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1.
J Med Virol ; 95(9): e29065, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37661566

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5' LTR but not 3' LTR. The activation of the 5' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.


Assuntos
Vírus Linfotrópico T Tipo 1 Humano , Leucemia de Células T , Adulto , Humanos , Vírus Linfotrópico T Tipo 1 Humano/genética , Expressão Gênica , Infecção Persistente , RNA
2.
Acta Pharmacol Sin ; 44(4): 801-810, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36216899

RESUMO

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.


Assuntos
Necroptose , Proteínas Quinases , Camundongos , Animais , Humanos , Proteínas Quinases/metabolismo , Reposicionamento de Medicamentos , Apoptose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
3.
J Musculoskelet Neuronal Interact ; 23(1): 122-130, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36856107

RESUMO

OBJECTIVE: To identify different key genes and pathways between males and females by studying differentially expressed genes (DEGs). METHODS: The gene expression data of GSE123568 were downloaded from GEO database, including osteonecrosis of the femoral head (ONFH) samples from 3 females and 7 males, and DEGs between different gender were identified with R software. Protein-protein interaction (PPI) network was constructed to further analyze the interactions between overlapping DEGs, and finally, GO, KEGG and gene set enrichment analysis (GSEA) were conducted for enrichment analysis. RESULTS: 131 DEGs were identified between ONFH females and ONFH males, including 76 up-regulated genes and 55 down-regulated genes. And 10 hub genes were identified in PPI network, including SLC4A1, GYPA, CXCL8, IFIT1, GBP5, IFI44, IFI44L, IFIT3, KEL and AHSP. Functional enrichment analysis revealed that these genes were mainly enriched in cGMP-PKG signaling pathway, Fatty acid degradation, Non-alcoholic fatty liver disease, Systemic lupus erythematosus, Hematopoietic cell lineage and NO-cGMP-PKG signaling. CONCLUSIONS: NO-cGMP-PKG signaling may play an important role in the occurrence and development of ONFH. SLC4A1, GYPA, CXCL8, GBP5 and AHSP may be key genes associated with gender difference in the progression of ONFH, which may be ideal targets or prognostic markers for the treatment of ONFH.


Assuntos
Cabeça do Fêmur , Osteonecrose , Fatores Sexuais , Feminino , Humanos , Masculino , Biologia Computacional , Osteonecrose/genética
4.
Chin J Physiol ; 66(5): 379-387, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37929350

RESUMO

Prostate cancer (PCa) is a common cancer and the leading cause of cancer-related death in men. To investigate the role of pre-mRNA processing factor 19 (PRPF19) in proliferation, migration of PCa, and evaluate the potential ability of PRPF19 as a therapeutic target. PRPF19 expression was analyzed from The Cancer Genome Atlas and GEPIA databank. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate the transcription of PRPF9 and solute carrier family 40 member 1 (SLC40A1). Immunohistochemistry (IHC) was used to test PRPF9 expression in PCa tissues. The cell viability and 5-ethynyl-2'-deoxyuridine incorporation analysis were performed to assess cell proliferation. Transwell assay was performed to investigate the migration and invasion of cancer cells. Western blot was used to measure the expression level of PRPF9, E-cadherin, Vimentin and α-smooth muscle actin (α-SMA), SLC40A1, LC3, Beclin-1 and ATG7. Immunofluorescence assay was performed to measure LC3 expression in PCa cells. The bioinformatic analysis revealed PRPF19 was highly expressed in PCa which was certified by qRT-PCR, western blot and IHC detection in PCa tissues. The proliferation of PCa cells could be promoted by PRPF19 overexpression and suppressed by PRPF19 knockdown. Moreover, the migration and invasion of PCa cells could be positively regulated by PRPF19 which promoted the expression of E-cadherin, Vimentin, and α-SMA. Furthermore, the expression of LC3, Beclin-1, and ATG7 was negatively regulated by PRPF19, indicating that PRPF19 inhibited autophagy in PCa cells. In the double knockdown of PRPF19 and SLC40A1, PRPF19 repressed the mRNA and reduced protein level of SLC40A1, and SLC40A1 antagonized effects of PRPF19 on proliferation, migration and autophagy of PCa cells. PRPF19 promoted proliferation and migration, and inhibited autophagy in PCa by attenuating SLC40A1 expression, indicating PRPF19 was a potential therapeutic target for PCa treatment.


Assuntos
Autofagia , Neoplasias da Próstata , Fatores de Processamento de RNA , Humanos , Masculino , Proteína Beclina-1 , Caderinas , Proliferação de Células , Enzimas Reparadoras do DNA , Proteínas Nucleares , Neoplasias da Próstata/genética , Fatores de Processamento de RNA/genética , Vimentina
5.
Aesthet Surg J ; 43(11): NP924-NP933, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37158152

RESUMO

BACKGROUND: Adipose-derived stem cells (ADSCs) are crucial in cell-assisted lipotransfer (CAL). ADSC-derived exosomes could improve the survival of CAL. Almost all relevant research now ignores ADSCs in favor of studying the proangiogenic potential of extracellular vesicles (EVs) on human umbilical vein endothelial cells (HUVECs). OBJECTIVES: Given the significance of ADSCs in CAL, the authors sought to verify that EVs from ADSCs under hypoxia treatment can enhance the angiogenic potential of ADSCs. METHODS: EVs were harvested from human ADSCs (hADSCs) under normoxia and hypoxia. A Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation of hADSCs. By examining the expression of CD31, vascular endothelial growth factor receptor 2, and vascular endothelial growth factor, the pro-angiogenic differentiation potential was assessed. Moreover, a tube formation experiment was carried out to evaluate the pro-angiogenic differentiation potential. RESULTS: Hypoxic EVs showed more significant pro-proliferative and pro-angiogenic potential. Angiogenesis was more vigorous in hADSCs treated with hypoxic EVs than in those treated with nomorxic EVs. The hADSCs treated with hypoxic EVs expressed higher angiogenic markers, according to real-time polymerase chain reaction (RT-PCR) and Western blot analysis, which revealed more angiogenic marker expression in hypoxic EV-treated hADSCs. The same result was demonstrated by tube formation on Matrigel in vitro. CONCLUSIONS: Hypoxic EVs significantly increased the proliferation and angiogenic differentiation potential of hADSCs. Hypoxic EV-treated ADSCs may be beneficial to CAL and prevascularized tissue-engineered constructs.


Assuntos
Tecido Adiposo , Vesículas Extracelulares , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neovascularização Fisiológica , Diferenciação Celular , Vesículas Extracelulares/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia/metabolismo , Células-Tronco , Proliferação de Células
6.
J Cogn Neurosci ; 34(8): 1416-1428, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35579988

RESUMO

In conditional reasoning, the reasoner must draw a conclusion based on a conditional or "If…, then…" proposition. Previous studies have reported that reversing the premises can effectively promote modus tollens reasoning (a form of conditional reasoning), but subsequent experimental studies have found no such effect. Therefore, to further examine this issue and reveal the cognitive mechanism of conditional reasoning, we asked two groups of healthy volunteers (traditional and inverted premise order groups) to evaluate a set of visually presented conditional tasks (modus ponens/modus tollens) under fMRI. The results indicated that the inverted condition activated more brain regions associated with working memory, including the angular gyrus (BA 39), precuneus (BA 7), inferior parietal lobe, and middle frontal gyrus. The resulting common activation map was used to define the ROIs and perform dynamic causal modeling for the effective connectivity analysis, containing the medial frontal gyrus, hippocampus, cerebellum, and middle occipital gyrus in the right hemisphere and the inferior occipital gyrus in the left hemisphere. The results of intrinsic connections in the optimal model selected by Bayesian model selection showed that the connection strength was stronger in the inverted group rather than in the traditional group, which may indicate that the reversal of the premise order promotes connectivity between brain regions. Despite the lack of a premise order effect, we did discover a neuronal separation between the inverted and traditional conditions, which lends support to the mental model theory to some extent.


Assuntos
Mapeamento Encefálico , Encéfalo , Teorema de Bayes , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Resolução de Problemas
7.
Opt Lett ; 47(22): 5953-5956, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37219145

RESUMO

We demonstrate a two-dimensional vector bending sensor based on a hole-assisted three-core fiber (HATCF) coupler. The sensor is built by splicing a section of HATCF between two single-mode fibers (SMFs). The resonance couplings between the center core and the two suspended cores of the HATCF occur at different wavelengths. Two completely discrete resonance dips are observed. The bending response of the proposed sensor is investigated over a 360° range. The bending curvature and direction can be identified by interrogating the wavelengths of the two resonance dips, and a maximum curvature sensitivity of -50.62 nm/m-1 is achieved at 0° direction. Moreover temperature sensitivity of the sensor is less than -34.9 pm/°C.

8.
Acta Pharmacol Sin ; 43(10): 2678-2686, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35228653

RESUMO

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cisteína , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Musculoskelet Neuronal Interact ; 22(3): 393-400, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36046996

RESUMO

OBJECTIVES: The present study aimed to identify different key genes and pathways between postmenopausal females and males by studying differentially expressed genes (DEGs). METHODS: GSE32317 and GSE55457 gene expression data were downloaded from the GEO database, and DEGs were discovered using R software to obtain overlapping DEGs. The interaction between overlapping DEGs was further analyzed by establishing the protein-protein interaction (PPI) network. Finally, GO and KEGG were used for enrichment analysis. RESULTS: 924 overlapping DEGs between postmenopausal women and men with osteoarthritis (OA) were identified, including 674 up-regulated genes and 249 down-regulated ones. And 10 hub genes were identified in the PPI network, including BMP4, KDM6A, JMJD1C, NFATC1, PRKX, SRF, ZFX, LAMTOR5, UFD1L and AMBN. The findings of the functional enrichment analysis suggested that these genes were predominantly expressed in MAPK signaling pathway as well as the Thyroid hormone signaling pathway, indicating that those two pathways may be involved in onset and disease progression of OA in postmenopausal patients. CONCLUSION: BMP4, KDM6A, JMJD1C, PRKX, ZFX and LAMTOR5 are expected to play crucial roles in disease development in postmenopausal patients and may be ideal targets or prognostic markers for the treatment of OA.


Assuntos
Biologia Computacional , Osteoartrite , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Histona Desmetilases , Humanos , Histona Desmetilases com o Domínio Jumonji , Masculino , Osteoartrite/genética , Osteoartrite/metabolismo , Oxirredutases N-Desmetilantes , Caracteres Sexuais
10.
Microb Pathog ; 151: 104751, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33482261

RESUMO

Blastocystis is one of the most common causative agents of intestinal diseases, which can cause enteric diseases in animals and humans. However, limited data is available on the prevalence or subtypes of Blastocystis infections in farmed pigs in southern China. In this study, a total of 396 fecal samples were collected from farmed pigs in three provinces in southern China in 2016, and screened for Blastocystis by PCR amplification of the small subunit rRNA (SSU rRNA) gene fragment. One hundred and seventy (42.93%) of the examined fecal samples were detected Blastocystis-positive, and two known zoonotic subtypes ST1 and ST5 were identified, with ST5 being the predominate subtype. Moreover, gender, age and region were considered as risk factors that associated with Blastocystis infection in farmed pigs. The present study revealed the prevalence and subtypes of Blastocystis infections in farmed pigs in southern China, which provided essential data for the control of Blastocystis infections in pigs, other animals and humans in China.


Assuntos
Infecções por Blastocystis , Blastocystis , Animais , Blastocystis/genética , Infecções por Blastocystis/epidemiologia , Infecções por Blastocystis/veterinária , China/epidemiologia , Fezes , Variação Genética , Filogenia , Prevalência , Suínos
11.
Microb Pathog ; 158: 105025, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34090984

RESUMO

Yunling cattle is an unique cattle breed distributed in Yunnan Province, southwestern China. It is yet to know whether Yunling cattle are infected with Giardia duodenalis and Cryptosporidium spp.. The objectives of the present study were to investigate the prevalence and characterize the assemblages of G. duodenalis and species of Cryptosporidium spp. in Yunling cattle in Yunnan province. The overall prevalence of G. duodenalis and Cryptosporidium spp. were 10.49% (41/391) and 0.77% (3/391), respectively. The age was considered as the risk factor for Yunling cattle infection with G. duodenalis (χ2 = 8.082, OR = 2.56, P = 0.004). Two assemblages of G. duodenalis, assemblage A (n = 1) and assemblage E (n = 40), were identified by amplification of the ß-giardin (bg) and glutamate dehydrogenase (gdh) gene loci using the nested PCR methods. Furthermore, Cryptosporidium andersoni (n = 1) and Cryptosporidium ryanae (n = 2) were detected by nested PCR targeting the small subunit (SSU) rRNA gene. This is the first report of G. duodenalis and Cryptosporidium spp. in Yunling cattle in China, which provided baseline date for further studies of the prevalence, genetic identity, and public health potential of these parasites in Yunling cattle.


Assuntos
Criptosporidiose , Cryptosporidium , Giardia lamblia , Giardíase , Animais , Bovinos , China/epidemiologia , Criptosporidiose/epidemiologia , Cryptosporidium/genética , Fezes , Genótipo , Giardia lamblia/genética , Giardíase/epidemiologia , Giardíase/veterinária , Prevalência
12.
An Acad Bras Cienc ; 93(2): e20190431, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33656049

RESUMO

Oil Tea (Camellia oleifera) is an important woody edible oil plant in China. Oil Tea suffers from low rate of fruit set during production, which is related to poor pollination and fertilization. Pollen vigor is directly related to pollination and fertilization. Using the interspecific hybrid Y3 (C. grijsii × C. oleifera) as plant material, we studied the effects of sucrose, H3BO3, MgSO4, and IAA on pollen germination using an orthogonal design to determine the best culture medium. Results indicated that pollen germination rates were significantly affected by medium components and ranged from 29.13% to 56.84%. Pollen tube length was the longest in the T5 medium surpassing the control group by 489.36 µm. MgSO4 turned out to be the most important germination medium component having great effect on the pollen germination rate. The optimal culture medium to promote pollen tube growth of Oil Tea Y3 was: 1% agar, 150 g·L-1 sucrose, 0.15 g·L-1 H3BO3, 0.07 g·L-1 MgSO4, and 0.01 g·L-1 IAA. The results of this paper may provide information for foliar application of Mg and IAA, which can improve pollen tube growth of Oil Tea in practice.


Assuntos
Pólen , Polinização , China , Meios de Cultura , Germinação , Chá
13.
Biol Reprod ; 103(5): 1121-1131, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32744313

RESUMO

Mammalian spermatozoa are highly polarized cells characterized by compartmentalized cellular structures and energy metabolism. Adenylate kinase (AK), which interconverts two ADP molecules into stoichiometric amounts of ATP and AMP, plays a critical role in buffering adenine nucleotides throughout the tail to support flagellar motility. Yet the role of the major AK isoform, AK1, is still not well characterized. Here, by using a proteomic analysis of testis biopsy samples, we found that AK1 levels were significantly decreased in nonobstructive azoospermia patients. This result was further verified by immunohistochemical staining of AK1 on a tissue microarray. AK1 was found to be expressed in post-meiotic round and elongated spermatids in mouse testis and subsequent mature sperm in the epididymis. We then generated Ak1 knockout mice, which showed that AK1 deficiency did not induce any defects in testis development, spermatogenesis, or sperm morphology and motility under physiological conditions. We further investigated detergent-modeled epididymal sperm and included individual or mixed adenine nucleotides to mimic energy stress. When only ADP was available, Ak1 disruption largely compromised sperm motility, manifested as a smaller beating amplitude and higher beating frequency, which resulted in less effective forward swimming. The energy restriction/recover experiments with intact sperm further addressed this finding. Besides, decreased AK activity was observed in sperm of a male fertility disorder mouse model induced by cadmium chloride. These results cumulatively demonstrate that AK1 was dispensable for testis development, spermatogenesis, or sperm motility under physiological conditions, but was required for sperm to maintain a constant adenylate energy charge to support sperm motility under conditions of energy stress.


Assuntos
Adenilato Quinase/genética , Metabolismo Energético/fisiologia , Infertilidade Masculina/genética , Motilidade dos Espermatozoides/genética , Adenilato Quinase/metabolismo , Animais , Epididimo/metabolismo , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteômica , Espermátides/metabolismo , Espermatozoides/metabolismo
14.
Nanotechnology ; 31(48): 485404, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-32931476

RESUMO

Due to its high capacity (1675 mAh g-1), Li-S batteries have been considered as one of the ideal energy storage systems. The grand challenges of lithium-sulfur batteries are sulfur immobilization and improving electrical conductivity of cathode composite. The carbon-sulfur (C-S) composites and the polar materials (Ni(OH)2, TiO2, MnO2, TiS2, Co9S8, etc) integration have been proven to be two of the most effective routes to achieving good Li-S battery performance. However, each strategy has drawbacks: the C-S composites have low volume density and the polar materials are often lack of electrical conductivity. Therefore, the hybridization of carbon and polar materials shall provide synergistic effects achieving ideal sulfur cathode. Herein, a hybrid material with carbon-coated NiS nanoparticles grown on graphene sheets was synthesized through a hydrothermal reaction followed by two steps of annealing. The obtained composite has a well-balanced ratio between graphene and NiS. An optimized energy density was demonstrated in lithium-sulfur cells.

15.
Bioorg Med Chem ; 28(15): 115601, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32631570

RESUMO

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC50 value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC50 value of 0.42 µM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.


Assuntos
Benzazepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Tiazóis/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzazepinas/síntese química , Benzazepinas/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Tiazóis/síntese química , Tiazóis/metabolismo , Fatores de Transcrição/metabolismo
16.
Bioorg Med Chem ; 28(13): 115574, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32546302

RESUMO

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Piridinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzofuranos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenilpropionatos/química , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ratos Sprague-Dawley , Sulfonas/farmacologia
17.
Bioorg Chem ; 103: 104138, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32745760

RESUMO

Tumor immunotherapy based on specific tumor antigen has become the focus for breast cancer, and research into cancer/testes antigens (CTA) is progressing. As an important member in the CTA, NY-ESO-1 plays a crucial role in the treatment and prognosis of breast cancer. In this study, we aimed to improve the binding ability to MHC by designing and synthesizing stable NY-ESO-1-derived peptides, based on NetMHC 4.0 webserver (http://www.cbs.dtu.dk/services/NetMHC/) and HLP webserver (http://crdd.osdd.net/raghava/hlp/pep_both.htm). Moreover, after modification of the lead compound, affinity of the peptides to human leukocyte antigen-A2 (HLA-A2) was determined by a flow cytometry and an inverted fluorescence microscope in T2 cells that show high expression of HLA-A2. The results demonstrated that the affinity of peptides II-4 and II-10 to HLA-A2 was significantly better when compared to others (II-Lead, II-1 ~ II-3, II-5 ~ II-9, II-11 ~ II-15). Further studies indicated that II-4 and II-10, especially II-4, significantly promoted the maturation of HLA-A2-positive human peripheral blood-derived dendritic cells (DCs) from morphology and surface markers, the activation of CD8 + T lymphocytes, and the type-specific killing effect on HLA-A2+/NY-ESO-1+ MDA-MB-231 cells. Molecular docking studies suggested a strong interaction between peptide II-4 and HLA-A2, thereby indicating that the II-4 is a promising candidate with antigenic potential in the field of immunotherapy that needs more studies.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/tratamento farmacológico , Antígeno HLA-A2/imunologia , Peptídeos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Estrutura Molecular , Peptídeos/química , Peptídeos/imunologia , Relação Estrutura-Atividade
18.
Parasitol Res ; 119(8): 2733-2740, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32617726

RESUMO

Amebiasis is a worldwide parasitic zoonosis, with symptoms of abdominal discomfort, indigestion, diarrhea, and even death. However, limited information about the prevalence of Entamoeba spp. in experimental nonhuman primates (NHPs) in southwestern China is available. The objective of the current study was to investigate the frequency and species identity of Entamoeba to evaluate potential zoonotic risk factors for Entamoeba spp. infection in experimental NHPs. A total of 505 fecal samples were collected from NHPs (macaques) and analyzed by PCR analysis the small subunit rRNA (SSU rRNA) gene of Entamoeba spp. Forty-seven specimens were positive for Entamoeba spp., and the prevalence of Entamoeba spp. was 9.31% (47/505). Significant differences in the prevalence rates among the three breeds (P = 0.002 < 0.01, df = 2, χ2 = 12.33) and feed types (P = 0.001 < 0.01, df = 1, χ2 = 10.12) were observed. Altogether, four Entamoeba species, including E. dispar (57.44%), E. chattoni (29.78%), E. histolytica (6.38%), and E. coli (6.38%), were identified by DNA sequence analysis. The results suggested a low prevalence but high diversity of Entamoeba species in experimental NHPs in Yunnan Province, southwestern China. Results of this study contribute to the knowledge of the genetic characteristics of Entamoeba spp. in NHPs.


Assuntos
Entamoeba/genética , Entamebíase/veterinária , Macaca/parasitologia , Infecções Protozoárias em Animais/epidemiologia , Infecções Protozoárias em Animais/parasitologia , Animais , Animais de Laboratório , China/epidemiologia , DNA de Protozoário/genética , Entamoeba/classificação , Entamoeba/isolamento & purificação , Entamebíase/epidemiologia , Entamebíase/parasitologia , Entamebíase/transmissão , Fezes/parasitologia , Epidemiologia Molecular , Prevalência , Infecções Protozoárias em Animais/transmissão , RNA Ribossômico/genética , Subunidades Ribossômicas Menores/genética , Análise de Sequência de DNA
19.
Parasitol Res ; 119(9): 2813-2819, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32583163

RESUMO

Cryptosporidium is an opportunistic protozoan parasite that can inhabit in the gastrointestinal tract of various hosts. Cryptosporidium infection in black-boned goats and black-boned sheep may pose a threat to the survival and productivity, causing considerable economic losses to the livestock industry. However, it is yet to know whether black-boned goats and black-boned sheep in China are infected with Cryptosporidium. Thus, the objective of the present study was to investigate the prevalence and associated risk factors of Cryptosporidium infection in black-boned goats and black-boned sheep in Yunnan province, China. A total of 590 fecal samples were obtained from black-boned goats and black-boned sheep from five counties in Yunnan province, and the prevalence and species distribution of Cryptosporidium were determined by amplification of the 18S rDNA fragment using the nested PCR. The overall Cryptosporidium prevalence was 13.2% (78/590), with 18.0% (55/305) in black-boned goats and 8.1% (23/285) in black-boned sheep. The age and sampling site were identified as main factors that result in significant differences in Cryptosporidium prevalence. Three species, namely C. muris, C. xiaoi, and C. ubiquitum, were identified in black-boned goats and black-boned sheep in the present study, with C. muris (46/78) as the predominant species. This is the first report of Cryptosporidium infection in black-boned goats and black-boned sheep in China, and the findings will facilitate better understanding, prevention, and control of Cryptosporidium infection in black-boned goats and black-boned sheep in China.


Assuntos
Criptosporidiose/epidemiologia , Cryptosporidium/isolamento & purificação , Doenças das Cabras/parasitologia , Reação em Cadeia da Polimerase/veterinária , Doenças dos Ovinos/parasitologia , Animais , China/epidemiologia , Cryptosporidium/classificação , Cryptosporidium/genética , Fezes/parasitologia , Trato Gastrointestinal/parasitologia , Cabras/parasitologia , Prevalência , RNA Ribossômico 18S/genética , Fatores de Risco , Ovinos/parasitologia
20.
Parasitol Res ; 119(2): 741-748, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31897788

RESUMO

Blastocystis is an enteral eukaryote with an omnipresent existence in animals and humans globally. Animals have been proposed to be a major reservoir for the transmission of Blastocystis to individuals due to their high prevalence and large amount of zoonotic subtypes. However, limited data on Blastocystis infection in experimental macaques in China exists. The objective of the current study was to investigate the frequency and subtypes of Blastocystis infection in macaques in southwestern China. A total of 505 fecal samples were collected from experimental macaques in Yunnan province and were analyzed by nested PCR and phylogenetic analyses on the basis of small subunit rRNA (SSU rRNA) gene fragments. A total of 235 specimens were positive for Blastocystis sp., and the prevalence of Blastocystis sp. was 46.5% (235/505). Significant differences in prevalence were also observed among the various species of macaques (P < 0.0133, df = 2, χ2 = 8.64) and the different feed types (P < 0.0093, df = 1, χ2 = 6.77). Moreover, three zoonotic subtypes, ST1, ST3, and ST5, were identified by DNA sequence analysis. There were mainly single subtype infections with some mixed subtype infections, and the predominant subtype was ST3. The results suggested a high prevalence and diversified subtypes in macaques in Yunnan province, southwestern China. Macaques are likely to be potential reservoirs capable of zoonotic transmission of Blastocystis sp. to humans. To our knowledge, this study is the first large-scale systematic analysis of Blastocystis sp. colonization in Yunnan province in the subtropics of China; these results contribute to the in-depth study of genetic characteristics and the prevention, control, and treatment of Blastocystis sp. in macaques in Yunnan province and other regions.


Assuntos
Infecções por Blastocystis/epidemiologia , Infecções por Blastocystis/veterinária , Blastocystis/classificação , Blastocystis/genética , Animais , Blastocystis/isolamento & purificação , Infecções por Blastocystis/parasitologia , China/epidemiologia , Fezes/parasitologia , Variação Genética/genética , Humanos , Macaca , Filogenia , Reação em Cadeia da Polimerase , Prevalência , Zoonoses/parasitologia
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