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1.
Hepatology ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34545586

RESUMO

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) has become a worldwide epidemic, which is a common clinical condition predisposing to advanced liver diseases. A large and growing unmet therapeutic need for this condition reflects incomplete understanding of its pathogenesis. In current study, we identified a transcription factor Zinc Fingers and Homeoboxes 2 (ZHX2) in hepatocytes as a protective factor against steatohepatitis. APPROACH & RESULTS: We found that hepatic ZHX2 was significantly suppressed in NASH models and steatotic hepatic cells. Hepatocyte-specific ablation of ZHX2 exacerbated NASH-related phenotypes in mice, including lipid accumulation, enhanced inflammation, and hepatic fibrosis. Conversely, hepatocyte-specific overexpression of ZHX2 significantly alleviated the progression of NASH in an experimental setting. Integrated analysis of transcriptomic profiling and chromatin immunoprecipitation sequencing data demonstrated that the Phosphatase and Tensin Homologue (PTEN) was a target gene of ZHX2 in hepatocyte. ZHX2 bound to the promoter of PTEN gene and subsequently promoted the transcription of PTEN, which mediated the beneficial role of ZHX2 against NASH. CONCLUSION: In conclusion, current findings unfolded a protective role of ZHX2 against NASH progression by transcriptionally activating PTEN. These findings shed light on the therapeutic potential of targeting ZHX2 for treating NASH and related metabolic disorders.

2.
Nat Commun ; 12(1): 4065, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210971

RESUMO

Strategies that enable intermolecular site-selective C-H bond functionalisation of organic molecules provide one of the cornerstones of modern chemical synthesis. In chloroalkane synthesis, such methods for intermolecular site-selective aliphatic C-H bond chlorination have, however, remained conspicuously rare. Here, we present a copper(I)-catalysed synthetic method for the efficient site-selective C(sp3)-H bond chlorination of ketones, (E)-enones and alkylbenzenes by dichloramine-T at room temperature. A key feature of the broad substrate scope is tolerance to unsaturation, which would normally pose an immense challenge in chemoselective aliphatic C-H bond functionalisation. By unlocking dichloramine-T's potential as a chlorine radical atom source, the product site-selectivities achieved are among the most selective in alkane functionalisation and should find widespread utility in chemical synthesis. This is exemplified by the late-stage site-selective modification of a number of natural products and bioactive compounds, and gram-scale preparation and formal synthesis of two drug molecules.


Assuntos
Domínio Catalítico , Cobre/química , Cetonas/química , Sulfonamidas/química , Produtos Biológicos/química , Carbono/química , Catálise , Halogenação , Hidrogênio/química , Temperatura
3.
Biomark Med ; 15(9): 615-622, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34037458

RESUMO

Aim: Hepatocellular carcinoma (HCC) is considered to be the third leading cause of cancer death. The homologous gene of TP53 is significant in the occurrence and development of cancer. This study explored the relationship between TP53 rs28934571 polymorphism and HCC risk in Guangxi, China. Materials & methods: We first screened the association through bioinformatics. Additionally, a case-control study was performed to further verify the relationship between gene polymorphism and HCC risk after collecting clinical characteristics. Results: Results showed that allele A on TP53 rs28934571 was a risk factor for HCC and mutation from C to A on TP53 rs28934571 would increase the risk of poor prognosis of HCC. Conclusion: Therefore, the study concluded that TP53 rs28934571 may become a diagnostic indicator in judging the prognosis of HCC.

4.
Nat Commun ; 12(1): 1714, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731701

RESUMO

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-ß induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.


Assuntos
Neoplasias Ósseas/secundário , Carcinogênese , Transição Epitelial-Mesenquimal , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Acetilação , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzilaminas/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Ciclamos/uso terapêutico , Docetaxel/uso terapêutico , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Mutação , Osteogênese , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
5.
J Neuroeng Rehabil ; 18(1): 42, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627142

RESUMO

BACKGROUND: Compared with traditional physical therapy for stroke patients, lower extremity exoskeletons can provide patients with greater endurance and more repeatable and controllable training, which can reduce the therapeutic burden of the therapist. However, most exoskeletons are expensive, heavy or require active power to be operated. Therefore, a lighter, easy to wear, easy to operate, low-cost technology for stroke rehabilitation would be a welcome opportunity for stroke survivors, caregivers and clinicians. One such device is the Kickstart Walk Assist system and the purpose of this study was to determine feasibility of using this unpowered exoskeleton device in a sample of stroke survivors. METHODS: Thirty stroke survivors were enrolled in the study and experienced walking with the Kickstart exoskeleton device that provided spring-loaded assistance during gait. After 5 days of wearing the exoskeleton, participants were evaluated in the two states of wearing and not wearing the exoskeleton. Outcome measures included: (a) spatio-temporal gait measures, (b) balance measures and (c) exoskeleton-use feedback questionnaire. RESULTS: In comparison to not wearing the device, when participants wore the Kickstart walking system, weight bearing asymmetry was reduced. The time spent on the 10-m walk test was also reduced, but there was no difference in the timed-up-and-go test (TUGT). Gait analysis data showed reduction in step time and double support time. Stroke survivors were positive about the Kickstart walking system's ability to improve their balance, speed and gait. In addition, their confidence level and willingness to use the device was also positive. CONCLUSIONS: These findings show the feasibility of using the Kickstart walking system for improving walking performance in stroke survivors. Our future goal is to perform a longer duration study with more comprehensive pre- and post-testing in a larger sample of stroke survivors. Trial registration Chinese Clinical Trial Registry, ChiCTR2000032665. Registered 5 May 2020-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=53288.


Assuntos
Exoesqueleto Energizado , Equilíbrio Postural , Reabilitação do Acidente Vascular Cerebral/instrumentação , Caminhada , Adulto , Idoso , Estudos de Viabilidade , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/reabilitação , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Sobreviventes
6.
PLoS One ; 15(11): e0242179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33201900

RESUMO

OBJECTIVE: This study aims to explore the mechanism of the miR-424-5p/E2F7 axis in hepatocellular carcinoma (HCC) and provide new ideas for targeted therapy of HCC. METHODS: Bioinformatics analysis was used to identify the target differentially expressed miRNA in HCC and predict its target gene. qRT-PCR was employed to verify the expression of miR-424-5p and E2F7 mRNA in HCC cells. Western blot was performed to detect the effect of miR-424-5p ectopic expression on the protein expression of E2F7. CCK-8 was used to detect proliferative activity of HCC cells and flow cytometry was carried out for analyzing cell cycle distribution. Dual luciferase reporter assay was conducted to verify the direct targeting relationship between miR-424-5p and E2F7. RESULTS: We observed that miR-424-5p was down-regulated in HCC cells. CCK-8 showed that overexpression of miR-424-5p inhibited cell proliferation, and flow cytometry showed that miR-424-5p could block cells in G0/G1 phase. E2F7 was up-regulated in HCC cells, and E2F7 overexpression could facilitate the proliferative ability of HCC cells and promote the cell cycle progressing from G0/G1 to S phase. Furthermore, dual-luciferase reporter assay indicated that miR-424-5p could directly down-regulate E2F7 expression. Analysis on cell function demonstrated that miR-424-5p inhibited the proliferation of HCC cells and blocked cell cycle at G0/G1 phase by targeting E2F7. CONCLUSION: Our results proved that E2F7 was a direct target of miR-424-5p, and miR-424-5p could regulate cell cycle and further inhibit the proliferation of HCC cells by targeting E2F7.


Assuntos
Carcinoma Hepatocelular/metabolismo , Fator de Transcrição E2F7/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , Carcinoma Hepatocelular/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Fator de Transcrição E2F7/metabolismo , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo
7.
Lab Chip ; 20(24): 4582-4591, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33052990

RESUMO

To track dynamically varying and physiologically relevant biomarker profiles in sweat, autonomous wearable platforms are required to periodically sample and analyze sweat with minimal or no user intervention. Previously reported sweat sensors are functionally limited to capturing biomarker information at one time-point/period, thereby necessitating repeated user intervention to increase the temporal granularity of biomarker data. Accordingly, we present a compact multi-compartment wearable system, where each compartment can be activated to autonomously induce/modulate sweat secretion (via iontophoretic actuation) and analyze sweat at set time points. This system was developed following a hybrid-flex design and a vertical integration scheme-integrating the required functional modules: miniaturized iontophoresis interfaces, adhesive thin film microfluidic-sensing module, and control/readout electronics. The system was deployed in a human subject study to track the diurnal variation of sweat glucose levels in relation to the daily food intake. The demonstrated autonomous operation for diurnal sweat biomarker data acquisition illustrates the system's suitability for large-scale and longitudinal personal health monitoring applications.


Assuntos
Técnicas Biossensoriais , Dispositivos Eletrônicos Vestíveis , Biomarcadores , Humanos , Iontoforese , Microfluídica , Suor
8.
Nat Commun ; 11(1): 4405, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879320

RESUMO

Active biofluid management is central to the realization of wearable bioanalytical platforms that are poised to autonomously provide frequent, real-time, and accurate measures of biomarkers in epidermally-retrievable biofluids (e.g., sweat). Accordingly, here, a programmable epidermal microfluidic valving system is devised, which is capable of biofluid sampling, routing, and compartmentalization for biomarker analysis. At its core, the system is a network of individually-addressable microheater-controlled thermo-responsive hydrogel valves, augmented with a pressure regulation mechanism to accommodate pressure built-up, when interfacing sweat glands. The active biofluid control achieved by this system is harnessed to create unprecedented wearable bioanalytical capabilities at both the sensor level (decoupling the confounding influence of flow rate variability on sensor response) and the system level (facilitating context-based sensor selection/protection). Through integration with a wireless flexible printed circuit board and seamless bilateral communication with consumer electronics (e.g., smartwatch), contextually-relevant (scheduled/on-demand) on-body biomarker data acquisition/display was achieved.


Assuntos
Biomarcadores/análise , Técnicas Analíticas Microfluídicas/métodos , Microfluídica , Técnicas Biossensoriais , Epiderme/química , Humanos , Suor/química , Dispositivos Eletrônicos Vestíveis
9.
Proc Natl Acad Sci U S A ; 117(32): 19017-19025, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719130

RESUMO

To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals' drug transcourse profiles (semi)continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target's redox signature. However, the target's redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy-centering on engineering the molecule-surface interactions-to simultaneously mitigate biofouling and create an "undistorted potential window" within which the target drug's voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays, R 2 ∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.


Assuntos
Acetaminofen/análise , Monitoramento de Medicamentos/métodos , Saliva/química , Suor/química , Acetaminofen/administração & dosagem , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/instrumentação , Humanos , Medicina de Precisão , Dispositivos Eletrônicos Vestíveis
10.
Biochim Biophys Acta Mol Basis Dis ; 1866(11): 165890, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32599143

RESUMO

Disruptions of the circadian rhythm and reduced circulating levels of the circadian hormone melatonin predispose to ischemic stroke. Although the nuclear receptor RORα is considered as a circadian rhythm regulator and a mediator of certain melatonin effects, its potential role in cerebral ischemia-reperfusion (CI/R) injury and in the neuroprotective effects of melatonin remain undefined. Here, we observed that CI/R injury in RORα-deficient mice was associated with greater cerebral infarct size, brain edema, and cerebral apoptosis compared with wild-type model. In contrast, transgenic mice with brain-specific overexpression of RORα versus non-transgenic controls exerted significantly reduced infarct volume, brain edema and apoptotic response induced by CI/R. Mechanistically, RORα deficiency was found to exacerbate apoptosis pathways mediated by endoplasmic-reticulum stress and mitochondria and aggravate oxidative/nitrative stress after CI/R. Further studies revealed that RORα deficiency intensified the activation of nuclear factor-κB signaling induced by CI/R. Given the emerging evidence of RORα as an essential melatonin activity mediator, we further investigated the RORα roles in melatonin-exerted neuroprotection against acute ischemic stroke. Melatonin treatment significantly decreased infarct volume and cerebral apoptosis; mitigated endoplasmic reticulum stress and mitochondrial dysfunction; and inhibited CI/R injury-induced oxidative/nitrative stress and nuclear factor-κB activation, which was eradicated in RORα-deficient mice. Collectively, current findings suggest that RORα is a novel endogenous neuroprotective receptor, and a pivotal mediator of melatonin's suppressive effects against CI/R injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/genética , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/genética , Infarto Cerebral/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/genética , Transdução de Sinais/efeitos dos fármacos
11.
Sci Adv ; 6(12): eaaz0007, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32219164

RESUMO

To render high-fidelity wearable biomarker data, understanding and engineering the information delivery pathway from epidermally retrieved biofluid to a readout unit are critical. By examining the biomarker information delivery pathway and recognizing near-zero strained regions within a microfluidic device, a strain-isolated pathway to preserve biomarker data fidelity is engineered. Accordingly, a generalizable and disposable freestanding electrochemical sensing system (FESS) is devised, which simultaneously facilitates sensing and out-of-plane signal interconnection with the aid of double-sided adhesion. The FESS serves as a foundation to realize a system-level design strategy, addressing the challenges of wearable biosensing, in the presence of motion, and integration with consumer electronics. To this end, a FESS-enabled smartwatch was developed, featuring sweat sampling, electrochemical sensing, and data display/transmission, all within a self-contained wearable platform. The FESS-enabled smartwatch was used to monitor the sweat metabolite profiles of individuals in sedentary and high-intensity exercise settings.


Assuntos
Técnicas Biossensoriais , Técnicas Eletroquímicas , Dispositivos Eletrônicos Vestíveis , Biomarcadores , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Desenho de Equipamento , Humanos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodos , Suor/metabolismo
12.
ACS Sens ; 5(1): 265-273, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31909594

RESUMO

Wearable drug monitoring targeting epidermally retrievable biofluids (e.g., sweat) can enable a variety of applications, including drug compliance/abuse monitoring and personalized therapeutic drug dosing. In that regard, voltammetry-based approaches are suitable because they uniquely leverage the electroactive nature of target drug molecules for quantification, eliminating the reliance on the availability of recognition elements. However, to adapt such approaches for the envisioned application, three main challenges must be addressed: (1) constructing a sensitive voltammetric sensing interface with high signal-to-background ratio, (2) decoupling the confounding effect of endogenous electroactive species (naturally present in complex biofluid matrices) and baseline variation, and (3) realizing wireless voltammetric excitation and signal acquisition/transmission. To this end, first, a framework for the quantification of electroactive drugs is presented, which centers on the evaluation and determination of suitable sensing electrodes and characterization of the interference from a panel of physiologically relevant electroactive species. This framework was utilized to establish the design space and operational settings for the development of a coupled sensing system and analytical framework to render sample-to-answer drug readouts in complex biofluid matrices. The presented design framework and sensing system can serve as a basis for future wearable sensor development efforts aiming to monitor electroactive species such as pharmaceutical molecules.


Assuntos
Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/métodos , Eletrodos/normas , Dispositivos Eletrônicos Vestíveis/normas , Humanos
13.
ACS Sens ; 5(1): 93-102, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31786928

RESUMO

Recent advances in microelectronics, microfluidics, and electrochemical sensing platforms have enabled the development of an emerging class of fully integrated personal health monitoring devices that exploit sweat to noninvasively access biomarker information. Despite such advances, effective sweat sampling remains a significant challenge for reliable biomarker analysis, with many existing methods requiring active stimulation (e.g., iontophoresis, exercise, heat). Natural perspiration offers a suitable alternative as sweat can be collected with minimal effort on the part of the user. To leverage this phenomenon, we devised a thin hydrogel micropatch (THMP), which simultaneously serves as an interface for sweat sampling and a medium for electrochemical sensing. To characterize the performance of the THMP, caffeine and lactate were selected as two representative target molecules. We demonstrated the suitability of the sampling method to track metabolic patterns, as well as to render sample-to-answer biomarker data for personal monitoring (through coupling with an electrochemical sensing system). To inform its potential application, this biomarker sampling and sensing system is incorporated within a distributed terminal-based sensing network, which uniquely capitalizes on the fingertip as a site for simultaneous biomarker data sampling and user identification.


Assuntos
Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Hidrogéis/química , Suor/química , Dispositivos Eletrônicos Vestíveis/normas , Humanos
14.
J Sport Rehabil ; 29(5): 588-593, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31094638

RESUMO

CONTEXT: One of the possible mechanisms leading to secondary impingement syndrome may be the strength imbalance of shoulder rotators which is known as functional control ratio (FCR). The FCR is a ratio dividing the eccentric peak torque of the external rotators by the concentric peak torque of the internal rotators. Previous studies have focused on the reproducibility and reliability of isokinetic assessment, but there is little information on the influence of variable shoulder positions on FCR. OBJECTIVE: To compare shoulder FCR across 3 different shoulder abduction positions during isokinetic assessment. DESIGN: Cross-sectional study. SETTING: Biomechanics laboratory. PARTICIPANTS: Thirty-one healthy young university students (age 22.35 [0.95] y, weight 60.52 [9.31] kg, height 168.23 [9.47] cm). INTERVENTIONS: The concentric peak torque of internal rotators and eccentric peak torque of external rotators of right shoulder were measured on an isokinetic dynamometer. MAIN OUTCOME MEASURES: Concentric peak torque of the internal rotators and eccentric peak torque of the external rotators, measured using an isokinetic dynamometer. RESULTS: The concentric peak torque of internal rotators was significantly lower at 120° shoulder abduction compared with other positions (P < .001). The FCR was significantly higher at 120° shoulder abduction than 90° (P = .002) or 60° (P < .001) shoulder abduction because of the lower concentric peak torque. No significant difference was found in the FCR between the other 2 shoulder positions (P = .14). CONCLUSIONS: Shoulder position variations may influence FCR because of weakness of the internal rotators. Rehabilitation and injury prevention training programs should specifically focus on strengthening the internal rotators at more elevated angles of shoulder abduction.


Assuntos
Postura/fisiologia , Manguito Rotador/fisiopatologia , Articulação do Ombro/fisiologia , Ombro/fisiologia , Peso Corporal , Estudos Transversais , Feminino , Humanos , Cinética , Masculino , Debilidade Muscular/fisiopatologia , Músculos Peitorais/fisiopatologia , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Torque , Adulto Jovem
15.
Nat Cell Biol ; 21(10): 1273-1285, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548606

RESUMO

Chromosome translocation is a major cause of the onset and progression of diverse types of cancers. However, the mechanisms underlying this process remain poorly understood. Here, we identified a non-homologous end-joining protein, IFFO1, which structurally forms a heterotetramer with XRCC4. IFFO1 is recruited to the sites of DNA damage by XRCC4 and promotes the repair of DNA double-strand breaks in a parallel pathway with XLF. Interestingly, IFFO1 interacts with lamin A/C, forming an interior nucleoskeleton. Inactivating IFFO1 or its interaction with XRCC4 or lamin A/C leads to increases in both the mobility of broken ends and the frequency of chromosome translocation. Importantly, the destruction of this nucleoskeleton accounts for the elevated frequency of chromosome translocation in many types of cancer cells. Our results reveal that the lamin A/C-IFFO1-constituted nucleoskeleton prevents chromosome translocation by immobilizing broken DNA ends during tumorigenesis.


Assuntos
Carcinogênese/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas de Ligação a DNA/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Lamina Tipo A/metabolismo , Translocação Genética , Animais , Carcinoma/genética , Cromossomos Humanos , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Proteínas de Filamentos Intermediários/genética , Camundongos , Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/química , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Associadas à Matriz Nuclear/fisiologia
16.
Lab Chip ; 19(18): 2966-2972, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31397462

RESUMO

We report a wearable electrofluidic actuation system, which exploits the alternating current electrothermal (ACET) effects to engineer biofluid flow profiles on the body. The wearable ACET flow is induced with the aid of corrosion-resistant electrode configurations (fabricated on a flexible substrate) and custom-developed, wirelessly programmable high frequency (MHz) excitation circuitry. Various tunable flow profiles are demonstrated with the aid of the devised flexible ACET electrode configurations, where the induced profiles are in agreement with the ACET theory and simulation. The demonstrated capabilities rendered by the presented system create new degrees of freedom for implementing advanced bioanalytical operations for future lab-on-the-body platforms.


Assuntos
Técnicas Analíticas Microfluídicas , Dispositivos Eletrônicos Vestíveis , Eletrodos , Humanos , Técnicas Analíticas Microfluídicas/instrumentação , Temperatura
17.
Genes Dev ; 33(19-20): 1397-1415, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31467087

RESUMO

DNA repair by homologous recombination (HR) is essential for genomic integrity, tumor suppression, and the formation of gametes. HR uses DNA synthesis to repair lesions such as DNA double-strand breaks and stalled DNA replication forks, but despite having a good understanding of the steps leading to homology search and strand invasion, we know much less of the mechanisms that establish recombination-associated DNA polymerization. Here, we report that C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis. Mice with targeted mutations in Hrob are infertile due to depletion of germ cells and display phenotypes consistent with a prophase I meiotic arrest. The HROB-MCM8-MCM9 pathway acts redundantly with the HELQ helicase, and cells lacking both HROB and HELQ have severely impaired HR, suggesting that they underpin two major routes for the completion of HR downstream from RAD51. The function of HROB in HR is reminiscent of that of gp59, which acts as the replicative helicase loader during bacteriophage T4 recombination-dependent DNA replication. We therefore propose that the loading of MCM8-MCM9 by HROB may similarly be a key step in the establishment of mammalian recombination-associated DNA synthesis.


Assuntos
Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Recombinação Homóloga/genética , Proteínas de Manutenção de Minicromossomo/metabolismo , Animais , Linhagem Celular , DNA Helicases/metabolismo , Feminino , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Infertilidade/genética , Masculino , Camundongos Endogâmicos C57BL , Deleção de Sequência , Células Sf9
18.
Lab Chip ; 19(17): 2844-2853, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31359008

RESUMO

The large-scale deployment of wearable bioanalytical devices for general population longitudinal monitoring necessitates rapid and high throughput manufacturing-amenable fabrication schemes that render disposable, low-cost, and mechanically flexible microfluidic modules capable of performing a variety of bioanalytical operations within a compact footprint. The spatial constraints of previously reported wearable bioanalytical devices (with microfluidic operations confined to 2D), their lack of biofluid manipulation capability, and the complex and low-throughput nature of their fabrication process inherently limit the diversity and frequency of end-point assessments and prevent their deployment at large scale. Here, we devise a simple, scalable, and low-cost "CAD-to-3D Device" fabrication and integration scheme, which renders 3D and complex microfluidic architectures capable of performing biofluid sampling, manipulation, and sensing. The devised scheme is based on laser-cutting of tape-based substrates, which can be programmed at the software-level to rapidly define microfluidic features such as a biofluid collection interface, microchannels, and VIAs (vertical interconnect access), followed by the vertical assembly of pre-patterned layers to realize the final device. To inform the utility of our fabrication scheme, we demonstrated three representative devices to perform sweat collection (with visualizable secretion profile), sample filtration, and simultaneous biofluid actuation and sensing (using a sandwiched-interface). Our devised scheme can be adapted for the fabrication and manufacturing of current and future wearable bioanalytical devices, which in turn will catalyze the large-scale production and deployment of such devices for general population health monitoring.


Assuntos
Líquidos Corporais/química , Técnicas Eletroquímicas/economia , Técnicas Analíticas Microfluídicas/economia , Dispositivos Eletrônicos Vestíveis/economia , Técnicas Eletroquímicas/instrumentação , Eletrodos , Humanos , Técnicas Analíticas Microfluídicas/instrumentação
19.
J Pineal Res ; 67(2): e12579, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30958896

RESUMO

Exercise-induced physiological hypertrophy provides protection against cardiovascular disease, whereas disease-induced pathological hypertrophy leads to heart failure. Emerging evidence suggests pleiotropic roles of melatonin in cardiac disease; however, the effects of melatonin on physiological vs pathological cardiac hypertrophy remain unknown. Using swimming-induced physiological hypertrophy and pressure overload-induced pathological hypertrophy models, we found that melatonin treatment significantly improved pathological hypertrophic responses accompanied by alleviated oxidative stress in myocardium but did not affect physiological cardiac hypertrophy and oxidative stress levels. As an important mediator of melatonin, the retinoid-related orphan nuclear receptor-α (RORα) was significantly decreased in human and murine pathological hypertrophic cardiomyocytes, but not in swimming-induced physiological hypertrophic murine hearts. In vivo and in vitro loss-of-function experiments indicated that RORα deficiency significantly aggravated pathological cardiac hypertrophy, and notably weakened the anti-hypertrophic effects of melatonin. Mechanistically, RORα mediated the cardioprotection of melatonin in pathological hypertrophy mainly by transactivation of manganese-dependent superoxide dismutase (MnSOD) via binding to the RORα response element located in the promoter region of the MnSOD gene. Furthermore, MnSOD overexpression reversed the pro-hypertrophic effects of RORα deficiency, while MnSOD silencing abolished the anti-hypertrophic effects of RORα overexpression in pathological cardiac hypertrophy. Collectively, our findings provide the first evidence that melatonin exerts an anti-hypertrophic effect on pathological but not physiological cardiac hypertrophy via alleviating oxidative stress through transactivation of the antioxidant enzyme MnSOD in a RORα-dependent manner.


Assuntos
Cardiomegalia/metabolismo , Melatonina/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Mutantes , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Superóxido Dismutase/genética
20.
J Pineal Res ; 67(2): e12581, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31009101

RESUMO

Rupture of vulnerable plaques is the main trigger of acute cardio-cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture-prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE-/- mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor-related orphan receptor-α (RORα) mediated melatonin-exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte-derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα-STATs pathway in a RORα-dependent manner. In summary, our data provided the first evidence that melatonin-RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture-prone vulnerable plaques.


Assuntos
Aterosclerose/metabolismo , Macrófagos/metabolismo , Melatonina/farmacologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/patologia , Humanos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Transdução de Sinais/genética
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