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1.
Acta Pharmaceutica Sinica ; (12): 242-250, 2022.
Article in Chinese | WPRIM | ID: wpr-913180

ABSTRACT

There are two serious obstacles to tumor immunotherapy. Firstly, the immune response of the tumor is seriously reduced due to immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumor. The second obstacle is the dense and complex heterogeneous structures, which seriously prevent the nanoparticles (NPs) from penetrating deeper into tumor tissue. Immunogenic cell death (ICD) induced by doxorubicin (DOX) is an effective method to enhance tumor immune activity. However, interferon-γ (IFN-γ) secreted by cytotoxic T lymphocytes (CTL) after ICD induction would increase the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and enhance ITM. IDO1 siRNA would reduce the expression of IDO1 protein, regulate the tumor immunosuppressive microenvironment and regulate ITM, so as to enhance the ICD effect of DOX. In this paper, a novel charge conversional, particle size reduction and highly penetrable NPs based on a pH sensitive copolymer poly(ethylene glycol)-poly-L-lysine-2,3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLD) and polyamidoamine (PAMAM) dendrimers to achieve deep delivery of tumor tissue. DOX and IDO1 siRNA were encapsulated to achieve efficient tumor immunotherapy. Preparation and cell level experiments showed that PLD material had significant pH sensitivity. Results of 3D tumor penetrable experiment in vitro showed that adding the pH sensitive material PLD significantly improved the permeability of the preparation. In addition, 4T1 tumor model was established for BALB/c mice and all animal experiments were displayed in according with the requirements of the Animal Experiment Ethics Committee of Shenyang Pharmaceutical University. The results of in vivo efficacy experiments and tissue experiments evaluated that IDO1 siRNA significantly improved the ICD effect owing to DOX, so as to significantly inhibit tumor growth.

2.
Acta Pharmaceutica Sinica ; (12): 109-121, 2022.
Article in Chinese | WPRIM | ID: wpr-913176

ABSTRACT

Cancer is considered as one of the major diseases endangering human health in the world, it is urgent to find a safer and more efficient treatment for cancer therapy. Gene therapy with ribonucleic acid (RNA) drugs could regulate the expression of tumor related genes, and exhibit good anti-tumor therapeutic potential in preclinical and clinical trials. Based on the differences between tumor tissues and normal tissues in microenvironment signal characteristics such as pH, specific enzyme concentration or redox gradient, various microenvironment responsive nanocarriers had been studied and developed to deliver RNA drugs to tumor tissues and cells, improving the anti-tumor efficacy of RNA drugs and reducing toxic and side effects. This paper reviews the pathophysiological characteristics of tumor microenvironment and various strategies of tumor microenvironment responsive nanocarriers, in order to provide reference for the design of safe and efficient RNA drug delivery system for cancer therapy.

3.
Acta Pharmaceutica Sinica ; (12): 188-199, 2022.
Article in Chinese | WPRIM | ID: wpr-913163

ABSTRACT

The non-specific accumulation and release of drugs are the main factors affecting the therapeutic effect as well as causing toxic side effects of chemotherapeutic drugs. Nowadays, the application of nanotechnology and responsive drug release is an important strategy to improve the tumor-specific accumulation of drugs and reduce their side effects. In this study, an α-enolase targeted peptide (ETP)-modified polyethylene glycol poly-lysine block copolymer loaded with oxaliplatin prodrug was synthesized first, and then, polymer-coating Fe3O4 nanoparticles were prepared by phase transfer dialysis method to improve the blood circulation stability and tumor targeting of oxaliplatin. At the same time, the physicochemical properties, reductant-responsive drug release, cellular uptake, tumor targeting and other biological functions of ETP modified oxaliplatin-loaded Fe3O4 nanoparticles were studied in vitro and in vivo. First, the results of reductant-triggered drug release study showed that the drug-loaded nanoparticles could achieve rapid release of more than 80% of the prototype oxaliplatin within 3 h under the reduction conditions simulating the tumor cytoplasmic microenvironment. Secondly, the results of flow cytometry showed that the modification of ETP could increase the ratio of cellular uptake of drug-loaded nanoparticles in tumor cells, and the way that drug-loaded nanoparticles endocytosed by tumor cells were mainly through the energy-dependent and receptor protein and fossin-mediated endocytosis pathway. The animal procedures were approved by the Institutional Animal Care and Use Committee of School of Pharmacy of Fudan University. Moreover, the results of pharmacokinetic experiment showed that the area under the curve (AUC0-∞) of oxaliplatin could be significantly increased by nano-formulation which was about 5 times than that of free oxaliplatin. Besides, the pharmacokinetic results also showed that the drug-loaded Fe3O4 nanoparticles constructed by covalent linkage and chelation had good overall stability in vivo. Finally, the in vivo imaging results showed that ETP modification could increase tumor accumulation of drug-loaded nanoparticles, which would be conducive to the efficacy of oxaliplatin in tumor lesions. In summary, the oxaliplatin-loaded Fe3O4 nanoparticles with the capability of reductant-responsive drug release have good drug release characteristics, blood circulation stability and tumor targeting ability, and have the potential to improve the anti-tumor therapeutic effect of oxaliplatin.

4.
Journal of Clinical Hepatology ; (12): 97-103, 2022.
Article in Chinese | WPRIM | ID: wpr-913159

ABSTRACT

Objective To investigate the value of transient elastography (TE) in the staging of hepatic fibrosis in patients with autoimmune liver disease (ALD). Methods PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP databases were searched for English and Chinese articles on TE in the staging of hepatic fibrosis in ALD published from January 2000 to January 2021. Two reviewers independently performed data extraction for the articles included, and QUADAS2 was used for quality assessment. The bivariate mixed effects model in Stata 15.0 software was used to perform the Meta-analysis. Results A total of 11 articles were included, with 1041 patients in total. In the diagnosis of significant hepatic fibrosis (F≥2), TE had a pooled sensitivity of 0.81 (95% CI : 0.75-0.86), a specificity of 0.87(95% CI 0.79-0.92), and an area under the receiver operating characteristic curve (AUC) of 0.91(95% CI 0.88-0.93); in the diagnosis of advanced hepatic fibrosis (F≥3), TE had a pooled sensitivity of 0.81(95% CI 0.74-0.87), a sensitivity of 0.90(95% CI 0.85-0.93), and an AUC of 0.92(95% CI 0.90-0.94); in the diagnosis of early-stage liver cirrhosis (F4), TE had a pooled sensitivity of 0.87(95% CI 0.74-0.93), a specificity of 0.93(95% CI 0.87-0.97), and an AUC of 0.96(95% CI 0.94-0.97). Conclusion TE has a good diagnostic value in evaluating significant liver fibrosis, advanced liver fibrosis, and early-stage liver cirrhosis in patients with ALD, especially with a relatively high diagnostic accuracy for early-stage liver cirrhosis.

5.
Journal of Clinical Hepatology ; (12): 220-223, 2022.
Article in Chinese | WPRIM | ID: wpr-913147

ABSTRACT

Immune checkpoint inhibitors can enhance the anti-tumor effect of T cells by blocking the negative regulatory signal of T cells, and meanwhile, they may also cause the imbalance of immune tolerance or normal immune hyperfunction, thus leading to immune hepatitis. This article mainly reviews the therapeutic mechanism of immune checkpoint inhibitors, their mechanism in causing the adverse reaction of liver injury, related risk factors, and incidence rate and summarizes the treatment methods for liver injury caused by immune checkpoint inhibitors. It is believed that while promoting anti-tumor immunity, immune checkpoint inhibitors may cause non-homogeneous immune-related liver injury due to the specificity of non-tumor tissue targets, and the main purpose of treatment is to restore immune homeostasis. Therefore, the management of patients using immune checkpoint inhibitors often requires a balance between treatment window, toxicity, and treatment of specific injury, as well as multidisciplinary collaboration.

6.
Article in Chinese | WPRIM | ID: wpr-940997

ABSTRACT

OBJECTIVE@#To investigate the introduction of vegetables and fruits in 4-8 months old infants, and to describe the maternal and infants' characteristics associated with the introduction of vegetables and fruits.@*METHODS@#Mother-infant dyads (n=228) were recruited from 12 to 16 weeks postpartum and formally entered the study at 4 months of age. Data collected via face to face interview at 4-8 months postpartum, including the timing and types of added vegetables and fruits, as well as a variety of maternal and infant characteristics (n=204). Rank sum test and multiple linear regression were used to analyze the maternal and infant characteristics related to the introduction of vegetables and fruits.@*RESULTS@#The time of introducing vegetables was concentrated at the age of 7 months, and the time of adding fruits was mainly at 6 months. Fruits were added earlier than vegetables (P < 0.001), and the variety of the added fruits was higher than that of vegetables (P=0.045). 48% (n=98) of infants had no more than three types of fruits and vegetables at 8 months. Only 9.8% (n=20) had added more than 10 kinds of fruits and vegetables at 8 months. Green leafy vegetables were the most commonly added vegetable, and apple was the most popular fruit. Compared with women who were 35 years of age or younger, women beyond 35 years old introduced vegetables to their babies 0.6 months later. 4-month-old exclusively breastfed infants had vegetables 0.4 months later than mixed-fed infants. Women with a bachelor's degree or above added 2-3 more types of fruits and vegetables to their babies than those with junior high school education and below.@*CONCLUSION@#The adding time of fruits was earlier than that of vegetable. Apples and green leafy vegetables are commonly added. Women with lower educational backgrounds add fewer types of fruits and vegetables to their babies. Mothers who choose exclusive breastfeeding and those over 35 years of age at childbirth add vegetables to their babies later than others. They should be targeted for health promotion programs that aim to improve the intake of fruits and vegetables among infants.


Subject(s)
Adult , Beijing , Breast Feeding , Female , Follow-Up Studies , Fruit , Humans , Infant , Infant, Newborn , Vegetables
7.
Chinese Journal of Oncology ; (12): 761-766, 2022.
Article in Chinese | WPRIM | ID: wpr-940936

ABSTRACT

Objective: To explore the surgical strategy of nipple areola complex (NAC) management in central breast cancer. Methods: A retrospective analysis was conducted on 164 cases of central breast cancer who underwent surgery treatment from December 2017 to December 2020 in the Breast Center of Beijing Tongren Hospital, Capital Medical University. Prior to the surgery, the tumor-nipple distance (TND) and the maximum diameter of the tumor were measured by magnetic resonance imaging (MRI). The presence of nipple invagination, nipple discharge, and nipple ulceration (including nipple Paget's disease) were recorded accordingly. NAC was preserved in patients with TND≥0.5 cm, no signs of NAC invasion (nipple invagination, nipple ulceration) and negative intraoperative frozen pathological margin. All patients with signs of NAC involvement, TND<0.5 cm or positive NAC basal resection margin confirmed by intraoperative frozen pathology underwent NAC removal. χ(2) test or Fisher exact test was used to analyze the influencing factors. Results: Of the 164 cases of central breast cancer, 73 cases underwent breast-conserving surgery, 43 cases underwent nipple-areola complex sparing mastectomy (NSM), 34 cases underwent total mastectomy, and the remaining 14 cases underwent skin sparing mastectomy (SSM). Among the 58 cases of NAC resection (including 34 cases of total mastectomy, 14 cases of SSM, and 10 cases of breast-conserving surgery), 25 cases were confirmed tumor involving NAC (total mastectomy in 12 cases, SSM in 9 cases, and breast-conserving surgery in 4 cases). The related factors of NAC involvement included TND (P=0.040) and nipple invagination (P=0.031). There were no correlations between tumor size (P=0.519), lymph node metastasis (P=0.847), bloody nipple discharge (P=0.742) and NAC involvement. During the follow-up period of 12 to 48 months, there was 1 case of local recurrence and 3 cases of distant metastasis. Conclusions: For central breast cancer, data suggest that patients with TND≥0.5cm, no signs of NAC invasion (nipple invagination, nipple ulceration) and negative NAC margin in intraoperative frozen pathology should be treated with NAC preservation surgery, whereas for those with TND<0.5 cm or accompanied by signs of NAC invasion, NAC should be removed. In addition, nipple reconstruction can be selected to further improve the postoperative appearance of patients with central breast cancer.


Subject(s)
Breast Neoplasms/surgery , Female , Humans , Mammaplasty/methods , Mastectomy/methods , Nipples/surgery , Retrospective Studies
8.
Article in Chinese | WPRIM | ID: wpr-940727

ABSTRACT

ObjectiveTo explore the inhibitory effect of Bushen Jiedu prescription (BSJDP) on the metastasis of colorectal cancer (CRC) via activation of M2 tumor-associated macrophages (M2-TAMs) in vivo. MethodThe model of xenograft tumor was established with C57BL/6 mice, and then the model mice were randomly assigned into blank control group, Bushen Jiedu recipe-low dose (11.2 g·kg-1) group (BSJDP-L), and Bushen Jiedu Recipe-high dose (22.4 g·kg-1) group (BSJDP-H). Tumors were abolished when the volume reached 1.5-2.0 cm3. The mice were sacrificed 28 days post tumor abolishing and then the lung metastasis was observed. Histopathological changes in lung metastasis were examined by hematoxylin-eosin (HE) staining of metastasis tissues, and immunofluorescence (IF) staining was employed to observe the effect of BSJDP on tumor apoptosis and hypoxia. Flow cytometry was performed to analyze the macrophages M1/M2 ratio of tumor tissue. The expression levels of the genes (Arg1, CD206, and CD163) associated with the polarization of M2-TAMs were determined by Real-time fluorescent quantitative polymerase chain reaction (Real-time PCR). ResultThe metastasis rate was 70%, 40%, and 10% in the blank control group, BSJDP-L group, and BSJDP-H group, respectively. The lower metastasis rates of BSJDP-L and BSJDP-H groups proved that BSJDP significantly inhibited lung metastasis of CRC. Compared with the blank control group, BSJDP-L and BSJDP-H reduced the tumor cell infiltration in tumor tissue (P<0.01), increased the apoptosis of tumor cells, alleviated the hypoxic environment, and down-regulated the expression of Arg1, CD206, and CD163 in the tumor tissue (P<0.01). In addition, the ratio of M2 macrophages ranked in a descending order of blank control group (34.867%) > BSJDP-L group (22.033%) > BSJDP-H group (11.633%) (P<0.01). ConclusionBSJDP inhibits the lung metastasis of CRC by inhibiting the activation of M2-TAMs in the tumor microenvironment.

9.
Article in Chinese | WPRIM | ID: wpr-940704

ABSTRACT

ObjectiveTo investigate the influencing factors of intestinal metaplasia or atypical hyperplasia in chronic atrophic gastritis (CAG) patients and establish a prediction model. MethodThe clinical records and laboratory examination data of 335 CAG patients treated in the department of gastroenterology of the Second Affiliated Hospital of the Anhui University of Chinese Medicine from June 2016 to June 2021 were collected. Single and multiple Logistic regression analyses were used to explore the influencing factors of intestinal metaplasia or atypical hyperplasia in CAG patients by SPSS 26.0. A prediction model was constructed based on the data of the related influencing factors. In addition, 115 CAG patients diagnosed in the First Affiliated Hospital of Anhui Medical University from June 2019 to June 2021 were selected as external validation samples to verify and evaluate the prediction efficiency of the constructed prediction model. ResultMultiple Logistic regression analysis showed that pepsinogen Ⅰ[odds ratio(OR) 0.994,95% confidence interval(CI) (0.990,0.999),P<0.05],the number of focus[OR 6.765,95% CI(3.831,11.945),P<0.01], and Helicobacter pylori (Hp) infection[OR 0.546,95% CI(0.335,0.888),P<0.05] were independent risk factors for intestinal metaplasia or atypical hyperplasia in CAG patients(P<0.05). The formula of the prediction model is as follows:P=-1.558+0.606×Hp infection-0.006×pepsinogen Ⅰ+1.912×the number of focus. The receiver operating characteristic (ROC) curve showed the specific parameters as below: the area under the ROC curve of 0.76,the Youden index of 0.443,the best cut-off value of 0.52,sensitivity of 0.533,and specificity of 0.910. The prediction model was applied to the data of patients in the validation group for validation,and the predictive efficiency of the model was tested by decision curve analysis (DCA). The results showed that the model had a good fit and high predictive value. ConclusionPepsinogen Ⅰ,the number of focus, and Hp infection are independent risk factors for intestinal metaplasia or atypical hyperplasia in CAG patients. The prediction model constructed based on these factors has a good fit and high predictive value,which can provide references for the classification of CAG patients and the formulation of individual treatment protocols.

10.
Article in Chinese | WPRIM | ID: wpr-940687

ABSTRACT

ObjectiveTo explore the effect of Xiao Xianxiongtang (XXXT) on the transforming growth factor (TGF)-β1-induced invasion, metastasis, and epithelial-mesenchymal transition (EMT) of gastric cancer MGC-803 cells and the underlying mechanism. MethodThe molecular docking between XXXT and nuclear factor of activated T cells (NFAT) was performed by CB-DOCK (http://clab.labshare.cn/cb-dock/). The invasion and metastasis model of MGC-803 cells was established with 10 μg·L-1 TGF-β1. MGC-803 cells were classified into blank group, model group, 0.1 g·L-1 XXXT group, 0.2 g·L-1 XXXT group, and 0.4 g·L-1 XXXT group. For further clarifying the key role of Wnt5a/Ca2+/NFAT signaling pathway in the inhibition of XXXT on gastric cancer, MGC-803 cells were transfected with Wnt5a overexpression plasmid, and then the cells were classified into blank plasmid group, Wnt5a-OE group, blank plasmid + XXXT (0.4 g·L-1) group, and Wnt5a-OE + XXXT (0.4 g·L-1) group. Cell viability was determined by cell counting kit-8 (CCK-8) assay, cell invasion and migration ability by Transwell invasion assay and wound healing assay, expression of EMT-related proteins (E-cadherin, N-cadherin, Vimentin, Snail) and Wnt5a/Ca2+/NFAT signaling pathway-related key proteins [Wnt5a, calcineurin (CaN), NFAT1, and p-NFAT1] by Western blot, and changes in intracellular Ca2+ concentration by immunofluorescence assay. ResultMolecular docking suggested that XXXT acted on Wnt5a/Ca2+/NFAT signaling pathway. XXXT (0.1, 0.2, 0.4 g·L-1) significantly promoted the loss of MGC-803 cell viability (P<0.05,P<0.01). It inhibited cells from invading the transwell lower chamber and slowed down the healing of cell wounds in a dose-dependent manner (P<0.05, P<0.01). Moreover, it promoted the expression of E-cadherin while suppressed the expression of N-cadherin, Vimentin, and Snail (P<0.05, P<0.01). Further experiments showed that XXXT could inhibit the expression of Wnt5a, CaN, NFAT1, and p-NFAT1, and reduce the nuclear expression of NFAT1 and the transcription activity mediated by NFAT1, so as to reduce the cellular Ca2+ concentration (P<0.05, P<0.01). XXXT can reverse the effect of Wnt5a (P<0.05, P<0.01). ConclusionXXXT can attenuate the invasion, metastasis, and EMT of MGC-803 cells via the Wnt5a/Ca2+/NFAT pathway, thereby weakening the tumor-promoting effect of TGF-β1. In summary, XXXT may exert therapeutic effect on gastric cancer by regulating the invasion, metastasis, and EMT of gastric cancer cells.

11.
Article in Chinese | WPRIM | ID: wpr-940633

ABSTRACT

ObjectiveTo optimize the extraction and purification process of Gardeniae Fructus for industrial production, and to obtain the total iridoid and total crocin extracts. MethodOrthogonal test was used to optimize the water extraction process by taking contents of geniposide, genipin gentiobioside, gardenoside, crocin-1 and crocin-2 as indicators and the decocting time, decocting times and water amount as factors. The purification process was optimized by single factor test, and four different types of macroporous adsorption resins were screened. The process conditions such as resin type, maximum loading amount, water washing amount, ethanol concentration, ethanol dosage, and flow rate of sample loading were mainly investigated. In addition, the drying methods (vacuum drying and spray drying) of the extract were investigated, and a pilot scale-up verification test was carried out. ResultThe optimal water extraction process of Gardeniae Fructus was to add 15, 10 times the amount of water for decocting twice, 1 h each time. The optimal purification process was as follows:the water extract through SP825L macroporous resin column, the amount of crude drug-the amount of resin (1∶1.5), the sample loading flow rate of 3 BV h-1, adding 2 BV of water to remove impurities, adding 4 BV of 30% ethanol to obtain the iridoid part, then adding 3 BV of 70% ethanol to obtain the crocin part, collecting the ethanol lotion, and drying at 70 ℃. Under these conditions, the extraction amount of total iridoids was 590.75 mg·g-1 with the transfer rate of 70.48%, and the yield of dry extract was 8.89%. The extraction amount of total crocins was 83.37 mg·g-1 with the transfer rate of 22.20%, and the dry extract yield was 2.60%. ConclusionThe optimized extraction and purification process is stable and feasible with high extraction rate of active components, which is suitable for the industrial extraction and purification of active parts of Gardeniae Fructus.

12.
Article in Chinese | WPRIM | ID: wpr-940621

ABSTRACT

ObjectiveTo explore the mechanism underlying the intervention of Gegen Qinliantang (GQL) in vulnerable plaques in atherosclerosis (AS) of ApoE-/- mice by regulating the polarization of macrophages. MethodTwelve normal C57BL/6CNC mice were used as the control group, and 60 ApoE-/- mice of the same line were randomized into 5 groups: model group, low-dose, middle-dose, and high-dose GQL groups (GQL-D, GQL-Z, and GQL-G groups, respectively), and atorvastatin group (western medicine group). High-fat diet was used for modeling. The control group and the model group were given (ig) equal volume of sterile distilled water, and GQL-D, GQL-Z, GQL-G, and western medicine groups received (ig) corresponding concentration of drugs for 8 weeks. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were detected with biochemical methods. The distribution of plaques in the aortic region was observed based on oil red O staining and hematoxylin-eosin (HE) staining. Serum levels of M1 pro-inflammatory factors tumor necrosis factor (TNF)-α and interleukin (IL)-6 and M2 anti-inflammatory factors IL-13 and transforming growth factor (TGF)-β were detected by enzyme-linked immunosorbent assay (ELISA). Protein expression of macrophage mannose receptor CD206/arginase-1 (Arg-1) and CD206/inducible nitric oxide synthase (iNOS) was determined by double-labeling immunofluorescence, and mRNA expression of aortic Arg-1 and iNOS by real-time polymerase chain reaction (PCR). ResultLevels of TG, TC, and LDL-C were significantly lower and HDL-C level was significantly higher in the GQL-Z, GQL-G, and western medicine groups than in the model group. As the concentration of GQL rose, the area with plaques gradually shrunk and the color became lighter. The staining areas of the GQL-G group and the western medicine group were the most scattered. The administration groups showed significant increase in the protein levels of Arg-1 and CD206, significant decrease in the protein level of iNOS, significant rise of Arg-1 mRNA level, and significant drop of iNOS mRNA level (P<0.05). ConclusionGQL intervenes in the vulnerable plaques in AS by improving lipid metabolism, inhibiting macrophage M1 polarization, promoting macrophage M2 polarization, and further improving the inflammatory microenvironment.

13.
Article in Chinese | WPRIM | ID: wpr-940620

ABSTRACT

ObjectiveThis study aims to explore the potential molecular mechanism of Gegen Qinliantang (GQL) in the intervention of atherosclerosis (AS) based on network pharmacology and molecular docking. MethodThe active components and targets of each medicinal in GQL were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and AS-related genes from 7 databases. Thereby, the anti-AS targets of GQL were screened out. Cytoscape 3.8.0 was employed to construct the "component-target" network, and STRING the protein-protein interaction (PPI) network. Core targets were screened out with CytoNCA. R clusterProfiler was used for Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of target genes, which were then visualized. Finally, molecular docking of the top ten active components with the core targets of AS was performed and the binding affinity was compared with that between atorvastatin and the core targets. ResultIn the end, 150 active components of GQL, 20 289 AS targets, and 213 common targets were retrieved, and 48 core common targets were screened out. They were mainly involved in the GO terms of nuclear receptor activity, ligand activation, and transcription factor activity and the pathways of fluid shear force and AS, advanced glycation end products-receptor for advanced glycation end products (AGE/RAGE), interleukin-17 (IL-17), tumor necrosis factor (TNF), Toll-like receptor pathways and other signaling pathways closely related to AS. The molecular docking results showed that the effective components of GQL had high binding affinity to core targets of AS, and the binding affinity was even higher than that between the atorvastatin and core targets. The five groups with high binding affinity were puerarin-TNF, baicalein-inducible nitric oxide synthase 2 (NOS2), puerarin-NOS2, and formononetin-NOS2, wogonin-NOS2. ConclusionThe above result provides new ideas for further exploration of this classical decoction.

14.
Article in Chinese | WPRIM | ID: wpr-940552

ABSTRACT

The increasing incidence of obesity and diabetes has made diabetic kidney disease (DKD) the main cause of chronic kidney disease and end-stage renal disease. Despite current pharmacological interventions for blood glucose control and renin-angiotensin system inhibition, the risk of kidney disease progression and complications remains high. At present, the pathogenesis of DKD has been clarified to be related to chronic inflammatory response, oxidative stress, glucose and lipid metabolism disorders, and hemodynamic abnormalities. According to recent studies, the programmed cell deaths (PCD) of renal intrinsic cells such as pyroptosis and necroptosis play a key role in the occurrence and development of DKD. Pyroptosis and necroptosis, the two newly discovered routes of PCD, can protect the hosts from being invaded by microbial pathogens, but their dysregulation is associated with multiple autoimmunity and autoinflammatory responses. Pyroptosis and necroptosis are closely interlinked and cross-regulated. Different from apoptosis, these two cellular suicide mechanisms cause membrane rupture and release of cell contents through their respective gasdermin D (GSDMD) and mixed lineage kinase domain-like protein (MLKL), with damage-associated molecular patterns (DAMPs) and inflammatory cytokines like interleukin-1β (IL-1β) involved to trigger inflammation, and chronic inflammatory responses are key factors leading to the progression of DKD. Traditional Chinese medicine (TCM) has long been employed for the prevention and treatment of DKD and the resulting clinical outcomes are remarkable. TCM has been proved to exert a protective effect against DKD by affecting the expression of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, receptor-interacting protein kinase 3 (RIPK3), and MLKL. This paper reviewed the relationship of pyroptosis and necroptosis with DKD and its intervention with TCM.

15.
Article in Chinese | WPRIM | ID: wpr-940529

ABSTRACT

ObjectiveIn order to explore the changes of chemical constituents in Plantaginis Semen before and after stir-frying, ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) was used to rapidly identify and semi-quantitatively analyze the differential components in Plantaginis Semen processed at different stir-frying time. MethodWaters ACQUITY UPLC BEH C18 column (2.1 mm×100 mm, 1.8 μm) was employed with the mobile phase of 0.1% formic acid aqueous solution (A)-acetonitrile (B) for gradient elution (0-1 min, 5%-10%B; 1-2 min, 10%-15%B; 2-10 min, 15%-20%B; 10-12 min, 20%-40%B; 12-13 min, 40%-100%B; 13-14 min, 100%-5%B; 14-15 min, 5%B), the flow rate was 0.3 mL·min-1, the column temperature was 40 ℃, and the injection volume was 3 μL. Electrospray ionization (ESI) was applied for mass spectrometric analysis under positive and negative ion modes, and the scanning range was m/z 50-1 500. MarkerLynx 4.1 software was used to find the differential compounds, and the intensity of each ion peak in samples with different stir-frying time was compared to study the content variations of these compounds. ResultA total of 20 components with potential significant differences were found, among which 17 were identified and 3 were unknown, mainly including phenylethanoid glycosides, iridoid glycosides, alkaloids and others. After processing, the peak intensities of 7 compounds, such as sucrose, geniposidic acid, verbascoside and plantagoguanidinic acid A, in Plantaginis Semen decreased. The peak intensities of orobanchoside, dianthoside and plantain D increased first and then decreased during the stir-frying process. The peak intensities of 10 compounds (decaffeoylacteoside, calceolarioside A, isoacteoside, etc.) increased, and 9 of them were newly generated components. ConclusionThe content and composition of the chemical components in Plantaginis Semen changed significantly after stir-frying, which may be related to the reduction of laxative effect and the enhancement of antidiarrheal and diuretic activities of Plantaginis Semen after stir-frying.

16.
Article in Chinese | WPRIM | ID: wpr-940527

ABSTRACT

ObjectiveA feedforward control model for dry granulation of polysaccharide components was established to guide the adjustment and optimization of critical process parameters (CPPs) in the design space, so as to reduce the impact of fluctuations in raw materials properties on the quality of medicines. MethodTaking Astragali Radix extract powder as the model drug, the design space of dry granulation CPPs was determined by Box-Behnken design. Astragali Radix mixed powder with different powder properties were prepared by mixture design, the variance inflation factor (VIF) was used to diagnose the multicollinearity of the powder properties, and principal component analysis (PCA) was used to extract the characteristic data of the model. Radial basis function neural network (RBFNN) was used to establish a feedforward control model for reflecting the relationship between the powder properties of polysaccharide components, dry granulation CPPs and one-time molding rate. ResultThe design space for dry granulation CPPs of polysaccharide components was 16-35 Hz for feeding speed, 10-23 Hz for roller speed, and 10-46 kg·cm-2 for roller pressure. The established RBFNN feedforward control model had a good predictive effect on the one-time molding rate of dry granulation of polysaccharide components, which could be used to guide the adjustment and optimization of CPPs in the design space, the relative error was 0.38%-6.73%, and the average relative error was 3.42%. ConclusionThe established feedforward control model can well reflect the relationship between the powder properties of the polysaccharide components, the dry granulation CPPs and the one-time molding rate of the granules, which can be used to guide the adjustment and optimization of CPPs in the design space, reduce the impact of material property fluctuation on product quality, and provide ideas for promoting the quality of traditional Chinese medicine from passive control to active control.

17.
Article in Chinese | WPRIM | ID: wpr-940497

ABSTRACT

ObjectiveTo explore the mechanism of herbal pair Astragali Radix-Puerariae Lobatae Radix (AR-PLR) against type 2 diabetes mellitus (T2DM) based on network pharmacology and experimental verification. MethodThe active ingredients and targets of AR and PLR were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The related targets of T2DM were retrieved from disease databases and the common targets of drugs and diseases were extracted. The protein-protein interaction (PPI) network was analyzed and constructed by STRING and the network topology of key targets was analyzed by Cytoscape 3.7.1. Then gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) enrichment analyses of core targets were carried out by DAVID to explore its possible molecular mechanism. The T2DM model was induced in rats by the high-fat diet combined with tail intravenous injection of streptozocin. The rats were divided into a normal group,a model group,a metformin group,and high-,medium- and low-dose AR-PLR groups. After four weeks of intragastric administration,the serum levels of fasting blood sugar (FBS),fasting insulin(FINS),aspartate aminotransferase(AST),alanine aminotransferase(ALT),triglyceride(TG),total cholesterol(TC),low-density lipoprotein cholesterin(LDL-C),high-density lipoprotein cholesterin (HDL-C),interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) of rats in each group were measured. The protein expression of insulin receptor substrate-2(IRS-2),phosphatidylinositol 3-kinase(PI3K),protein kinase B(Akt), and forkhead box transcription factor O1(FoxO1) in rat liver was detected by Western blot. ResultA total of 131 core targets of AR-PLR in the treatment of T2DM were screened out by network pharmacology, where Akt1,mitogen-activated protein kinase 1 (MAPK1),TNF-α,and IL-6 were critical. As revealed by KEGG enrichment analysis, AR-PLR exerted the hypoglycemic effect mainly through the PI3K/Akt,TNF, and FoxO signaling pathways. Compared with the model group,the high- and medium-dose AR-PLR groups showed reduced FBS and FINS levels and increased glycogen level (P<0.05,P<0.01),all the AR-PLR groups showed decreased levels of AST,ALT,TG, and LDL-C (P<0.05,P<0.01), the high- and low-dose AR-PLR groups showed decreased TC levels (P<0.05). Compared with the model group, the high- and medium-dose AR-PLR groups showed reduced levels of IL-6 and TNF-α(P<0.05,P<0.01), and the high-dose AR-PLR group showed increased expression of IRS-2, Akt, p-Akt, PI3K, and p-PI3K, and decreased expression of FoxO1 protein(P<0.05). ConclusionAR-PLR has the characteristics of multi-component,Multi-target and multi-pathway in the treatment of T2DM. This herbal pair may regulate the PI3K/Akt/FoxO1 signaling pathway through IL-6, TNF-α, and other targets to affect insulin resistance, glycogen synthesis, gluconeogenesis, glucose transport, inflammation, immune response, and other processes, thereby treating T2DM.

18.
Article in Chinese | WPRIM | ID: wpr-940422

ABSTRACT

ObjectiveTo study the possible molecular mechanism of baicalein (BAI)-mediated focal adhesion kinase (FAK) in the regulation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway to inhibit the proliferation and migration of gastric cancer HGC-27 cells. MethodThe gastric epithelial GES-1 cells and gastric cancer HGC-27 cells were respectively treated with BAI (0, 5, 15, 25, and 50 μmol·L-1) for 48 h, and then methyl thiazolyl tetrazolium (MTT) assay was adopted to detect effect of BAI on cell proliferation. Western blot (WB) was employed to detect the expression of FAK and the proteins related to epithelial-mesenchymal transition (EMT) and PI3K signaling pathway after intervention with different concentrations of BAI. The HGC-27 cells stably overexpressing FAK were constructed with lentivirus-mediated transfection technique, and the transfection of FAK was detected through WB and green fluorescent protein (GFP). The cells were divided into empty vector (NC) group, BAI group, FAK overexpression group, and BAI-treated FAK overexpression group, and cell proliferation activity was detected by MTT assay. The colony formation and cell migration were observed via colony formation assay and Transwell migration assay, respectively. The expression of proteins involved in EMT and PI3K signaling pathways were detected by Western blot. ResultCompared with the NC group, BAI (15, 25 and 50 μmol·L-1) inhibited the proliferation of HGC-27 cells in a dose-dependent manner (P<0.05, P<0.01) while did not affect that of GES-1 cells. BAI (5, 15 and 25 μmol·L-1) down-regulated the expression level of p-FAK (P<0.05, P<0.01). Compared with NC group, FAK overexpression group showed up-regulated expression level of FAK in HGC-27 cells. The HGC-27 cells in both NC group and FAK overexpression group had green fluorescence. Compared with NC group, BAI inhibited the growth, colony formation, and migration, while FAK overexpression promoted those of HGC-27 cells. The treatment of FAK overexpression group with BAI inhibited the enhancement of cell proliferation and migration (P<0.05). WB showed that compared with NC group, BAI (15, 25 μmol·L-1) significantly up-regulated the expression of E-cadherin protein and down-regulated that of Vimentin, Snail, p-PI3K, and p-Akt protein in HGC-27 cells (P<0.05, P<0.01). Compared with NC group, FAK overexpression group showed down-regulated expression of E-cadherin, up-regulated expression of p-FAK, Vimentin, and Snail, and increased ratios of p-FAK/FAK, p-PI3K/PI3K and p-Akt/Akt (P<0.05). This phenomenon would be reversed after BAI treatment. ConclusionBAI can affect the proliferation and migration of gastric cancer HGC-27 cells by mediating FAK to regulate PI3K/Akt signaling pathway.

19.
Article in Chinese | WPRIM | ID: wpr-940402

ABSTRACT

ObjectiveTo systematically analyze the chemical components of QiLing Wenshen (QLWS) formula and explore the key active components and mechanism of the formula in the treatment of polycystic ovary syndrome (PCOS). MethodThe chemical components of QLWS formula were systematically identified by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) combined with comparison with reference substances, literature data, and databases. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SwissADME were employed to screen the active components for network pharmacological analysis. SwissTargetPrediction, GeneCards, DisGeNET, and DrugBank were used to obtain the potential components and targets of the formula for the treatment of PCOS. The protein-protein interaction (PPI) network was constructed via STRING database for further screening of the core targets. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of core targets were carried out with DAVID database. Molecular docking was performed in MOE 2019. ResultA total of 90 components of QLWS formula were identified, and 32 active components and 45 core targets for treating PCOS were obtained. GO annotation obtained 429 terms and KEGG pathway enrichment screened out 110 signaling pathways, mainly involving phosphatidylin-ositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, estrogen signaling pathway, and hypoxia inducible factor-1 (HIF-1) signaling pathway. The molecular docking revealed that key active components in QLWS formula were icariin, salvianolic acid A\B\C, wogonin, magnoflorine, etc., which may play a role in treating PCOS through regulating mitogen-activated protein kinase 1 (MAPK1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 3 (MAPK3), etc. ConclusionThis study preliminarily predicted that several key active components of QLWS formula could treat PCOS via multiple targets and multiple pathways based on UPLC-Q-TOF/MSE and network pharmacology, which could provide ideas and references for the study of pharmacodynamic material basis and mechanism of action of the formula.

20.
Article in Chinese | WPRIM | ID: wpr-940346

ABSTRACT

ObjectiveTo study the effect and mechanism of Wuwei Xiaoduyin in treating rat renal mesangial cells (HBZY-1) induced by lipopolysaccharide (LPS) through the nuclear factor-κB (NF-κB) signaling pathway. MethodRat HBZY-1 cells were randomly assigned into the normal group, model group, benazepril (50 μmol·L-1) group, and high- and low-dose (2.75 and 0.69 g·kg-1) Wuwei Xiaoduyin groups. The normal group, model group, and benazepril group were treated with 10% normal rat serum, and the Wuwei Xiaoduyin groups with 10% medicated serum. Except the normal group, the other four groups were treated with LPS (100 ng·mL-1) for modeling in vitro. The changes of cell morphology were observed under optical microscope. The expression of NF-κB p65 was detected by immunofluorescence (IF) method. Methyl thiazolyl tetrazolium (MTT) colorimetry was employed to detect cytotoxicity and cell proliferation. The levels of interleukin-1β (IL-1β), intercellular adhesion molecule-1 (ICAM-1), laminin (LN), and fibronectin (FN) in cell supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of IL-1β, FN, and NF-κB p65 were measured by real-time fluorescence quantitative PCR. The protein levels of phosphorylated inhibitor of NF-κB kinase β (p-IKKβ), phosphorylated NF-κB inhibitor (p-IκBα), and NF-κB p65 were determined by Western blot. ResultCompared with the normal group, the modeling increased cell proliferation (P<0.01), elevated the levels of IL-1β, ICAM-1, LN, and FN in cell supernatant (P<0.01), and up-regulated the mRNA levels of IL-1β, FN, and NF-κB p65 (P<0.01) and the protein levels of p-IKKβ, p-IκBα, and NF-κB p65 (P<0.01). Such changes were recovered by benazepril and Wuwei Xiaoduyin (P<0.05, P<0.01). ConclusionWuwei Xiaoduyin can mitigate the inflammatory injury of renal mesangial cells induced by LPS by inhibiting the NF-κB signaling pathway.

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