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1.
Pharmaceuticals (Basel) ; 15(9)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36145288

RESUMO

Enterovirus A71 (EV-A71) infection is a major cause of hand, foot, and mouth disease (HFMD), which may be occasionally associated with severe neurological complications. There is currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its critical importance in the regulation of cell growth, differentiation, and survival, has been shown to be essential for virus replication. In this study, we investigated the anti-EV-A71 activity of vemurafenib, a clinically approved B-Raf inhibitor used in the treatment of late-stage melanoma. Vemurafenib exhibits potent anti-EV-A71 effect in cytopathic effect inhibition and viral load reduction assays, with half maximal effective concentration (EC50) at nanomolar concentrations. Mechanistically, vemurafenib interrupts both EV-A71 genome replication and assembly. These findings expand the list of potential antiviral candidates of anti-EV-A71 therapeutics.

2.
JHEP Rep ; 4(10): 100546, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36052220

RESUMO

Background & Aims: HEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV (Rocahepevirus ratti; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection. Methods: In this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored. Results: A high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats (p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection. Conclusions: We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients. Lay summary: Convenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans.

3.
Cell Rep Med ; 3(9): 100743, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36084644

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hint that BA.2 is similarly potent regarding antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is less dependent on transmembrane protease serine 2 (TMPRSS2) for virus entry in comparison with BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates and replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Our study indicates that BA.2 is similarly attenuated in lungs compared with BA.1 but is potentially more transmissible because of its better replication at the nasal turbinates.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Humanos , Camundongos , SARS-CoV-2/genética , Serina , Virulência
4.
Food Funct ; 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36125096

RESUMO

As a tropical medicinal plant, Sonneratia apetala is mainly distributed in the southeast coastal areas of China. Recently, the hypouricemic effect of Sonneratia apetala leaves and branches (SAL) has been reported, but the active compound and its mechanism are unclear. Thus, this study aims to explore the effective fraction of SAL and the mechanism of its active compound on uric acid formation and excretion. SAL was extracted with ethyl acetate and concentrated to obtain solvent-free extracts (SAL-EA). The remains fraction (SAL-E) and the supernatant fraction (SAL-S) of SAL resulting from water extraction and alcohol precipitation were collected and dried. The effects of different fractions were explored on hyperuricemic mice. SAL-S showed excellent activities in decreasing the levels of uric acid (UA), blood urea nitrogen (BUN), and creatinine (CRE) in serum and in attenuating kidney damage. Then, the active compound gallic acid (GA) identified by HPLC was assayed for its mechanism of regulating uric acid metabolism in hyperuricemic mice. The hypouricemic effect of GA was probably associated with the downregulation of URAT1 and GLUT9, upregulation of ABCG2 and decreased activities of adenosine deaminase (ADA) and xanthine oxidase (XOD). Moreover, GA suppressed the level of MDA, IL-6, IL-1ß, TNF-α, TGF-ß1, COX-2 and cystatin-C (Cys-C), and enhanced the activities of SOD, GSH-Px, CAT, and Na+-K+-ATPase (NKA) in the kidneys. These results indicated that GA protects against hyperuricemia-induced kidney injury via suppressing oxidative stress and inflammation as well as decreasing the serum levels of UA by regulating urate transporters.

5.
Int J Mol Sci ; 23(15)2022 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-35955657

RESUMO

Starch-gluten interactions are affected by biopolymer type and processing. However, the differentiation mechanisms for gluten-starch interactions during heating have not been illuminated. The effects of glutens from two different wheat flours (a weak-gluten (Yangmai 22, Y22) and a medium-strong gluten (Yangmai 16, Y16)) on starch's (S) structural and physicochemical properties during heating and their molecular interactions were investigated in this study. The results showed that gluten hindered the gelatinization and swelling of starch during heating when temperature was below 75 °C, due to competitive hydration and physical barriers of glutens, especially in Y22. Thus, over-heating caused the long-range molecular order and amylopectin branches of starch to be better preserved in the Y22-starch mixture (Y22-S) than in the Y16-starch mixture (Y16-S). Meanwhile, the starch's degradation pattern during heating in turn influenced the polymerization of both glutens. During heating, residual amylopectin branching points restricted the aggregation and cross-linking of gluten proteins due to steric hindrance. More intense interaction between Y16 and starch during heating mitigated the steric hindrance in starch-gluten networks, which was due to more residual short-range ordered starch and hydrogen bonds involved in the formation of starch-gluten networks in Y16-S during heating.


Assuntos
Glutens , Calefação , Amilopectina , Farinha , Glutens/química , Amido/metabolismo
6.
Plants (Basel) ; 11(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35956447

RESUMO

With global climate change, waterlogging stress is becoming more frequent. Waterlogging stress inhibits root growth and physiological metabolism, which ultimately leads to yield loss in wheat. Waterlogging priming has been proven to effectively enhance waterlogging tolerance in wheat. However, it is not known whether waterlogging priming can improve the offspring's waterlogging resistance. Here, wheat seeds that applied waterlogging priming for one generation, two generations and three generations are separately used to test the hypoxia stress tolerance in wheat, and the physiological mechanisms are evaluated. Results found that progeny of primed plants showed higher plant biomass by enhancing the net photosynthetic rate and antioxidant enzyme activity. Consequently, more sugars are transported to roots, providing a metabolic substrate for anaerobic respiration and producing more ATP to maintain the root growth in the progeny of primed plants compared with non-primed plants. Furthermore, primed plants' offspring promote ethylene biosynthesis and further induce the formation of a higher rate of aerenchyma in roots. This study provides a theoretical basis for improving the waterlogging tolerance of wheat.

7.
Emerg Microbes Infect ; 11(1): 2093-2101, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35943779

RESUMO

The replication and pathogenicity of SARS-CoV-2 Omicron BA.2 are comparable to that of BA.1 in experimental animal models. However, BA.2 has rapidly emerged to overtake BA.1 to become the predominant circulating SARS-CoV-2 variant worldwide. Here, we compared the replication fitness of BA.1 and BA.2 in cell culture and in the Syrian hamster model of COVID-19. Using a reverse genetics approach, we found that the BA.1-specific spike mutation G496S compromises its replication fitness, which may contribute to BA.1 being outcompeted by BA.2 in the real world. Additionally, the BA.1-unique G496S substitution confers differentiated sensitivity to therapeutic monoclonal antibodies, which partially recapitulates the immunoevasive phenotype of BA.1 and BA.2. In summary, our study identified G496S as an important determinant during the evolutionary trajectory of SARS-CoV-2.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Monoclonais , Cricetinae , Humanos , Mesocricetus , Mutação de Sentido Incorreto , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
8.
J Med Virol ; 2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36031726

RESUMO

In 2019, an outbreak of pharyngoconjunctival fever (PCF) occurred at a swimming center in Zhejiang Province, China. A total of 97 (13.55%) of the 716 amateur swimmers had illnesses, with 24 patients (24.74%) hospitalized in the pediatric ward. Human adenovirus serotype 7 (HAdV-7) was isolated from one concentrated water from the swimming pool, and 20 of 97 positive cases without liver damage. This outbreak led to a nosocomial outbreak in the pediatric ward, in which 1 nurse had a fever and was confirmed to be adenovirus positive. The hexon, fiber, and penton genes from 20 outbreak cases, 1 water sample, and 1 nurse had 100% homology. Furthermore, 2 cases admitted to the pediatric ward, 2 parents, and 1 doctor were confirmed to be human coronaviruses (HCoV-229E) positive. Finally, all outbreak cases had fully recovered, regardless of a single infection (adenovirus or HCoV-229E) or coinfection of these two viruses simultaneously. Thus, PCF and acute respiratory disease outbreaks in Zhejiang were caused by the completely homologous type 7 adenovirus and HCoV-229E, respectively. The swimming pool water contaminated with HAdV-7 was most likely the source of the PCF outbreak, whereas nosocomial transmission might be the source of HCoV-229E outbreak.

9.
Eur J Cancer ; 174: 176-184, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36030556

RESUMO

BACKGROUND: In a portion of patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer, clinical complete response (cCR) could be achieved after anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. However, no data are available concerning the safety of omitting surgery and adopting immunotherapy as a curative-intent treatment for these patients. METHODS: We retrospectively collected a series of patients with dMMR/MSI-H rectal adenocarcinoma who had cCR after receiving anti-PD-1 immunotherapy and adopted immunotherapy as curative-intent treatment from six institutions. Survival outcomes were analysed using the Kaplan-Meier method. RESULTS: Nineteen patients were included with a median age of 48 (range 19-63). One patient was diagnosed with stage I disease, four with stage II disease and fourteen with stage III disease. Sixteen patients received anti-PD-1 immunotherapy as the first line of therapy, and eleven patients were treated with single-agent anti-PD-1 antibodies. The median time from the start of treatment to cCR was 3.8 (range 0.7-6.5) months. During a median follow-up of 17.1 (range 3.1-33.5) months since achieving cCR, no local or distant relapse was observed. Two-year local recurrence-free survival, distant metastasis-free survival, disease free-survival and overall survival for the whole cohort were 100%, 100%, 100% and 100%, respectively. CONCLUSIONS: For patients with dMMR/MSI-H locally advanced rectal cancer who achieved cCR during anti-PD-1 immunotherapy, adopting immunotherapy as curative-intent treatment might be an alternative option. Longer follow-up and larger cohorts are warranted to verify this innovative treatment approach.


Assuntos
Neoplasias Colorretais , Neoplasias Retais , Estudos de Coortes , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Humanos , Imunoterapia , Instabilidade de Microssatélites , Recidiva Local de Neoplasia , Neoplasias Retais/genética , Neoplasias Retais/terapia , Estudos Retrospectivos
10.
mBio ; 13(4): e0194422, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35938726

RESUMO

The human upper respiratory tract, specifically the nasopharyngeal epithelium, is the entry portal and primary infection site of respiratory viruses. Productive infection of SARS-CoV-2 in the nasal epithelium constitutes the cellular basis of viral pathogenesis and transmissibility. Yet a robust and well-characterized in vitro model of the nasal epithelium remained elusive. Here we report an organoid culture system of the nasal epithelium. We derived nasal organoids from easily accessible nasal epithelial cells with a perfect establishment rate. The derived nasal organoids were consecutively passaged for over 6 months. We then established differentiation protocols to generate 3-dimensional differentiated nasal organoids and organoid monolayers of 2-dimensional format that faithfully simulate the nasal epithelium. Moreover, when differentiated under a slightly acidic pH, the nasal organoid monolayers represented the optimal correlate of the native nasal epithelium for modeling the high infectivity of SARS-CoV-2, superior to all existing organoid models. Notably, the differentiated nasal organoid monolayers accurately recapitulated higher infectivity and replicative fitness of the Omicron variant than the prior variants. SARS-CoV-2, especially the more transmissible Delta and Omicron variants, destroyed ciliated cells and disassembled tight junctions, thereby facilitating virus spread and transmission. In conclusion, we establish a robust organoid culture system of the human nasal epithelium for modeling upper respiratory infections and provide a physiologically-relevant model for assessing the infectivity of SARS-CoV-2 emerging variants. IMPORTANCE An in vitro model of the nasal epithelium is imperative for understanding cell biology and virus-host interaction in the human upper respiratory tract. Here we report an organoid culture system of the nasal epithelium. Nasal organoids were derived from readily accessible nasal epithelial cells with perfect efficiency and stably expanded for more than 6 months. The long-term expandable nasal organoids were induced maturation into differentiated nasal organoids that morphologically and functionally simulate the nasal epithelium. The differentiated nasal organoids adequately recapitulated the higher infectivity and replicative fitness of SARS-CoV-2 emerging variants than the ancestral strain and revealed viral pathogenesis such as ciliary damage and tight junction disruption. Overall, we established a human nasal organoid culture system that enables a highly efficient reconstruction and stable expansion of the human nasal epithelium in culture plates, thus providing a facile and robust tool in the toolbox of microbiologists.


Assuntos
COVID-19 , Mucosa Nasal , Organoides , SARS-CoV-2 , COVID-19/virologia , Humanos , Mucosa Nasal/virologia , Organoides/virologia , SARS-CoV-2/classificação , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Técnicas de Cultura de Tecidos
11.
Nature ; 609(7928): 785-792, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35922005

RESUMO

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.


Assuntos
COVID-19 , Coronavírus da Síndrome Respiratória do Oriente Médio , Animais , Caspase 6 , Caspases , Proteínas do Nucleocapsídeo de Coronavírus , Cricetinae , Cisteína , Dipeptidil Peptidase 4 , Humanos , Interferons , Mesocricetus , Camundongos , SARS-CoV-2
12.
Mitochondrial DNA B Resour ; 7(7): 1252-1254, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35814174

RESUMO

Lindera chienii Cheng 1934 is an important medicine plant. The first complete plastid genome sequence of L. chienii was assembled and analyzed in this study. The plastid genome is 152,744 bp in length with a GC content of 39.15%, contains a large single-copy region of 93,767 bp and a small single-copy region of 18,843 bp, which were separated by a pair of inverted repeat regions of 20,067 bp. A total of 128 genes were detected in the plastid genome, including eight ribosomal RNA genes, 36 transfer RNA genes, and 81 protein-coding genes. The phylogenomic analysis based on plastid genomes supports the close relationships among Lindera chienii, L. megaphylla and Litsea acutivena.

13.
Free Radic Biol Med ; 188: 447-458, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35809767

RESUMO

MTH1 protein can sanitize the damaged (d)NTP pool and MTH1 inhibitors have been developed to impede the growth of rapidly proliferating tumor cells; however, the effect of MTH1 inhibition on breast cancer stemness has not been reported yet. Here, we constructed breast cancer cell lines with the stable depletion of MTH1. MTH1 suppression clearly increased the ratio of CD44+CD24-/low subpopulations and promoted the formation of tumorspheres in MCF7 and T47D cells. RNA expression profiling, RT-qPCR and Western blotting showed the upregulation of master stem cell transcription factors Sox2, Oct4 and Nanog in MTH1 knockdown cells. GSEA suggested and Western blotting verified that MTH1 knockdown increased the expression of phosphorylated STAT3 (Tyr705). Furthermore, we indirectly demonstrated that the increased concentration of 8-oxo-dGTP and 8-oxo-GTP in MTH1-knockdown cells and exogenous 8-oxoGTP, rather than 8-oxo-dGTP, could significantly increase the phosphorylation of STAT3. In conclusion, this work indicates that MTH1 inhibition increased the proportion of breast cancer stem cells (BCSCs) and promoted stemness properties in MCF7 cells.


Assuntos
Neoplasias da Mama , Fator de Transcrição STAT3 , Neoplasias da Mama/patologia , Enzimas Reparadoras do DNA , Feminino , Humanos , Células MCF-7 , Células-Tronco Neoplásicas/metabolismo , Monoéster Fosfórico Hidrolases , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Ativação Transcricional , Regulação para Cima
14.
Plants (Basel) ; 11(13)2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35807696

RESUMO

Nitrogen (N) supply and seed rate (SR) are two essential factors that affect the accumulation and partitioning of N and dry matter (DM) and, therefore, grain yield (GY) and N use efficiency (NUE). The objective of this experiment was to optimize N application and SR to regulate wheat growth and increase both GY and NUE. The results revealed that net photosynthetic rate (Pn), stomatal conductance (Gs), chlorophyll content, and activities of metabolic enzymes (NR and GS) significantly increased with increasing of N levels while decreasing SR. Plant tillers, GY, DM before anthesis, and N translocation, N agronomic efficiency (NAE), N recovery efficiency (NRE), and N uptake efficiency (NUPE) were highest in a combined treatment of N235 and SR180. However, N levels beyond 235 kg ha-1 significantly decreased NAE, NRE, and NUPE. By increasing SR from 135 to 180 kg ha-1 an increase of 12.9 % and 9.1% GY and NUPE, respectively, was observed. Based on this result, we estimate that 1 kg N ha-1 might be replaced by an increase of approximately 0.6 kg ha-1 SR. Our study suggested that using a combination of N and SR (N235 + SR180) could attain maximum GY and improve NUE parameters.

16.
Surg Endosc ; 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906459

RESUMO

BACKGROUND: The role of laparoscopic-assisted natural orifice specimen extraction (LA-NOSE) colectomy in the treatment of left-sided colon cancer has not been well defined, and there remains confusion about how to conveniently exteriorize specimens through natural orifices. Therefore, we introduced a homemade invention, the Cai tube, to facilitate the extraction of specimens and compared the clinical outcomes of LA-NOSE with conventional laparoscopic (CL) colectomy for left-sided colon cancer. METHODS: From March 2015 to August 2017, patients with left-sided colon cancer were randomly divided into LA-NOSE and CL groups. Specimens were extracted through the anus with the help of a Cai tube (Patent Number: ZL201410168748.2) in the LA-NOSE group. The primary outcome measure was postoperative pain. Secondary outcomes were the duration of operation, postoperative recovery, surgical morbidity, pathological quality of the specimen, and long-term outcomes, including 3-year overall survival, disease-free survival, local recurrence, and overall recurrence. RESULTS: A total of 60 patients (30 per group) were recruited for this study. None of the patients required emergency conversion to conventional laparoscopic or open surgery during the operation. The postoperative maximum pain score was significantly lower in the LA-NOSE group (mean 2.5 vs. 5.1, P = 0.001), as was the additional analgesia requirement (mean 2/30 vs. 10/30, P = 0.021). Patients in the LA-NOSE group experienced a shorter first time to passage of flatus (mean 2.2 vs. 3.1 days, P = 0.026). All patients could control their defecation at 6 months after surgery. The comparison between the two groups showed no significant differences in the operative time, bleeding volume, postoperative hospital stay, surgical morbidity rates, number of lymph nodes harvested, or resection margin status. The mean follow-up was 48 months (range 7-59) and was similar in both groups. The results showed no differences in long-term outcomes between the two groups. CONCLUSION: In the treatment of left-sided colon cancer, compared with conventional laparoscopic colectomy, LA-NOSE colectomy using the Cai tube exhibited lower postoperative pain, shorter recovery of gastrointestinal function, and similar long-term outcomes. REGISTRATION NUMBER: ChiCTR-OOR-15007060 ( http://www.chictr.org.cn/ ).

17.
Cell Commun Signal ; 20(1): 111, 2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35870943

RESUMO

BACKGROUND: The screening biomarkers for early detection of colorectal cancer (CRC) is lacking. The aim is to identify epigenetic silenced genes and clarify its roles and underlying mechanism in CRC. We conducted integrative analyses of epigenome-wide Human Methylation 450 K arrays and transcriptome to screen out candidate epigenetic driver genes with transcription silencing. Methylated silencing HAND2 were identified and verified in large CRC cohort. The mechanism of HAND2 expression by promoter inhibition were clarified both in vitro and vivo assays. Cell biofunctional roles of HAND2 methylation was investigated in CRC cells. HAND2 reconstitution were constructed by lentivirus plasmid and tumor xenograft model of HAND2 were built subcutaneously. Genomic mRNA analysis by RNA-sequencing and subsequent GSEA analysis were performed to identify potential target of HAND2 and qPCR/WB was conducted to identify the results. RESULTS: We firstly reported high frequency of HAND2 methylation in promoter in CRC and hypermethylation was negatively correlated with expression silencing and leaded to poor survival in several CRC cohort patients. 5-Aza treatment to demethylated HAND2 could revert its expression in CRC cells. Functionally, HAND2 reconstitution can inhibit cell proliferation, invasion and migration in vitro. In tumor xenograft, HAND2 reconstruction significantly repressed tumor growth when compared to control vector. Thousands of aberrant expressed genes were observed in the heatmap of RNA-sequencing data. HAND2 reconstitution could bind to ERK and reduce its phosphorylation by CoIP assay. These above results showed HAND2 reconstitution perturbed the activation of MAPK/ERK signaling by reduction of ERK phosphorylation. CONCLUSIONS: HAND2 is one tumor suppressor by targeting ERK signaling and one potential epigenetic driver gene in CRC. Video Abstract.


Assuntos
Neoplasias Colorretais , Inativação Gênica , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Metilação de DNA/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , RNA/metabolismo , Fatores de Transcrição/metabolismo
18.
Neuropsychiatr Dis Treat ; 18: 1441-1453, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35859802

RESUMO

Objective: Growth arrest-specific protein 6 (Gas6) may harbor protective effects in acute brain injury. This study was designed to determine the relation of serum Gas6 levels to severity and prognosis after traumatic brain injury (TBI). Methods: In this prospective cohort study of 114 controls and 114 patients with severe TBI, multivariate analysis was used to assess relationships between serum Gas6 levels, Glasgow coma scale (GCS) score, Rotterdam computed tomography (CT) score, postinjury 180-day mortality, overall survival and poor prognosis (Extended Glasgow outcome scale score 1-4). Results: Significantly increased serum Gas6 levels of patients (median, 10.3 ng/mL versus 32.5 ng/mL; P < 0.001), as compared with controls, were independently correlated with Rotterdam CT score (t = 3.629, P < 0.001) and GCS score (t=-3.393, P = 0.001), and independently predicted 180-day mortality (odds ratio, 1.078; 95% confidence interval (CI), 1.007-1.154), overall survival (hazard ratio, 1.074; 95% CI, 1.012-1.139) and poor prognosis (odds ratio, 1.129; 95% CI, 1.059-1.205). Areas under receiver operating characteristic curve (AUCs) of serum Gas6 levels for discriminating risks of 180-day mortality and poor prognosis were 0.785 (95% CI, 0.699-0.857) and 0.793 (95% CI, 0.707-0.863), respectively; and serum Gas6 levels above 30.9 ng/mL and 28.3 ng/mL predicted 180-day mortality and poor prognosis with maximum Youden indices of 0.451 and 0.468, respectively. The predictive ability of serum Gas6 levels for mortality was similar to those of GCS score (AUC, 0.833; 95% CI, 0.751-0.896; P = 0.286) and Rotterdam CT score (AUC, 0.823; 95% CI, 0.740-0.888; P = 0.432). The discriminatory capability of serum Gas6 levels for the risk of poor prognosis was in the range of GCS score (AUC, 0.846; 95% CI, 0.766-0.906; P = 0.178) and Rotterdam CT score (AUC, 0.831; 95% CI, 0.750-0.895; P = 0.368). Conclusion: Serum Gas6 may appear as a promising biochemical parameter for aiding in the assessment of trauma severity and prediction of prognosis among patients with severe TBI.

19.
Int J Biol Sci ; 18(12): 4744-4755, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874954

RESUMO

Viruses exploit the host lipid metabolism machinery to achieve efficient replication. We herein characterize the lipids profile reprogramming in vitro and in vivo using liquid chromatography-mass spectrometry-based untargeted lipidomics. The lipidome of SARS-CoV-2-infected Caco-2 cells was markedly different from that of mock-infected samples, with most of the changes involving downregulation of ceramides. In COVID-19 patients' plasma samples, a total of 54 lipids belonging to 12 lipid classes that were significantly perturbed compared to non-infected control subjects' plasma samples were identified. Among these 12 lipid classes, ether-linked phosphatidylcholines, ether-linked phosphatidylethanolamines, phosphatidylcholines, and ceramides were the four most perturbed. Pathway analysis revealed that the glycerophospholipid, sphingolipid, and ether lipid metabolisms pathway were the most significantly perturbed host pathways. Phosphatidic acid phosphatases (PAP) were involved in all three pathways and PAP-1 deficiency significantly suppressed SARS-CoV-2 replication. siRNA knockdown of LPIN2 and LPIN3 resulted in significant reduction of SARS-CoV-2 load. In summary, these findings characterized the host lipidomic changes upon SARS-CoV-2 infection and identified PAP-1 as a potential target for intervention for COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , Células CACO-2 , Ceramidas , Éteres , Glicerofosfolipídeos , Humanos , Metabolismo dos Lipídeos , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo
20.
Int J Biol Sci ; 18(12): 4714-4730, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874959

RESUMO

The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , ATP Citrato (pro-S)-Liase , Humanos , Pandemias , Replicação Viral/genética
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