surgery. Case 2 was diagnosed with laryngeal MALT lymphoma and underwent radiotherapy. Case 3 was diagnosed with angioimmunoblastic T-cell lymphoma, and was treated with radiotherapy and chemotherapy. Case 4 had MALT lymphoma in the glottic area with a malignant thyroid tumor, and was treated with radiotherapy and chemotherapy after surgery. More reports and research on this disease are needed.
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Introduction: Osimertinib, a third-generation EGFR-TKI, is known for its high efficacy against brain metastases (BM) in non-small cell lung cancer (NSCLC) due to its ability to penetrate the blood-brain barrier. This study aims to evaluate the use of brain MRI radiomics in predicting the intracranial efficacy to osimertinib in NSCLC patients with BM. Materials and methods: This study analyzed 115 brain metastases from NSCLC patients with the EGFR-T790M mutation treated with second-line osimertinib. The primary endpoint was intracranial response, and the secondary endpoint was intracranial progression-free survival (iPFS). We performed tumor delineation, image preprocessing, and radiomics feature extraction. Using a 5-fold cross-validation strategy, we built radiomic models with eight feature selectors and eight machine learning classifiers. The models' performance was evaluated by the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. Results: The dataset of 115 brain metastases was divided into training and validation sets in a 7:3 ratio. The radiomic model utilizing the mRMR feature selector and stepwise logistic regression classifier showed the highest predictive accuracy, with AUCs of 0.879 for the training cohort and 0.786 for the validation cohort. This model outperformed a clinical-MRI morphological model, which included age, ring enhancement, and peritumoral edema (AUC: 0.794 for the training cohort and 0.697 for the validation cohort). The radiomic model also showed strong performance in calibration and decision curve analyses. Using a radiomic-score threshold of 199, patients were classified into two groups with significantly different median iPFS (3.0 months vs. 15.4 months, p < 0.001). Conclusion: This study demonstrates that MRI radiomics can effectively predict the intracranial efficacy of osimertinib in NSCLC patients with brain metastases. This approach holds promise for assisting clinicians in personalizing treatment strategies.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) and metabolic-associated fatty liver disease (MAFLD) are both metabolic disorders that negatively impact the cardiovascular system. This study comprehensively analyzed the additive effect of MAFLD on left ventricular function and global strain in T2DM patients by cardiac magnetic resonance (CMR). METHODS: Data of 261 T2DM patients, including 109 with and 152 without MAFLD, as well as 73 matched normal controls from our medical center between June 2015 and March 2022 were retrospectively analyzed. CMR-derived parameters, including LV function and global strain parameters, were compared among different groups. Univariate and multivariate linear regression analyses were conducted to investigate the impact of various factors on LV function and global strain. RESULTS: Our investigation revealed a progressive deterioration in LV functional parameters across three groups: control subjects, T2DM patients without MAFLD, and T2DM patients with MAFLD. Statistically significant increases in left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), left ventricular mass index (LVMI) were observed, along with decreases in left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI). Among these three groups, significant reductions were also noted in the absolute values of LV global radial, circumferential, and longitudinal peak strains (GRPS, GCPS, and GLPS), as well as in peak systolic (PSSR) and peak diastolic strain rates (PDSR). MAFLD was identified as an independent predictor of LVEF, LVMI, LVGFI, GRPS, GCPS, and GLPS in multivariate linear analysis. Besides, the incidence of late gadolinium enhancement was higher in MAFLD patients than in non-MAFLD patients (50/109 [45.9%] vs. 42/152 [27.6%], p = 0.003). Furthermore, escalating MAFLD severity was associated with a numerical deterioration in both LV function parameters and global strain values. CONCLUSIONS: This study thoroughly compared CMR parameters in T2DM patients with and without MAFLD, uncovering MAFLD's adverse impact on LV function and deformation in T2DM patients. These findings highlight the critical need for early detection and comprehensive management of cardiac function in T2DM patients with MAFLD.
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Diabetes Mellitus Tipo 2 , Imagem Cinética por Ressonância Magnética , Valor Preditivo dos Testes , Disfunção Ventricular Esquerda , Função Ventricular Esquerda , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Idoso , Fatores de Risco , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/complicações , Volume Sistólico , Adulto , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/etiologia , Fenômenos BiomecânicosRESUMO
Targeting the heat shock protein-90 (Hsp90) chaperone machinery in various cancers with 200 monotherapy or combined-therapy clinical trials since 1999 has not yielded any success of food and drug administration approval. Blames for the failures were unanimously directed at the Hsp90 inhibitors or tumors or both. However, analyses of recent cellular and genetic studies together with the Hsp90 data from the Human Protein Atlas database suggest that the vast variations in Hsp90 expression among different organs in patients might have been the actual cause. It is evident now that Hsp90ß is the root of dose-limiting toxicity (DLT), whereas Hsp90α is a buffer of penetrated Hsp90 inhibitors. The more Hsp90α, the safer Hsp90ß, and the lower DLT are for the host. Unfortunately, the dramatic variations of Hsp90, from total absence in the eye, muscle, pancreas, and heart to abundance in reproduction organs, lung, liver, and gastrointestinal track, would cause the selection of any fair toxicity biomarker and an effective maximum tolerable dose (MTD) of Hsp90 inhibitor extremely challenging. In theory, a safe MTD for the organs with high Hsp90 could harm the organs with low Hsp90. In reverse, a safe MTD for organs with low or undetectable Hsp90 would have little impact on the tumors, whose cells exhibit average 3-7% Hsp90 over the average 2-3% Hsp90 in normal cells. Moreover, not all tumor cell lines tested follow the "inhibitor binding-client protein degradation" paradigm. It is likely why the oral Hsp90 inhibitor TAS-16 (Pimitespib), which bypasses blood circulation and other organs, showed some beneficiary efficacy by conveniently hitting tumors along the gastrointestinal track. The critical question is what the next step will be for the Hsp90 chaperone as a cancer therapeutic target.
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Wild animals, as a vital component of our natural world, serve a crucial role in preserving ecological equilibrium and biodiversity. By delving into the genetic constitution of wild animal populations, the evolutionary history, genetic diversity, and adaptation mechanisms could be explored, thereby informing conservation strategies and safeguarding the future of these species. In order to study the genetic information of wild animals, it is necessary to extract high purity and high concentration of wild animal genomic DNA. In this work, a hydrophobic magnetic deep eutectic solvent (HMDES) based vortexed extraction was developed for the extraction of genomic DNA from leopard cat (Prionailurus bengalensis), hairy-crowned deer (Elaphodus cephalophus) and muntjac (Muntiacus reevesi) muscle tissue, respectively. Extraction conditions like the pH value, extraction time, temperature and the amount of HMDES used were optimized by single-factor experiments. Under the optimized condition, genomic DNA could be selectively extracted from the three animal tissues. The limits of detection (LOD) and limits of quantification (LOQ) of the proposed method were 2.86 ng/µL and 8.66 ng/µL, respectively. Meanwhile, the relative standard deviation (RSD) of the method precision and repeatability were 1.64 % and 5.57 % at 20 ng/µL, showing the method has good precision and repeatability. After extraction, the DNA extracted into the HMDES droplets can be quickly recovered and the HMDES can be recycled and reused. The method proposed is a fast, environmental-friendly and high efficient extraction strategy for purification and enrichment of genomic DNA from leopard cat, hairy-crowned deer and muntjac tissues.
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DNA , Cervos , Cervo Muntjac , Animais , Cervo Muntjac/genética , DNA/isolamento & purificação , DNA/química , Interações Hidrofóbicas e Hidrofílicas , Solventes/química , Limite de Detecção , Felidae/genética , GenomaRESUMO
Metal-organic frameworks (MOFs) have attained broad research attention in the areas of sensors, resistive memories, and optoelectronic synapses on the merits of their intriguing physical and chemical properties. In this review, recent progress on the synthesis of MOFs and their electronic applications is introduced and discussed. Initially, the crystal structures and properties of MOFs encompassing optical, electrical, and chemical properties are discussed in brief. Subsequently, advanced synthesis methods for MOFs are introduced, categorized into hydrothermal approach, microwave synthesis, mechanochemical synthesis, and electrochemical deposition. After that, the various roles of MOFs in widespread applications, including sensing, information storage, optoelectronic synapses, machine learning, and artificial intelligence, are discussed, highlighting their versatility and the innovative solutions they provide to long-standing challenges. Finally, an outlook on remaining challenges and a future perspective for MOFs are proposed.
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The skin epidermis is continually influenced by a myriad of internal and external elements. At its basal layer reside epidermal stem cells, which fuels epidermal renovation and hair regeneration with powerful self-renewal ability, as well as keeping diverse signals that direct their activity under surveillance with quick response. The importance of epidermal stem cells in wound healing and immune-related skin conditions has been increasingly recognized, and their potential for clinical applications is attracting attention. In this review, we delve into recent advancements and the various physiological and psychological factors that govern distinct epidermal stem cell populations, including psychological stress, mechanical forces, chronic aging, and circadian rhythm, as well as providing an overview of current methodological approaches. Furthermore, we discuss the pathogenic role of epidermal stem cells in immune-related skin disorders and their potential clinical applications.
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Células Epidérmicas , Células-Tronco , Humanos , Células-Tronco/citologia , Animais , Epiderme , Pele/patologia , CicatrizaçãoRESUMO
Cell secretion repairs tissue damage and restores homeostasis throughout adult life. The extracellular heat shock protein-90alpha (eHsp90α) has been reported as an exosome cargo and a potential driver of wound healing. However, neither the mechanism of secretion nor the genetic evidence for eHsp90α in wound healing has been substantiated. Herein, we show that tissue injury causes massive deposition of eHsp90α in tissues and secretion of eHsp90α by cells. Sequential centrifugations of conditioned medium from relevant cell lines revealed the relative distributions of eHsp90α in microvesicle, exosome and trypsin-sensitive supernatant fractions to be approximately <2%, <4% and >95%, respectively. Establishing the cell-number-to-interstitial-fluid-volume (CIF) ratio for the microenvironment of human tissues as 1 × 109 cells: 1 mL interstitial fluid enabled us to predict the corresponding tissue concentrations of eHsp90α in these fractions as 3.74 µg/mL, 5.61 µg/mL and 178 µg/mL. Remarkably, the 178 µg/mL eHsp90α matches the previously reported 100-300 µg/mL of recombinant eHsp90α whose topical application promotes maximum wound healing in animal models. More importantly, we demonstrate that two parallel secretory autophagy-regulating gene families, the autophagy-regulating (AR) genes and the Golgi reassembly-stacking protein (GRASP) genes work together to mediate the secretion of the physiological concentration of eHsp90α to promote wound healing. Thus, utilization of the CIF ratio-based extrapolation method may enable investigators to rapidly predict biomarker targets from cell-conditioned-medium data.
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Autofagia , Líquido Extracelular , Proteínas de Choque Térmico HSP90 , Cicatrização , Humanos , Proteínas de Choque Térmico HSP90/metabolismo , Animais , Líquido Extracelular/metabolismo , Camundongos , Via Secretória , Masculino , Exossomos/metabolismo , Linhagem CelularRESUMO
Sirtuin 1 (SIRT1) is a histone deacetylase and plays diverse functions in various physiological events, from development to lifespan regulation. Here, in Parkinson's disease (PD) model mice, we demonstrated that SIRT1 ameliorates parkinsonism, while SIRT1 knockdown further aggravates PD phenotypes. Mechanistically, SIRT1 interacts with and deacetylates pyruvate kinase M2 (PKM2) at K135 and K206, thus leading to reduced PKM2 enzyme activity and lactate production, which eventually results in decreased glial activation in the brain. Administration of lactate in the brain recapitulates PD-like phenotypes. Furthermore, increased expression of PKM2 worsens PD symptoms, and, on the contrary, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice. Collectively, our data indicate that excessive lactate in the brain might be involved in the progression of PD. By improving lactate homeostasis, SIRT1, together with PKM2, are likely drug targets for developing agents for the treatment of neurodegeneration in PD.
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Encéfalo , Homeostase , Ácido Láctico , Piruvato Quinase , Sirtuína 1 , Sirtuína 1/metabolismo , Sirtuína 1/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Piruvato Quinase/metabolismo , Piruvato Quinase/genética , Camundongos , Ácido Láctico/metabolismo , Humanos , Acetilação/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Hormônio da Tireoide , Hormônios Tireóideos/metabolismo , Naftoquinonas/farmacologiaRESUMO
Yes-associated protein (YAP) is a key oncogene in the Hippo tumor suppression pathway, historically challenging to target due to its intrinsically disordered nature. Leveraging recent advances in high-throughput screening that identified several YAP binders, we employed proteolysis-targeting chimera technology to develop a series of YAP degraders. Utilizing NSC682769, a known YAP binder, linked with VHL ligand 2 or pomalidomide via diverse linkers, we synthesized degraders including YZ-6. This degrader not only recruits the E3 ligase VHL for the rapid and sustained degradation of YAP but also effectively inhibits its nuclear localization, curtailing YAP/TEAD-mediated transcription in cancer cell lines such as NCI-H226 and Huh7. This dual action significantly diminishes YAP's oncogenic activity, contributing to the potent antiproliferative effects observed both in vitro and in a Huh7 xenograft mouse model. These results underscore the potential of PROTAC-mediated YAP degradation as a strategy for treating YAP-driven cancers.
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Proteínas Adaptadoras de Transdução de Sinal , Proteólise , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Proteólise/efeitos dos fármacos , Animais , Fatores de Transcrição/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Linhagem Celular Tumoral , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteínas Intrinsicamente Desordenadas/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/síntese química , Talidomida/química , Proliferação de Células/efeitos dos fármacos , Camundongos Nus , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Quimera de Direcionamento de ProteóliseRESUMO
Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein-stimulated pancreatitis models, Sec16a+/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.