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1.
Virology ; 597: 110147, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38905921

RESUMO

The glycoprotein GP64 of alphabaculovirus is crucial for viral entry and fusion. Here, we investigated the N-glycosylation patterns of Bombyx mori nucleopolyhedrovirus (BmNPV) GP64 and its signal peptide (SP) cleaved form, SPΔnGP64, along with their impacts on viral infectivity and fusogenicity. Through deglycosylation assays, we confirmed N-glycosylation of BmNPV GP64 on multiple sites. Mutational analysis targeting predicted N-glycosylation sites revealed diverse effects on viral infectivity and cell fusion. Particularly noteworthy were mutations at sites 175, which resulted in complete loss of infectivity and fusion capacity. Furthermore, LC-MS/MS analysis uncovered unexpected non-classical N-glycosylation sites, including N252, N302, N367, and N471, with only N302 and N471 identified in SPΔnGP64. Subsequent investigation highlighted the critical roles of these residues in BmNPV amplification and fusion, underscoring the essentiality of N367 glycosylation for GP64 fusogenicity. Our findings provide valuable insights into the non-classical glycosylation landscape of BmNPV GP64 and its functional significance in viral biology.


Assuntos
Bombyx , Nucleopoliedrovírus , Internalização do Vírus , Nucleopoliedrovírus/genética , Nucleopoliedrovírus/metabolismo , Nucleopoliedrovírus/fisiologia , Glicosilação , Animais , Bombyx/virologia , Bombyx/metabolismo , Proteínas do Envelope Viral/metabolismo , Proteínas do Envelope Viral/genética , Glicoproteínas/metabolismo , Glicoproteínas/genética , Sinais Direcionadores de Proteínas , Espectrometria de Massas em Tandem , Mutação
2.
J Virol ; 97(3): e0004123, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36916914

RESUMO

Baculovirus budded virus (BV) acquires its envelope and viral membrane fusion proteins from the plasma membrane (PM) of the host cell during the budding process. However, this classical BV egress pathway has been questioned because an intracellularly localized membrane fusion protein, SPΔnGP64 (glycoprotein 64 [GP64] lacking the signal peptide [SP] n region), was assembled into the envelope to generate infective BVs in our recent studies. Here, we identify an additional pathway for Bombyx mori nucleopolyhedrovirus (BmNPV) BV assembly and release that differs, in part, from the currently accepted model for the egress pathway of baculovirus. Electron microscopy showed that during infection, BmNPV-infected cells contained many newly formed multivesicular body (MVB)-like compartments that included mature virions at 30 h postinfection (p.i.). Immunoelectron microscopy demonstrated that the MVBs contained CD63, an MVB endosome marker, and GP64, a BmNPV fusion glycoprotein. MVB fusion with the PM and the release of mature virions, together with naked nucleocapsids, were observed at the cell surface. Furthermore, MVB egress mediated the translocation of SPΔnGP64 to the PM, which induced cell-cell fusion until 36 h p.i. This BV egress pathway can be partially inhibited by U18666A incubation and RNA interference targeting MVB biogenesis genes. Our findings indicate that BmNPV BVs are enveloped and released through MVBs via the cellular exosomal pathway, which is a subordinate BV egress pathway that produces virions with relatively inferior infectivity. This scenario has significant implications for the elucidation of the BmNPV BV envelopment pathway. IMPORTANCE BmNPV is a severe pathogen that infects mainly Bombyx mori, a domesticated insect of economic importance, and accounts for approximately 15% of economic losses in sericulture. BV production plays a key role in systemic BmNPV infection of larvae. Despite the progress made in the functional gene studies of BmNPV, BmNPV BV egress is ill-understood. This study reports a previously unreported MVB envelopment pathway in BmNPV BV egress. To our knowledge, this is the first report of a baculovirus using dual BV egress pathways. This specific BV egress mechanism explains the cause of the non-PM-localized SPΔnGP64-rescued gp64-null bacmid infectivity, elucidating the reason underlying the retention of SP by BmNPV GP64. The data obtained elucidate an alternate molecular mechanism of baculovirus BV egress.


Assuntos
Bombyx , Nucleopoliedrovírus , Animais , Corpos Multivesiculares , Liberação de Vírus , Linhagem Celular , Nucleopoliedrovírus/genética , Nucleopoliedrovírus/metabolismo , Proteínas Virais de Fusão/genética
3.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166281, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610472

RESUMO

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The occurrence and development of CRC are complicated processes. Obesity and dysbacteriosis have been increasingly regarded as the main risk factors for CRC. Understanding the etiology of CRC from multiple perspectives is conducive to screening for some potential drugs or new treatment strategies to limit the serious side effects of conventional treatment and prolong the survival of CRC patients. Melatonin, a natural indoleamine, is mainly produced by the pineal gland, but it is also abundant in other tissues, including the gastrointestinal tract, retina, testes, lymphocytes, and Harder's glands. Melatonin could participate in lipid metabolism by regulating adipogenesis and lipolysis. Additionally, many studies have focused on the potential beneficial effects of melatonin in CRC, such as promotion of apoptosis; inhibition of cell proliferation, migration, and invasion; antioxidant activity; and immune regulation. Meaningfully, gut microbiota is the main determinant of all aspects of health and disease (including obesity and tumorigenesis). The gut microbiota is of great significance for understanding the relationship between obesity and increased risk of CRC. Although the current understanding of how the melatonin-mediated gut microbiota coordinates a variety of physiological and pathological activities is fairly comprehensive, there are still many unknown topics to be explored in the face of a complex nutritional status and a changeable microbiota. This review summarizes the potential links among melatonin, lipid metabolism, gut microbiota, and CRC to promote the development of melatonin as a preventive and therapeutic agent for CRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Melatonina/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia
4.
Pharmaceuticals (Basel) ; 14(8)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34451919

RESUMO

Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals.

5.
Int J Mol Sci ; 21(6)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245084

RESUMO

Hyperuricemia is a central risk factor for gout and increases the risk for other chronic diseases, including cardiometabolic disease, kidney disease, and hypertension. Overproduction of urate is one of the main reasons for hyperuricemia, and dietary factors including seafoods, meats, and drinking are contributed to the development of it. However, the lack of a suitable animal model for urate metabolism is one of the main reasons for the delay and limitations of hyperuricemia research. Combining evolutionary biological studies and clinical studies, we conclude that chicken is a preferred animal model for hyperuricemia. Thus, we provided chickens a high-protein diet (HPD) to evaluate the changes in the serum urate levels in chickens. In our study, the HPD increased the serum urate level and maintained it at a long-term high level in chickens. Long-term high serum urate levels induced an abnormal chicken claw morphology and the precipitation of monosodium urate (MSU) in joint synovial fluid. In addition, a long-term HPD also decreased the glomerular filtration rate and induced mild renal injury. Most importantly, allopurinol and probenecid displayed the positive effects in decreasing serum urate and then attenuated hyperuricemia in chicken model. These findings provide a novel model for hyperuricemia and a new opportunity to further investigate the effects of long-term hyperuricemia on other metabolic diseases.


Assuntos
Dieta Rica em Proteínas/efeitos adversos , Gota/patologia , Hiperuricemia/etiologia , Alopurinol/uso terapêutico , Estruturas Animais/anormalidades , Animais , Galinhas/sangue , Cristalização , Modelos Animais de Doenças , Gota/sangue , Hiperuricemia/sangue , Hiperuricemia/diagnóstico por imagem , Hiperuricemia/tratamento farmacológico , Rim/lesões , Fígado/metabolismo , Probenecid/uso terapêutico , Líquido Sinovial/metabolismo , Ácido Úrico/sangue
6.
Cells ; 9(2)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093272

RESUMO

Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light-12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Luz , Metabolismo dos Lipídeos/efeitos dos fármacos , Melatonina/metabolismo , Melatonina/farmacologia , Animais , Linhagem Celular , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Resistência à Insulina/efeitos da radiação , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/efeitos da radiação
7.
Molecules ; 24(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336903

RESUMO

It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.


Assuntos
Metabolismo Energético , Nutrientes/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Humanos , Especificidade de Órgãos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais
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