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1.
Curr Opin Pharmacol ; 61: 12-20, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34547701

RESUMO

Serine lies at a critical node in biological processes involved in supplying intermediates for redox homeostasis, nucleotide, or lipid biosynthesis and one-carbon metabolism-coupled methyl donor production. Recently, dietary serine supplementation has been reported to modulate cellular serine levels and ameliorate neurological abnormalities induced by serine deficiency. Moreover, growing evidence showed that serine supplementation also alleviates fatty liver, encephalopathy, diabetes mellitus, and related complications, indicating the possibility of serine supplementation as a complementary therapeutic option. However, considering the serine addiction observed in tumorigenesis and tumor development, limitations may exist regarding the application of dietary serine supplementation in patients with cancer. Here, we assess recent research toward the mechanistic understanding of serine supplementation in various diseases to improve our cognition on modulating serine levels in different patients.

2.
Dev Cell ; 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34428430

RESUMO

The mechanism of vulnerability to pediatric low-grade gliomas (pLGGs)-the most common brain tumor in children-during development remains largely unknown. Using mouse models of neurofibromatosis type 1 (NF1)-associated pLGGs in the optic pathway (NF1-OPG), we demonstrate that NF1-OPG arose from the vulnerability to the dependency of Mek-Erk/MAPK signaling during gliogenesis of one of the two developmentally transient precursor populations in the optic nerve, brain-derived migrating glial progenitors (GPs), but not local progenitors. Hyperactive Erk/MAPK signaling by Nf1 loss overproduced GPs by disrupting the balance between stem-cell maintenance and gliogenesis of hypothalamic ventricular zone radial glia (RG). Persistence of RG-like GPs initiated NF1-OPG, causing Bax-dependent apoptosis in retinal ganglion cells. Removal of three Mek1/Mek2 alleles or transient post-natal treatment with a low-dose MEK inhibitor normalized differentiation of Nf1-/- RG-like GPs, preventing NF1-OPG formation and neuronal degeneration. We provide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.

3.
Cancer Lett ; 521: 210-223, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34428517

RESUMO

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide and lacks effective treatment. Herein, we found that the antifungal Natamycin (NAT) exhibits antitumor activity by inducing apoptosis both in vitro and in vivo. Mechanistically, NAT downregulates the expression of Peroxiredoxin 1 (PRDX1) by promoting ubiquitination-mediated degradation, thereby leading to increased reactive oxygen species (ROS) accumulation and subsequent apoptosis. Exogenous overexpression of PRDX1 or N-acetyl-l-cysteine (NAC) pretreatment abrogates NAT-induced cytotoxicity in PLC/PRF/5 and Huh7 cells, suggesting the vital role of ROS in the antitumor properties of NAT. Of note, downregulation of PRDX1 decreases the phosphorylation of AKT, thereby inducing cytoprotective autophagy and combinational use of NAT and chloroquine (CQ) achieves better anti-tumor efficacy. Moreover, NAT acts synergistically with sorafenib (SOR) in HCC suppression. Collectively, our study provides an important molecular basis for NAT-induced cell death and suggests that the antifungal NAT holds the potential to be repurposed as an anticancer drug for HCC treatment.

4.
Brain Behav ; 11(8): e2277, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34232562

RESUMO

OBJECTIVES: Early recognition and intervention of patients with the anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis are important to achieve a better prognosis. The study aims to summarize the real-world perspectives of anti-NMDAR encephalitis patients in China via electronic medical records (EMRs). METHODS: Using EMRs of patients from 2013 to 2019 from West China Hospital in China, a retrospective research was conducted to demonstrate the temporary rank of clinical characteristics and disease prognosis of anti-NMDAR encephalitis. The modified Rankin Scale (mRS) scores were used to divide the anti-NMDAR-encephalitis into two groups (poor prognosis vs. good prognosis). Chi-square test and logistic regression were used to analyze factors associated with prognosis. RESULTS: Here, 78 patients were included. The most common clinical characteristics are cognitive dysfunction (86.0%) and thought disorder (86.0%). Cognitive dysfunction, thought disorder, and seizures tended to appear soon after prodrome symptoms. Logistics analysis results showed that cognitive dysfunction (OR = 4.48, 95% CI = 1.09-18.47), the score of (GCS ≤ 8) (OR = 4.52, 95% CI = 1.18-17.32), positive antibodies in serum (OR = 4.89, 95% CI = 1.19-20.13) and delay immunotherapy (OR = 4.76, 95% CI = 1.79-12.60) were risk factors of poor clinical outcomes. CONCLUSIONS: There are two peaks in the development of autoimmune encephalitis (AE). The first peak is cognitive dysfunction, and the second peak is autonomic dysfunction. Cognitive dysfunction and GCS score ≤8 at admission, antibodies positive in serum, and delay immunotherapy were risk factors for a poor prognosis at discharge.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Humanos , Imunoterapia , Prognóstico , Receptores de N-Metil-D-Aspartato , Estudos Retrospectivos , Fatores de Risco
5.
DNA Cell Biol ; 40(7): 979-987, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34227845

RESUMO

Long noncoding RNA X-inactive specific transcript (XIST) has been identified as a crucial regulator in neurodegenerative disorders. However, the role and mechanism of XIST in ischemic stroke remain elusive. In our study, we found that XIST expression was upregulated in both mice subjected to middle cerebral artery occlusion and oxygen-glucose deprivation (OGD)-treated neurons. Functional assays disclosed that the interference of XIST accelerated viability, and suppressed apoptosis and caspase-3 activity in OGD-treated neurons. Moreover, XIST interacted with miR-98, and miR-98 targeted BTB-to-CNC homology 1 (BACH1). miR-98 silencing or BACH1 overexpression counteracted XIST knockdown-mediated effects on cell viability and apoptosis in OGD-treated neurons. In conclusion, our data demonstrated that XIST facilitated the progression of ischemic stroke through regulating the miR-98/BACH1 axis. These findings might provide a novel therapeutic strategy for ischemic stroke treatment.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , AVC Isquêmico/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Apoptose/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Isquemia Encefálica/genética , Sobrevivência Celular/genética , China , Glucose/metabolismo , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Neurônios/metabolismo , Oxigênio/metabolismo , RNA Longo não Codificante/metabolismo , Acidente Vascular Cerebral/genética
6.
Nat Commun ; 12(1): 4310, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262026

RESUMO

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Macrófagos/transplante , Fotoquimioterapia/métodos , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos/química , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Indóis/administração & dosagem , Indóis/química , Indóis/farmacologia , Raios Infravermelhos , Macrófagos/química , Nanomedicina , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxaliplatina/administração & dosagem , Oxaliplatina/química , Oxaliplatina/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia
7.
Mol Med Rep ; 24(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34109421

RESUMO

Alexander disease (AxD) is a cerebral white matter disease affecting a wide range of ages, from infants to adults. In the present study, two cases of bulbospinal form AxD were reported, and a preliminary exploration of AxD was conducted thorough clinical, functional magnetic resonance imaging (fMRI) and functional analyses. In total, two de novo mutations in the glial fibrillary acidic protein (GFAP) gene (c.214G>A and c.1235C>T) were identified in unrelated patients (one in each patient). Both patients showed increased regional neural activity and functional connectivity in the cerebellum and posterior parietal cortex according to fMRI analysis. Notably, grey matter atrophy was discovered in the patient with c.214G>A variant. Functional experiments revealed aberrant accumulation of mutant GFAP and decreased solubility of c.1235C>T variant. Under pathological conditions, autophagic flux was activated for GFAP aggregate degradation. Moreover, transcriptional data of AxD and healthy human brain samples were obtained from the Gene Expression Omnibus database. Gene set enrichment analysis revealed an upregulation of immune­related responses and downregulation of ion transport, synaptic transmission and neurotransmitter homeostasis. Enrichment analysis of cell­specific differentially expressed genes also indicated a marked inflammatory environment in AxD. Overall, the clinical features of the two patients with bulbospinal form AxD were thoroughly described. To the best of our knowledge, the brain atrophy pattern and spontaneous brain functional network activity of patients with AxD were explored for the first time. Cytological experiments provided evidence of the pathogenicity of the identified variants. Furthermore, bioinformatics analysis found that inflammatory immune­related reactions may play a critical role in AxD, which may be conducive to the understanding of this disease.

8.
Retina ; 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34173364

RESUMO

PURPOSE: To determine the relationship between large and medium-sized choroidal vessels and choriocapillaris (CC) using the three-dimensional choroidal vascularity index (3D CVI) and percentage of flow deficits (FD%). METHODS: Prospective observational study. The main outcome measures included choroidal volume parameters (3D CVI, mean choroidal thickness (MCT), total choroidal volume (TCV), choroidal luminal volume (LV), and choroidal stromal volume (SV)), CC parameters (FD%, average area of FD (FDa), and FD count (FDc)), and age and axial length (AL). RESULTS: A total of 63 healthy individuals with an average age of 40.60 ± 12.32 years were included in this study. Univariate analysis showed that FD% (R = 0.295, P = 0.019) and FDa (R = 0.276, P = 0.028) were significantly positively associated with 3D CVI and FDc was negatively associated with 3D CVI (R = -0.297, P = 0.018). After adjusting for age and AL, a significant correlation between FD% and 3D CVI (R = 0.264, P = 0.039), and between FDa and 3D CVI remained (R = 0.267, P = 0.037). However, no significant correlation was found between FDc and 3D CVI after adjusting for AL (R = -0.220, P = 0.085). CONCLUSION: In healthy individuals, choroidal vessel dilatation as suggested by elevated 3D CVI may lead to decreased CC perfusion, which was correlated with an enlarged FDa in CC.

9.
Oncogene ; 40(19): 3394-3407, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33875786

RESUMO

Poorly differentiated colorectal cancer (CRC) is characterized by aggressive invasion and stromal fibroblast activation, which results in rapid progression and poor therapeutic consequences. However, the regulatory mechanism involved remains unclear. Here, we showed that ZNF37A, a member of KRAB-ZFP family, was upregulated in poorly differentiated CRCs and associated with tumor metastasis. ZNF37A enhanced the metastatic potential of multiple CRC cell lines and promoted distant metastasis in an orthotopic CRC model. Further investigation attributed the ZNF37A-exacerbated metastasis to increased extracellular TGF-ß and the consequent activation of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME). Mechanistically, ZNF37A formed a complex with KAP1 and bound to the promoter of THSD4, a TME modulator, to suppress its transcription, which is required for ZNF37A-mediated TGF-ß activation and CRC metastasis. Collectively, our study indicates that ZNF37A promotes TGF-ß signaling in CRC cells and activates CAFs by transcriptionally repressing THSD4 to drive CRC metastasis, implicating ZNF37A as a potential biomarker for CRC differentiation and progression.

11.
Phys Chem Chem Phys ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900337

RESUMO

Topological insulation is widely predicted in two-dimensional (2D) materials realized by epitaxial growth or van der Waals (vdW) exfoliation. Such 2D topological insulators (TI's) host many interesting physical properties such as the quantum spin Hall effect and superconductivity. Here, we extend the search of 2D TI's into the exfoliatable non-vdW 2D crystals. We find that three-dimensional Dirac semimetals A3Bi (A = Na, K, Rb) (P3[combining macron]c1) can be exfoliated into 2D materials with exfoliation energies of 0.479-0.990 J m-2. Our careful examination of the topological invariants of exfoliated A3Bi monolayers/multilayers by using two well-established approaches reveals that bilayer and tetralayer Na3Bi are 2D TI's. It is found that the band gap of 2D TI's can be significantly increased by external strain. We further find that the predicted 2D TI's possess interesting hidden Rashba-like spin textures. Our results suggest a new arena to search for two-dimensional topological insulators and spintronic materials.

12.
Acta Biochim Biophys Sin (Shanghai) ; 53(5): 528-537, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33674828

RESUMO

In clinic, perioperative neurocognitive disorder is becoming a common complication of surgery in old patients. Neuroinflammation and blood-brain barrier (BBB) disruption are important contributors for cognitive impairment. Atorvastatin, as a strong HMG-CoA reductase inhibitor, has been widely used in clinic. However, it remains unclear whether atorvastatin could prevent anesthesia and surgery-induced BBB disruption and cognitive injury by its anti-inflammatory property. In this study, aged C57BL/6J mice were used to address this question. Initially, the mice were subject to atorvastatin treatment for 7 days (10 mg/kg). After a simple laparotomy under 1.5% isoflurane anesthesia, Morris water maze was performed to assess spatial learning and memory. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the inflammatory response, BBB integrity, and cell apoptosis. Terminal-deoxynucleotidyl transferase mediated nick end labeling assay was used to assess cell apoptosis. The fluorescein sodium and transmission electron microscopy were used to detect the permeability and structure of BBB. The results showed that anesthesia and surgery significantly injured hippocampal-dependent learning and memory, which was ameliorated by atorvastatin. Atorvastatin could also reverse the surgery-induced increase of systemic and hippocampal cytokines, including IL-1ß, TNF-α, and IL-6, accompanied by inhibiting the nuclear factor kappa-B (NF-κB) pathway and Nucleotide-Binding Oligomerization Domain, or Leucine Rich Repeat and Pyrin Domain Containing 3 (NLRP3) inflammasome activation, as well as hippocampal neuronal apoptosis. In addition, surgery triggered an increase of BBB permeability, paralleled by a decrease of the ZO-1, occludin, and Claudin 5 proteins in the hippocampus. However, atorvastatin treatment could protect the BBB integrity from the impact of surgery, by up-regulating the expressions of ZO-1, occludin, and Claudin 5. These findings suggest that atorvastatin exhibits neuroprotective effects on cognition in aged mice undergoing surgery.


Assuntos
Envelhecimento/metabolismo , Atorvastatina/efeitos adversos , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/metabolismo , Inflamassomos/metabolismo , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Envelhecimento/patologia , Animais , Atorvastatina/farmacologia , Barreira Hematoencefálica/patologia , Disfunção Cognitiva/etiologia , Camundongos
13.
Graefes Arch Clin Exp Ophthalmol ; 259(8): 2149-2156, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33625562

RESUMO

PURPOSE: To investigate the relationship between leakage index on ultra-widefield fluorescence angiography (UWFFA) in different regions of retina and its correlation with cystoid macular edema (CME) in central retinal vein occlusion (CRVO) eyes. METHODS: Patients with naïve non-ischemic CRVO that had undergone UWFFA were identified. UWFFA images in the late phase were used to analyze the leakage index, which was performed by a semi-automatic method using ImageJ. The UWFFA images were subdivided into four regions by concentric circles centered on the macula for analysis. Optical coherence tomography (OCT) images were used to identify the presence of CME and obtain central macular thickness (CMT). RESULTS: A total of 57 eyes from 57 CRVO patients were analyzed in this study, including 43 eyes with CME and 14 eyes without CME. The leakage index in panretinal, peri-macular area (PMA), and near-peripheral area (NPA) was significantly different between eyes with CME and eyes without CME. Leakage index of PMA, NPA, mid-peripheral area (MPA), and panretinal area was significantly correlated with CMT, particularly the PMA. CONCLUSIONS: The distribution of leakage is different between patients with CME and patients without CME. The contribution of leakage index in different regions to CME was different, most predominant in PMA and NPA, and the closer to the center of the macula, the stronger the correlation between leakage index and CMT. A linear correlation was observed between CMT and the leakage index of panretinal area and all regions except far-peripheral area (FPA).


Assuntos
Edema Macular , Oclusão da Veia Retiniana , Angiofluoresceinografia , Humanos , Edema Macular/diagnóstico , Edema Macular/etiologia , Retina/diagnóstico por imagem , Oclusão da Veia Retiniana/complicações , Oclusão da Veia Retiniana/diagnóstico , Acuidade Visual
14.
Interdiscip Sci ; 13(1): 61-72, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33411162

RESUMO

Assessing pulmonary lesions using computed tomography (CT) images is of great significance to the severity diagnosis and treatment of coronavirus disease 2019 (COVID-19)-infected patients. Such assessment mainly depends on radiologists' subjective judgment, which is inefficient and presents difficulty for those with low levels of experience, especially in rural areas. This work focuses on developing a radiomics signature to quantitatively analyze whether COVID-19-infected pulmonary lesions are mild (Grade I) or moderate/severe (Grade II). We retrospectively analyzed 1160 COVID-19-infected pulmonary lesions from 16 hospitals. First, texture features were extracted from the pulmonary lesion regions of CT images. Then, feature preselection was performed and a radiomics signature was built using a stepwise logistic regression. The stepwise logistic regression also calculated the correlation between the radiomics signature and the grade of a pulmonary lesion. Finally, a logistic regression model was trained to classify the grades of pulmonary lesions. Given a significance level of α = 0.001, the stepwise logistic regression achieved an R (multiple correlation coefficient) of 0.70, which is much larger than Rα = 0.18 (the critical value of R). In the classification, the logistic regression model achieved an AUC of 0.87 on an independent test set. Overall, the radiomics signature is significantly correlated with the grade of a pulmonary lesion in COVID-19 infection. The classification model is interpretable and can assist radiologists in quickly and efficiently diagnosing pulmonary lesions. This work aims to develop a CT-based radiomics signature to quantitatively analyze whether COVID-19-infected pulmonary lesions are mild (Grade I) or moderate/severe (Grade II). The logistic regression model established based on this radiomics signature can assist radiologists to quickly and efficiently diagnose the grades of pulmonary lesions. The model calculates a radiomics score for a lesion and is interpretable and appropriate for clinical use.


Assuntos
COVID-19/diagnóstico por imagem , COVID-19/patologia , Pulmão/diagnóstico por imagem , Pulmão/virologia , Adulto , Idoso , Algoritmos , Área Sob a Curva , Calibragem , Feminino , Humanos , Modelos Logísticos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Curva ROC , SARS-CoV-2/fisiologia , Tomografia Computadorizada por Raios X , Adulto Jovem
15.
Antioxid Redox Signal ; 34(13): 979-1003, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32631077

RESUMO

Significance: Metabolic reprogramming is considered to be a critical adaptive biological event that fulfills the energy and biomass demands for cancer cells. One hallmark of metabolic reprogramming is reduced oxidative phosphorylation and enhanced aerobic glycolysis. Such metabolic abnormalities contribute to the accumulation of reactive oxygen species (ROS), the by-products of metabolic pathways. Emerging evidence suggests that ROS can in turn directly or indirectly affect the expression, activity, or subcellular localization of metabolic enzymes, contributing to the moonlighting functions outside of their primary roles. This review summarizes the multifunctions of metabolic enzymes and the involved redox modification patterns, which further reveal the inherent connection between metabolism and cellular redox state. Recent Advances: These noncanonical functions of metabolic enzymes involve the regulation of epigenetic modifications, gene transcription, post-translational modification, cellular antioxidant capacity, and many other fundamental cellular events. The multifunctional properties of metabolic enzymes further expand the metabolic dependencies of cancer cells, and confer cancer cells with a means of adapting to diverse environmental stimuli. Critical Issues: Deciphering the redox-manipulated mechanisms with specific emphasis on the moonlighting function of metabolic enzymes is important for clarifying the pertinence between metabolism and redox processes. Future Directions: Investigation of the redox-regulated moonlighting functions of metabolic enzymes will shed new lights into the mechanism by which metabolic enzymes gain noncanonical functions, and yield new insights into the development of novel therapeutic strategies for cancer treatment by targeting metabolic-redox abnormalities. Antioxid. Redox Signal. 34, 979-1003.

16.
Chemosphere ; 262: 127477, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799136

RESUMO

Focus on the safety of herbal medicines has mainly been directed towards the presence of intrinsic toxicity, as found in the cases of renal and hepatic dysfunction caused by aristolochic acids. However, contamination from extrinsic hazards may impart an even greater reduction in their safety and efficacy. This study reveals that pesticides were present in the majority (88%) of a comprehensive cross-section (n = 1771) of herbal medicine samples. Alarmingly, more than half (59%) contained pesticides over the European Pharmacopoeia (EP) limit, and 43% of them contained 35 varieties of banned, extremely toxic pesticides, eight of which were detected at levels over 500 times higher than the default Maximum Residue Limit (MRL). DDTs, carbofuran, and mevinphos were confirmed as being among the most risk-inducing pesticides by three different risk assessment methods, reported to produce carcinogenic, genotoxic, reproductive, and developmental effects, in addition to carrying nephrotoxicity and hepatotoxicity. In light of these findings, and withstanding that extrinsic hazards can be controlled unlike intrinsic toxicity, the authors here strongly recommend the application of herbal medicine quality-control measures and solutions to safeguard against a neglected but certainly potentially serious health risk posed to the majority of the global population that consumes herbal medicines.


Assuntos
Contaminação de Medicamentos , Medicamentos de Ervas Chinesas/análise , Praguicidas/análise , Carbofurano , Cromatografia Gasosa , Cromatografia Líquida/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Resíduos de Praguicidas/análise , Medição de Risco , Espectrometria de Massas em Tandem/métodos
17.
Signal Transduct Target Ther ; 5(1): 228, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028808

RESUMO

Resistance to cancer therapy is a major barrier to cancer management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance, the latter of which is the focus that will be discussed here. Such non-mutational processes are largely driven by tumor cell plasticity, which renders tumor cells insusceptible to the drug-targeted pathway, thereby facilitating the tumor cell survival and growth. The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial-mesenchymal transition, acquisition properties of cancer stem cells, and trans-differentiation potential during drug exposure. From observations in various cancers, this concept provides an opportunity for investigating the nature of anticancer drug resistance. Over the years, our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased. This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs, which are likely to improve patient outcomes in clinical practice.

18.
BMJ Open ; 10(10): e041671, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082197

RESUMO

OBJECTIVES: The COVID-19 outbreak has caused enormous strain on healthcare systems, and healthcare trainees, which comprise the future healthcare workforce, may be a vulnerable group. It is essential to assess the psychological distress experienced by healthcare trainees during the COVID-19 outbreak. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study with 4184 healthcare trainees at Sichuan University in China was implemented during 7-13 February 2020. Participants were grouped by training programmes (medicine, medical technology and nursing) and training stages (undergraduate, postgraduate and residency). MAIN OUTCOMES: COVID-19-related psychological distress and acute stress reaction (ASR) were assessed using the Kessler 6-item Psychological Distress Scale and the Impact of Event Scale-Revised, respectively. We estimated the ORs of distress by comparing trainees across programmes and training stages using multivariable logistic regression. RESULTS: Significant psychological distress was found in 1150 (30.90%) participants and probable ASR in 403 (10.74%). Compared with the nursing trainees, the medical trainees (OR 1.54, 95% CI 1.22 to 1.95) reported a higher burden of psychological distress during the outbreak, while the medical technology trainees (OR 1.25, 95% CI 0.97 to 1.62) reported similar symptom scores. Postgraduates (OR 1.55, 95% CI 1.16 to 2.08) in medicine had higher levels of distress than their undergraduate counterparts did, whereas the nursing residents (OR 0.38, 95% CI 0.20 to 0.71) reported a lower burden than did nursing undergraduates. A positive association was found between having active clinical duties during the outbreak and distress (OR 1.17, 95% CI 0.98 to 1.39), particularly among the medical trainees (OR 1.85, 95% CI 1.47 to 2.33) and undergraduates (OR 4.20, 95% CI 1.61 to 11.70). No clear risk patterns of ASR symptoms were observed. CONCLUSIONS: Medical trainees, particularly postgraduates and those with active clinical duties, were at risk for psychological distress during the COVID-19 outbreak. Stress management may be considered for high-risk healthcare trainees.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Angústia Psicológica , Estresse Psicológico/epidemiologia , Adulto , COVID-19 , China/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/psicologia , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Pneumonia Viral/complicações , Pneumonia Viral/psicologia , SARS-CoV-2 , Estresse Psicológico/etiologia , Adulto Jovem
19.
Drug Resist Updat ; 53: 100720, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32892147

RESUMO

Despite the development of targeted therapy, drug resistance remains a primary hindrance to curative treatment of various cancers. Among several novel approaches to overcome drug resistance, modulating N6-methyladenosine (m6A) RNA modification was found to be an important strategy in various types of cancer cells. Considered as one of the most common epigenetic RNA modifications, m6A regulates multiple biological processes including cellular proliferation, metabolism, and metastasis through modulation of RNA splicing, degradation, and translation, leading to anticancer drug resistance. This regulatory network is orchestrated mainly by several m6A regulators, including "writers", "readers", and "erasers". It is encouraging that several small molecules targeting m6A regulators have shown great potential in overcoming drug resistance in different cancer cell types, two of which entacapone and meclofenamate, are currently undergoing evaluation. However, the m6A modification participates in complex biological processes and its functions are context-dependent, which has challenged the clinical application of targeting the m6A modification in cancer therapy. In this review, we discuss the molecular mechanisms underlying the m6A modification in regulating anticancer drug resistance through modulation of drug-target interaction and drug-mediated cell death signaling. Alteration of the m6A modification interferes with drug efficacy through modulation of the expression of multidrug efflux transporters (e.g., ABCG2, ABCC9, ABCC10), drug metabolizing enzymes (e.g., CYP2C8), and drug targets (e.g., p53 R273 H). Furthermore, alterations of the m6A modification may protect cells from drug-mediated cell death by regulating DNA damage repair (e.g., p53, BRCA1, Pol κ, UBE2B, and ERCC1), downstream adaptive response (e.g., critical regulators of apoptosis, autophagy, pro-survival signaling, and oncogenic bypass signaling), cell stemness, and tumor microenvironment (e.g., ITGA6, ITGB3, and PD-1). We particularly highlight recent advances in therapeutic strategies targeting the m6A modification with the aim to surmount chemoresistance. The comprehensive understanding of the role of the m6A modification integrated with combined therapeutic strategies, should facilitate the development of future therapeutic strategies to circumvent or surmount drug resistance, thus enhancing therapeutic efficacy.

20.
Theranostics ; 10(23): 10360-10377, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32929354

RESUMO

Breast cancer (BC) is the most common female malignancy and the second leading cause of cancer-related death worldwide. In spite of significant advances in clinical management, the mortality of BC continues to increase due to the frequent occurrence of treatment resistance. Intensive studies have been conducted to elucidate the molecular mechanisms underlying BC therapeutic resistance, including increased drug efflux, altered drug targets, activated bypass signaling pathways, maintenance of cancer stemness, and deregulated immune response. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are intimately involved in BC therapy resistance through multiple modes of action. Therefore, an in-depth understanding of the implication of lncRNAs in resistance to clinical therapies may improve the clinical outcome of BC patients. Here, we highlight the role and underlying mechanisms of lncRNAs in regulating BC treatment resistance with an emphasis on lncRNAs-mediated resistance in different clinical scenarios, and discuss the potential of lncRNAs as novel biomarkers or therapeutic targets to improve BC therapy response.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , RNA Longo não Codificante/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , RNA Longo não Codificante/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia
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