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1.
Leukemia ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635784

RESUMO

FZR1 has been implicated as a master regulator of the cell cycle and quiescence, but its roles and molecular mechanisms in the pathogenesis of severe aplastic anemia (SAA) are unclear. Here, we report that FZR1 is downregulated in SAA HSCs compared with healthy control and is associated with decreased quiescence of HSC. Haploinsufficiency of Fzr1 shows impaired quiescence and self-renewal ability of HSC in two Fzr1 heterozygous knockout mouse models. Mechanistically, FZR1 insufficiency inhibits the ubiquitination of RUNX1 protein at lysine 125, leading to the accumulation of RUNX1 protein, which disturbs the quiescence of HSCs in SAA patients. Moreover, downregulation of Runx1 reversed the loss of quiescence and impaired long-term self-renew ability in Fzr1+/- HSCs in vivo and impaired repopulation capacity in BM from SAA patients in vitro. Our findings, therefore, raise the possibility of a decisive role of the FZR1-RUNX1 pathway in the pathogenesis of SAA via deregulation of HSC quiescence.

2.
Anat Rec (Hoboken) ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34636492

RESUMO

Spinal cord injury (SCI) is one of the serious central nervous system injuries and the incidence of SCI continues to increase. Previous studies have indicated that electroacupuncture (EA) is beneficial for promoting recovery after SCI. In the present study, we attempted to evaluate how EA can promote the neural repair in SCI model rats by observing changes in the Notch signaling pathway. Experimental rats were randomly divided into four groups. Each group had its own intervention period: 1 day, 7 days, 14 days, and 28 days, and five randomized subgroups: blank control (B) group, blank electroacupuncture (BE) group, sham operation (S) group, model control (M) group and EA group. Animals in the EA group and the BE group were treated with EA at Dazhui (GV14) and Mingmen (GV4) acupoints for 20 min. After the intervention period, the Basso-Beattie-Bresnahan (BBB) score was used to evaluate the neurological function. We found that BBB score increased in EA-treated groups. Hematoxylin and eosin staining was used to observe pathological changes in the injured spinal cord and the results showed that EA therapy could promote the repair of injured spinal cord tissue. Immunohistochemistry and Western blot methods were used to detect the expression of proteins Delta1, Presenilin1, Hes1, and Hes5 in the injured spinal cord. The results showed that the expression levels of Delta1, Presenilin1, Hes1, and Hes5 increased significantly after SCI and decreased after EA treatment. Our study suggested that the possible mechanism by which EA could benefit the recovery after SCI in rats may include inhibiting the Notch signaling pathway and regulating the downstream proteins expression. In addition, our study can provide reference for selecting acupoints and treatment cycle in the treatment of SCI.

3.
Bioengineered ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34592889

RESUMO

Exosomes are emerging tools for transporting lipids, proteins, microRNAs (miRNAs), or other biomarkers for clinical purposes. They have produced widespread concern in managing human diseases, including osteosarcoma (OS). This study focuses on the function of serum-derived exosomal miR-15a in the growth of OS cells and the mechanism of action. Differentially expressed genes between OS and normal samples were screened using two datasets GSE70367 and GSE65071. miR-15a was poorly expressed, whereas GATA-binding protein 2 (GATA2) and murine double minute 2 (MDM2) were abundantly expressed in OS samples. miR-15a and its target mRNAs, including GATA2, were enriched in the p53 signaling pathway. miR-15a directly targets GATA2 mRNA to inhibit its expression, whereas GATA2 activates the transcription of MDM2, a negative regulator of p53. Overexpression of GATA2 and MDM2 promoted proliferation and cell cycle progression of MG-63 cells, whereas miR-15a blocked this axis and suppressed cell growth. miR-15a was identified as a major cargo of serum-derived exosomes, and exosomes conveying miR-15a were internalized by OS cells. This study demonstrated that miR-15a suppresses the GATA2/MDM2 axis to inhibit the proliferation and invasiveness of OS cells in vitro through the p53 signaling pathway.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34595543

RESUMO

PURPOSE: To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH). METHODS: We compared the clinical features of 37 children with MAP2K1-mutated LCH with those of the BRAFV600E mutation group (n = 133) and no known mutation group (n = 59) in the same period. RESULTS: We found 13 mutations of the MAP2K1 gene, which were mainly concentrated at p.53-62 and p.98-103. The most common mutation site was c.172_186del (12/37). Compared with the BRAFV600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single-system multiple bone involvement (P = 0.022), with later disease onset (P = 0.029) as well as less involvement of risk organs, especially liver (P = 0.024). There was no significant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival rate of first-line treatment (ChiCTR1900025783, 07/09/2019) in MAP2K1-mutated patients was 65.6% ± 9.5%. The prognosis of patients with lung involvement was poor [HR (95% CI) = 6.312 (1.769-22.526), P = 0.005]. More progression or relapses could be found in patients with bony thorax involvement (8/17 vs. 2/20, P = 0.023), yet involvements in other sites of bones, such as craniofacial bone involvement (8/26 vs. 2/11, P = 0.688) and limb bone involvement (5/12 vs. 5/25, P = 0.240), were not correlated to disease progression or relapse. CONCLUSION: The children with MAP2K1-mutated LCH have specific clinical features requiring clinical stratification and precise treatment. MAP2K1-mutated patients with lung involvement (especially with bony thorax involvement) had poor prognosis.

7.
Anat Rec (Hoboken) ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469051

RESUMO

Alzheimer's disease (AD) is a fatal neurodegenerative disease for which currently no cure is available. Electroacupuncture (EA) has been widely used in China as an alternative therapeutic approach for neurological diseases. The cognitive decline in patients with AD has been reported to be closely related to the deposition of amyloid-ß (Aß) in the hippocampus of the brain, and the Morris water maze (MWM) test is a widely used method for assessing the behavior of animal models. In this study, the MWM test was performed to evaluate the effects of EA treatment on cognitive function and memory, and the micro-positron emission tomography scan was used to assess the hippocampal Aß deposition. The results showed that the cognitive function of APP/PS1 mice was significantly improved and the rate of [18F]AV-45 uptake was reduced in the EA group, compared with the AD group. Our study suggested that EA can exert a therapeutic effect in AD by improving spatial learning and memory and inhibiting the hippocampal Aß deposition.

8.
Ecotoxicol Environ Saf ; 225: 112763, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34544025

RESUMO

In this research, micro Coix lacryma-jobi L. vertical flow constructed wetlands (VFCWs) were set up using domestic sewage (DWS) and 1/2 Hoagland nutrient solution (HNS) as VFCWs water sources. 0, 20 mg L-1 and 40 mg L-1 of Cr6+ (in the form of K2Cr7O2) were added into the water sources separately in order to study the response of Coix lacryma-jobi L. under Cr6+ stress. The results showed that the inhibition rates of Cr6 + on plant height, stem diameter, shoot and root dry weight treated with HNS were 2.88~10.16%, 5.12~11.86%, 3.53~6.51% and 2.89~6.34% higher than those in DWS treatment. SEM analysis showed that the nuclear bilayer membrane was slightly damaged, the chromatin decreased and the number of mitochondrial cristae decreased when treated with 20 mg L-1 of Cr6+, however, organelle damage was more severe under 40 mg L-1 of Cr6+exposure. The X-ray energy spectrum analysis results indicated that the accumulation of chromium in epidermis and endodermis were higher than those in stele. The contents of total Cr in roots, stems and leaves treated with HNS were higher than those of DWS treatment. The highest content of Cr was observed in cell wall (32.12-188.1 mg kg-1), followed by vacuole (5.0-38.14 mg kg-1). The contents of Cr in each subcellular component in roots, stems, and leaves treated with HNS were higher than those of DWS, except for organelle components in the 14th week. DWS was used as water influent, the contents of easily migrated combined Cr (ETM) in roots, stems and leaves were significantly lower than those in HNS treatment. Improving the nutritional conditions of constructed wetlands might be beneficial to the improvement of their ability to purify chrome-containing waste water.


Assuntos
Coix , Cromo/toxicidade , Esgotos , Águas Residuárias , Áreas Alagadas
9.
Sci Total Environ ; : 150546, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34582862

RESUMO

The concentrations of 75 polychlorinated naphthalene (PCN) congeners in 95 human serum samples from the Fengjiang electronic waste dismantling area and Huangyan District in Taizhou City (Zhejiang Province, China) were determined. Thyroid hormone (FT3, FT4, TSH, and TRH) concentrations in the samples were also determined. The total PCN concentrations in the samples from Fengjiang and Huangyan were 1.29 × 104-4.28 × 105 and 8.29 × 102-6.45 × 105 pg/g lipid, respectively. The less-chlorinated (Cl1-3) PCN concentrations were relatively high in all of the samples, and the concentrations in the samples from the two areas were not significantly different. The sums of the combustion-related PCN congener concentrations were significantly higher in the samples from Fengjiang than in the samples from Huangyan, and the sums of the more-chlorinated (Cl4-8) PCNs were slightly higher in the samples from Fengjiang than in the samples from Huangyan. The relationship between the PCN concentration and age indicated that electronic waste controls have decreased human exposure to PCNs but that attention should still be paid to exposure to less-chlorinated PCNs. The main PCN congeners that contributed to the toxic equivalent concentrations were markedly different for the samples from Fengjiang and Huangyan. CN-66/67 was dominant for the Fengjiang samples and CN-10 was dominant for the Huangyan samples. Attention should be paid to the risks posed by less-chlorinated PCNs to human health. CN-1, CN-2, and CN-20 concentrations are related to human thyroid hormone levels, and the relationships between less-chlorinated PCN concentrations and thyroid hormone concentrations should be further studied.

10.
BMJ Open ; 11(9): e045655, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518248

RESUMO

INTRODUCTION: Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder that presents with abdominal pain/discomfort and altered bowel patterns. IBS has multiple potential causes for which conventional medicines have had limited success, resulting in a significant number of patients who do not sensitively respond to pharmacotherapy for a period of 12 months and who develop a continuing symptom profile (described as refractory IBS) and seek help through (non)pharmacological treatments. The aim of this study is to investigate the efficacy and safety of acupuncture therapy for refractory IBS on the basis of conventional treatments. METHODS AND ANALYSIS: A total of 170 eligible patients who meet the Rome IV criteria for refractory IBS will be randomly allocated to receive acupuncture or sham acupuncture. Each patient will receive 12 sessions of acupuncture over 4 weeks and a 4-week follow-up. The primary outcome will be the IBS Symptom Severity Score. Secondary outcomes will include the proportion of participants experiencing adequate relief of global IBS symptoms, the weekly frequency of defecation, the stool properties assessed by the Bristol Grading Scale, the Work and Social Adjustment Scale, the IBS-Quality of Life score, and the Self-Rating Depression Scale and Self-Rating Anxiety Scale anxiety and depression scores. Outcome measures will be collected at baseline, 2 and 4 weeks of the intervention, and 6 and 8 weeks after the intervention. Categorical variables will be compared with Fisher's exact test or the Wilcoxon rank-sum test, and continuous variables will be compared using Student's t-test or the Wilcoxon rank-sum test. ETHICS AND DISSEMINATION: The entire project has been approved by the ethics committees of Beijing University of Chinese Medicine (2020BZYLL0507) and Sichuan Province Regional Institution for Conducting Research on Traditional Chinese Medicine (2020KL-025). The outcomes of the trial will be disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04276961.

12.
Ann Surg Oncol ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426885

RESUMO

OBJECTIVE: The aim of this study was to explore the occurrence and prognostic value of perineural invasion (PNI) as a classic tumor pathological feature in esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively enrolled 794 ESCC patients who underwent radical esophagectomy at Shanghai Chest Hospital from 2017 to 2018. The incidence, associated factors, and prognosis of PNI were analyzed. RESULTS: PNI was identified in 15.7% (125/794) of patients. The presence of PNI was significantly associated with depth of invasion (p < 0.001), pN stage (p = 0.008), tumor stage (p < 0.001), and lymphovascular invasion (LVI; p < 0.001). Multivariate logistic regression analysis demonstrated that advanced pT stage and LVI were independently associated with the presence of PNI, while multivariate Cox regression analysis demonstrated that PNI was not an independent risk factor for poor overall survival (OS) or recurrence-free survival (RFS) in ESCC patients (OS hazard ratio [HR] 0.688, 95% confidence interval [CI] 0.448-1.056, p = 0.087; RFS HR 0.837, 95% CI 0.551-1.273, p = 0.406). In the PNI-positive patient subgroup, adjuvant therapy was associated with better OS and RFS. CONCLUSION: PNI correlates with, and may be a concomitant consequence of, LVI and advanced tumor invasion (T3-4) in ESCC patients. Although PNI was not identified as an independent prognostic indicator, our results suggest ESCC patients with PNI should be considered for adjuvant therapy.

13.
Lancet ; 398(10302): 759-771, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454674

RESUMO

BACKGROUND: First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. METHODS: We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. FINDINGS: Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. INTERPRETATION: Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. FUNDING: Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrevida
14.
Materials (Basel) ; 14(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361392

RESUMO

As the applications of heterogeneous materials expand, aluminum laminates of similar materials have attracted much attention due to their greater bonding strength and easier recycling. In this work, an alloy design strategy was developed based on accumulative roll bonding (ARB) to produce laminates from similar materials. Twin roll casting (TRC) sheets of the same composition but different cooling rates were used as the starting materials, and they were roll bonded up to three cycles at varying temperatures. EBSD showed that the two TRC sheets deformed in distinct ways during ARB processes at 300 °C. Major recrystallizations were significant after the first cycle on the thin sheet and after the third cycle on the thick sheet. The sheets were subject to subsequent aging for better mechanical properties. TEM observations showed that the size and distribution of nano-precipitations were different between the two sheet sides. These nano-precipitations were found to significantly promote precipitation strengthening, and such a promotive effect was referred to as hetero-deformation induced (HDI) strengthening. Our work provides a new promising method to prepare laminated heterogeneous materials with similar alloy TRC sheets.

15.
Biotechnol Lett ; 43(10): 1989-1999, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34392452

RESUMO

OBJECTIVES: In our previous study, citrate was used as auxiliary energy substance for improving cAMP fermentation performance, however, the regulation mechanism of citrate on improved cAMP contents was not clear. To elucidate the regulation mechanism, cAMP fermentations with/without citrate addition were conducted in a 7 L fermentor using Arthrobacter sp. CCTCC 2013431 and assays on key enzymes activities, energy metabolism level, amino acids contents and peroxidation level were performed. RESULTS: With 3 g/L-broth sodium citrate added, cAMP concentration and conversion yield from glucose reached 4.34 g/L and 0.076 g/g which were improved by 30.7% and 29.8%, respectively, when compared with those of control. Citrate changed carbon flux distribution among different routes and more carbon flux was directed into pentose phosphate pathway beneficial to cAMP synthesis. Meanwhile, energy metabolism together with precursor amino acids levels were improved significantly owing to strengthened metabolic intensity of tricarboxylate cycle by exogenous citrate utilization which provided energy and substance basis for cAMP production. Moreover, higher glutamate synthesis and oxidative stress caused by citrate addition consumed excessive NADPH derived from pentose phosphate pathway by which feedback suppression for pentose phosphate pathway was relieved efficiently. CONCLUSION: Citrate promoted cAMP fermentation production by Arthrobacter sp. CCTCC 2013431 due to enhanced precursor amino acids, energy metabolism level and relieved feedback suppression for pentose phosphate pathway.

16.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120229, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34371316

RESUMO

In this paper, a one-dimensional shallow convolutional neural network structure combined with elastic nets (1D-SCNN-EN) was firstly proposed to predict the glucose concentration of blood by Raman spectroscopy. A total of 106 different blood glucose spectra were obtained by Fourier transform (FT) Raman spectroscopy. The one-dimensional shallow convolutional neural network, with elastic nets added to the full connected layer, was presented to capture multiple deep features and reduce the complexity of the model. The 1D-SCNN-EN model has a better performance than conventional approaches (partial least squares and support vector machine). The root mean squared error of calibration (RMSEC), the root mean squared error of prediction (RMSEP), the determination coefficient of prediction (RP2), and the residual predictive deviation of prediction (RPD) were 0.10262, 0.11210, 0.99403, and 12.94601, respectively. The experiment results showed that the 1D-SCNN-EN model has a higher prediction accuracy and stronger robustness than the other regression models. The overall studies indicated that the 1D-SCNN-EN model looked promising for predict the glucose concentration of blood by Raman spectroscopy when the sample size is small.

17.
Chemosphere ; 286(Pt 2): 131725, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34352539

RESUMO

The development of biosensors is critical to reducing potential risks associated with contamination accidents. However, the application of microbial electrochemical sensors for water biotoxicity monitoring is hampered by the lack of an indicator with high response magnitudes. In this study, microbial electrochemical sensors were fabricated with interdigitated electrode arrays (IDAs), and indicators from various electrochemical analyses were comprehensively investigated. Only the peak of cyclic voltammetry (CV) was highly linearly correlated with the commonly used current indicator during the enrichment of the electroactive biofilm. The resistance fitted from the electrochemical impedance spectroscopy (EIS) data provided a comparable and even higher inhibition ratio (IR) than the current during toxicity assessments. The differential pulse voltammetry (DPV) did not exhibit a higher sensitivity than the CV peak. However, no clear response was observed in the real-time impedance analysis for use in water biotoxicity monitoring. Most of the microbes were in the propidium iodide (PI)-permeable state after the toxicity assessments, although the current was fully recovered. This study demonstrates the potential to use EIS data as indicators of water biotoxicity using microbial electrochemical sensors.

18.
Nat Commun ; 12(1): 4457, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294701

RESUMO

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Idoso , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Código das Histonas/genética , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Oncogenes , Fatores de Transcrição/genética
19.
Ecotoxicol Environ Saf ; 222: 112513, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34274839

RESUMO

The heavy metals pollution and related health issues were widely reported in e-waste sites, while the impacts of e-waste exposure on the essential trace elements have been neglected. The aim of this study was focused on the internal Cu, Fe, Mn and Zn levels in the residents from an e-waste site and the potential endocrine disrupting effects of these essential trace elements on the hypothalamic-pituitary-thyroid (HPT) axis. This was a cross-sectional study that 87 subjects were recruited from the e-waste site and 81 from the reference site. The results indicated that the e-waste exposed group had significantly lower Fe, Mn level when compared with the reference group (p < 0.05). Cu and Zn were also lower in the exposed group but the differences were not statistically significant. The exposed group had significantly higher TSH level and Fe was significantly associated with TSH in the females (ß (95% CI): - 1.892 (-3.309, -0.475), p = 0.009), rather than in males or all subjects. The exposed group also showed oxidative stress which was indicated by the increased concentrations of MDA and 8-iso-PG. It was further indicated the elevated MDA was mediated by the increase of TSH in the females but not directly related to Fe. In conclusion, the e-waste exposed group showed a decrease of essential trace elements, an increase of TSH and oxidative stress. The decreased Fe was related to the elevated TSH in the females, which further indirectly mediated the increase of oxidative stress. The results suggested that the internal exposure levels and the potential health effects of the essential trace elements in populations from e-waste sites should be of more concern. And the women might be more vulnerable and they need more protection to against the adverse health effects from e-waste.


Assuntos
Resíduo Eletrônico , Oligoelementos , Estudos Transversais , Feminino , Hormônios , Humanos , Masculino , Glândula Tireoide/química , Oligoelementos/análise
20.
Oncogene ; 40(34): 5302-5313, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34247189

RESUMO

The prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory due to limited effective treatment options. In this work, we investigated the therapeutic efficacy of Terbinafine for HCC and the underlying mechanism. The influence of Terbinafine on cell growth, 3D spheroid formation, clonogenic survival, and protein synthesis was investigated in human HCC cell lines. Co-immunoprecipitation, immunofluorescence, and other techniques were employed to explore how Terbinafine exerts its anticancer effect. Subcutaneous tumorigenicity assay, orthotopic and patient-derived xenograft (PDX) HCC models were used to evaluate the anticancer effect of Terbinafine monotherapy and the combinatorial treatment with Terbinafine and sorafenib against HCC. The anticancer activity of Terbinafine was Squalene epoxidase (SQLE)-independent. Instead, Terbinafine robustly suppressed the proliferation of HCC cells by inhibiting mTORC1 signaling via activation of AMPK. Terbinafine alone or in combination with sorafenib delayed tumor progression and markedly prolonged the survival of tumor-bearing mice. The synergy between Terbinafine and sorafenib was due to concomitant inhibition of mTORC1 and induction of severe persistent DNA double-strand breaks (DSBs), which led to the delayed proliferation and accelerated cell death. Terbinafine showed promising anticancer efficacy in preclinical models of HCC and may serve as a potential therapeutic strategy for HCC.

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