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1.
Food Funct ; 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35678194

RESUMO

Excessive reactive oxygen species (ROS) accumulation is involved in the pathogenesis of liver fibrosis and damage, specifically in the developing embryo that is extremely sensitive to oxidative stress. Herein, a liver injury model in chick embryo was established by using 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH), which was used to investigate the effect of cyclo(-Phe-Phe) (CPP), a natural dipeptide found in foods and beverages. The results showed that CPP significantly alleviated AAPH-induced liver pathological damage, hepatic dysfunction and inhibited the excessive production of ROS in both chick embryo liver and HepG2 cells. Additionally, CPP increased the antioxidative activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as elevated the level of glutathione (GSH), suggesting that CPP combating liver injury probably depends on its antioxidant capability. Mechanistically, CPP upregulated the mRNA and protein expression of heme oxyense-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO1) in vivo and in vitro, along with promoting the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) while inhibiting its degradation through binding with Kelch-like ECH-associated protein 1 (Keap1). In conclusion, this study proposes a potential peptide drug for the treatment of hepatic damage induced by oxidative stress and also unravels its mechanism of action.

2.
Acta Pharm Sin B ; 12(1): 197-209, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35127380

RESUMO

The relationship between chronic psychological stress and tumorigenesis has been well defined in epidemiological studies; however, the underlying mechanism remains underexplored. In this study, we discovered that impaired macrophage phagocytosis contributed to the psychological stress-evoked tumor susceptibility, and the stress hormone glucocorticoid (GC) was identified as a principal detrimental factor. Mechanistically, GC disturbed the balance of the "eat me" signal receptor (low-density lipoprotein receptor-related protein-1, LRP1) and the "don't eat me" signal receptor (signal regulatory protein alpha, SIRPα). Further analysis revealed that GC led to a direct, glucocorticoid receptor (GR)-dependent trans-repression of LRP1 expression, and the repressed LRP1, in turn, resulted in the elevated gene level of SIRPα by down-regulating miRNA-4695-3p. These data collectively demonstrate that stress induces the imbalance of the LRP1/SIRPα axis and entails the disturbance of tumor cell clearance by macrophages. Our findings provide the mechanistic insight into psychological stress-evoked tumor susceptibility and indicate that the balance of LRP1/SIRPα axis may serve as a potential therapeutic strategy for tumor treatment.

3.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4208-4213, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467734

RESUMO

In this study, emotional stress-induced herpes simplex virus type 1(HSV-1) susceptibility model was employed to simu-late the pathological state of " depression-induced liver fire", and the protection effect of Qingre Xiaoyanning(QX) in clearing liver fire was investigated. BALB/c mice were randomly divided into a normal group, a HSV-1 group, a restraint stress + HSV-1 group,low-(0. 658 g·kg~(-1)) and high-dose(1. 316 g·kg~(-1)) QX groups, and an acyclovir group. Except for the normal group and the HSV-1 group, the mice in other groups received daily restraint stress for 6 h from day 3 of medication. On day 9 of medication, mice were anesthetized by isoflurane and infected intranasally with HSV-1. Survival rate, weight change, encephalitis symptoms, and eye injury of mice were recorded for 14 d after virus infection. Hematoxylin-eosin(HE) staining and immunohistochemical staining were used to detect pathological changes and HSV-1 antigen distribution. Plaque assay was performed to detect the titer of HSV-1. The protein ex-pression of ICP27 in the mouse brain was detected by Western blot. The experimental results showed that QX could increase the survival rate of HSV-1-infected mice loaded with emotional stress(P<0. 001), reduce the titer of HSV-1 in the mouse brain(P<0. 01), relieve brain inflammation(P<0. 05) and eye injury(P<0. 05), down-regulate the expression of ICP27 related to HSV-1(P<0. 05), and decrease the distribution of HSV-1 antigen in the mouse brain. The results demonstrated that QX significantly reduced the susceptibility to HSV-1 induced by emotional stress, which is expected to provide a theoretical basis for the treatment and preven-tion of HSV-1 infection and promote the clinical development and application of Chinese medicine effective in clearing liver fire.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Angústia Psicológica , Animais , Cápsulas , Camundongos , Camundongos Endogâmicos BALB C
4.
Pathobiology ; 88(4): 289-300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34130294

RESUMO

INTRODUCTION: Follicular thyroid carcinoma (FTC) is more aggressive than the most common papillary thyroid carcinoma (PTC). However, the current research on FTC is less than PTC. Here, we investigated the effects of long noncoding RNA (lncRNA) GAS5 and miR-221-3p in FTC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect GAS5 and miR-221-3p expression in the FTC tissues and cells. Cell proliferation was assessed by CCK8 and EdU assays. Flow cytometry was performed to determine the cell cycle. The dual-luciferase reporter assay was employed to validate the binding relationship of GAS5/miR-221-3p and miR-221-3p/cyclin-dependent kinase inhibitor 2B (CDKN2B). Western blot was conducted to measure the protein level of CDKN2B. RESULTS: Our results displayed that GAS5 was downregulated, while miR-221-3p was upregulated in FTC tissues and cells. What's more, overexpression of GAS5 or miR-221-3p inhibition induced G0/G1 phase arrest and inhibited cell proliferation of FTC cells. GAS5 acted as a sponge of miR-221-3p, and CDKN2B was a target gene of miR-221-3p. Additionally, GAS5 inhibited cell cycle and proliferation of FTC cells via reducing miR-221-3p expression to enhance CDKN2B expression. CONCLUSION: GAS5 induced G0/G1 phase arrest and inhibited cell proliferation via targeting miR-221-3p/CDKN2B axis in FTC. Thus, GAS5 may be a potential therapeutic target for the treatment of FTC.


Assuntos
Adenocarcinoma Folicular/genética , Ciclo Celular/genética , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Glândula Tireoide/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Humanos , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/patologia
5.
J Agric Food Chem ; 69(25): 7016-7027, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34060828

RESUMO

Daily intake of tea has been known to relate to a low risk of depression. In this study, we report that a special variety of tea in China, Camellia assamica var. kucha (kucha), possesses antidepressant effects but with less adverse effects as compared to traditional tea Camellia sinensis. This action of kucha is related to its high amount of theacrine, a purine alkaloid structurally similar to caffeine. We investigated the antidepressant-like effects and mechanisms of theacrine in chronic water immersion restraint stress and chronic unpredictable mild stress mice models. PC12 cells and primary hippocampal neural stem cells were treated with stress hormone corticosterone (CORT) to reveal the potential antidepression mechanism of theacrine from the perspective of adult hippocampus neurogenesis. Results of behavioral and neurotransmitter analysis showed that intragastric administration of theacrine significantly counteracted chronic stress-induced depression-like disorders and abnormal 5-hydroxytryptamine (5-HT) metabolism with less central excitability. Further investigation from both in vivo and in vitro experiments indicated that the antidepressant mechanism of theacrine was associated with promoting adult hippocampal neurogenesis, via the modulation of the phosphodiesterase-4 (PDE4)/cyclic adenosine monophosphate (cAMP)/cAMP response-element binding (CREB)/brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway. Collectively, our findings could promote the prevalence of kucha as a common beverage with uses for health care and contribute to the development of theacrine as a potential novel antidepressant medicine.


Assuntos
Alcaloides , Camellia sinensis , Animais , Antidepressivos , Fator Neurotrófico Derivado do Encéfalo/genética , China , Depressão/tratamento farmacológico , Hipocampo , Camundongos , Neurogênese , Purinas , Ratos , Estresse Psicológico , Chá , Ácido Úrico/análogos & derivados
6.
Food Chem ; 345: 128812, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33601655

RESUMO

Due to complex matrixes and specific reagent deficiency, the rapid detection of histamine is still a challenge to date. Based on the high peroxidase-like activity of iron-cobalt co-doped carbon dots, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) was established for histamine detection using the mimic enzyme labeled with histamine antibody (His-Ab). Through the competitive binding of the labeled His-Ab to solid-phase and sample antigens, histamine content was detected with a linear range of 2.5-150 µg mL-1. The detection limit based on 3σ/K was 0.50 mg kg-1, which was much lower than those of commercial His-kit and HPLC methods. The ic-ELISA method was applied to histamine detection in fish samples with the recovery of (103.4 ± 0.5)%, which was in accord with those of commercial His-kit and HPLC methods. The results indicated that the established ic-ELISA method was suitable for rapid detection of histamine in fish samples with high accuracy, sensitivity and stability.


Assuntos
Peixes/metabolismo , Histamina/análise , Pontos Quânticos/química , Animais , Anticorpos/química , Anticorpos/imunologia , Carbono/química , Cobalto/química , Ensaio de Imunoadsorção Enzimática , Histamina/imunologia , Ferro/química , Limite de Detecção , Reprodutibilidade dos Testes , Alimentos Marinhos/análise
7.
Cell Death Differ ; 28(6): 1971-1989, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33432112

RESUMO

During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A2. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.


Assuntos
Ferroptose/genética , Fagocitose/genética , Fosfatidiletanolaminas/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Humanos , Camundongos , Microambiente Tumoral
8.
Theranostics ; 11(1): 222-256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391472

RESUMO

Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, etc. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, etc. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.


Assuntos
Macroautofagia/fisiologia , Mitofagia/fisiologia , Autofagia/fisiologia , Humanos , Organelas
9.
Phytomedicine ; 80: 153398, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33130474

RESUMO

BACKGROUND: Celastrol, a pentacyclic triterpenoid quinonemethide isolated from several spp. of Celastraceae family, exhibits anti-inflammatory activities in a variety of diseases including arthritis. PURPOSE: This study aims to investigate whether the inhibition of NLRP3 inflammasome is engaged in the anti-inflammatory activities of celastrol and delineate the underlying mechanism. METHODS: The influence of celastrol on NLRP3 inflammasome activation was firstly studied in lipopolysaccharide (LPS)-primed mouse bone marrow-derived macrophages (BMDMs) and phorbol 12-myristate 13-acetate (PMA)-primed THP-1 cells treated with nigericin. Reconstituted inflammasome was also established by co-transfecting NLRP3, ASC, pro-caspase-1 and pro-IL-1ß in HEK293T cells. The changes of inflammasome components including NLRP3, ASC, pro-caspase-1/caspase-1 and pro-IL-1ß/IL-1ß were examined by enzyme-linked immunosorbent assay (ELISA), western blotting and immunofluorescence. Furthermore, Propionibacterium acnes (P. acnes)/LPS-induced liver injury and monosodium urate (MSU)-induced gouty arthritis in mice were employed in vivo to validate the inhibitory effect of celastrol on NLRP3 inflammasome. RESULTS: Celastrol significantly suppressed the cleavage of pro-caspase-1 and pro-IL-1ß, while not affecting the protein expressions of NLRP3, ASC, pro-caspase-1 and pro-IL-1ß in THP-1 cells, BMDMs and HEK293T cells. Celastrol suppressed NLRP3 inflammasome activation and alleviated P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis. Mechanism study revealed that celastrol could interdict K63 deubiquitination of NLRP3, which may concern interaction of celastrol and BRCA1/BRCA2-containing complex subunit 3 (BRCC3), and thereby prohibited the formation of NLRP3, ASC and pro-caspase-1 complex to block the generation of mature IL-1ß. CONCLUSION: Celastrol suppresses NLRP3 inflammasome activation in P. acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3, which presents a novel insight into inhibition of celastrol on NLRP3 inflammasome and provides more evidences for its application in the therapy of inflammation-related diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/tratamento farmacológico , Fígado/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Triterpenos/farmacologia , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Células HEK293 , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/microbiologia , Fígado/patologia , Lisina/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Triterpenos Pentacíclicos , Propionibacterium acnes/patogenicidade , Células THP-1 , Ubiquitinação/efeitos dos fármacos , Ácido Úrico/toxicidade
10.
Acta Pharmacol Sin ; 42(4): 518-528, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32724177

RESUMO

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson's disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg-1·d-1, i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg-1·d-1, i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP+-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12α-Syn A53T) cells, treatment with GM1 ganglioside (40 µM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP+-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12α-Syn A53T cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12α-Syn A53T cells and the MPP+-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.


Assuntos
Autofagia/efeitos dos fármacos , Gangliosídeo G(M1)/uso terapêutico , Neuroproteção/efeitos dos fármacos , Doença de Parkinson Secundária/tratamento farmacológico , alfa-Sinucleína/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular Tumoral , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Doença de Parkinson Secundária/induzido quimicamente , Ratos
11.
Acta Pharm Sin B ; 10(12): 2323-2338, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33354504

RESUMO

Herpes simplex virus type 1 (HSV-1) is a ubiquitous and widespread human pathogen, which gives rise to a range of diseases, including cold sores, corneal blindness, and encephalitis. Currently, the use of nucleoside analogs, such as acyclovir and penciclovir, in treating HSV-1 infection often presents limitation due to their side effects and low efficacy for drug-resistance strains. Therefore, new anti-herpetic drugs and strategies should be urgently developed. Here, we reported that baicalein, a naturally derived compound widely used in Asian countries, strongly inhibited HSV-1 replication in several models. Baicalein was effective against the replication of both HSV-1/F and HSV-1/Blue (an acyclovir-resistant strain) in vitro. In the ocular inoculation mice model, baicalein markedly reduced in vivo HSV-1/F replication, receded inflammatory storm and attenuated histological changes in the cornea. Consistently, baicalein was found to reduce the mortality of mice, viral loads both in nose and trigeminal ganglia in HSV-1 intranasal infection model. Moreover, an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication. Further investigations unraveled that dual mechanisms, inactivating viral particles and inhibiting IκB kinase beta (IKK-ß) phosphorylation, were involved in the anti-HSV-1 effect of baicalein. Collectively, our findings identified baicalein as a promising therapy candidate against the infection of HSV-1, especially acyclovir-resistant strain.

12.
Signal Transduct Target Ther ; 5(1): 202, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32943610

RESUMO

Although stress has been known to increase the susceptibility of pathogen infection, the underlying mechanism remains elusive. In this study, we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus (H1N1) and obviously aggravated lung inflammation. Corticosterone (CORT), a main type of glucocorticoids in rodents, was secreted in the plasma of stressed mice. We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling (MAVS) protein-transduced IFN-ß production without affecting its mRNA level, while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice. Mechanistically, the effect of CORT was mediated by proteasome-dependent degradation of MAVS, thereby resulting in the impediment of MAVS-transduced IFN-ß generation in vivo and in vitro. Furthermore, RNA-seq assay results indicated the involvement of Mitofusin 2 (Mfn2) in this process. Gain- and loss-of-function experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS. Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2 (HR1), MAVS (C-terminal/TM) and SYVN1 (TM). Collectively, our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a 'fine tuning' of antiviral innate immunity in response to influenza infection under stress.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Corticosterona/farmacologia , GTP Fosfo-Hidrolases/metabolismo , Vírus da Influenza A Subtipo H1N1/metabolismo , Interferon beta/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Proteólise/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Ubiquitina/metabolismo , Animais , Masculino , Camundongos
13.
Cell Death Dis ; 11(9): 781, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32951003

RESUMO

Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1-Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Lactamas/farmacologia , Lignanas/farmacologia , Fígado/lesões , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo
14.
Theranostics ; 10(20): 9032-9049, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32802177

RESUMO

Rationale: Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that can cause a variety of clinical syndromes including mucocutaneous disease and HSV-1 encephalitis (HSE). Here, we characterize the molecular mechanisms underlying the susceptibility to HSV-1 under stressful conditions. Methods: Restraint stress and corticosterone (CORT, a primary stress hormone) were respectively used to establish HSV-1 susceptible model in vivo and in vitro. Viral titers were determined by plaque assay. Western blotting, immunofluorescence, transmission electron microscopy (TEM), qRT-PCR, H&E staining, IHC staining and flow cytometry were employed to evaluate virus-related protein expressions and detect the activation of autophagy. Loss- and gain-function assays, co-immunoprecipitation (co-IP) technique and autophagy agonist/antagonist treatments were applied in mechanistic experiments. Results: Restraint stress increased the susceptibility of mouse brain to HSV-1. Similarly, CORT treatment enhanced the susceptibility of neural cells to HSV-1. Furthermore, PML protein level in HSV-1 infected brain tissues and neural cells was remarkably decreased by stress treatment in vivo or CORT treatment in vitro, while its transcriptional level was not affected. Notably, a striking decline in protein expressions of ICP27 and gB was observed in PML-overexpressing cells, which was reversed by CORT treatment. By contrast, protein expression of gB was increased by knockdown with si-PML in virus-infected SH-SY5Y cells. We further discovered that CORT-driven PML degradation was dependent on the activation of autophagy in a ULK1-independent manner, rather than proteasome pathway. Bafilomycin A1 (BaF1) attenuated the augmentation effect of CORT on HSV-1 infection. The expressions of viral proteins were reduced in LC3-depleted cells, and the degradation of PML by CORT-induced autophagy was prevented in cells with LC3 knockdown by RNAi. Interestingly, PML was revealed to interact with the autophagic cargo receptor P62 and the autophagic effector protein LC3. Additionally, CORT failed to increase gB protein level when PML was silenced, providing direct evidence linking autophagic degradation of PML and CORT-induced virus susceptibility. Conclusion: Our results revealed that restraint stress/CORT increased HSV-1 susceptibility by delivering PML into autolysosomes for degradation. The results obtained from in vitro and in vivo models not only demonstrated the adverse effects of stress on HSV-1 infection, but also systematically investigated the underlying molecular mechanisms. These discoveries broaden our understanding of the interplay between host and viruses, and a comprehensive understanding of the role of autophagy in viral infection will provide information for future development of innovative drugs against viral infection.


Assuntos
Autofagia/imunologia , Corticosterona/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Proteína da Leucemia Promielocítica/imunologia , Animais , Encéfalo/imunologia , Linhagem Celular , Chlorocebus aethiops , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/imunologia , Células Vero , Proteínas Virais/imunologia , Replicação Viral/imunologia
15.
FASEB J ; 34(8): 10998-11014, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32619083

RESUMO

Chronic stress-evoked depression has been implied to associate with the decline of adult hippocampal neurogenesis. Caffeine has been known to combat stress-evoked depression. Herein, we aim to investigate whether the protective effect of caffeine on depression is related with improving adult hippocampus neurogenesis and explore the mechanisms. Mouse chronic water immersion restraint stress (CWIRS) model, corticosterone (CORT)-established cell stress model, a coculture system containing CORT-treated BV-2 cells and hippocampal neural stem cells (NSCs) were utilized. Results showed that CWIRS caused obvious depressive-like disorders, abnormal 5-HT signaling, and elevated-plasma CORT levels. Notably, microglia activation-evoked brain inflammation and inhibited neurogenesis were also observed in the hippocampus of stressed mice. In comparison, intragastric administration of caffeine (10 and 20 mg/kg, 28 days) significantly reverted CWIRS-induced depressive behaviors, neurogenesis recession and microglia activation in the hippocampus. Further evidences from both in vivo and in vitro mechanistic experiments demonstrated that caffeine treatment significantly suppressed microglia activation via the A2AR/MEK/ERK/NF-κB signaling pathway. The results suggested that CORT-induced microglia activation contributes to stress-mediated neurogenesis recession. The antidepression effect of caffeine was associated with unlocking microglia activation-induced neurogenesis inhibition.


Assuntos
Cafeína/farmacologia , Corticosterona/farmacologia , Hipocampo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Microglia/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Phytomedicine ; 77: 153281, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32707370

RESUMO

BACKGROUND: Oxidative damage of dopaminergic neurons is the fundamental causes of Parkinson's disease (PD) that has no standard cure at present. Theacrine, a purine alkaloid from Chinese tea Kucha, has been speculated to benefit the neurodegeneration in PD, through similar actions to its chemical analogue caffeine, albeit excluding side effects. Theacrine has nowadays gained a lot of interest for its multiple benefits, while the investigations are weak and insufficient. HYPOTHESIS/PURPOSE: It is well-known that tea has a wide range of functions, especially in the prevention and treatment of neurodegenerative diseases. Theacrine is an active monomer compound in Camellia assamica var. kucha Hung T. Chang & H.S.Wang (Kucha), which appears to be effective and safe in PD therapy. The aim of this study is to examine its actions in diverse PD models and explore the mechanisms. STUDY DESIGN: For determination of theacrine's effects, we employed diverse oxidative damage-associated PD models, including 6-OHDA-treated rats, MPTP-treated mice/zebrafish and MPP+-treated SH-SY5Y cells, and using caffeine, selegiline and depranyl as positve control. For investigation and verification of the mechanisms, we utilized approaches testing mitochondrial function-related parameters and enzyme activity as well as applied gene knockdown and overexpression. METHODS: We employed behavioral tests including spontaneous activity, pole, swimming, rotarod and gait, immunohistochemistry, HPLC, flow cytometry, immunohistochemistry, Western blot, gene knockdown by siRNA and overexpression by plasmid in this study. RESULTS: Theacrine is demonstrated to retrieve the loss of dopaminergic neurons and the damages of behavioral performance in multiple animal models of PD (6-OHDA-treated rats and in MPTP-treated mice and zebrafish). The followed data of MPP+-treated SH-SY5Y cells indicate that theacrine relieves apoptosis resulted from oxidative damage and mitochondrial dysfunction. Further investigations illustrate that theacrine activates SIRT3 directly. It is of advantage to prevent apoptosis through SIRT3-mediated SOD2 deacetylation that reduces ROS accumulation and restores mitochondrial function. This concept is elaborated by 3TYP that inhibits SIRT3 enzyme activity and knockdown/overexpression of SIRT3 gene, demonstrating a crucial role of SIRT3 in theacrine-benefited dopaminergic neurons. CONCLUSION: Theacrine prevents apoptosis of dopaminergic neurons through directly activating SIRT3 which deacetylating SOD2 and restoring mitochondrial functions.


Assuntos
Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Sirtuína 1/metabolismo , Ácido Úrico/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Camellia/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Oxidopamina/farmacologia , Transtornos Parkinsonianos/patologia , Ratos Sprague-Dawley , Ácido Úrico/farmacologia , Peixe-Zebra/embriologia
17.
Biosci Biotechnol Biochem ; 84(8): 1621-1628, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32419644

RESUMO

A critical pathogenic factor in the development of lethal liver failure is cell death induced by the accumulation of lipid reactive oxygen species. In this study, we discovered and illuminated a new mechanism that led to alcoholic liver disease via ferroptosis, an iron-dependent regulated cell death. Study in vitro showed that both necroptosis inhibitor and ferroptosis inhibitors performed significantly protective effect on alcohol-induced cell death, while apoptosis inhibitor and autophagy inhibitor had no such effect. Our data also indicated that alcohol caused the accumulation of lipid peroxides and the mRNA expression of prostaglandin-endoperoxide synthase 2, reduced the protein expression of the specific light-chain subunit of the cystine/glutamate antiporter and glutathione peroxidase 4. Importantly, ferrostatin-1 significantly ameliorated liver injury that was induced by overdosed alcohol both in vitro and in vivo. These findings highlight that targeting ferroptosis serves as a hepatoprotective strategy for alcoholic liver disease treatment.


Assuntos
Cicloexilaminas/farmacologia , Etanol/toxicidade , Ferroptose/efeitos dos fármacos , Ferro/metabolismo , Hepatopatias Alcoólicas/genética , Fígado/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Clorometilcetonas de Aminoácidos/farmacologia , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Feminino , Ferroptose/genética , Regulação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Imidazóis/farmacologia , Indóis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/etiologia , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais , Vitamina E/farmacologia
18.
J Ethnopharmacol ; 256: 112824, 2020 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-32259664

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tianma Gouteng granules (TG), a clinical prescription of traditional Chinese medicine, has been clinically applied to treat Parkinson's disease (PD) in combination with Madopar, as included in the Chinese Pharmacopoeia (2015). TG has the potential to decrease the susceptibility of PD pharmacologically, however the mechanisms need detailed demonstration. AIM OF THE STUDY: To evaluate the pharmacological activities, as well as the possible mechanism of TG in diverse models of PD. MATERIALS AND METHODS: 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice, were utilized as PD animal models. Rotarod, locomotor activity, inclined plane and traction tests were used for behavioral assessment. Immunohistochemistry was used for tyrosine hydrolase determination. Western blot were conducted for detection of 4-HNE and 15-lipoxygenase-1 (ALOX15). The interactions of ALOX15 with the components in TG were predicted by molecular docking approach. RESULTS: Lipid peroxidation was involved in dopaminergic neuron damage in 6-OHDA-induced rat models. In MPTP-treated mice, the inhibition of lipid peroxidation improved behavioral and pathological symptoms of PD. The lipid peroxidation-related protein, ALOX15 was found to be the key factor in PD process in diverse PD models including 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice. TG treatment significantly relieved behavioral and pathological symptoms of MPTP-induced PD mouse models with a potential mechanism of alleviating ALOX15-induced lipid peroxidation. Moreover, the results of molecular docking analysis show that compounds in TG might have interactions with ALOX15. CONCLUSIONS: TG effectively improved the behavioral and dopaminergic neuron damage in diverse PD models. The mechanism of this action may be related to the direct inhibition of ALOX15 and the relief of lipid peroxidation.


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular/métodos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/metabolismo
19.
Nat Commun ; 11(1): 1473, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193380

RESUMO

Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.


Assuntos
Cafeína/metabolismo , Metiltransferases/metabolismo , Chá/enzimologia , Ácido Úrico/análogos & derivados , Sítios de Ligação , Vias Biossintéticas , Cafeína/química , Clonagem Molecular , Cristalografia por Raios X , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Metilação , Metiltransferases/química , Folhas de Planta/química , Proteínas Recombinantes/metabolismo , Chá/genética , Transcrição Genética , Ácido Úrico/química , Ácido Úrico/metabolismo
20.
Acta Pharm Sin B ; 10(3): 383-398, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32140387

RESUMO

Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, is able to establish a lifelong latent infection in the human host. Following primary replication in mucosal epithelial cells, the virus can enter sensory neurons innervating peripheral tissues via nerve termini. The viral genome is then transported to the nucleus where it can be maintained without producing infectious progeny, and thus latency is established in the cell. Yin-Yang balance is an essential concept in traditional Chinese medicine (TCM) theory. Yin represents stable and inhibitory factors, and Yang represents the active and aggressive factors. When the organism is exposed to stress, especially psychological stress caused by emotional stimulation, the Yin-Yang balance is disturbed and the virus can re-engage in productive replication, resulting in recurrent diseases. Therefore, a better understanding of the stress-induced susceptibility to HSV-1 primary infection and reactivation is needed and will provide helpful insights into the effective control and treatment of HSV-1. Here we reviewed the recent advances in the studies of HSV-1 susceptibility, latency and reactivation. We included mechanisms involved in primary infection and the regulation of latency and described how stress-induced changes increase the susceptibility to primary and recurrent infections.

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