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1.
Journal of Preventive Medicine ; (12): 253-257, 2022.
Article in Chinese | WPRIM | ID: wpr-920762

ABSTRACT

Abstract@#As the largest human microecosystem, intestinal microorganisms participate in human material and energy metabolisms and pose a significant impact on human health. Diabetes mellitus is likely to cause imbalance of abundance and component alterations in intestinal microorganisms, and reduce the diversity and balance, leading to intestinal microflora dysregulation. It has been shown that intestinal microflora dysregulation may promote diabetes development and progression through the reduction of intestinal microbial metabolites, inflammatory reaction and insulin resistance. This review summarizes the involvement of intestinal microorganisms in the pathogenesis of diabetes through metabolites including short-chain fatty acid, bile acid and lipopolysaccharide, and describes the current status of intestinal microorganisms-mediated treatments for diabetes, so as to provide the theoretical basis for the researches on diabetes and intestinal microorganisms.

2.
Article in Chinese | WPRIM | ID: wpr-906284

ABSTRACT

Objective:To explore the effect of chemical compound of aconitum alkaloid on the lipopolysaccharide (LPS)-induced inflammatory response of RAW264.7 macrophages and investigate its mechanism. Method:The chemical compounds of Aconitum Kusnezoffii Reichb were collected from TCMSP database with consideration of oral bioavailability (OB)≥30% and drug-likeness (DL)≥0.18. The potential targets of each chemical component were predicted with use of Pubchem database and Swiss Target Prediction database. Rheumatoid arthritis (RA) targets were collected from GeneCards database and selected by intersection screening. Gene ontology (GO) classification enrichment and Pathway enrichment analysis were carried out with use of DAVID database. Cytoscape was used to construct "Chemical Compound-Potential Targets-Pathway-Disease" network. Protein-protein interaction (PPI) network was constructed by using STRING database and Cytoscape software. RAW264.7 macrophages were stimulated by LPS to establish macrophage inflammation model <italic>in vitro</italic>. Western blot was used to detect the effects of chemical compounds on the expression of tumor necrosis factor-<italic>α</italic> (TNF-<italic>α</italic>) and cyclooxygenase-2 (COX-2) in RAW264.7 cells induced by LPS, as well as on the expression of JAK kinase and nuclear transcription factor- kappa B (NF-<italic>κ</italic>B) signal pathway. Result:A total of 27 chemical compounds were obtained by searching TCMSP database and consulting literature (OB≥30%, DL≥0.18). 12 chemical compounds were obtained after screening. 177 potential targets were obtained after database prediction and screening, and 97 targets were obtained as potential targets for the treatment of RA after intersection between 177 potential targets and 4 329 RA targets. A total of 32 biological processes (BP), 5 cellular components (CC), and 12 molecular functions (MF) were enriched by DAVID database. The construction of network topology map showed that different chemical compounds can act on the same target and the same chemical compound can also act on different targets in the treatment of RA. Aconitum alkaloid can be connected with the same pathway through different targets or with different pathways through the same target, indicating that different targets may have synergistic effect, which fully reflected the complex multi-compound, multi-targets and multi-pathways mechanism. Different concentrations of LPS in stimulation (0-200 μg·L<sup>-1</sup>) can significantly up-regulate the expression of COX-2 protein in RAW264.7 macrophages (<italic>P</italic><0.05), indicating that the inflammatory model was successful. Compared with the normal group, the expression of TNF-<italic>α</italic> and COX-2 protein in the inflammatory model of RAW264.7 cells increased significantly(<italic>P</italic><0.05), while the expression of TNF-<italic>α</italic> and COX-2 protein in bulleyaconitine A(BLA), songorine, yunaconitine and karacoline groups decreased in varying degrees compared with the model group (<italic>P</italic><0.05). Compared with the normal group, the expression of IRAK4, NF-<italic>κ</italic>B, JAK1 and STAT3 in the inflammatory model of RAW264.7 cells were significantly increased (<italic>P</italic><0.05), while such levels in BulleyaconitineA, songorine, yunaconitine and Karacoline groups were significantly lower than those in the model group(<italic>P</italic><0.05). Conclusion:Based on systematic pharmacology and <italic>in vitro</italic> experiments, the related targets and signal pathways were analyzed to provide new insights into the pathogenesis of RA, reveal the molecular mechanism of aconitum alkaloid in the treatment of RA, and provide new ideas for the application of Mongolian medicine in modern medicine.

3.
Article in Chinese | WPRIM | ID: wpr-905957

ABSTRACT

Objective:To observe the activation of microglia and the expression of inflammatory factors in hippocampus of mice with depression-like behavior after mother-infant separation (MS) combined with lipopolysaccharide (LPS) stress, and to explore the possible anti-depression mechanisms of Wenyang (WY), Jieyu (JY), and Wenyang Jieyu (WYJY) prescriptions from the perspective of warming Yang and relieving depression. Method:Seventy offspring mice were randomly divided into a normal group (<italic>n</italic>=10), a LPS stress group (<italic>n</italic>=10), and a modeling group (<italic>n</italic>=50). After undergoing 8 h·d<sup>-1 </sup>mother-infant separation during postnatal day 5 (PD<sub>5</sub>)–PD<sub>14</sub>, mice in the modeling group were further divided into the MS + LPS group, WY group, JY group, WYJY group, and fluoxetine (FLU) group, with 10 in each group. The birth date of the offspring mice was recorded as PD<sub>0</sub>. The mice in the normal, LPS, and MS + LPS groups were fed a normal diet during PD<sub>21</sub>–PD<sub>90</sub>, while those in the other groups were treated with the mixtures of corresponding drugs and feed, followed by seven-day intraperitoneal injection of LPS since PD<sub>91</sub> for inducing depression. The depression-like behavior of mice in each group was detected in the open-field, O-maze, and social interaction tests. The protein expression of microglia-specific ionized calcium-binding adaptor molecule 1 (Iba-1) in the hippocampus was assayed by immunohistochemistry, and the mRNA expression of interleukin-1<italic>β </italic>(IL-1<italic>β</italic>), interleukin-6 (IL-6), tumor necrosis factor-<italic>α </italic>(TNF-<italic>α</italic>), Iba-1, and glucocorticoid receptor (GR) by real-time fluorescence quantitative PCR (Real-time PCR). Result:Compared with the normal group, the LPS group exhibited significantly reduced residence time at the central area within 5 min (<italic>P</italic><0.01) and shortened total exercise distance (<italic>P</italic><0.01). In the MS + LPS group, the open-arm activity time and the total activity distance decreased significantly (<italic>P</italic><0.01, <italic>P</italic><0.05), whereas the training, discrimination and exploration time increased significantly (<italic>P</italic><0.01). The expression of Iba-1 in hippocampal CA1 region of mice in the LPS and MS + LPS groups was remarkably elevated (<italic>P</italic><0.01). Compared with the LPS group, the MS + LPS group displayed significantly prolonged distance of 5-min exercise (<italic>P</italic><0.05), increased training, discrimination and exploration time (<italic>P</italic><0.05, <italic>P</italic><0.01), and up-regulated Iba-1 expression in hippocampal CA1 area (<italic>P</italic><0.01). As revealed by comparison with the MS + LPS group, both the total 5-min exercise distance (<italic>P</italic><0.01) and the training and discrimination time (<italic>P</italic><0.01, <italic>P</italic><0.05) of mice in each administration group was significantly shortened. The discrimination and exploration time of mice in the JY, WYJY, and FLU groups was significantly reduced (<italic>P</italic><0.01), and the expression of Iba-1 in hippocampal CA1 region of mice in each administration group was significantly down-regulated (<italic>P</italic><0.01). Conclusion:The warming Yang and relieving depression method helps to inhibit the occurrence and development of depression due to its efficacy in activating microglia in hippocampus of depression mice and lowering the expression of IL-1<italic>β</italic>, IL-6, and TNF-<italic>α</italic>.

4.
Article in Chinese | WPRIM | ID: wpr-875673

ABSTRACT

Objective To study the effect of nicotinamide mononucleotide (NMN) on the mortality of the lipopoly-saccharide (LPS)-induced endotoxic shock mouse model. Methods 10-week-old C57BL/6J male mice were randomly divided into groups, and were injected intraperitoneally (i.p.) with LPS (10 mg/kg) to induce endotoxic shock models. NMN was i.p. injected in three ways: (1) 0.5 h after modeling, doses of 10, 30, 100 and 300 mg/kg; (2) 0.5 h before modeling, doses of 30, 100, 300 and 600 mg/kg; or (3) 0.5 and 12 h after modeling, dose of 300 mg/kg each time. The death times of each group were recorded, and the survival curves were drawn. Results Compared with the solvent control group, NMN at different doses given 0.5 h after or before modeling didn’t improve the survival rate or delay the death time of endotoxic shock mice; But when given at 0.5 and 12 h 300 mg/kg after modeling, NMN accelerated the death of mice and increased the mortality of mice. NMN products by two manufacturers showed similar effects. Conclusion NMN has no therapeutic effect on LPS-induced endotoxic shock, and repeated administration of NMN after endotoxic shock will increase the mortality.

5.
International Eye Science ; (12): 411-416, 2021.
Article in Chinese | WPRIM | ID: wpr-873434

ABSTRACT

@#AIM: To explore the effect of lycium barbarum polysaccharides(LBP)on inflammatory response of human retinal pigment epithelial cells(ARPE-19)induced by lipopolysaccharide(LPS)and its possible signal pathway.<p>METHODS: ARPE-19 cells were stimulated by LPS <i>in vitro</i> to construct the inflammatory injury cell model. Primarily, the cells were divided into five groups randomly. The blank group was cultured in complete medium, and the LPS group was stimulated with complete medium containing 10μg/mL LPS for 24h. The low, medium and high concentration LBP groups were incubated with complete medium importing 0.1, 0.5 and 1mg/mL LBP for 24h separately, and then stimulated with complete medium containing 10μg/mL LPS for 24h. We used the CCK-8 method to observe the cell survival rate, real-time fluorescent quantitative PCR to detect the mRNA expression of inflammatory factors and Western blot to test the changes of phosphorylated protein within the signaling pathway of NF-κB/MAPK.<p>RESULTS: Compared with normal cells, the survival rate of ARPE-19 cells was decreased after the LPS stimulation. With the increase of exogenous LBP concentration, the survival rate of ARPE-19 cell was gradually increased, while the inflammatory factors expression of cytokines IL-1β, IL-6 and MCP-1 were reduced accompany with the phosphorylated proteins(p-p65, P-IκBα, p-JNK, p-ERK and p-p38)of NF-κB/MAPK signaling pathway were decreased.<p>CONCLUSION: LBP prevents LPS-induced inflammatory response of ARPE-19 by inhibiting the intracellular inflammatory factors and the phosphorylation of the related protein within NF-κB/MAPK signaling pathway.

6.
International Eye Science ; (12): 217-221, 2021.
Article in Chinese | WPRIM | ID: wpr-862414

ABSTRACT

@#AIM: To further explore effective drugs for dry eye treatment by isolating and culturing lacrimal gland epithelial cells<i> in vitro</i>, establishing a dry eye cell model and analyzing relevant inflammatory factors. <p>METHODS: Rabbit lacrimal gland epithelial cells were <i>in vitro</i> isolated and cultured, and the activity and purity of primary cells were identified by cell proliferation experiment and immunofluorescence experiment. In addition, 0.5 times IC<sub>50</sub> of lipopolysaccharide LPS and TNF-α were used respectively to stimulate rabbit lacrimal gland epithelial cells and then establish two dry eye cell models. Finally, through cell proliferation experiment, ELISA and flow cytometry, the biological characteristics of these two dry eye cell models were compared. <p>RESULTS:After 12h of culture, the primary cells of lacrimal gland epithelial cells basically adhered to the wall of culture bottles; and 48h later, the cells stretched and almost each of them presented a shape of a long triangle. The activity of primary cells of lacrimal gland epithelium was 92%, and the positive rate of marker Pan-rkeratin was more than 90%, which accorded with the experimental requirements. The IC<sub>50</sub> of LPS and TNF-α are 20μg/mL and 4.996ng/mL respectively. After 12h of intervention with LPS(10μg/mL)and TNF-α(2.5ng/mL), the cell activity of the two groups was significantly lower than that of control group(<i>P</i><0.01); compared between these two groups, the apoptosis rate of TNF-α group is higher than that of LPS group(<i>P</i><0.01). The levers of IL-1β and IL-6 in the cell supernatants of the two groups were significantly higher than those of the control group(<i>P</i><0.01); compared between the two groups, IL-1β and IL-6 in TNF-α group were significantly higher than those in LPS group(<i>P</i><0.01). It was suggested that TNF-α was superior to LPS in simulating inflammatory response of dry eye. <p>CONCLUSION: This study successfully established a relatively simple and rapid rabbit dry eye cell model with high cell purity and stability, which provided a more stable <i>in vitro</i> experimental model for the basic research on the function of rabbit lacrimal gland epithelial cells and dry eye.

7.
Article in English | WPRIM | ID: wpr-862226

ABSTRACT

@#BACKGROUND: Acute respiratory distress syndrome (ARDS) causes substantial mortalities. Alveolar epithelium is one of the main sites of cell injuries in ARDS. As an important kind of microRNAs (miRNAs), microRNA-145 (miR-145) has been studied in various diseases, while its role in ARDS has not been investigated. METHODS: Lipopolysaccharide (LPS) was intratracheally instilled to establish a rat ARDS model. Cytokines from bronchoalveolar lavage fluid (BALF) were measured using rat tumor necrosis factor-α and interleukin-6 enzyme-linked immunosorbent assay kits (R&D Systems), and the pathological structures were evaluated using hematoxylin and eosin (H&E) staining and transmission electron microscope; the lung miR-145 messenger RNA (mRNA) was detected using quantitative polymerase chain reaction. Bioinformatics focused on the target genes and possible pathways of gene regulation. RESULTS: A rat model of LPS-induced ARDS was successfully established. The miR-145 was down-regulated in the LPS-induced ARDS lung, and mitochondrial dysfunction was observed in alveolar epithelial cells, most obviously at 72 hours after LPS. TargetScan and miRDB databases were used to predict the target genes of miR-145. A total of 428 overlapping genes were identified, seven genes were associated with mitochondrial function, and Ogt, Camk2d, Slc8a3, and Slc25a25 were verified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, and Gene Ontology (GO) biological process was mainly enriched in signal transduction and transcription regulation. CONCLUSIONS: The miR-145 is down-regulated in LPS-induced ARDS, and affects its downstream genes targeting mitochondrial functions.

8.
Article in Chinese | WPRIM | ID: wpr-847092

ABSTRACT

BACKGROUND: Porcine pancreatic islet transplantation is a common treatment for diabetes mellitus, but inflammatory reaction and oxidative stress can lead to poor long-term effect. It has been confirmed that transplantation of porcine bone marrow mesenchymal stem cells with islets can improve graft function. However, it has not been reported that porcine bone marrow mesenchymal stem cells regulate the expression of miR-299-5p in islet cells to regulate the function and survival rate of islet β cells. OBJECTIVE: To investigate the effects of bone marrow mesenchymal stem cells in pigs on functional impairment of islet in pig by regulating the JNK/C-Jun pathway through the miR-299-5p/SIAH1 molecular axis. METHODS: Lipopolysaccharide was used to induce functional impairment of porcine islet cells, which were co-cultured with bone marrow mesenchymal stem cells for 24 hours. Interleukin-6, interleukin-1β, tumor necrosis factor-α, reactive oxygen species, superoxide dismutase and insulin levels in islet cells were detected by ELISA. Hoechst 33258 staining was used to observe apoptosis. Annexin V-FITC/PI was used to detect the apoptosis rate of porcine islet cells. Western blotting was used to detect the expression of SIAH1 and proteins associated with JNK/C-Jun pathway. The expression of miRNAs in porcine islet cells was detected by qPCR. The dual-luciferase reporter gene assay verified the targeting relationship between miR-299-5p and SIAH1. RESULTS AND CONCLUSION: (1) Bone marrow mesenchymal stem cells in pigs inhibited the up-regulation of interleukin-6, interleukin-1β, tumor necrosis factor-α, reactive oxygen species and pro-apoptotic effects, and also inhibited the down-regulation of superoxide dismutase and insulin secretion induced by lipopolysaccharide. (2) Bone marrow mesenchymal stem cells of pigs significantly upregulated miR-299-5p expression. miR-299-5p inhibited activation of the JNK/C-Jun pathway by down-regulating SIAH1 expression. (3) Results indicate that bone marrow mesenchymal stem cells of pigs inhibit the activation of the JNK/C-Jun pathway, inhibit the inflammatory response, oxidative stress and apoptosis of islet cells in pigs, and promote the secretion of insulin by regulating the miR-299-5p/SIAH1 axis, hereby improving the functional damage of porcine islet cells.

9.
Acta Pharmaceutica Sinica ; (12): 1544-1550, 2021.
Article in Chinese | WPRIM | ID: wpr-881551

ABSTRACT

Idiosyncratic drug-induced liver injury (IDILI) is an unpredictable serious adverse drug reaction, which only occurs in a minority of special susceptible individuals. Although the mechanism of IDILI has not been fully understood, several hypotheses have been proposed to explain the action mode and specific mechanism of IDILI. Of these hypotheses, inflammatory stress hypothesis is one of the most important theories. Under the condition of inflammatory stress, drugs interact with inflammation and mediate the occurrence of IDILI through a variety of mechanisms, which can induce the production of inflammatory cytokines, activate coagulation system, affect the activity of metabolites, induce cholestasis, affect mitochondrial damage, and others. This review will summarize the main mechanisms and influencing factors of IDILI mediated by inflammatory stress, in order to provide a reference for preclinical drug development and basic research on drug-induced liver injury.

10.
Acta Pharmaceutica Sinica B ; (6): 373-393, 2021.
Article in English | WPRIM | ID: wpr-881142

ABSTRACT

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

11.
Frontiers of Medicine ; (4): 292-301, 2021.
Article in English | WPRIM | ID: wpr-880958

ABSTRACT

The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA + LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the antiinflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, IκBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.


Subject(s)
Animals , Cytokines , Hyaluronic Acid , Lipopolysaccharides , Mice , NF-kappa B/metabolism , Signal Transduction , Toll-Like Receptor 4
12.
Article in English | WPRIM | ID: wpr-880649

ABSTRACT

OBJECTIVES@#Human periodontal ligament cells (hPDLCs) are important source of periodontal tissue reconstruction. Under chronic inflammation, the multi-directional differentiation potential and chemotaxis in hPDLCs are decreased. Therefore, inhibiting inflammatory microenvironment and improving the functional characteristics of stem cells can better promote periodontal tissue reconstruction. This study was to investigate the effect of astaxanthin (AST) on lipopolysaccharide (LPS)-induced inflammation in hPDLCs and the underlying mechanisms.@*METHODS@#hPDLCs were isolated and cultured in vitro, and vimentin and keratin immunocytochemical staining were used to identify hPDLCs. CCK-8 assay was used to measure the effects of AST (1, 5, 10, 20, 50, 100, and 200 μmol/L) on proliferation of hPDLCs. Quantitative RT-PCR (RT-qPCR) and ELISA were used to measure the mRNA and protein expression of inflammatory factors (IL-6, IL-1β, and TNF-α) in the control (Con) group, the LPS group, and the LPS+AST (5, 10, 20, and 50 μmol/L) group. Western blotting was used to detect the protein expression of IKBα, phosphorylated IKBα (p-IKBα), and p65 in the Con group, the LPS group, the AST (20 μmol/L) group, and the LPS+AST (20 μmol/L) group. After 10 μmol/L PDTC treatment, the mRNA and protein expressions of IL-6, IL-1β, and TNF-α were detected by RT-qPCR and ELISA.@*RESULTS@#Cell morphology and immunocytochemical staining showed that the cells were in line with the characteristics of hPDLCs. Treatment with AST could promote the proliferation of hPDLCs, which reached the peak at 20 μmol/L. The mRNA and protein expressions of IL-6, IL-1β, and TNF-α in the LPS group were higher than those in the Con group (all @*CONCLUSIONS@#AST promotes the proliferation of hPDLCs, which is related to suppression of LPS-induced the secretion of inflammatory factors via inhibiting the activation of NF-κB signaling pathway.


Subject(s)
Cells, Cultured , Humans , Inflammation/chemically induced , Lipopolysaccharides , NF-kappa B , Periodontal Ligament , Tumor Necrosis Factor-alpha/genetics , Xanthophylls
13.
Article in English | WPRIM | ID: wpr-880574

ABSTRACT

OBJECTIVE@#To demonstrate the anti-inflammatory activity of Brassica napus L. hydrosols (BNH) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells.@*METHODS@#Composition analysis of BNH was conducted via gas chromatography-mass spectrometry after BNH were extracted. The nitric oxide (NO) production was measured using the Griess assay. Prostaglandin E@*RESULTS@#Compared with LPS-stimulated cells, BNH markedly decreased the generation of NO and PGE@*CONCLUSION@#The anti-inflammatory activities of BNH were mediated via blockage of the NF-κB signaling pathways in LPS-stimulated RAW 264.7 cells.

14.
Article in English | WPRIM | ID: wpr-880536

ABSTRACT

OBJECTIVE@#To investigate the effects of emodin on inflammation and autophagy in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and reveal its underlying mechanism.@*METHODS@#3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was conducted to find the appropriate dose for emodin. RAW264.7 cells pretreated with different concentrations (0-50 μmol/L) of emodin or vehicle for 2 h prior to exposure to LPS for 16 h. Cell morphology was examined and propidium iodide staining was used to examine cell cycle. Expressions of inflammation-related proteins [nuclear factor-kappaB (NF-κ B) and I-kappaB (I κ B)α] and autophagy-related proteins [light chain (LC)3, P62/sequestosome 1, mammalian target of rapamycin (mTOR), and p-mTOR] were examined using Western blot analysis. Expression of inflammation-related cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were detected by enzyme-linked immunosorbent assay. Autophagy was examined with LC3B fluorescence intensity and aggregation. The effect of emodin on autophagy was conducted with an autophagy inhibitor, 3-methyladenine (3-MA).@*RESULTS@#The expression of NF-κ B in LPS-induced cells was significantly increased (P<0.01) and simultaneously I κ B α decreased compared with the normal cell (P<0.05). The expressions of TNF-α, IL-β, and IL-6 proteins in the LPS-induced RAW264.7 cells were significantly higher than in the normal cell (P<0.05 or P<0.01). LPS increased the percentage of cells in the G@*CONCLUSION@#Emodin could inhibit inflammation of mice RAW264.7 macrophages induced by LPS, possibly through activating autophagy.

15.
Acta Pharmaceutica Sinica B ; (6): 3060-3091, 2021.
Article in English | WPRIM | ID: wpr-922737

ABSTRACT

Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.

16.
Chinese Journal of Biotechnology ; (12): 3300-3309, 2021.
Article in Chinese | WPRIM | ID: wpr-921426

ABSTRACT

In Gram-negative bacteria, lipopolysaccharide transport (Lpt) protein LptA and LptC form a complex to transport LPS from the inner membrane (IM) to the outer membrane (OM). Blocking the interaction between LptA and LptC will lead to the defect of OM and cell death. Therefore, Lpt protein interaction could be used as a target to screen new drugs for killing Gram-negative bacteria. Here we used biolayer interferometry (BLI) assay to detect the interaction between LptA and LptC, with the aim to develop a method for screening the LptA/LptC interaction blockers in vitro. Firstly, LptC and LptA with or without signal peptide (LptAfull or LptAno signal) were expressed in E. coli BL21(DE3). The purified proteins were then labeled with biotin and the super streptavidin (SSA) biosensor was blocked with diluent. The biotin labeled protein sample was mixed with the sensor, and then the binding of the protein with a series of diluted non biotinylated protein was detected. At the same time, non-biotinylated protein was used as a control. The binding of biotinylated protein to a small molecule IMB-881 and the blocking of interaction were also detected by the same method. In the blank control, the biosensor without biotinylated protein was used to detect the serially diluted samples. The signal response constant was calculated by using steady analysis. The results showed that biotinylated LptC had a good binding activity with LptAfull and LptAno signal with KD value 2.9e⁻⁷±7.9e⁻⁸ and 6.0e⁻⁷±2.8e⁻⁸, respectively; biotinylated LptAno signal had a good binding activity with LptC, with a KD value of 9.6e⁻⁷±7.2e⁻⁸. All binding curves showed obvious fast binding and fast dissociation morphology. The small molecule compound IMB-881 can bind to LptA to block the interaction between LptA and LptC, but has no binding activity with LptC. In summary, we developed a method for detecting the LptA/LptC interaction based on the BLI technology, and confirmed that this method can be used to evaluate the blocking activity of small molecule blockers, providing a new approach for the screening of LptA/LptC interaction blockers.


Subject(s)
Carrier Proteins , Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Interferometry , Membrane Proteins/metabolism
17.
Acta Pharmaceutica Sinica B ; (6): 2880-2899, 2021.
Article in English | WPRIM | ID: wpr-888892

ABSTRACT

Aberrant activation of NLRP3 inflammasome in colonic macrophages strongly associates with the occurrence and progression of ulcerative colitis. Although targeting NLRP3 inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the intestinal inflammation is modulated remains controversial. By focusing on the flavonoid lonicerin, one of the most abundant constituents existed in a long historical anti-inflammatory and anti-infectious herb

18.
Acta Pharmaceutica Sinica B ; (6): 2859-2879, 2021.
Article in English | WPRIM | ID: wpr-888891

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ

19.
Acta Pharmaceutica Sinica B ; (6): 2798-2818, 2021.
Article in English | WPRIM | ID: wpr-888888

ABSTRACT

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

20.
Acta Pharmaceutica Sinica B ; (6): 2768-2782, 2021.
Article in English | WPRIM | ID: wpr-888886

ABSTRACT

Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1

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