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Atractylodin is a major compound in the rhizome of Atractylodes lancea, an oriental herbal medicine used for the treatment of gastrointestinal diseases, including dyspepsia, nausea, and diarrhea. Recent studies have shown that atractylodin exerts anti-inflammatory effects in various inflammatory diseases. Herein, we investigated the anti-colitis effects of atractylodin and its molecular targets. We determined the non-cytotoxic concentration of atractylodin (50 μM) using a cell proliferation assay in colonic epithelial cells. We found that pretreatment with atractylodin significantly inhibits tumor necrosis factor-α-induced phosphorylation of nuclear factor-κ-light-chain-enhancer of activated B in HCT116 cells. Through docking simulation analysis, luciferase assays, and in vitro binding assays, we found that atractylodin has an affinity for peroxisome proliferator-activated receptor alpha (PPARα). Daily administration of atractylodin (40 mg/kg) increased the survival rate of mice in a dextran sodium sulfate-induced colitis mouse model. Thus, atractylodin can be a good strategy for colitis therapy through inducing PPARα-dependent pathways. [ABSTRACT FROM AUTHOR]

The induction of apoptosis is a useful strategy in anti-cancer research. Various Moon Hyung Yang (MHY) compounds have been developed as novel anti-cancer drug candidates; in the present study, the pro-apoptotic effects of (Z)-5-(3-ethoxy-4- hydroxybenzylidene)-2-thioxothiazolidin-4-one (MHY695) on HCT116 human colon cancer cells were assessed. MTT assays were performed to investigate the dose-dependent cytotoxic effects of MHY695 on HCT116 cells. Immunofluorescence staining and flow cytometry analyses were performed to identify apoptotic cell death, and western blot analysis was used to investigate the apoptotic-signaling pathways. A mouse xenograft model was also used to determine the effects of MHY695 in vivo. MHY695 decreased the viability of HCT116 cells and induced apoptotic cytotoxicity. The apoptotic mechanisms induced by MHY695 involved the dephosphorylation of Bcl-2-associated agonist of cell death protein following protein kinase B inactivation, induced myeloid leukaemia cell differentiation protein and BH3-interacting domain death agonist truncation, caspase-3 and −9 activation and poly (ADP-ribose) polymerase cleavage. In addition, MHY695 significantly suppressed tumor growth in the mouse xenograft model, compared with the vehicle control. Notably, MHY695 exhibited potent anti-cancer effects in four different types of human colon cancer cell line, including Caco-2, DLD-1, HT-29 and HCT116. Additionally, MHY695 showed reduced cytotoxicity in NCM460, normal colonic epithelial cells. Furthermore, MHY-induced cytotoxicity in colon cancer cells was independent of the tumor suppressor protein p53. Collectively, these observations suggested that MHY695 may be a novel drug for the treatment of colon cancer. [ABSTRACT FROM AUTHOR]

Abstract Senescence marker protein 30 (SMP30) is a calcium-binding protein whose expression decreases during senescence. SMP30 deficiency increases susceptibility to cytokine-induced apoptosis in the liver and to radiation-induced apoptosis in the small intestine. Furthermore, colonic epithelial cell death is associated with the severity of colitis. Therefore, in the present study, we investigated the function of SMP30 during intestinal inflammation. In SMP30 deficient mice, colitis was significantly exacerbated as demonstrated by increased mortality (p = 0.001), body weight loss (p = 0.0105 at day 8), rectal bleeding (p = 0.0047 at day 8) and diarrhea (p = 0.0030 at day 8), histological scores (ulcers, p = 0.0002; edema, p = 0.0125; leukocyte infiltration, p = 0.0016) and productions of pro-inflammatory cytokines (IL-1α, p = 0.0452; IL-6, p = 0.0074; G-CSF, p = 0.0036). In addition, greater proportions of apoptotic cells and lower levels of anti-apoptotic marker proteins (total PARP-1 and Bcl-2) were observed in the inflamed intestines of SMP30 deficient mice than in wild type controls. In vitro experiments on colonic epithelial cells showed that stable SMP30 expression inhibited but that SMP30 siRNA expression increased TNF-α-induced apoptosis. SMP30 inhibition decreased Nrf2 mRNA expression levels (p < 0.0001), but SMP30 overexpression increased Nrf2 mRNA expression levels (p = 0.0495). The underlying mechanism by which SMP30 protected cells appeared to be by inhibiting Nrf2 ubiquitination and Keap1 expression, and thus enhancing Nrf2 activity. Moreover, SMP30 deficiency increased the incidence of colitis-associated colon cancer as determined by increased mortality (p = 0.0572) and average polyp number (p = 0.0277). Collectively, these findings suggest that SMP30 protects intestinal epithelial cells from apoptosis and this can contribute to amelioration of colitis and colitis-associated colon cancer. Highlights • SMP30 deficiency exacerbates colitis and colitis-associated colon cancer. • SMP30 prevents epithelial cells from cytokine-induced cell death. • SMP30 increases Nrf2 activity by inhibiting Nrf2 ubiquitination and Keap1 expression. • Protective effect of SMP30 is mediated by increased Nrf2 activity. [ABSTRACT FROM AUTHOR]

Neurons depend on mitochondria for homeostasis and survival, and thus, mitochondrial dysfunction has been implicated in neurodegenerative diseases, including Parkinson’s disease (PD). Increasing evidence indicates the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), protects neurons against neurodegeneration and enhances neural plasticity. Here, the authors evaluated the protective effects of intraperitoneally (i.p.) administered low dose DNP in an acute mouse model of PD. Mice were administered DNP (1 or 5 mg/kg) for 12 consecutive days, and then on day 13, MPTP (20 mg/kg, i.p.) was administered four times (with 2 h intervals between injections) to induce PD. It was found that MPTP-induced motor dysfunction was ameliorated in the DNP-treated mice versus vehicle-treated controls. Additionally, DNP effectively attenuated dopaminergic neuronal loss observed in MPTP treated mice. Moreover, in primary cultured neurons, DNP at 10 μM, but not at 100 μM, prevented MPP + -induced cell death and mitochondrial membrane potential (MMP) reduction. In addition, DNP was observed to cause the nuclear translocation of Nrf2 in primary neurons. Taken together, these findings of the present study suggest that DNP protects dopaminergic neurons against neurodegeneration and maintains MMP integrity in PD by activating adaptive stress responses. [ABSTRACT FROM AUTHOR]

[Display omitted] A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of colorectal cancer (CRC) can be affected by various inflammatory mediators, such as tumor necrosis factor, nuclear factor kappa B, interleukins, and interferons. Moreover, these inflammatory mediators can be reciprocally affected by gut microbiota. This review demonstrates the correlation of gut microbiota, inflammatory mediators, and CRC by summarizing studies with germ-free animals, antibiotic-treated animals, fecal microbiota transplantation, administration of specific microbiota, transgenic mice, and experimental models of CRC. It is clear that gut microbiota affect CRC through inflammatory mediators, though whether they promote or inhibit CRC depends on the context. Therefore, modulation of gut microbiota can be a good strategy for CRC prevention and control or be adjunctive therapy for CRC. Inflammatory mediators modulate inflammatory pathways during the development of colorectal cancer. Inflammatory mediators secreted by both immune and tumor cells can influence carcinogenesis, progression, and tumor metastasis. The gut microbiota, which colonize the entire intestinal tract, especially the colon, are closely linked to colorectal cancer through an association with inflammatory mediators such as tumor necrosis factor, nuclear factor kappa B, interleukins, and interferons. This association may be a potential therapeutic target, since therapeutic interventions targeting the gut microbiota have been actively investigated in both the laboratory and in clinics and include fecal microbiota transplantation and probiotics. [ABSTRACT FROM AUTHOR]

N‐Acetylserotonin (NAS) is an intermediate in the melatonin biosynthetic pathway. We investigated the anti‐inflammatory activity of NAS by focusing on its chemical feature oxidizable to an electrophile. NAS was readily oxidized by reaction with HOCl, an oxidant produced in the inflammatory state. HOCl‐reacted NAS (Oxi‐NAS), but not NAS, activated the anti‐inflammatory nuclear factor erythroid 2‐related factor 2 (Nrf2)‐heme oxygenase (HO)‐1 pathway in cells. Chromatographic and mass analyses demonstrated that Oxi‐NAS was the iminoquinone form of NAS and could react with N‐acetylcysteine possessing a nucleophilic thiol to form a covalent adduct. Oxi‐NAS bound to Kelch‐like ECH‐associated protein 1, resulting in Nrf2 dissociation. Moreover, rectally administered NAS increased the levels of nuclear Nrf2 and HO‐1 proteins in the inflamed colon of rats. Simultaneously, NAS was converted to Oxi‐NAS in the inflamed colon. Rectal NAS mitigated colonic damage and inflammation. The anticolitic effects were significantly compromised by the coadministration of an HO‐1 inhibitor. [ABSTRACT FROM AUTHOR]

Protease-activated receptor 2 (PAR2) alleviates intestinal inflammation by upregulating autophagy. PAR2 also modulates tight junctions through β-arrestin signaling. Therefore, we investigated the effect of PAR2-induced autophagy on intestinal epithelial tight junctions and permeability. RT-PCR, Western blot analysis, and immunoprecipitation were performed to investigate the underlying molecular mechanisms by which PAR2 regulates autophagy and intestinal epithelial tight junctions. Inhibition of PAR2 by GB83, a PAR2 antagonist, decreased the expression of autophagy-related and tight-junction-related factors in Caco-2 cells. Moreover, inhibition of PAR2 decreased intestinal transepithelial electrical resistance. When PAR2 was activated, intestinal permeability was maintained, but when autophagy was suppressed by chloroquine, intestinal permeability was significantly increased. In addition, the prolongation of ERK1/2 phosphorylation by PAR2–ERK1/2–β-arrestin assembly was reduced under autophagy inhibition conditions. Therefore, PAR2 induces autophagy to regulate intestinal epithelial permeability, suggesting that it is related to the β-arrestin–ERK1/2 pathway. In conclusion, regulating intestinal epithelial permeability through PAR2-induced autophagy can help maintain mucosal barrier integrity. Therefore, these findings suggest that the regulation of PAR2 can be a suitable strategy to treat intestinal diseases caused by permeability dysfunction. [ABSTRACT FROM AUTHOR]

Intestinal wound healing is a new therapeutic goal for inflammatory bowel disease (IBD) as complete healing of the mucosa is the key element of clinical remission in IBD. Previous studies showed that termination of inflammation can be achieved by adding pro-resolving lipids like DHA and EPA exogenously. However, the roles of these lipids in mucosal healing have not been investigated. To recapitulate intestinal healing process, mice were received dextran sodium sulfate (DSS) for 7 days in the drinking water followed by regular tap water for 5 additional days. DSS-induced intestinal inflammation featuring body weight loss, histological tissue damage, increased cytokine production and infiltration of inflammatory cells was gradually reduced upon switching to water. To investigate whether endogenous lipids play a role in mucosal healing, the lipidomics analysis of mouse serum was performed. Reduced levels of arachidonic acid, the biosynthetic precursor of prostaglandin F (PGF)2α, 19H-PGF1α, the metabolite of prostacyclin, and 20H-PGF2α, the metabolite of PGF2α, suggest subsiding inflammation. In contrast, increased levels of an active metabolite of resolvin D1 along with decreased levels of its precursor DHA as well as decreased levels of the precursor of resolvin E, 18-hydroxy-eicosapentaenoic acid, suggest inauguration of mucosal healing by endogenous lipids. Furthermore, exogenously supplied fish oil enhanced the process even further. These results suggest the presence of mucosal healing regulated by endogenous pro-healing lipids and also indicate that the remission state of IBD could be prolonged by enhancing the levels of these lipids. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy. [ABSTRACT FROM AUTHOR]