Astragaloside IV remodels gastric inflammation-cancer transformation by modulating the CXCL5-CXCR2 axis-mediated epithelial-mesenchymal transition.

Objective To evaluate the value of serum pepsinogen (PG) on atrophic gastritis and gastric cancer screening and to explore the best cut-off values of serum pepsinogen for atrophic gastritis screening in Weihai City. Methods Three hundred and sev-enty-four patients with gastroduodenal diseases were recruited, and these patients were divided into 4 groups based on endoscopic and histopathological findings:chronic superficial gastritis (CSG) group, chronic atrophic gastritis (CAG) group, gastric cancer (GC) group, and peptic ulcer (PU) group. The serum pepsinogen was detected by immunoturbidimetry. Results The PGI level and the PG Ⅰ/PGⅡ ratio (PGR) were significantly decreased in GC and CAG groups (P<0.01). The PGI level and PGR in GC and atrophic cor-pus gastritis groups were significantly different from the ones in atrophic antral gastritis group (P<0.01). The best cut-off values of the serum PGI and PGR for the atrophic gastritis screening were 76.50 ng/ml and 3.68, respectively. Conclusion The serum PGI and PGR automatic detection by immunoturbidimetry could be useful for screening gastric cancer and atrophic gastritis patients, and serum PGⅠ< 76. 50 ng/ml and PGR < 3.68 were the best cut-off values for atrophic gastritis screening in Weihai City. Key words: Pepsinogen; Atrophic gastritis; Gastric cancer; Immtmoturbidimetry; Best cut-off value

The protective role of Astragaloside IV in adriamycin-induced renal injury: A focus on macrophage polarization and PPARγ activation.

Epithelial‐mesenchymal transition (EMT) plays an important role in idiopathic pulmonary fibrosis (IPF). Astragaloside IV (ASV), a natural saponin from astragalus membranaceus, has shown anti‐fibrotic property in bleomycin (BLM)‐induced pulmonary fibrosis. The current study was undertaken to determine whether EMT was involved in the beneficial of ASV against BLM‐induced pulmonary fibrosis and to elucidate its potential mechanism. As expected, in BLM‐induced IPF, ASV exerted protective effects on pulmonary fibrosis and ASV significantly reversed BLM‐induced EMT. Intriguing, transforming growth factor‐β1 (TGF‐β1) was found to be up‐regulated, whereas Forkhead box O3a (FOXO3a) was hyperphosphorylated and less expressed. However, ASV treatment inhibited increased TGF‐β1 and activated FOXO3a in lung tissues. TGF‐β1 was administered to alveolar epithelial cells A549 to induce EMT in vitro. Meanwhile, stimulation with TGF‐β1‐activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway and induced FOXO3a hyperphosphorylated and down‐regulated. It was found that overexpression of FOXO3a leading to the suppression of TGF‐β1‐induced EMT. Moreover, ASV treatment, similar with the TGF‐β1 or PI3K/Akt inhibitor, reverted these cellular changes and inhibited EMT in A549 cells. Collectively, the results suggested that ASV significantly inhibited TGF‐β1/PI3K/Akt‐induced FOXO3a hyperphosphorylation and down‐regulation to reverse EMT during the progression of fibrosis.

Astragaloside IV attenuates glycated albumin-induced epithelial-to-mesenchymal transition by inhibiting oxidative stress in renal proximal tubular cells

Astragaloside IV attenuates lipopolysaccharide induced liver injury by modulating Nrf2-mediated oxidative stress and NLRP3-mediated inflammation

BackgroundChronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD.MethodsTo evaluate the effects of AS-IV, CD4+ T cells received different concentrations of AS-IV. CD4+ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4+ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues.ResultsAS-IV with concentration exceeding 40 µM inhibited CD4+ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1β, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression.ConclusionsAS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although chemotherapy is the primary means in colorectal cancer treatment, it is burdenerd by adverse drug effects. Drug-resistance is one of the most important challenges for chemotherapy and epithelial-mesenchymal transition (EMT) plays critical role in the development of drug resistance. Aims: The aim of this study was to investigate the mechanisms underlying the effect of astragaloside IV (AS-IV) on miR-134 expression, EMT and chemotherapeutic sensitivity in CRC. Methods: Cell proliferation, transfection assay, western blot, real-time PCR, cell migration and invasion assay and luciferase reporter assay were used to detect the effects of AS-IV on CRC. Results: AS-IV significantly inhibited CRC cell migration and invasion by inducing miR-134 expression. Moreover, AS-IV and miR-134 increased the sensitivity of CRC tumors to oxaliplatin (OXA) chemotherapy. cAMP responsive element-binding protein 1 (CREB1), which was required for CRC cells migration, invasion and drug sensitivity, was significantly down-regulated by AS-IV. Conclusions: Our results indicated that AS-IV inhibited CRC EMT by inducing miR-134 expression which significantly down-regulated the CREB1 signaling pathway, and therefore increased the sensitivity to chemotherapy. Our findings provided new insight into the mechanisms of chemotherapy-resistant CRC, and may open new therapeutic options in the treatment of this devastating disease.

Objective To investigate the expression and function of microRNA (miRNA, miR)-429 in human gastric precancerous lesions. Methods The expression of miR-429 in gastric cancer tissues (n=50), gastric tissues with chronic atrophic gastritis (n=60) and normal gastric tissues (n=60) was detected by real-time quantitative polymerase chain reaction (PCR). Human Gastric Epithelial cell strain-1 (GES-1) was transformed into gastric cancer precancerous lesion (PLGC) cell model by tumor necrosis factor-α (TNF-α). PLGC cells were detected by cell counting kit-8 (CCK-8) method using the miR-429 lentivirus and lentivirus negative control. The target gene of miR-429 was predicted by targetscan, and the expression level of target gene was deteceted by Western blotting. Results The expression of miR-429 in gastric tissue of 54 patients (90%, 54/60) with chronic atrophic gastritis was lower than that of normal gastric tissue, of which 37 cases (61.7%, 37/60) decreased more than 2 times. What’s more, the expression of miR-429 in the chronic atrophic gastric tissues with metaplasia and atypical hyperplasia was statistically much more significant (P=0.012). The expression of miR-429 in all gastric cancer tissues was lower than that in normal gastric tissues and chronic atrophic gastric tissues (all P=0.003), and the expression level was negatively correlated with lymph node metastasis, adjacent vascular invasion and TNM staging. The growth of PLGC cells was significantly inhibited at 5th day after transfection with miR-429, and the absorbance (0.852±0.023) was significantly reduced as compared with the control group (1.488±0.031, P=0.000). The expression of CDC25B in the transfection group (the target gene of miR-429 found by targetscan) was significantly lower than that of control group. Conclusion The expression of miR-429 in the gastric tissue of chronic atrophic gastritis and gastric cancer tissues was significantly down-regulated, and it could inhibit the development of gastric precancerous lesions to gastric cancer and the invasion and metastasis of gastric cancer. CDC25B might be the target gene of miR-429. Key words: Gastric precancerous lesions; Gastric cancer; Chronic atrophic gastritis; MicroRNA; Gene CDC25B

BackgroundSenescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson’s disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.MethodsLong culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP+)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers.ResultsWe found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP+-induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence.ConclusionsOur findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

Pulmonary fibrosis (PF) remains a devastating disease with limited therapeutic options. Astragaloside IV (AS-IV), a natural compound from Astragalus mongholicus (AM), has shown promise as a possible treatment for fibrosis. However, a systematic evaluation of its therapeutic efficacy and underlying mechanisms is lacking. This meta-analysis synthesizes preclinical evidence to assess the therapeutic potential of AS-IV in PF. Preclinical literature published before 16 August 2024, was systematically retrieved and screened across eight major databases, including PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Data Knowledge Service Platforms (Wanfang), China Science and Technology Journal Database (CQVIP), and China Biological Medicine Database (CBM). The risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool, and meta-analysis was conducted using STATA 18.0. The underlying mechanisms were also summarized. This systematic review and meta-analysis encompassed 23 in vivo animal studies comprising a total of 518 animals. The methodological quality scores of the included studies ranged from 3 to 6 points. The overall analysis demonstrated that AS-IV significantly reduced key indicators of PF in animal models, including PF score [SMD = -2.56, 95% CI (-3.47, -1.65), P < 0.01, I 2 = 72.6%]; pulmonary inflammation scores [SMD = -2.18, 95% CI (-3.09, -1.27), P < 0.01, I 2 = 70.2%]; hydroxyproline (HYP) content [SMD = -4.31, 95% CI (-5.67, -2.95), P < 0.01, I 2 = 83.1%]; lung index [SMD = -3.43, 95% CI (-4.75, -2.10), P < 0.01, I 2 = 79.5%]; and α-smooth muscle actin (α-SMA) levels [SMD = -4.79, 95% CI (-6.01, -3.56), P < 0.01, I 2 = 55.3%]. Sensitivity analyses confirmed the robustness of these results. However, the asymmetry observed in the funnel plot suggests potential publication bias. Further analysis revealed that AS-IV modulates key biomarkers involved in the epithelial-mesenchymal transition (EMT) process and mitigates extracellular matrix (ECM) remodeling. Additionally, AS-IV reduces the levels of inflammatory markers and oxidative stress indicators, thereby exerting a significant intervention in PF. This meta-analysis demonstrates that AS-IV consistently ameliorates BLM-induced PF through multiple mechanisms, including inhibition of EMT, ECM remodeling, inflammation, and oxidative stress. These findings support further investigation of AS-IV as a multi-target therapeutic agent for PF. identifier CRD42024604432.

Objective To investigate the expression of gastrin, cyclooxygenase-2(COX-2) and Ki-67 in dif-ferent gastric mucosal lesions and to assess the role of gastrin and COX-2 in the sequence of gastric carcinogenesis and its relationship. Methods 96 samples with different gastric mucosal lesions were obtained by gastroscope. The expression of gastrin,COX-2 and Ki-67 was examined with immunohistochemical staining technique(EnVision). Re-sults Positive rates of gastrin expression in chronic superficial gastritis (CSG), chronic atrophic gastritis (CAG), intestinal metaplasia(IM),dysplasia(Dy) and gastric cancer(GC) were 58.8 % ,30. 0% ,57.9 % ,68.2% and 77.8% ,respectively, and there were significant differences between GC and CAG(P<0.05). Positive rates of COX-2 expression in CSG,CAG,IM,Dy and GC were 41.2 % ,45.0% ,68.4 % ,72.7% and 88.9% respectively, andthere were significant differences between GC and CAG(P<0.05). Ki-67 proliferation index (PI) from CSG, CAG, IM, Dy to GC also had an increasing tendency. From CAG to GC,the expression of gastrin and COX-2 was positively correlated with PI (P<0.05). The expression between gastrin and COX-2 was correlated significantly in gastric pre-cancerous lesions (P<0.01). PI was increased significantly in group with co-expression of gastrin and COX-2. Con-clusion Gastrin expression is decreased in CAG. From CAG to GC, gastrin expression is increased gradually. COX-2 expression has an increasing tendency in the sequence of gastric cancerization. From CSG to GC, PI is gradually in-creased. Gastrin and COX-2 co-promote proliferation of gastric epithelial cells,and gastrin may take part in up-regu-lation of COX-2 expression in gastric precancerous. Key words: Gastric cancer; Gastrin; Cyclooxygenase-2; Precancerous

Background: Atrophic gastritis, a risk factor for gastric cancer, is a late consequence of Helicobacter pylori infection in approximately one-third of the infected patients. It has been suggested that gastric cancer would develop less frequently if H. pylori were eradicated. However, the prevalence of H. pylori infection may be underestimated in patients with atrophic gastritis and intestinal metaplasia if only biopsy-based diagnostic methods are used. Methods: We compared histology, 13C-urea breath test (13C-UBT), and serology in H. pylori diagnostics in 50 male patients with atrophic corpus gastritis. Results: H. pylori was detected in 15 (30%) patients by histology and in 14 (28%) by 13C-UBT, whereas increased serum antibody levels indicating H. pylori infection were found in 41 (82%) patients (P < 0.0001 between serology and both histology and 13C-UBT). H. pylori infection was associated with atrophic corpus gastritis in 84% of the present patients (in one patient with normal antibody titres H. pylori was defined histologically). Conclusions: H. pylori infection would have been missed in most patients with atrophic gastritis without the analysis of H. pylori antibodies. Therefore, in patients with atrophic gastritis, the use of serology is encouraged in diagnosing H. pylori infection.

This study aimed to explore the mechanisms by which Astragaloside IV (AS-IV), a major bioactive component of Astragalus membranaceus, mitigates high-glucose-induced peritoneal fibrosis (PF) in peritoneal dialysis (PD). Using both in vivo (uremic rat model) and in vitro (human peritoneal mesothelial cells) approaches, we observed that AS-IV treatment was associated with a significant attenuation of PF. This effect was mediated through the inhibition of epithelial-mesenchymal transition (EMT) and fibrosis. In vivo, AS-IV reduced extracellular matrix deposition and collagen accumulation, downregulated EMT and fibrosis markers (α-SMA, collagen IV), and restored E-cadherin levels. Notably, these changes correlated with the downregulation of ENKUR, pPI3K, and pAkt. The in vitro results corroborated these findings, showing that AS-IV suppressed EMT without cytotoxic effects. Our data indicate that AS-IV may exert antifibrotic effects via modulation of the ENKUR/PI3K/Akt signaling pathway, suggesting a potential target for the prevention of PF.

Objective To detect serum level of long noncoding RNA (lncRNA) BC200 in gastric cancer(GC) patients, and investigate its relationship with clinical features, and evaluate its diagnostic value for GC. Methods A case-control study was performed. From November 2014 to July 2015, serum levels of lncRNA BC200 were detected by real-time quantitative polymerase chain reaction in 124 patients with GC, 41 patients with atrophic gastritis and 59 normal controls who were hospitalized in Qilu Hospital of Shandong University. Meanwhile, serum carcinoembryonic antigen (CEA) and carbohydrate antigen 72-4 (CA72-4) were detected by electrochemical luminescence immunoassay. Serum levels of lncRNA BC200, before and 3, 7, 10, 30, 100 days after radical operation in another 31 patients with GC were determined. The sensitivity and specificity of serum lncRNA BC200, CEA and CA72-4 were analyzed by using of the receiver operating characteristic (ROC) curve. The comparison between two groups was performed with Mann-Whitney U test and the comparison among many groups was conducted with Kruskal-Wallis H test. Results Serum levels of lncRNA BC200 in GC patients with stage Ⅰ and Ⅱ[1.041(0.794, 1.462)]and stage Ⅲ and Ⅳ[1.290(0.978, 1.794)]were significantly higher than those in patients with precancerous lesion[0.969(0.699, 1.219)]and normal controls[0.801(0.556, 1.599)](H=54.68, P<0.000 1). Compared with pre-operation[1.120(0.859, 1.663)], the serum BC200 levels decreased significantly in 10 days[0.903(0.724, 1.182)](U=55.0, P<0.000 1), 30 days[0.759(0.671, 1.037)](U=299.0, P=0.026 1), and 100 days[0.478(0.378, 0.635)](U=41.0, P<0.000 1) after surgery. The area under the receiver operating characteristics curve(AUC) of serum lncRNA BC200 was 0.865 for GC diagnosis, which was significantly higher than that of serum CA72-4(AUC=0.699)or CEA(AUC=0.807). The AUC of combined detection of three tests was 0.934. Conclusion Serum lncRNA BC200 levels are significantly increased in GC patients, which may be used as a potential biomarker in GC diagnosis and monitoring.(Chin J Lab Med, 2017, 40: 138-142) Key words: Stomach neoplasms; RNA, long noncoding; Tumor markers, biological

How to Manage a Patient With Gastric Intestinal Metaplasia: An International Perspective