Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 541
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34639452

RESUMO

The collaborative assessment and health risk evaluation of heavy metals (HMs) enrichment in soils and tea leaves are crucial to guarantee consumer safety. However, in high soil HM geochemical background areas superimposed by human activities, the health risk associated with HMs in soil-tea systems is not clear. This study assessed the HMs concentration (i.e., chromium (Cr), cadmium (Cd), arsenic (As), and lead (Pb)) in tea leaves and their relationship with soil amounts in the southwest region of China to evaluate the associated health risk in adults. The results revealed that the average soil concentration of Cr was the highest (79.06 mg kg-1), followed by Pb (29.27 mg kg-1), As (14.87 mg kg-1), and Cd (0.18 mg kg-1). Approximately 0.71, 4.99, 7.36, and 10.21% of soil samples exceeded the threshold values (NY/T 853-2004) for Pb, Cr, As, and Cd, respectively. Furthermore, the average concentration of Pb, As, and Cd in tea leaves was below the corresponding residue limits, but Cr was above the allowed limits. Correlation analysis revealed that the Pb, Cr, As, and Cd amounts in tea leaves were positively correlated to their soil amounts (p < 0.01) with an R2 of 0.203 **, 0.074 **, 0.036 **, and 0.090 **, respectively. Additionally, approximately 40.38% of the samples were found to be contaminated. Furthermore, spatial distribution statistical analysis revealed that Lancang was moderately contaminated, while Yingjiang, Zhenkang, Yongde, Zhenyuan, Lüchun, Jingdong, Ximeng, and Menglian were slightly contaminated areas. The target hazard quotients (THQ; health risk assessment) of Pb, Cr, As, and Cd and the hazard index (HI) of all the counties were below unity, suggesting unlikely health risks from tea consumption.

2.
Front Public Health ; 9: 729778, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621721

RESUMO

Objective: This study aimed to evaluate the effects of intensified Chinese special rectification activity on clinical antibiotic use (CSRA) policy on a tertiary-care teaching hospital. Methods: A 48-month longitudinal dataset involving inpatients, outpatients, and emergency patients were collected. Study period included pre-intervention stage (adopting soft measures like systemic training) and post-intervention stage (applying antibiotic control system to intensify CSRA policy). Antibiotic use was evaluated by antibiotic use rate (AUR) or antibiotic use density (AUD). Economic indicator was evaluated by antibiotic cost in prescription or antibiotic expenditure in hospitalization. Data was analyzed by interrupted time series (ITS) analysis. Results: The medical quality indicators remained stable or improved during the study period. AUR of inpatients (AURI) declined 0.553% per month (P = 0.025) before the intervention and declined 0.354% per month (P = 0.471) after the intensified CSRA policy was implemented. AUD, expressed as defined daily doses per 100 patients per day (DDDs/100PD), decreased by 1.102 DDDs/100PD per month (P = 0.021) before and decreased by 0.597 DDDs/100PD per month (P = 0.323) thereafter. The ratio of antibiotic expenditure to medication expenditure (AE/ME) decreased by 0.510% per month (P = 0.000) before and fell by 0.096% (P = 0.000) per month thereafter. AE per patient decreased by 25.309 yuan per month (P = 0.002) before and decreased by 7.987 yuan per month (P = 0.053) thereafter. AUR of outpatient (AURO) decreased by 0.065% per month before (P = 0.550) and decreased by 0.066% per month (P = 0.994) thereafter. The ratio of antibiotic cost to prescription cost in outpatient (ACO/PCO) decreased by 0.182% per month (P = 0.506) before and decreased by 0.216% per month (P = 0.906) thereafter. AUR of emergency patient (AURE) decreased by 0.400% per month (P = 0.044) before and decreased by 0.092% per month (P = 0.164) thereafter. The ratio of antibiotic cost to prescription cost in emergency patient (ACE/PCE) decreased by 0.616% per month (P < 0.001) before and decreased by 0.151% per month (P < 0.001) thereafter. Conclusions: Implementation of CSRA policy was associated with declining antibiotic use and antibiotic expenditure in inpatients, outpatients, and emergency patients. However, it is also important to note that the declining trend of antibiotic consumption slowed due to the limited capacity for decline in the later stages of CSRA intervention.

3.
J Clin Pharm Ther ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34664290

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Prolonged antibiotic prophylaxis after total joint arthroplasty (TJA) may not assist in minimizing postoperative complications, however, data based on the Chinese population have been limited. The purpose of this study is to investigate the effect of antibiotic prophylaxis on postoperative complications after TJA in Chinese patients. METHODS: We retrospectively reviewed 990 patients undergoing elective primary TJA surgery from January 2016 to June 2019. Patients who received a short course (≤3 days) of antibiotic prophylaxis were compared with those who received a longer course (>3 days). Logistic regression analysis and subgroup analysis were performed to control for potential confounders. Beyond that, survival analysis was used to determine the cumulative incidence of postoperative complications. RESULTS AND DISCUSSION: Follow-up to 12 months after surgery, the prevalence of system complications in the longer course group and the short course group were 5.1% and 3.9%, respectively (p = 0.451). Similarly, no statistical differences in incisional complications (1.5% vs. 1.8%, p > 0.999) and periprosthetic joint infection (PJI) (1.0% vs. 1.0%, p > 0.999) were observed between the two groups. After performing logistic regression analysis and survival analysis, no potential association was found between the course of antibiotic prophylaxis and postoperative complications. In addition, prolonged antibiotic prophylaxis conferred no benefit for high-risk obese patients. WHAT IS NEW AND CONCLUSION: Extended antibiotic prophylaxis did not result in a statistically significant and clinically meaningful reduction in postoperative complications. Therefore, we recommended that the duration of antibiotic prophylaxis in TJA should be shortened to 3 days or less in the Chinese population.

4.
Pharmacol Res Perspect ; 9(6): e00870, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34664792

RESUMO

Zanubrutinib is a highly selective, potent, orally available, targeted covalent inhibitor (TCI) of Bruton's tyrosine kinase (BTK). This work investigated the in vitro drug metabolism and transport of zanubrutinib, and its potential for clinical drug-drug interactions (DDIs). Phenotyping studies indicated cytochrome P450 (CYP) 3A are the major CYP isoform responsible for zanubrutinib metabolism, which was confirmed by a clinical DDI study with itraconazole and rifampin. Zanubrutinib showed mild reversible inhibition with half maximal inhibitory concentration (IC50 ) of 4.03, 5.69, and 7.80 µM for CYP2C8, CYP2C9, and CYP2C19, respectively. Data in human hepatocytes disclosed induction potential for CYP3A4, CYP2B6, and CYP2C enzymes. Transport assays demonstrated that zanubrutinib is not a substrate of human breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP)1B1/1B3, organic cation transporter (OCT)2, or organic anion transporter (OAT)1/3 but is a potential substrate of the efflux transporter P-glycoprotein (P-gp). Additionally, zanubrutinib is neither an inhibitor of P-gp at concentrations up to 10.0 µM nor an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, and OAT3 at concentrations up to 5.0 µM. The in vitro results with CYPs and transporters were correlated with the available clinical DDIs using basic models and mechanistic static models. Zanubrutinib is not likely to be involved in transporter-mediated DDIs. CYP3A inhibitors and inducers may impact systemic exposure of zanubrutinib. Dose adjustments may be warranted depending on the potency of CYP3A modulators.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34651253

RESUMO

Increasing evidence suggests that antibiotic administration causes gut injury, negatively affecting nutrient digestion, immune regulation, and colonization resistance against pathogens due to the disruption of gut microbiota. However, the time-course effects of therapeutic antibiotics on alterations of gut microbes and short-chain fatty acids (SCFAs) in young swine are still unknown. In this study, twenty piglets were assigned into two groups and fed commercial diets with or without lincomycin in the first week for a 28-day trial period. Results showed that 1-week lincomycin exposure (LE) did reduce the body weight on day 14 (p = 0.0450) and 28 (p = 0.0362). The alpha-diversity notably reduced after 1-week LE, and then gradually raised and reached the control group level in the second week on cessation of LE, indicated by the variation of Sobs, Chao, Shannon, and ACE index (p < 0.05). Beta-diversity analysis revealed that the distinct microbial cluster existed persistently for the whole trial period between two groups (p < 0.001). The relative abundance of most microbes including fiber-degrading (e.g., Agathobacter and Coprococcus), beneficial (e.g., Lactobacillus and Mitsuokella), or pathogenic bacteria (e.g., Terrisporobacter and Lachnoclostridium) decreased (LDA score > 3), and the concentration of SCFAs also diminished in the feces of 1-week lincomycin-administrated young swine, indicating that therapeutic LE killed most bacteria and reduced SCFA production with gut dysbiosis occurring. After the LE stopped, the state of gut dysbiosis gradually attenuated and formed new gut-microbe homeostasis distinct from microbial homeostasis of young pigs unexposed to lincomycin. The increased presence of potential pathogens, such as Terrisporobacter, Negativibacillus, and Escherichia-Shigella, and decreased beneficial bacteria, such as Lactobacillus and Agathobacter, were observed in new homeostasis reshaped by short-lincomycin administration (LDA score > 3 or p < 0.05), adversely affecting gut development and health of young pigs. Collectively, these results suggested that severe disruption of the commensal microbiota occurred after short-term LE or termination of LE in young swine. KEY POINTS: • Therapeutic lincomycin exposure induced gut dysbiosis, killing most bacteria and reducing short-chain fatty acid production. • Gut dysbiosis gradually attenuated and formed new homeostasis after lincomycin exposure stopped. • The new homeostasis, increased Escherichia-Shigella etc. and decreased Lactobacillus etc., was potentially harmful to gut health.

6.
Anal Chem ; 93(40): 13727-13733, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34596402

RESUMO

As an early-stage tumor biomarker, microRNA (miRNA) has clinical application potential and its sensitive and accurate detection is significant for early tumor diagnosis. In this study, a photoelectrochemical (PEC) biosensing platform was fabricated for ultrasensitive miRNA-141 detection, which is based on a photocurrent polarity-switchable system using CdS quantum dots (QDs) in the presence of a 5,10,15,20-tetrakis (4-aminophenyl)-21H,23H-porphine (Tph-2H)-coated glassy carbon electrode (GCE). As an excellent photoactive material, Tph-2H has a narrow band gap that effectively gathers photoelectrons under visible light irradiation and improves the transfer ability of photogenerated electrons. Further, the detection sensitivity of miRNA-141 could be significantly improved by combining an enzyme-assisted recycle amplification reaction and a magnetic bead-based separation strategy. The proposed photocurrent polarity-switchable PEC biosensor could efficiently eliminate the false-positive or false-negative signals and achieve a wide linear response range from 1 fM to 1 nM with a low detection limit of 0.33 fM for miRNA-141, providing a potentially alternative solution for detecting other biomarkers in bioanalysis and clinical diagnosis.


Assuntos
Biomarcadores Tumorais/análise , Técnicas Biossensoriais , MicroRNAs/análise , Pontos Quânticos , Técnicas Eletroquímicas , Humanos , Limite de Detecção
7.
ACS Chem Neurosci ; 12(19): 3672-3682, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34505505

RESUMO

Protein kinase C (PKC) isozymes play essential roles in biological processes, and activation of PKC is proposed to alleviate the symptoms of a variety of diseases. It would be of great significance to find effective pharmacological modulators of PKC isozymes that can be translated for clinical use. Here, using in vitro activity assay, we demonstrated that green tea extract (-)-epigallocatechin-3-gallate (EGCG) dose-dependently activated PKCα with a half effective concentration (EC50) of 0.49 µM. We also performed surface plasmon resonance analysis and found that EGCG binds PKCα with an equilibrium dissociation constant (KD) value of 4.11 × 10-6 mol/L. Further computational flexible docking analysis revealed that EGCG interacted with the catalytic C3-C4 domain of PKCα (PDB: 4RA4) through establishing polar hydrogen bonds with V420, T401, E387, and K368 of PKCα, and the benzene ring group of EGCG hydrophobically interacted with the hydrophobic pocket formed by L345, M470, I479, and V353 of PKCα. Interestingly, the PKCα-selective blocker Ro-32-0432 could compete with EGCG for the same substrate-binding pocket of PKCα. Moreover, we found that EGCG dose-dependently improved the spatial memory, object recognition ability, and hippocampal long-term potentiation of ovariectomized mice, which was offset by Ro-32-0432. Collectively, our findings reveal a novel PKCα agonist and open the way to a new perspective on PKCα pharmacology and the treatment of PKCα-related diseases, including cognitive impairment.

8.
PLoS One ; 16(8): e0256028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383815

RESUMO

China is shifting from the stage of large-scale bridge construction to the stage of equal emphasis on the construction and maintenance of bridges. The problems of low efficiency and high cost in bridge inspection are becoming more and more prominent, which threaten people's life safety. In this paper, the deterioration state prediction model of concrete beam bridge under Boosting DT C5.0 was established as the basis, and optimization suggestions were put forward in terms of bridge inspection standards and processes, which aims to perfect the bridge inspection mechanism, realize the fine management of the bridge and prolong the service life of the bridge. Research shows that: first, the bridge inspection standard with a single index should be improved into the bridge inspection standard with multiple indexes, so as to scientifically determine the bridges that need to be inspected and optimize the allocation of maintenance resources. Second, the bridge deterioration state prediction model is used to add a screening mechanism for the bridge in the inspection plan, which can effectively reduce the workload of bridge inspection and enhance the inspection efficiency. Third, the deterioration phenomenon of coexistence between adjacent traffic assets should be fully considered and the linkage inspection mechanism of adjacent traffic assets should be established to improve the effect of bridge inspection.

9.
Int J Mol Sci ; 22(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34445732

RESUMO

Infection with viruses, such as the lactate dehydrogenase-elevating virus (LDV), is known to trigger the onset of autoimmune anemia through the enhancement of the phagocytosis of autoantibody-opsonized erythrocytes by activated macrophages. Type I interferon receptor-deficient mice show enhanced anemia, which suggests a protective effect of these cytokines, partly through the control of type II interferon production. The development of anemia requires the expression of Fcγ receptors (FcγR) I, III, and IV. Whereas LDV infection decreases FcγR III expression, it enhances FcγR I and IV expression in wild-type animals. The LDV-associated increase in the expression of FcγR I and IV is largely reduced in type I interferon receptor-deficient mice, through both type II interferon-dependent and -independent mechanisms. Thus, the regulation of the expression of FcγR I and IV, but not III, by interferons may partly explain the exacerbating effect of LDV infection on anemia that results from the enhanced phagocytosis of IgG autoantibody-opsonized erythrocytes.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Infecções por Arterivirus/imunologia , Interferons/metabolismo , Vírus Elevador do Lactato Desidrogenase/imunologia , Receptores de IgG/metabolismo , Anemia Hemolítica Autoimune/virologia , Animais , Infecções por Arterivirus/virologia , Interações Hospedeiro-Patógeno , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose
10.
Adv Ther ; 38(10): 5116-5126, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34417989

RESUMO

INTRODUCTION: The survival of patients with relapsed small cell lung cancer (SCLC) has achieved little progress in the last several decades. ALTER1202 confirmed the efficacy and safety of anlotinib as a third- or further-line option for relapsed SCLC. This study aimed to assess the cost-effectiveness of anlotinib compared with placebo as third- or further-line treatment for advanced SCLC in China. METHODS: A Markov model was developed to simulate the process of advanced SCLC and estimate the incremental cost-effectiveness ratio (ICER) of anlotinib versus placebo. The health outcomes and utilities were derived from the ALTER1202 (NCT03059797) and published sources, respectively. Total costs were calculated from the perspective of Chinese society. One-way and probabilistic sensitivity analyses (PSA) were conducted to explore the model uncertainties. RESULTS: Anlotinib was estimated to result in an additional 0.12 quality-adjusted life-years (QALYs) at an incremental cost of $2131.32, resulting in an ICER of $17,741.94/QALY. The ICER did not exceed the willingness-to-pay (WTP) threshold of $30,833 per QALY, which was three times the gross domestic product (GDP) per capita of China in 2019. One-way sensitivity analysis showed that the cost of anlotinib exerted the maximum influence on the result of the model, followed by the utility of progression-free survival (PFS) state in the anlotinib group and median overall survival (mOS) in the anlotinib group. In PSA, the probability of anlotinib being cost-effective was 26.6% and 78.5% when the WTP threshold was one and three times the GDP per capita, respectively. CONCLUSION: Anlotinib is likely to be a cost-effective option compared with placebo for patients with relapsed SCLC who experience failure of at least two lines of chemotherapy in China.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , China , Análise Custo-Benefício , Humanos , Indóis , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Anos de Vida Ajustados por Qualidade de Vida , Quinolinas , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
11.
J Inorg Biochem ; 223: 111558, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34329998

RESUMO

Photo-chemotherapy (PCT) reveals great potential in hepatocellular carcinoma (HCC) treatment, therefore the construct of smart PCT nano-agents with high photothermal conversion efficiency and accurate drug delivery is of great significant. Herein, a novel hybrid nanomaterial MGO-TCA-FA has been designed and constructed by grafting the triformyl cholic acid (TCA) and folic acid (FA) on the surface of Fe3O4 modified graphene oxide (MGO). The doxorubicin hydrochloride (DOX) as a model drug could be effectively loaded on the MGO-TCA-FA via hydrogen bonding and π-π stacking (the drug loading amount was 1040 mg/g). The formed MGO-TCA-FA@DOX has been developed to be an effective PCT nanoplatform with the advantages of multiple-targeted drug delivery, near-infrared light (NIR) and pH triggered drug release, and photothermal conversion efficiency. In vitro experiments showed that compared with other cancer cells and normal liver cells, MGO-TCA-FA@DOX could specifically target liver cancer cells and presented significant killing ability to liver cancer cells. More importantly, in vivo experiments indicated that PCT synergistic therapy (MGO-TCA-FA@DOX) revealed the best tumor inhibition (the tumor inhibition rate was about 85%) compared with chemotherapy and photothermal therapy alone. Thus, this study supplied a viable multiple-targeted PCT nano-agent for chemo-photothermal combination therapy of liver cancer.

12.
Ann Palliat Med ; 10(6): 6425-6437, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237964

RESUMO

BACKGROUND: There is a close relationship between cardiovascular risk factors and polycystic ovary syndrome (PCOS), and omega-3 fatty acids may have a key role in improving cardiovascular risk factors. We conducted the current systematic review and meta-analysis to evaluate the effect of omega-3 fatty acid supplementation on cardiovascular risk factors in patients with PCOS. METHODS: We searched 4 databases including PubMed (MEDLINE), Cochrane Library, Embase, and Web of Science from inception to February 2021. We included randomized controlled trials (RCTs) that reported the effects of omega-3 fatty acid treatment for PCOS. According to the Cochrane system evaluation guide manual, 2 researchers independently assessed the methodological quality of the included studies. We pooled results using either a fixed effect model or random effect model. RESULTS: We identified 314 articles, of which 10 met the criteria for inclusion, involving 778 participants. The pooled results suggested an association between the supplementation of omega-3 fatty acids and a reduction in serum insulin [-2.58 pmol/L, 95% confidence interval (CI): -3.34 to -1.82 pmol/L, P<0.00001, I2=0], homeostatic model assessment of insulin resistance (HOMA-IR) (-0.57, 95% CI: -0.75 to -0.40 L, P<0.00001, I2=2%), serum total cholesterol (TC) (-6.87 mg/dL, 95% CI: -10.28 to -3.47 mg/dL, P<0.0001, I2=95%), serum triglyceride (-4.03 mg/dL, 95% CI: -5.53 to -2.52 mg/dL, P<0.00001, I2=97%), serum low-density lipoprotein cholesterol (LDL-C) (-6.64 mg/dL, 95% CI: -11.58 to -1.70 mg/dL, P=0.008, I2=99%), serum very low-density lipoprotein cholesterol (VLDL-C) (-3.29 mg/L, 95% CI: -6.54 to -0.05 mg/L, P=0.05, I2=72%), serum high-sensitivity C-reactive protein (hs-CRP) (-8.97mg/dL, 95% CI: -17.66 to -0.28 mg/dL, P=0.04, I2=99%), an improvement in serum high-density lipoprotein cholesterol (HDL-C) (2.94 mg/dL, 95% CI: 0.63 to 5.26 mg/dL, P=0.01, I2=87%), but no effect on serum glucose (-0.76 mg/dL, 95% CI: -1.71 to 0.19 mg/dL, P=0.12, I2=73%) was found. DISCUSSION: The current meta-analysis demonstrated that omega-3 fatty acid supplementation for women with PCOS resulted in a statistical improvement in insulin, HOMA-IR, TC, triglyceride, LDL-C, VLDL-C, and HDL-C, but did not affect serum glucose. The limitation of this paper is due to the lack of included research literature.


Assuntos
Ácidos Graxos Ômega-3 , Resistência à Insulina , Síndrome do Ovário Policístico , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico
13.
Nucleic Acids Res ; 49(13): 7476-7491, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34197614

RESUMO

Poly (ADP-ribose) polymerase inhibitor (PARPi)-based therapies initially reduce tumor burden but eventually lead to acquired resistance in cancer patients with BRCA1 or BRCA2 mutation. To understand the potential PARPi resistance mechanisms, we performed whole-genome CRISPR screens to discover genetic alterations that change the gene essentiality in cells with inducible depletion of BRCA2. We identified that several RNA Polymerase II transcription Mediator complex components, especially Cyclin C (CCNC) as synthetic survival targets upon BRCA2 loss. Total mRNA sequencing demonstrated that loss of CCNC could activate the transforming growth factor (TGF)-beta signaling pathway and extracellular matrix (ECM)-receptor interaction pathway, however the inhibition of these pathways could not reverse cell survival in BRCA2 depleted CCNC-knockout cells, indicating that the activation of these pathways is not required for the resistance. Moreover, we showed that the improved survival is not due to restoration of homologous recombination repair although decreased DNA damage signaling was observed. Interestingly, loss of CCNC could restore replication fork stability in BRCA2 deficient cells, which may contribute to PARPi resistance. Taken together, our data reveal CCNC as a critical genetic determinant upon BRCA2 loss of function, which may help the development of novel therapeutic strategies that overcome PARPi resistance.


Assuntos
Proteína BRCA2/genética , Ciclina C/genética , Proteína BRCA2/metabolismo , Sistemas CRISPR-Cas , Sobrevivência Celular , Dano ao DNA , Replicação do DNA , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Complexo Mediador/genética , Complexo Mediador/fisiologia , Reparo de DNA por Recombinação , Estresse Fisiológico/genética
14.
Nucleic Acids Res ; 49(14): 8214-8231, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34320214

RESUMO

Because of essential roles of DNA damage response (DDR) in the maintenance of genomic integrity, cellular homeostasis, and tumor suppression, targeting DDR has become a promising therapeutic strategy for cancer treatment. However, the benefits of cancer therapy targeting DDR are limited mainly due to the lack of predictive biomarkers. To address this challenge, we performed CRISPR screens to search for genetic vulnerabilities that affect cells' response to DDR inhibition. By undertaking CRISPR screens with inhibitors targeting key DDR mediators, i.e. ATR, ATM, DNAPK and CHK1, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Specifically, we identified YWHAE loss as a key determinant of sensitivity to CHK1 inhibition. We showed that KLHL15 loss protects cells from DNA damage induced by ATM inhibition. Moreover, we validated that APEX1 loss sensitizes cells to DNAPK inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results enhance the understanding of DDR pathways and will facilitate the use of DDR-targeting agents in cancer therapy.


Assuntos
Proteínas 14-3-3/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinase 1 do Ponto de Checagem/genética , Dano ao DNA/genética , Proteína Quinase Ativada por DNA/genética , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Sistemas CRISPR-Cas/genética , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Instabilidade Genômica/genética , Humanos , Proteínas dos Microfilamentos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
15.
Biomed Res Int ; 2021: 6648429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239930

RESUMO

Species of Tulipa (Liliaceae) are of great horticultural importance and are distributed across Europe, North Africa, and Asia. The Tien Shan Mountain is one of the primary diversity centres of Tulipa, but the molecular studies of Tulipa species from this location are lacking. In our study, we assembled four Tulipa plastid genomes from the Tien Shan Mountains, T. altaica, T. iliensis, T. patens, and T. thianschanica, combined with the plastid genome of T. sylvestris to compare against other Liliaceae plastid genomes. We focussed on the species diversity and evolution of their plastid genomes. The five Tulipa plastid genomes proved highly similar in overall size (151,691-152,088 bp), structure, gene order, and content. With comparative analysis, we chose 7 mononucleotide SSRs from the Tulipa species that could be used in further population studies. Phylogenetic analyses based on 24 plastid genomes robustly supported the monophyly of Tulipa and the sister relationship between Tulipa and Amana, Erythronium. T. iliensis, T. thianschanica, and T. altaica were clustered together, and T. patens was clustered with T. sylvestris, with our results clearly demonstrating the relationships between these five Tulipa species. Our results provide a more comprehensive understanding of the phylogenomics and comparative genomics of Tulipa.


Assuntos
Genomas de Plastídeos , Plastídeos/genética , Tulipa/genética , Evolução Biológica , Códon , DNA de Plantas/genética , Evolução Molecular , Ordem dos Genes , Genômica , Liliaceae/genética , Repetições de Microssatélites , Nucleotídeos/genética , Filogenia , Polimorfismo de Nucleotídeo Único
16.
J Am Chem Soc ; 143(25): 9314-9319, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34154323

RESUMO

All radical S-adenosylmethionine (radical-SAM) enzymes, including the noncanonical radical-SAM enzyme diphthamide biosynthetic enzyme Dph1-Dph2, require at least one [4Fe-4S](Cys)3 cluster for activity. It is well-known in the radical-SAM enzyme community that the [4Fe-4S](Cys)3 cluster is extremely air-sensitive and requires strict anaerobic conditions to reconstitute activity in vitro. Thus, how such enzymes function in vivo in the presence of oxygen in aerobic organisms is an interesting question. Working on yeast Dph1-Dph2, we found that consistent with the known oxygen sensitivity, the [4Fe-4S] cluster is easily degraded into a [3Fe-4S] cluster. Remarkably, the small iron-containing protein Dph3 donates one Fe atom to convert the [3Fe-4S] cluster in Dph1-Dph2 to a functional [4Fe-4S] cluster during the radical-SAM enzyme catalytic cycle. This mechanism to maintain radical-SAM enzyme activity in aerobic environments is likely general, and Dph3-like proteins may exist to keep other radical-SAM enzymes functional in aerobic environments.

17.
Int J Epidemiol ; 50(4): 1384-1393, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34113988

RESUMO

A primary goal of longitudinal studies is to examine trends over time. Reported results from these studies often depend on strong, unverifiable assumptions about the missing data. Whereas the risk of substantial bias from missing data is widely known, analyses exploring missing-data influences are commonly done either ad hoc or not at all. This article outlines one of the three primary recognized approaches for examining missing-data effects that could be more widely used, i.e. the shared-parameter model (SPM), and explains its purpose, use, limitations and extensions. We additionally provide synthetic data and reproducible research code for running SPMs in SAS, Stata and R programming languages to facilitate their use in practice and for teaching purposes in epidemiology, biostatistics, data science and related fields. Our goals are to increase understanding and use of these methods by providing introductions to the concepts and access to helpful tools.


Assuntos
Biometria , Modelos Estatísticos , Viés , Bioestatística , Humanos , Estudos Longitudinais
18.
Bioorg Med Chem Lett ; 43: 128080, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33964439

RESUMO

Saponin is an active component of many phytomedicine, which has extensive pharmacology effects. Meanwhile, it is reported that cytotoxicity, especially hemolysis and hepatotoxicity, in pentacyclic triterpenoid saponin (PTS) hindered their further development and application. Surface activity, a unique physical property of saponins, is believed to be related to membrane toxicity. However, the correlation between the surface activity and cytotoxicity of saponins is still unexplained. In this paper, our aim was to explore the relationship between surface activity-cytotoxicity of pulchinenosides and the hepatotoxicity mechanism of PTS in vitro. The surface activity of different saponins was investigated by contact angle, surface free energy (SFE), and oil/water partition coefficient (log Papp). In the cytotoxicity study, the hemolysis and hepatotoxicity activity of different saponins was compared by HD50 of erythrocyte and MTT, flow cytometry and LDH assay in LO2 cells respectively. And in the hepatotoxicity mechanism study, western blot was used for observing the expression of proteins related to apoptosis and exploring the liver injury mechanism of PTS. The results suggested that the influences of surface activity on hepatocytes and erythrocytes were different, indicating that the correlation of surface activity-cytotoxicity could provide more information for development of PTS. And the result of hepatotoxicity mechanism study of saponins suggested that endogenous and exogenous apoptotic pathways could be the potential targets of PTS, which could not only provide basis for clinical monitoring and treatment of the toxicity in saponins, but also provide more reference for the clinical application of PTS and phytomedicine containing PTS.

19.
J Am Acad Audiol ; 32(3): 186-194, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34030194

RESUMO

BACKGROUND: Balance dysfunction is a complex, disabling health condition that can present with multiple phenotypes and etiologies. Data regarding prevalence, characterization of dizziness, or associated factors is limited, especially in an African American population. PURPOSE: The aim of the study is to characterize balance dysfunction presentation and prevalence in an African American cohort, and balance dysfunction relationship to cardiometabolic factors. RESEARCH DESIGN: The study design is descriptive, cross sectional analysis. STUDY SAMPLE: The study sample consist of N = 1,314, participants in the Jackson Heart Study (JHS). DATA COLLECTION AND ANALYSIS: JHS participants were presented an initial Hearing health screening questionnaire (N = 1,314). Of these, 317 participants reported dizziness and completed a follow-up Dizziness History Questionnaire. Descriptive analysis was used to compare differences in the cohorts' social-demographic characteristics and cardiometabolic variables to the 997 participants who did not report dizziness on the initial screening questionnaire. Based on questionnaire responses, participants were grouped into dizziness profiles (orthostatic, migraine, and vestibular) to further examine differences in cardiometabolic markers as related to different profiles of dizziness. Logistical regression models were adjusted for age, sex, education, reported noise exposure, and hearing sensitivity. RESULTS: Participants that reported any dizziness were slightly older and predominantly women. Other significant complaints in the dizzy versus nondizzy cohort included hearing loss, tinnitus, and a history of noise exposure (p < 0.001). Participants that reported any dizziness had significantly higher prevalence of hypertension, blood pressure medication use, and higher body mass index (BMI). Individuals with symptoms alluding to an orthostatic or migraine etiology had significant differences in prevalence of hypertension, blood pressure medication use, and BMI (p < 0.001). Alternatively, cardiometabolic variables were not significantly related to the report of dizziness symptoms consistent with vestibular profiles. CONCLUSION: Dizziness among African Americans is comparable to the general population with regards to age and sex distribution, accordingly to previously published estimates. Participants with dizziness symptoms appear to have significant differences in BMI and blood pressure regulation, especially with associated orthostatic or migraine type profiles; this relationship does not appear to be conserved in participants who present with vestibular etiology symptoms.

20.
Biochemistry (Mosc) ; 86(5): 568-576, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33993864

RESUMO

Recent studies have predominantly focused on the role of B cells in metabolic diseases, yet the function of B cells in adipose homeostasis remains unclear. Pax transactivation domain-interacting protein (PTIP), a licensing factor for humoral immunity, is necessary for B cell development and activation. Here, using mice that lack PTIP in B cells (PTIP-/- mice), we explored the role of B cells in adipose homeostasis under physiological conditions. Fat deposition in 8-week-old mice was measured by micro-CT, and PTIP-/- mice presented a marked decrease in the deposition of subcutaneous adipose tissue (SAT). Untargeted lipidomics revealed that the triglyceride composition in SAT was altered in PTIP-/- mice. In addition, there was no difference in the number of adipocyte progenitor cells in the SAT of wild-type (WT) and PTIP-/- mice as measured by flow cytometry. To study the effects of steady-state IgM and IgG antibody levels on fat deposition, PTIP-/- mice were injected intraperitoneally with serum from WT mice once every 3-4 days for 4 weeks. The iSAT mass of the recipient mice showed no significant increase in comparison to the controls after 4 weeks of injections. Our findings reveal that PTIP plays an essential role in regulating subcutaneous adipocyte size, triglyceride composition, and fat deposition under physiological conditions by controlling B cells. The decreased subcutaneous fat deposition in PTIP-/- mice does not appear to be related to the number of adipocyte progenitor cells. The steady-state levels of IgM and IgG antibodies in vivo are not associated with the subcutaneous fat deposition.


Assuntos
Linfócitos B/metabolismo , Proteínas de Ligação a DNA/genética , Gordura Subcutânea/metabolismo , Animais , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos , Células-Tronco , Gordura Subcutânea/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...