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1.
Pharmacol Res ; 203: 107178, 2024 May.
Article in English | MEDLINE | ID: mdl-38583686

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.


Subject(s)
Bleomycin , Macrophage Activation , Macrophages , Animals , Humans , Male , Mice , Bleomycin/toxicity , Idiopathic Pulmonary Fibrosis/pathology , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/immunology , Janus Kinase 2/metabolism , Lung/pathology , Lung/metabolism , Lung/immunology , Lung/drug effects , Macrophages/metabolism , Macrophages/immunology , Mice, Inbred C57BL , Mice, Knockout , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/chemically induced , Receptors, Interleukin/metabolism , Signal Transduction , STAT3 Transcription Factor/metabolism , THP-1 Cells
2.
Int J Health Plann Manage ; 39(4): 993-1008, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38200625

ABSTRACT

INTRODUCTION: The benefits of involving patients and carers include improving health outcomes and safety, reducing costs and enhancing an open, accountable and equitable relationship between service providers and users. However, the willingness for involvement and participation is largely affected by a range of factors, including those at the micro, meso and macro levels. As the previous studies have given much attention to the factors at the individual level, it is worthwhile to explore the factors at the broader levels of the policy and institutional contexts. The objective of the research is to understand how the policy and institutional contexts in China affect how patients wish to be involved in their health care delivery. METHODS: An abductive research strategy was used to generate emergent hypotheses in the first stage of data construction. In the second stage of fieldwork, hypotheses were tested using the deductive approach. Three local hospitals in Shandong Province, China, were selected. The case study method was designed with qualitative methods of policy documents and interviews. Interviews included health professionals, health board managers, local administrators and service users. Thematic analysis and framework analysis were conducted. RESULTS: Four policy and institutional contexts were identified: insufficient policy support, the current institutional design of involving users, the heterogeneity of organisational autonomy and resources, as well as the demography of the population of service users. CONCLUSIONS: As a policy strategy at the state level, there is a lack of policy support for patient involvement and participation in the Chinese health system. The heterogeneity of the institutional context of health facilities plays a key role in affecting how patients wish to be involved in health care delivery.


Subject(s)
Delivery of Health Care , Health Policy , Humans , China , Delivery of Health Care/organization & administration , Patient Participation , Interviews as Topic , Qualitative Research , Male
3.
Bull Environ Contam Toxicol ; 112(2): 37, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38353759

ABSTRACT

The adsorption/desorption of Rhodamine B (RhB) on Polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC) microplastics (MPs) was investigated in this study. The results showed that RhB adsorption on the selected MPs was fast. The adsorption coefficients (Kd) of RhB were 2036 ± 129, 1557 ± 91, and 63 ± 8.5 L kg- 1 for PS, PP, and PVC, respectively. RhB adsorption on PS and PP increased with increasing temperature and decreasing ionic strength, whereas RhB adsorption on PVC showed a completely opposite trend. The binding strength of RhB on the three types of MPs was weak as demonstrated by the high total desorption percentage, which ranged from 79.59 ~ 89.39%. This study shows that PP and PS MPs can accumulate RhB in the aquatic environment and their potential combined toxic risks should be taken seriously.


Subject(s)
Microplastics , Water , Adsorption , Microplastics/toxicity , Plastics , Polypropylenes , Polystyrenes
4.
Curr Issues Mol Biol ; 45(2): 918-935, 2023 Jan 19.
Article in English | MEDLINE | ID: mdl-36826004

ABSTRACT

The clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 system (Cas9) has been used at length to optimize multiple aspects of germplasm resources. However, large-scale genomic research has indicated that novel variations in crop plants are attributed to single-nucleotide polymorphisms (SNPs). Therefore, substituting single bases into a plant genome may produce desirable traits. Gene editing by CRISPR/Cas9 techniques frequently results in insertions-deletions (indels). Base editing allows precise single-nucleotide changes in the genome in the absence of double-strand breaks (DSBs) and donor repair templates (DRTs). Therefore, BEs have provided a new way of thinking about genome editing, and base editing techniques are currently being utilized to edit the genomes of many different organisms. As traditional breeding techniques and modern molecular breeding technologies complement each other, various genome editing technologies have emerged. How to realize the greater potential of BE applications is the question we need to consider. Here, we explain various base editings such as CBEs, ABEs, and CGBEs. In addition, the latest applications of base editing technologies in agriculture are summarized, including crop yield, quality, disease, and herbicide resistance. Finally, the challenges and future prospects of base editing technologies are presented. The aim is to provide a comprehensive overview of the application of BE in crop breeding to further improve BE and make the most of its value.

5.
Int J Mol Sci ; 23(7)2022 Apr 05.
Article in English | MEDLINE | ID: mdl-35409377

ABSTRACT

Drought and salinity stresses are significant abiotic factors that limit rice yield. Exploring the co-response mechanism to drought and salt stress will be conducive to future rice breeding. A total of 1748 drought and salt co-responsive genes were screened, most of which are enriched in plant hormone signal transduction, protein processing in the endoplasmic reticulum, and the MAPK signaling pathways. We performed gene-coding sequence haplotype (gcHap) network analysis on nine important genes out of the total amount, which showed significant differences between the Xian/indica and Geng/japonica population. These genes were combined with related pathways, resulting in an interesting mechanistic draft called the 'gcHap-network pathway'. Meanwhile, we collected a lot of drought and salt breeding varieties, especially the introgression lines (ILs) with HHZ as the parent, which contained the above-mentioned nine genes. This might imply that these ILs have the potential to improve the tolerance to drought and salt. In this paper, we focus on the relationship of drought and salt co-response gene gcHaps and their related pathways using a novel angle. The haplotype network will be helpful to explore the desired haplotypes that can be implemented in haplotype-based breeding programs.


Subject(s)
Droughts , Oryza , Chromosome Mapping , Haplotypes/genetics , Oryza/genetics , Plant Breeding , Quantitative Trait Loci
6.
Lipids Health Dis ; 17(1): 203, 2018 Aug 29.
Article in English | MEDLINE | ID: mdl-30157856

ABSTRACT

BACKGROUND: FGF21 is a critical endogenous regulator in energy homeostasis and systemic glucose and lipid metabolism. Despite intensive study of the metabolic functions of FGF21, its important role in heart disease needs further exploration. Apoptosis induced by ox-LDL in vascular endothelial cells is an important step in the progress of atherosclerosis. METHODS: The effects of FGF21 treatment on apoptosis induced by ox-LDL were tested in HUVECs. The role of FGF21 in atherosclerosis was studied by evaluating its function in apolipoprotein E double knockout (apoE-/-) mice. RESULTS: We found that apoptosis in HUVECs was alleviated by FGF21 treatment. The effects of FGF21 were independent of the ERK1/2 pathway and were mediated through inhibition of the Fas signaling pathway. FGF21 suppressed the development of atherosclerosis, and the administration of FGF21 ameliorated Fas-mediated apoptosis in apoE-/- mice. CONCLUSION: FGF21 protects against apoptosis in HUVECs by suppressing the expression of Fas; furthermore, FGF21 alleviated atherosclerosis by ameliorating Fas-mediated apoptosis in apoE-/- mice.


Subject(s)
Apolipoproteins E/deficiency , Apoptosis , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Fibroblast Growth Factors/therapeutic use , fas Receptor/metabolism , Animals , Apolipoproteins E/metabolism , Apoptosis/drug effects , Cytoprotection/drug effects , Fibroblast Growth Factors/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Lipoproteins, LDL/pharmacology , MAP Kinase Signaling System/drug effects , Mice, Inbred C57BL , Mice, Knockout
7.
Med Sci Monit ; 22: 1999-2005, 2016 Jun 12.
Article in English | MEDLINE | ID: mdl-27289442

ABSTRACT

BACKGROUND Surgery combined with chemotherapy is an important therapy for non-small cell lung cancer (NSCLC). However, chemotherapy drug resistance seriously hinders the curative effect. Studies show that DNA repair genes ERCC1 and BRCA1 are associated with NSCLC chemotherapy, but their expression and mechanism in NSCLC chemotherapy drug-resistant cells has not been elucidated. MATERIAL AND METHODS NSCLC cell line A549 and drug resistance cell line A549/DDP were cultured. Real-time PCR and Western blot analyses were used to detect ERCC1 and BRCA1 mRNA expression. A549/DDP cells were randomly divided into 3 groups: the control group; the siRNA-negative control group (scramble group); and the siRNA ERCC1 and BRCA1siRNA transfection group. Real-time PCR and Western blot analyses were used to determine ERCC1 and BRCA1 mRNA and protein expression. MTT was used to detect cell proliferation activity. Caspase 3 activity was tested by use of a kit. Western blot analysis was performed to detect PI3K, AKT, phosphorylated PI3K, and phosphorylated AKT protein expression. RESULTS ERCC1 and BRCA1 were overexpressed in A549/DDP compared with A549 (P<0.05). ERCC1 and BRCA1siRNA transfection can significantly reduce ERCC1 and BRCA1 mRNA and protein expression (P<0.05). Downregulating ERCC1 and BRCA1 expression obviously inhibited cell proliferation and increased caspase 3 activity (P<0.05). Downregulating ERCC1 and BRCA1 significantly decreased PI3K and AKT phosphorylation levels (P<0.05). CONCLUSIONS ERCC1 and BRCA1 were overexpressed in NSCLC drug-resistant cells, and they regulated lung cancer occurrence and development through the phosphorylating PI3K/AKT signaling pathway.


Subject(s)
BRCA1 Protein/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , DNA Repair/genetics , DNA-Binding Proteins/genetics , Endonucleases/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , A549 Cells , Antineoplastic Combined Chemotherapy Protocols/pharmacology , BRCA1 Protein/biosynthesis , Cell Line, Tumor , DNA-Binding Proteins/biosynthesis , Down-Regulation/drug effects , Drug Resistance, Neoplasm/genetics , Endonucleases/biosynthesis , Female , Humans , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Transfection
8.
Tumour Biol ; 35(5): 4667-72, 2014 May.
Article in English | MEDLINE | ID: mdl-24420154

ABSTRACT

Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase, especially the rate-limiting determinant of telomerase activity. Accumulating evidence has suggested that TERT could modulate the expression of numerous genes including interleukin 6 (IL-6), an important cytokine for the development of lung cancer. It has been reported that TERT polymorphism rs2736100T/G is associated with increased susceptibility to non-small cell lung cancer (NSCLC). However, the mechanism remains unclear. In the current study, we investigated the association between rs2736100T/G and NSCLC in 1,552 NSCLC and 1,602 healthy controls. Data revealed that the prevalence of TG and GG genotypes were significantly elevated in patients than in controls (odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.01-1.39; p = 0.040 and OR = 1.46; 95% CI, 1.19-1.78; p < 0.001, respectively). The association was more prominent in patients with lung adenocarcinoma than those with squamous cell carcinoma (p = 0.039). When analyzing the function of the polymorphism, we observed a significantly augmented level of IL-6 in subjects with GG genotype than those with GT and TT genotypes. Interestingly, the upregulation of IL-6 by GG genotype was 2.3-fold higher in lung adenocarcinoma compared to squamous cell carcinoma. These results suggest that the rs2736100T/G polymorphism modulates IL-6 expression and may play a unique role in lung adenocarcinoma.


Subject(s)
Adenocarcinoma/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Interleukin-6/genetics , Lung Neoplasms/genetics , Polymorphism, Single Nucleotide , Telomerase/genetics , Adenocarcinoma/etiology , Adenocarcinoma of Lung , Adult , Aged , Carcinoma, Non-Small-Cell Lung/etiology , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Interleukin-6/blood , Lung Neoplasms/etiology , Male , Middle Aged , Up-Regulation
9.
Int Immunopharmacol ; 131: 111774, 2024 Apr 20.
Article in English | MEDLINE | ID: mdl-38489971

ABSTRACT

Corona Virus Disease 2019 (COVID-19) is an infectious disease that seriously endangers human life and health. The pathological anatomy results of patients who died of the COVID-19 showed that there was an excessive inflammatory response in the lungs. It is also known that most of the COVID-19 infected patients will cause different degrees of lung damage after infection, and may have pulmonary fibrosis remaining after cure. Macrophages are a type of immune cell population with pluripotency and plasticity. In the early and late stages of infection, the dynamic changes of the balance and function of M1/M2 alveolar macrophages have a significant impact on the inflammatory response of the lungs. In the early stage of pulmonary fibrosis inflammation, the increase in the proportion of M1 type is beneficial to clear pathogenic microorganisms and promote the progress of inflammation; in the later stage of fibrosis, the increase in the number of M2 type macrophages can inhibit the inflammatory response and promote the degradation of fibrosis. As a potential treatment drug for new coronavirus pneumonia, favipiravir is in the process of continuously carried out relevant clinical trials. This study aims to discuss whether the antiviral drug favipiravir can suppress inflammation and immune response by regulating the M1/M2 type of macrophages, thereby alleviating fibrosis. We established a bleomycin-induced pulmonary fibrosis model, using IL-4/13 and LPS/IFN-γ cell stimulating factor to induce macrophage M1 and M2 polarization models, respectively. Our study shows that favipiravir exerts anti-fibrotic effects mainly by reprogramming M1/M2 macrophages polarization, that is, enhancing the expression of anti-fibrotic M1 type, reducing the expression of M2 type pro-fibrotic factors and reprogramming it to anti-fibrotic phenotype. Aspects of pharmacological mechanisms, favipiravir inhibits the activation of JAK2-STAT6 and JAK2-PI3K-AKT signaling by targeting JAK2 protein, thereby inhibiting pro-fibrotic M2 macrophages polarization and M2-induced myofibroblast activation. In summary, favipiravir can reduce the progression of pulmonary fibrosis, we hope to provide a certain reference for the treatment of pulmonary fibrosis.


Subject(s)
Amides , COVID-19 , Pneumonia , Pulmonary Fibrosis , Pyrazines , Humans , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Bleomycin/adverse effects , Phosphatidylinositol 3-Kinases/metabolism , Macrophages , Inflammation/metabolism , Fibrosis , Pneumonia/metabolism , COVID-19/metabolism
10.
Int Immunopharmacol ; 132: 111999, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38581994

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.


Subject(s)
Idiopathic Pulmonary Fibrosis , Immunosuppressive Agents , Mice, Inbred C57BL , Monocytes , Tacrolimus , Tacrolimus/therapeutic use , Tacrolimus/pharmacology , Animals , Monocytes/drug effects , Monocytes/immunology , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/immunology , Idiopathic Pulmonary Fibrosis/pathology , Mice , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/pharmacology , Humans , Lymphocytes/drug effects , Lymphocytes/immunology , Immunity, Innate/drug effects , Indoles/therapeutic use , Indoles/pharmacology , Macrophages/drug effects , Macrophages/immunology , Disease Progression , Lung/pathology , Lung/drug effects , Lung/immunology , Cells, Cultured , Male , Cytokines/metabolism , Myofibroblasts/drug effects , Cell Differentiation/drug effects , Disease Models, Animal
11.
J Mater Chem B ; 11(12): 2778-2788, 2023 03 22.
Article in English | MEDLINE | ID: mdl-36891927

ABSTRACT

The development of hemostatic materials suitable for diverse emergency scenarios is of paramount significance, and there is growing interest in wound-site delivery of hemostasis-enhancing agents that can leverage the body's inherent mechanisms. Herein we report the design and performance of a biomimetic nanoparticle system enclosing tissue factor (TF), the most potent known blood coagulation trigger, which was reconstituted into liposomes and shielded by the liposome-templated CaCO3 mineralization. The mineral coatings, which mainly comprised water-soluble amorphous and vateritic phases, synergized with the lipidated TF to improve blood coagulation in vitro. These coatings served as sacrificial masks capable of releasing Ca2+ coagulation factors or propelling the TF-liposomes via acid-aided generation of CO2 bubbles while endowing them with high thermostability under dry conditions. In comparison to commercially available hemostatic particles, CaCO3 mineralized TF-liposomes yielded significantly shorter hemostasis times and less blood loss in vivo. When mixed with organic acids, the CO2-generating formulation further improved hemostasis by delivering TF-liposomes deep into actively bleeding wounds with good biocompatibility, as observed in a rat hepatic injury model. Therefore, the designed composite mimicry of coagulatory components exhibited strong hemostatic efficacy, which in combination with the propulsion mechanism would serve as a versatile approach to treating a variety of severe hemorrhages.


Subject(s)
Hemostatics , Thromboplastin , Rats , Animals , Thromboplastin/pharmacology , Liposomes/pharmacology , Carbon Dioxide , Blood Coagulation , Hemostatics/pharmacology , Hemorrhage
12.
Zhongguo Zhong Yao Za Zhi ; 37(21): 3236-9, 2012 Nov.
Article in Zh | MEDLINE | ID: mdl-23397720

ABSTRACT

OBJECTIVE: To optimize the process for preparing genipin with enzymolyzed geniposide by an orthogonal experiment. METHOD: The optimal enzymolysis process was selected by an orthogonal experiment, with the concentration of geniposide as the index as well as enzyme quantity, pH of enzymolysis solution, enzymolysis time and enzymolysis temperature as considerations. RESULT: The optimal hydrolysis conditions were as follow: rough genipin samples at the concentration of 40 g x L(-1) were selected and shook on a table concentrator at a speed of 100 r x min(-1), added with beta-glucosidase-geniposide 1 : 1 (weight proportion), with pH of enzymolysis solution at 4.5, hydrolyzation temperature at 50 degrees C, the conversion rate of genipin could reach 85.8%. CONCLUSION: The process is so stable and feasible that it can provide theoretical basis for the preparation of genipin with enzymolyzed geniposide.


Subject(s)
Iridoids/chemistry , Hydrolysis , Technology, Pharmaceutical
13.
Comput Intell Neurosci ; 2022: 9702112, 2022.
Article in English | MEDLINE | ID: mdl-35755758

ABSTRACT

With the increasing communication between countries, machine translation has become an important way of communication between ethnic groups in different language systems. In order to further improve the coverage mechanism and vocabulary translation quality of the machine translation model of neural network, this paper will study the machine translation English lexical analysis system based on simple recurrent neural network. In order to improve the effect of word alignment, marking and attention mechanism are introduced into the English lexical analysis model. The experimental results show that the tagging of named entity words in the system can reduce the problem of unregistered words. Combined with the attention mechanism, it can significantly improve the effect of word alignment and label recall. It not only improves the controllability of translation but also has a positive impact on the quality of translation and its application effect in specific scenes. The evaluation of translation quality indicators shows that the system can effectively improve the accuracy and quality of Chinese-English translation.


Subject(s)
Language , Translations , Humans , Natural Language Processing , Neural Networks, Computer , Vocabulary
14.
Dalton Trans ; 51(24): 9357-9368, 2022 Jun 21.
Article in English | MEDLINE | ID: mdl-35674094

ABSTRACT

Precise control of the structures and magnetic properties of a molecular material constitutes an important challenge to realize tailor-made magnetic function. Herein, we report that the ligand-directed coordination self-assembly of a dianionic cobalt(II) mononuclear complex and selective organic linkers has led to two distinct dicobalt(II) complexes, [Co2(pdms)2(bpym)3]·2MeCN (1) and [Co(pdms)(bipm)]2·3DMF (2) (H2pdms = 1,2-bis(methanesulfonamide)benzene; bpym = 2,2'-bipyrimidine; bimp = 1,4-bis[(1H-imidazol-1-yl)methyl]benzene). Structural analyses revealed that complexes 1 and 2 are discrete binuclear molecules containing two neutral {Co(pdms)} species bridged by bpym and bimp ligands, respectively, forming an exchange-coupled CoII2 dimer and a rare CoII2 metallocycle. Magnetic studies found that 1 exhibits considerable antiferromagnetic interactions transferred by the bpym bridge while negligible magnetic interactions in 2 due to the long bimp ligands. Interestingly, both the complexes show significant magnetic anisotropy and thus exhibit slow magnetic relaxation under an external dc field originating from spin-lattice relaxation. Detailed theoretical calculations were further applied to understand the magnetic interactions and magnetic anisotropy in 1 and 2. The foregoing results highlight that coordination solids with programmed structures and magnetic properties can be designed and prepared through a judicious selection of molecular complex building blocks and organic linkers.

15.
J Pestic Sci ; 47(3): 118-124, 2022 Aug 20.
Article in English | MEDLINE | ID: mdl-36479455

ABSTRACT

Fifteen novel pyridine carboxamide derivatives bearing a diarylamine-modified scaffold were designed, synthesized, and their antifungal activity was evaluated. Preliminary bioassay results showed that some of the synthesized compounds exhibited moderate to good in vitro antifungal activity. Further, compound 6-chloro-N-(2-(phenylamino)phenyl)nicotinamide (3f) displayed good in vivo antifungal activity against Botrytis cinerea. The enzymatic test on B. cinerea succinate dehydrogenase (SDH) showed that the inhibitory activity possessed by compound 3f equally matches that of thifluzamide. Molecular docking results demonstrated that compound 3f could commendably dock with the active site of SDH via stable hydrogen bonds and hydrophobic interactions, suggesting the possible binding modes of the title compounds with SDH. The results above revealed that the target compounds would be the leading fungicide compound for further investigation.

16.
Int Immunopharmacol ; 113(Pt A): 109424, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36461589

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause and characterized by excessive proliferation of fibroblasts and the irregular remodeling of extracellular matrix (ECM), which ultimately cause the severe distortion of the alveolar architecture. The median survival of IPF patients is 2-5 years. IPF patients are predominantly infiltrated by M2 macrophages during the course of disease development and progression. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition. In the process of M2 macrophage polarization, JAK2/STAT3 signaling plays a key role, thus, targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach to the potential treatment of IPF. Tacrolimus is a macrolide antibiotic that as a specific inhibitor of T-lymphocyte function and has been used widely as an immunosuppressant in human organ transplantation. In this study we explored the potential effect and mechanism of tacrolimus on pulmonary fibrosis in vivo and vitro. Here, we found that tacrolimus is capable of suppressing M2 macrophages polarization by inhibiting pro-fibrotic factors secreted by M2 macrophages. This effect further alleviates M2-induced myofibroblast activation, thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, recovering of lung function, ultimately relieving the progression of fibrosis in vivo. Mechanistically, we found that tacrolimus can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2. Our findings indicate a potential anti-fibrotic effect of tacrolimus by regulating macrophage polarization and might be meaningful in clinical settings.


Subject(s)
Bleomycin , Idiopathic Pulmonary Fibrosis , Macrophages , Tacrolimus , Humans , Bleomycin/adverse effects , Cytokines , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/immunology , Janus Kinase 2/immunology , Macrophages/drug effects , Macrophages/immunology , STAT3 Transcription Factor/immunology , Tacrolimus/pharmacology , Tacrolimus/therapeutic use
17.
Sci Adv ; 8(38): eabo0987, 2022 Sep 23.
Article in English | MEDLINE | ID: mdl-36129984

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that pyruvate kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor-ß1 (TGF-ß1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)-induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-ß1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-ß1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-ß type I receptor (TßR1), decreased TßR1 ubiquitination, and stabilized TßR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-ß1 signaling and is a key factor in fibrosis progression.

18.
Front Pharmacol ; 12: 722122, 2021.
Article in English | MEDLINE | ID: mdl-34675804

ABSTRACT

Objective: To compare the efficacy of various listed Chinese patent medicines combined with letrozole in the treatment of ovulation disorders using network meta-analysis (NMA). Methods: We conducted a systematic literature search in PubMed, Cochrane Central Register of Controlled Trials, Embase, Chinese Biomedical Literature, China National Knowledge Infrastructure, Wanfang, and VIP Information databases up to June 2020. Randomized controlled trials reporting Chinese patent medicine combined with letrozole for ovulation disorders were included. The Stata 13 and WinBUGS1.43 software were used for data analysis. Results: A total of 24 randomized controlled trials were included, involving 2,318 patients. The results showed that when compared with patients using only letrozole, the ovulation rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, or Dingkun Dan, and Fufan Xuanju capsules showed the greatest improvement; the pregnancy rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, or Dingkun Dan; and the endometrial thickness on the day of follicular maturity was greater in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, Bailing capsules, or Dingkun Dan. In terms of the sequencing of NMA results, Fufang Xuanju capsules combined with letrozole gave the best results in improving the ovulation rate and increasing the endometrial thickness, while Dingkun Dan combined with letrozole achieved the best results for improving the pregnancy rate. Conclusion: Letrozole combined with Chinese patent medicine is more effective than letrozole alone in the treatment of ovulation disorders. Fufang Xuanju capsules is good at improving the ovulation rate and increasing the endometrial thickness. Dingkun Dan is good at improving the pregnancy rate. The appropriate choice of treatment should be made according to the actual clinical situation. This study is registered with the International Prospective Register of Systematic Reviews (CRD42020200603).

19.
Acta Biochim Biophys Sin (Shanghai) ; 42(12): 847-53, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21062789

ABSTRACT

DNA immunization is an efficient method for high-affinity monoclonal antibody generation. Here, we describe the generation of several high-quality monoclonal antibodies (mAbs) against retinol-binding protein 4 (RBP4), an important marker for kidney abnormality and dysfunction, with a combination method of DNA priming and protein boost. The mAbs generated could bind to RBP4 with high sensitivity and using these mAbs, an immunocolloidal gold fast test strip was constructed. The strip can give a result in <5 min and is very sensitive with a detection limit of about 1 ng/ml. A small-scale clinical test revealed that the result of this strip was well in accordance with that of an enzyme-labeled immunosorbent assay kit currently available on the market. Consequently, it could be useful for more convenient and faster RBP4 determination in the clinic.


Subject(s)
Antibodies, Monoclonal/immunology , DNA/immunology , Gold Colloid , Immunization/methods , Kidney Diseases/pathology , Retinol-Binding Proteins, Plasma/immunology , Base Sequence , DNA/genetics , Enzyme-Linked Immunosorbent Assay/methods , Humans , Kidney Diseases/genetics , Reagent Kits, Diagnostic , Reagent Strips , Retinol-Binding Proteins, Plasma/genetics , Sensitivity and Specificity
20.
Acta Crystallogr C Struct Chem ; 75(Pt 7): 877-882, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-31271375

ABSTRACT

High-nuclearity metal clusters have received considerable attention not only because of their diverse architectures and topologies, but also because of their potential applications as functional materials in many fields. To explore new types of clusters and their potential applications, a new nickel(II) cluster-based mixed-cation coordination polymer, namely poly[hexakis[µ4-(2-carboxylatophenyl)sulfanido]di-µ3-chlorido-tri-µ2-hydroxido-octanickel(II)sodium(I)], [Ni8NaCl2(OH)3(C7H4O2S)6]n, 1, was synthesized using nickel chloride hexahydrate and mercaptobenzoic acid (H2mba) as starting reactants under hydrothermal conditions. The material was characterized by single-crystal X-ray diffraction (SCXRD), Fourier transform IR spectroscopy, thermogravimetric analysis, powder X-ray diffraction and X-ray photoelectron spectroscopy analysis. SCXRD shows that 1 consists of a hexanuclear nickel(II) [Ni6] cluster, dinuclear NiII nodes and a mononuclear NaI node, resulting in the formation of a complex covalent three-dimensional network. In addition, a tightly packed NiO/C&S nanocomposite is fabricated by sintering the coordination precursor at 400 °C. The uniform nanocomposite consists of NiO nanoparticles, incompletely carbonized carbon and incompletely vulcanized sulfur. When used as a supercapacitor electrode, the synthesized composite shows an extra-long cycling stability (>5000 cycles) during the charge/discharge process.

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