scholarly journals Upregulation of activin signaling in experimental colitis

2009 ◽  
Vol 297 (4) ◽  
pp. G768-G780 ◽  
Author(s):  
You-Qing Zhang ◽  
Silvia Resta ◽  
Barbara Jung ◽  
Kim E. Barrett ◽  
Nora Sarvetnick
Keyword(s):  
Epithelial Cells ◽  
Growth Inhibition ◽  
Experimental Colitis ◽  
Inflammatory Cells ◽  
Treated Group ◽  
Activin Signaling ◽  
Mediators Of Inflammation ◽  
Induced Apoptosis

Several lines of studies have suggested that activins are critical mediators of inflammation and tissue repair. As activins and their receptors are expressed in the gastrointestinal tract, we tested the hypothesis that activin signaling is involved in the development of colitis by using two murine models of colitis induced by dextran sodium sulfate (DSS) or in mdr1a−/− mice. By immunohistochemistry, expression of activins was found increased in both models and correlated with the severity of inflammation. Activin expression was observed in macrophages as well as in some nonmacrophage cells. Furthermore, while activin receptors are normally expressed in colonic epithelial cells, their expression was further increased in both epithelial cells and inflammatory cells in inflamed colonic mucosa. Moreover, in vitro studies showed that activin A inhibited proliferation and induced apoptosis of intestinal epithelial cells, and this growth inhibition was largely reversed by administration of the activin inhibitor, follistatin. Because we also observed an increased number of apoptotic epithelial cells in both colitis models, the upregulation of activins occurring in colitis could be involved both in the inflammatory process and in growth inhibition of the intestinal epithelium. Importantly, in vivo administration of follistatin attenuated inflammatory cell infiltration during colitis. Rectal bleeding was reduced, and the integrity of epithelium was preserved in the DSS/follistatin-treated group compared with the group treated with DSS alone. Bromodeoxyuridine incorporation studies showed an increase in proliferative epithelial cells in the DSS/follistatin-treated group, suggesting that follistatin accelerates epithelial cell proliferation/repair during colitis. Overall, our results reveal that activin signaling may play an important role in the pathogenesis and resolution of colitis. These findings suggest new therapeutic options in inflammatory bowel diseases.

scholarly journals Efficacy of Pyrus elaeagnifolia subsp. elaeagnifolia in acetic acid–induced colitis model

2019 ◽  
Vol 17 (1) ◽  
pp. 13-22 ◽  
Author(s):  
Mert Ilhan ◽  
Esra Küpeli Akkol ◽  
Hakkı Taştan ◽  
Fatma Tuğçe Gürağaç Dereli ◽  
Ibrahim Tümen
Keyword(s):  
Acetic Acid ◽  
Caspase 3 ◽  
Folk Medicine ◽  
Experimental Colitis ◽  
Treated Group ◽  
Meoh Extract ◽  
Colon Tissue ◽  
Snake Bites

AbstractIn Turkish folk medicine, the fruits of Pyrus elaeagnifolia subsp. elaeagnifolia have been used to treat diarrhea and detoxify poisonous snake bites by enlarging the wound. The aim of the study was to confirm the ethnopharmacological usage of the plant using in vivo and in vitro models. Experimental colitis was performed under anesthesia by intrarectal administration of acetic acid in rats, and the extracts were administered orally. The colonic malondialdehyde (MDA), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nitrite levels, in addition to the myeloperoxidase (MPO) and caspase-3 activities, were measured to determine the effects of the plant extracts. The methanol (MeOH) extract revealed a significant decrease in MPO and caspase-3 levels. The MeOH extract was found to have the highest total tannin content. It was also found to have significant antioxidant (p ˂ 0.01) and anti-inflammatory activities (p ˂ 0.05) in acetic acid induced colitis rat model . According to our results, the present study exhibited a decrease in MDA, nitrite, IL-6, and TNF-α levels in the colon tissue and blood in the MeOH extract treated group. The findings of this study can help in treating various disorders, such as Clostridium difficile infection, irritable bowel syndrome, and inflammatory bowel diseases.

scholarly journals Doxorubicin Induces Senescence in Intestinal Epithelial Cells

2021 ◽  
Author(s):  
Mandy Biraud ◽  
Jocsa Cortes ◽  
Paul Cray ◽  
Guy Kunzmann ◽  
Javid Mohammed ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Homogeneous Population ◽  
Doxorubicin Treatment ◽  
Induced Apoptosis

AbstractDoxorubicin treatment induces DNA damage and apoptosis in rapidly dividing cell types like intestinal epithelial cells. This has been demonstrated both in vivo and in vitro. In certain cell types some cells do not undergo DNA damage-induced apoptosis in response to doxorubicin but instead become senescent. Induction of senescence in these cells can lead to dysfunction and chronic inflammation, which can lead to more damage. We questioned whether a single dose of doxorubicin would be able to induce apoptosis and senescence in intestinal epithelial cells in vitro. For these studies, we exposed IEC-6 small intestinal epithelial cells to doxorubicin to evaluate whether senescence is induced in a relatively homogeneous population of intestinal epithelial cells. Although some cells underwent apoptosis, those that did not showed traits of senescence. Our studies showed that doxorubicin treatment increased cell size and increased expression of senescence-associated β-galactosidase. Concomitantly, we observed increased mRNA expression of several genes associated with a senescence-associated secretory phenotype including IL-6, Ptges, Faim2, and Cdkn1a and decreased expression of Sirt1. We also observed release of HMGB1, a cellular alarmin, from treated cells. Together, these data suggest that doxorubicin induces senescence in intestinal epithelial cells. Furthermore, our data indicate that cellular responses to a DNA damaging agent, such as doxorubicin, can differ within a population of cells suggesting differing levels of sensitivity within a relatively homogenous cell population. Further studies are needed to delineate the mechanisms that determine whether a cell moves down an apoptotic or senescent pathway following DNA damage.

Carfilzomib, An Irreversible Proteasome Inhibitor, Induces Long-Term Growth Inhibition of Mantle Cell Lymphoma In Vivo,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3740-3740
Author(s):  
Liang Zhang ◽  
Jianfei Qian ◽  
Zhishuo Ou ◽  
Luhong Sun ◽  
Kejie Zhang ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Mantle Cell ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract Abstract 3740 Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome, thus, novel therapeutic agents are urgently needed. The proteasome inhibitors are small molecular agents which show significant anti-tumor effect in patients with relapsed/refractory MCL. Carfilzomib, an irreversible proteasome inhibitor with selectivity for the chymotrypsin-like active site, inhibits the proliferation of MCL cells in vitro, as well as the reversible proteasome inhibitor bortezomib. Unlike bortezomib, carfilzomib is good-tolerated and does not induce severe neuropathy in patients. Therefore, carfilzomib can be used in higher dose than bortezomib in vivo. Our study was undertaken to evaluate the therapeutic efficacy of carfilzomib on MCL cells both in vitro and in vivo compared with bortezomib. Four human MCL cell lines, MINO, Jeko-1, MAVER, and NCEB-1, freshly isolated primary MCL cells from the patients with relapsed/refractory MCL, were treated with carfilzomib or bortezomib. A 3H-thymidine incorporation assay showed that both carfilzomib and bortezomib displayed the same dose-dependent manner in inducing growth inhibition of the MCL cells. Similarly, flow cytometry analysis with fluorescence-labeled Annexin V and propidium iodide showed that carfilzomib induced apoptosis of MCL cells in the same dose-dependent manner with bortezomib. However, under the tolerable dose of each of the two proteasome inhibitors, they had different therapeutic effect in a MCL-bearing mouse model established in severe combined immunodeficient (SCID) mice. MINO cells (5 × 106) were inoculated subcutaneously into the right flank of SCID mice. Three weeks later, after palpable tumors developed, mice were treated intravenously with carfilzomib (5 mg/kg) on day 1 and day2, for 5 cycles, or treated intraperitoneally with bortezomib (1 mg/kg) on days 1, 4, 7 and 10, per 21 days. Tumor growth was almost abrogated after treatment with carfilzomib compared with bortezomib, and the survival time of tumor-bearing mice was significantly prolonged in the carfilzomib-treated mice versus bortezomib-treated mice. Notably, Increasing the frequency or dose of bortezomib treatment was unable because the mice were too suffered in toxicity to tolerate the treatment. Western blot analysis showed that carfilzomib induced apoptosis in caspase-dependent manner as well as bortezomib. Carfilzomib inhibited the phosphorylation of IκB, STAT3, and AKT and irreversibly blocked the release of NFκB to nuclei. In conclusion, carfilzomib displays the same anti-tumor effect and mechanism with bortezomib on MCL cells in vitro. However, carfilzomib but not bortezomib is well tolerated without severe side effect in vivo. Carfilzomib significantly inhibits tumor growth and prolongs survival indicating that carfilzomib is a potential agent in MCL chemotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mycobacterium avium Infection of Epithelial Cells Results in Inhibition or Delay in the Release of Interleukin-8 and RANTES

1999 ◽  
Vol 67 (10) ◽  
pp. 5069-5075 ◽  
Author(s):  
Felix J. Sangari ◽  
Mary Petrofsky ◽  
Luiz E. Bermudez
Keyword(s):  
Epithelial Cells ◽  
Mycobacterium Avium ◽  
Intestinal Mucosa ◽  
Inflammatory Cells ◽  
Interleukin 8 ◽  
Cell Culture Supernatant ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ht 29

ABSTRACT Mycobacterium avium is an opportunistic pathogen in AIDS patients, who acquire the infection mainly through the gastrointestinal tract. Previous studies in vitro have shown thatM. avium invades epithelial cells of both intestinal and laryngeal origin. In addition, M. avium enters the intestinal mucosa of healthy mice. Because M. aviuminvasion of the intestinal mucosa in vivo initially is not accompanied by significant influx of inflammatory cells, we sought to determine whether M. avium would trigger chemokine release upon entry into epithelial cells by using HT-29 intestinal and HEp-2 laryngeal epithelial cell lines. Chemokine synthesis was measured both by the presence of specific mRNA and protein secretion in the cell culture supernatant as determined by enzyme-linked immunosorbent assay. Infection of HT-29 intestinal cells with M. avium did not induce the release of interleukin-8 (IL-8) or RANTES for up to 7 days postinfection. However, infection of HEp-2 cells resulted in the release of IL-8 and RANTES at 72 h. Similar findings were observed with other AIDS M. avium isolates belonging to different serovars. Secretion of IL-8 by HEp-2 cells was dependent upon bacterial uptake. In addition, prior infection with M. aviumsuppressed IL-8 production by HT-29 cells infected withSalmonella typhimurium. Our results suggest that M. avium infection of epithelial cells is associated with a delay in IL-8 and RANTES production which, in the case of HT-29, is prolonged up to 1 week. These findings may explain the weak inflammatory response after intestinal mucosa invasion in mice and are probably related with the ability of the bacterium to evade the host’s immune response.

scholarly journals PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Dou ◽  
Hang Tong ◽  
Yichun Yang ◽  
Han Zhang ◽  
Hua Gan
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Induced Apoptosis

We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.

scholarly journals Epithelial Toll-Like Receptor 5 Is Constitutively Localized in the Mouse Cecum and Exhibits Distinctive Down-Regulation during Experimental Colitis

2006 ◽  
Vol 13 (1) ◽  
pp. 132-138 ◽  
Author(s):  
Cesar F. Ortega-Cava ◽  
Shunji Ishihara ◽  
Mohammad A. K. Rumi ◽  
M. M. Aziz ◽  
Hideaki Kazumori ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Experimental Colitis ◽  
Proximal Colon ◽  
Northern Blotting ◽  
Toll Like Receptor ◽  
Down Regulation ◽  
Ifn Γ ◽  
Tlr5 Expression

ABSTRACT We recently demonstrated that the pattern recognition receptors (PRRs) toll-like receptor 2 (TLR2), TLR4, and CD14 are expressed in mouse colonic epithelium in a compartmentalized manner. Here we report the localization of TLR5, the receptor for bacterial flagellin, and its distinctive down-regulation during experimental colitis. Guts from normal BALB/c mice and those with dextran sodium sulfate (DSS)-induced colitis were compared. Each gut was divided into seven segments (stomach, small intestine [three parts], and colon [three parts]), and epithelial cells and crypt units were collected by scraping and EDTA treatment, respectively. Northern blotting showed that TLR5 mRNA was preferentially expressed in the epithelium of the proximal colon in normal mice. Laser capture microdissection coupled to reverse transcriptase PCR confirmed this localization. TLR5 protein expression reflected mRNA expression, as evidenced by Western blotting. In mice with acute colitis, inflammation occurred mainly in the distal colon. Interestingly, while TLR2, TLR4, and CD14 were up-regulated in the inflamed colon, TLR5 was down-regulated at both the mRNA and protein levels. Decreased TLR5 expression was more evident during chronic colitis. Additional in vitro studies using a mouse cell line, Colon-26, showed that gamma interferon (IFN-γ) time- and dose-dependently down-regulates TLR5. In conclusion, epithelial cells, mainly in the proximal colon, constitutively express TLR5. TLR5 expression is down-regulated in vivo during acute and chronic DSS-induced colitis, in contrast to the expression of TLR2, TLR4, and CD14. The mechanism governing TLR5 regulation may therefore differ from that controlling other PRRs. Finally, IFN-γ may be involved in down-regulating TLR5 expression.

scholarly journals RhoB Alteration Is Necessary for Apoptotic and Antineoplastic Responses to Farnesyltransferase Inhibitors

2000 ◽  
Vol 20 (16) ◽  
pp. 6105-6113 ◽  
Author(s):  
Ai-xue Liu ◽  
Wei Du ◽  
Jeh-Ping Liu ◽  
Thomas M. Jessell ◽  
George C. Prendergast
Keyword(s):  
Growth Inhibition ◽  
Malignant Cell ◽  
Homozygous Deletion ◽  
Farnesyltransferase Inhibitors ◽  
Human Carcinoma ◽  
Adenovirus E1a ◽  
Geranylgeranyltransferase I ◽  
Induced Apoptosis

ABSTRACT Farnesyltransferase inhibitors (FTIs) are in clinical trials, but how they selectively inhibit malignant cell growth remains uncertain. One important player in this process appears to be RhoB, an endosomal Rho protein that regulates receptor trafficking. FTI treatment elicits a gain of the geranylgeranylated RhoB isoform (RhoB-GG) that occurs due to modification of RhoB by geranylgeranyltransferase I in drug-treated cells. Notably, this event is sufficient to mediate antineoplastic effects in murine models and human carcinoma cells. To further assess this gain-of-function mechanism and determine whether RhoB-GG has a necessary role in drug action, we examined the FTI response of murine fibroblasts that cannot express RhoB-GG due to homozygous deletion of the rhoB gene. Nullizygous (−/−) cells were susceptible to cotransformation by adenovirus E1A plus activated H-Ras but defective in their FTI response, despite complete inhibition of H-Ras prenylation. Actin cytoskeletal and phenotypic events were disrupted in −/− cells, implicating RhoB-GG in these effects. Interestingly, −/− cells were resistant to FTI-induced growth inhibition under anchorage-dependent but not anchorage-independent conditions, indicating that, while RhoB-GG is sufficient, it is not necessary for growth inhibition under all conditions. In contrast, −/− cells were resistant to FTI-induced apoptosis in vitro and in vivo. Significantly, the apoptotic defect of −/− cells compromised the antitumor efficacy of FTI in xenograft assays. This study offers genetic proof of the hypothesis that RhoB-GG is a crucial mediator of the antineoplastic effects of FTIs.

Bleomycin initiates apoptosis of lung epithelial cells by ROS but not by Fas/FasL pathway

2006 ◽  
Vol 290 (4) ◽  
pp. L790-L796 ◽  
Author(s):  
Shulamit B. Wallach-Dayan ◽  
Gabriel Izbicki ◽  
Pazit Y. Cohen ◽  
Regina Gerstl-Golan ◽  
Alan Fine ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Lung Epithelial ◽  
Induced Apoptosis

Epithelial cells are considered to be a main target of bleomycin-induced lung injury, which leads to fibrosis in vivo. We studied the characteristics of in vitro bleomycin-induced apoptosis in a mouse lung epithelial (MLE) cell line. Bleomycin caused an increase of reactive oxygen species (ROS) resulting in oxidative stress, mitochondrial leakage, and apoptosis. These were associated with elevated caspase-8 and resultant caspase-9 activity and with upregulation of Fas expression. Glutathione and inhibitors of caspase-8 or caspase-9, but not of FasL, inhibited these effects, suggesting their dependence on ROS, caspase-8 and -9, in a Fas/FasL-independent pathway. However, postbleomycin-exposed MLE cells were more sensitive to Fas-mediated apoptosis. These results demonstrate that the initial bleomycin-induced oxidative stress causes a direct apoptotic effect in lung epithelial cells involving a regulatory role of caspase-8 on caspase-9. Fas represents an amplification mechanism, and not a direct trigger of bleomycin-induced epithelial cell apoptosis.

Healing effects of curcumin nanoparticles in deep tissue injury mouse model.

2020 ◽  
Vol 18 ◽  
Author(s):  
Zirui Zhang ◽  
Shangcong Han ◽  
Panpan Liu ◽  
Xu Yang ◽  
Jing Han ◽  
...  
Keyword(s):  
Wound Healing ◽  
Mrna Expression ◽  
Tissue Injury ◽  
Inflammatory Cells ◽  
Pcr Analysis ◽  
Protective Effects ◽  
Deep Tissue ◽  
Deep Tissue Injury

Background: Chronic inflammation and lack of angiogenesis are the important pathological mechanisms in deep tissue injury (DTI). Curcumin is a well-known anti-inflammatory and antioxidant agent. However, curcumin is unstable under acidic and alkaline conditions, and can be rapidly metabolized and excreted in the bile, which shortens its bioactivity and efficacy. Objective: This study aimed to prepare curcumin-loaded poly (lactic-co-glycolic acid) nanoparticles (CPNPs) and to elucidate the protective effects and underlying mechanisms of wound healing in DTI models. Methods: CPNPs were evaluated for particle size, biocompatibility, in vitro drug release and their effect on in vivo wound healing. Results : The results of in vivo wound closure analysis revealed that CPNP treatments significantly improved wound contraction rates (p<0.01) at a faster rate than other three treatment groups. H&E staining revealed that CPNP treatments resulted in complete epithelialization and thick granulation tissue formation, whereas control groups resulted in a lack of compact epithelialization and persistence of inflammatory cells within the wound sites. Quantitative real-time PCR analysis showed that treatment with CPNPs suppressed IL-6 and TNF-α mRNA expression, and up-regulated TGF-β, VEGF-A and IL-10 mRNA expression. Western blot analysis showed up-regulated protein expression of TGF-β, VEGF-A and phosphorylatedSTAT3. Conclusion: Our results showed that CPNPs enhanced wound healing in DTI models, through modulation of the JAK2/STAT3 signalling pathway and subsequent upregulation of pro-healing factors.

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