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Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-ß-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.
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An effective intramolecular C-H arylation reaction catalyzed by a bimetallic catalytic system Pd(OAc)2/CuI for the synthesis of fluorine-substituted carbazoles from corresponding N-phenyl-2-haloaniline derivatives under ligand free conditions is demonstrated. The established method is effective for both N-phenyl-2-bromoaniline and N-phenyl-2-chloroaniline, and requires the low loading of Pd(OAc)2 (0.5 mol%). A series of new fluorinated carbazoles were synthesized in excellent yields using the protocol (>83%, 19 examples) and were fully characterized by (1)H, (13)C and (19)F NMR spectral data, HRMS and elemental analysis. All compounds were evaluated for their antibacterial activities against four bacteria (Bacillus subtilis, Staphylococcus aureus, Escherichia coli and methicillin-resistant S. aureus with resistance to gentamicin) by serial dilution technique. All tested compounds showed antibacterial activity against three test strains (S. aureus, B. subtilis and MRSA), and most of these compounds displayed pronounced antimicrobial activities against these three strains with low MIC values ranging from 0.39 to 6.25 µg/mL. Among them, compounds 7 and 14 exhibited potent inhibitory activity better than reference drugs meropenem and streptomycin. Three compounds (2, 4 and 5) showed antibacterial activity against E. coli. with MIC values from 12.5 to 25 µg/mL.
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Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbazóis/síntese química , Carbazóis/farmacologia , Cobre/química , Flúor/química , Paládio/química , Antibacterianos/química , Bacillus subtilis/efeitos dos fármacos , Carbazóis/química , Catálise , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organometálicos/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Light-chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains within the proximal tubular epithelial cells, which is usually classified into crystalline and noncrystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Here, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ light chains restricted) and antigen-undetermined MN in a male patient. The patient presented with low-molecular-weight proteinuria, increased serum creatinine levels, and incomplete Fanconi syndrome. To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens, which may enrich our recognition of monoclonal gammopathy of renal significance with synchronous MN.
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pH could play vital role in the wound healing process due to the bacterial metabolites, which is one essential aspect of desirable wound dressings lies in being pH-responsive. This work has prepared a degradable hyaluronic acid hydrogel dressing with wound pH response-ability. The aldehyde-modified hyaluronic acid (AHA) was obtained, followed by complex mixture formation of eugenol and oregano antibacterial essential oil in the AHA-CMCS hydrogel through the Schiff base reaction with carboxymethyl chitosan (CMCS). This hydrogel composite presents pH-responsiveness, its disintegration mass in acidic environment (pH = 5.5) is 4 times that of neutral (pH = 7.2), in which the eugenol release rate increases from 37.6 % to 82.1 %. In vitro antibacterial and in vivo wound healing investigations verified that hydrogels loaded with essential oils have additional 5 times biofilm removal efficiency, and significantly accelerate wound healing. Given its excellent anti-biofilm and target-release properties, the broad application of this hydrogel in bacteria-associated wound management is anticipated.
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Antibacterianos , Biofilmes , Ácido Hialurônico , Hidrogéis , Óleos Voláteis , Cicatrização , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Cicatrização/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Concentração de Íons de Hidrogênio , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Quitosana/química , Quitosana/análogos & derivados , Quitosana/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Testes de Sensibilidade Microbiana , BandagensRESUMO
Nifedipine is a potent antihypertensive medication classified as a dihydropyridine calcium channel blocker. The objective of this trial was to assess the bioequivalence of a 30-mg nifedipine controlled-release tablet and a reference drug in a cohort of healthy Chinese individuals. Two independent open-label, randomized, single-dose, crossover studies were conducted, 1 under fasting conditions (N = 44, with 1 participant dropping out midway) and the other under fed conditions (N = 44, with 4 participants dropping out midway). Plasma concentrations of nifedipine were determined using liquid chromatography-mass spectrometry, and pharmacokinetic (PK) parameters were calculated using noncompartmental analysis with Phoenix WinNonlin 8.0 software. In both fasting and fed studies, reasonable bioequivalence was observed for the PK parameters of both the test product and the reference drug. A good safety profile was demonstrated for both the test product and reference drug, with no serious adverse events reported, and both were similarly well tolerated. An important observation with food coadministration was that systemic exposure to nifedipine (based on area under the curve, AUC0-∞) was reduced by approximately 12%. The bioequivalence of the test product and reference drug under fasting/fed conditions in healthy subjects in China was demonstrated by the study results.
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Área Sob a Curva , Bloqueadores dos Canais de Cálcio , Estudos Cross-Over , Preparações de Ação Retardada , Jejum , Interações Alimento-Droga , Nifedipino , Comprimidos , Equivalência Terapêutica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Povo Asiático , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , China , População do Leste Asiático , Voluntários Saudáveis , Nifedipino/farmacocinética , Nifedipino/administração & dosagem , Nifedipino/efeitos adversosRESUMO
BACKGROUND AND AIMS: The potential of urinary-derived extracellular vesicle (uEV) microRNAs (miRNAs) as noninvasive molecular biomarkers for identifying early-stage renal cell carcinoma (RCC) patients is rarely explored. The present study aims to explore the possibility of uEV miRNAs as novel molecular biomarkers for distinguishing early-stage RCC. MATERIALS AND METHODS: uEVs were extracted by ExoQuick-TC™ kit and miRNA concentrations were measured by RT-qPCR. ROC curves and bioinformatics analysis were employed to predict the diagnostic efficacy and regulatory mechanisms of dysregulated miRNAs. RESULTS: Through a multiphase case-control study on uEV miRNAs screening, training, and validation in RCC cells (ACHN, Caki-1) and control cells (HK-2) and in uEVs of 125 RCC patients and 128 age- and sex-matched controls, we successfully identified four uEVs miRNAs (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR-203a-3p) were significantly and stably upregulated in RCC in vitro and in vivo. When adjusted with estimated glomerular filtration rate (eGFR), the AUC of the three-uEV miRNA panel (miR-135b-5p, miR-200c-3p, and miR-203a-3p) was 0.785 (95 % CI = 0.729-0.842, P < 0.0001) for discriminating RCC patients from controls. Notably, this panel exhibited similar performance in distinguishing early-stage (stage â ) RCC patients, with an AUC of 0.786 (95 %CI = 0.727-0.844, P < 0.0001). Bioinformatics analysis predicted that candidate miRNAs were involved in cancer progressing. CONCLUSION: Our study identified a four uEV miRNAs panel (miR-135b-5p, miR-196b-5p, miR-200c-3p, and miR-203a-3p) may serve as an auxiliary noninvasive indication of early-stage RCC.
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Carcinoma de Células Renais , Vesículas Extracelulares , Neoplasias Renais , MicroRNAs , Humanos , MicroRNAs/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Estudos de Casos e Controles , Biomarcadores Tumorais/genética , Biomarcadores , Vesículas Extracelulares/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/genéticaRESUMO
Cat-scratch disease (CSD) is an anthropozoonotic infection caused by Bartonella henselae, and it is one of the most common causes of lymph node infections in children and adolescents. B. henselae, belonging to the genus Bartonella, is a common human pathogen of human beings. CSD commonly develops as a result of cat scratches and bites or when injured skin comes into contact with cat saliva. The manifestation of CSD clinically differs for each patient based on their immune system. Individuals who have healthy immune systems generally manifest minimal clinical symptoms and do not necessitate any form of treatment. However, patients who have hypo-immunity require prompt medical attention due to the potential manifestation of severe symptoms that affect multiple systems of the body. Long latency and atypical clinical manifestations are characteristics of CSD. Bartonella isolation and identification are challenging procedures that require specialized equipment. There is no gold standard method for CSD diagnosis, and misdiagnosis and missed diagnosis rates are typically high. We present the case of a middle-aged male patient who developed fever, chills, anal distension, dizziness, and muscle pain for 10 days. The patient had a documented history of cat bites 1 month prior to the onset of symptoms. Following admission, he underwent an examination to determine superficial lymphadenopathy and hypoimmunity. Additionally, he had a fever during the disease. As the patient refused a needle biopsy of lymph nodes, metagenomic next-generation sequencing (mNGS) was employed and B. henselae was detected in the peripheral blood. The patient was diagnosed with CSD and treated with a combination of azithromycin and doxycycline. The fever symptoms were alleviated, and the patient was ultimately discharged. As a result of this case, we suggest that mNGS be used as a crucial supplementary diagnostic tool for individuals with compromised immune systems who may have CSD, especially when conventional diagnostic methods are inconclusive.
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Bartonella henselae , Bartonella , Doença da Arranhadura de Gato , Criança , Pessoa de Meia-Idade , Adolescente , Humanos , Masculino , Doença da Arranhadura de Gato/diagnóstico , Doença da Arranhadura de Gato/tratamento farmacológico , Bartonella henselae/genética , Linfonodos/patologia , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
AIM: To evaluate the regulation of the aberrant expression of collagen type IV alpha 1 chain (COL4A1) in the development of age-related cataract (ARC). METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analysis were employed to evaluate the expression of COL4A1 in ARC patients and healthy controls. The proliferation, apoptosis, cell cycle and epithelial-mesenchymal transition (EMT) of human lens epithelial cell (HLE-B3) were further analyzed under the condition of COL4A1 gene silence. Alteration of gene expression at mRNA level after knockdown COL4A1 were also evaluated by qRT-PCR on HLE-B3 cells. RESULTS: The aberrant expression of COL4A1 was identified a clinically associated with the ARC. Silencing of COL4A1 promoted the apoptosis and inhibited the proliferation of HLE-B3 by blocking the cell cycle. Moreover, COL4A1 gene silence didn't affect the cytoskeleton of HLE-B3 but down-regulated the Collagen type IV Alpha 2 Chain (COL4A2), paired box 6 (PAX6), procollagen-lysine 2-oxoglutarate 5-dioxygenases 1 (PLOD1) and procollagen-lysine 2-oxoglutarate 5-dioxygenases 2 (PLOD2) expression levels in HLE-B3 cells. Silencing the COL4A1 gene induced EMT of the HLE-B3 cells by promoting the transforming growth factor beta (TGF-ß) expression. CONCLUSION: Silencing of COL4A1 induces S-phase arrest, also inhibits the proliferation and enhance HLE-B3 apoptosis and EMT, and down-regulates the expression of COL4A2, PAX6, PLOD1 and PLOD2. Thus, the expression alteration of COL4A1 may play a critical role in the pathogenesis of ARC.
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Purpose: Nosocomial infection (NI) is associated with poor prognosis. The present study assessed the clinical and microbiological characteristics of NI patients in the intensive care unit (ICU) and investigated the clinical impact and risk factors for NI in ICU patients. Patients and Methods: An observational study was conducted in an adult general ICU. The electronic medical records of all patients admitted to the ICU for >2 days from 2018-2020 were analyzed retrospectively. Multivariate regression models were used to analyze the risk factors for NI in ICU patients. Propensity score-matching (PSM) was used to control the confounding factors between the case and control groups, thus analyzing the clinical impact of NIs. Results: The present study included 2425 patient admissions, of which 231 (9.53%) had NI. Acinetobacter baumannii (33.0%) was the most common bacteria. Long-term immunosuppressive therapy, disturbance of consciousness, blood transfusion, multiple organ dysfunction syndromes (MODS), treatment with three or more antibiotics, mechanical ventilation (MV), tracheotomy, the urinary catheter (UC), nasogastric catheter, and central venous catheter (CVC) were risk factors for NI in the ICU patients. After PSM, patients with NI had a prolonged length of stay (LOS) in the ICU and hospital, significant hospitalization expenses (all p<0.001), increased mortality (p=0.027), and predicted mortality (p=0.007). The differences in the ICU and hospital LOSs among three pathogens were statistically significant (p<0.001); the results of the Escherichia coli infection group were lower than the other two pathogenic groups. Conclusion: NI was associated with poor outcomes. The risk factors for NI identified in this study provided further insight into preventing NI.
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OBJECTIVE: To investigate the radiosensitized target of Fuzheng Zengxiao Formula. METHODS: The pulmonary adenocarcinoma (PAa) nude mice of tumor transplantation model were prepared and divided into four groups: Group I (blank control group, n = 10), Group II (simple radiotherapy group, n = 10), Group III (radiotherapy plus Fuzheng Zengxiao Formula, n = 10) and Group IV (radiotherapy plus metronidazole, n = 10). Radiation of X-rays was given to the tumors in Group I, II and III when they were averagely about 1 centimetre in diameter. 23 hours later, the tumors were taken, the total proteins were extracted, and the protein contents were determined. The proteins were isolated with two dimensional gel electrophoresis, and the differentially expressed proteins were analyzed with mass spectrometry and identified by protein database. RESULTS: Six significant proteins, including apolipoprotein E, ceratin75, S100A9, cyclophilin A, S100A10 and hemoglobin, were determined. Compared with Group I, apolipoprotein E and ceratin75 highly expressed in the Group II; compared with Group II, S100A9, cyclophilin A and hemoglobin had high expression in the Group III; compared with Group II, S100A9, cyclophilin A, S100A10 and hemoglobin had high expression in the Group IV; compared with Group IV, S100A9 and S100A10 had low expression and hemoglobin had high expression in Group III. CONCLUSION: The radiosensitization of Fuzheng Zengxiao Formula is related with the improvement of hypoxia state; and possibly S100A9 and cyclophilin A are the target proteins of Fuzheng Zengxiao Formula in radiosensitization.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Radiossensibilizantes/administração & dosagem , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Modelos Animais de Doenças , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos da radiação , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Nus , ProteômicaRESUMO
Extracellular ATP (eATP) is an important biological signal transduction molecule. Although a variety of detection methods have been extensively used in ATP sensing and analysis, accurate detection of eATP remains difficult due to its extremely low concentration and spatiotemporal distribution. Here, an eATP measurement strategy based on tetrahedral DNA (T-DNA)-modified electrode sensing platform and hybridization chain reaction (HCR) combined with G-quadruplex/Hemin (G4/Hemin) DNAzyme dual signal amplification is proposed. In this strategy, ATP aptamer and RNA-cleaving DNAzyme were combined to form a split aptazyme. In the presence of ATP, this aptazyme hydrolyzes the cleaving substrate strand with high selectivity, releasing cleaved ssDNA, which are captured by the T-DNA assembled on the electrode surface, triggering an HCR on the electrode surface to form numerous linker sequences of the HCR dsDNA product. When G-quadruplex@AuNPs (G4) spherical nucleic acid enzymes (SNAzymes) with other linkers are used as nanocatalyst tags, they are captured by HCR dsDNA through sticky linkers present on the electrode surface. An amplified electrochemical redox current signal is generated through SNAzyme-mediated catalysis of H2O2, enabling easy detection of picomole amounts of ATP. Using this strategy, eATP levels released by tobacco suspension cells were accurately measured and the distribution and concentration of eATP released on the surface of an Arabidopsis leaf was determined.
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Técnicas Biossensoriais , DNA Catalítico , Nanopartículas Metálicas , Trifosfato de Adenosina , DNA , DNA Catalítico/metabolismo , Técnicas Eletroquímicas , Eletroquímica , Ouro , Peróxido de Hidrogênio , Hibridização de Ácido NucleicoRESUMO
INTRODUCTION: This study aimed to examine the medication prescriptions for hypertension in a class 1 and grade A hospital in Shanxi province to provide references for clinical rational drug use. METHODS: An inpatient medical record inquiry system was used to evaluate the use of antihypertensives in a hypertensive population (age ≥ 18 years old) who received a prescription for one or more antihypertensives between January 2017 and December 2019. The hypertensive population was categorized into grades (1, 2, and 3), age groups, and different comorbidities to analyze the medication prescriptions. Drug analysis included angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor antagonist (ARB), calcium channel blocker (CCB), diuretics, and beta-receptor blockers (B-RB). SPSS16.0 was used for statistical analysis, including one-way analysis of variance (ANOVA,) chi-squared test, and multifactor logistic regression analysis. RESULTS: The overall control rate of blood pressure was 60.79%. The control rates of single, double, triple, and quadruple antihypertensives were 70.08%, 59.97%, 56.27%, and 45.23%, respectively. There were more cases of grade 3 than grades 1 and 2. The 18-65 years group was larger than the 66-79 years and ≥ 80 years groups. With the increase in grade, the prescription rate of the single drug decreased and the prescription rate of the combination drug increased, but this phenomenon was not obvious in different age groups. The most common drug prescribed for monotherapy was CCB; CCB combined with B-RB had the highest drug use in the double group by age or grade. Statistically significant differences were detected in the type of comorbidities between different age groups (P < 0.001), while only some differences were observed between different grades. Also, statistically significant differences were observed in the drugs prescribed for patients with hypertension with different comorbidities (P < 0.001). Factors influencing the efficiency of antihypertensives included sex, age, diabetes, heart failure, and usage of CCB and B-RB. The prescription rate of ARB combined with B-RB was relatively higher in grade 2 cases. B-RB was the primary drug for patients with diabetes, significantly increasing the blood glucose level. CONCLUSIONS: The medication prescription of this hospital was in line with the requirements of China's hypertension prevention and treatment guidelines. The pathophysiology of patients with hypertension in different age groups, increased use of combination drugs, and rational drug requirement should be considered when prescribing drugs.