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1.
Nat Commun ; 15(1): 4745, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834553

RESUMO

Functional interactions between brain regions can be viewed as a network, enabling neuroscientists to investigate brain function through network science. Here, we systematically evaluate 768 data-processing pipelines for network reconstruction from resting-state functional MRI, evaluating the effect of brain parcellation, connectivity definition, and global signal regression. Our criteria seek pipelines that minimise motion confounds and spurious test-retest discrepancies of network topology, while being sensitive to both inter-subject differences and experimental effects of interest. We reveal vast and systematic variability across pipelines' suitability for functional connectomics. Inappropriate choice of data-processing pipeline can produce results that are not only misleading, but systematically so, with the majority of pipelines failing at least one criterion. However, a set of optimal pipelines consistently satisfy all criteria across different datasets, spanning minutes, weeks, and months. We provide a full breakdown of each pipeline's performance across criteria and datasets, to inform future best practices in functional connectomics.


Assuntos
Encéfalo , Conectoma , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Conectoma/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Processamento de Imagem Assistida por Computador/métodos , Masculino , Adulto , Feminino , Rede Nervosa/fisiologia , Rede Nervosa/diagnóstico por imagem , Mapeamento Encefálico/métodos , Adulto Jovem
2.
bioRxiv ; 2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38766080

RESUMO

Background: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions. Methods: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders. Results: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use. Conclusions: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

3.
Colloids Surf B Biointerfaces ; 240: 113990, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38810468

RESUMO

Chemodynamic therapy (CDT), which employs intracellular H2O2 to produce toxic hydroxyl radicals to kill cancer cells, has received great attention due to its specificity to tumors. However, the relatively insufficient endogenous H2O2 and the short-lifetime and limited diffusion distance of •OH compromise the therapeutic efficacy of CDT. Mitochondria, which play crucial roles in oncogenesis, are highly vulnerable to elevated oxidative stress. Herein, we constructed a mitochondria-mediated self-cycling system to achieve high dose of •OH production through continuous H2O2 supply. Cinnamaldehyde (CA), which can elevate H2O2 level in the mitochondria, was loaded in Cu(II)-containing metal organic framework (MOF), termed as HKUST-1. After actively targeting mitochondria, the intrinsic H2O2 in mitochondria of cancer cells could induce degradation of MOF, releasing the initial free CA. The released CA further triggered the upregulation of endogenous H2O2, resulting in the subsequent adequate release of CA and the final burst growth of H2O2. The cycle process greatly promoted the Fenton-like reaction between Cu2+ and H2O2 and induced long-term high oxidative stress, achieving enhanced chemodynamic therapy. In a word, we put forward an efficient strategy for enhanced chemodynamic therapy.


Assuntos
Acroleína , Peróxido de Hidrogênio , Estruturas Metalorgânicas , Mitocôndrias , Estresse Oxidativo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Acroleína/farmacologia , Acroleína/química , Acroleína/análogos & derivados , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Cobre/química , Cobre/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Radical Hidroxila/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Tamanho da Partícula , Linhagem Celular Tumoral , Propriedades de Superfície
4.
Alzheimers Dement ; 20(5): 3364-3377, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38561254

RESUMO

INTRODUCTION: We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-ß/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS: Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks. DISCUSSION: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties. HIGHLIGHTS: Aß and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties.


Assuntos
Substância Branca , Proteínas tau , Humanos , Substância Branca/patologia , Masculino , Feminino , Idoso , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Peptídeos beta-Amiloides/metabolismo , Cognição/fisiologia , Imagem de Tensor de Difusão , Testes Neuropsicológicos , Disfunção Cognitiva/patologia , Fatores de Risco
7.
Sci Rep ; 14(1): 2087, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38267458

RESUMO

Methane-air explosion is one of the major disasters in industrial process. The explosion strength could be influenced by the crushed coal gangue, which is widely distributed in coal mine gob and roadway. To understand the influence of the coal gangue on gas explosion, an experimental system with a 0.2 × 0.2 × 3.0 m3 pipeline was designed and explosion experiments of coal gangue with 5 blockage length-diameter ratios (ratio of axial blockage length to pipeline equivalent diameter) were carried out. The results show that coal gangue can cause significant disturbances to the flame front, resulting in a violent acceleration of the explosion flame. The overpressure ratio presents a negative exponential function distribution with the blockage length-diameter ratio. The influence range increases with the blockage length-diameter ratio under the condition of rich fuel, and reaches the maximum when equivalent ratio is 1.237. The explosion intensity is more sensitive to the blockage length-diameter ratio for the equivalent ratio equals 1.0 and 1.237. The formation of high-intensity explosion should be avoided by controlling the accumulation state of the overlying rock in coal mining.

8.
Nano Lett ; 24(4): 1341-1350, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38252869

RESUMO

In situ drug synthesis using the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has attracted considerable attention in tumor therapy because of its satisfactory effectiveness and reduced side-effects. However, the exogenous addition of copper catalysts can cause cytotoxicity and has hampered biomedical applications in vivo. Here, we design and synthesize a metal-organic framework (MOF) to mimic copper chaperone, which can selectively modulate copper trafficking for bioorthogonal synthesis with no need of exogenous addition of copper catalysts. Like copper chaperones, the prepared ZIF-8 copper chaperone mimics specifically bind copper ions through the formation of coordination bonds. Moreover, the copper is unloaded under the acidic environment due to the dissipation of the coordination interactions between metal ions and ligands. In this way, the cancer cell-targeted copper chaperone mimics can selectively transport copper ions into cells. Regulation of intracellular copper trafficking may inspire constructing bioorthogonal catalysis system with reduced metal cytotoxicity in live cells.


Assuntos
Alcinos , Cobre , Cobre/farmacologia , Cobre/química , Alcinos/química , Azidas/química , Reação de Cicloadição , Catálise , Íons
9.
Diabetes Obes Metab ; 26(5): 1582-1592, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38246697

RESUMO

AIM: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN). MATERIALS AND METHODS: Adults with obesity were classified per Morningness-Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m2) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2). A 120 min euglycaemic-hyperinsulinaemic clamp (40 mU/m2/min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD; conduit artery), post-ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast-enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp-derived plasma endothelin-1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide-mediated vasodilation. Aerobic fitness (VO2max) and body composition (dual-energy X-ray absorptiometry) were also collected. RESULTS: MORN had a higher VO2max compared with INT (p < .01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co-varying for VO2max (both p ≤ .02). INT also had a lower fasting nitrate (p = .03) and arginine (p = .07). Higher MEQ correlated with elevated FMD (r = 0.33, p = .03) and lower post-ischaemic flow velocity (r = -0.33, p = .03) as well as shear rate (r = -0.36, p = .02) at 120 min. CONCLUSION: When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction.


Assuntos
Doenças Cardiovasculares , Resistência à Insulina , Adulto , Humanos , Feminino , Cronotipo , Nitratos , Obesidade , Artéria Braquial/fisiologia , Insulina , Endotélio Vascular , Vasodilatação , Arginina
10.
J Mater Chem B ; 12(6): 1429-1445, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38251708

RESUMO

Dental caries is a multifactorial disease primarily mediated by biofilm formation, resulting in a net loss of mineral content and degradation of organic matrix in dental hard tissues. Caries lesions of varying depths can result in demineralization of the superficial enamel, the formation of deep cavities extending into the dentin, and even pulp infection. Electrospun nanofibers (ESNs) exhibit an expansive specific surface area and a porous structure, closely mimicking the unique architecture of the natural extracellular matrix (ECM). This unique topography caters to the transport of small molecules and facilitates localized therapeutic drug delivery, offering great potential in regulating cell behavior, and thereby attracting interest in ESNs' applications in the treatment of caries lesions and the reconditioning of the affected dental tissues. Thus, this review aims to consolidate the recent developments in ESNs' applications for caries lesions. This review begins with an introduction to the electrospinning technique and provides a comprehensive overview of the biological properties and modification methods of ESNs, followed by an introduction outlining the basic pathological processes, classification and treatment requirements of caries lesions. Finally, the review offers a detailed examination of the research progress on the ESNs' application in caries lesions and concludes by addressing the limitations.


Assuntos
Cárie Dentária , Nanofibras , Humanos , Dentina , Cárie Dentária/metabolismo , Suscetibilidade à Cárie Dentária , Regeneração
11.
Am J Physiol Endocrinol Metab ; 326(3): E258-E267, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38170166

RESUMO

Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at weeks 0 and 12. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (P < 0.05) and muscle microvascular blood flow (P < 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (P = 0.02), lowered peripheral and aortic systolic (each P < 0.01), diastolic (each P < 0.05), mean arterial (each P < 0.01), and pulse pressures (each P < 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each P = 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each P < 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.NEW & NOTEWORTHY The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.


Assuntos
Diabetes Mellitus Tipo 2 , Glucosídeos , Resistência à Insulina , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Miocárdio/metabolismo , Insulina/metabolismo , Biomarcadores , Perfusão
12.
J Clin Endocrinol Metab ; 109(4): 1041-1050, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-37951842

RESUMO

CONTEXT: Vascular insulin resistance is commonly observed in obesity and diabetes; yet, insulin action across the vascular tree and the relationship between insulin responses at different vascular locations remains incompletely defined. OBJECTIVE: To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments. METHODS: This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated. RESULTS: Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin's ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV. CONCLUSION: Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted.


Assuntos
Doenças Cardiovasculares , Hiperinsulinismo , Resistência à Insulina , Rigidez Vascular , Adulto , Humanos , Resistência à Insulina/fisiologia , Ácidos Graxos não Esterificados , Estudos Cross-Over , Análise de Onda de Pulso , Insulina , Músculo Esquelético/fisiologia , Artéria Braquial
13.
Small ; 20(8): e2306760, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37821404

RESUMO

Autophagosome-tethering compound (ATTEC) technology has recently been emerging as a novel approach for degrading proteins of interest (POIs). However, it still faces great challenges in how to design target-specific ATTEC molecules. Aptamers are single-stranded DNA or RNA oligonucleotides that can recognize their target proteins with high specificity and affinity. Here, ATTEC is combined with aptamers for POIs degradation. As a proof of concept, pathological protein α-synuclein (α-syn) is chosen as the target and an efficient α-syn degrader is generated. Aptamer as a targeting warhead of α-syn is conjugated with LC3B-binding compound 5,7-dihydroxy-4-phenylcoumarin (DP) via bioorthogonal click reaction. It is demonstrated that the aptamer conjugated with DP is capable of clearing α-syn through LC3 and autophagic degradation. These results indicate that aptamer-based ATTECs are a versatile approach to degrade POIs by taking advantage of the well-defined different aptamers for targeting diverse proteins, which provides a new way for the design of ATTECs to degradation of targeted proteins.


Assuntos
Autofagossomos , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Autofagossomos/metabolismo , Autofagia , Lisossomos/metabolismo , Oligonucleotídeos/metabolismo
14.
J Clin Endocrinol Metab ; 109(6): 1464-1473, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38157408

RESUMO

CONTEXT: The role of circular RNAs (circRNAs) in type 1 diabetes (T1D) is largely unknown. OBJECTIVE: We aimed to identify some circRNAs as differential diagnostic biomarkers for T1D to distinguish between patients with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). METHODS: The circRNA expression profiles were determined by Arraystar human circRNA microarray in T1D compared to controls (n = 6 each). The differentially expressed circRNAs were validated by real-time quantitative polymerase chain reaction using a validation cohort with 20 T1D and 20 controls. The diagnostic performances of the candidate circRNAs and the clinical parameters were assessed using the logistic least absolute shrinkage and selection operator (LASSO) regression model in a larger cohort with 457 individuals, including patients with T1D, T2D, and LADA, and controls. RESULTS: We identified 110 differentially expressed circular transcripts (53 upregulated and 57 downregulated) in T1D patients compared with controls. Further analysis showed that the levels of hsa_circRNA_405498 and hsa_circRNA_100033 were significantly downregulated in T1D compared to controls (both P < .05). Moreover, the expression levels of these 2 circRNAs showed sequential downregulation from controls, patients with T2D, LADA, to T1D (P < .05). The area under the curve (AUC) of receiver operating characteristic plots in logistic LASSO regression model showed high diagnostic accuracy for combination model with the 2 circRNAs and some clinical parameters in distinguishing T1D from LADA (AUC = 0.915), T2D (AUC = 0.993), and controls (AUC = 0.992). CONCLUSION: Our study demonstrated that hsa_circRNA_405498 and hsa_circRNA_100033 are promising novel differential diagnostic biomarkers for T1D.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , RNA Circular , Humanos , RNA Circular/genética , Masculino , Feminino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/diagnóstico , Diagnóstico Diferencial , Biomarcadores/análise , Adulto , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Estudos de Casos e Controles , Perfilação da Expressão Gênica , RNA/genética , Diabetes Autoimune Latente em Adultos/diagnóstico , Diabetes Autoimune Latente em Adultos/genética , Diabetes Autoimune Latente em Adultos/sangue , Adulto Jovem
15.
Clin Oral Investig ; 28(1): 35, 2023 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-38147166

RESUMO

OBJECTIVES: Biomimetic mineralization mediated by proteins and peptides is a promising strategy for enamel repair, and its specific application model needs more research. In this work, we exploited a liposomal delivery system for a novel peptide (DK5) derived from histatin-1 (DK5-Lips) as a new biomimetic mineralization strategy against initial enamel caries. MATERIALS AND METHODS: The DK5-Lips was prepared using calcium acetate gradient method and then the in vitro release, salivary stability, and cytotoxicity were studied. Initial enamel caries was created in bovine enamel blocks and subjected to pH-cycling model treated with DK5-Lips. Surface microhardness testing, polarized light microscopy (PLM), and transverse microradiography (TMR) were analyzed. Then the biocompatibility of DK5-Lips was evaluated in the caries model of Sprague-Dawley rats, and the anti-caries effect was assessed using Micro-CT analysis, Keyes scores, and PLM in vivo. RESULTS: DK5-Lips provided a mean particle size of (97.63 ± 4.94)nm and encapsulation efficiency of (61.46 ± 1.44)%, exhibiting a sustained release profile, excellent stability in saliva, and no significant toxicity on human gingival fibroblasts (HGFs). The DK5-Lips group had higher surface microhardness recovery, shallower caries depth, and less mineral loss in bovine enamel. Animal experiments showed higher volume and density values of residual molar enamel, lower Keyes score, and shallower lesion depth of the DK5-Lips group with good biocompatibility. CONCLUSION: As a safe and effective application model, DK5-Lips could significantly promote the remineralization of initial enamel caries both in vitro and in vivo. CLINICAL RELEVANCE: The potential of liposome utilization as vehicle for oral delivery of functional peptides may provide a new way for enamel restoration.


Assuntos
Cárie Dentária , Ratos , Humanos , Animais , Bovinos , Ratos Sprague-Dawley , Cárie Dentária/tratamento farmacológico , Histatinas , Lipossomos , Cariostáticos , Suscetibilidade à Cárie Dentária , Peptídeos/farmacologia
16.
Chem Sci ; 14(40): 11192-11202, 2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-37860639

RESUMO

The ability to regulate mitophagy in a living system with small molecules remains a great challenge. We hypothesize that adding fragments specific to the key autophagosome protein LC3 to mitochondria will mimic receptor-mediated mitophagy, thus engaging the autophagy-lysosome pathway to induce mitochondrial degradation. Herein, we develop a general biochemical approach to modulate mitophagy, dubbed mito-ATTECs, which employ chimera molecules composed of LC3-binding moieties linked to mitochondria-targeting ligands. Mito-ATTECs trigger mitophagy via targeting mitochondria to autophagosomes through direct interaction between mito-ATTECs and LC3 on mitochondrial membranes. Subsequently, autophagosomes containing mitochondria rapidly fuse with lysosomes to facilitate the degradation of mitochondria. Therefore, mito-ATTECs circumvent the detrimental effects related to disruption of mitochondrial membrane integrity by inducers routinely used to manipulate mitophagy, and provide a versatile biochemical approach to investigate the physiological roles of mitophagy. Furthermore, we found that sustained mitophagy lead to mitochondrial depletion and autophagic cell death in several malignant cell lines (lethal mitophagy). Among them, apoptosis-resistant malignant melanoma cell lines are particularly sensitive to lethal mitophagy. The therapeutic efficacy of mito-ATTECs has been further evaluated by using subcutaneous and pulmonary metastatic melanoma models. Together, the mitochondrial depletion achieved by mito-ATTECs may demonstrate the general concept of inducing cancer cell lethality through excessive mitochondrial clearance, establishing a promising therapeutic paradigm for apoptosis-resistant tumors.

17.
Clin Chim Acta ; 548: 117503, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37536520

RESUMO

Saliva is a versatile biofluid that contains a wide variety of biomarkers reflecting both physiologic and pathophysiologic states. Saliva collection is noninvasive and highly applicable for tests requiring serial sampling. Furthermore, advances in test accuracy, sensitivity and precision for saliva has improved diagnostic performance as well as the identification of novel markers especially in oral disease processes. These include dental caries, periodontitis, oral squamous cell carcinoma (OSCC) and Sjögren's syndrome (SS). Numerous growth factors, enzymes, interleukins and cytokines have been identified and are the subject of much research investigation. This review highlights current procedures for successful determination of saliva biomarkers including preanalytical factors associated with sampling, storage and pretreatment as well as subsequent analysis. Moreover, it provides an overview of the diagnostic applications of these salivary biomarkers in common oral diseases.


Assuntos
Carcinoma de Células Escamosas , Cárie Dentária , Neoplasias Bucais , Síndrome de Sjogren , Humanos , Saliva/química , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas/patologia , Biomarcadores/metabolismo , Síndrome de Sjogren/metabolismo , Biomarcadores Tumorais/metabolismo
18.
Nano Lett ; 23(14): 6424-6432, 2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37395701

RESUMO

Artificial metalloenzymes (ArMs) are gaining much attention in life sciences. However, the function of the present ArMs for disease treatment is still in its infancy, which may impede the possible therapeutic potential. Herein, we construct an antibody engineered ArM by using the Fc region of IgG and bioorthogonal chemistry, which endows the ArM with the capability of manipulating cell-cell communication and bioorthogonal catalysis for tumor immuno- and chemotherapy. Specially, Fc-Pd ArM is modified on the cancer cell surface by metabolic glycoengineering to catalyze the bioorthogonal activation of prodrug for tumor chemotherapy. More importantly, the antibody-based ArM can mediate cell-cell communication between cancer cells and NK cells, activating the ADCC effect for immunotherapy. In vivo antitumor applications suggest that the ArM can not only eliminate primary tumor but also inhibit tumor lung metastasis. Our work provides a new attempt to develop artificial metalloenzymes with cell-cell communication the ability for bioorthogonal catalysis and combination therapy.


Assuntos
Metaloproteínas , Neoplasias , Humanos , Células Matadoras Naturais , Neoplasias/patologia , Anticorpos , Espaço Extracelular , Metaloproteínas/metabolismo , Linhagem Celular Tumoral
19.
J Am Chem Soc ; 145(30): 16658-16668, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37486170

RESUMO

Pyroptosis is an inflammatory form of programmed cell death that holds great promise in cancer therapy. However, autophagy as the crucial pyroptosis checkpoint and the self-protective mechanism of cancer cells significantly weakens the therapeutic efficiency. Here, a bioorthogonal pyroptosis nanoregulator is constructed to induce pyroptosis and disrupt the checkpoint, enabling high-efficiency pyroptosis cancer therapy. The nanoregulator allows the in situ synthesis and accumulation of the photosensitizer PpIX in the mitochondria of cancer cells to directly produce mitochondrial ROS, thus triggering pyroptosis. Meanwhile, the in situ generated autophagy inhibitor via palladium-catalyzed bioorthogonal chemistry can disrupt the pyroptosis checkpoint to boost the pyroptosis efficacy. With the biomimetic cancer cell membrane coating, this platform for modulating pyroptosis presents specificity to cancer cells and poses no harm to normal tissue, resulting in a highly efficient and safe antitumor treatment. To our knowledge, this is the first report on a disrupting intrinsic protective mechanism of cancer cells for tumor pyroptosis therapy. This work highlights that autophagy as a checkpoint plays a key regulative role in pyroptosis therapy, which would motivate the future design of therapeutic regimens.


Assuntos
Neoplasias , Piroptose , Apoptose , Autofagia , Biomimética , Membrana Celular
20.
Neuroimage ; 278: 120276, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37451374

RESUMO

The relationship between structural and functional connectivity in the brain is a key question in connectomics. Here we quantify patterns of structure-function coupling across the neocortex, by comparing structural connectivity estimated using diffusion MRI with functional connectivity estimated using both neurophysiological (MEG-based) and haemodynamic (fMRI-based) recordings. We find that structure-function coupling is heterogeneous across brain regions and frequency bands. The link between structural and functional connectivity is generally stronger in multiple MEG frequency bands compared to resting state fMRI. Structure-function coupling is greater in slower and intermediate frequency bands compared to faster frequency bands. We also find that structure-function coupling systematically follows the archetypal sensorimotor-association hierarchy, as well as patterns of laminar differentiation, peaking in granular layer IV. Finally, structure-function coupling is better explained using structure-informed inter-regional communication metrics than using structural connectivity alone. Collectively, these results place neurophysiological and haemodynamic structure-function relationships in a common frame of reference and provide a starting point for a multi-modal understanding of structure-function coupling in the brain.


Assuntos
Conectoma , Neocórtex , Humanos , Magnetoencefalografia/métodos , Encéfalo/fisiologia , Imageamento por Ressonância Magnética/métodos , Mapeamento Encefálico/métodos , Conectoma/métodos , Hemodinâmica , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia
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