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Cisplatin-induced renal tubular injury largely restricts the wide-spread usage of cisplatin in the treatment of malignancies. Identifying the key signaling pathways that regulate cisplatin-induced renal tubular injury is thus clinically important. PARVB, a focal adhesion protein, plays a crucial role in tumorigenesis. However, the function of PARVB in kidney disease is largely unknown. To investigate whether and how PARVB contributes to cisplatin-induced renal tubular injury, a mouse model (PARVB cKO) was generated in which PARVB gene was specifically deleted from proximal tubular epithelial cells using the Cre-LoxP system. In this study, we found depletion of PARVB in proximal tubular epithelial cells significantly attenuates cisplatin-induced renal tubular injury, including tubular cell death and inflammation. Mechanistically, PARVB associates with transforming growth factor-ß-activated kinase 1 (TAK1), a central regulator of cell survival and inflammation that is critically involved in mediating cisplatin-induced renal tubular injury. Depletion of PARVB promotes cisplatin-induced TAK1 degradation, inhibits TAK1 downstream signaling, and ultimately alleviates cisplatin-induced tubular cell damage. Restoration of PARVB or TAK1 in PARVB-deficient cells aggravates cisplatin-induced tubular cell injury. Finally, we demonstrated that PARVB regulates TAK1 protein expression through an E3 ligase ITCH-dependent pathway. PARVB prevents ITCH association with TAK1 to block its ubiquitination. Our study reveals that PARVB deficiency protects against cisplatin-induced tubular injury through regulation of TAK1 signaling and indicates targeting this pathway may provide a novel therapeutic strategy to alleviate cisplatin-induced kidney damage.
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Cisplatino , MAP Quinase Quinase Quinases , Camundongos Knockout , Transdução de Sinais , Cisplatino/efeitos adversos , Cisplatino/toxicidade , Animais , MAP Quinase Quinase Quinases/metabolismo , MAP Quinase Quinase Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Túbulos Renais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de SinalRESUMO
Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.
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Nefropatias , Podócitos , Camundongos , Animais , Podócitos/metabolismo , Glomérulos Renais/metabolismo , Nefropatias/metabolismo , Transdução de Sinais , Proteinúria/metabolismoRESUMO
BACKGROUND: Chronic renal failure (CRF) referred to chronic progressive renal parenchymal damage caused by various causes, with metabolite retention and imbalance of water, electrolyte, and acid-base balance as the main clinical manifestations. Secondary hyperparathyroidism (sHPT) was a common complication in maintenance hemodialysis patients with CRF. Nuclear factor IB (NFIB) was a newly found tumor suppressor gene in various cancers. The present study aimed to illustrate the role of NFIB in sHPT clinical diagnosis and treatment response. METHODS: A retrospective, case-control study, including 189 patients with sHPT and 106 CRF patients without sHPT, compared with 95 controls. Serum NFIB and 1,25(OH)2 D3 levels were measured by RT-qPCR and ELISAs, respectively. ROC analysis was conducted to verify the diagnostic value of NFIB in sHPT. Spearman's correlation analysis was conducted to verify the association between NFIB and bone mineral density (BMD) scores. After 6 months of treatment, the variance of NFIB and 1,25(OH)2 D3 in different groups was recorded. RESULTS: The expression of NFIB was significantly lower in serum samples from sHPT and non-sHPT CRF patients, compared to controls. Clinicopathological information verified sHPT was associated with NFIB, parathyroid hormone (PTH), serum calcium, serum phosphorus, time of dialysis, and serum 1,25(OH)2 D3 levels. Spearman's correlation analysis illustrated the positive correlation between NFIB levels and BMD scores. At receiver operator characteristic (ROC) curve analysis, the cutoff of 1.6508 for NFIB was able to identify patients with sHPT from healthy controls; meanwhile, NFIB could also discriminate sHPT among CRF patients as well (cutoff = 1.4741). Furthermore, we found that during 6 months of treatment, NFIB levels were gradually increased, while PTH and serum P levels were decreased. CONCLUSIONS: Serum NFIB was a highly accurate tool to identify sHPT from healthy controls and CRF patients. Due to its simplicity, specificity, and sensitivity, this candidate can be proposed as a first-line examination in the diagnostic workup in sHPT.
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Biomarcadores/sangue , Cálcio/sangue , Hiperparatireoidismo Secundário/diagnóstico , Fatores de Transcrição NFI/sangue , Vitamina D/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Hiperparatireoidismo Secundário/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos RetrospectivosRESUMO
Our study investigated the differences in pharmacokinetics of three major components of crude Cimicifuga foetida L. and its fried product and honey- and liquor-prepared products. A rapid and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry approach was established for determing caffeic acid, isoferulic acid and ferulic acid in rat plasma. The approach has good linearity, precision, accuracy, recovery and stability. Phenolic acid was rapidly absorbed. The times to peak concentration were shorter in the processed group than those for the crude product, with their values of <30 min. The peak concentration values of caffeic acid and isoferulic acid were higher in the crude group than in the processed groups (p < 0.05). Area under the curve values of the three phenolics in the crude group were significantly higher than those of the processed groups (p < 0.05).
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Cimicifuga/química , Cinamatos/sangue , Cinamatos/farmacocinética , Medicamentos de Ervas Chinesas , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cinamatos/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Modelos Lineares , Masculino , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodosRESUMO
We introduce a fast compensation scheme to realize arbitrary focusing after propagation through a scattering sample. Theoretical analysis of the effect of cross terms on multi-point focusing is conducted based on the transmission matrix theory. The results show that the cross-term influence is very significant, which needs to be considered. The Multi-Population Genetic Algorithm is adopted to retrieve the input mode for the suppression of the cross-term effect. In order to realize fast compensation and reduce measurement noise, the off-axis holographic method is used to measure the large transmission matrix, which reduces the number of measurements compared with the traditional method. In the experiment, after retrieving the input phase, we obtain a high-quality focal output, and the signal-to-noise ratio is increased by 13.6 dB.
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Phase matching is a necessary condition for achieving high-efficiency optical-frequency conversion. To date, practical means of accomplishing phase matching in homogeneous crystals remain limited, despite considerable efforts. Herein, we report a new class of methods aimed at achieving quasiperfect phase matching, based on controllable birefringence produced via the linear electro-optic effect, termed "voltage-tuning phase matching." The wave vectors of the induced polarization and the generated fields can be matched and maintained along the direction of propagation by introducing an external electric field. We analyze the validity and feasibility of this method theoretically and demonstrate it experimentally by applying the linear electro-optic effect and fourth-harmonic generation simultaneously in a partially deuterated KH_{2}PO_{4} crystal. Quasiperfect phase matching is achieved systematically over a temperature range of the initial phase-matching temperature ±2 °C. Moreover, this method can overcome the limitation of the birefringence in traditional technologies and provides new functionalities for conventional nonlinear materials as well as low-birefringence and isotropic materials. This technology may significantly impact the study of optical-frequency conversion and has promise for a broad range of applications in nonlinear optics.
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BACKGROUND This study investigated the molecular mechanism of the effect of CD44 on the recurrence of EGC after ESD, including the potential regulator and signaling pathways of CD44. MATERIAL AND METHODS We searched the miRNA online database (www.mirdb.org) with the "seed sequence" located within the 3'-UTR of the target gene, and performed luciferase assay to test the miRNA/mRNA relationship. We also determined the expression of CD44 in the EGC and control samples. In addition, statistical analysis was used to explore the role of miR-328 as a biomarker to predict the recurrence after ECD. RESULTS We validated CD44 to be the direct gene via luciferase reporter assay system. We also established the negative regulatory relationship between miR-328 and CD44 via studying the relative luciferase activity at different concentrations of miR-328 mimics. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CD44 among different groups (recurrence-positive and recurrence-negative) or cells treated with different concentrations of miR-328 mimics/inhibitors, indicating the negative regulatory relationship between miR-328 and CD44. We also investigated the relative viability of EGC cells when transfected with miR-328 mimics (50 nM and 100 nM) and miR-328 inhibitors (100 nM) to validate miR-328 to be negatively interfering with the viability of EGC cells. miR-328 was also recognized as a potential biomarker to predict recurrence after ESD in EGC patients via analysis of the recurrence-free rate among different groups of EGC patients. CONCLUSIONS The expression level of miR-328 can function as a predictive biomarker of recurrence after ECD in patients with EGC via targeting CD44.
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Biomarcadores Tumorais/biossíntese , Receptores de Hialuronatos/metabolismo , MicroRNAs/biossíntese , Recidiva Local de Neoplasia/genética , Neoplasias Gástricas/genética , Regiões 3' não Traduzidas , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ressecção Endoscópica de Mucosa/métodos , Endoscopia Gastrointestinal/métodos , Feminino , Gastroscopia/métodos , Humanos , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
Escherichia coli K4 synthesizes a capsular polysaccharide (CPS) consisting of a fructose-branched chondroitin (GalNAc-GlcA(fructose)n), which is a biosynthetic precursor of chondroitin sulfate. Here, the role of kfoE in the modification of the chondroitin backbone was investigated using knock-out and recombinant complementation experiments. kfoE disruption and complementation had no significant effect on cell growth. CPS production was increased by 15 % in the knock-out strain, and decreased by 21 % in the knock-out strain complemented with recombinant kfoE. CPS extracted from the knock-out strain was chondroitin, whereas CPS extracted from the complemented strain was a fructose-branched chondroitin. The results demonstrated that the kfoE gene product altered the fructose group at the C3 position of the GlcA residue during production of K4CPS.
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Escherichia coli/genética , Escherichia coli/metabolismo , Hexosiltransferases/genética , Hexosiltransferases/metabolismo , Polissacarídeos Bacterianos/biossíntese , Escherichia coli/citologia , Técnicas de Inativação de Genes , Teste de Complementação GenéticaRESUMO
Stroke is a leading cause of long-term disability and mortality worldwide, necessitating effective rehabilitation strategies for successful recovery. Traditional Chinese medicine (TCM) has gained recognition as a complementary and alternative approach in stroke rehabilitation, owing to its unique syndromes that offer valuable insights for personalized treatment plans. This study aims to elucidate the correlation between TCM syndromes observed during the recovery phase of stroke and the associated neurological deficits. Syndromes such as Blood stasis, Phlegm-dampness, Qi deficiency, and Yin deficiency were systematically examined, while standardized neurological assessments, encompassing motor function, sensory perception, and cognitive abilities, were employed to evaluate the extent of neurological impairment. Rigorous statistical analyses were conducted to discern potential correlations between TCM syndromes and the severity of neurological deficits. The results revealed statistically significant positive associations between certain TCM syndromes, particularly Blood stasis and Phlegm-dampness, and heightened neurological deficits during the recovery phase post-stroke. These findings suggest that these syndromes may serve as indicators of more severe brain injury post-stroke, thereby guiding the development of tailored rehabilitation strategies. By establishing robust connections between TCM syndromes and neurological deficits, this study contributes to advancing our understanding of stroke recovery through an integrated approach that incorporates TCM principles. Moreover, it underscores the potential benefits of integrating TCM into conventional rehabilitation protocols, offering valuable insights for healthcare professionals and potentially improving patient outcomes.
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Medicina Tradicional Chinesa , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Medicina Tradicional Chinesa/métodos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/métodos , Feminino , Recuperação de Função Fisiológica , Masculino , Pessoa de Meia-Idade , Idoso , Síndrome , Doenças do Sistema Nervoso/reabilitaçãoRESUMO
Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome-lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29-mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency-induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin-SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression.
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Autofagia , Moléculas de Adesão Celular , Proliferação de Células , Lisossomos , Proteínas Qb-SNARE , Proteínas Qc-SNARE , Proteínas R-SNARE , Humanos , Proteínas R-SNARE/metabolismo , Proteínas R-SNARE/genética , Proteínas Qb-SNARE/metabolismo , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/metabolismo , Proteínas Qc-SNARE/genética , Lisossomos/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Autofagossomos/metabolismo , Células HeLa , Linhagem Celular Tumoral , Ligação Proteica , Proteínas SNARE/metabolismo , Proteínas SNARE/genética , Fusão de Membrana , Proteínas Qa-SNARERESUMO
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124â¯200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Reprodutibilidade dos Testes , Biomarcadores TumoraisRESUMO
OBJECTIVES: This systematic review aimed to qualitatively synthesise existing literature to examine the clinical nursing experiences of final-year nursing students during the COVID-19 pandemic and provide recommendations for the effective management of clinical placement of nursing students. DESIGN: A qualitative systematic review was conducted and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. DATA SOURCES: Five electronic databases were searched and qualitative studies were included for analysis if they focussed on the clinical nursing experiences of final-year nursing students during the COVID-19 pandemic. REVIEW METHODS: Data synthesis was conducted by extracting all findings, developing categories, and producing synthesised findings. RESULTS: Four synthesised findings were concluded: 1) facing the unknown and willingness to help, 2) challenging the clinical environment, 3) transition improving professional identity, and 4) finding ways out of the pandemic. CONCLUSIONS: The transition of nursing students to clinical nursing practice during the pandemic is a personally and professionally challenging process, while nursing students try to adapt to the changing clinical environment and enhance their professional identity. Nursing managers and health policymakers should acknowledge the challenges encountered by nursing students during the pandemic and support the professional growth of future nursing teams by providing high-quality supervision.
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COVID-19 , Enfermeiros Administradores , Estudantes de Enfermagem , Humanos , Pandemias , Pesquisa QualitativaRESUMO
The Ediacaran Period marks a pivotal time in geodynamo evolution when the geomagnetic field is thought to approach the weak state where kinetic energy exceeds magnetic energy, as manifested by an extremely high frequency of polarity reversals, high secular variation, and an ultralow dipole field strength. However, how the geodynamo transitioned from this state into one with more stable field behavior is unknown. Here, we address this issue through a high-resolution magnetostratigraphic investigation of the ~494.5 million-year-old Jiangshanian Global Standard Stratotype and Point (GSSP) section in South China. Our paleomagnetic results document zones with rapid reversals, stable polarity and a ~80 thousand-year-long interval without a geocentric axial dipole field. From these changes, we suggest that for most of the Cambrian, the solid inner core had not yet grown to a size sufficiently large to stabilize the geodynamo. This unusual field behavior can explain paleomagnetic data used to define paradoxical true polar wander, supporting instead the rotational stability of the solid Earth during the great radiation of life in the Cambrian.
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Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits KrasG12D-driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Camundongos , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-myc , Transdução de Sinais , Neoplasias PancreáticasRESUMO
In order to further improve the detection performance of the wearable heart rate sensor for human physiological and biochemical signals and body kinematics performance, the wearable heart rate sensor module was optimized by using nanofibers. Nanoparticle-doped graphene films were prepared by adding nanoparticles to a graphene oxide solution. The prepared film was placed in toluene, and the nanoparticles were removed to complete the preparation of a graphene film with a porous microstructure. The graphene film and the conductive film together formed a wearable heart rate sensor module. The strain response test of the porous graphene film wearable heart rate sensor module verifies the validity of the research in this paper. The resistance change of the wearable heart rate sensor module based on the PGF-2 film is 8 to 16 times higher than that of the RGO film, and the sensitivity is better, proving that the sensor module designed by this method shows significant application potential in human motion detection.
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Grafite , Nanofibras , Dispositivos Eletrônicos Vestíveis , Grafite/química , Frequência Cardíaca , Humanos , Movimento (Física)RESUMO
A palladium-catalyzed carbonylative Sonogashira/annulation reaction for the synthesis of indolo[1,2-b]isoquinolines has been developed. Tetracyclic 6/5/6/6 indoline skeletons were synthesized in moderate to good yields from easily available 2-bromo-N-(2-iodophenyl)benzamides and terminal alkynes. Notably, this efficient methodology established three C-C bonds and a C-N bond through a one-step transformation and provided a new method for the synthesis of indolo[1,2-b]isoquinoline derivatives.
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Objective: To study the pharmacological activity and the mechanism of action of natural compounds derived from 6,7-dimethoxycoumarin on the differentiation of human chronic myeloid leukemia K562 cells. Methods: We use MTT assay (Sigma-Aldrich, USA) to detect cell viability; use flow cytometry to analyze DNA content for cell cycle analysis; use benzidine staining to synthesize hemoglobin to determine K562 cell differentiation; use western blot analysis and qPCR to detect the expression levels of FOX03, P27, CDK4, and their phosphorylation; and use the AOBS laser scanning confocal system (Leica, Wetzlar, Germany) to analyze and quantify the number of positive green spots. The statistical methods used are one-way analysis of variance (ANOVA) and Dunnett's test to analyze within and between groups. Results: In order to explore the effect of 6,7-dimethoxycoumarin on the differentiation of K562 cell erythrocytes, it was concluded that 6,7-dimethoxycoumarin promotes the differentiation of K562 cell erythrocytes; the proliferation of K562 cells was detected by MTT method, and the results showed that 6,7-dimethoxycoumarin can inhibit the proliferation of K562 cells; to evaluate the effect of 6,7-dimethoxycoumarin on the proliferation of K562 cells, the results showed that 6,7-dimethoxycoumarin increased the expression of FOXO3, P27, CDK4, and CDK65, and decreased the phosphorylation of CDK4 and CDK6 proteins. To further explore the effect of knocking out FOXO3 on cell differentiation, the results show that 6,7-dimethoxycoumarin can reduce the differentiation and proliferation of K562 cells by increasing the expression of FOXO3. Conclusion: This study extended the understanding of the pharmacological activity of 6,7-dimethoxycoumarin and may provide a potential new target for the treatment of chronic myelogenous leukemia. However, we still need to further study the specific molecular capabilities of 6.7 dimethylcoumarin to understand their possible capture mechanism.
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Background: The mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma. Methods: Mice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset. Results: The survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000). Conclusion: Alas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.
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Physcion 8-O-ß-glucopyranoside (PSG), an anthraquinone extracted from Rumex japonicus Houtt, has various pharmacological effects, however, the effect of PSG on liver fibrosis and its related mechanism remain to be determined. We here showed that PSG ameliorated liver injury and liver fibrosis, decreased collagen deposition and inhibited inflammation in carbon tetrachloride (CCl4)-induced rats. Consistent with the in vivo results, PSG suppressed the transforming growth factor-ß1 (TGF-ß1)-induced cell viability, liver fibrosis and secretion of inflammatory factors in hepatic stellate cells (HSCs). Interestingly, PSG increased the enzyme activity and promoter activity of sirtuin 3 (SIRT3) in fibrotic liver and activated HSCs. In addition, PSG notably increased the mRNA and protein expression of SIRT3 both in vivo and in vitro. Depletion of SIRT3 either by using 3-TYP (SIRT3 selective inhibitor) or SIRT3 siRNA attenuated the anti-inflammatory effect of PSG in activated HSCs. Further study found that TGF-ß1 increased the nuclear expression of NF-κB p65, but showed no obvious effect on the total NF-κB p65 expression. Compared to the control adenovirus (Ad.mk), overexpression of SIRT3 by infecting adenovirus encoding SIRT3 (Ad.SIRT3) notably decreased the nuclear expression of NF-κB p65 in activated HSCs. Our results demonstrated that PSG attenuated inflammation by regulating SIRT3-mediated NF-κB P65 nuclear expression in liver fibrosis, providing novel molecular insights into the anti-fibrotic effect of PSG.
Assuntos
Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Emodina/análogos & derivados , Glucosídeos/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Sirtuínas/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Tetracloreto de Carbono , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/metabolismo , Emodina/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/enzimologia , Cirrose Hepática Experimental/patologia , Masculino , Ratos Sprague-Dawley , Transdução de Sinais , Sirtuínas/genéticaRESUMO
Background: Evidence on the association of non-alcoholic fatty liver disease (NAFLD), a public health concern, with dietary fiber intake is inconsistent. Objective: To investigate the relationship between dietary fiber intake from different sources and NAFLD risk in US adults. Methods: Data were collected from the 2007-2014 National Health and Nutrition Examination Survey. NAFLD was defined as a United States Fatty Liver Index ≥30, and dietary fiber intake was assessed through two 24-h dietary recall interviews. Logistic regression and restricted cubic spline models were used to explore the relationship of dietary intakes of total, cereal, fruit, and vegetable fiber with NAFLD risk. Results: A total of 6,613 participants, aged more than 20 years, were included in this study. After adjusting for multiple confounding factors, the odds ratios and 95% confidence intervals of NAFLD for the highest quartile vs. lowest quartile intakes of total, cereal, fruit, and vegetable fiber were 0.12 (0.08-0.16), 0.25 (0.19-0.33), 0.41 (0.33-0.52), and 0.42 (0.32-0.56), respectively. In stratified analyses by sex and age, statistically significant negative associations of dietary intakes of total, cereal, fruit, and vegetable fiber with NAFLD risk were observed in all participants. Dose-response analysis indicated a non-linear correlation between NAFLD risk and dietary intake of total fiber, whereas the relationship was linear for cereal, fruit, and vegetable fiber intakes. Conclusion: Total, cereal, fruit, and vegetable fiber intakes exhibit negative correlations with NAFLD risk in the general adult population in the United States.