Irsogladine

Irsogladine (Dicloguamine) is an orally active gastric mucosal protective agent. Irsogladine inhibits breast cancer recurrence and lung metastasis in nude mice. Irsogladine inhibits the transcriptional activities of NF-κB and AP-1, suppresses the activities of PDE and PDE4 to elevate intracellular cAMP levels, and activates TRPV1 and K_ATP channels. Irsogladine enhances iNOS expression, NO production, and the activation of cAMP-responsive elements. Irsogladine inhibits the development and progression of intestinal polyps in Apc-mutant mice. Irsogladine alleviates oxidative stress, increases gastric mucosal blood flow, and stimulates the production of endogenous prostaglandins. Irsogladine promotes insulin secretion in MIN6 cells. Irsogladine inhibits tumor angiogenesis, cancer cell proliferation, and the production of proinflammatory cytokines. Irsogladine exerts protective effects on astrocytes in ethanol/hydrochloric acid-induced gastric ulcers in mice. Irsogladine prevents colitis in IL-10 gene-deficient mice by reducing the production of IL-12 and IL-23. Irsogladine upregulates gap junction intercellular communication in pancreatic cancer cells via the PKA pathway. Irsogladine is applicable to research related to breast cancer, intestinal polyposis, gastric ulcer, spontaneous colitis, glioma, liver cancer, and pancreatic cancer^{[1][2][3][4][5][6][7][8]}. In Vitro:Irsogladine (1-100 μM; 48 h) inhibits the proliferation of HUVEC and MDA-MB-435 cells by 15% at the concentration of 100 μM^[1].
Irsogladine maleate (100-200 μM; 24-48 h) inhibits the transcriptional activity of AP-1 and NF-κB in Caco-2 cells^[2].
Irsogladine maleate (100-200 μM; 24 h) inhibits the basal transcriptional activity of NF-κB in HCT-15 cells^[2].
Irsogladine (1-10 μM; 24 h) significantly enhances the antiproliferative effects of NO donors SNAP and NONOate on glomerular mesangial cells^[4].
Irsogladine (10 μM; 24 h) slightly upregulates the expression of connexin 43 in rat glomerular mesangial cells, and significantly enhances the SNAP (HY-121526)-induced increase in connexin 43 expression in these cells^[4].
Irsogladine (10 μM; 1 h) causes a small but significant increase in intracellular cAMP levels in rat glomerular mesangial cells, and exerts a synergistic effect on elevating cAMP levels when used in combination with SNAP in these cells^[4].
Irsogladine (10 μM; 1 h) weakly activates PKA in rat glomerular mesangial cells and potently enhances SNAP-induced PKA activation in these cells^[4].
Irsogladine (0.1-100 μM; 24 h) synergistically activates CRE^[4] in rat glomerular mesangial cells when used in combination with NO donors (SNAP, SNP (HY-B0564), NONOate) or cytokine-induced endogenous NO.
Combination treatment with irsogladine (10 μM; 24 h) and either the sGC activator Bay 41-2272 (HY-12376) or the PDE3-interacting cGMP analog 8-bromo-cGMP (HY-101379A) synergistically activates CRE and PKA in rat glomerular mesangial cells^[4].
Irsogladine (10 μM; 24 h) significantly enhances cytokine (TNF-α + IL-1β)-induced iNOS expression and NO production in rat glomerular mesangial cells^[4].
Irsogladine (1.0×10^-8-1.0×10^-5 M; 30 min pre-incubation, 60 min co-incubation with glucose) increases insulin secretion by 1.7-fold at a concentration of 1.0×10^-5 M, and this effect depends on functional gap junctions and the cAMP-PKA pathway^[5].
Irsogladine (1.0×10^-5 M; 30 min) increases the levels of plasma membrane-associated Cx36 protein and cAMP in MIN6 cells^[5].
Irsogladine (10^-7-10^-4 M; 24 h) dose-dependently inhibits the gene expression and protein secretion of IL-12p40 and IL-23p19, suppresses IL-23 secretion, and reduces TNF-α mRNA expression in J774A.1 mouse monocyte/macrophage cells^[6].
Irsogladine (10^-6-10^-4 M; 5 days) specifically inhibits the proliferation of human microvascular endothelial cells and human umbilical vein endothelial cells^[7].
Irsogladine (10^-6-10^-4 M; 3 days) inhibits U251-induced tube formation in human microvascular endothelial cells^[7].
Irsogladine malate (10^-6 M; administered for 3-5 days until 90-95% confluence) significantly upregulates GJIC between human pancreatic cancer cells PANC-1^[8].
Irsogladine malate (10^-8-10^-6 M; treated for 3-5 days until 90-95% confluence) dose-dependently increases the levels of phosphorylated Cx43 (P1, P2) in the membrane fraction of human pancreatic cancer cell line PANC-1^[8].
Irsogladine malate (10^-6 M; treated for 3-5 days until 90-95% confluence) induces the relocalization of Cx43 protein from the cytoplasm to the intercellular borders in human pancreatic cancer cells PANC-1^[8].
Irsogladine malate (10^-6 M; treated for 3-5 days until 90-95% confluence) significantly increases intracellular cAMP levels in PANC-1 human pancreatic cancer cells^[8]. In Vivo:Irsogladine (120 mg/kg, intragastric administration, once daily for 5 consecutive weeks) reduces the breast tumor recurrence rate by 39.6%, decreases lung metastasis volume by 48.4%, and reduces the number of lung metastatic foci by 63.9% in MDA-MB-435 xenograft nude mice that have undergone tumor resection, without altering the body weight of the mice^[1].
Irsogladine maleate (5-50 ppm; administered via diet; ad libitum access; 8 weeks) inhibits intestinal polyp formation in male Min mice (reducing the total number of polyps to 69.3% and 66.1% of that in the control group, respectively), and its mechanism of action involves, in part, inhibition of the NF-κB signaling pathway and reduction of reactive carbonyl species associated with oxidative stress^[2].
Irsogladine maleate (ad libitum access for 25 consecutive weeks) inhibits the development of gastrointestinal tumors in male Wistar rats with gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine and promoted by glyoxal^[2].
Irsogladine maleate (125 ppm; administered via diet; ad libitum access; 35 weeks) completely inhibits liver tumorigenesis (0% incidence) in male F344 rats initiated with diethylnitrosamine and promoted with phenobarbital^[2].
Irsogladine (1-10 mg/kg; p.o.; single administration; 1 h prior to ulcer induction) exerts a dose-dependent gastroprotective effect against ethanol/hydrochloric acid-induced gastric ulcers in male ICR mice, with an 84.2% injury inhibition rate at the dose of 10 mg/kg. Its action is partially mediated by elevated cAMP levels, enhanced prostaglandin activity, opening of K_ATP channels, and antioxidant properties^[3].
Irsogladine (100 ppm; p.o.; daily; for 10 consecutive weeks) prevents spontaneous colitis in IL-10^−/− mice by reducing the colonic histological score to 1.6 and inhibiting cytokine expression in the Th1/Th17 pathway via suppression of IL-12 and IL-23 production^[6].
Irsogladine (30-120 mg/kg; p.o.; daily; for 4 consecutive weeks) dose-dependently inhibits glioma tumor growth and reduces tumor microvessel density in BALB/c nu/nu mice. Specifically, the dose of 60 mg/kg/day reduces tumor volume by approximately 50%, while the dose of 120 mg/kg/day decreases microvessel count to approximately 30% of the control level^[7].
Irsogladine (30-60 mg/kg; p.o.; daily; for 7 consecutive days) inhibits liver cancer-induced tumor neovascularization in the dorsal air sac of mice. Specifically, the dose of 60 mg/kg/day completely blocks the formation of tumor-specific neovasculature without affecting pre-existing blood vessels^[7].