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1.
Carbohydr Polym ; 275: 118673, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34742409

RESUMO

Chitosan oligosaccharides (COS) are a derivative of low molecular weight chitosan and are potent natural antimicrobial agents. The antimicrobial activity of COS against Aspergillus flavus and Aspergillus fumigatus was evaluated by minimum inhibitory concentration (MIC) and inhibition of mycelial growth. The MICs of COS against these two fungi were 31.2 and 15.6 mg/mL, respectively. COS treatment rendered fungal mycelia wrinkled and deformed with a fractured appearance. COS also increased cellular permeability leading to a significant leakage of cellular components indicating membrane damage. This compound also dose-dependently reduced chitin production and enhanced chitinase activity while enhancing the accumulation of reactive oxygen species (ROS). These characteristics suggested that COS has inhibitory effects against food spoilage fungi and acts on the cell wall and membrane and alters cellular metabolism. COS shows promise for food industry applications since it is non-toxic to higher organisms.

2.
Sci Immunol ; 6(60)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34723044

RESUMO

Radiotherapy (RT) is an important anti-cancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared to ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a dramatic increase of TNF-α- and inducible nitric oxide synthase (iNOS)-producing inflammatory macrophages in local and distal non-irradiated (distal) tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell-derived IFN-γ are crucial for increasing inflammatory macrophage levels in IR and RA treated tumors. Notably, whereas CD8+ T cells are required for the antitumor response to IR, CD4+ T cells are required for the effectiveness of the IR and RA combination. Combination treatment with RA enhanced the abscopal response when radiation and PD-L1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR plus RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.

4.
Ann Transl Med ; 9(17): 1391, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34733943

RESUMO

Background: Feminization-1 (FEM-1) is considered a substrate recognition subunit of CUL2-RING E3 ubiquitin ligase complexes, which refers to sex determination by modulating TRA-1 stability in C. elegans. The function of mammalian orthologous gene of FEM-1 remains to be elucidated. Methods: The expression of FEM1C in colorectal cancer (CRC) cells was interfered by small interference RNA (siRNA) transfection, and Cell counting kit-8 (CCK-8) assay, colony formation assay and transwell assay were performed. In order to estimate the function on metastasis, stable knockdown FEM1C cells were used to established liver and lung metastasis models. In addition, the expression of FEM1C in normal tissues, adenomas and tumor tissues were analyzed, and the relationship between FEM1C expression level and prognosis was analyzed by Kaplan-Meier method. Results: Here, we report that the elimination of FEM1C, one of the members of FEM-1, significantly promoted the migration and invasion of colorectal cancer (CRC) cells in vitro and promoted liver and lung metastases in vivo. It also showed that the removal of FEM1C improved the proliferation ability of CRC cells. In particular, the cell shape changed from epithelial to fibroblast-like morphology. The tight cell monolayer was transformed into a dispersed distribution. Furthermore, it was demonstrated that FEM1C is down-regulated in tissues of CRC compared to normal tissues, and the high expression of FEM1C positively correlates with a good prognosis in patients with CRC. GSEA analysis showed that EMT signatures was enriched in FEM1C knockdown groups. Conclusions: Down-regulation of FEM1C promotes proliferation and metastasis, and FEM1C may be a tumor suppressor in the development of CRC.

5.
Nat Biomed Eng ; 5(11): 1261-1273, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34725504

RESUMO

Bispecific T-cell engagers (BiTEs) preferentially targeting tumour-associated antigens and stimulating CD3-mediated signalling are being used in patients to treat acute B-cell lymphoblastic leukemia. However, the potency of BiTEs in solid tumours is limited by their short half-life and their severe toxicity at relevant therapeutic doses. Here we report the design and in vivo performance of a bispecific antibody that simultaneously targets the murine T-cell co-receptor CD3ε and the murine immune checkpoint programmed-death ligand 1 (PD-L1). In multiple syngeneic tumour models, the bispecific antibody generated higher antitumour immune responses than conventional BiTEs targeting tumour-associated antigens and CD3ε. We found that the durable antigen-specific T-cell responses resulted from the rejuvenation of CD8 T cells, owing to the blockade of PD-L1 on dendritic cells (but not on tumour cells) and co-stimulation by B7-1&2 (a peripheral membrane protein on dendritic cells). Bispecific T-cell engagers targeting dendritic cells rather than tumour cells may represent a general means of T-cell rejuvenation for durable cancer immunotherapy.

6.
Front Immunol ; 12: 689065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733269

RESUMO

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The US FDA has approved several therapeutics and vaccines worldwide through the emergency use authorization in response to the rapid spread of COVID-19. Nevertheless, the efficacies of these treatments are being challenged by viral escape mutations. There is an urgent need to develop effective treatments protecting against SARS-CoV-2 infection and to establish a stable effect-screening model to test potential drugs. Polyclonal antibodies (pAbs) have an intrinsic advantage in such developments because they can target rapidly mutating viral strains as a result of the complexity of their binding epitopes. In this study, we generated anti-receptor-binding domain (anti-RBD) pAbs from rabbit serum and tested their safety and efficacy in response to SARS-CoV-2 infection both in vivo and ex vivo. Primary human bronchial epithelial two-dimensional (2-D) organoids were cultured and differentiated to a mature morphology and subsequently employed for SARS-CoV-2 infection and drug screening. The pAbs protected the airway organoids from viral infection and tissue damage. Potential side effects were tested in mouse models for both inhalation and vein injection. The pAbs displayed effective viral neutralization effects without significant side effects. Thus, the use of animal immune serum-derived pAbs might be a potential therapy for protection against SARS-CoV-2 infection, with the strategy developed to produce these pAbs providing new insight into the treatment of respiratory tract infections, especially for infections with viruses undergoing rapid mutation.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Sítios de Ligação , Brônquios/citologia , COVID-19/genética , COVID-19/terapia , Células Epiteliais , Perfilação da Expressão Gênica , Humanos , Imunização Passiva , Camundongos , Mutação , Testes de Neutralização , Organoides , Coelhos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
7.
Front Oncol ; 11: 723131, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745945

RESUMO

Objective: Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. Insulin-like growth-factor-binding proteins (IGFBPs) were initially identified as passive inhibitors that combined with insulin-like growth factors (IGFs) in serum. However, more recent data have shown that they have different expression patterns and a variety of functions in the development and occurrence of cancers. Thus, their various roles in cancer still need to be elucidated. This study aimed to explore the IGFBPs and their prognostic value as markers in gastric cancer. Methods: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, cBioPortal, GeneMANIA, and TIMER were used to analyze the differential expression, prognostic value, genetic alteration, and association with immune cell infiltration of IGFPBs in gastric cancer. Results: Expression levels of IGFBP3, IGFBP4, and IGFBP7 were significantly elevated in gastric cancer tissues, whereas those of IGFBP1 were reduced in normal tissues. IGFBP1/5/7 expression was significantly associated with overall survival whereas IGFBP6/7 expression was significantly correlated with disease-free survival in gastric cancer patients. IGFBP3/5/6/7 were associated with clinical cancer stage. Gene ontology and Kyoto Encyclopedia of Genes and Genome analyses showed that IGFBP3/5/7 were mainly enriched in focal adhesion, extracellular matrix structural constituent, cell-substratist junction, extracellular structure, and matrix organization. Stomach adenocarcinoma (STAD) and gastric cancer had more IGFBP1-7 mutations than other tumor types. Hub gene analysis showed that TP53 and IGF2 expression was significantly elevated in STAD patients; PLG, PAPPA, AFP, and CYR61 were associated with overall survival rate; and IGFALS, PLG, IGF1, AHSG, and FN1 were associated with disease-free survival. Finally, IGFBP3-7 were all associated with cancer-associated fibroblast infiltration in STAD, colon adenocarcinoma, and rectal adenocarcinoma. Conclusion: Our study provides a comprehensive analysis and selection of IGFBPs as prognostic biomarkers in STAD. This was the first bioinformatic analysis study to describe the involvement of IGFBPs, especially IGFBP7, in gastric cancer development through the extracellular matrix.

8.
Beilstein J Org Chem ; 17: 2462-2476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630726

RESUMO

Great progress has been made in the tandem annulation of enynes in the past few years. This review only presents the corresponding reactions of 1,3-enyne structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly introduce the applications of the products and the reaction mechanisms for the synthesis of corresponding N-heterocycles.

9.
Oxid Med Cell Longev ; 2021: 8388258, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659640

RESUMO

Oxidative stress (OS) arises when the body is subjected to harmful endogenous or exogenous factors that overwhelm the antioxidant system. There is increasing evidence that OS is involved in a number of diseases, including ovarian cancer (OC). OC is the most lethal gynecological malignancy, and risk factors include genetic factors, age, infertility, nulliparity, microbial infections, obesity, smoking, etc. OS can promote the proliferation, metastasis, and therapy resistance of OC, while high levels of OS have cytotoxic effects and induce apoptosis in OC cells. This review focuses on the relationship between OS and the development of OC from four aspects: genetic alterations, signaling pathways, transcription factors, and the tumor microenvironment. Furthermore, strategies to target aberrant OS in OC are summarized and discussed, with a view to providing new ideas for clinical treatment.

10.
Mil Med Res ; 8(1): 53, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34663467

RESUMO

The present study demonstrates that the down-regulation of peroxisome proliferator-activated receptor-α (PPARα) results in chronic low ambient temperature (LT) exposure-induced cardiac dysfunction and remodeling, emphasizing the therapeutic potential of PPARα activation strategies (e.g. fenofibrate treatment) in LT-associated cardiac injury.

11.
Dis Markers ; 2021: 5340240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712369

RESUMO

Background: Epithelial-mesenchymal transition (EMT) is significantly associated with the invasion and development of esophageal squamous cell carcinoma (ESCC). However, the importance of EMT-related long noncoding RNA (lncRNA) is little known in ESCC. Methods: GSE53624 (N = 119) and GSE53622 (N = 60) datasets retrieved from the Gene Expression Omnibus (GEO) database were used as training and external validation cohorts, respectively. GSE53624 and GSE53622 datasets were all sampled from China. Then, the prognostic value of EMT-related lncRNA was comprehensively investigated by weighted coexpression network analysis (WGCNA) and COX regression model. Results: High expression of PLA2G4E-AS1, AC063976.1, and LINC01592 significantly correlated with the favorable overall survival (OS) of ESCC patients, and LINC01592 had the greatest contribution to OS. Importantly, ESCC patients were divided into low- and high-risk groups based on the optimal cut-off value of risk score estimated by the multivariate COX regression model of these three lncRNA. Patients with high risk had a shorter OS rate and restricted mean survival time (RMST) than those with low risk. Moreover, univariate and multivariate COX regression revealed that risk stratification, age, and TNM were independent prognostic predictors, which were used to construct a nomogram model for individualized and visualized prognosis prediction of ESCC patients. The calibration curves and time-dependent ROC curves in the training and validation cohorts suggested that the nomogram model had a good performance. Interestingly, clear trends indicated that risk score positively correlated with tumor microenvironment (TME) scores and immune checkpoints TIGIT, CTLA4, and BTLA. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that PLA2G4E-AS1, AC063976.1, and LINC01592 were primarily associated with TNF signaling pathway, NF-kappa B signaling pathway, and ECM-receptor interaction. Conclusion: We developed EMT-related lncRNA PLA2G4E-AS1, AC063976.1, and LINC01592 for prognostic prediction and risk stratification of Chinese ESCC patients, which might provide deep insight for personalized prognosis prediction in Chinese ESCC patients and be potential biomarkers for designing novel therapy.

12.
J Bone Oncol ; 31: 100392, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34712553

RESUMO

Chordomas are low-grade malignancies accounting for 1-4% of primary bone malignancies. Moreover, local recurrences increase the rate of metastasis. Our previous study identified the far upstream element (FUSE)-binding protein 1 (FUBP1) as a biomarker and potential therapeutic target for chordoma. In this study, lncRNA KRT8P41 was identified as a lncRNA positively correlated with FUBP1. In chordoma patients, higher lncRNA KRT8P41 expression was correlated with a poorer prognosis. LncRNA KRT8P41 silencing significantly inhibited chordoma cell proliferation and invasion. miR-193a was negatively correlated with lncRNA KRT8P41 and FUBP1; lncRNA KRT8P41 inhibited miR-193a expression, and miR-193a inhibited FUBP1 expression. Furthermore, miR-193a directly bound to lncRNA KRT8P41 and FUBP1 and lncRNA KRT8P41 competed with FUBP1 for miR-193a binding and relieved miR-193a-mediated FUBP1 inhibition. LncRNA KRT8P41 silencing inhibited, whereas miR-193a inhibition promoted chordoma cell proliferation and invasion; the inhibition of miR-193a attenuated the roles of lncRNA KRT8P41. Within chordoma tissues, the expression of miR-193a was decreased, and the expression of FUBP1 increased compared to normal control tissues. LncRNA KRT8P41 exhibited a positive correlation with FUBP1 and a negative correlation with miR-193a in vivo. Therefore, it was concluded that lncRNA KRT8P41, miR-193a-3p, and FUBP1 form a lncRNA-miRNA-mRNA axis, modulating the proliferation and invasion of chordoma cells.

13.
Molecules ; 26(20)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34684716

RESUMO

Lipid deposition in the kidney can cause serious damage to the kidney, and there is an obvious epithelial-mesenchymal transition (EMT) and fibrosis in the late stage. To investigate the interventional effects and mechanisms of phenolic compounds from Mori Cortex on the EMT and fibrosis induced by sodium oleate-induced lipid deposition in renal tubular epithelial cells (NRK-52e cells), and the role played by CD36 in the adjustment process, NRK-52e cells induced by 200 µmol/L sodium oleate were given 10 µmoL/L moracin-P-2″-O-ß-d-glucopyranoside (Y-1), moracin-P-3'-O-ß-d-glucopyranoside (Y-2), moracin-P-3'-O-α-l-arabinopyranoside (Y-3), and moracin-P-3'-O-[ß-glucopyranoside-(1→2)arabinopyranoside] (Y-4), and Oil Red O staining was used to detect lipid deposition. A Western blot was used to detect lipid deposition-related protein CD36, inflammation-related protein (p-NF-κB-P65, NF-κB-P65, IL-1ß), oxidative stress-related protein (NOX1, Nrf2, Keap1), EMT-related proteins (CD31, α-SMA), and fibrosis-related proteins (TGF-ß, ZEB1, Snail1). A qRT-PCR test detected inflammation, EMT, and fibrosis-related gene mRNA levels. The TNF-α levels were detected by ELISA, and the colorimetric method was used to detects SOD and MDA levels. The ROS was measured by flow cytometry. A high-content imaging analysis system was applied to observe EMT and fibrosis-related proteins. At the same time, the experiment silenced CD36 and compared the difference between before and after drug treatment, then used molecular docking technology to predict the potential binding site of the active compounds with CD36. The research results show that sodium oleate can induce lipid deposition, inflammation, oxidative stress, and fibrosis in NRK-52e cells. Y-1 and Y-2 could significantly ameliorate the damage caused by sodium oleate, and Y-2 had a better ameliorating effect, while there was no significant change in Y-3 or Y-4. The amelioration effect of Y-1 and Y-2 disappeared after silencing CD36. Molecular docking technology showed that the Y-1 and Y-2 had hydrogen bonds to CD36 and that, compared with Y-1, Y-2 requires less binding energy. In summary, moracin-P-2″-O-ß-d-glucopyranoside and moracin-P-3'-O-ß-d-glucopyranoside from Mori Cortex ameliorated lipid deposition, EMT, and fibrosis induced by sodium oleate in NRK-52e cells through CD36.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Morus/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular , China , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Fibrose , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Org Lett ; 23(21): 8402-8406, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34664971

RESUMO

A unified method for direct C4-H halogenation of indoles has been accomplished with the assistance of anthranilic acids as suitable transient directing groups. Exclusive site selectivity (one out of five potential reactive sites) as well as good functional group tolerance was obtained to install three kinds of halogen atoms (Cl, Br and I, respectively) by using inexpensive N-halosuccinimides (NXS) as halogen sources under mild conditions. Taking advantage of the rich functional groups in the product, a diversity of nitrogen-containing heterocycles were facily constructed via one-step late-stage derivations.

15.
J Food Sci ; 86(11): 4991-5003, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34699076

RESUMO

Craft beer because of its fresh flavor, unique taste, and rich nutrition is becoming more popular to consumers. Compared with industry beer, craft beer is often nonfiltered and nonpasteurized, for this reason, it has a short shelf life and is more susceptible to microbial spoilage, which may cause the quality deterioration of craft beer and the formation of biogenic amine as a harmful factor for consumer's health. In this study, the 23 beer-spoilage bacteria were isolated from craft beer, which were identified as 15 Lactobacillus (L.) brevis, 3 L. plantarum, 1 L. parabuchneri, 2 L. paracasei, and 2 Pediococcus damnosus. Among 23 beer-spoilage isolates, 20 representatives were able to form tyramine, histamine, putrescine, cadaverine, and/or tryptamine in MRS broth. The nine Lactobacillus strains were incubated in beer and produced tyramine, histamine, putrescine, cadaverine, and/or tryptamine during beer storage process. Logistic and Gompertz model could be adopted to respectively describe the kinetics of microorganism growth and biogenic amine formation. The relationship between the biogenic amines and biomass was simulated by Luedeking-Piret model very well, and showed that the formation of biogenic amine was mainly bacteria growth-associated in beer. These findings may be helpful for finding the preventive measures to control biogenic amine formation and for enhancing the safety of craft beer. PRACTICAL APPLICATION: The selection of the biogenic amine-producing spoilage bacteria from craft beer and the investigation their kinetics of the growth and biogenic amines production under beer environmental conditions was very helpful for finding preventive measures to eliminate or reduce biogenic amine formation and for appropriate increase in food safety.

16.
Nat Commun ; 12(1): 5866, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620867

RESUMO

Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.


Assuntos
Antineoplásicos/imunologia , Imunidade , Interferon Tipo I/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Haplorrinos , Imunoterapia , Cinética , Camundongos , Microambiente Tumoral
17.
J Colloid Interface Sci ; 608(Pt 1): 344-354, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34626980

RESUMO

Prussian blue (PB) is a safe photothermal agent for tumor therapy, yet poor photothermal effect and single therapeutic function severely restrict its further clinical applications. Herein, a biodegradable "Nano-donut" (CMPB-MoS2-PEG) is fabricated for magnetic resonance (MR) imaging and enhanced photothermal therapy (PTT)/ chemodynamic therapy (CDT)/chemotherapy through responsive catalysis in tumor microenvironment (TME). The "Nano-donut" is organically composed of Cu/Mn ions doped-PB and MoS2. The porous donut structure of CMPB-MoS2-PEG endows them as a carrier for delivery of doxorubicin hydrochloride (DOX) to tumor site. The framework of Nano-donut specifically decomposes in TME due to the reaction between Fe2+/Fe3+ and H2O2. The multivalent elements (Cu/Fe/Mn ions) decrease the bandgap and then enhance CDT by synergistically catalyzing H2O2 into toxic ·OH. Meanwhile, the Mn4+ also reacts with H2O2 to generate O2, improving the hypoxia of TME and enhancing the chemotherapy effect of released DOX. The MoS2 mingles in the PB, which significantly enhances photothermal conversion efficiency (η) effect of PB from 16.02% to 38.0%. In addition, Fe3+ as T2-weighted MR imaging agent can achieve MR imaging-guided therapy. The data clearly shows Nano-donut/DOX nanocomposites (NCs) have a remarkable inhibition for cancer cells and excellent biological safety in tumor treatment.

18.
Front Vet Sci ; 8: 737160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552978

RESUMO

Gout is a disease involving abnormal purine metabolism that is widespread in mammals and birds. Goose is especially susceptible for gout in early stage. However, a few studies investigated the ontogenetic pattern of goslings with purine metabolic abnormality. Our studies were conducted to investigate whether persistent purine metabolic abnormality would lead to aggravation of visceral inflammation and intestinal microbiota dysbiosis in goose. A total of 132 1-day-old Magang geese were randomly divided into six replicates and fed a high-calcium and protein meal-based diet from 1 to 28 days. The experiment lasted for 28 days. Liver and kidney damages were observed in 14- and 28-day-old Magang geese, and liver inflammation increased with increasing age. In 28-day-old Magang geese, serum CAT and liver GSH-Px activity were significantly reduced. Furthermore, jejunum intestinal barrier was impaired and the abundance of Bacteroides was significantly reduced at the genus level. Collectively, the high-calcium and high-protein (HCP) meal-based diet caused liver and kidney damage in 28-day-old Magang geese, leading to hyperuricemia and gout symptoms, and the intestinal barrier is impaired and the intestinal flora is disrupted.

19.
J Virol ; : JVI0125321, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586857

RESUMO

Over the past 20 years, Severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), have all emerged, causing severe epidemic human respiratory diseases throughout the globe. Developing broad spectrum drugs would be invaluable in responding to new emerging coronaviruses of the future and could address unmet urgent clinical needs. Main protease (Mpro, also known as 3CLpro) has a major role in the replication of a coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. We show that a natural product, noncovalent inhibitor shikonin, can pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63 and HCoV-229E with micromolar IC50 values. Structures of the main protease of different coronavirus genus, SARS-CoV from betacoronaviruses and HCoV-NL63 from alphacoronaviruses, were determined by X-ray crystallography and reveals that the inhibitor interacts with key active-site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses, as well as emerging coronaviruses in the future. Given the importance of main protease for the coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. Importance The current pandemic has created an urgent need for broad spectrum inhibitors of SARS-CoV-2. Main protease is relatively conservative compared with the spike protein and thus is one of the most promising drug targets for developing anticoronavirus agents. We have solved crystal structures of main protease of SARS-CoV and HCoV-NL63 bound to shikonin. The structures provide important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad spectrum anticoronavirus ligands as new therapeutic agents.

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