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Broccoli sprouts are promising functional food sources and their taste and flavor play a pivotal role in the acceptance of consumers. In this study, the flavor profiles of three varieties of broccoli sprouts, namely Bi Lv, You Xiu, and Lv Hua, were comprehensively characterized using HS-SPME-GC/MS analysis. A total of 364 volatile and flavor components across 15 chemical classes were successfully identified. The results revealed a majority of volatile metabolites exhibiting upregulation during the germination process, leading to an enhancement in taste intensity after germination, particularly for umami and sweet tastes, which was associated with an increase in associated amino acids and sugar content. Although the total glucosinolate content in broccoli sprouts has decreased compared to seeds, it remains the primary contributor to the bitterness of broccoli sprouts. The present study elaborated on the flavor contribution of broccoli sprouts, supporting the cultivation and consumption of them as a nutritious food.
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Parthenolide is a germacrane sesquiterpene lactone separated from the traditional medicinal plant feverfew. Previous studies have shown that parthenolide possesses many pharmacological activities, involving anti-inflammatory and anticancer activities. However, the antitumor mechanism of parthenolide has not been fully elucidated. Thus, we investigate the potential antitumor mechanisms of parthenolactone. We predicted through network pharmacology that parthenolide may target HIF-1α to interfere with the occurrence and development of cancer. We found that parthenolide inhibited PD-L1 protein synthesis through mTOR/p70S6K/4EBP1/eIF4E and RAS/RAF/MEK/MAPK signaling pathways and promoted PD-L1 protein degradation through the lysosomal pathway, thereby inhibiting PD-L1 expression. Immunoprecipitation and Western blotting results demonstrated that parthenolide inhibited PD-L1 expression by suppressing HIF-1α and RAS cooperatively. We further proved that parthenolide inhibited cell proliferation, migration, invasion, and tube formation via down-regulating PD-L1. Moreover, parthenolide increased the effect of T cells to kill tumor cells. In vivo xenograft assays further demonstrated that parthenolide suppressed the growth of tumor xenografts. Collectively, we report for the first time that parthenolide enhanced T cell tumor-killing activity and suppressed cell proliferation, migration, invasion, and tube formation by PD-L1. The current study provides new insight for the development of parthenolide as a novel anticancer drug targeting PD-L1.
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Antígeno B7-H1 , Proliferação de Células , Sesquiterpenos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Humanos , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The citri red mite, Panonychus citri (McGregor), is an important citrus pest worldwide, causing enormous economic losses to citrus production. Bifenazate is a widely used acaricide for controlling P. citri. The detoxification mechanism of bifenazate is not clear in P. citri. RESULTS: PcGSTMu2, a significantly upregulated GST gene, was identified by the transcriptome analysis of P. citri after bifenazate exposure. The expression level of PcGSTMu2 was significantly increased after bifenazate exposure. By using RNAi of PcGSTMu2, the susceptibility of P. citri to bifenazate was significantly increased. Protein modeling and docking of PcGSTMu2 with GSH and bifenazate indicated the potential amino acid residues for binding in the active site. Heterologous expression and in vitro functional assays further revealed that PcGSTMu2 could deplete bifenazate. CONCLUSION: These results indicated that PcGSTMu2 plays an important role in the detoxification of bifenazate in P. citri and provides the molecular foundation for understanding bifenazate metabolism in P. citri. © 2024 Society of Chemical Industry.
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The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Thiazole derivatives have been reported to have diverse biological activities, especially in terms of anti-tumor. Consequently, we hypothesized that the introduction of a thiazole functional group in PD was likely to improve the biological potency. Here, three series of PD derivatives containing a thiazole moiety were synthesized, including (a) sulfonyl-containing thiazole derivatives (5 a-l), (b) urea-containing thiazole derivatives (7 a-i), and (c) thiourea-containing thiazole derivatives (9 a-i), and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. The results showed that about 1/3 of the target compounds showed moderate or strong HIF-1α inhibitory activity, among which compounds 5 d and 7 b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42â µM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50â µM. Molecular docking experiments were also performed to investigate the structure-activity relationship. Compounds 5 d and 7 b can be used as leads for further study and development of novel antitumor drugs.
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Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.
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Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Colangiocarcinoma , Transição Epitelial-Mesenquimal , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Humanos , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Prognóstico , Masculino , Metabolismo dos Lipídeos , Movimento Celular , Feminino , Proliferação de Células , Transcriptoma , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND AND OBJECTIVES: Feeding intolerance (FI) is a common problem in late preterm infants (34 weeks ≤ gestational age < 37 weeks). This study aimed to evaluate the efficacy and safety of phentolamine combined with B vitamins in treating FI in late preterm infants and to explore its effects on gastrointestinal symptoms, inflammation and complications. METHODS AND STUDY DESIGN: We randomly assigned 118 late preterm infants with FI to a treatment group (n = 56) or a control group (n = 62). The treatment group received intravenous phentolamine and intramuscular B vitamins, whereas the control group received basic treatment only. We measured the time of disappearance of gastrointestinal symptoms, the time of basal at-tainment, the time of hospitalisation, the incidence of complications, the concentrations of inflammatory markers and the overall effective rate of treatment. RESULTS: The treatment group had a shorter duration of gastrointestinal symptoms than did the control group (p < 0.01). The treatment group also had lower concentrations of inflammatory markers and a higher overall effective rate than did the control group (p < 0.05). There was no difference between the two groups in the time of hospitalisation, basal attainment, weight re-covery and the incidence of complications (p > 0.05). CONCLUSIONS: Phentolamine and B vitamins can reduce gastrointestinal symptoms and inflammation in late preterm infants with FI but do not affect the occurrence of complications.
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Recém-Nascido Prematuro , Fentolamina , Complexo Vitamínico B , Feminino , Humanos , Recém-Nascido , Masculino , Intolerância Alimentar , Gastroenteropatias/tratamento farmacológico , Fentolamina/administração & dosagem , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/uso terapêuticoRESUMO
In our chemical investigation into Penicillium sp. UJNMF0740 derived from mangrove sediment, fourteen indole diterpene analogs, including four new ones, are purified by multiple chromatographic separation methods, with their structures being elucidated by the analyses of NMR, HR-ESIMS, and ECD data. The antibacterial and neuroprotective effects of these isolates were examined, and only compounds 6 and 9 exhibited weak antibacterial activity, while compounds 5, 8, and 10 showed protective effects against the injury of PC12 cells induced by 6-hydroxydopamine (6-OHDA). Additionally, compound 5 could suppress the apoptosis and production of reactive oxygen species (ROS) in 6-OHDA-stimulated PC12 cells as well as trigger the phosphorylation of PI3K and Akt. Taken together, our work enriches the structural diversity of indole diterpenes and hints that compounds of this skeleton can repress the 6-OHDA-induced apoptosis of PC12 cells via regulating the PI3K/Akt signaling pathway, which provides evidence for the future utilization of this fascinating class of molecules as potential neuroprotective agents.
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Diterpenos , Fármacos Neuroprotetores , Penicillium , Ratos , Animais , Células PC12 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Oxidopamina/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Penicillium/química , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Diterpenos/farmacologia , Diterpenos/química , Indóis/farmacologia , Indóis/química , Antibacterianos/farmacologia , Fármacos Neuroprotetores/farmacologiaRESUMO
Smoking carcinogen nicotine-derived nitrosamine ketone (NNK) is the most potent contributor to lung adenocarcinoma (LUAD) development, but the mechanism has not been fully elucidated. Here, we reported that fatty acid translocase CD36 was significantly overexpressed in both human LUAD tissues and NNK-induced A/J mice LUAD tumors. The overexpressed CD36 was positively correlated with Src kinase activation, smoking status, metastasis, and worse overall survival of patients with smoking history. Upon NNK binding with α7 nicotinic acetylcholine receptor (α7nAChR), sarcolemmal CD36 was increased and it interacted with surface α7nAChR and cytosol Src simultaneously, which in turn activated Src and downstream pro-carcinogenic kinase ERK1/2 and Akt, and finally caused LUAD cells to form subcutaneous and pulmonary metastatic tumors. This process could be blocked by CD36 knockdown and CD36 irreversible inhibitor SSO. Furthermore, the effect of NNK was inhibited obviously in CD36-/- A/J mice. Thus, targeting CD36 may provide a breakthrough therapy of LUAD.
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Obesity/overweight and lipid metabolism disorders have become increased risk factors for lung cancer. Fatty acid translocase CD36 promotes cellular uptake of fatty acids. Whether and how CD36 facilitates lung adenocarcinoma (LUAD) growth in high-fat environment is unknown. Here, we demonstrated that palmitic acid (PA) or high-fat diet (HFD) promoted LUAD cell proliferation and metastasis in a CD36-dependent manner. Mechanistically, CD36 translocated from cytoplasm to cell membrane and interacted with Src kinase upon PA stimulation in human LUAD cells. Akt and ERK, downstream of Src, were then activated to mediate LUAD cell proliferation and metastasis. Furthermore, PA treatment promoted CD36 sarcolemmal translocation, where it activated Rac1 and upregulated MMP-9 through Src-Akt/ERK pathway, resulting in redistribution of cortactin, N-WASP and Arp2/3, and finally led to occurrence of finger-like protrusions of actin on cell surface to enhance cell metastasis. Compared with normal-chew diet (NCD) mice, the HFD group exhibited higher level of blood free fatty acid (FFA) and cholesterol (TC), developed larger xenograft LUAD tumors and enhanced tumor cell metastatic potential, which were accompanied by obvious sarcolemmal actin remodeling and were blocked by simultaneous CD36 knockdown in LUAD cells. Consistently, xenografted and tail vein-injected scramble-RNA-A549 cells but not CD36-shRNA-A549 in HFD mice formed metastatic LUAD tumors on the lung. CD36 inhibitor SSO significantly inhibited LUAD cell metastasis to the lung. Collectively, CD36 initiates Src signaling to promote LUAD cell proliferation and actin remodeling-involved metastasis under high-fat environment. Our study provides the new insights that CD36 is a valid target for LUAD therapy.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Actinas , Adenocarcinoma de Pulmão/genética , Antígenos CD36/genética , Proliferação de Células , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismoRESUMO
OBJECTIVE: To investigate the effects of acupuncture on JNK pathway and autophagy level in rats with intracerebral hemorrhage ï¼ICHï¼ and explore the partial mechanism of acupuncture against ICH. METHODS: SD rats were randomly divided into blank group, model group and acupuncture group. Each group was divided into Day 1, Day 3 and Day 7 subgroups respectively, with 5 rats in each group. The autologous blood injection was adopted to duplicate rat model of ICH. In the acupuncture group, the needle was inserted from "Baihui" ï¼GV20ï¼ towards "Qubin" ï¼GB7ï¼ on the affected side, stimulating for 30 min each time, once dailyï¼ the same acupuncture technique was opera-ted in each subgroup for 1, 3 and 7 days, separately. Using Bederson scale, the neurological deficit was evaluated in each group. Western blot was adopted to detect the protein expression levels of Beclin1, LC3â /â ¡, phosphorylated c-Jun amino-terminal kinase ï¼p-JNKï¼ and the phosphorylated ï¼pï¼-c-Jun around hematoma lesion of the brain tissue of rats in each group. RESULTS: After treatment, the neurological deficit score of rats in the model group was higher than that of the blank group at each time point ï¼P<0.05ï¼, and the score of the acupuncture group started declining since the 3rd day of treatment when compared with the model group ï¼P<0.05ï¼. At each time point, compared with the blank group, the protein expression levels of LC3â /â ¡, Beclin1, p-c-Jun and p-JNK was increased ï¼P<0.01ï¼. Compared with the model group, the protein expression level of LC3â /â ¡ was reduced ï¼P<0.05ï¼ï¼ the protein expression levels of Beclin1, p-c-Jun and p-JNK was increased ï¼P<0.05, P<0.01ï¼ on day 3 and 7 in the acupuncture group. CONCLUSION: Acupuncture can activate the JNK pathway in the brain tissue of rats with ICH and increase the level of autophagy, thereby improving the neurological function of the rats with ICH.
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Terapia por Acupuntura , Sistema de Sinalização das MAP Quinases , Animais , Ratos , Ratos Sprague-Dawley , Proteína Beclina-1 , Hemorragia Cerebral/genética , Hemorragia Cerebral/terapia , AutofagiaRESUMO
To explore the pollution characteristics and sources of heavy metals in atmospheric deposition in a typical lead-zinc smelting city, 511 effective atmospheric deposition samples from 22 points in different functional areas of a city in Henan Province were collected monthly during 2021. The concentrations and spatial-temporal distribution of heavy metals were analyzed. The geo-accumulation index method and health risk assessment model were utilized to evaluate the heavy metal pollution degree. The sources of heavy metals were quantitatively analyzed using a positive matrix factorization (PMF) model. The results showed that the average concentrations of ω(Pb), ω(Cd), ω(As), ω(Cr), ω(Cu), ω(Mn), ω(Ni), and ω(Zn) in atmospheric deposition samples were 3185.77, 78.18, 273.67, 149.50, 453.60, 810.37, 54.38, and 2397.38 mg·kg-1, respectively, which were all higher than the soil background values of Henan Province. All heavy metals except Mn had significant seasonal variation characteristics. The concentrations of Pb, Cd, As, and Cu in the industrial area with lead-zinc smelting were significantly higher than those in other functional areas, and the concentration of Zn was the highest in the residential mixed area. The results of the geo-accumulation index showed that the pollution of Cd and Pb were the most serious, followed by that of Zn, Cu, and As, which belonged to the serious-extreme pollution category. The main exposure route of non-carcinogenic risk was hand-mouth intake. Pb and As posed the greatest non-carcinogenic risk to children in all functional areas. The carcinogenic risks of Cr, As, Cd, and Ni through the respiratory system to humans were all below the threshold values. The analysis of the PMF model showed that the main sources of heavy metals in atmospheric deposition were industrial pollution sources (39.7%), transportation sources (28.9%), secondary dust sources (14.4%), incineration and coal combustion sources (9.3%), and natural sources (7.8%).
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Injury to the anterior talofibular ligament (ATFL) is a common acute injury of the lateral foot ligament. Untimely and improper treatment significantly affects the quality of life and rehabilitation progress of patients. The purpose of this paper is to review the anatomy and the current methods of diagnosis and treatment of acute injury to the ATFL. The clinical manifestations of acute injury to the ATFL include pain, swelling, and dysfunction. At present, non-surgical treatment is the first choice for acute injury of the ATFL. The standard treatment strategy involves the "peace and love" principle. After initial treatment in the acute phase, personalized rehabilitation training programs can be followed. These may involve proprioception training, muscle training, and functional exercise to restore limb coordination and muscle strength. Static stretching and other techniques to loosen joints, acupuncture, moxibustion massage, and other traditional medical treatments can relieve pain, restore range of motion, and prevent joint stiffness. If the non-surgical treatment is not ideal or fails, surgical treatment is feasible. Currently, arthroscopic anatomical repair or anatomical reconstruction surgery is commonly used in clinical practice. Although open Broström surgery provides good results, the modified arthroscopic Broström surgery has many advantages, such as less trauma, rapid pain relief, rapid postoperative recovery, and fewer complications, and is more popular with patients. In general, when treating acute injury to the ATFL, treatment management and methods should be timely and reasonably arranged according to the specific injury scenario and attention should be paid to the timely combination of multiple therapies to achieve the best treatment results.
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BACKGROUND: Development of clinically effective neuroprotective agents for stroke therapy is still a challenging task. Microglia play a critical role in brain injury and recovery after ischemic stroke. Traditional Chinese herbal medicines (TCHMs) are based on a unique therapeutic principle, have various formulas, and have long been widely used to treat stroke. Therefore, the active compounds in TCHMs and their underlying mechanisms of action are attracting increasing attention in the field of stroke drug development. PURPOSE: To summarize the regulatory mechanisms of TCHM-derived natural compounds on the microglial response in animal models of ischemic stroke. METHODS: We searched studies published until 10 April 2023 in the Web of Science, PubMed, and ScienceDirect using the following keywords: natural compounds, natural products or phytochemicals, traditional Chinese Medicine or Chinese herbal medicine, microglia, and ischemic stroke. This review was prepared according to PRISMA (Preferred Reporting Item for Systematic Reviews and Meta-Analysis) guidelines. RESULTS: Natural compounds derived from TCHMs can attenuate the M1 phenotype of microglia, which is involved in the detrimental inflammatory response, via inhibition of NF-κB, MAPKs, JAK/STAT, Notch, TLR4, P2X7R, CX3CR1, IL-17RA, the NLRP3 inflammasome, and pro-oxidant enzymes. Additionally, the neuroprotective response of microglia with the M2 phenotype can be enhanced by activating Nrf2/HO-1, PI3K/AKT, AMPK, PPARγ, SIRT1, CB2R, TREM2, nAChR, and IL-33/ST2. Several clinical trials showed that TCHM-derived natural compounds that regulate microglial responses have significant and safe therapeutic effects, but further well-designed clinical studies are needed. CONCLUSIONS: Further research regarding the direct targets and potential pleiotropic or synergistic effects of natural compounds would provide a more reasonable approach for regulation of the microglial response with the possibility of successful stroke drug development.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Microglia , Fosfatidilinositol 3-Quinases , Extratos Vegetais/farmacologia , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
BACKGROUND: The flavonoid galangin (3,5,7-trihydroxyflavone) is derived from the root of Alpinia officinarum Hance, an edible and medicinal herb. Galangin has many biological activities, such as anti-inflammatory, anti-microbial, anti-viral, anti-obesogenic, and anti-oxidant effects. However, the anti-tumor mechanism of galangin remains unclear. PURPOSE: To elucidate the anti-tumor mechanisms of galangin in vitro and in vivo. METHODS: MTT, western blotting, immunoprecipitation, RT-PCR, and immunofluorescence assays were used to assess the mechanism of galangin inhibiting PD-L1 expression. The effect of galangin on T cell activity was analyzed in Hep3B/T cell co-cultures. Colony formation, EdU, migration, and invasion assays were performed to explore the effect of galangin on cancer progression and metastasis. Anti-tumor effects of galangin were investigated in a xenograft model. RESULTS: Galangin inhibited PD-L1 expression dose-dependently, which plays a major role in tumor progression. Moreover, galangin blocked STAT3 activation through the JAK1/JAK2/Src signaling pathway and Myc activation through the Ras/RAF/MEK/ERK signaling pathway. Galangin reduced PD-L1 expression by suppressing STAT3 and Myc cooperatively. Galangin increased the killing effect of T cells on tumor cells in Hep3B/T cell co-cultures. Moreover, galangin inhibited tumor cell proliferation, migration, and invasion through PD-L1. In vivo experiments showed that galangin suppressed tumor growth. CONCLUSION: Galangin enhances T-cell activity and inhibits tumor cell proliferation, migration, and invasion through PD-L1. The current study emphasizes the anti-tumor properties of galangin, offering new insights into the development of tumor therapeutics targeting PD-L1.
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Antígeno B7-H1 , Linfócitos T , Humanos , Antígeno B7-H1/metabolismo , Ligantes , Linhagem Celular Tumoral , Linfócitos T/metabolismo , Flavonoides/farmacologia , Apoptose , Proliferação de Células , Fator de Transcrição STAT3/metabolismoRESUMO
Introduction: Microorganisms play a critical role in soil biogeochemical cycles, but it is still debated whether they influence soil biogeochemical processes through community composition and diversity or not. This study aims to investigate variation in bacterial community structure across different soils and its correlation to soil multifunctionality. Soil samples were collected from five typical farmland zones along distinct climatic gradients in China. Methods: The high-throughput sequencing (Illumina MiSeq) of 16S rRNA genes was employed to analyze bacterial community composition in each soil sample. Multivariate analysis was used to determine the difference in soil properties, microbial community and functioning, and their interactions. Results: Cluster and discrimination analysis indicated that bacterial community composition was similar in five tested soil samples, but bacterial richness combined with soil enzyme activities and potential nitrification rate (PNR) contributed most to the differentiations of soil samples. Mantel test analysis revealed that bacterial community composition and richness were more significantly shaped by soil nutrient conditions and edaphic variables than bacterial diversity. As for soil multifunctionality, soil microbial community level physiological profiles were little affected by abiotic and biotic factors, while soil enzymes and PNR were also significantly related to bacterial community composition and richness, in addition to soil N and P availability. Conclusion: Cumulatively, soil enzymes' activities and PNR were greatly dependent on bacterial community composition and richness not diversity, which in turn were greatly modified by soil N and P availability. Therefore, in the future it should be considered for the role of fertilization in the modification of bacterial community and the consequent control of nutrient cycling in soil.
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Pancreatic ß-cell apoptosis is a key feature of diabetes and can be induced by chronic exposure to saturated fatty acids (FAs). However, the underlying mechanisms remain poorly understood. We presently evaluated the role of Mcl-1 and mTOR in mice fed with high-fat-diet (HFD) and ß-cells exposed to the overloaded palmitic acid (PA). Compared with normal-chow-diet (NCD)-fed mice, HFD group showed impaired glucose tolerance after two months. Along with the diabetes progression, pancreatic islets first became hypertrophic and then atrophic, the ratio of ß-cell:α-cell increased in the islets of four months HFD-fed mice while decreased after six months. This process was accompanied by significantly increased ß-cell apoptosis and AMPK activity, and decreased Mcl-1 expression and mTOR activity. Consistently, glucose-induced insulin secretion dropped. In terms of mechanism, PA with lipotoxic dose could activate AMPK, which in turn inhibited ERK-stimulated Mcl-1Thr163 phosphorylation. Meanwhile, AMPK blocked Akt activity to release Akt inhibition on GSK3ß, followed by GSK3ß-initiated Mcl-1Ser159 phosphorylation. The context of Mcl-1 phosphorylation finally led to its degradation by ubiquitination. Also, AMPK inhibited the activity of mTORC1, resulting in a lower level of Mcl-1. Suppression of mTORC1 activity and Mcl-1 expression positively related to ß-cell failure. Alteration of Mcl-1 or mTOR expression rendered different tolerance of ß-cell to different dose of PA. In conclusion, lipid oversupply-induced dual modulation of mTORC1 and Mcl-1 finally led to ß-cell apoptosis and impaired insulin secretion. The study may help further understand the pathogenesis of ß-cell dysfunction in case of dyslipidemia, and provide promising therapeutic targets for diabetes.
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Insulina , Proteínas Proto-Oncogênicas c-akt , Camundongos , Animais , Insulina/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Regulação para Baixo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ácido Palmítico/farmacologia , ApoptoseRESUMO
Achalasia cardia, type of esophageal dynamic disorder, is a relatively rare primary motor esophageal disease characterized by the functional loss of plexus ganglion cells in the distal esophagus and lower esophageal sphincter. Loss of function of the distal and lower esophageal sphincter ganglion cells is the main cause of achalasia cardia, and is more likely to occur in the elderly. Histological changes in the esophageal mucosa are considered pathogenic; however, studies have found that inflammation and genetic changes at the molecular level may also cause achalasia cardia, resulting in dysphagia, reflux, aspiration, retrosternal pain, and weight loss. Currently, the treatment options for achalasia focus on reducing the resting pressure of the lower esophageal sphincter, helping to empty the esophagus and relieve symptoms. Treatment measures include botulinum toxin injection, inflatable dilation, stent insertion, and surgical myotomy (open or laparoscopic). Surgical procedures are often subject to controversy owing to concerns about safety and effectiveness, particularly in older patients. Herein, we review clinical epidemiological and experimental data to determine the prevalence, pathogenesis, clinical presentation, diagnostic criteria, and treatment options for achalasia to support its clinical management.
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Citrus peel has long been used in traditional medicine in Asia to treat common cold, dyspepsia, cough, and phlegm. Narirutin-a flavanone-7-O-glycoside-is the major flavonoid in citrus peel, and has anti-oxidative, anti-allergic, and anti-inflammatory activities. However, the anti-inflammatory mechanism of narirutin has not been fully elucidated. This study is aimed to investigate the effects of narirutin on the Nod-like receptor protein 3 (NLRP3)-mediated inflammatory response in vitro and in vivo, and determine the underlying mechanism. THP-1 differentiated macrophages and bone marrow-derived macrophages (BMDMs) were used for in vitro experiments, while dextran sulfate sodium (DSS)-induced colitis and alum-induced peritonitis mouse models were constructed to test inflammation in vivo. Narirutin suppressed secretion of interleukin (IL)-1ß and pyroptosis in lipopolysaccharide (LPS)/ATP-stimulated macrophages. Narirutin decreased the expression of NLRP3 and IL-1ß in the LPS-priming step through inhibition of NF-κB, MAPK and PI3K /AKT signaling pathways. Narirutin inhibited NLRP3-ASC interaction to suppress NLRP3 inflammasome assembly. Furthermore, oral administration of narirutin (300 mg/kg) alleviated inflammation symptoms in mice with peritonitis and colitis. These results suggest that narirutin exerts its anti-inflammatory activity by suppressing NLRP3 inflammasome activation via inhibition of the NLRP3 inflammasome priming processes and NLRP3-ASC interaction in macrophages.
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Colite , Flavanonas , Peritonite , Animais , Camundongos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Flavanonas/farmacologia , Colite/induzido quimicamente , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Peritonite/metabolismoRESUMO
Myocardial infarction (MI) is one of the diseases with high fatality rate. Berberine (BBR) is a monomer compound with various biological functions. And some studies have confirmed that BBR plays an important role in alleviating cardiomyocyte injury after MI. However, the specific mechanism is unclear. In this study, we induced a model of MI by ligation of the left anterior descending coronary artery and we surprisingly found that BBR significantly improved ventricular remodeling, with a minor inflammatory and oxidative stress injury, and stronger angiogenesis. Moreover, BBR inhibited the secretion of Wnt5a/ß-catenin pathway in macrophages after MI, thus promoting the differentiation of macrophages into M2 type. In summary, BBR effectively improved cardiac function of mice after MI, and the potential protective mechanism was associated with the regulation of inflammatory responses and the inhibition of macrophage Wnt5a/ß-catenin pathway in the infarcted heart tissues. Importantly, these findings supported BBR as an effective cardioprotective drug after MI.
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Berberina , Infarto do Miocárdio , Camundongos , Animais , Berberina/farmacologia , beta Catenina/metabolismo , Miocárdio , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos , Macrófagos/metabolismoRESUMO
(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.