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1.
J Cell Sci ; 135(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33912962

RESUMO

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and late endosomes/lysosomes (LE/lys) are emerging as critical hubs for diverse cellular events, and changes in their extents are linked to severe neurological diseases. While recent studies show that the synaptotagmin-like mitochondrial-lipid-binding (SMP) domain-containing protein PDZD8 may mediate the formation of ER-LE/lys MCSs, the cellular functions of PDZD8 remain largely elusive. Here, we attempt to investigate the lipid transfer activities of PDZD8 and the extent to which its cellular functions depend on its lipid transfer activities. In accordance with recent studies, we demonstrate that PDZD8 is a protrudin (ZFYVE27)-interacting protein and that PDZD8 acts as a tether at ER-LE/lys MCSs. Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro. Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain.

2.
Mol Biol Cell ; : mbcE21030097, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34133214

RESUMO

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER-mitochondrial interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting-associated protein 13D (VPS13D) in the negative regulation of ER-mitochondrial MCSs. VPS13D suppression results in extensive ER-mitochondrial tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in the mitochondrial morphology, mitochondrial cellular distribution and mitochondrial DNA synthesis. Together our results suggest that VPS13D negatively regulates the ER-mitochondrial MCSs partially through its interactions with VCP/p97. [Media: see text].

3.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(4): 432-437, 2021 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33967092

RESUMO

Cardio-facio-cutaneous (CFC) syndrome is an extremely rare autosomal dominant genetic disease due to BRAF and other gene mutations. The main characteristics of the patients are craniofacial deformities, cardiac malformations, skin abnormalities, delay of language and motor development, gastrointestinal dysfunction, intellectual disability, and epilepsy. In this case, the child has a typical CFC syndrome face and developmental delay. The gene results of the second-generation sequencing technology showed that there was a mutation site c.1741A>G (p. Asn581Asp) (heterozygous) in exon 14 of the BRAF (NM_004333.5) gene. The mutation was not observed in the child's parents. The above-mentioned mutation may be a de novo mutation. There is no effective therapy for this disease so far.


Assuntos
Anormalidades Múltiplas , Displasia Ectodérmica , Cardiopatias Congênitas , Criança , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento , Cardiopatias Congênitas/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
4.
Chemosphere ; 280: 130597, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33932906

RESUMO

The fate of As(V) in subsurface environments is strongly affected by ubiquitous iron oxides. Defects are commonly present in natural hematite, while the impacts of defects on the active sites and complexation mechanism of hematite for As(V) remain poorly understood. In this study, the defect-rich hematite was employed to investigate the surface charge characteristics and As(V) adsorption behavior using potentiometric acid-base titration and CD-MUSIC model in comparison with corresponding defect-poor hematite. The total arsenate-active site density (5.7 sites/nm2) on defective hematite includes 1.2 sites/nm2 of original sites and 4.5 sites/nm2 of Fe vacancy-induced sites. The result revealed that the vacant Fe3+ sites in defective hematite was compensated by the protons in solution, thus resulting in a considerable increase in site density as well as positive charge. The CD-MUSIC modeling results demonstrated that the presence of Fe vacancies in hematite is beneficial to the improvement in affinity constants for both monodentate and bidentate arsenate complexes. The high adsorption capacity of defective hematite (2.60 µmol/m2) compared to defect-free hematite (1.33 µmol/m2) is attributed to its large affinity constants as well as its more active surface sites, thereby playing a vital role in reducing the threats of heavy metals in the environment.

5.
J Fungi (Basel) ; 7(4)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808107

RESUMO

The effects of a static magnetic field (SMF) on Monascus ruber M7 (M. ruber M7) cultured on potato dextrose agar (PDA) plates under SMF treatment at different intensities (5, 10, and 30 mT) were investigated in this paper. The results revealed that, compared with the control (CK, no SMF treatment), the SMF at all tested intensities did not significantly influence the morphological characteristics of M. ruber M7, while the intracellular and extracellular Monascus pigments (MPs) and extracellular citrinin (CIT) of M. ruber M7 were increased at 10 and 30 mT SMF but there was no impact on the MPs and CIT at 5 mT SMF. The transcriptome data of M. ruber M7 cultured at 30 mT SMF on PDA for 3 and 7 d showed that the SMF could increase the transcriptional levels of some relative genes with the primary metabolism, including the carbohydrate metabolism, amino acid metabolism, and lipid metabolism, especially in the early growing period (3 d). SMF could also affect the transcriptional levels of the related genes to the biosynthetic pathways of MPs, CIT, and ergosterol, and improve the transcription of the relative genes in the mitogen-activated protein kinase (MAPK) signaling pathway of M. ruber M7. These findings provide insights into a comprehensive understanding of the effects of SMF on filamentous fungi.

6.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805414

RESUMO

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named "Fu-Pen-Zi"), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4-10), five oleanane-type (3, 11-14), and six cucurbitane-type (15-20) triterpenoids, together with five ent-kaurane-type diterpenoids (21-25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,ß-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC50 values of 0.08, 0.61, and 1.60 µM, respectively.

7.
Clin Chim Acta ; 518: 17-21, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33705764

RESUMO

BACKGROUND: It has been reported that de novo heterozygous variants of DEAF1 can cause DEAF1-associated neurodevelopmental disorder. The purpose of this article is to explore the clinical and genetic characteristics of Chinese patients harboring de novo DEAF1 variants. METHODS: We assembled a cohort of six unrelated patients with de novo variants in DEAF1. Clinical and genetic features of these patients were summarized. RESULTS: Each child showed intellectual disability (ID)/ global developmental delay (GDD). Severe language impairment was prominent. Behavior problems, seizures, sleep disturbance, and a high pain threshold were common features. DEAF1-related seizures were reported to be difficult to treat or intractable. Seizures in our cohort were almost all treatable. Valproic acid was the most commonly used drug. Five heterozygous missense mutations of DEAF1 gene were identified, three of which (p.W234C, p.L203P, p.H275Q) were not published in literature before. CONCLUSION: Mutations of DEAF1 gene should be considered in ID/GDD patients with a nonspecific phenotype, comprising intellectual disability, prominent speech delay, abnormal behaviors, especially autism. In our study, DEAF1-related epilepsy is completely treatable in Eastern-Asian individuals when compared to patients in other regions, and valproic acid can be used as a first choice. The knowledge of DEAF1-related neurodevelopmental disorder and the de novo variant database of DEAF1 were expanded.

8.
Nat Commun ; 12(1): 1252, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623047

RESUMO

Upon starvation, cells rewire their metabolism, switching from glucose-based metabolism to mitochondrial oxidation of fatty acids, which require the transfer of FAs from lipid droplets (LDs) to mitochondria at mitochondria-LD membrane contact sites (MCSs). However, factors responsible for FA transfer at these MCSs remain uncharacterized. Here, we demonstrate that vacuolar protein sorting-associated protein 13D (VPS13D), loss-of-function mutations of which cause spastic ataxia, coordinates FA trafficking in conjunction with the endosomal sorting complex required for transport (ESCRT) protein tumor susceptibility 101 (TSG101). The VPS13 adaptor-binding domain of VPS13D and TSG101 directly remodels LD membranes in a cooperative manner. The lipid transfer domain of human VPS13D binds glycerophospholipids and FAs in vitro. Depletion of VPS13D, TSG101, or ESCRT-III proteins inhibits FA trafficking from LDs to mitochondria. Our findings suggest that VPS13D mediates the ESCRT-dependent remodeling of LD membranes to facilitate FA transfer at mitochondria-LD contacts.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Ácidos Graxos/metabolismo , Gotículas Lipídicas/metabolismo , Mitocôndrias/metabolismo , Proteínas/metabolismo , Fatores de Transcrição/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Fluorescência , Células HEK293 , Humanos , Modelos Biológicos , Proteínas Mutantes/metabolismo , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas/química
9.
J Hazard Mater ; 411: 125072, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-33453668

RESUMO

A novel CeO2 doped high silica ZSM-5(CeO2@HSZSM-5) composite was originally fabricated via ammonia precipitation for the catalytic ozonation of sulfamethoxazole (SMX). Physicochemical properties have been investigated through electron microscope, Raman spectroscopy, X-ray photoelectron spectroscopy, etc. The prepared nanometer CeO2@HSZSM-5 had a much higher specific surface (348-395 m2/g), a finer crystallite size (8.2-33.5 nm) and superior stability. Temperature-programmed desorption and reduction analysis revealed that the formed CeO2 nanoparticles on the surface of CeO2@HSZSM-5 could improve the reducibility of surface-capping oxygen, induce more oxygen vacancies and promote oxygen migration. CeO2@HSZSM-5 exhibited excellent catalytic performance for SMX mineralization in the pH range of environmental waters. The great enhancement of CeO2@HSZSM-5 catalytic activity was ascribed to the conversion of O3 into active oxygen involved in SMX mineralization, including .OH, O2.- and 1O2. This work provides a reference for the removal of pollutants by zeolite supported Ce catalytic ozonation process in water.

10.
BMC Cancer ; 20(1): 1194, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33287747

RESUMO

BACKGROUND: Due to the increased risk of viral infection and the severe shortage of medical resources during the pandemic of COVID-19, most hospitals in the epidemic areas significantly reduced non-emergency admissions and services, if not closed. As a result, it has been difficult to treat cancer patients on time, which adversely affects their prognosis. To address this problem, cancer centers must develop a strategic plan to manage both inpatients and outpatients during the pandemic, provide them with the necessary treatment, and at the same time prevent the spread of the virus among patients, visitors and medical staff. METHODS: Based upon the epidemic situation in Zhejiang Province, China, the number of running non-emergency medical wards in the Zhejiang Cancer Hospital was gradually increased in a controlled manner. All staff of the hospital received COVID-19 preventive training and was provided with three different levels of protection according to the risks of their services. Only patients without a known history of SARS-CoV-2 contact were eligible to schedule an appointment. Body temperature was measured on all patients upon their arrival at the hospital. Chest CT image, blood cell counting and travel/contact history were investigated in patients with fever. Respiratory tract samples, such as sputum and throat swabs, from all patients, including those clinically suspected of SARS-CoV-2 infection, were collected for nucleic acid detection of SARS-CoV-2 before treatment. RESULTS: A total of 3697 inpatients and 416 outpatients seeking cancer treatment were enrolled from February 1 to April 3, 2020, in compliance with the hospital's infection-control interventions. The clinicopathological parameters of the patients were summarized herein. 4237 samples from 4101 patients produced negative RNA testing results. Four clinically suspected patients all presented negative RNA test results and were excluded from the SARS-CoV-2 infection through follow-up retesting and monitoring. Seven patients with only N-gene positive results were retested, followed by CT scan and SARS-CoV-2 contact history investigation. All of them were finally diagnosed as non-infected patients. There was one outpatient who was confirmed positive by virus RNA test and then followed up. She might be an asymptomatic laboratory-confirmed case. During the study period, there was no SARS-CoV-2 infection among staff, patients and escorts of patients in the Zhejiang Cancer Hospital. CONCLUSION: This study suggested our infection-control interventions, including viral nucleic acid test, could be used as a reliable method to screen cancer patients in the area with moderate COVID-19 prevalence. Cancer may not be a high-risk factor of SARS-CoV-2 infection.

11.
Bioorg Chem ; 105: 104445, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33197848

RESUMO

Rare and endangered plants (REPs) and their associated endophytes survived in unique habitats are promising sources for natural product-derived drug discovery. In this study, six new (cephaloverines A-F, 1-6, resp.) and 16 known (11-26) cephalotaxine-type alkaloids, together with three new (oliverbiflavones A-C, 7-9, resp.) and 11 known (27-37) biflavonoids were isolated and characterized from the twigs and leaves of Cephalotaxus oliveri, an endangered plant endemic to China. Meanwhile, a preliminary investigation on the secondary metabolites from a selected fungal endophyte (i.e., Alternaria alternate Y-4-2) associated with the title plant led to the isolation of 21 structurally distinct polyketides including one new dimeric xanthone (10). The new structures (1-10) with the absolute configurations were determined by detailed spectroscopic analyses, electronic circular dichroism (ECD) or Na2MoO4-induced ECD, the modified Mosher's method, and some chemical transformations. Compounds 1-4 are the first representatives of naturally occurring N-oxides of cephalotaxine esters, while compounds 7-9 have a special structural feature of having a C-methylated biflavonoid skeleton. The Cephalotaxus alkaloids with ester side-chains at C-3 (1-6, 13-22, and 26) and four biflavonoids (27-29 and 34) were found to show pronounced cytotoxicities against a small panel of human cancer cell lines (A549, NCI-H460, HL60, NCI-H929, and RPMI-8226), with IC50 values mainly ranging from 0.003 to 9.34 µM. The most potent compound, deoxyharringtonine (16), generally exhibited IC50 values less than 10 nM. The structure-activity relationship (SAR) of the aforementioned Cephalotaxus alkaloids was briefly discussed.

12.
Environ Res ; : 110383, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33137313

RESUMO

Accurate prediction of the environmental fate of Pb depends on the understanding of Pb coordination to mineral surfaces. Here, the proton and Pb adsorption and speciation on hematite nanocrystals with different exposed crystallographic facets were investigated. High-resolution transmission electron microscopy images revealed that hematite nanoplates (HNP) were of 75.3 ± 9.5% (001) facets and 24.6 ± 9.3% (012) facets, while hematite nanocubes (HNC) were of 76.0 ± 11.1% (012) facets and 24.0 ± 3.2% (110) facets. Our modeling results revealed that the proton affinity constant (log KH) of ≡FeOH-0.5 and ≡Fe3O-0.5 was 7.8 and 10.8 on hematite (012) facets, and changed to 7.7 and 11.7 on (110) facets, respectively. Owing to the different atomic arrangements, (012) facets not only have higher adsorption performance for Pb, but also present a greater dependence on pH than (110) facets. Additionally, our modeling further indicated that (012) facets bind Pb via both bidentate and tridentate complexes, while (110) facets bind Pb only through bidentate complexes at pH 3.0-6.5. These results facilitate a more detailed understanding of the complex species of Pb on hematite surface while also provide new insight into the reactivity mechanism of individual hematite facets.

13.
Thorax ; 75(12): 1047-1057, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33077617

RESUMO

INTRODUCTION: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma. METHODS: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b -/- mice were used for allergic models. RESULTS: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b -/- mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. CONCLUSION: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.

14.
Front Pediatr ; 8: 495, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984209

RESUMO

The coronavirus disease (COVID-19) is the most severe public health problem facing the world currently. Social distancing and avoidance of unnecessary movements are preventive strategies that are being advocated to prevent the spread of the causative virus [severe acute respiratory syndrome (SARS)-CoV2]. It is known that epileptic children need long term treatments (antiepileptic drugs and/or immunosuppressive agents) as well as close follow up due to the nature of the disease. In addition, it is clear that epilepsy can concur with other chronic illnesses which can lower body immunity. As a result, epileptic children have high risk of acquiring this novel disease due to weak/immature immune system. Of concern, the management of children with epilepsy has become more challenging during this outbreak due to the prevention measures that are being taken. Although children with controlled seizures can be managed at home, it is challenging for pediatricians when it comes to cases with uncontrolled seizures/severe cases. To this end, we provide recommendations for the management of epileptic children at home, outpatient and inpatient settings.

15.
Nat Biomed Eng ; 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958897

RESUMO

The clinical applicability of porcine xenotransplantation-a long-investigated alternative to the scarce availability of human organs for patients with organ failure-is limited by molecular incompatibilities between the immune systems of pigs and humans as well as by the risk of transmitting porcine endogenous retroviruses (PERVs). We recently showed the production of pigs with genomically inactivated PERVs. Here, using a combination of CRISPR-Cas9 and transposon technologies, we show that pigs with all PERVs inactivated can also be genetically engineered to eliminate three xenoantigens and to express nine human transgenes that enhance the pigs' immunological compatibility and blood-coagulation compatibility with humans. The engineered pigs exhibit normal physiology, fertility and germline transmission of the 13 genes and 42 alleles edited. Using in vitro assays, we show that cells from the engineered pigs are resistant to human humoral rejection, cell-mediated damage and pathogenesis associated with dysregulated coagulation. The extensive genome engineering of pigs for greater compatibility with the human immune system may eventually enable safe and effective porcine xenotransplantation.

16.
J Perianesth Nurs ; 35(6): 630-634, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32778494

RESUMO

PURPOSE: To determine the spectrum of critical incidents in postanesthesia care unit (PACU) and the possible prediction and prevention of the worse scenario-associated critical incidents. DESIGN: A retrospective observational study. METHODS: The critical incidents in PACU comprising 92,136 patients were recorded. The incidents included the following disorders: delayed recovery, pain, bleeding, hypothermia, unplanned transfer to intensive care unit, shivering, agitation, nausea and vomiting, and respiratory or cardiovascular-related critical incidents. We then performed descriptive analyses and t test or χ2 test on the collected data. FINDINGS: A total of 1,760 critical incidents were recorded in 1,417 patients among 92,136 patients. Most critical incidents were associated with the patients after general anesthesia and general or gynecologic surgery. The most common critical incidents noted in the present study were pain, followed by cardiovascular-related and respiratory-related incidents. The average length of stay in PACU was 61.50 ± 44.40 minutes for the patients with critical incidents and 28.50 ± 19.40 minutes for the patients without critical incidents. CONCLUSIONS: Critical incidents lead to longer length of stay in the PACU. Regular inspection and immediate response for critical incidents in the PACU is essential for the maintenance of the quality of the immediate postoperative care.

17.
Anal Chem ; 92(18): 12216-12225, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32786439

RESUMO

The 18O/16O (and 15N/14N) ratio of natural nitrate (NO3-) and nitrite (NO2-) can be used to extract valuable information about their source and fate as environmental contaminants, their metabolism as macronutrients in plants and animals, and their behavior in the N biogeochemical cycle. We developed an accurate, precise, sensitive (minimum sample size: 0.2 µg NO3--equivalent), and reliable (minimal oxygen exchange, loss, or gain) method to selectively isolate and purify nitrate and nitrite from natural water, soil, air, and plant materials by strong anion exchange (SAX) for low- to normal-salinity samples or strong cation exchange (SCX) for high-salinity samples, followed by quantitative conversion to their respective benzyl esters, which can be separated and individually analyzed for δ18O (and potentially δ15N) by gas chromatography (GC)/pyrolysis/GC/isotope-ratio mass spectrometry (IRMS). The method compares favorably with the currently popular bacterial denitrification and chemical reduction methods, in terms of sensitivity and reliability, and has the potential to simultaneously measure δ15N and δ18O of nitrate and nitrite from natural samples of various origins.

18.
J Nat Prod ; 83(7): 2129-2144, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32633512

RESUMO

A phytochemical investigation of the MeOH extract of the leaves and twigs of Amentotaxus argotaenia, a relict vulnerable coniferous species endemic to China, led to the isolation and characterization of 35 diterpenoids/norditerpenoids. Twenty of these are new, including 11 ent-kaurane-type (amentotaxins C-M, 1-11, respectively), three icetexane-type [= 9(10→20)abeo-abietane-type (amentotaxins N-P, 12-14, respectively)], four ent-labdane-type (amentotaxins Q-T, 15-18, respectively), and two isopimarane-type [amentotaxins U (19) and V (20)] compounds. Their structures were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction, the modified Mosher's method, and electronic circular dichroism data analyses. Compounds 1-9 are rare 18-nor-ent-kaurane-type diterpenoids featuring a 4ß,19-epoxy ring. All the isolates were evaluated for their cytotoxic effects against a small panel of cultured human cancer cell lines (HeLa, A-549, MDA-MB-231, SKOV3, Huh-7, and HCT-116), and some of them exhibited cytotoxicities with IC50 values ranging from 1.5 to 10.0 µM.

19.
Cell Death Dis ; 11(6): 418, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32488007

RESUMO

The original version of this article contained an error in the spelling of the author Yuchen Chen, which was incorrectly given as Yuhuan Chen. This has now been corrected in both the PDF and HTML versions of the article.

20.
Cell Death Dis ; 11(5): 348, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393790

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. The mechanisms underlying NSCLC tumorigenesis are incompletely understood. Transfer RNA (tRNA) modification is emerging as a novel regulatory mechanism for carcinogenesis. However, the role of tRNA modification in NSCLC remains obscure. In this study, HPLC/MS assay was used to quantify tRNA modification levels in NSCLC tissues and cells. tRNA-modifying enzyme genes were identified by comparative genomics and validated by qRT-PCR analysis. The biological functions of tRNA-modifying gene in NSCLC were investigated in vitro and in vivo. The mechanisms of tRNA-modifying gene in NSCLC were explored by RNA-seq, qRT-PCR, and rescue assays. The results showed that a total of 18 types of tRNA modifications and up to seven tRNA-modifying genes were significantly downregulated in NSCLC tumor tissues compared with that in normal tissues, with the 2'-O-methyladenosine (Am) modification displaying the lowest level in tumor tissues. Loss- and gain-of-function assays revealed that the amount of Am in tRNAs was significantly associated with expression levels of FTSJ1, which was also downregulated in NSCLC tissues and cells. Upregulation of FTSJ1 inhibited proliferation, migration, and promoted apoptosis of NSCLC cells in vitro. Silencing of FTSJ1 resulted in the opposite effects. In vivo assay confirmed that overexpression of FTSJ1 significantly suppressed the growth of NSCLC cells. Mechanistically, overexpression of FTSJ1 led to a decreased expression of DRAM1. Whereas knockdown of FTSJ1 resulted in an increased expression of DRAM1. Furthermore, silencing of DRAM1 substantially augmented the antitumor effect of FTSJ1 on NSCLC cells. Our findings suggested an important mechanism of tRNA modifications in NSCLC and demonstrated novel roles of FTSJ1 as both tRNA Am modifier and tumor suppressor in NSCLC.

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