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1.
Acta Trop ; 225: 106179, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34627758

RESUMO

Babesiosis is an emerging zoonotic disease that is typically caused by Babesia microti infection. Clinical treatment of B. microti infection is challenging; hence, it is crucial to find new effective drugs. The current laboratory screening methods for anti-B. microti drugs are not optimized. We conducted drug-suppressive and drug-therapeutic tests to investigate whether use of an immunosuppressant and the target gene-based qPCR are helpful to reduce the number of animals affected and to improve parasite detection in an immunocompetent mouse model. These results were verified by subpassage test. In the drug-suppressive test, no B. microti were observed after immunosuppressant administration or in subpassage mice in the 100 mg/kg robenidine hydrochloride (ROBH) group. The opposite results were observed in the control, 50 mg/kg ROBH, atovaquone (ATO) + azithromycin (AZM), and proguanil hydrochloride (PGH) groups. Significant differences were observed in the EIR and target gene relative values (both P < 0.001) between the control group and any ROBH groups. In the drug-therapeutic test, recrudescence occurred in the 50 mg/kg ROBH, ATO+AZM, and control groups. This was not observed in the 100 mg/kg ROBH group after immunosuppressant administration. Similar findings were observed in the subpassage test. This suggests that a 4-day anti-B. microti drug-suppressive test can be used in preliminary drug screening. Potentially effective drugs can be verified by immunosuppressant test in subsequent drug-therapeutic tests. Thus, a laboratory evaluation method of anti-B. microti drug efficacy was optimized, which is highly accurate and requires a short drug screening time.


Assuntos
Babesia microti , Babesiose , Preparações Farmacêuticas , Animais , Babesiose/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Camundongos
2.
Front Immunol ; 12: 754208, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733286

RESUMO

The autonomic nervous system has been studied for its involvement in the control of macrophages; however, the mechanisms underlying the interaction between the adrenergic receptors and alternatively activated macrophages (M2) remain obscure. Using FVB wild-type and beta 2 adrenergic receptors knockout, we found that ß2-AR deficiency alleviates hepatobiliary damage in mice infected with C. sinensis. Moreover, ß2-AR-deficient mice decrease the activation and infiltration of M2 macrophages and decrease the production of type 2 cytokines, which are associated with a significant decrease in liver fibrosis in infected mice. Our in vitro results on bone marrow-derived macrophages revealed that macrophages from Adrb2-/- mice significantly decrease M2 markers and the phosphorylation of ERK/mTORC1 induced by IL-4 compared to that observed in M2 macrophages from Adrb2+/+ . This study provides a better understanding of the mechanisms by which the ß2-AR enhances type 2 immune response through the ERK/mTORC1 signaling pathway in macrophages and their role in liver fibrosis.

3.
Food Funct ; 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34812830

RESUMO

The gut microbiome is known to be involved in depression development. Thus, phytochemicals changing gut microbiota may alleviate depression-like behaviors. Coniferyl ferulate (CF) is a long studied natural product and known to alleviate psychiatric disorders. However, its mechanism of action remains unclear. In this experimental study, oral administration of 50 mg kg-1 CF once daily attenuated weight loss and depression-like and anxiety-like behaviors induced by chronic unpredicted mild stress (CUMS) in mice. Four weeks of CF administration significantly ameliorated colonic inflammation, lowered the levels of IL-6, IL-1ß, and TNF-α, and restructured the gut microbiome, and microbial metabolism. Intestinal microbiota can impact the development and function of the brain via the microbiota-gut-brain axis. Therefore, oral administration of CF is a promising nutritional strategy to treat CUMS-induced depression via the regulation of microbiota and microbial metabolism.

4.
Proc Natl Acad Sci U S A ; 118(46)2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34772807

RESUMO

Chronic infection with liver flukes (such as Clonorchis sinensis) can induce severe biliary injuries, which can cause cholangitis, biliary fibrosis, and even cholangiocarcinoma. The release of extracellular vesicles by C. sinensis (CsEVs) is of importance in the long-distance communication between the hosts and worms. However, the biological effects of EVs from liver fluke on biliary injuries and the underlying molecular mechanisms remain poorly characterized. In the present study, we found that CsEVs induced M1-like activation. In addition, the mice that were administrated with CsEVs showed severe biliary injuries associated with remarkable activation of M1-like macrophages. We further characterized the signatures of miRNAs packaged in CsEVs and identified a miRNA Csi-let-7a-5p, which was highly enriched. Further study showed that Csi-let-7a-5p facilitated the activation of M1-like macrophages by targeting Socs1 and Clec7a; however, CsEVs with silencing Csi-let-7a-5p showed a decrease in proinflammatory responses and biliary injuries, which involved in the Socs1- and Clec7a-regulated NF-κB signaling pathway. Our study demonstrates that Csi-let-7a-5p delivered by CsEVs plays a critical role in the activation of M1-like macrophages and contributes to the biliary injuries by targeting the Socs1- and Clec7a-mediated NF-κB signaling pathway, which indicates a mechanism contributing to biliary injuries caused by fluke infection. However, molecules other than Csi-let-7a-5p from CsEVs that may also promote M1-like polarization and exacerbate biliary injuries are not excluded.

5.
Anat Rec (Hoboken) ; 304(11): 2566-2578, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34636498

RESUMO

COVID-19 (coronavirus) has spread all over the world with a high infection rate. Currently, there are no targeted therapeutic drugs for COVID-19 as well as for stress induced by COVID-19. The unpredictable events of COVID-19 can trigger feelings of fear, worry, or unease in people, leading to stress-related disorders such as depression and anxiety. It has been reported that individuals, including COVID-19 patients, medical staff, and ordinary people, are under both physical and psychological pressure, and many of them have developed depression or anxiety during this pandemic. Traditional Chinese medicine (TCM) has been widely used in treating depression with relatively better safety and efficacy and may have an important role in treating stress-related disorders induced by COVID-19. In this review, we collected the common TCM treatment methods including Qigong, Acupuncture, Five Elements Musical Therapy, Five Elements Emotional Therapy, and Chinese herbal medicine from the databases of PubMed and the China National Knowledge Internet to illustrate the effect of TCM on depression. The better knowledge of TCM and implementation of TCM in COVID-19 clinics may help to effectively improve depression induced by COVID-19, may assist people to maintain a healthy physical and mental quality, and may alleviate the current shortage of medical resources.


Assuntos
COVID-19/epidemiologia , COVID-19/terapia , Depressão/epidemiologia , Depressão/terapia , Medicina Tradicional Chinesa/métodos , Terapia por Acupuntura/métodos , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Qigong/métodos , Resultado do Tratamento
6.
Curr Neuropharmacol ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551699

RESUMO

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone ß-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

7.
Parasit Vectors ; 14(1): 472, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521449

RESUMO

BACKGROUND: Various stimuli, including Clonorchis sinensis infection, can cause liver fibrosis. Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) with massive production of extracellular matrix (ECM). Our previous study showed that the TGF-ß1-induced Smad signaling pathway played a critical role in the activation of HSCs during liver fibrosis induced by worm infection; however, the mechanisms that modulate the TGF-ß/Smad signaling pathway are still poorly understood. Accumulating evidence demonstrates that miRNAs act as an important regulator of activation of HSCs during liver fibrosis. METHODS: The target of miR-497 was determined by bioinformatics analysis combined with a dual-luciferase activity assay. LX-2 cells were transfected with miR-497 inhibitor and then stimulated with TGF-ß1 or excretory/secretory products of C. sinensis (CsESPs), and activation of LX-2 was assessed using qPCR or western blot. In vivo, the mice treated with CCl4 were intravenously injected with a single dose of adeno-associated virus serotype 8 (AAV8) that overexpressed anti-miR-497 sequences or their scramble control for 6 weeks. Liver fibrosis and damage were assessed by hematoxylin and eosin (H&E) staining, Masson staining, and qPCR; the activation of the TGF-ß/Smad signaling pathway was detected by qPCR or western blot. RESULTS: In the present study, the expression of miR-497 was increased in HSCs activated by TGF-ß1 or ESPs of C. sinensis. We identified that Smad7 was the target of miR-497 using combined bioinformatics analysis with luciferase activity assays. Transfection of anti-miR-497 into HSCs upregulated the expression of Smad7, leading to a decrease in the level of p-Smad2/3 and subsequent suppression of the activation of HSCs induced by TGF-ß1 or CsESPs. Furthermore, miR-497 inhibitor delivered by highly-hepatotropic (rAAV8) inhibited TGF-ß/smads signaling pathway by targeting at Smad7 to ameliorate CCL4-induced liver fibrosis. CONCLUSIONS: The present study demonstrates that miR-497 promotes liver fibrogenesis by targeting Smad7 to promote TGF-ß/Smad signaling pathway transduction both in vivo and in vitro, which provides a promising therapeutic strategy using anti-miR-497 against liver fibrosis.

8.
J Ethnopharmacol ; 279: 114396, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34246738

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The overall therapeutic effect of traditional Chinese medicine formulae (TCMF) was achieved by the interactions of multiple components with multiple targets. However, current pharmacology research strategies have struggled to identify effective substance groups and encountered challenges in elucidating the underlying mechanisms of TCMF. AIM: In this study, a comprehensive strategy was proposed and applied to elucidate the interactions of the multiple components that underlie the functions of the famous TCMF: Xian-Ling-Gu-Bao (XLGB) capsule on bone metabolism in vivo and to elucidate the molecular mechanisms underlying the effects of XLGB on bone cells, especially on osteoblasts. METHODS: The efficacy of XLGB in the protection against bones loss in ovariectomized (OVX) rats was confirmed by Micro-CT analysis. The anti-osteoporosis mechanism involved in the systemic regulatory actions of XLGB was elucidated by transcriptome sequencing analysis on bone marrow mesenchymal stem cells isolated from OVX rats. Moreover, the components absorbed in XLGB-treated plasma were characterized by mass spectrometry analysis, and subsequently, a standardized preparation process of drug-containing plasma was established. The synergistic osteogenic effect of the multiple components in plasma was investigated by a combination and then knockout of components using pre-osteoblast MC3T3-E1 cells. In order to decipher the underlying mechanism of XLGB, the targets of the absorbed components on bone were predicted by target prediction and network pharmacology analysis, then several interactions were validated by biochemical and cell-based assay. RESULTS: A total of 18 genes, including HDC, CXCL1/2, TNF, IL6 and Il1b, were newly found to be the major target genes regulated by XLGB. Interestingly, we found that a combination of the three absorbed components, i.e. MSP, rather than their single form at the same concentration, stimulated the formation of calcified nodules in MC3T3-E1 cells, suggesting a synergistic effect of these components. Besides, target prediction and experimental validation confirmed the binding affinity of corylin and icaritin for estrogen receptor α and ß, the inhibitory activity of isobavachin and isobavachalcone on glycogen synthase kinase-3ß, and the inhibitory activity of isobavachalcone on cathepsin K. The cell-based assay further confirmed the result of the biochemical assay. A network that integrated absorbed components of XLGB-targets-perturbation genes-pathways against osteoporosis was established. CONCLUSION: Our current study provides a new systemic strategy for discovering active ingredient groups of TCM formulae and understanding their underlying mechanisms.

9.
Pathogens ; 10(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072858

RESUMO

Cryptosporidium spp., Entamoeba histolytica, Giardia duodenalis, and Blastocystis sp. infections have been frequently reported as etiological agents for gastroenteritis, but also as common gut inhabitants in apparently healthy individuals. Between July 2016 and March 2017, stool samples (n = 507) were collected from randomly selected individuals (male/female ratio: 1.1, age range: 38-63 years) from two sentinel hospitals in Tengchong City Yunnan Province, China. Molecular (PCR and Sanger sequencing) methods were used to detect and genotype the investigated protist species. Carriage/infection rates were: Blastocystis sp. 9.5% (95% CI: 7.1-12.4%), G. duodenalis 2.2% (95% CI: 1.1-3.8%); and E. histolytica 2.0% (95% CI: 0.9-3.6%). Cryptosporidium spp. was not detected at all. Overall, 12.4% (95% CI: 9.7-15.6) of the participants harbored at least one enteric protist species. The most common coinfection was E. histolytica and Blastocystis sp. (1.0%; 95% CI: 0.3-2.2). Sequence analyses revealed that 90.9% (10/11) of the genotyped G. duodenalis isolates corresponded to the sub-assemblage AI. The remaining sequence (9.1%, 1/11) was identified as sub-assemblage BIV. Five different Blastocystis subtypes, including ST3 (43.7%, 21/48), ST1 (27.1%, 13/48), ST7 (18.8%, 9/48), ST4 (8.3%, 4/48), and ST2 (2.1%, 1/48) were identified. Statistical analyses confirmed that (i) the co-occurrence of protist infections was purely random, (ii) no associations were observed among the four protist species found, and (iii) neither their presence, individually or jointly, nor the patient's age was predictors for developing clinical symptoms associated with these infections. Overall, these protist mono- or coinfections are asymptomatic and do not follow any pattern.

10.
J Org Chem ; 86(16): 11177-11188, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34043349

RESUMO

A secondary metabolites investigation on Biscogniauxia sp. 71-10-1-1 was carried out, which led to the obtention of nine new diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9) and two new isoprenylbenzoic acid-type meroterpeniods (10-11). The structures of these isolates were established on the basis of multispectroscopic analyses, ECD, and 13C chemical shifts calculations, and single-crystal X-ray diffraction. Among them, biscognin A (1) is the first diisoprenyl-cyclohexene-type meroterpenoid with a unique 2-isopropyl-6'-methyloctahydro-1'H-spiro[cyclopropane-1,2'-naphthalene] skeleton. Biscognienyne F (5) is the first diisoprenyl-cyclohexene-type meroterpenoid with a cyclic carbonate. The anti-inflammatory assays of the majority of compounds were evaluated, which exhibited that compounds 3 and 5 can obviously inhibit pro-inflammatory cytokines TNF-α and IL-6 productions. This is the first report for diisoprenyl-cyclohexene-type meroterpenoids with anti-inflammatory activity. Moreover, the possible biogenetic pathways of the majority of compounds (1-5) are proposed.


Assuntos
Cicloexenos , Terpenos , Anti-Inflamatórios/farmacologia , Vias Biossintéticas , Cristalografia por Raios X , Cicloexenos/farmacologia , Terpenos/farmacologia
11.
Front Pharmacol ; 12: 586788, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912031

RESUMO

Purpose: It is revealed that Xiaoyaosan could reduce glutamate level in the hippocampus of depressed rats, whose metabolism leads to the pathophysiology of depression. However, the underlying mechanism remains unclear. This study aims to explore the effect of Xiaoyaosan on glutamate metabolism, and how to regulate the excitatory injury caused by glutamate. Methods: Rats were induced by chronic unpredictable mild stress, then divided into control, vehicle (distilled water), Xiaoyaosan, fluoxetine, vehicle (DMSO), Xiaoyaosan + Ly294002 and Ly294002 groups. Ly294002 was microinjected into the lateral ventricular catheterization at 5 mM. Xiaoyaosan (2.224 g/kg) and fluoxetine (2.0 mg/kg) were orally administered for three weeks. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to assess depressive behavior. The glutamate and corticosterone (CORT) levels were detected by ELISA. Western blot, immunochemistry or immunofluorescence were used to detect the expressions of NR2B, MAP2, PI3K and P-AKT/Akt in the hippocampal CA1 region. The mRNA level of MAP2, NR2B and PI3K were detected by RT-qPCR. Results: Compared to the rats in control group, body weight and food intake of CUMS rats was decreased. CUMS rats also showed depression-like behavior as well as down regulate the NR2B and PI3K/Akt signaling pathway. Xiaoyaosan treatments could increase food intake and body weight as well as improved time spent in the central area, total distance traveled in the OFT. Xiaoyaosan could also decrease the immobility time as well as increase the sucrose preference in SPT. Moreover, xiaoyaosan decreased the level of glutamate in the hippocampal CA1 region and serum CORT in CUMS rats. Furthermore, xiaoyaosan improved the expression of MAP2 as well as increased the expression of NR2B, PI3K and the P-AKT/AKT ratio in the hippocampal CA1 region in the CUMS rats. Conclusion: Xiaoyaosan treatment can exert the antidepressant effect by rescuing hippocampal neurons loss induced by the glutamate-mediated excitotoxicity in CUMS rats. The underlying pathway maybe through NR2B and PI3K/Akt signaling pathways. These results may suggest the potential of Xiaoyaosan in preventing the development of depression.

12.
Front Immunol ; 12: 616343, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717108

RESUMO

Babesia microti is a protozoan that infects red blood cells. Babesiosis is becoming a new global threat impacting human health. Rhoptry neck proteins (RONs) are proteins located at the neck of the rhoptry and studies indicate that these proteins play an important role in the process of red blood cell invasion. In the present study, we report on the bioinformatic analysis, cloning, and recombinant gene expression of two truncated rhoptry neck proteins 2 (BmRON2), as well as their potential for incorporation in a candidate vaccine for babesiosis. Western blot and immunofluorescence antibody (IFA) assays were performed to detect the presence of specific antibodies against BmRON2 in infected mice and the localization of N-BmRON2 in B. microti parasites. In vitro experiments were carried out to investigate the role of BmRON2 proteins during the B. microti invasion process and in vivo experiments to investigate immunoprotection. Homologous sequence alignment and molecular phylogenetic analysis indicated that BmRON2 showed similarities with RON2 proteins of other Babesia species. We expressed the truncated N-terminal (33-336 aa, designated rN-BmRON2) and C-terminal (915-1171 aa, designated rC-BmRON2) fragments of the BmRON2 protein, with molecular weights of 70 and 29 kDa, respectively. Western blot assays showed that the native BmRON2 protein is approximately 170 kDa, and that rN-BmRON2 was recognized by serum of mice experimentally infected with B. microti. Immunofluorescence analysis indicated that the BmRON2 protein was located at the apical end of merozoites, at the opposite end of the nucleus. In vitro red blood cell invasion inhibition studies with B. microti rBmRON2 proteins showed that relative invasion rate of rN-BmRON2 and rC-BmRON2 group is 45 and 56%, respectively. Analysis of the host immune response after immunization and B. microti infection showed that both rN-BmRON2 and rC-BmRON2 enhanced the immune response, but that rN-BmRON2 conferred better protection than rC-BmRON2. In conclusion, our results indicate that truncated rhoptry neck protein 2, especially its N-terminal fragment (rN-BmRON2), plays an important role in the invasion of host red blood cells, confers immune protection, and shows good potential as a candidate vaccine against babesiosis.


Assuntos
Antígenos de Protozoários/imunologia , Babesia microti/imunologia , Babesiose/prevenção & controle , Interações Hospedeiro-Parasita/imunologia , Proteínas de Protozoários/imunologia , Vacinas Protozoárias/imunologia , Animais , Antígenos de Protozoários/genética , Babesia microti/genética , Modelos Animais de Doenças , Eritrócitos/imunologia , Eritrócitos/parasitologia , Imunofluorescência , Expressão Gênica , Imunização , Camundongos , Filogenia , Transporte Proteico , Proteínas de Protozoários/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
13.
Iran J Parasitol ; 16(1): 122-135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33786054

RESUMO

Background: Trichinellosis is a serious food-borne parasitic zoonosis, thus finding high quality antigens is the key to serodiagnosis of trichinosis. This article reports the characterization and sensitivity of four recombinant proteins expressed by four genes (Wn10, Zh68, T668, and Wm5) from different developmental stages of Trichinella spiralis for the diagnosis of trichinellosis in mice. Methods: This study was conducted in Jilin University and National Institute of Parasitic Diseases of Chinese Center for Disease Control and Prevention in 2017-2018. The structures and functions of the proteins encoded by four genes were predicted by bioinformatics analysis. The four genes were cloned and expressed, and the recombinant proteins were purified. Anti-Trichinella IgM and IgG antibodies in the sera of mice infected with T. spiralis from 1-45 d post-infection (dpi) were evaluated by ELISA. Results: The optimal antigen epitopes of four proteins (P1, P2, P3, and P4) encoded by the four genes from T- and B-cells were predicted, and four purified recombinant proteins (r-P1, r-P2, r-P3, and r-P4) were successfully produced. For IgM, the antibody levels detected by the four recombinant antigens were approximately equal to the cut-off value. Anti-Trichinella IgG antibodies were first detected by r-P1 at 8 dpi, followed by r-P2, r-P3, and r-P4 at 10 dpi, 14 dpi, and 16 dpi, respectively, and the antibody levels remained high until 45 dpi. Conclusion: The recombinant antigens r-P1, r-P2, r-P3, and r-P4 could be antigens that react with antibodies, they showed high sensitivity in the detection of anti-Trichinella IgG antibodies in mice. Among these proteins, r-P1 may be a candidate antigen for the detection of anti-Trichinella IgG antibodies in the early infection phase and exhibited the best sensitivity among the antigens.

14.
Biomed Pharmacother ; 135: 111204, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33548869

RESUMO

BACKGROUND: Progestational stress has been proven to be a risk for the neural development of offspring, especially in the hippocampus. However, whether Chaihu Shugan San (CSS) can ameliorate hippocampal neural development via the regulation of brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors (NMDAR) 2A (NR2A) and 2B (NR2B), and the mechanism of such action remains unclear. METHODS: Thirty-six female rats were randomly allocated into control, chronic immobilization stress (CIS) and CSS groups according to the random number table, respectively. The male offspring were fed for 21 days after birth then randomly divided into the same three groups (6 rats/group) as the female rats. Female rats, except for the control group, underwent 21-day CIS to established a progestational stress anxiety-like model which was evaluated by body weight, the elevated plus-maze (EPM) test and serum dopamine (DA) measured using an enzyme-linked immunosorbent assay (ELISA). The expression levels of estrogen receptors (ERα/ERß) and progesterone receptor (PR) in female rat ovaries were quantified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The hippocampal tissue in the 21-day offspring was observed by hematoxylin-eosin (HE) staining. The concentration of BDNF, NR2A, and NR2B were measured by RT-qPCR and immunohistochemistry in the CA3 and dentate gyrus (DG) regions of offsprings' hippocampus. RESULTS: Compared with the female control group, significant differences in body weight, EPM test and DA concentration were observed in the CIS group, meanwhile, the concentration of ERα (P < 0.05), PR (P < 0.05) and ERß in the ovaries were decreased. In the offsprings' hippocampus of the CIS group, the chromatin of the nucleus was edge set and with condensed and irregular morphology nucleus, and the cytoplasm was unevenly stained with spaces around the cells, moreover, the expression levels of BDNF, NR2A, and NR2B were also declined (P < 0.05). However, Chaihu Shugan San reversed these changes, especially the BDNF in the DG region (P < 0.05), and NR2A and NR2B in the CA3 and DG region (P < 0.05). CONCLUSIONS: CSS could ameliorate the neural development of the hippocampus in offspring damaged by anxiety-like progestational stress in female rats via regulating the expression levels of ERα, ERß, and PR in female rat ovaries and BDNF, NR2A, and NR2B in the hippocampus of their offspring.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Receptores de N-Metil-D-Aspartato/metabolismo , Estresse Psicológico/tratamento farmacológico , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Idade Gestacional , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Ovário/efeitos dos fármacos , Ovário/metabolismo , Gravidez , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Restrição Física , Transdução de Sinais , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-33505499

RESUMO

Depression is the neurological manifestation most commonly associated with gastrointestinal diseases. The release of inflammatory cytokines mediated by TLR4/NLRP3 inflammasome signaling-induced immunoinflammatory activation may represent a common pathogenic process underlying the development of gastrointestinal diseases and depression. Clinical studies have indicated that Xiaoyaosan (XYS) can relieve depressive behavior by improving gastrointestinal symptoms. We previously demonstrated that XYS can reduce colonic inflammation in a rat model of chronic unpredictable mild stress; however, the precise anti-inflammatory mechanisms involved remain unclear. Here, we investigated whether XYS can ameliorate depressive behavior through regulating the TLR4/NLRP3 inflammasome signaling pathway, thereby inhibiting immunoinflammatory activation and reducing colonic proinflammatory cytokine levels. Fifty-two healthy male Sprague-Dawley rats were randomly divided into four groups (control, model, XYS, and fluoxetine). The latter three groups were subjected to 21 days of chronic restraint stress to generate a model of stress-induced depression. XYS and fluoxetine were administered intragastrically. Behavioral changes in the rats were assessed after 21 days. Serum and colon samples were collected, and the relative levels of the inflammation indicators IL-6, IL-1ß, and TNF-α were determined by ELISA. Pathological changes in colon tissue were assessed by hematoxylin and eosin staining. The levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, and TRAF6 were detected by immunohistochemistry, while the gene and protein expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 were detected by quantitative polymerase chain reaction (qPCR) and Western blotting. The results indicated that XYS could improve the depressive-like behavior and the weight loss of rats with stress-induced depression. Furthermore, depressed rats treated with XYS exhibited decreased expression levels of TLR4, MyD88, NF-κB-p65, TAK1, IRAK1, TRAF6, NLRP3, ASC, and caspase-1 in colonic tissue; reduced colon and serum concentrations of the inflammatory factors IL-6, IL-1ß, and TNF-α; and lowered levels of colonic inflammation.

16.
J Pharm Biomed Anal ; 193: 113721, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33147537

RESUMO

Lonicerae japonicae flos.(LJF) was widely used as a drug to treat upper respiratory tract infection or a tea to clear heat in Asian countries for thousands of years. Despite of its curative effects confirmed by modern pharmacological methods, its functional materials and mechanism against influenza were still unclear and needed further investigation. In this study, an integrated strategy based on in vivo substances profiling and network pharmacology was proposed and applied to screen out the potential anti-influenza substances and mechanism of LJF. An UHPLC/Q-TOF MS method was utilized to profile the chemical components in LJF and their metabolites in rats. The targets of absorbed prototypes were predicted by Swiss Target Prediction, and they were further analyzed by String and Kyoto Encyclopedia of Genes and Genomes (KEGG). As a result, a total of 126 chemical components mainly featuring three chemical structure types were characterized, including 70 iridoid glycosides, 17 caffeoylquinic acids, 24 flavonoids, and 15 other types compounds. Among them, ten N-contained iridoid glycosides were characterized as potential novel compounds. Moreover, 141 xenobiotics (74 prototypes and 67 metabolites) were clearly screened out in rat plasma and urine after ingestion of LJF. Phase II reactions (sulfation, glucuronidation, methylation) and phase I reactions (dehydroxylation, hydrogenation, hydrolysis, N-heterocyclization) were the main metabolic reactions of LJF in rats. Further, a total of 338 targets were predicted and TNF, PTGS2 and EGFR were the three main targets involved in the pathology of influenza. In addition to normal NF-κB pathway, T cell signal pathway and mTOR signal pathway were the other patterns for LJF to achieve its anti-flu effects. Our work provided the meaningful data for further pharmacological validation of LJF against influenza, and a new strategy was also proposed for minimizing the process to reveal the mechanism and functional basis of TCMs.


Assuntos
Medicamentos de Ervas Chinesas , Influenza Humana , Lonicera , Animais , Cromatografia Líquida de Alta Pressão , Dissecação , Medicamentos de Ervas Chinesas/farmacologia , Ratos
17.
Front Pharmacol ; 11: 588508, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178026

RESUMO

Starting from December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and unprecedented health crisis across the globe. While the development of cure is at full speed, less attention and fewer effort have been spent on the prevention of this rapidly spreading respiratory infectious disease. Although so far, several vaccine candidates have advanced into clinical trials, limited data have been released regarding the vaccine efficacy and safety in human, not mention the long-term effectiveness of those vaccines remain as open question yet. Natural products and herbal medicines have been historically used for acute respiratory infection and generally show acceptable toxicity. The favorable stability for oral formulation and ease of scaling up manufacture make it ideal candidate for prophylactic. Hereby, we summarized the most recent advance in SARS-CoV-2 prevention including vaccine development as well as experimental prophylactics. Mainly, we reviewed the natural products showing inhibitory effect on human coronavirus, and discussed the herbal medicines lately used for COVID-19, especially focused on the herbal products already approved by regulatory agency with identifiable patent number. We demonstrated that to fill in the response gap between appropriate treatment and commercially available vaccine, repurposing natural products and herbal medicines as prophylactic will be a vigorous approach to stop or at least slow down SARS-CoV-2 transmission. In the interest of public health, this will lend health officials better control on the current pandemic.

18.
PLoS Negl Trop Dis ; 14(10): e0008643, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33044969

RESUMO

BACKGROUND: Clonorchis sinensis, a fluke dwelling in the intrahepatic bile ducts causes clonorchiasis, which affect about 15 million people wide-distributed in eastern Asia. During C. sinensis infection, worm-host interaction results in activation of patterns recognition receptors (PRRs) such as Toll-like receptors (TLRs) and further triggers immune responses, which determines the outcome of the infection. However, the mechanisms by which pathogen-associated molecules patterns from C. sinensis interact with TLRs were poorly understood. In the present study, we assumed that the molecules from C. sinensis may regulate host immune responses via TLR2 signaling pathway. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we have identified a ~34 kDa CsHscB from C. sinensis which physically bound with TLR2 as demonstrated by molecular docking and pull-down assay. We also found that recombinant CsHscB (rCsHscB) potently activates macrophage to express various proteins including TLR2, CD80, MHCII, and cytokines like IL-6, TNF-α, and IL-10, but rCsHscB failed to induce IL-10 in macrophages from Tlr2-/- mice. Moreover, ERK1/2 activation was required for rCsHscB-induced IL-10 production in macrophages. In vivo study revealed that rCsHscB triggered a high production of IL-10 in the wild-type (WT) but not in Tlr2-/- mice. Consistently, the phosphorylation of ERK1/2 was also attenuated in Tlr2-/- mice compared to the WT mice, after the treatment with rCsHscB. CONCLUSIONS/SIGNIFICANCE: Our data thus demonstrate that rCsHscB from C. sinensis interacts with TLR2 to be endowed with immune regulatory activities, and may have some therapeutic implications in future beyond parasitology.


Assuntos
Clonorquíase/imunologia , Clonorchis sinensis/imunologia , Proteínas de Choque Térmico/metabolismo , Interleucina-10/metabolismo , Animais , Clonorquíase/parasitologia , Proteínas de Helminto/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Proteínas Recombinantes , Receptor 2 Toll-Like
19.
Eur J Pharmacol ; 887: 173379, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758567

RESUMO

Bufadienolides are cardioactive C24 steroids with an α-pyrone ring at position C17. In the last ten years, accumulating studies have revealed the anticancer activities of bufadienolides and their underlying mechanisms, such as induction of autophagy and apoptosis, cell cycle disruption, inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and stemness, and multidrug resistance reversal. As Na+/K+-ATPase inhibitors, bufadienolides have inevitable cardiotoxicity. Short half-lives, poor stability, low plasma concentration and oral bioavailability in vivo are obstacles for their applications as drugs. To improve the drug potency of bufadienolides and reduce their side effects, prodrug strategies and drug delivery systems such as liposomes and nanoparticles have been applied. Therefore, systematic and recapitulated information about the antitumor activity of bufadienolides, with special emphasis on the molecular or cellular mechanisms, prodrug strategies and drug delivery systems, is of high interest. Here, we systematically review the anticancer effects of bufadienolides and the molecular or cellular mechanisms of action. Research advancements regarding bufadienolide prodrugs and their tumor-targeting delivery strategies are critically summarized. This work highlights recent scientific advances regarding bufadienolides as effective anticancer agents from 2011 to 2019, which will help researchers to understand the molecular pathways involving bufadienolides, resulting in a selective and safe new lead compound or therapeutic strategy with improved therapeutic applications of bufadienolides for cancer therapy.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Bufanolídeos/metabolismo , Bufanolídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Bufanolídeos/química , Linhagem Celular Tumoral , Humanos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/uso terapêutico
20.
J Leukoc Biol ; 108(2): 493-508, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32678943

RESUMO

A wealth of evidence supports the role of tumor immunotherapy as a vital therapeutic option in cancer. In recent decades, accumulated studies have revealed the anticancer activities of natural products and their derivatives. Increasing interest has been driven toward finding novel potential modulators of tumor immunotherapy from natural products, a hot research topic worldwide. These works of research mainly focused on natural products, including polyphenols (e.g., curcumin, resveratrol), cardiotonic steroids (e.g., bufalin and digoxin), terpenoids (e.g., paclitaxel and artemisinins), and polysaccharide extracts (e.g., lentinan). Compelling data highlight that natural products have a promising future in tumor immunotherapy. Considering the importance and significance of this topic, we initially discussed the integrated research progress of natural products and their derivatives, including target T cells, macrophages, B cells, NKs, regulatory T cells, myeloid-derived suppressor cells, inflammatory cytokines and chemokines, immunogenic cell death, and immune checkpoints. Furthermore, these natural compounds inactivate several key pathways, including NF-κB, PI3K/Akt, MAPK, and JAK/STAT pathways. Here, we performed a deep generalization, analysis, and summarization of the previous achievements, recent progress, and the bottlenecks in the development of natural products as tumor immunotherapy. We expect this review to provide some insight for guiding future research.


Assuntos
Produtos Biológicos/farmacologia , Fatores Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Resultado do Tratamento
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