RESUMO
Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research.
Assuntos
Alcaloides , Anti-Infecciosos , Alcaloides/química , Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Isoquinolinas/farmacologia , Isoquinolinas/químicaRESUMO
Pancreatic cancer is the fourth most lethal malignancy and is characterized by poor immunogenicity. Pancreatic cancer cells have various strategies to suppress host immune response, evade immune defenses, and facilitate tumor growth and development. As a mode of long-range intercellular communication, cancer-derived exosomes contribute to impairment of the immune system. However, the mechanisms that induce changes in the activities of signal transduction pathways in immune cells, which are influenced by tumor-derived exosomes, are poorly understood. We (1) treated peripheral T lymphocytes with pancreatic cancer-derived exosomes, tagged CD63 with tdTomato, to trace exosome transfer from pancreatic cancer cells to T lymphocytes; (2) carried out a cytotoxicity assay of exosome-treated T lymphocytes using the Real Time Cellular Analysis system; (3) performed RNA sequencing and gene set enrichment analysis to explore the pivotal signaling pathway that mediates apoptosis in exosome-treated T lymphocytes; and (4) demonstrated the role of p38 mitogen-activated protein kinase (MAPK) and endoplasmic reticulum (ER) stress in exosome-induced T-lymphocyte apoptosis. In conclusion, these results indicate that pancreatic cancer cells secrete exosomes, which are taken up by T lymphocytes to activate p38 MAPK, and then induce ER stress-mediated apoptosis, ultimately causing immunosuppression.
Assuntos
Apoptose/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Exossomos/metabolismo , Neoplasias Pancreáticas/metabolismo , Linfócitos T/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Células PC-3 , Transdução de Sinais/fisiologiaRESUMO
Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC50 value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi.
Assuntos
Trifosfato de Adenosina/metabolismo , Antifúngicos/farmacologia , Botrytis/efeitos dos fármacos , Humulus/química , Peroxidação de Lipídeos/efeitos dos fármacos , Xantonas/farmacologia , Botrytis/crescimento & desenvolvimentoRESUMO
Water dynamics on the protein surface mediate both protein structure and function. However, many questions remain about the role of the protein hydration layers in protein fluctuations and how the dynamics of these layers relate to specific protein properties. The fish eye lens protein γM7-crystallin (γM7) is found in vivo at extremely high concentrations nearing the packing limit, corresponding to only a few water layers between adjacent proteins. In this study, we conducted a site-specific probing of hydration water motions and side-chain dynamics at nine selected sites around the surface of γM7 using a tryptophan scan with femtosecond spectroscopy and NMR nuclear spin relaxation (NSR). We observed correlated fluctuations between hydration water and protein side chains on the time scales of a few picoseconds and hundreds of picoseconds, corresponding to local reorientations and network restructuring, respectively. These motions are heterogeneous over the protein surface and relate to the various steric and chemical properties of the local protein environment. Overall, we found that γM7 has relatively slower water dynamics within the hydration shell than a similar ß-sheet protein, which may contribute to the high packing limit of this unique protein.
Assuntos
Cristalinas/química , Proteínas/química , Água/química , Modelos Moleculares , Espectrometria de Fluorescência , Propriedades de SuperfícieRESUMO
The HUS1 checkpoint clamp component (HUS1), which is a member of an evolutionarily conserved, genotoxin-activated checkpoint complex (Rad9-Rad1-Hus1 [9-1-1] complex), is involved in cell cycle arrest and DNA repair in response to DNA damage. We conducted this study to investigate the biological significances of HUS1 expression in hepatocellular carcinoma (HCC) development. The mRNA and protein expression levels of HUS1 were determined using Real-time PCR and Western blot, respectively. One hundered and twenty four paraffin sections from HCC tissues were analyzed by immunohistochemistry to assess the association between HUS1 expression and clinicopathological characteristics of patients. The Kaplan-Meier method was performed to calculate the OS and RFS curves. Cell proliferation and colony formation assays, cell migration and invasion assays and cell cycle assays were used to determine the suppressor role of HUS1 in vitro. A mouse model was used to determine the effect of HUS1 on tumorigenesis. The expression of HUS1 was significantly decreased in HCC cell lines and tissues, and low HUS1 expression was associated with poor prognosis of HCC patients. Upregulation of HUS1 expression inhibited the cell proliferation, colony formation, migration, and invasion, as well as arrested cell cycle at G0/G1 in HCC cells in vitro. Moreover, sufficient HUS1 expression inhibited the tumor growth in nude mice. Our study revealed for the first time that HUS1 is a potential tumor suppressor that might produce an antitumor effect in human HCC. Furthermore, HUS1 may serve as a prognostic indicator and could be used for therapeutic application in HCC patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Pancreatic cancer is characterized by a highly immunosuppressive tumor microenvironment and evasion of immune surveillance. Although programmed cell death 1 receptor (PD-1) blockade has achieved certain success in immunogenic cancers, the responses to the PD-1 antibody are not effective or sustained in patients with pancreatic cancer. METHODS: Firstly, PD-1 expressions on peripheral CD8+ T-lymphocytes of patients with pancreatic cancer and healthy donors were measured. In in vitro study, peripheral T-lymphocytes were isolated and treated with nivolumab and/or interferon-γ, and next, PD-1-blockade effects, proliferations, cytokine secretions and cytotoxic activities were tested after different treatments. In in vivo study, mice bearing subcutaneous pancreatic cancer cell lines were treated with induced T-lymphocytes and tumor sizes were measured. RESULTS: PD-1 protein expression is increased on peripheral CD8+ T cells in patients with pancreatic ductal adenocarcinoma compared with that in health donor. PD-1 expression on CD8+ T-lymphocytes was decreased by nivolumab in a concentration-dependent manner in vitro. IFN-γ could directly down-regulate expression of PD-1 in vitro. Furthermore, the combination therapy of nivolumab and IFN-γ resulted in greatest effect of PD-1-blockde (1.73 ± 0.78), compared with IFN-γ along (18.63 ± 0.82) and nivolumab along (13.65 ± 1.22). Moreover, the effects of nivolumab plus IFN-γ largest promoted the T-lymphocytes function of proliferations, cytokine secretions and cytotoxic activities. Most importantly, T-lymphocytes induced by nivolumab plus IFN-γ presented the best repression of tumor growth. CONCLUSIONS: IFN-γ plus a PD-1-blockading agent could enhance the immunologic function and might play a crucial role in effective adoptive transfer treatments of pancreatic cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Interferon gama/farmacologia , Nivolumabe/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Interferon gama/administração & dosagem , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/genética , Carga Tumoral/efeitos dos fármacosRESUMO
Realgar as a kind of arsenic agent is currently used to treat APL in China. The effectiveness and low toxicity of realgar have been verified, lower than arsenic trioxide. Although the therapeutic efficacy of realgar is blocked severely by its poor insolubility in water. In our lab, we addressed this problem by obtaining realgar bioleaching solution (RBS) from microbiological leaching technique. To develop a tradition Chinese medicinal formula (TCMF) for clinical application realgar is usually used with other herbs. However, treated realgar with RBS has not been evaluated in TCMF contain realgar. In the present study we used NB4 to investigate the effects of novel Realgar-Indigo naturalis formula (FRBS) on cell proliferation and apoptosis. We used MTT assay to measure anti proliferative activity of FRBS. We further study the effects of FRBS on cell growth and apoptosis according flow cytometry, DNA fragmentation assay and Fluorescence microscopy and Western blot. The results revealed that FRBS significantly inhibited growth in a dose-dependent manner, and induced apoptosis in NB4 cells. NB4 cell inhibitory response to FRBS at 2µg ml-1 of arsenic concentration was twofold higher, dissimilar to RIF, and induced apoptosis more effectively. Further, a higher expression of caspase-3, caspase-9 and cytochrome C from increased from FRBS. RBS can substitute the traditional realgar powder in RIF in order to provide a novel and promising Realgar-Indigo naturalis formula to treat acute promyelocytic leukemia.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Arsênio/administração & dosagem , Arsênio/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologiaRESUMO
Bioleaching is a promising process for 350 million tons Jinchuan low-grade pentlandite. But, Jinchuan pentlandite has lots of magnesium and high concentration of Mg2+ is harmful to bioleaching microorganisms. Thus, finding a way to improve the adaption of microorganisms to Mg2+ is a key for bioleaching. In the study, we found that oxidizing activity, bioleaching ability and biofilm formation of A.f were inhibited by Mg2+ stress. In addition, we analyzed mRNA and small RNA (sRNA) of Acidithiobacillus ferrooxidans (A.f) under Mg2+ stress by strand-specific RNA-sequencing (ssRNA-seq). After the bioinformatics process, 2475 coding genes were obtained, and there were 33 differential expression genes (DEGs) in 0.1 M-VS-Con, including 28 down-regulated and 5 up-regulated, whereas 52 DEGs were obtained in 0.5 M-VS-Con, including 28 down-regulated and 24 up-regulated. Gene ontology analysis showed most of DEGs were involved in catalytic activity, metabolic process and single-organism process. Furthermore, we identified 636 sRNA and some differential expression sRNA that may respond to Mg2+ stress. Further analysis of DEGs suggested that Mg2+ stress reduced biofilm formation perhaps through inhibiting Type IV Pili-related gene expression and inhibited bacterial activity perhaps through affecting carbon fixation. The study provided the foundation to understand the mechanisms of Mg2+ resistance in A.f and may be helpful to improve bioleaching ability for pentlandit.
Assuntos
Acidithiobacillus/genética , Magnésio/metabolismo , RNA Bacteriano/genética , Acidithiobacillus/fisiologia , Fímbrias Bacterianas/genética , Fímbrias Bacterianas/metabolismo , Análise de Sequência de RNA , Estresse Fisiológico , TranscriptomaRESUMO
A Gram-stain-positive, motile and rod-shaped bacterium, designated strain LZ2T, was isolated from a sample of orchard soil from Laizhou city, Shandong province, PR China. On the basis of 16S rRNA gene sequence analysis, strain LZ2T was closely related to members of the genus Sporosarcina, sharing highest levels of sequence similarity with Sporosarcina pasteurii NCIMB 8841T (98.8â%), Sporosarcina soli I80T (95.9â%). The value for the DNA-DNA relatedness between strain LZ2T and Sporosarcina pasteurii NCIMB 8841T was 39.8±1.7â%. Growth occurred at 10-44 °C (optimum, 30-35 °C), pH 5.0-11.0 (optimum pH 9.0-10.0); NaCl concentrations of up to 7.0â% (w/v) were tolerated. The dominant respiratory quinone was MK-7 and the G+C content was 39.2 mol%. The major fatty acids were anteiso-C15â:â0 and iso-C15â:â0. The major polar lipids of strain LZ2T were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and an unidentified phospholipid. Based on phenotypic and chemotaxonomic characteristics, and phylogenetic data strain LZ2T represents a novel species of the genus Sporosarcina, for which the name Sporosarcina terrae sp. nov. (type strain LZ2T=KACC 18822T=MCCC 1K03174T) is proposed.
Assuntos
Filogenia , Microbiologia do Solo , Sporosarcina/classificação , Agricultura , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , DNA Ribossômico/genética , Ácidos Graxos/química , Hibridização de Ácido Nucleico , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Sporosarcina/genética , Sporosarcina/isolamento & purificação , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMO
N-trans-feruloyloctopamine (FO) isolated from Garlic skin was identified as the primary antioxidant constituents, however, the effect of which on HCC invasion is still unclear. Herein, the FO was synthesized and its antitumor activities were evaluated in HCC cell lines. Cellular functional analyses have revealed that the reformed FO owns strong abilities of inhibiting cell proliferation and invasion in HCC cells. Molecular data have further showed that FO could significantly decrease the phosphorylation levels of Akt and p38 MAPK. In addition, the expression of Slug was inhibited and the level of E-cadherin increased. Molecular docking analysis indicates that the H-bond and hydrophobic interactions were critical for FO and E-cadherin binding, but FO did not seem to act directly on phosphorylated Akt and p38 MAPK. We have thus concluded that reformed FO inhibits cell invasion might be directly through EMT related signals (E-cadherin) and indirectly through PI3K/Akt, p38 MAPK signaling pathways. FO might be a promising drug in HCC treatment and prognosis.
Assuntos
Carcinoma Hepatocelular/patologia , Ácidos Cumáricos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Invasividade Neoplásica/prevenção & controle , Octopamina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Octopamina/farmacologiaRESUMO
Realgar is a naturally occurring arsenic sulfide (or Xionghuang, in Chinese). It contains over 90% tetra-arsenic tetra-sulfide (As4S4). Currently, realgar has been confirmed the antitumor activities, both in vitro and in vivo, of realgar extracted using Acidithiobacillus ferrooxidans (A. ferrooxidans). Bioleaching, a new technology to greatly improve the use rate of arsenic extraction from realgar using bacteria, is a novel methodology that addressed a limitation of the traditional method for realgar preparation. The present systematic review reports on the research progress in realgar bioleaching and its antitumor mechanism as an anticancer agent. A total of 93 research articles that report on the biological activity of extracts from realgar using bacteria and its preparation were presented in this review. The realgar bioleaching solution (RBS) works by inducing apoptosis when it is used to treat tumor cells in vitro and in vivo. When it is used to treat animal model organisms in vivo, such as mice and Caenorhabditis elegans, tumor tissues grew more slowly, with mass necrosis. Meanwhile, the agent also showed obvious inhibition of tumor cell growth. Bioleaching technology greatly improves the utilization of realgar and is a novel methodology to improve the traditional method.
Assuntos
Acidithiobacillus thiooxidans/metabolismo , Antineoplásicos/farmacologia , Arsenicais/farmacologia , Sulfetos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Arsenicais/química , Arsenicais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Células K562 , Sulfetos/química , Sulfetos/metabolismo , Fenômenos ToxicológicosRESUMO
During human immunodeficiency virus type 1 (HIV-1) maturation, three different forms of nucleocapsid (NC) protein-NCp15 (p9 + p6), NCp9 (p7 + SP2) and NCp7-appear successively. A mutant virus expressing NCp15 shows greatly reduced infectivity. Mature NCp7 is a chaperone protein that facilitates remodeling of nucleic acids (NAs) during reverse transcription. To understand the strict requirement for NCp15 processing, we compared the chaperone function of the three forms of NC. NCp15 anneals tRNA to the primer-binding site at a similar rate as NCp7, whereas NCp9 is the most efficient annealing protein. Assays to measure NA destabilization show a similar trend. Dynamic light scattering studies reveal that NCp15 forms much smaller aggregates relative to those formed by NCp7 and NCp9. Nuclear magnetic resonance studies suggest that the acidic p6 domain of HIV-1 NCp15 folds back and interacts with the basic zinc fingers. Neutralizing the acidic residues in p6 improves the annealing and aggregation activity of NCp15 to the level of NCp9 and increases the protein-NA aggregate size. Slower NCp15 dissociation kinetics is observed by single-molecule DNA stretching, consistent with the formation of electrostatic inter-protein contacts, which likely contribute to the distinct aggregate morphology, irregular HIV-1 core formation and non-infectious virus.
Assuntos
Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Linhagem Celular , DNA/metabolismo , DNA de Cadeia Simples/metabolismo , DNA Viral/metabolismo , HIV-1/fisiologia , Humanos , Dados de Sequência Molecular , Precursores de Proteínas/metabolismo , Estrutura Terciária de Proteína , RNA de Transferência/metabolismo , RNA Viral/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/químicaRESUMO
A Gram-stain-variable, rod-shaped, non-motile and endospore-forming bacterium, designated strain HZ1T, was isolated from a sample of bank side soil from Hangzhou city, Zhejiang province, PR China. On the basis of 16S rRNA gene sequence analysis, strain HZ1T was closely related to members of the genus Paenibacillus, sharing the highest levels of sequence similarity with Paenibacillus agarexedens DSM 1327T (94.4 %), Paenibacillus sputi KIT00200-70066-1T (94.4 %). Growth occurred at 15-42 °C (optimum 30-37 °C), pH 5.0-9.5 (optimum pH 7.0-8.0) and NaCl concentrations of up to 6.0 % (w/v) were tolerated (optimum 0.5 %). The dominant respiratory quinone was MK-7 and the DNA G+C content was 40.1âmol%. The major fatty acids were anteiso-C15 : 0 and iso-C16 : 0. The major polar lipids of strain HZ1T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and several unknown lipids. The diagnostic diamino acid found in the cell-wall peptidoglycan was meso-diaminopimelic acid. Based on its phenotypic and chemotaxonomic characteristics and phylogenetic data, strain HZ1T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus ripae sp. nov. (type strain HZ1T = CCTCC AB 2014276T = LMG 28639T) is proposed.
Assuntos
Paenibacillus/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Graxos/química , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Paenibacillus/genética , Paenibacillus/isolamento & purificação , Peptidoglicano/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMO
In our searching for novel tyrosinase inhibitors from natural sources, (S)-N-trans-feruloyloctopamine isolated from garlic skin was found to be a potential mushroom tyrosinase inhibitor. Here, we examined the effects of the potential tyrosinase inhibitor in B16F10 cells on intracellular melanin contents, cytotoxicity, and the signaling mechanism involved in the expression of tyrosinase. The results showed the inhibitor displayed little or no cytotoxicity at all concentrations examined and decreased the relative melanin contents in a dose-dependent manner in the α-MSH-stimulated B16F10 cells. Real-time PCR and Western blot analysis showed that it inhibits melanogenesis signaling by down-regulates mRNA and protein expression levels of tyrosinase, which leads to a lower melanin contents. These results suggested that (S)-N-trans-feruloyloctopamine was an ideal tyrosinase inhibitor, and could be used in food and medical industry.
Assuntos
Ácidos Cumáricos/farmacologia , Inibidores Enzimáticos/farmacologia , Alho/química , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Melaninas/metabolismo , Melanoma/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/genética , Octopamina/análogos & derivados , Agaricales/enzimologia , Animais , Linhagem Celular Tumoral , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Melanoma/patologia , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Octopamina/química , Octopamina/isolamento & purificação , Octopamina/farmacologia , Relação Estrutura-AtividadeRESUMO
In our searching for novel antioxidants from natural sources, N-trans-Caffeoyldopamine which was from natural product was found to be a potential compound for its remarkable antioxidant activity. Isoniazid (INH) and Rifampicin (RFP) is widely used for the treatment of Tuberculosis (TB) as the first line drugs, have been known to be potentially hepatotoxic and may lead to drug-induced liver injury. Oxidative stress has been regarded as the major mechanism of the hepatotoxicity. Therefore, in this study, the possible protective effects of N-trans-Caffeoyldopamine was investigated in the hepatotoxicity caused by INH and RFP in rats. Results showed that serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and hepatic malondialdehyde (MDA) content were reduced dramatically, and hepatic superoxide dismutase (SOD) activity and glutathione (GSH) content were restored remarkably by N-trans-Caffeoyldopamine co-administration, as compared to the INH-RFP treated rats (p<0.01). Moreover, the histopathological damage of liver and the number of apoptotic hepatocytes were also significantly ameliorated by the treatment. It is therefore suggested that N-trans-Caffeoyldopamine can provide a definite protective effect against acute hepatic injury caused by INH and RFP in rats, which may mainly be associated with its antioxidative effect. Mechanisms studies indicated that it inhibited the lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation.
Assuntos
Produtos Biológicos/farmacologia , Ácidos Cafeicos/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dopamina/análogos & derivados , Isoniazida/toxicidade , Fígado/efeitos dos fármacos , Rifampina/toxicidade , Animais , Produtos Biológicos/química , Ácidos Cafeicos/farmacologia , Dopamina/química , Dopamina/farmacologia , Fígado/patologia , Estrutura Molecular , RatosRESUMO
BACKGROUND: Prediction of postoperative survival for hilar cholangiocarcinoma (HCCA) remains difficult although there have been a variety of clinical classification and staging systems. This study was designed to validate and compare some of the major HCCA staging systems in use today. In addition, we sought to build up a new staging system modified from Jarnagin-Blumgart (J-B) classification for HCCA, to predict survival better. METHODS: A total of 154 consecutive cases of HCCA including 95 surgical patients between 2005 and 2014 were enrolled in this study. The clinical and pathological data were recorded retrospectively and three commonly used classification methods: Bismuth-Corlette (B-C) classification, TNM staging, and J-B classification were performed to analyze the correlations with resectability and survival. Chi-square test, Kaplan-Meier analysis, and kappa statistics were used to compare and confirm the relationships between the variables and survival. RESULTS: For all 154 patients, the resection rate of J-B T1 was 68.6% (48/70), higher than that of J-B T2 (44.8%, P = 0.007). J-B T2 also showed a higher resectability than J-B T3 (19.2%, P = 0.025). There was no significant difference in resectability within the groups B-C type and TNM stages. We set up a new staging system based on J-B classification, tumor differentiation, distant metastasis (N2 or M1 of TNM stage), and resection integrality. The total survival predictive accuracy was 69.5% (kappa = 0.547), higher than that of TNM staging and J-B classification. CONCLUSIONS: J-B classification was more useful than B-C classification, while its value for predicting survival did not exceed TNM staging system. The new staging system, based on J-B classification, provides a better method to stratify HCCA patients during the operation.
Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Tumor de Klatskin/mortalidade , Tumor de Klatskin/patologia , Estadiamento de Neoplasias , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/classificação , Neoplasias dos Ductos Biliares/cirurgia , Feminino , Seguimentos , Humanos , Tumor de Klatskin/classificação , Tumor de Klatskin/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Cuidados Pré-Operatórios , Prognóstico , Taxa de SobrevidaRESUMO
Ras genes are frequently activated in human cancers, but the mutant Ras proteins remain largely "undruggable" through the conventional small-molecule approach owing to the absence of any obvious binding pockets on their surfaces. By screening a combinatorial peptide library, followed by structure-activity relationship (SAR) analysis, we discovered a family of cyclic peptides possessing both Ras-binding and cell-penetrating properties. These cell-permeable cyclic peptides inhibit Ras signaling by binding to Ras-GTP and blocking its interaction with downstream proteins and they induce apoptosis of cancer cells. Our results demonstrate the feasibility of developing cyclic peptides for the inhibition of intracellular protein-protein interactions and of direct Ras inhibitors as a novel class of anticancer agents.
Assuntos
Peptídeos Cíclicos/metabolismo , Proteínas ras/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Drug testing has many test elements. It aims to prevent unqualified drugs from entering the market and ensure drug safety. The existing artificial intelligence (AI) online monitoring system identifies active ingredients in the process of use. Owing to their openness, data are easy to be lost, failing to meet user needs and inducing a specific impact on the use of the monitoring system. With the continuous development of computer and measurement technologies, various biochemical data are increasing at an unprecedented speed, and numerous databases are emerging. Extracting patterns from considerable known data and experimental facts is an essential task for a wide range of biological and chemical workers. Pattern recognition is one of the essential technologies for data mining. It is widely used in industry, agriculture, national defense, biomedicine, meteorology, astronomy, and other fields. To improve the effect of the online drug ingredient recognition system, this study used AI to design an online drug ingredient recognition-embedded monitoring system and applied AI to the teaching field to improve teaching efficiency. First, this study constructed the framework of the AI online drug ingredient recognition-embedded monitoring system and introduced the process of online drug ingredient recognition. Then, it introduced the pattern recognition method, constructed the pattern recognition system, and presented the pattern recognition algorithm and the algorithm evaluation index. Afterward, it used pattern recognition to conduct a qualitative analysis of the infrared spectrum of drug components and introduced the overall process of the qualitative analysis. In addition, this study employed AI to implement changes to the embedded system instruction in colleges and universities, summarizing the current issues. The impact of drug component recognition and the educational impact of embedded systems were investigated in the experimental portion. The experimental findings demonstrated the excellent accuracy, sensitivity, specificity, and Matthew correlation coefficient of the online drug component recognition-integrated monitoring system in this work. Compared with that of other systems, its average drug component recognition accuracy was above 0.85. Students in five majors reported high levels of satisfaction with the embedded system teaching, which is better for delivering college instruction.
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BACKGROUND: Research has linked enlarged perivascular spaces (EPVS) to cerebral venous reflux (CVR) in patients with hypertensive intracerebral hemorrhage, but it is unclear whether this association exists in recent small subcortical infarct (RSSI) patients. OBJECTIVE: This study aimed to investigate the correlation between EPVS and CVR in patients with RSSI. METHOD: This study included 297 patients, selected from patients with RSSI in the lenticulostriate artery admitted to the Department of Neurology of the First Affiliated Hospital of Zhengzhou University. CVR was assessed by time-of-flight magnetic resonance angiography (TOF-MRA). The relationship between EPVS and CVR was studied using multiple logistic regression analysis. RESULTS: This study included patients with an average age of 59.84±12.27 years, including 201 males (67.7%). CVR was observed in 40 (13.5%) patients. Compared to the group without CVR, the proportions of male patients and patients with a history of smoking and drinking were higher in the CVR group. The proportions of high-grade EPVS in the centrum semiovale region [23 cases (57.5%) vs. 108 cases (42.0%), p =0.067] and the basal ganglia region [30 cases (75.0%) vs. 133 cases (51.8%), p =0.006] were higher in the CVR group. After multiple logistic regression analysis, high-grade EPVS in the basal ganglia region was still associated with CVR (OR, 2.68; 95% CI, 1.22-5.87; p =0.014). CONCLUSION: In the population with RSSI, EPVS in basal ganglia is significantly associated with CVR, suggesting a close relationship between venous dysfunction and the formation of EPVS.
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BACKGROUND: Superior mesenteric artery (SMA) injuries rarely occur during blunt abdominal injuries, with an incidence of < 1%. The clinical manifestations mainly include abdominal hemorrhage and peritoneal irritation, which progress rapidly and are easily misdiagnosed. Quick and accurate diagnosis and timely effective treatment are greatly significant in managing emergent cases. This report describes emergency rescue by a multidisciplinary team of a patient with hemorrhagic shock caused by SMA rupture. CASE SUMMARY: A 55-year-old man with hemorrhagic shock presented with SMA rupture. On admission, he showed extremely unstable vital signs and was unconscious with a laceration on his head, heart rate of 143 beats/min, shallow and fast breathing (frequency > 35 beats/min), and blood pressure as low as 20/10 mmHg (1 mmHg = 0.133 kPa). Computed tomography revealed abdominal and pelvic hematocele effusion, suggesting active bleeding. The patient was suspected of partial rupture of the distal SMA branch. The patient underwent emergency mesenteric artery ligation, scalp suture, and liver laceration closure. In view of conditions with acute onset, rapid progression, and high bleeding volume, key points of nursing were conducted, including activating emergency protocol, opening of the green channel, and arranging relevant examinations with various medical staff for quick diagnosis. The seamless collaboration of the multidisciplinary team helped shorten the preoperative preparation time. Emergency laparotomy exploration and mesenteric artery ligation were performed to mitigate hemorrhagic shock while establishing efficient venous accesses and closely monitoring the patient's condition to ensure hemodynamic stability. Strict measures were taken to avoid intraoperative hypothermia and infection. CONCLUSION: After 3.5 h of emergency rescue and medical care, bleeding was successfully controlled, and the patient's condition was stabilized. Subsequently, the patient was transferred to the intensive care unit for continuous monitoring and treatment. On the sixth day, the patient was weaned off the ventilator, extubated, and relocated to a specialized ward. Through diligent medical intervention and attentive nursing, the patient made a full recovery and was discharged on day 22. The follow-up visit confirmed the patient's successful recovery.