Protective effects of panax notoginseng saponin on dextran sulfate sodium-induced colitis in rats through phosphoinositide-3-kinase protein kinase B signaling pathway inhibition.
三七总皂苷通过抑制蛋白激酶 B 信号通路对葡聚糖硫酸钠诱导的大鼠结肠炎 phosphoinositide-3-kinase 保护作用
- 作者列表："Lu QG","Zeng L","Li XH","Liu Y","Du XF","Bai GM","Yan X
BACKGROUND:Intestinal inflammation is a common digestive tract disease, which is usually treated with hormone medicines. Hormone medicines are effective to some extent, but long-term use of them may bring about many complications. AIM:To explore the protective effects of panax notoginseng saponin (PNS) against dextran sulfate sodium (DSS)-induced intestinal inflammatory injury through phosphoinositide-3-kinase protein kinase B (PI3K/AKT) signaling pathway inhibition in rats. METHODS:Colitis rat models were generated via DSS induction, and rats were divided into control (no modeling), DSS, DSS + PNS 50 mg/k, and DSS + PNS 100 mg/kg groups. Then, the intestinal injury, oxidative stress parameters, inflammatory indices, tight junction proteins, apoptosis, macrophage polarization, and TLR4/AKT signaling pathway in colon tissues from rats in each of the groups were detected. The PI3K/AKT signaling pathway in the colon tissue of rats was blocked using the PI3K/AKT signaling pathway inhibitor, LY294002. RESULTS:Compared with rats in the control group, rats in the DSS group showed significantly shortened colon lengths, and significantly increased disease activity indices, oxidative stress reactions and inflammatory indices, as well as significantly decreased expression of tight junction-associated proteins. In addition, the DSS group showed significantly increased apoptotic cell numbers, and showed significantly increased M1 macrophages in spleen and colon tissues. They also showed significantly decreased M2 macrophages in colon tissues, as well as activation of the PI3K/AKT signaling pathway (all P < 0.05). Compared with rats in the DSS group, rats in the DSS + PNS group showed significantly lengthened colon lengths, decreased disease activity indices, and significantly alleviated oxidative stress reactions and inflammatory responses. In addition, this group showed significantly increased expression of tight junction-associated proteins, significantly decreased apoptotic cell numbers, and significantly decreased M1 macrophages in spleen and colon tissues. This group further showed significantly increased M2 macrophages in colon tissues, and significantly suppressed activation of the PI3K/AKT signaling pathway, as well as a dose dependency (all P < 0.05). When the PI3K/AKT signaling pathway was inhibited, the apoptosis rate of colon tissue cells in the DSS + LY294002 group was significantly lower than that of the DSS group (P < 0.05). CONCLUSION:PNS can protect rats against DSS-induced intestinal inflammatory injury by inhibiting the PI3K/AKT signaling pathway, and therefore may be potentially used in the future as a drug for colitis.
背景: 肠道炎症是一种常见的消化道疾病，常用激素类药物治疗。激素药物在一定程度上是有效的，但长期使用可能会带来许多并发症。 目的: 探讨三七总皂苷 (PNS) 通过 phosphoinositide-3-kinase 蛋白激酶 B (PI3K/AKT) 对葡聚糖硫酸钠 (DSS) 诱导的肠道炎症损伤的保护作用。大鼠信号通路抑制。 方法: 通过 DSS 诱导产生结肠炎大鼠模型，将大鼠分为对照 (无造模) 、 DSS + PNS 50 mg/k 、和 DSS + PNS 100 mg/kg 组。然后，肠损伤，氧化应激参数，炎症指标，紧密连接蛋白，细胞凋亡，巨噬细胞极化,并检测各组大鼠结肠组织中 TLR4/AKT 信号通路。使用 PI3K/AKT 信号通路抑制剂 ly294002 阻断大鼠结肠组织中的 PI3K/AKT 信号通路。 结果: 与对照组大鼠相比，DSS 组大鼠结肠长度明显缩短，疾病活动指数、氧化应激反应和炎症指标明显增加,以及紧密连接相关蛋白的表达显著降低。此外，DSS 组显示凋亡细胞数量显著增加，脾脏和结肠组织中 M1 巨噬细胞显著增加。它们还显示结肠组织中的 M2 巨噬细胞显著减少，以及 PI3K/AKT 信号通路的激活 (均 P <0.05)。与 DSS 组大鼠相比，DSS + PNS 组大鼠结肠长度明显延长，疾病活动指数降低，氧化应激反应和炎症反应明显减轻。此外，该组显示紧密连接相关蛋白的表达显著增加，凋亡细胞数量显著减少，脾脏和结肠组织中的 M1 巨噬细胞显著减少。该组进一步显示结肠组织中 M2 巨噬细胞显著增加，PI3K/AKT 信号通路的激活显著抑制，且呈剂量依赖性 (均 P <0.05)。抑制 PI3K/AKT 信号通路时，DSS + LY294002 组结肠组织细胞凋亡率明显低于 DSS 组 (P <0.05)。 结论: PNS 可通过抑制 PI3K/AKT 信号通路对 DSS 诱导的大鼠肠道炎症损伤起到保护作用，因此有可能作为治疗结肠炎的药物。
METHODS:Shigella species cause diarrheal disease globally. Shigellosis is typically characterized by bloody stools and colitis with mucosal damage and is the leading bacterial cause of diarrheal death worldwide. After the pathogen is orally ingested, it invades and replicates within the colonic epithelium through mechanisms that rely on its type III secretion system (T3SS). Currently, oral infection-based small animal models to study the pathogenesis of shigellosis are lacking. Here, we found that orogastric inoculation of infant rabbits with Shigella flexneri resulted in diarrhea and colonic pathology resembling that found in human shigellosis. Fasting animals prior to S. flexneri inoculation increased the frequency of disease. The pathogen colonized the colon, where both luminal and intraepithelial foci were observed. The intraepithelial foci likely arise through S. flexneri spreading from cell to cell. Robust S. flexneri intestinal colonization, invasion of the colonic epithelium, and epithelial sloughing all required the T3SS as well as IcsA, a factor required for bacterial spreading and adhesion in vitro Expression of the proinflammatory chemokine interleukin 8 (IL-8), detected with in situ mRNA labeling, was higher in animals infected with wild-type S. flexneri versus mutant strains deficient in icsA or T3SS, suggesting that epithelial invasion promotes expression of this chemokine. Collectively, our findings suggest that oral infection of infant rabbits offers a useful experimental model for studies of the pathogenesis of shigellosis and for testing of new therapeutics.IMPORTANCEShigella species are the leading bacterial cause of diarrheal death globally. The pathogen causes bacillary dysentery, a bloody diarrheal disease characterized by damage to the colonic mucosa and is usually spread through the fecal-oral route. Small animal models of shigellosis that rely on the oral route of infection are lacking. Here, we found that orogastric inoculation of infant rabbits with S. flexneri led to a diarrheal disease and colonic pathology reminiscent of human shigellosis. Diarrhea, intestinal colonization, and pathology in this model were dependent on the S. flexneri type III secretion system and IcsA, canonical Shigella virulence factors. Thus, oral infection of infant rabbits offers a feasible model to study the pathogenesis of shigellosis and to develop and test new therapeutics.
METHODS:PURPOSE:To quantify the effects of absorbed radiation dose on healthy liver parenchyma following radioembolisation (RE) using [99mTc]TcMebrofenin to analyse both global and regional liver function. METHODS:Patients having RE to treat hepatic disease underwent a [99mTc]TcMebrofenin hepatobilliary scintigraphy (HBS) study at both baseline and 8 weeks following treatment. Changes in global liver uptake rate were compared with healthy liver absorbed dose measures derived from the post-treatment 90Y PET/CT, including average dose, minimum dose to 70% of the volume (D70) and volume receiving at least 50 Gy (V50). Changes in functional burden associated with treatment and spared liver volumes in patients receiving lobar RE were also assessed, as were changes experienced by regional volumes corresponding to various dose ranges. Standard liver function pathology tests (LFTs) (bilirubin, albumin, ALP, AST, ALT and GGT) were examined for changes between baseline and post-treatment. RESULTS:Thirty-five patients were included in the study, of which, 9 had lobar treatment. A significant linear correlation was found between both baseline global liver uptake rate (negative) and D70 with change in global liver uptake rate. Patients undergoing lobar treatments demonstrated a shift in functional burden, and a significant difference was seen between the mean dose corresponding to liver volumes that increased their functional burden (9 Gy) and those that decreased their functional burden (35 Gy). No baseline LFTs predicted a decrease in global liver function; however, D70 demonstrated a linear correlation with changes in bilirubin and GGT. CONCLUSIONS:Given the significant negative relationship between baseline and change in global liver uptake rate, baseline HBS studies should not be used alone to disqualify patients considered for RE. In terms of treatment planning and evaluation, D70 may be the most appropriate metric of dose, with values greater than 15 Gy indicative of a likely drop in global liver function. The evidence of increasing functional burden in spared liver volumes suggests that patients at risk of complications could benefit from a lobar approach to treatment.
METHODS:NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for inflammatory bowel diseases. In this study, we found that Libertellenone M (Lib M), a secondary metabolite from the endophytic fungus Phomopsis sp. S12, has anti-inflammatory potential both in vitro and in vivo. Lib M selectively inhibited the expression of proinflammatory cytokine IL-1β and IL-18 in LPS-activated macrophages. The cleavage of pro-caspase 1 was remarkably reduced by Lib M in macrophages stimulated with three NLRP3 inflammasome activators. Administering Lib M attenuated dextran sulfate sodium-induced experimental acute colitis in mice and significantly reduced the production of these cytokines and cleaved caspase 1 in colon tissues. Apart from inhibition of NLRP3 inflammasome assembly, Lib M also suppressed NF-κB nuclear translocation in macrophages. Taken together, these findings suggest that Lib M-mediated inhibition of NLRP3 inflammasome activation could protect against colitis-like inflammatory diseases, and that this compound derived from a plant-associated fungus might inspire the exploration of novel immunosuppressive agents.