Induction of cancer cell death is an established treatment strategy, but chemotherapy drug-mediated apoptosis can be evaded by many tumors. Pyroptosis is a type of inflammatory programmed cell death (PCD) that is important for organism immunity. Tubeimoside-I (TBMS1) is a plant-derived component that exhibits antitumor activity. However, it is unclear how TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC). In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells and releases pro-inflammatory cytokines. Mechanistically, we found that TBMS1 inhibits CRC cell proliferation and migration and induces pyroptosis by activating caspase-3 and cleaving gasdermin E (GSDME) through the inhibition of PKM2. In the animal experiments, TBMS1 attenuated the weight of solid tumors, increased the proportion of CD8 + cytotoxic T cells, and reduced the content of M2-type macrophages in the spleen of tumor-bearing mice. Furthermore, TBMS1 inhibited M2-type polarization by blocking STAT6 pathway activation in RAW 264.7 cells. To sum up, our findings suggest that TBMS1 triggers pyroptosis in CRC by acting on the PKM2/caspase-3/GSDME signaling pathway. Additionally, it modulates the antitumor immune response in CRC murine models. This study provides a promising basis for the potential use of TBMS1 in treating CRC.

目的:探究薯蓣皂苷(Dioscin)诱导人结肠癌HCT-116细胞、RKO细胞凋亡的作用及机制.方法:通过将体外培养的HCT-116细胞和RKO细胞分为对照组和不同浓度的药物组,采用CCK-8实验分析Dioscin对细胞增殖的抑制作用,可见分光光度法检测细胞LDH活性的变化;借助DNA含量检测法、Annexin V-FITC/PI双染法和流式细胞术检测细胞凋亡情况;DCFH-DA荧光探针法检测细胞活性氧簇(ROS)含量的变化;采用荧光探针法和可见分光光度法分别检测细胞超氧化物含量及细胞超氧化物歧化酶(SOD)活性的变化,Western印迹法检测凋亡相关蛋白的表达情况.结果:在24 h、48 h处理时间下,与对照组相比,HCT-116细胞Dioscin组(2、4、6、8、10μmol/L)、RKO细胞Dioscin组(5、10、15、20、25μmol/L)都明显抑制了结肠癌细胞的增殖活性(均P<0.05),且HCT-116、RKO细胞经Dioscin处理后,细胞膜破坏,细胞LDH释放量较对照组增多(P<0.05,P<0.01);与对照组相比,Dioscin作用HCT-116、RKO细胞后,DNA含量暴露增多(P<0.05,P<0.001),细胞凋亡率上调(P<0.001,P<0.01),ROS水平升高(P<0.05,P<0.001),超氧化物含量增多(均P<0.001),SOD表达降低(P<0.05,P<0.001);Western印迹结果表明,与对照组相比,Dioscin可以抑制HCT-116、RKO细胞蛋白p-Akt(P<0.01,P<0.001)、Nrf2(均P<0.001)、Bcl-2(均P<0.001)的表达,促进蛋白cleaved Caspase-9(P<0.001,P<0.01)的表达.结论:薯蓣皂苷可能通过PI3K/Akt/Nrf2信号通路激活氧化应激反应,从而抑制结肠癌细胞生长,促进其凋亡.

Background: Chronic pancreatitis (CP) is a common and frequently occurring disease. Pancreaticoduodenectomy (PD), pylorus-preserving pancreaticoduodenectomy (PPPD), and duodenum-preserving pancreatic head resection (DPPHR) are important treatment options for patients with chronic pancreatitis. The Beger and Frey procedures are 2 main duodenum-preserving techniques in duodenum-preserving pancreatic head resection (DPPHR) strategies. We conducted this systematic review and meta-analysis to compare the clinical efficacy of DPPHR versus PD, the Beger procedure versus PD, the Frey procedure versus PD, and the Beger procedure versus the Frey procedure in the treatment of pancreatitis. The optimal surgical option for chronic pancreatitis is still under debate. The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy of different surgical strategies for chronic pancreatitis. Methods: Five databases (PubMed, Medline, SinoMed, Embase, and Cochrane Library) were searched with the limitations of human subjects and randomized controlled trials (RCTs) text. Data were extracted by 2 of the coauthors independently and analyzed using the RevMan statistical software, version 5.3. Weighted mean differences (WMDs), risk ratios (RRs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration's Risk of Bias Tool was used to assess the risk of bias. Results: Seven studies involving a total of 385 patients who underwent the surgical treatments were assessed. The methodological quality of the trials ranged from low to moderate and included PD (n = 134) and DPPHR (n = 251 [Beger procedure = 100; Frey procedure = 109; Beger or Frey procedure = 42]). There were no significant differences between DPPHR and PD in post-operation mortality (RR = 2.89, 95% CI = 0.31–26.87, P = 0.36), pain relief (RR = 1.09, 95% CI = 0.94–1.25, P = 0.26), exocrine insufficiency (follow-up time > 60 months: RR = 0.91, 95% CI = 0.72–1.15, P = 0.41), and endocrine insufficiency (RR = 0.75, 95% CI = 0.52–1.08, P = 0.12). Concerning the follow-up time < 60 months, the DPPHR group had better results of exocrine insufficiency (RR = 0.22, 95% CI = 0.08–0.62, P = 0.04). However, operation time (P < 0.0001), blood transfusion (P = 0.02), hospital stay (P = 0.0002), postoperation morbidity (P = 0.0007), weight gain (P < 0.00001), quality of life (P = 0.01), and occupational rehabilitation (P = 0.007) were significantly better for patients who underwent the DPPHR procedure compared with the PD procedure. The comparison results of the Frey procedure and PD showed that both procedures had an equal effect in the pain relief, postoperation mortality, exocrine and endocrine function, and quality of life (QoL) (P > 0.05), whereas patients who underwent the Frey procedure had significantly reduced operative times (P < 0.05) and less blood transfusions (P < 0.05). Comparing the Beger procedure to the PD procedure, there were no significant differences in hospital stay, blood transfusion, postoperation morbidity or mortality, pain relief, weight gain, exocrine insufficiency, and occupational rehabilitation (P > 0.05). Two studies comparing the Beger and Frey procedures showed no differences in postoperative morbidity, pain relief, exocrine insufficiency, and quality of life (P > 0.05). In terms of operative time, blood transfusion, hospital stay, postoperation morbidity, weight gain, quality of life, and occupational rehabilitation, the results also favored duodenum-preserving pancreatic head resection (DPPHR) strategies. Conclusion: All procedures are equally effective for the management of pain, postoperation morbidity, exocrine insufficiency, and endocrine insufficiency for chronic pancreatitis. Improved short- and long-term outcomes, including operative time, blood transfusion, hospital stay, quality of life, weight gain, and occupational rehabilitation make DPPHR a more favorable surgical strategy for patients with chronic pancreatitis. Further, relevant trails are eager to prove these findings.

Sargentodoxa cuneata, containing syringaresinol and its glycoside liriodendrin as the main bioactive compounds, is a well-known traditional Chinese medicine for treating intestinal inflammation. In our preliminary study, liriodendrin inhibited NF-kB activation in sepsis-induced acute lung injury. The present study was designed to investigate its effect on dextran sulfate sodium (DSS)-induced colitis in a mouse model and to explore the possible related mechanisms. Experimental colitis was established by giving mice drinking water containing 3% (w/v) DSS for 7days. The mice were pretreated with liriodendrin (100mg/kg/day, intragastrically) 3days before DSS treatment. We determined the effects of liriodendrin on disease activity index (DAI), colon length, histopathological examination, antioxidants, and anti-inflammatory activities. Our results showed that liriodendrin greatly decreased MPO and MDA activities and significantly increased SOD and GPx activities in the colon. Moreover, liriodendrin improved DAI, colon length and histological damage in colon and reduced the levels of pro-inflammatory cytokines, such as TNF-a, IL-1β and IL-6. Meanwhile, assessments by western blot revealed that liriodendrin significantly suppressed the activation of Akt and NF-κB pathways and up-regulated the expression of ERβ in the colon. In vitro, liriodendrin down-regulated production of pro-inflammatory cytokines and suppressed NF-κB signalling pathways in LPS-induced RAW 264.7 macrophages in a concentration-dependent manner. In addition, syringaresinol, the hydrolysate of liriodendrin, more potently down-regulated production of pro-inflammatory cytokines and suppressed NF-κB and Akt signalling pathways in LPS-induced RAW 264.7 macrophages,which were abolished by using a pure ER antagonist, ICI182, 780. Taken together, liriodendrin-mediated suppression of inflammatory damage in the colon may be attributable to the in vivo transformation to syringaresinol and liriodendrin may be a promising therapeutic approach preventive agent for colitis treatment.

Ly‐GDI is an inhibitory protein of Rho GTPases. Growing evidences indicate that Ly‐GDI plays an essential role in regulating actin cytoskeletal alteration which is indispensible for the process such as phagocytosis. However, the role of Ly‐GDI in inflammation remains largely unknown. In the current study, we found that Ly‐GDI expression was significantly decreased in the IgG immune complex‐injured lungs. To determine if Ly‐GDI might regulate the lung inflammatory response, we constructed adenovirus vectors that could mediate ectopic expression of Ly‐GDI (Adeno‐Ly‐GDI). In vivo mouse lung expression of Ly‐GDI resulted in a significant attenuation of IgG immune complex‐induced lung injury, which was due to the decreased pulmonary permeability and lung inflammatory cells, especially neutrophil accumulation. Upon IgG immune complex deposition, mice with Ly‐GDI over‐expression in the lungs produced significant less inflammatory mediators (TNF‐α, IL‐6, MCP‐1, and MIP‐1α) in bronchoalveolar lavage fluid when compared control mice receiving airway injection of Adeno‐GFP. Mechanically, IgG immune complex‐induced NF‐κB activity was markedly suppressed by Ly‐GDI in both alveolar macrophages and lungs as measured by luciferase assay and electrophoretic mobility shift assay. These findings suggest that Ly‐GDI is a critical regulator of inflammatory injury after deposition of IgG immune complexes and that it negatively regulates the lung NF‐kB activity.