Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.

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Wei Chang an Pill Alleviates TNBS-induced Ulcerative Colitis Through Inhibition of EMTProcess

10.21203/rs.3.rs-139702/v1 ◽

2021 ◽

Author(s):

Yaxin Qi ◽

Lijuan Chai ◽

Min Zhang ◽

Sitong Jia ◽

Lin Wang ◽

...

Keyword(s):

Ulcerative Colitis ◽

Body Weight ◽

Epithelial Mesenchymal Transition ◽

Activity Index ◽

Pharmaceutical Preparation ◽

Damage Index ◽

The Body ◽

Active Ingredients ◽

Mesenchymal Transition ◽

Anti Inflammatory

Abstract Background: Wei Chang An pill (WCA) is a traditional Chinese pharmaceutical preparation which has been widely used to treat various gastrointestinal diseases including Ulcerative colitis (UC). The aim of our study was investigate the inhibitory effect and mechanism of WCA in the treatment of 2,4,6-trinitro-benzenesulfonic acid (TNBS)-induced UC in rats.Methods: We established the TNBS-induced UC model and then WCA was administrated orally for one week. Body weight, colon lengths, Disease Activity Index (DAI) score and Colon Mucosa Damage Index (CMDI) score were recorded. The expression of cytokines factors in LPS-stimulated THP-1 cells was recorded to evaluate the anti-inflammatory effects of WCA and its herb active ingredients. Immunohistochemistry and immunofluorescence were used to evaluate the Epithelial-Mesenchymal Transition (EMT) process in UC rats and Caco-2 cells which were induced by LPS-stimulated THP-1 cells uponWCA treatment.Results: WCA significantly decreased the body weight loss, higher DAI and CMDI score, colon length shortening and histological damage in UC rats. Furthermore, both of the activities of myeloperoxidase dismutase (MPO) and the mRNA expressions of cytokine in UC tissues were significantly inhibited. In THP-1 cells, the mRNA expressions of IP-10, TNF-α, IL-6 and IkBα were significantly suppressed by WCA or its active ingredients. In UC rats and Caco-2 cells, both of their EMT process were strongly suppressed by WCA.Conclusion: These results show that through improving inflammatory microenvironment to inhibit the EMT process, WCA retarded the development of UC in rats to play its anti-inflammatory effect.

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Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.118.251371 ◽

2018 ◽

Vol 367 (3) ◽

pp. 483-493 ◽

Cited By ~ 8

Author(s):

Babak Baban ◽

Cristina Marchetti ◽

Hesam Khodadadi ◽

Aneeq Malik ◽

Golnaz Emami ◽

...

Keyword(s):

Acute Kidney Injury ◽

T Cell ◽

Leucine Zipper ◽

Kidney Injury ◽

Cell Polarization ◽

Protective Effects ◽

T Cell Polarization

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The Protection of Crocin Against Ulcerative Colitis and Colorectal Cancer via Suppression of NF-κB-Mediated Inflammation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.639458 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shanshan Teng ◽

Jie Hao ◽

Hui Bi ◽

Congcong Li ◽

Yongfeng Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Ulcerative Colitis ◽

Conformational Changes ◽

Protein Interactions ◽

Activity Index ◽

Disease Activity Index ◽

Protective Effects ◽

Protein Protein Interactions ◽

Anti Inflammatory ◽

Factor Α

Background: In China, the incidence of ulcerative colitis (UC) is increasing every year, but the etiology of UC remains unclear. UC is known to increase the risk of colorectal cancer (CRC). The aim of this study was to investigate the protective effects of crocin against UC and CRC in mouse models.Methods: Crocin was used to treat the dextran sodium sulfate (DSS)-induced UC mice for 3 weeks, and ApcMinC/Gpt mice with colorectal cancer for 8 weeks. Proteomics screening was used to detect changes in the protein profiles of colon tissues of UC mice. Enzyme-linked immunosorbent assays and western blot were used to verify these changes.Results: Crocin strongly reduced the disease activity index scores of UC mice, and improved the pathological symptoms of the colonic epithelium. The anti-inflammatory effects of crocin were indicated by its regulation of the activity of various cytokines, such as interleukins, via the modulation of nuclear factor kappa-B (NF-κB) signaling. Crocin significantly suppressed tumor growth in ApcMinC/Gpt mice and ameliorated pathological alterations in the colon and liver, but had no effects on spleen and kidney. Additionally, crocin significantly decreased the concentrations of interleukins and tumor necrosis factor-α in the sera and colon tissues, suggesting its anti-inflammatory effects related to NF-κB signaling. Finally, 12-h incubation of SW480 cells with crocin caused cell cycle arrest, enhanced the apoptotic rate, promoted the dissipation of mitochondrial membrane potential, and the over-accumulation of reactive oxygen species. From the theoretical analyses, phosphorylated residues on S536 may enhance the protein-protein interactions which may influence the conformational changes in the secondary structure of NF-κB.Conclusion: The protective effects of crocin on UC and CRC were due to its suppression of NF-κB-mediated inflammation.

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Preserved Th2 lymphocytes improve prognosis of diabetic patients undergoing TAVR

European Heart Journal ◽

10.1093/ehjci/ehaa946.1869 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Hoffmann ◽

A Berkowitsch ◽

S Mas-Peiro ◽

F Boeckling ◽

T Rasper ◽

...

Keyword(s):

T Cell ◽

Aortic Stenosis ◽

Cell Polarization ◽

T Cell Subsets ◽

Th2 Cells ◽

Diabetic Patients ◽

Th1 Cells ◽

Cell Counts ◽

T Cell Polarization ◽

Sts Score

Abstract Introduction Previous studies have shown that presence of diabetes (DM) worsens outcome of patients after transfemoral aortic valve (TAVR). DM has been associated with pathological T-lymphocyte (T-cell) polarization, marked by decreased anti-inflammatory Th2 cells and increased pro-inflammatory Th1 cells. However, the risk-modulatory impact of T-cell polarization in diabetic patients with severe aortic stenosis has not been shown thus far. In this study we assessed the role of T-cell subsets in diabetic patients undergoing TAVR. Methods and results A total of 129 patients (76% male, median age [IQR]: 83 years [79–86]) admitted for TAVR at the University Clinic Frankfurt were enrolled. The patients were evaluated using classical risk scores and the Th1/Th2 T-cell polarization was assessed using flow cytometry. The endpoint of the study was all-cause death. Kaplan-Meier survival, ROC curve analysis and Mann-Whitney-U-Test were used in statistical analysis. The differences were considered significant by error probability p<0.05. Twenty-six patients died within follow up of 274 (188–367) days. The conventional risk parameters were distributed as follows: STS score: 3.45 (2.47–4.97), LVEF: 60% (45–65), CRP: 0.33 mg/dl (0.15–0.79), hsTropT: 24.5 pg/ml (16.5–40.0), IL6: 6.7 pg/ml (4.1–12.2), Hb: 12.3 g/dl (11.00–13,75), Creatinine: 1.15 mg/dl (0.93–1.54), Th1 cells = 79.88 cells/μl (55.69–122.16), Th2 cells: 25.31 cells/μl (19.69–38.33), NT-proBNP: 2033 pg/ml (1076–5531). All these parameters were associated with mortality. Hence, only Hb (AUC=0.761), NT-proBNP (AUC=0.726), Th2 cells (AUC=0.712) and STS score (AUC=0.737) provided AUC>0.7. Diabetes was revealed to be significantly associated with mortality in patients with and without DM (15/48 (31%) vs. 11/81 (14%), respectively, P=0.019). There were no significant differences in the counts of Th-cell subsets between diabetic and non-diabetic patients (Th1 (90.95 (62.41–154.22) vs 76.36 (53.16–100.49), P=0.072); Th2 (29.18 (20.13–43.77) vs 24.74 (20.27- 35.11), p=0.245), for DM and non-DM respectively). However, the survival rate in patients with DM and Th2 cell counts higher than or equal to the calculated optimal cut-off of 24.3 cells/μl was comparable with patients without DM (25/28 (89%) vs. 36/38 (95%), p=0.453). In contrast, diabetic patients with reduced Th2 cells (<24.3 cells/μl) were much more likely to die (10/15 (67%) vs. 8/34 (24%), p=0.003, patients with DM and without, respectively). Conclusion Our results show for the first time a risk-modulatory impact of T-cell immunity in diabetic patients with severe degenerative aortic stenosis. Reduced Th2 cells are strongly associated with mortality in patients considered for TAVR and significantly deteriorate prognosis in patients with concomitant diabetes. Funding Acknowledgement Type of funding source: None

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The combination of indirubin and isatin attenuates dextran sodium sulfate induced ulcerative colitis in mice

Biochemistry and Cell Biology ◽

10.1139/bcb-2018-0041 ◽

2018 ◽

Vol 96 (5) ◽

pp. 636-645 ◽

Cited By ~ 6

Author(s):

Wenyan Gao ◽

Luding Zhang ◽

Xiaoqian Wang ◽

Li Yu ◽

Changhong Wang ◽

...

Keyword(s):

Ulcerative Colitis ◽

Body Mass ◽

Inflammatory Diseases ◽

Activity Index ◽

Single Agent ◽

Disease Activity Index ◽

Mapk Signaling ◽

Protective Effects ◽

Epithelial Cell Apoptosis ◽

Anti Inflammatory

Indirubin and isatin have been used in the treatment of inflammatory diseases due to their anti-inflammatory properties. This study aimed to evaluate the combined effect of indirubin and isatin on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). UC was induced by the administration of 3% (w/v) DSS solution, and then the model mice were administered indirubin (10 mg/kg body mass) and (or) isatin (10 mg/kg body mass) by gavage once daily for 7 days. The results showed that indirubin and isatin, individually or combined, significantly inhibited weight loss, lowered disease activity index (DAI), ameliorated pathological changes, decreased the levels of pro-inflammatory mediators and myeloperoxidase (MPO) activity, increased the expression of anti-inflammatory cytokines and Foxp3, suppressed CD4+ T cell infiltration, and inhibited oxidative stress and epithelial cell apoptosis. Additionally, indirubin and isatin, both individually and combined, can also inhibit activation of the NF-κB and MAPK pathways induced by DSS. The protective effect of combination therapy against UC was superior to that of single-agent treatment. These results suggest that indirubin combined with isatin attenuates DSS-induced UC, and changes to the NF-κB and MAPK signaling pathways may mediate the protective effects of indirubin and isatin in UC.

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