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2.
Thorac Cancer ; 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34219384

RESUMO

Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and transforming growth factor ß (TGFß) pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

3.
J Alzheimers Dis ; 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34219730

RESUMO

BACKGROUND: Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer's disease (AD); however, the exact effect and mechanism remain unknown. OBJECTIVE: To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice. METHODS: AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain. RESULTS: 3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-ß42 (Aß 42) and Aß 40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3ß (GSK3ß) inactivation via upregulating GSK3ß (pSer9). CONCLUSION: These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aß production and tau phosphorylation, which is related to GSK3ß inactivation.

4.
PLoS Genet ; 17(7): e1009680, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34252082

RESUMO

The evolution of insecticide resistance represents a global constraint to agricultural production. Because of the extreme genetic diversity found in insects and the large numbers of genes involved in insecticide detoxification, better tools are needed to quickly identify and validate the involvement of putative resistance genes for improved monitoring, management, and countering of field-evolved insecticide resistance. The avermectins, emamectin benzoate (EB) and abamectin are relatively new pesticides with reduced environmental risk that target a wide number of insect pests, including the beet armyworm, Spodoptera exigua, an important global pest of many crops. Unfortunately, field resistance to avermectins recently evolved in the beet armyworm, threatening the sustainable use of this class of insecticides. Here, we report a high-quality chromosome-level assembly of the beet armyworm genome and use bulked segregant analysis (BSA) to identify the locus of avermectin resistance, which mapped on 15-16 Mbp of chromosome 17. Knockout of the CYP9A186 gene that maps within this region by CRISPR/Cas9 gene editing fully restored EB susceptibility, implicating this gene in avermectin resistance. Heterologous expression and in vitro functional assays further confirm that a natural substitution (F116V) found in the substrate recognition site 1 (SRS1) of the CYP9A186 protein results in enhanced metabolism of EB and abamectin. Hence, the combined approach of coupling gene editing with BSA allows for the rapid identification of metabolic resistance genes responsible for insecticide resistance, which is critical for effective monitoring and adaptive management of insecticide resistance.

5.
Ying Yong Sheng Tai Xue Bao ; 32(7): 2290-2300, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34313045

RESUMO

How to accurately model species macro-richness patterns and endemism centers is a key focus of biodiversity conservation efforts and a hot biogeographical topic. Southwest China is one of regions with high Fagaceae species richness, the species diversity patterns and driving mechanisms are unclear. In this study, the distribution pattern of species richness (SR), weighted endemism (WE), and corrected weighted endemism (CWE) indices were estimated based on 7258 occurrence points of 161 Fagaceae species in Southwest China using both occurrence-to grid method and species distribution model (SDM). We used the spatial autoregressive (SAR) model to analyze the relationship between diversity indices and environmental factors. Overall, the three SDM-simulated diversity indices were more continuous in values than that of the occurrence-to grid method, though the distributions of those indices obtained by the two methods were similar. The areas with high SR value were mainly distributed in the south edge of Yunnan, north Guangxi and southwest Guangxi (62-89 species). The maximum of WE concentrated in south Yunnan and west Guangxi (1.77-5.02). The highest CWE (0.07-0.17) was found in southeast Tibet, Qinling-Daba Mountains, southwest Guangxi, and southeast Yunnan. The SAR models showed significant effect of precipita-tion in the driest month, standard deviations of seasonal temperature, altitude range and soil organic carbon content on SR. The effects of precipitation in the driest month, standard deviations of seaso-nal temperature, potential evaporation and altitude range on the WE were significant. The precipitation in the driest month, standard deviations of seasonal temperature, historical temperature change, coefficient of variation of enhanced vegetation index and altitude variation had significant effects on the CWE. The R2 of SAR model for SR, WE and CWE was 0.857, 0.733, 0.593, respectively, being higher than that of ordinary least squares (OLS) (R2=0.689, 0.425, 0.422). In conclusion, water availability, climate seasonality, habitat heterogeneity, historical climate change and soil condition were the most important factors limiting the distribution of SR and WE of Fagaceae in Southwest China. The SR and WE centers of Fagaceae were located in south and southeast Yunnan, southwest Guangxi, west Guangxi, Qinling-Daba Mountains, and southeast Tibet, where should be adequately protected.

6.
Int J Food Microbiol ; 354: 109320, 2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34229231

RESUMO

Campylobacter spp., such as Campylobacter jejuni and Campylobacter coli, are important zoonotic Gram-negative pathogens that cause acute intestinal diseases in humans. The optrA gene, encoding an ATP-binding cassette F (ABC-F) protein that confers resistance to oxazolidinones and phenicols, has been found in C. coli in China. In this study, the optrA gene was first identified in C. jejuni collected from retail meat in China from 2013 to 2016. Nine strains, isolated from a pigeon meat sample, carry the optrA gene. The molecular characteristics of the optrA-positive strains were determined by whole genome sequencing. Pulsed-field gel electrophoresis, multilocus sequence typing, and single nucleotide polymorphism analyses demonstrated that the nine optrA-positive isolates were genetically homogeneous. Phylogenetic characteristics and sequence comparison revealed that optrA was located on a chromosome-borne multidrug resistance genomic island. The optrA gene along with the tet(O) gene formed two different translocatable units (TUs), thereby supporting the transmission of TU-associated resistance genes. The emergence and spread of such TUs and strains are of great concern in terms of food safety, and measures must be implemented to avoid their dissemination in other Gram-negative bacteria and food chains.

7.
Cells ; 10(7)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202084

RESUMO

Male infertility is a multifactorial disease with a strong genetic background. Abnormal sperm morphologies have been found to be closely related to male infertility. Here, we conducted whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Two novel hemizygous mutations were identified in USP26, an X-linked gene preferentially expressed in the testis and encoding a deubiquitinating enzyme. These USP26 variants are extremely rare in human population genome databases and have been predicted to be deleterious by multiple bioinformatics tools. Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring hemizygous USP26 variants showed a highly aberrant morphology and ultrastructure of the sperm heads and flagella. Real-time quantitative PCR and immunoblotting assays revealed obviously reduced levels of USP26 mRNA and protein in the spermatozoa from men harboring hemizygous deleterious variants of USP26. Furthermore, intracytoplasmic sperm injections performed on infertile men harboring hemizygous USP26 variants achieved satisfactory outcomes. Overall, our study demonstrates that USP26 is essential for normal sperm morphogenesis, and hemizygous USP26 mutations can induce X-linked asthenoteratozoospermia. These findings will provide effective guidance for the genetic and reproductive counseling of infertile men with asthenoteratozoospermia.

8.
Front Immunol ; 12: 683577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248967

RESUMO

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.

9.
Nat Struct Mol Biol ; 28(7): 554-563, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34239123

RESUMO

Transient receptor potential vanilloid member 1 (TRPV1) is a Ca2+-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conformational transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.

10.
J Chem Phys ; 154(24): 244301, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34241365

RESUMO

Photoionization cross sections (PICSs) for the products of the reaction from CN with toluene, including benzonitrile and o/m/p-cyanotoluene, were obtained at photon energies ranging from ionization thresholds to 14 eV by tunable synchrotron vacuum ultraviolet photoionization mass spectrometry (SVUV-PIMS). Theoretical calculations based on the frozen-core Hartree-Fock approximation and Franck-Condon simulations were carried out to cross-verify the measured PICS. The results show that the photoionization cross sections of benzonitrile and cyanotoluene isomers are similar. The generalized charge decomposition analysis was used to investigate the components of the highest occupied molecular orbital (HOMO) and HOMO-1. It was found that the HOMO and HOMO-1 of benzonitrile and cyanotoluene isomers are dominated by the features of the benzene ring, indicating that the substitution of CN and methyl has a minor influence on the PICS of the studied molecules. The reported PICS on benzonitrile and cyanotoluene isomers in the present work could contribute to the near-threshold PIMS experiments and determine the ionization and dissociation rates in interstellar space for these crucial species. The theoretical analysis on characteristics of molecular orbitals provides clues to estimating the PICS of similar substituted aromatic compounds.

11.
Biol Reprod ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34296254

RESUMO

Recurrent pregnancy loss (RPL) is defined as the loss of two or more consecutive pregnancies before the 20 weeks of gestation. Recurrent pregnancy loss affects about 1-2% of couples trying to conceive; however, the mechanisms leading to this complication are largely unknown. Our previous studies using comparative proteomics identified 314 differentially expressed proteins (DEPs) in the placental villous. In this study, we identified 5479 proteins from a total of 34,157 peptides in decidua of patients with early recurrent pregnancy loss (Data are available via ProteomeXchange with identifier PXD023849). Further analysis identified 311 DEPs in the decidua tissue; and 159 proteins were highly expressed while 152 proteins were lowly expressed. These 311 proteins were further analyzed by using Ingenuity Pathway Analysis (IPA). The results suggested that 50 DEPs played important roles in the embryonic development. Upstream analysis of these DEPs revealed that AGT was the most important upstream regulator. Furthermore, protein - protein interaction (PPI) analysis of the embryonic development DEPs from the placental villous and decidua was performed in the STRING database. This study identified several proteins specifically associated with embryonic development in decidua of patients with early recurrent pregnancy loss. Therefore, these results provide new insights into potential biological mechanisms, that may ultimately inform recurrent pregnancy loss.

12.
Environ Res ; : 111737, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34302827

RESUMO

During nitrification, the varieties of microbial structures, metabolic pathways and functional profiles in four parallel laboratory-scale sequencing batch reactors (SBRs) with 0.5, 5, 10 and 15 mg/L of free ammonia (FA) concentrations were analyzed by high-throughput sequencing of the 16S rRNA gene. The SBRs were named S0.5, S5, S10 and S15, respectively. Ammonia removal via the nitrate pathway was achieved in S0.5 and S5 throughout the whole experimental period, while ammonia removal via the nitrite pathway was established in S10 and S15 after 89 and 146 day, respectively. The key finding of this study is that both the microbial diversity and richness were significantly affected (p < 0.05) by the FA concentration at different taxonomic levels. The most dominant taxa of S5, S10 and S15 were same, and mainly included Thauera while S0.5 was mainly composed of Zoogloea. Linear discriminant analysis (LDA) effect size (LEfSe) analysis was used to identify unique biomarkers in SBR activated sludge (AS) sample. The functional genera and enzyme in the four SBRs are similar but different in abundance and they are responsible for the removal of organics and nitrogen. Moreover, metabolic pathways are similar by PICRUSt analysis. The relative proportions of pathway-specific genes involved in some metabolic pathways differed to some extent. The ammonia oxidation rate was positively linked to Nitrosomonas and amo (both Spearman correlation coefficients (ρ) = 0.777) while the nitrite oxidation rate was positively linked to Nitrospira (ρ = 0.777) by co-occurrence network analysis. This work deciphered the response of microbial characteristics to different FA constraints in AS process and could provide helpful information for revealing the biological mechanism of FA inhibition on nitrogen removal.

13.
Materials (Basel) ; 14(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34300974

RESUMO

In order to investigate the effect of temperature on the microstructure evolution and mechanical response in the transverse direction of a wrought AZ31 (AZ31-TD) alloy under a high strain rate, the dynamic compression was conducted using Split Hopkinson Pressure Bar (SHPB) apparatus and a resistance-heated furnace under 1000 s-1 at 20-250 °C. By combining optical and EBSD observations, the microstructure's evolution was specifically analyzed. With the help of theoretically calculated Schmid Factors (SF) and Critical Resolved Shear Stress (CRSS), the activation and development deformation mechanisms are systematically discussed in the current study. The results demonstrated that the stress-strain curves are converted from a sigmoidal curve to a concave-down curve, which is caused by the preferentially and main deformation mechanism {101¯2} tension twinning gradually converting to simultaneously exist with the deformation mechanism of a non-basal slip at an elevated temperature, then completing with each other. Finally, the dynamic recrystallization (DRX) and non-basal slip are largely activated and enhanced by temperature elevated to weaken the {101¯2} tension twinning.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34244092

RESUMO

OBJECTIVE: Presently, the prone position is necessary for popliteal vein puncture access, but it makes the patients uncomfortable and does not allow traditional femoral or jugular access. To address these deficiencies, this study introduces two new methods, anterior and medial access carried out in the supine position. METHODS: Venous interventions with punctures in the popliteal vein of 120 limbs in 97 patients were performed during the period from February 2017 to April 2019. After puncture, venographic guidance was achieved by dorsal vein injection of contrast medium. Interventional therapy was performed after puncture and insertion of the introducer sheath. RESULTS: In all, 120 limbs were punctured in the popliteal vein, with technical success in 118 (98.3% in total) cases: 100%, 96.1%, and 100% successful punctures in, respectively, 32 anterior, 49 medial, and 37 posterior access cases. A comparison of the three groups revealed that the fluoroscopy time and duration of puncture were longer in the medial and anterior access groups than in the posterior access group. The rate of intra-operative and post-operative complications was 7.5% (9/120), with no statistically significant difference between the three access groups. Compared with the pre-operative median score of 2.5, the post-operative SVS (Society of Vascular Surgery) score of the popliteal vein was reduced to 1.5 in the anterior and 0.5 in the medial groups. CONCLUSION: Medial and anterior puncture of the popliteal vein in the supine position can be used as a safe alternative in venous endovascular therapy. The two new methods can mitigate frailty or respiratory problems resulting from the prone position and facilitate traditional femoral and jugular access.

15.
Cancer Res ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34244237

RESUMO

Optical imaging (OI) provides real-time clinical imaging capability and simultaneous molecular, morphological, and functional information of disease processes. In this study, we present a new interventional OI technique which enables in vivo visualization of three distinct pathological zones of ablated tumor periphery for immediate detection of residual tumors during a radiofrequency ablation (RFA) session. Rabbits with orthotopic hepatic tumors were divided into two groups (n=8/group): incomplete RFA and complete RFA. Indocyanine green (ICG)-based interventional OI was used to differentiate three pathological zones ̶ ablated tumor, transition margin, and residual tumor or surrounding normal liver ̶ with quantitative comparison of signal-to-background ratios (SBR) among the three zones and between incompletely and completely ablated tumors. Subsequent ex-vivo OI and pathologic correlation were performed to confirm the findings of interventional OI. Interventional OI could differentiate incompletely or completely ablated tumor peripheries, thus permitting identification of residual tumor. This technique may open new avenues for immediate assessment of tumor eradication during a single interventional ablation session.

16.
Artigo em Inglês | MEDLINE | ID: mdl-34244823

RESUMO

PURPOSE: To identify the potential genes in human trabecular meshwork (TM) related to primary open-angle glaucoma (POAG). METHODS: First, long noncoding RNA (LncRNA) and mRNA expression profiles in TM samples from 4 control subjects and 4 POAG patients were accessed by microarray analyses. Then, twenty lncRNAs were validated by real-time quantitative PCR in the same samples from microarray analyses. Finally, eight highly expressed lncRNAs were further tested by real-time quantitative PCR in TM from 8 normal controls and 19 POAG patients. Expression data were normalized and analyzed using the R software. Pathway analyses were performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: A total of 2179 lncRNAs and 923 mRNAs in the TM of POAG patients were significantly upregulated, and 3111 lncRNAs and 887 mRNAs were significantly downregulated. ENST00000552367, ENST00000582505, ENST00000609130, NR_029395, NR_038379, and ENST00000586949 expression levels were significantly higher in the TM from a different cohort of POAG patient than normal controls. CONCLUSION: ENST00000552367, ENST00000582505, ENST000006091- 30, NR_029395, NR_038379, and ENST00000586949 may play essential roles in the development of POAG.

17.
Chin J Traumatol ; 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34272118

RESUMO

OBJECTIVE: To describe and assess the repair technique and perioperative management for cerebrospinal fluid (CSF) leak resulting from extensive anterior skull base fracture via extradural anterior skull base approach. METHODS: This was a retrospective review conducted at the Department of Neurosurgery of the Shanghai Tenth People's Hospital from January 2015 to April 2020. Patients with traumatic CSF rhinorrhea resulting from extensive anterior skull base fracture treated surgically via extended extradural anterior skull base approach were included in this study. The data of medical and radiological records, surgical approaches, repair techniques, peritoperative management, surgical outcome and postoperative follow-up were analyzed. Surgical repair techniques were tailored to the condition of associated injuries of the scalp, bony and dura injuries and associated intracranial lesions. Patients were followed up for the outcome of CSF leak and surgical complications. Data were presented as frequency and percent. RESULTS: Thirty-five patients were included in this series. The patients' mean age was 33 years (range 11-71 years). Eight patients were treated surgically within 2 weeks; while the other 27 patients, with prolonged or recurrent CSF rhinorrhea, received the repair surgery at 17 days to 10 years after the initial trauma. The mean overall length of follow-up was 23 months (range 3-65 months). All the patients suffered from frontobasal multiple fractures. The basic repair tenet was to achieve watertight seal of the dura. The frontal pericranial flap alone was used in 20 patients, combined with temporalis muscle and/or its facia in 10 patients. Free fascia lata graft was used instead in the rest 5 patients. No CSF leak was found in all the patients at discharge. There was no surgical mortality in this series. Bilateral anosmia was the most common complication. At follow-up, no recurrent CSF leak or meningitis occurred. No patients developed mucoceles, epidural abscess or osteomyelitis. One patient ultimately required ventriculoperitoneal shunt because of progressive hydrocephalus. CONCLUSION: Traumatic CSF rhinorrhea associated with extensive anterior skull base fractures often requires aggressive treatment via extended intracranial extradural approach. Vascularized tissue flaps are ideal grafts for cranial base reconstruction, either alone or in combination with temporalis muscle and its fascia---fascia lata sometimes can be opted as free autologous graft. The approach is usually reserved for patients with traumatic CSF rhinorrhea in complex frontobasal injuries.

18.
J Ethnopharmacol ; 280: 114413, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34265379

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma kwangsiensis S. G. Lee & C. F. Liang (Guangxi ezhu, in Chinese) has been used as a traditional Chinese medicine (TCM) for approximately 2000 years. Curcumol is one of the major bioactive components of this herb, which has been demonstrated possesses anti-cancer properties, and was recorded in the Chinese Pharmacopoeia 2020 edition. However, most studies mainly focused on the superficial anti-cancer activity, the underlying mechanism remains poorly understood. AIM OF THE STUDY: In the present study, we aimed to investigate the anti-tumor effect of Curcumol on hepatocellular carcinoma (HCC), and elucidate its underlying mechanism from the perspective of epigenetic modification. MATERIALS AND METHODS: The potential anti-cancer properties of Curcumol were evaluated in HepG2 and SMMC-7721 cells. Its effects on cell growth, cell cycle, apoptosis and migration were examined in these HCC cells. Moreover, the lncRNA HOX transcript antisense intergenic RNA (Hotair) and histone methylatic modification were detected by qPCR and Western blotting assays. RESULTS: In the present study, Curcumol was illustrated to suppress cell growth in HCC cells via inducing apoptosis and cell cycle arrest. And it was also found that Curcumol inhibited the invasion and metastasis of HCC as well. As for the mechanism investigation, it was showed that lncRNA Hotair was significantly downregulated by Curcumol in HCC cells. As is well known, Hotair recruited histone methyltransferase enhancer of zeste homolog 2 (EZH2) to exert transcriptional regulation. Our results showed that EZH2 were downregulated by Curcumol in HCC cells, and thus disrupted the trimethylation of H3K9 and H3K27 which were specifically catalyzed by EZH2. CONCLUSIONS: In conclude, our results demonstrated that Curcumol suppressed tumor growth and metastasis via an Hotair/EZH2/histone modification regulatory axis.

19.
J Ethnopharmacol ; 280: 114411, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34265380

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acute-on-chronic liver failure (ACLF) is a key complication of chronic hepatitis, with a relatively high mortality rate and limited treatment options, which dramatically threatens human lives. Yi-Qi-Jian-Pi formula (YQJPF) is a herbal compound commonly used to treat liver failure. AIM OF THE STUDY: The purpose of this research is to discuss the potential molecular biological effect and mechanism of YQJPF in ACLF. MATERIALS AND METHODS: In this study, we created a rat model of ACLF by CCl4-, LPS- and D-Galactosamine (D-Gal) and an in vitro model of LPS-induced hepatocyte damage. The specific components of YQJPF and potential mechanism were explored based on bioinformatics analyses. Furthermore, we verified the effect of YQJPF on ACLF using immunohistochemistry, RT-qPCR, western blotting, and flow cytometry. RESULTS: Our research demonstrated that, after YQJPF treatment, hepatocyte injury in rats was relieved. Bioinformatics analysis showed that PI3K/AKT, HIF-1, mitochondrial apoptosis pathways played prominent roles. YQJPF promoted HIF-1α protein expression and exerted protective effects against hypoxic injury, simultaneously reducing mitochondrial ROS production, suppressing hepatocyte apoptosis. Furthermore, we showed that YQJPF accelerates PI3K/AKT pathway activation, a known broad-spectrum inhibitor of PI3K. LY294002, which was used for reverse verification, suppressed the effect of YQJPF on hypoxic injury and ROS-mediated hepatocyte apoptosis. CONCLUSIONS: YQJPF ameliorates liver injury by suppressing hypoxic injury and ROS-mediated hepatocyte apoptosis by modulating the PI3K/AKT pathway.

20.
Free Radic Biol Med ; 173: 41-51, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34271106

RESUMO

Reactive oxygen species (ROS)/reactive nitrogen species (RNS)-mediated ferroptosis becomes a novel effective target for anti-cancer treatment. In the present study, we tested the hypothesis that 18-ß-glycyrrhetinic acid (GA), an active compound from medicinal herbal Licorice, could induce the production of ROS/RNS, increase lipid peroxidation and trigger ferroptosis in MDA-MB-231 triple negative breast cancer cells. To confirm the GA's anti-cancer effects, we detected cell viability, apoptosis and ferroptosis in the MDA-MB-231 cells. To explore the effects of GA on inducing ferroptosis, we measured mitochrondrial morphology, ROS/RNS production, lipid peroxidation, ferrous ion, glutathione (GSH), System Xc-, GPX4, glutathione peroxidases (GPX), NADPH oxidase and iNOS in the MDA-MB-231 cells. The major discoveries are included as below: (1) GA treatment selectively decreased cell viability and induced ferroptosis companied with the increased lipid peroxidation and ferrous ion in the MDA-MB-231 triple negative breast cancer cells. Iron chelator deferoxamine mesylate (DFO) and ferroptosis inhibitor Ferrostatin-1 abolished the effects of GA. (2) GA treatment up-regulated the expression and activity of NADPH oxidase and iNOS, and increased ROS/RNS productions (O2•-, •OH, NO and ONOO-) in the MDA-MB-231 cells; (3) GA down-regulated the expression of SLC7A11 of System Xc-, decreased glutathione (GSH) level and inhibited GPX activity. Taken together, GA could promote the productions of ROS and RNS via activating NADPH oxidases and iNOS, and decreasing GSH and GPX activity, subsequently aggravating lipid peroxidation and triggering ferroptosis in triple-negative breast cancer cells.

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