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2.
J Leukoc Biol ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38814954

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. ß-amyloid (Aß) is one of the typical pathological features of AD, and its accumulation leads to neuronal death from oxidative stress. Here, we found that hederagenin (HG), a natural product, exhibits anti-tumor, anti-inflammatory, anti-depressant, anti-neurodegenerative biological activities. However, whether HG has anti-Aß activity remains unclear. Based on the characteristics of HG, it is hypothesized that HG has biological activity against Aß injury. Therefore, Aß-injured SH-SY5Y cells were constructed, and the protective effect of HG against Aß injury was further evaluated using C. elegans. The results showed that HG increased superoxide dismutase activity, effectively reduced Aß-induced oxidative damage, and reduced apoptosis via the PI3 K/Akt signaling pathway. HG inhibited Aß deposition and delayed senescence and paralysis in the C. elegans strain, CL4176. HG showed inhibitory effects on Aß; therefore, more natural active products are expected to be applied in AD therapy.

3.
J Environ Radioact ; 276: 107448, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38749215

RESUMO

Among environment contaminants, 210Pb and 210Po have gained significant research attention due to their radioactive toxicity. Moss, with its exceptional adsorption capability for these radionuclides, serves as an indicator for environmental 210Pb and 210Po pollution. The paper reviews a total of 138 articles, summarizing the common methods and analytical results of 210Pb and 210Po research in moss. It elucidates the accumulation characteristics of 210Pb and 210Po in moss, discusses current research challenges, potential solutions, and future prospects in this field. Existing literature indicates limitations in common measurement techniques for 210Pb and 210Po in moss, characterized by high detection limits or lengthy sample processing. The concentration of 210Pb and 210Po within moss display substantial variations across different regions worldwide, ranging from

Assuntos
Briófitas , Radioisótopos de Chumbo , Polônio , Monitoramento de Radiação , Radioisótopos de Chumbo/análise , Polônio/análise , Briófitas/química , Monitoramento de Radiação/métodos
4.
Toxicon ; 243: 107747, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38714236

RESUMO

Breast cancer is still the leading cause of death among women worldwide. Due to the lack of effective drug targets, triple-negative breast cancer has a worse prognosis and higher mortality compared with other types of breast cancer, and chemotherapy is still the main treatment for triple-negative breast cancer at present. Quercetin (QUE) is a flavonoid compound found in a variety of fruits and vegetables. The mechanism of QUE has been extensively studied, such as prostate cancer, colon cancer, ovarian cancer, etc. However, the anti-tumor immune mechanism of QUE in triple-negative breast cancer remains unclear. Therefore, we assessed the anti-tumor immune effects of QUE on triple-negative breast cancer using both 4T1 cells and a xenograft mouse model of 4T1 cells. In vitro, we examined the inhibitory effects of QUE on 4T1 cells and its molecular mechanisms through MTT, Transwell, ELISA, and Western blotting. In vivo, by establishing a xenograft mouse model, we utilized flow cytometry, immunohistochemistry, ELISA, and Western blotting to evaluate the anti-tumor immune effects of QUE on triple-negative breast cancer. The results indicate that QUE inhibits the proliferation, migration, and invasion of 4T1 cells, concurrently significantly suppressing the IL-6/JAK2/STAT3 signaling pathway. Furthermore, it depletes Treg cell content in 4T1 xenograft mice, thereby improving the tumor immune microenvironment and promoting the cytotoxicity of relevant tumor immune cells. These findings suggest that QUE may serve as a potential adjuvant for immune therapy in triple-negative breast cancer.


Assuntos
Interleucina-6 , Janus Quinase 2 , Quercetina , Fator de Transcrição STAT3 , Transdução de Sinais , Linfócitos T Reguladores , Neoplasias de Mama Triplo Negativas , Animais , Feminino , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Interleucina-6/metabolismo , Janus Quinase 2/efeitos dos fármacos , Janus Quinase 2/metabolismo , Camundongos Endogâmicos BALB C , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Toxicol Res (Camb) ; 13(1): tfae011, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38283821

RESUMO

The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.

6.
Int J Biol Macromol ; 259(Pt 1): 129259, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38191112

RESUMO

The influenza A virus (IAV) is a ubiquitous and continuously evolving respiratory pathogen. The intranasal vaccination mimicking natural infections is an attractive strategy for controlling IAVs. Multiepitope vaccines accurately targeting multiple conserved domains have the potential to broaden the protective scope of current seasonal influenza vaccines and reduce the risk of generating escape mutants. Here, multiple linear epitopes from the matrix protein 2 ectodomain (M2e) and the hemagglutinin stem domain (HA2) are fused with the Helicobacter pylori ferritin, a self-assembled nanocarrier and mucosal adjuvant, to develop a multiepitope nanovaccine. Through intranasal delivery, the prokaryotically expressed multiepitope nanovaccine elicits long-lasting mucosal immunity, broad humoral immunity, and robust cellular immunity without any adjuvants, and confers complete protection against H3N2 and H1N1 subtypes of IAV in mice. Importantly, this intranasal multiepitope nanovaccine triggers memory B-cell responses, resulting in secretory immunoglobulin A (sIgA) and serum immunoglobulin G (IgG) levels persisting for more than five months post-immunization. Therefore, this intranasal ferritin-based multiepitope nanovaccine represents a promising approach to combating respiratory pathogens.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Animais , Camundongos , Infecções por Orthomyxoviridae/prevenção & controle , Vírus da Influenza A Subtipo H3N2 , Nanovacinas , Imunidade nas Mucosas , Ferritinas , Anticorpos Antivirais , Adjuvantes Imunológicos/farmacologia , Administração Intranasal , Adjuvantes Farmacêuticos , Camundongos Endogâmicos BALB C
7.
Adv Healthc Mater ; 13(10): e2303531, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37983728

RESUMO

Seasonal influenza vaccines typically provide strain-specific protection and are reformulated annually, which is a complex and time-consuming process. Multiepitope vaccines, combining multiple conserved antigenic epitopes from a pathogen, can trigger more robust, diverse, and effective immune responses, providing a potential solution. However, their practical application is hindered by low immunogenicity and short-term effectiveness. In this study, multiple linear epitopes from the conserved stem domain of hemagglutinin and the ectodomain of matrix protein 2 are combined with the Helicobacter pylori ferritin, a stable self-assembled nanoplatform, to develop an influenza multiepitope nanovaccine, named MHF. MHF is prokaryotically expressed in a soluble form and self-assembles into uniform nanoparticles. The subcutaneous immunization of mice with adjuvanted MHF induces cross-reactive neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity, and cellular immunity, offering complete protection against H3N2 as well as partial protection against H1N1. Importantly, the vaccine cargo delivered by ferritin triggers epitope-specific memory B-cell responses, with antibody level persisting for over 6 months post-immunization. These findings indicate that self-assembled multiepitope nanovaccines elicit potent and long-lasting immune responses while significantly reducing the risk of vaccine escape mutants, and offer greater practicality in terms of scalable manufacturing and genetic manipulability, presenting a promising and effective strategy for future vaccine development.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Camundongos , Humanos , Nanovacinas , Vírus da Influenza A Subtipo H3N2 , Anticorpos Antivirais , Epitopos , Ferritinas/metabolismo , Camundongos Endogâmicos BALB C
8.
Int J Nanomedicine ; 18: 4635-4645, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37605734

RESUMO

Introduction: Broadly neutralizing antibodies (bNAbs) have the ability to neutralize a considerable breadth of genetically diverse human immunodeficiency virus (HIV) strains. Passive immunization can potentially provide protection against HIV infection in animal models. However, the direct antibody infusion effect is limited due to the short half-life and deficient immunogenicity of the antibody. As an alternative strategy, we propose the use of nano viral vectors, specifically the adeno-associated virus (AAV), to continuously and systematically produce bNAbs against HIV. Methods: Plasmids expressing bNAbs PG9, PG16, 10E8, and NIH45-46 antibodies were constructed, targeting three different epitopes of HIV. Additionally, the bNAbs gene mediated by rAAV8 was administered to generate long-term expression with a single injection. We established both single and combined immunization groups. The neutralizing activity of antibodies expressed in mice sera was subsequently evaluated. Results: The expression of bNAbs in BALB/c mice can last for >24 weeks after a single intramuscular injection of rAAV8. Further studies show that neutralization of the HIV pseudovirus by sera from co-immunized mice with rAAV8 expressing 10E8 and PG16 was enhanced compared with mice immunized with 10E8 or PG16 alone. Conclusion: The prolonged expression of neutralizing antibodies can be maintained over long periods in BALB/c mice. This combined immunization is a promising candidate strategy for HIV treatment.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Animais , Camundongos , Infecções por HIV/prevenção & controle , HIV-1/genética , Anticorpos Amplamente Neutralizantes , Anticorpos Neutralizantes , Imunização , Camundongos Endogâmicos BALB C
9.
Int J Mol Sci ; 24(9)2023 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-37176076

RESUMO

Alzheimer's disease (AD) is a specific neurodegenerative disease. This study adopts single-chain variable fragments (scFvs) as a potential immunotherapeutic precursor for AD. According to the remarkable effects of monoclonal antibodies, such as the depolymerization or promotion of Aß42 efflux by Crenezumab, Solanezumab, and 12B4, it is attractive to prepare corresponding scFvs targeting amyloid-ß-42 protein (Aß42) and investigate their biological activities. Crenezumab-like scFv (scFv-C), Solanezumab-like scFv (scFv-S), and 12B4-like scFv (scFv-12B4) were designed and constructed. The thermal stabilities and binding ability to Aß42 of scFv-C, scFv-S, and scFv-12B4 were evaluated using unfolding profile and enzyme-linked immunosorbent assay. As the results indicated that scFv-C could recognize Aß42 monomer/oligomer and promote the disaggregation of Aß42 fiber as determined by the Thioflavin-T assay, the potential mechanism of its interaction with Aß42 was investigated using molecular dynamics analysis. Interactions involving hydrogen bonds and salt bonds were predicted between scFv-C and Aß42 pentamer, suggesting the possibility of inhibiting further aggregation of Aß42. The successfully prepared scFvs, especially scFv-C, with favorable biological activity targeting Aß42, might be developed for a potentially efficacious clinical application for AD.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Anticorpos de Cadeia Única , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/química
10.
Nano Res ; 16(5): 7337-7346, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36820263

RESUMO

Current seasonal influenza vaccines confer only limited coverage of virus strains due to the frequent genetic and antigenic variability of influenza virus (IV). Epitope vaccines that accurately target conserved domains provide a promising approach to increase the breadth of protection; however, poor immunogenicity greatly hinders their application. The protruding (P) domain of the norovirus (NoV), which can self-assemble into a 24-mer particle called the NoV P particle, offers an ideal antigen presentation platform. In this study, a multiepitope nanovaccine displaying influenza epitopes (HMN-PP) was constructed based on the NoV P particle nanoplatform. Large amounts of HMN-PP were easily expressed in Escherichia coli in soluble form. Animal experiments showed that the adjuvanted HMN-PP nanovaccine induced epitope-specific antibodies and haemagglutinin (HA)-specific neutralizing antibodies, and the antibodies could persist for at least three months after the last immunization. Furthermore, HMN-PP induced matrix protein 2 extracellular domain (M2e)-specific antibody-dependent cell-mediated cytotoxicity, CD4+ and CD8+ T-cell responses, and a nucleoprotein (NP)-specific cytotoxic T lymphocyte (CTL) response. These results indicated that the combination of a multiepitope vaccine and self-assembled NoV P particles may be an ideal and effective vaccine strategy for highly variable viruses such as IV and SARS-CoV-2. Electronic Supplementary Material: Supplementary material is available in the online version of this article at 10.1007/s12274-023-5395-6.

11.
Phytomedicine ; 111: 154669, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36681055

RESUMO

BACKGROUND: Ovarian cancer is a serious threat to women's health, and resistance to chemotherapeutic drugs constitutes one of the principal reasons for ovarian cancer recurrence and the low overall survival rate. Therefore, it is of paramount importance to develop additional and more-effective drugs to combat resistance to chemotherapeutic drugs. Cucurbitacin B (CuB) is a natural compound found in food plants such as bitter gourd and pumpkin, and it manifests favorable antitumor effects on a variety of malignant tumors. PURPOSE: The present study aimed to determine the mechanism effects of CuB overcomes tumor-drug resistance in ovarian cancer. METHODS: We used CCK-8, Edu, flow cytometric assays and cisplatin-resistant ovarian cancer xenograft mouse model to evaluate the cellular proliferation, cellular apoptosis.and tumor growth. We subsequently applied a pharmacoproteomic approach to analyze the molecular mechanisms by which CuB inhibited the proliferation of cisplatin-resistant ovarian cancer cells. We also employed western blot and molecular docking experiments to verify elements of PI3K/Akt/mTOR pathway expression. RESULTS: We found that CuB inhibited cellular proliferation and promoted apoptosis in cisplatin-resistant ovarian cancer cell lines. We discerned that CuB inhibited tumor growth of xenograft mouse tumors. We ascertained that treatment of A2780-DDP cells with CuB resulted in the differential expression of 305 proteins, with 202 proteins downregulated and 103 proteins upregulated. Of these proteins, the mTOR protein was significantly downregulated in the drug-treated group. We also found that CuB inhibited PI3K, Akt, and mTOR and that it activated cGAS expression upstream of PI3K and inhibited ATR expression. Molecular docking experiments revealed that CuB was hydrogen-bonded to mTOR proteins at Gly (2142) and Thr (2207), with a binding force of -10.2 kcal/mol. CONCLUSION: Our study confirmed that cucurbitacin B inhibits the PI3K/Akt/mTOR signaling pathway, targets mTOR, suppresses the proliferation of cisplatin-resistant ovarian cancer cells.And we also found that cucurbitacin B induces DNA damage, activates cGASA and recruits IKBα,playing a crucial role in eliciting anti-tumor immunity. We herein uncovered a new use for CuB in inhibiting tumor-drug resistance, providing a novel approach to overcoming chemotherapeutic drug resistance in ovarian cancer.


Assuntos
Cisplatino , Neoplasias Ovarianas , Humanos , Feminino , Animais , Camundongos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Simulação de Acoplamento Molecular , Proteômica , Recidiva Local de Neoplasia , Serina-Treonina Quinases TOR/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proliferação de Células , Apoptose
12.
Curr Pharm Des ; 28(30): 2508-2517, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909279

RESUMO

BACKGROUND: Acute lung injury (ALI) is a serious respiratory disease with a high mortality rate, and there is an urgent need for a more effective treatment strategy. Andrographolide derivative AL-1 has been identified to possess anti-inflammatory activity. However, whether it could reduce LPS-induced lung injury in mice through inhibiting NLRP3 inflammasome activation and protecting lung permeability has not yet been elucidated. In the present research, we investigated the protective effect of AL-1 on ALI mice and demonstrated the potential mechanisms. METHODS: Male Balb/c mice were anesthetized with isoflurane, and ALI mice were induced by intratracheal instillation of LPS. The mice were euthanized after LPS administration for 12 h, then bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The levels of inflammatory factors were measured by ELISA assay, and HE staining and lung injury scoring were used to evaluate the pathological changes in the pulmonary tissues. Immunohistochemistry and immunofluorescence examination were conducted to detect the expression levels of related proteins. Western blot was performed to measure the levels of NLRP3 inflammasome and tight junction proteins. RESULTS: The study indicated that AL-1 effectively alleviated lung injury by reduction of proinflammatory cytokine levels, MPO activity, lung W/D ratio, and total protein levels. Furthermore, AL-1 improved pathological changes in lung tissue and significantly reduced the infiltration of inflammatory cells. Administration with AL-1 markedly inhibited the expression of NLRP3, ASC, Caspase-1, IL-1ß, gasdermin D (GSDMD), and VCAM-1 but increased the expression of ZO-1, Occludin, JAM-A, and Claudin-1. CONCLUSION: Taken together, these results demonstrated that AL-1 ameliorated pulmonary damage by inhibiting the activation of the NLRP3 inflammasome pathway and restoring TJ protein expression.


Assuntos
Lesão Pulmonar Aguda , Diterpenos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Caspase 1/metabolismo , Claudina-1/metabolismo , Citocinas/metabolismo , Diterpenos/farmacologia , Efrina-A5/metabolismo , Inflamassomos/metabolismo , Isoflurano , Lipopolissacarídeos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ocludina/metabolismo , Permeabilidade , Molécula 1 de Adesão de Célula Vascular/metabolismo
13.
PLoS One ; 17(8): e0273583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36006974

RESUMO

Sceletium tortuosum (SCT) has been utilized medicinally by indigenous Koi-San people purportedly for mood elevation. SCT extracts are reported to be neuroprotective and have efficacy in improving cognition. However, it is still unclear which of the pharmacological mechanisms of SCT contribute to the therapeutic potential for neurodegenerative disorders. Hence, this study investigated two aspects-firstly, the abilities of neuroprotective sub-fractions from SCT on scavenging radicals, inhibiting some usual targets relevant to Alzheimer's disease (AD) or Parkinson's disease (PD), and secondly utilizing the network pharmacology related methods to search probable mechanisms using Surflex-Dock program to show the key targets and corresponding SCT constituents. The results indicated sub-fractions from SCT could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, inhibit acetylcholinesterase (AChE), monoamine oxidase type B (MAO-B) and N-methyl-D-aspartic acid receptor (NMDAR). Furthermore, the results of gene ontology and docking analyses indicated the key targets involved in the probable treatment of AD or PD might be AChE, MAO-B, NMDAR subunit2B (GluN2B-NMDAR), adenosine A2A receptor and cannabinoid receptor 2, and the corresponding constituents in Sceletium tortuosum might be N-trans-feruloyl-3-methyldopamine, dihydrojoubertiamine and other mesembrine type alkaloids. In summary, this study has provided new evidence for the therapeutic potential of SCT in the treatment of AD or PD, as well as the key targets and notable constituents in SCT. Therefore, we propose SCT could be a natural chemical resource for lead compounds in the treatment of neurodegenerative disorders.


Assuntos
Mesembryanthemum , Doenças Neurodegenerativas , Acetilcolinesterase , Humanos , Mesembryanthemum/química , Monoaminoxidase , Farmacologia em Rede , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
14.
Appl Radiat Isot ; 181: 110072, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34968882

RESUMO

Thermoluminescence (TL) dating is one of the most significant chronological tools used in Quaternary research. However, for changes in the characteristics of quartz, the larger deviation is still a problem in TL dating, especially with the single-aliquot regeneration-does (SAR) procedure. In the SAR-TL protocol, changes in the characteristics of quartz inevitably cause a shift in the TL peak position and a reduction in the sensitivity of the TL peak during repetitive thermal treatment. In this paper, we studied the optimal TL parameters to minimize the effect of the above problems for TL dating. Based on the optimization experiment combining OSL and TL measurements, the optimal preheat temperature was found to be 300 °C for both silt-sized grains and sand-sized grains, which eliminates the remainder of the 325 °C TL signals and inhibits the 375 °C TL peak position shift. Referring to the test does in SAR-OSL dating protocol, the optimal test doses, 200 Gy and 250 Gy for the silt-sized grains and sand-sized grains respectively, were determined to correct the reduction in TL sensitivity, and they were added to improve the SAR-TL protocol. The improved SAR-TL protocol with the optimal measurement parameters, which we called the accurate-parametric SAR-TL protocol, improves the accuracy of quartz TL dating and expands the range of accurate TL dating. For the experimental doses of 400 Gy and 700 Gy, the relative error of De obtained by the accurate-parametric SAR-TL protocol was less than ±5.5% for both silt-sized grains and sand-sized grains. In addition, we discussed the application conditions of the accurate-parametric SAR-TL protocol and the method that obtains the same level of thermal lag for different luminescence measurement equipment.

15.
Front Pharmacol ; 12: 680336, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248629

RESUMO

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-ß-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2'-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2'-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.

16.
Exp Ther Med ; 21(2): 118, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33335581

RESUMO

Myocardial ischemia/reperfusion injury (MIRI) is an inevitable and unsolved clinical problem in the treatment of ischemic heart diseases. Compound DT-010 is a novel danshensu/tetramethylpyrazine derivative and was examined as a candidate for treating MIRI. In the present study, MTT, lactate dehydrogenase assay and Hoechst staining data indicated that DT-010 attenuated tert-butylhydroperoxide (t-BHP)-induced oxidative damage by increasing cell survival, reducing cell damage and decreasing apoptosis in H9c2 cardiomyocytes. Autophagy was assessed by western blotting for microtubule-associated protein 1A/1B-light chain 3 (LC3-II and LC3-I) expression, acridine orange and monodansylcadaverine staining for autophagosome formation and the monomeric red fluorescent protein-green fluorescent protein-LC3 assay for autophagic flow. t-BHP-induced cell damage was aggravated by the autophagy agonist rapamycin and alleviated by the autophagy blocker hydroxy-chloroquine, suggesting that autophagy was involved in t-BHP-induced cardiomyocyte injury. DT-010 pretreatment significantly prevented t-BHP-induced cell damage, which was partially but significantly abolished by rapamycin and significantly improved by hydroxy-chloroquine treatment. DT-010 treatment inhibited t-BHP-induced autophagy in H9c2 cells, reduced phosphorylation of 5'-AMP-activated protein kinase (AMPK) and promoted the phosphorylation of mTOR and unc-51 like autophagy activating kinase 1 (Ulk1). To conclude, DT-010 can serve as a potential candidate for myocardial ischemia-reperfusion injury therapy. The cardioprotective effects of DT-010 could be partially attributed to its inhibition of autophagy via the AMPK-mTOR-Ulk1 signaling pathway.

17.
Life Sci ; 241: 117164, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838135

RESUMO

AIMS: This study was to assess whether andrographolide derivative (AL-1) could restore mucosal homeostasis and regulate tight junctions through MLCK-dependent pathway in DSS-induced colitis mice. MAIN METHODS: Colitis mice model was induced by daily administration of 2.5% DSS for seven days. The therapeutic effect was determined by evaluating the histopathological changes and the pro-inflammatory cytokine level. In addition, the effects of AL-1 on tight junctions were examined by immunohistochemistry and Western blot. The expressions of factors in MLCK-dependent pathway were evaluated by immunofluorescence and Western blot. KEY FINDINGS: AL-1 protected the intestinal barrier function in DSS-induced colitis mice. These protective effects were achieved by maintaining the normal mucus secretion and preserving tight junctions via suppression of the MLCK-dependent pathway. SIGNIFICANCE: AL-1 could prevent the increase in the DSS-induced intestinal permeability. These data indicated that AL-1 could be a promising agent for UC treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Permeabilidade da Membrana Celular/fisiologia , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Permeabilidade da Membrana Celular/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Diterpenos/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinase de Cadeia Leve de Miosina/metabolismo , Fosforilação , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia
18.
Oxid Med Cell Longev ; 2019: 6138723, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687082

RESUMO

Trinitrobenzenesulfonic acid (TNBS) and dextran sodium sulfate (DSS) are commonly used to induce experimental murine ulcerative colitis (UC). Our recent study has demonstrated that a novel andrographolide derivative, AL-1, ameliorated TNBS-induced colitis in mice. However, the effect of AL-1 on DSS-induced murine colitis and the underlying mechanisms are yet unknown. In the present study, we aimed to investigate the therapeutic potential of AL-1 against DSS-induced UC in mice and to define its mechanisms of action. Oral administration of AL-1 attenuated body weight loss, reduced colon length shortening, lowered the disease activity index score, and alleviated colon histological damage. AL-1 significantly inhibited myeloperoxidase activity and suppressed immune inflammatory responses in colonic tissues. Moreover, AL-1 reversed DSS-altered expression of inflammatory cytokines in DSS-induced colitis mice. Importantly, the efficacy of 45 mg/kg of AL-1 was higher than that of 100 mg/kg of the positive control drugs 5-aminosalicylic acid and mesalazine. AL-1 decreased lipopolysaccharide-induced generation of reactive oxygen species and nitric oxide in cultured macrophages in vitro; it also reversed the altered expression of inflammatory cytokines. In both in vivo and in vitro studies, Western blot analysis revealed that AL-1 reduced the expression of phosphorylated NF-κB p65 and IκBα, downregulated the expression of iNOS and COX-2, and attenuated the expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), ERK, and JNK. In conclusion, AL-1 alleviated DSS-induced murine colitis by inhibiting activation of the NF-κB and MAPK signaling pathways. Our data suggest that AL-1 could be a potential new treatment for UC.


Assuntos
Colite/tratamento farmacológico , Colite/enzimologia , Diterpenos/uso terapêutico , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Colite/sangue , Colite/induzido quimicamente , Citocinas/sangue , Sulfato de Dextrana , Modelos Animais de Doenças , Diterpenos/farmacologia , Feminino , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/sangue , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
19.
Biochem Pharmacol ; 163: 416-424, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878550

RESUMO

The therapeutic efficacy of immunosuppressive agents has been intensively studied for colitis management. We synthesized a series of andrographolide derivatives and reported their structure-activity-relationship and anti-inflammatory activity in our previous studies. Among these derivatives, compound 3b exhibited the most potent immunosuppressive activity. In the present study, we assessed the efficacy of 3b in dextran sulfate sodium (DSS)-induced model of acute colitis. Compound 3b was administered intragastrically. The therapeutic effect of 3b was evaluated using disease score and immune cell infiltration. The effect of 3b on Toll-like receptor 4/NF-κB and ß-catenin signaling was primarily determined by using immunohistochemistry staining and quantitative real-time PCR. The crosstalk between NF-κB and ß-catenin signaling was then assessed in HCT-116 cells. Treatment with 3b significantly downregulated the disease activity index and suppressed the histologic evidence of inflammation in DSS-induced model of acute colitis. Compound 3b inhibited proinflammatory cytokine expression at both the serum and transcription levels. Treatment with 3b also upregulated the number of PCNA-positive and goblet cells in the intestinal crypt and the intestinal expression of mRNA levels of ß-catenin target genes. ß-Catenin level regulation affected the antiinflammation and anti-apoptotic activities of 3b. This study demonstrated that 3b, a novel andrographolide derivative, suppressed inflammation and significantly reversed colitis pathology. The outcome of colitis treatment with an immunosuppressive agent depends upon the intestinal expression and mutation status of ß-catenin.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Diterpenos/química , Animais , Anti-Inflamatórios/química , Células HCT116 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade
20.
Int Immunopharmacol ; 66: 109-118, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30447529

RESUMO

Acute lung injury (ALI) is a clinically severe respiratory disorder, and effective therapy is urgently needed. MN-08, a novel synthetic N-methyl-d-aspartate receptor (NMDAR) antagonist, was investigated for its effect on lipopolysaccharide (LPS)-induced ALI. In vitro, the protective effect of MN-08 on inflammatory response, oxidative stress, and tight junctions (TJs) structure was explored in LPS-induced RAW 264.7 cells and A549 cells. MN-08 markedly decreased (p < 0.001) the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS), whereas it moderately upregulated (p < 0.05) heme oxygenase (HO)-1 protein expression in LPS-induced RAW 264.7 cells. Moreover, MN-08 significantly inhibited (p < 0.001) cell apoptosis and improved (p < 0.001) protein expression of TJs in LPS-induced A549 cells. In vivo, the therapeutic effect of MN-08 was evaluated in the LPS-induced ALI model through intratracheal instillation in BALB/c mice. MN-08 administration dramatically attenuated (p < 0.001) pulmonary pathological changes and reduced (p < 0.001) the levels of glutamate, myeloperoxidase (MPO), malondialdehyde (MDA), and number of cells in BALF, whereas it increased (p < 0.05) superoxide dismutase (SOD) and glutathione (GSH) activities in ALI mice. Furthermore, MN-08 markedly blocked the mitogen-activated protein kinases (MAPKs)/nuclear translocation of nuclear factor-κB (NF-κB) signaling pathways in RAW 264.7 cells and lung tissues. These results indicate that MN-08 exhibits lung protection in an LPS-induced ALI model via anti-inflammatory and anti-oxidative activities.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Adamantano/análogos & derivados , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Células A549 , Lesão Pulmonar Aguda/induzido quimicamente , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Humanos , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
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