RESUMO
BACKGROUND: Programmed cell death (PCD) is a natural process in which cells undergo controlled self-destruction, which plays a crucial role in maintaining tissue homeostasis and eliminating damaged or unnecessary cells. The connection between PCD and osteosarcoma was explored in the present study. METHODS: Twelve types of PCD were collected for developing a prognostic signature in osteosarcoma using machine learning algorithms. The prognostic value, pathway annotation and drug prediction of the signature were explored. RESULTS: Telomerase reverse transcriptase (TERT) was found to be a potent hazardous marker in osteosarcoma and could facilitate the proliferation and migration of osteosarcoma. CONCLUSIONS: In summary, the present study has developed a prognostic signature for osteosarcoma and identifies TERT as a potent hazardous gene. The study suggests that further research is needed to address the underlying mechanism of how TERT affects the immune response in osteosarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Morte Celular/genética , Apoptose , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Algoritmos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genéticaRESUMO
BACKGROUND: Osteosarcoma is a very aggressive bone tumor mainly affecting teens and young adults. Disulfidptosis is a metabolic-related form of regulated cell death. However, the interconnection between disulfidptosis and osteosarcoma has not been explored. METHODS: In the present study, disulfidptosis-related clusters were identified in osteosarcoma using the nonnegative matrix factorization clustering method. PABPC3 was identified as a hazardous gene in osteosarcoma using machine learning algorithms, CoxBoost, and Random Survival Forest. The prognostic value, pathway annotation, immune characteristics, and drug prediction of PABPC3 were systematically explored. MTT (i.e., 3-(4, 5-dimethyl thiazol-2-yl)-2,5-diphenytetrazolium bromide), EdU (ie. 5-ethyny-2'-deoxvuridine), and Transwell assays were used for in vitro validation of PABPC3. RESULTS: The disulfidptosis-related clusters could distinguish survival outcomes of osteosarcoma patients. PABPC3 could predict survival outcomes, immune activity, and drug response in osteosarcoma patients. Besides, PABPC3 was proven to facilitate the proliferation and migration of osteosarcoma. CONCLUSIONS: The present study is expected to establish the bridge between disulfidptosis and osteosarcoma. PABPC3 is expected to be further explored as a therapeutic target in osteosarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Adulto Jovem , Humanos , Osteossarcoma/genética , Algoritmos , Análise por Conglomerados , Neoplasias Ósseas/genéticaRESUMO
Recently, the enhanced penetration and retention (EPR) effect of nano-preparations has been questioned. Whether the vascular endothelial cell gap (VECG) is the main transport pathway of nano-preparations has become a hot issue at present. Therefore, we propose an in vitro biomimetic experimental system that demonstrates the transvascular transport of nano-preparation. Based on the tumor growth process, the experimental system was used to simulate the change process of abnormal factors (vascular endothelial cell gap and interstitial fluid pressure (IFP)) in the tumor microenvironment. The influence of change in the abnormal factors on the enhanced penetration and retention effect of nano-preparation was explored, and simulation verification was performed. The results show that when the interstitial fluid pressure is close to the vascular fluid pressure (VFP), the transport of nano-preparation is obstructed, resulting in the disappearance of enhanced penetration and retention effect of the nano-preparation. This indicates that the pressure gradient between vascular fluid pressure and interstitial fluid pressure determines whether the enhanced penetration and retention effect of nano-preparations can exist.
Assuntos
Biomimética , Neoplasias , Humanos , Modelos Biológicos , Neoplasias/irrigação sanguínea , Simulação por Computador , Líquido Extracelular/metabolismo , Microambiente TumoralRESUMO
Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.
Assuntos
Fibrose Pulmonar Idiopática , Relaxina , Camundongos , Humanos , Animais , Relaxina/farmacologia , Relaxina/uso terapêutico , Bleomicina , Microesferas , Porosidade , Pulmão , Fibrose , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , ColágenoRESUMO
BACKGROUND: A disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) is involved in inflammation and fertility in women with polycystic ovary syndrome (PCOS). This study aims to assess the role of ADAMTS level in the outcomes of in vitro fertilization and embryo transfer (IVF-ET) in women with PCOS, using a meta-analytic approach. METHODS: We systematically searched Web of Science, PubMed, EmBase, and the Cochrane library to identify potentially eligible studies from inception until December 2021. Study assess the role of ADAMTS levels in patients with PCOS was eligible in this study. The pooled effect estimates for the association between ADAMTS level and IVF-ET outcomes were calculated using the random-effects model. RESULTS: Five studies involving a total of 181 patients, were selected for final analysis. We noted that ADAMTS-1 levels were positively correlated to oocyte maturity (r = 0.67; P = 0.004), oocyte recovery (r = 0.74; P = 0.006), and fertilization (r = 0.46; P = 0.041) rates. Moreover, ADAMTS-4 levels were positively correlated to oocyte recovery (r = 0.91; P = 0.001), and fertilization (r = 0.85; P = 0.017) rates. Furthermore, downregulation of ADAMTS-1, ADAMTS-4, ADAMTS-5, and ADAMTS-9 was associated with elevated follicle puncture (ADAMTS-1: weighted mean difference [WMD], 7.24, P < 0.001; ADAMTS-4: WMD, 7.20, P < 0.001; ADAMTS-5: WMD, 7.20, P < 0.001; ADAMTS-9: WMD, 6.38, P < 0.001), oocytes retrieval (ADAMTS-1: WMD, 1.61, P < 0.001; ADAMTS-4: WMD, 3.63, P = 0.004; ADAMTS-5: WMD, 3.63, P = 0.004; ADAMTS-9: WMD, 3.20, P = 0.006), and Germinal vesicle oocytes levels (ADAMTS-1: WMD, 2.89, P < 0.001; ADAMTS-4: WMD, 2.19, P < 0.001; ADAMTS-5: WMD, 2.19, P < 0.001; ADAMTS-9: WMD, 2.89, P < 0.001). Finally, the oocytes recovery rate, oocyte maturity rate, fertilization rate, cleavage rate, good-quality embryos rate, blastocyst formation rate, and clinical pregnancy rate were not affected by the downregulation of ADAMTS-1, ADAMTS-4, ADAMTS-5, and ADAMTS-9 (P > 0.05). CONCLUSIONS: This study found that the outcomes of IVF-EF in patients with PCOS could be affected by ADAMTS-1 and ADAMTS-4; further large-scale prospective studies should be performed to verify these results.
Assuntos
Síndrome do Ovário Policístico , Gravidez , Humanos , Feminino , Síndrome do Ovário Policístico/complicações , Estudos Prospectivos , Fertilização in vitro/métodos , Recuperação de Oócitos , Oócitos/fisiologia , Taxa de GravidezRESUMO
PROBLEM BACKGROUND: Penicillin was the first and most famous fungal secondary metabolite used as broad spectrum antibiotic that revolutionarised pharmaceutical research and also saved millions of lives. The over optimistic belief in 1967 that sufficient antibiotics had been discovered to defeat infectious diseases was quickly crashed with the appearance of multidrug resistant (MDR) bacteria in 1990s. This has posed a serious threat to mankind. Although scientists are making efforts to synthesize and discover new antibiotics there are not enough new drugs in pharmaceutical pipeline to beat the pace at which MDR bacteria are emerging. In view of this there is an urgent and serious medical need for new bioactive compounds to be discovered to treat infections caused by MDR pathogens. The present study is aimed to investigate the antibacterial potential of Aspergillus flavus originated compounds that may act as drug leads to treat future infections. METHODOLOGY: Among the 6 isolated fungal strains from the rhizosphere of Mentha piperetta, one was processed for isolation of secondary metabolites on the basis of preliminary antibacterial testing. Observation of morphological and microscopic features helped in identification of the fungal strain as Aspergillus flavus. Potato Dextrose Agar (PDA) medium was used for fungal growth while Czapec Yeast Broth (CYB) medium was used for production of fungal metabolites. Column chromatography technique was utilized for purification of compound from crude fungal extract and the mass of the compound was determined using Liquid Chromatography Mass Spectrometry (LCMS) method. Structure elucidation of the pure compound was performed using 500 Varian Nuclear Magnetic Resonance (NMR) machine. Docking was performed using Glide SP algorithm. Agar well diffusion method was used to determine the invitro antibacterial potential of the compound against two MDR bacterial strains i.e. Staphylococcus aureus and Proteus vulgaris. For this a total of 4 dose concentrations i.e. (100, 250, 500, 1000 µg mL- 1) of the compound were prepared and applied to bacterial strains on Mueller Hinton agar using tetracycline as control. RESULTS: The chemical name of the purified compound from A. flavus was determined as (2E)-3-[(3S, 4R)-8-hydroxy-3, 4-dimethyl-1-oxo-3, 4-dihydro-1H-2- benzopyran-7-yl] prop-2-enoic acid with the formula C14H14O5 and exact mass of 262.08. The in-Silico analysis showed that this compound has the potential to inhibit the binding pocket of S. aureus TyrRS (1JII) with docking score of - 8.67 Kcal mole- 1. The results obtained from invitro experiments were encouraging as at 1000 µg mL- 1 the compound showed 58.8% inhibition against S. aureus and 28% inhibition against P. vulgaris. CONCLUSIONS: The pure compound with formula C14H14O5 and exact mass of 262 exhibited antibacterial potential both insilico and invitro against both Gram negative and Gram positive bacteria. The compound was more active against S. aureus in comparison to P. vulgaris. From the obtained results it is concluded that this compound can be used as potent antibacterial candidate but further studies will be needed prior to its use as antibiotic.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Aspergillus flavus/química , Aspergillus flavus/metabolismo , Antibacterianos/metabolismo , Aspergillus flavus/genética , Aspergillus flavus/isolamento & purificação , Farmacorresistência Bacteriana , Mentha piperita/microbiologia , Testes de Sensibilidade Microbiana , Proteus vulgaris/efeitos dos fármacos , Proteus vulgaris/crescimento & desenvolvimento , Metabolismo Secundário , Microbiologia do Solo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
Having benefited from the combination of different therapeutic modalities, functionalized nanoplatforms with synergistic strategies have aroused great interest in anticancer treatment. Herein, an engineered, a biodegradable hollow mesoporous organosilica nanoparticle (HMON)-based nanoplatform was fabricated for photothermal-enhanced chemotherapy of tumor. For the first time, we demonstrated that HMONs could serve as nanocarriers for co-delivering of both the paclitaxel and photothermal agent new indocyanine green (IR820), denoted as Paclitaxel/IR820@ HMONs-PEG. The as-prepared nanosystem exhibited a high paclitaxel-loading capacity of 28.4%, much higher than most paclitaxel-loaded nanoformulations. Furthermore, incorporating thioether bonds (S-S) into the HMONs' framework endowed them with GSH-responsive biodegradation behavior, leading to the controllable release of drugs under a tumor reducing microenvironment, and hindered the premature release of paclitaxel. Upon being irradiated with an NIR laser, the obtained co-delivery nanosystem exhibited great photothermal properties generated from IR820. The fabricated nanocomposites could significantly suppress tumor growth under NIR laser irradiation, as validated by in vitro and in vivo assessments. Combined with outstanding biocompatibility, the constructed nanosystem holds great potential in combinational antitumor therapy.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Compostos de Organossilício/química , Paclitaxel/química , Fototerapia/métodos , Animais , Liberação Controlada de Fármacos , Feminino , Glutationa/metabolismo , Hipertermia Induzida , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Abnormal lipid accumulation in macrophages may lead to macrophages foaming, which is the most important pathological process of atherosclerosis. Atmospheric PM2.5 could enter the blood circulation and further affect the lipid metabolism of macrophages. But the underlying mechanism is not unclear. This study was undertaken to clarify the effect of PM2.5 on lipid metabolism in macrophages, and to explore the role of inflammatory reaction and JAK2/STAT3 signaling pathway in this process. METHOD: Macrophages derived from THP-1 cells were exposed to PM2.5 (0,100,200,400 µg/mL) for 6 h and 12 h. STAT3 agonist ColivelinTFA is used to specifically excite STAT3. The survival rate of macrophages was detected by CCK-8. The lipid levels in macrophages were detected by colorimetry. The levels of inflammatory factors secreted by macrophages were detected by ELISA. Q-PCR was used to detect the mRNA expression levels, and Western Blot was used to detect the protein expression levels of JAK2/STAT3 pathway genes. RESULT: The survival rate of macrophages was reduced by PM2.5, and the levels of TG, T-CHO and LDL-C of macrophages exposed to PM2.5 were increased. PM2.5 led to the increasing level of IL-6 and the decreasing level of IL-4, and the JAK2/STAT3 signaling pathway was inhibited by PM2.5. Colivelin TFA significantly decreased the increasing levels of TG, T-CHO and LDL-C levels, and increased the decreasing mRNA levels of IL-4, and LPL induced by PM2.5 (p < 0.05). DISCUSSION: PM2.5 could cause the lipid accumulation of macrophages by inhibiting the JAK2/STAT3 signaling pathway, and inflammatory responses may be involved in this process.
Assuntos
Macrófagos , Transdução de Sinais , Humanos , Inflamação/induzido quimicamente , Janus Quinase 2/genética , Lipídeos , Material Particulado/toxicidade , Fator de Transcrição STAT3/genéticaRESUMO
BACKGROUND: Mono-2-ethylhexyl phthalate (MEHP) is a major metabolite of di (2-ethylhexyl) phthalate (DEHP). Our previous researches have shown that MEHP can induce lipid accumulation in preadipocytes, while, the underlying mechanism is unclear. The present study was undertaken to clarify the effect of Notch pathway on lipid accumulation induced by MEHP. METHODS: 3T3-L1 preadipocytes were exposed to MEHP (0, 10, 50, 250 µM and 0.1%DMSO) for the whole differentiation phase. Then the level of TG and cell cycle were detected. RT-PCR was used to detect the mRNA expression and Western blot was used to detect the expression of protein by Notch pathway genes and lipid metabolic related genes. RESULTS: In this study, the level of TG in the 250 µM and 250 µM MEHP groups was significantly higher than that in the control, DMSO and 10 µM MEHP groups (P < 0.05). The relative mRNA level of Notch-1, Notch-3, Notch-4, Jagged-2 and Dll-4 in 250 µM group was higher than other groups (P < 0.05). The expression of Notch signal pathway proteins increased in MEHP treated groups, and the expression of Notch-2, Jagged-1, Jagged-2, Dll-1 and Dll-4 in 250 µM group were significantly higher than control group (P < 0.05). The expression of lipid metabolic related gene mRNA and protein increased in MEHP treated groups, and 250 µM MEHP group was higher than other groups (P < 0.05). The intracellular TG content was significantly correlated with the expression levels of Notch-1 and Jagged-2 mRNA (P < 0.05). CONCLUSION: In this study, we have found that MEHP exposure could increase the TG content in 3T3-L1 cells. The expression of Notch pathway mRNA and proteins were disturbed by the MEHP. Notch-1 and its ligand Jagged-2 play a critical role in the abnormal lipid metabolism in 3T3-L1 cells caused by MEHP.
Assuntos
Dietilexilftalato/análogos & derivados , Substâncias Perigosas/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Animais , Diferenciação Celular , Divisão Celular , Dietilexilftalato/toxicidade , Camundongos , Ácidos Ftálicos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Coronary computed tomography angiography (CCTA) is a noninvasive imaging modality to detect and diagnose coronary artery disease. Due to the limitations of equipment and the patient's physiological condition, some CCTA images collected by 64-slice spiral computed tomography (CT) have motion artifacts in the right coronary artery, left circumflex coronary artery and other positions. OBJECTIVE: To perform coronary artery motion artifact correction on clinical CCTA images collected by Siemens 64-slice spiral CT and evaluate the artifact correction method. METHODS: We propose a novel method based on the generative adversarial network (GAN) to correct artifacts of CCTA clinical images. We use CCTA clinical images collected by 64-slice spiral CT as the original dataset. Pairs of regions of interest (ROIs) cropped from original dataset or images with and without motion artifacts are used to train the dual-zone GAN. When predicting the CCTA images, the network inputs only the clinical images with motion artifacts. RESULTS: Experiments show that this network effectively corrects CCTA motion artifacts. Regardless of ROIs or images, the peak signal to noise ratio (PSNR), structural similarity (SSIM), mean square error (MSE) and mean absolute error (MAE) of the generated images are greatly improved compared to those of the input data. In addition, based on scores from physicians, the average score for the coronary artery artifact correction of the output images is higher. CONCLUSIONS: This study demonstrates that the dual-zone GAN has the excellent ability to correct motion artifacts in the coronary arteries and maintain the overall characteristics of CCTA clinical images.
Assuntos
Artefatos , Angiografia por Tomografia Computadorizada , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Humanos , Movimento (Física) , Razão Sinal-Ruído , Tomografia Computadorizada por Raios X/métodosRESUMO
The CNT-PDMS composite has been widely adopted in flexible devices due to its high elasticity, piezoresistivity, and biocompatibility. In a wide range of applications, CNT-PDMS composite sensors were used for resistive strain measurement. Accordingly, the percolation threshold 2%~4% of the CNT weight ratio in the CNT-PDMS composite was commonly selected, which is expected to achieve the optimized piezoresistive sensitivity. However, the linear range around the percolation threshold weight ratio (2%~4%) limits its application in a stable output of large strain (>20%). Therefore, comprehensive understanding of the electromechanical, mechanical, and electrical properties for the CNT-PDMS composite with different CNT weight ratios was expected. In this paper, a systematic study was conducted on the piezoresistivity, Young's modulus, conductivity, impedance, and the cross-section morphology of different CNT weight ratios (1 to 10 wt%) of the CNT-PDMS composite material. It was experimentally observed that the piezo-resistive sensitivity of CNT-PDMS negatively correlated with the increase in the CNT weight ratio. However, the electrical conductivity, Young's modulus, tensile strength, and the linear range of piezoresistive response of the CNT-PDMS composite positively correlated with the increase in CNT weight ratio. Furthermore, the mechanism of these phenomena was analyzed through the cross-section morphology of the CNT-PDMS composite material by using SEM imaging. From this analysis, a guideline was proposed for large strain (40%) measurement applications (e.g., motion monitoring of the human body of the finger, arm, foot, etc.), the CNT weight ratio 8 wt% was suggested to achieve the best piezoresistive sensitivity in the linear range.
Assuntos
Monitorização Fisiológica , Nanotubos de Carbono , Módulo de Elasticidade , Elasticidade , Condutividade Elétrica , Humanos , Resistência à TraçãoRESUMO
In this paper, ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS)-based metabolomics approach was used to explore the mechanism of Danggui Buxue Tang(DBT) in treating type 2 diabetes mellitus(T2 DM). T2 DM mice model was induced by high-sugar and high-fat fodder and streptozotocin(STZ). The routine indexes such as body weight, blood glucose, plasma insulin, IL-6 and related organ indexes were determined. The UHPLC-Q-TOF-MS technique was used to analyze the metabolism profile of serum samples between the control group and model group, and multiple statistical analysis methods including principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were used to screen and identify biomarkers. Metabolic profiling revealed 16 metabolites as the most potential biomarkers distinguishing mice in model group from those in control group. The metabolomics pathway analysis(MetPA) was used to investigate the underlying metabolic pathways. Seven major metabolic pathways such the valine, leucine and isoleucine biosynthesis, glycerophospholipid metabolism, primary bile acid biosynthesis, taurine and hypotaurine metabolism, phenylalanine metabolism, fatty acid metabolism and biosynthesis of unsaturated fatty acid. Eleven metabolites such as taurocholic acid and palmitic acid were down-regulated in T2 DM mice, and five metabolites such as L-leucine and leukotriene E4 were up-regulated. Moreover, the sixteen biomar-kers of each administration group had a trend of returning to mice in control group. The significantly-altered metabolite levels indicated that DBT can improve the progression of type 2 diabetes by increasing insulin sensitivity, regulating sugar and lipid metabolism disorders, and relieving inflammation.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolômica , Animais , Biomarcadores/metabolismo , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Espectrometria de Massas , CamundongosRESUMO
In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.
Assuntos
Adenosina/metabolismo , Neoplasias/metabolismo , Evasão Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Humanos , Imunoterapia , Neoplasias/terapiaRESUMO
BACKGROUND: Epidemiological studies have confirmed atmospheric PM2.5 could affect asthma, and dyslipidemia may be related to pathogenesis of asthma. Recent studies show Notch ligands had lipid combination domains which are responsible for regulating lipid levels. However, the effect of PM2.5 on asthmatic rats' lipid levels and the role of Notch signaling pathway is unclear. METHODS: Rats were treat with ovalbumin (OVA) to establish asthma models. Notch signaling pathway inhibitor (DAPT) was injected intraperitoneally. Asthmatic and healthy rats were exposed to different concentrations of PM2.5. Lung tissues were collected and the expression of Hes1 protein was detected by Western Blot. Blood samples were collected to detect the serum lipid levels. RESULTS: Hes1 expression levels in healthy and asthma pathway inhibition groups were lower than those in control groups. Compared with control group, rats exposed to PM2.5 in middle and high dose, the levels of TG and TC were decreased. Similar results were observed after exposure to the same concentration of PM2.5 in asthmatic rats. Rats, which were exposed to PM2.5 after being established the asthma model successfully, could exhibit more significant dyslipidemia than those with direct exposure. After Notch signaling pathway inhibited, TC and LDL in asthma pathway inhibition group were lower than those in healthy group. CONCLUSIONS: PM2.5 can affect the lipid levels of asthmatic rats through the Notch signaling pathway.
Assuntos
Asma/sangue , Dislipidemias/sangue , Expressão Gênica/efeitos dos fármacos , Material Particulado/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição HES-1/genética , Animais , Asma/induzido quimicamente , Asma/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diaminas/farmacologia , Modelos Animais de Doenças , Dislipidemias/induzido quimicamente , Dislipidemias/genética , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ovalbumina , Material Particulado/antagonistas & inibidores , Ratos , Ratos Wistar , Tiazóis/farmacologia , Fatores de Transcrição HES-1/metabolismo , Triglicerídeos/sangueRESUMO
Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200⯵M) for 24â¯h and 48â¯h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol. The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.
Assuntos
Dietilexilftalato/análogos & derivados , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Dietilexilftalato/toxicidade , Regulação para Baixo/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Janus Quinase 2/genética , Metabolismo dos Lipídeos/genética , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/genéticaRESUMO
Novel compounds and more efficient treatment options are urgently needed for the treatment of cystic echinococcosis (CE), which is caused by Echinococcus granulosus. The decoction of Sophora moorcroftiana (Fabaceae) has been used to treat parasitosis for years in traditional Tibetan medicine. The aim of this study was to screen insecticidal water-soluble alkaloids from S. moorcroftiana seeds and evaluate the therapeutic effects against CE and the immune response induced by the alkaloidal fraction. Low polarity compounds (E2-a) were isolated from water-soluble alkaloid (E2) and matrine and sophocarpine were identified as major components. The E2-a fraction was more effective against protoscoleces than other constituents from S. moorcroftiana. After 20 weeks of secondary infection with protoscoleces, mice were orally treated with E2-a (100 mg/kg/day) for 6 weeks to evaluate therapeutic and immunoregulatory activities. Compared with the untreated group, E2-a treatment induced a significant reduction in cyst weight (mean 2.93 g) (p < 0.05) and an impaired ultrastructural modification of the cyst. Interestingly, the application of E2-a resulted in a significant increased frequency of CD3+CD4+ T-cell subsets and decreased frequency of CD3+PD-1+ T-cell subsets, compared with protoscolece-infected mice without treatment. The E2-a fraction of S. moorcroftiana can inhibit the cyst development of CE and boost the specific immune response by reducing the expression of PD-1 and accelerate the cytokine secretion of antigen-specific T-cells. All data suggest the E2-a fraction from S. moorcroftiana seeds may be used as a new potential therapeutic option against E. granulosus infection.
Assuntos
Alcaloides/farmacologia , Anticestoides/farmacologia , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sophora/química , Animais , Equinococose/virologia , Feminino , Camundongos , Sementes/química , Organismos Livres de Patógenos EspecíficosRESUMO
OBJECTIVE: This work aimed to develop an alternative sustained-release thermosensitive praziquantel-loaded nanoemulsion (PZQ-NE) hydrogel for better schistosomiasis treatment. SIGNIFICANCE: PZQ-NE-dispersed chitosan/glycerol 2-phosphate disodium/HPMC (NE/CS/ß-GP/HMPC) hydrogel was successfully prepared to improve bioavailability of PZQ. METHODS: Solubility tests and pseudo-ternary phase diagrams were applied to screen optimal oils, surfactants and co-surfactants of NE. The hydrogels were characterized for gelling time, surface exudates, rheological properties and in vitro drug release. Formulation optimization of NE/CS/ß-GP/HMPC hydrogel was conducted by Box-Behnken experimental design combined with response surface methodology. In vitro cytotoxicity of hydrogel was studied by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The sustained-release property of PZQ in NE and optimized hydrogel was evaluated by pharmacokinetic study in rabbits. RESULTS: The formulation of PZQ-NE consisted of mass ratio of 12.5% capryol 90 containing PZQ (160 mg/g), 40% cremophor RH 40/tween 20 and transcutol HP (S/CoS = 2:1), 47.5% deionized water. PZQ releasing from NE/CS/ß-GP/HMPC hydrogels was best fitted to Higuchi model and governed by diffusion. Rheological investigation evidenced the themosensitive gelation of different hydrogel systems and their gel-like character at 37 °C. The optimized hydrogel formulation consisted of HPMC solution (103.69 mg/g), 3.03% (w/v) chitosan and 14.1% (w/v) ß-GP showed no cytotoxicity when the addition of NE was no more than 100 mg/g. Pharmacokinetic parameters indicated that NE/CS/ß-GP/HMPC hydrogel can significantly slow down drug elimination, prolong mean residence time and improve bioavailability of PZQ. CONCLUSIONS: NE/CS/ß-GP/HMPC hydrogel possessed sustained-release property and could be an alternative antischistosomal drug delivery system with improved therapeutic effect.
Assuntos
Preparações de Ação Retardada/química , Emulsões/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Nanopartículas/química , Praziquantel/química , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Quitosana/química , Preparações de Ação Retardada/metabolismo , Feminino , Glicerofosfatos/química , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Masculino , Praziquantel/metabolismo , Coelhos , Reologia , Solubilidade , Soluções/química , Tensoativos/química , TemperaturaRESUMO
In this study, mature female mice of the ICR strain were induced to superovultate, mated, and collected at either zygote or early morula stages. Embryos suspended in 1 M ethylene glycol in PBS containing 10 mg/L Snomax for 15 min, then transferred in sample holder to Linkam cryostage, cooled to and seeded at 7 °C, and then observed and photographed while being cooled to -70 °C at 0.5-20 °C/min. Intracellular ice formation (IIF) was observed as abrupt ''flashing''. Two types of flashing or IIF were observed in this study. Extracellular freezing occurred at a mean of -7.7 °C. In morulae, about 25% turned dark within ±1 °C of extracellular ice formation (EIF). These we refer to as "high temperature'' flashers. In zygotes, there were no high temperature flashers. All the zygotes flashed at temperatures well below the temperature for EIF. Presumably high temperature flashers were a consequence of membrane damage prior to EIF or damage from EIF. We shall not discuss them further. In the majority of cases, IIF occurred well below -7.7 °C; these we call ''low temperature'' flashers. None flashed with cooling rate (CR) of 0.5 °C/min in either zygotes or morulae. Nearly all flashed with CR of 4 °C/min or higher, but the distribution of temperatures is much broader with morulae than with zygotes. Also, the mean flashing temperature is much higher with morulae (-20.9 °C) than with zygotes (-40.3 °C). We computed the kinetics of water loss with respect to CR and temperature in both mouse zygotes and in morulae based on published estimates of Lp and it is Ea. The resulting dehydration curves combined with knowledge of the embryo nucleation temperature permits an estimate of the likelihood of IIF as a function of CR and subzero temperature. The agreement between these computed probabilities and the observed values are good.
Assuntos
Criopreservação/métodos , Gelo , Mórula , Zigoto , Animais , Crioprotetores/farmacologia , Etilenoglicol/farmacologia , Feminino , Congelamento , Cinética , Camundongos , Camundongos Endogâmicos ICR , TemperaturaRESUMO
OBJECTIVE: To observe different maintenance methods including vacuum-packing, storage together with tobacco, storage together with fennel, ethanol steam and sulfur fumigation for the protection of Codonopsis Radix against mildew and insect damage, and to analyze the content of polysaccharide and flavonoids of Codonopsis Radix tested in this studies, so as to look for the scientific maintenance methods replacing traditional sulfur fumigation. METHODS: Except for the sulfur fumigation, naturally air-dried Codonopsis Radix was used to investigate the maintenance effectiveness of the above methods, respectively. Mildew was observed by visual inspection, and the content of polysaccharide and flavonoids were determined by ultra-violet and visible spectrophotometer. Comprehensive evaluation was given based on the results of the different maintenance methods. RESULTS: Low-temperature vacuum-packing, ambient-temperature vacuum-packing and sulfur fumigation could keep Codonopsis Radix from mildew and insect damage for one year, but ambient-temperature vacuum-packing showed flatulent phenomenon; ethanol steam could keep Codonopsis Radix from mildew and insects for over half a year; storage together with tobacco or fennel did not have maintenance effect. The difference of polysaccharide and flavonoids contents of all tested Codonopsis Radix was not statistically significant. CONCLUSION: Low temperature vacuum-packing maintenance can replace traditional sulfur fumigation, and it can maintain the quality of Codonopsis Radix to a certain extent.
Assuntos
Codonopsis/química , Embalagem de Medicamentos/métodos , Armazenamento de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Plantas Medicinais/química , Flavonoides/análise , Fumigação , Raízes de Plantas/química , Polissacarídeos/análise , Controle de Qualidade , Enxofre/química , Tecnologia Farmacêutica/métodos , VácuoRESUMO
OBJECTIVE: To investigate the immune function of mice being given the extract of Codonopsis Radix maintained with sulfur fumigation. METHODS: Mice were divided into five groups. Except the normal control group, the mice were fed with the extract of Codonopsis Radix maintained with sulfur fumigation at the high,medium and low doses, as well as medium dose of Codonopsis Radix maintained with low-temperature vacuum method, respectively. Mice were treated once a day for 10 continuous days. Weight change,organ indexes, blood cell indices, macrophage phagocytic function, and IL-2 and IFN-γ levels were measured. RESULTS: Compared with normal control group, Codonopsis Radix maintained with sulfur fumigation at medium and high doses inhibited body weight increase of mice; white blood cell count of high dose group was significantly increased; significant increase of macrophage phagocytosis were observed for all groups except the normal control group; and spleen index and IFN-γ level of Codonopsis Radix maintained with sulfur fumigation medium dose group were increased significantly. CONCLUSION: Codonopsis Radix maintained with sulfur fumigation can promote mouse immune function to a certain degree. There was no difference in immune effect between Codonopsis Radix maintained with sulfur fumigation and low-temperature vacuum method during experimental period. However,taking the extract of Codonopsis Radix maintained with sulfur fumigation can exert negative effect on appetite and body weight in mice.