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1.
Artigo em Inglês | MEDLINE | ID: mdl-34563627

RESUMO

CONTEXT: Patients with gastric cancer experience health-related quality of life (HRQOL) decline during adjuvant chemotherapy following gastrectomy. OBJECTIVES: This pilot study aimed to evaluate the preliminary effect and feasibility of electro-acupuncture (EA) for HRQOL and symptom burden in these patients. METHODS: In this open-label, multi-center, parallel controlled trial, gastric cancer patients who planned to receive adjuvant chemotherapy were randomly assigned to receive high-dose EA (seven times each chemotherapy cycle for three cycles), low-dose EA (three times each chemotherapy cycle), or usual care only. The acupoints prescription consisted of bilateral ST36, PC6, SP4, and DU20, EX-HN3, and selected Back-shu points. Patients completed the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga) weekly, and the Edmonton Symptom Assessment System (ESAS). The primary outcome was the difference among the groups on the gastric cancer subscale (GaCS) of the FACT-Ga. RESULTS: Of the 66 randomized patients, 58 were analyzed according to intention-to-treat principle, and 45 were in the per-protocol set (PPS). The average scores in PPS of GaCS were 52.12±9.71, 51.85±12.36, and 45.37±8.61 in high-dose EA, low-dose EA, and control groups, respectively. EA was significantly associated with improved average GaCS scores when compared with control group (51.98±10.91 versus 45.37±8.61, p=0.039). EA treatment also produced ESAS relief at the end of intervention (14.36±12.28 versus 23.91±15.52, p=0.027). Participants in EA groups had fewer grade ≥3 leukopenia (0% versus 15.79%, p=0.031) and neutropenia (2.56% versus 26.31%, p=0.012). CONCLUSIONS: EA showed promising effects in improving HRQOL, controlling symptom burden, and reducing toxicity during adjuvant chemotherapy in gastric cancer patients. Future adequately powered trials are feasible and needed to confirm the specific effect of EA.

2.
J Med Chem ; 64(19): 14664-14701, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34550682

RESUMO

Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

3.
J Med Chem ; 64(17): 12548-12571, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34415148

RESUMO

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

4.
NMR Biomed ; : e4598, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34396597

RESUMO

Magnetic resonance acoustic radiation force imaging (MR-ARFI) is a promising tool for transcranial neurosurgery planning and monitoring. However, the ultrasound dose during ARFI is quite high due to the high intensity required and the repetitive ultrasound sonication. To reduce the ultrasound deposition and prevent unwanted neurological effects, undersampling in k-space data acquisition is adopted in the current study. Three reconstruction methods, keyhole, k-space hybrid and temporal differences (TED) compressed sensing, the latter two of which were initially proposed for MR thermometry, were applied to the in vivo transcranial focus localization based on MR-ARFI data in a retrospective way. The accuracies of the three methods were compared with the results from the fully sampled data as reference. The results showed that the keyhole method tended to smooth the displacement map and underestimate the peak displacement. The K-space hybrid method was better at recovering the displacement map and was robust to the undersampling pattern, while the TED method was more time efficient under a higher image resolution. For an image of a lower resolution, the K-space hybrid and TED methods were comparable in terms of accuracy when a high undersampling rate was applied. The results reported here facilitate the choice of appropriate undersampled reconstruction methods in transcranial focal localization based on MR-ARFI.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34146917

RESUMO

The liver is a multi-functional organ including metabolism, substance synthesis, detoxification, and various immune functions, and its role in immunity has attracted more and more attention. However, research on the liver immune response of fish infected by pathogenic bacteria is currently lacking. In this study, the transcriptomics and proteomics of the liver of Cynoglossus semilaevis infected with Vibrio anguillarum were analyzed. A total of 1470 genes and 497 proteins were differentially expressed in the pairwise comparison of obvious symptoms of infection (HOSG), no obvious symptoms of infection (NOSG) and PBS treatment (CG). Gene ontology and KEGG enrichment pathways analysis showed that differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were mainly enriched in toll-like receptors (TLRs), complement and coagulation cascades, nucleotide oligomerization domain (NOD)-like receptors (NLRs), mitogen-activated protein kinase (MAPK) and phagosome signaling pathways, which suggested the combined action of the five pathways were significant to enhance the liver immune defense. The combination of transcriptomic and proteomic analysis showed that ITGß1, C3, C5 and MRC1 were significantly up-regulated, which might play an important role in the liver immune response to the recognition of V. anguillarum, inflammatory response and phagocytosis. The transcriptome and proteome data we obtained provide information on some key genes and proteins for further study of the mechanism of liver immune response.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Linguado/imunologia , Proteoma/metabolismo , Transcriptoma , Vibrioses/microbiologia , Animais , Doenças dos Peixes/genética , Doenças dos Peixes/metabolismo , Doenças dos Peixes/microbiologia , Linguado/genética , Linguado/metabolismo , Linguado/microbiologia , Perfilação da Expressão Gênica , Imunidade , Proteoma/análise , Vibrio/fisiologia
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(2): 179-186, 2021 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-34137232

RESUMO

To investigate the effect of captopril on the dentin bonding durability of self-etch adhesive. Different concentrations of captopril ethanol solutions or captopril ethanol/water solutions were prepared to pretreat dentin as primer for the self-etch adhesives. The surface morphology of the dentin was observed with scanning electron microscopy (SEM). Based on the morphology analysis, the pretreatment condition was selected and two self-etch adhesives were employed to evaluate the improvement effect of the captopril pretreatment on the dentin bonding durability. : SEM showed that the pretreatment of captopril ethanol solutions and captopril ethanol/water solutions were able to remove the smear lay and partially expose collagen matrix. According to the SEM results, the pretreating condition of captopril ethanol/water solution with the pretreating time of was selected for further dentin bonding study. For Clearfil SEBOND system, the immediate bonding strength increased from to  (<0.05). After one-year aging, the bonding strength of the control group decreased markedly [(22.90±6.82) MPa, <0.05]; while the bonding strength of the captopril pretreated group kept steadily >0.05]. For Clearfil S BOND system, there was no significant difference in the immediate bonding strength between the experimental group [(4.07) MPa] and the control group[(4.11) MPa]. But after one-year aging, the bonding strength of the experimental group was higher than that of the control group <0.05]. : The pretreatment with captopril ethanol/water solution increases the dentin bonding strength of the self-etch adhesive systems and also improves the bonding durability.


Assuntos
Colagem Dentária , Adesivos Dentinários , Adesivos , Captopril , Dentina , Teste de Materiais , Microscopia Eletrônica de Varredura , Cimentos de Resina
7.
Dev Comp Immunol ; 123: 104156, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34077766

RESUMO

The complement component 6 (C6) gene is a component of the membrane attack complex (MAC), which causes rapid lytic destruction of bacteria. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene stability, including that of immune genes. However, current research on the function of C6 and its regulation by miRNAs is lacking. In the present study, we identified and characterized C6 and a novel miRNA, miR-727 (designated CsC6 and Cse-miR-727, respectively), of the half-smooth tongue sole (Cynoglossus semilaevis) that responded to infection with Vibrio anguillarum, a Gram-negative pathogen of marine fish. The full-length cDNA of CsC6 contained a 256 bp 5' untranslated region (5'-UTR), a 2820 bp open reading frame (ORF) encoding 939 amino acids, and a 205 bp 3'-UTR. SMART analysis showed that CsC6 contains typical C6 domains, including three TSP1 domains, one LDLa domain, one MACPF domain, two CCP domains and two FIMAC domains. CsC6 and Cse-miR-727 are widely expressed in the 13 tissues of half-smooth tongue sole, and their expression in immune tissues is significantly changed after V. anguillarum infection, generally showing an inverse trend. We confirmed that CsC6 was the target gene of Cse-miR-727 using the dual luciferase reporter assay and that Cse-miR-727 regulated CsC6 at the protein level using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The hepatic expression levels of not only the MAC components C7, C8α, C8ß, C8γ and C9 but also the MAPKs, NF-κß, AP-1, IL1ß, IL6 and TNFα, which are involved in many signaling pathways, changed significantly in half-smooth tongue sole following stimulation with the Cse-miR-727 agomir and inhibitor. This evidence suggested that CsC6 could be mediated by Cse-miR-727 to affect MAC assembly and immune signaling pathways in half-smooth tongue soles. To our best knowledge, this study is the first to investigate the regulatory mechanism and immune response of complement genes mediated by miRNAs in fish.

8.
J Appl Biomater Funct Mater ; 19: 22808000211023261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34102914

RESUMO

A slowly degradable bone scaffold can well maintain the balance between new bone regeneration and scaffold resorption, esp. for seniors or patients suffering from pathological diseases, because too fast degradation can lead to the loss of long-term biological stability and result in scaffold failure. In this present study, calcium phosphate silicate (CPS) and polydimethylsiloxane (PDMS) were blended in different ratios to formulate slurries for scaffold fabrication. The effects of crosslinked PDMS on the CPS material properties were first characterized and the most viable formulation of CPS-PDMS slurry was determined based on the aforementioned results to 3D fabricate scaffolds. The biocompatibility of CPS-PDMS was further evaluated based on the scaffold extract's cytotoxicity to osteoblast cells. Furthermore, real-time PCR was used to investigate the effects of scaffold extract to increase osteoblast proliferation. It is showed that the crosslinked PDMS interfered with CPS hydration and reduced both setting rate and compressive strength of CPS. In addition, CPS porosity was also found to increase with PDMS due to uneven water distribution as a result of increased hydrophobicity. Degradation and mineralization studies show that CPS-PDMS scaffold was slowly degradable and induced apatite formation. In addition, the in vitro analyses show that the CPS-PDMS scaffold did not exert any cytotoxic effect on osteoblast cells but could improve the cell proliferation via the TGFß/BMP signaling pathway. In conclusion, CPS-PDMS scaffold is proved to be slowly degradable and biocompatible. Further analyses are therefore needed to demonstrate CPS-PDMS scaffold applications in bone regeneration.

9.
Biomed Mater ; 16(4)2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34082402

RESUMO

Osteoporosis is detrimental to the health of skeletal structure and significantly increases the risks of bone fracture. Moreover, bone regeneration is adversely impaired by increased osteoclastic activities as a result of osteoporosis. In this study, we developed a novel formulation of injectable bone cement based on calcium phosphate silicate cement (CPSC) and leuprolide acetate (LA). Several combinations of LA-CPSC bone cement were characterized and, it is found that LA could increase the setting time and compressive strength of CPSC in a concentration-dependent manner. Moreover, thein vitroresults revealed that LA-CPSC was biocompatible and able to encourage the osteoblast proliferation via the mTOR signalling pathway. Furthermore, the LA-CPSC was implanted in the osteoporotic rats to evaluate its effectiveness to repair bone fractures under the osteoporotic conditions. The biomarker study and micro-CT analyses indicated that LA-CPSC could effectively reduce the osteoclast activities and promote the bone regeneration. In conclusion, our study demonstrated that LA-CPSC injectable bone cement should be a viable solution to repair bone fractures under the osteoporotic conditions.

10.
Dev Comp Immunol ; 122: 104135, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34004267

RESUMO

The pore-forming protein perforin is one of the effectors of cell-mediated killing via the granule exocytosis pathway. In this study, a genome-wide association study was conducted in Vibrio harveyi disease-resistant and disease-susceptible families of half smooth tongue sole (Cynoglossus semilaevis) to determine the genes accounting for host resistance, and a perforin homologue was identified, designated perforin-1 like (CsPRF1l). The full-length cDNA of CsPRF1l is 1835 bp, and encodes 514 amino acids. The CsPRF1l gene consists of 10 exons and 9 introns, spanning approximately 7 kb. The amino acid sequence of CsPRF1l shows 60.35, 54.03, 41.92, and 34.17% identities to Morone saxatilis PRF1l, Oryzias melastigma PRF1l, Danio rerio PRF1.5 and Homo sapiens PRF, respectively. Sequence analysis revealed the presence of membrane attack complex/perforin (MACPF) and C2 domains in CsPRF1l. Quantitative real-time PCR showed that CsPRF1l presented a higher intestinal expression level in disease-resistant families than in susceptible families. Tissue expression pattern analysis showed that CsPRF1l is present in most of the tested tissues and highly expressed in the intestine, brain, stomach and gills. After challenge with V. harveyi, CsPRF1l mRNA was markedly upregulated in the liver, spleen, kidney, intestine, gills and skin. In addition, the recombinant CsPRF1l protein exhibited obvious antimicrobial activity against V. harveyi in vitro and in a zebrafish model. Collectively, these data indicate that CsPRF1l modulates host immune defense against V. harveyi invasion and provide clues about the efficacy of rCsPRF1l in fish that will give rise to useful therapeutic applications for V. harveyi infection in C. semilaevis.

11.
Eur J Med Chem ; 220: 113482, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33906048

RESUMO

Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5), a member of the mitogen-activated protein kinase (MAPK) signaling pathway, is involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has emerged as a promising therapeutic strategy for inflammatory disease. A series of novel ASK1 inhibitors with 1H-indazole scaffold were designed, synthesized and evaluated for their ASK1 kinase activity and AP1-HEK293 cell inhibitory effect. Systematic structure-activity relationship (SAR) efforts led to the discovery of promising compound 15, which showed excellent in vitro ASK1 kinase activity and potent inhibitory effects on ASK1 in AP1-HEK293 cells. In a tumor necrosis factor-α (TNF-α)-induced HT-29 intestinal epithelial cell model, compound 15 exhibited a significantly protective effect on cell viability comparable to that of GS-4997; moreover, compound 15 exhibited no obvious cytotoxicity against HT-29 cells at concentrations up to 25 µM. Mechanistic research demonstrated that compound 15 suppresses phosphorylation in the ASK1-p38/JNK signaling pathway in HT-29 cells, and regulates the expression levels of apoptosis-related proteins. Altogether, these results show that compound 15 may serve as a potential candidate compound for the treatment of inflammatory bowel disease (IBD).


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Indazóis/farmacologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/síntese química , Indazóis/química , MAP Quinase Quinase Quinase 5/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Genomics ; 113(4): 1838-1844, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33819565

RESUMO

Based on 1572 re-sequenced Chinese tongue sole (Cynoglossus semilaevis), we investigated the accuracy of four genomic methods at predicting genomic estimated breeding values (GEBVs) of Vibrio harveyi resistance in C. semilaevis when SNPs varying from 500 to 500 k. All methods outperformed the pedigree-based best linear unbiased prediction when SNPs reached 50 k or more. Then, we developed an SNP array "Solechip No.1" for C. semilaevis breeding using the Affymetrix Axiom technology. This array contains 38,295 SNPs with an average of 10.5 kb inter-spacing between two adjacent SNPs. We selected 44 candidates as the parents of 23 families and genotyped them by the array. The challenge survival rates of offspring families had a correlation of 0.706 with the mid-parental GEBVs. This SNP array is a convenient and reliable tool in genotyping, which could be used for improving V. harveyi resistance in C. semilaevis coupled with the genomic selection methods.

13.
Dev Comp Immunol ; 121: 104091, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33819543

RESUMO

In mammals, Class II, major histocompatibility complex (MHC II) transactivator (CIITA) recognizes microbial pathogens and triggers immune responses. In Chinese tongue sole Cynoglossus semilaevis, Cs-CIITA was prevalently expressed in various tissues. Cs-CIITA, Cs-MHC IIA and Cs-MHC IIB were expressed significantly higher in skin in susceptible families infected with Vibrio harveyi, while higher expression of Cs-CIITA and Cs-MHC IIB was examined in liver in resistant families. In addition, the three genes were up-regulated in gill, skin, intestine, liver, spleen and kidney at 48 h or 72 h after V. harveyi infection. Furthermore, the three genes were co-expressed in the epithelial mucous cells of gill, skin, and intestine. Knockdown of Cs-CIITA regulates the expression of other inflammation-related genes, including CD40, IL-1ß, IL-8, RelB, NFκB, and Myd88. These results suggest that CIITA functions in the inflammatory responses of C. semilaevis against V. harveyi, via MHC II transcriptional regulation.

14.
J Med Chem ; 64(6): 2878-2900, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33719439

RESUMO

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present in newly diagnosed acute myeloid leukemia (AML) patients with an incidence rate of approximately 30%. Recently, many FLT3 inhibitors have been developed and exhibit positive preclinical and clinical effects against AML. However, patients develop resistance soon after undergoing FLT3 inhibitor treatment, resulting in short durable responses and poor clinical effects. This review will discuss the main mechanisms of resistance to clinical FLT3 inhibitors and summarize the emerging strategies that are utilized to overcome drug resistance. Basically, medicinal chemistry efforts to develop new small-molecule FLT3 inhibitors offer a direct solution to this problem. Other potential strategies include the combination of FLT3 inhibitors with other therapies and the development of multitarget inhibitors. It is hoped that this review will provide inspiring insights into the discovery of new AML therapies that can eventually overcome the resistance to current FLT3 inhibitors.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Descoberta de Drogas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Modelos Moleculares , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
15.
Invest New Drugs ; 39(5): 1222-1231, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33788074

RESUMO

Many studies have indicated that histone deacetylase inhibitors (HDACis) have a significant antitumor effect in cancer. Here we report a compound named LT-548-133-1 that not only acts as an HDAC inhibitor but also interferes with microtubule assembly to inhibit MCF-7 cell proliferation and induce apoptosis. Consistent with Chidamide, LT-548-133-1 inhibited HDAC activity and increased histone H3 acetylation. But the difference is that it significantly induced cell cycle G2/M arrest while Chidamide caused G0/G1 arrest in MCF-7 cells. By Western blotting, we found the accumulation of CyclinB1 and phosphorylated histone H3 in LT-548-133-1 treated cells. Immunofluorescence based microtubule-repolymerization experiments and immunofluorescence staining of cell microtubules and nuclei showed that LT-548-133-1inhibited microtubule-repolymerization and induced mitotic abnormalities. The decreased expression of Bcl-2 and the increased expression of Bax, p53, p21, and cleaved-Caspase3 indicated the occurrence of apoptosis. Flow cytometry results also showed an increase in the proportion of apoptotic cells after administration of LT-548-133-1 or Chidamide. Therefore, we demonstrated that LT-548-133-1 could act as an HDAC inhibitor while inhibiting microtubule-repolymerization, causing mitosis to be arrested in G2/M. These two effects ultimately lead to proliferation inhibition and apoptosis of MCF-7 cells.

16.
Dev Comp Immunol ; 120: 104043, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33621610

RESUMO

Long noncoding RNAs (lncRNAs) play a multifaceted role in transcriptional regulation and are important regulators of immune function. Scarce information is available regarding lncRNAs in fish. Peripheral blood mononuclear cells participate in the immune response of fish and aid resistance to infection with pathogenic microorganisms. Chitosan oligosaccharide can improve cellular and humoral immunity to enhance disease resistance in fish. In this study, we obtained peripheral blood leukocytes from half-smooth tongue sole and studied the effect of chitosan oligosaccharide on the lncRNA-mRNA expression profile of these cells using high-throughput sequencing and bioinformatics techniques. A total of 609 differentially expressed mRNAs and 50 differentially expressed lncRNAs were identified. The GO term enrichment analysis of the differentially expressed genes was annotated by 220 GO terms, 137 biological processes, 18 cellular components, and 65 molecular functions. Sixteen KEGG pathways, including immune signaling pathways, metabolism, and genetic information processing, were significantly enriched in differentially expressed genes. Thirty-six differentially expressed lncRNAs and 32 differentially expressed mRNAs produced a coexpression network containing 90 relationship pairs. The prediction of lncRNA target genes revealed 244 lncRNAs that potentially cis-regulated 294 differentially expressed mRNAs. qPCR verified that the expression levels of 17 differentially expressed lncRNAs and 15 differentially expressed mRNAs were consistent with the RNA-Seq results. Among them, 6 lncRNAs and 7 mRNAs were differentially expressed genes obtained from the prediction and analysis of lncRNA target genes, and 8 lncRNAs and 4 mRNAs were differentially expressed genes that participated in the construction of the coexpression network. In peripheral blood leukocytes after chitosan oligosaccharide treatment, as well as in peripheral blood and spleen after Vibrio anguillarum stimulation, lncRNAs and mRNAs showed significant differential expression. The results indicated that they may be related to the immune response, providing novel reference information for further research on the role of lncRNAs in immune regulation in half-smooth tongue sole.

17.
Bioorg Med Chem ; 29: 115856, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33199201

RESUMO

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.

18.
Eur J Med Chem ; 211: 113114, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33360793

RESUMO

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Indóis/uso terapêutico , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Humanos , Indóis/farmacologia , Estrutura Molecular
19.
Int J Biol Sci ; 16(16): 3163-3173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162822

RESUMO

Background: Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis. Methods: Therapeutic effect of BRD4 specific inhibitor JQ-1 on acute gouty arthritis was evaluated in vivo and in vitro. Pyroptosis was analyzed by Caspase-1/PI double staining and cleavage of gasdermin D (GSDMD). Expression of key factors involved in BRD4/NF-κB/NLRP3/GSDMD signaling pathway were measured by western blot, and colocalization of NLRP3 and ASC was detected using immunofluorescence. In addition, the role of BRD4 on monosodium uric acid crystals (MSU)-induced pyroptosis was verified in BRD4 siRNA-transfected THP-1 cells. Results: Pretreatment of JQ1 and BRD4 siRNA significantly suppressed pyroptosis and inhibited activation of p65 NF-κB signaling as well as NLRP3 inflammasome in THP-1 cells exposed to MSU. In vivo, JQ-1 administration could effectively attenuate joint swelling and synovial inflammation in rats treated by intra-articular injection of MSU. More importantly, MSU led to macrophage pyroptosis and Brd4/NF-κB/NLRP3/GSDMD signaling induction in rat synoviums, which was improved by JQ-1. Conclusions: Our study identifies the role of BRD4 in MSU-induced pyroptosis through regulating NF-κB/NLRP3/GSDMD signaling pathways, which provides a potential target for treatment of acute gouty arthritis.

20.
ACS Comb Sci ; 22(12): 873-886, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33146518

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is compared to "immortal cancer" in industry. Currently, SYK, BTK, and JAK are the three major targets of protein tyrosine kinase for this disease. According to existing research, marketed and research drugs for RA are mostly based on single target, which limits their efficacy. Therefore, designing multitarget or dual-target inhibitors provide new insights for the treatment of RA regarding of the specific association between SYK, BTK, and JAK from two signal transduction pathways. In this study, machine learning (XGBoost, SVM) and deep learning (DNN) models were combined for the first time to build a powerful integrated model for SYK, BTK, and JAK. The predictive power of the integrated model was proved to be superior to that of a single classifier. In order to accurately assess the generalization ability of the integrated model, comprehensive similarity analysis was performed on the training and the test set, and the prediction accuracy of the integrated model was specifically analyzed under different similarity thresholds. External validation was conducted using single-target and dual-target inhibitors, respectively. Results showed that our model not only obtained a high recall rate (97%) in single-target prediction, but also achieved a favorable yield (54.4%) in dual-target prediction. Furthermore, by clustering dual-target inhibitors, the prediction performance of model in various classes were proved, evaluating the applicability domain of the model in the dual-target drug screening. In summary, the integrated model proposed is promising to screen dual-target inhibitors of SYK/JAK or BTK/JAK as RA drugs, which is beneficial for the clinical treatment of rheumatoid arthritis.

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