Abstract:An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield 4-PBA-glutamic acid (PBA-GA) and 4-PBA-aspartic acid (PBA-AA) conjugates. The PBA derivatives were converted to 4-PBA in the cecal contents, and the conversion was greater with PBA-GA than t… Show more
“…This is not surprising since ER stress is emerging as a key signaling pathway involved in IBD pathogenesis and tissue dysfunction, driving the onset of inflammation [16,38,39]. It is also important to note that these results support the reliability of our model since a DNBS-mediated ER stress induction has also been described in an animal model of IBD [40]. Interestingly, the upregulation of these markers seems to be dose-dependent, potentially indicating increased tissue damage related to drug concentration, as also indicated by the dose-dependent upregulation of the stress protein TG2 [12].…”
Inflammatory bowel disease (IBD) is a complex, chronic, and dysregulated inflammatory condition which etiology is still largely unknown. Its prognosis and disease progression are highly variable and unpredictable. IBD comprises several heterogeneous inflammatory conditions ranging from Ulcerative Colitis (UC) to Crohn’s Disease (CD). Importantly, a definite, well-established, and effective clinical treatment for these pathologies is still lacking. The urgent need for treatment is further supported by the notion that patients affected by UC or CD are also at risk of developing cancer. Therefore, a deeper understanding of the molecular mechanisms at the basis of IBD development and progression is strictly required to design new and efficient therapeutic regimens. Although the development of animal models has undoubtedly facilitated the study of IBD, such in vivo approaches are often expensive and time-consuming. Here we propose an organ ex vivo culture (Gut-Ex-Vivo system, GEVS) based on colon from Balb/c mice cultivated in a dynamic condition, able to model the biochemical and morphological features of the mouse models exposed to DNBS (5–12 days), in 5 h. Indeed, upon DNBS exposure, we observed a dose-dependent: (i) up-regulation of the stress-related protein transglutaminase 2 (TG2); (ii) increased intestinal permeability associated with deregulated tight junction protein expression; (iii) increased expression of pro-inflammatory cytokines, such as TNFα, IFNγ, IL1β, IL6, IL17A, and IL15; (iv) down-regulation of the anti-inflammatory IL10; and (v) induction of Endoplasmic Reticulum stress (ER stress), all markers of IBD. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of IBD, in a time- and cost-effective manner.
“…This is not surprising since ER stress is emerging as a key signaling pathway involved in IBD pathogenesis and tissue dysfunction, driving the onset of inflammation [16,38,39]. It is also important to note that these results support the reliability of our model since a DNBS-mediated ER stress induction has also been described in an animal model of IBD [40]. Interestingly, the upregulation of these markers seems to be dose-dependent, potentially indicating increased tissue damage related to drug concentration, as also indicated by the dose-dependent upregulation of the stress protein TG2 [12].…”
Inflammatory bowel disease (IBD) is a complex, chronic, and dysregulated inflammatory condition which etiology is still largely unknown. Its prognosis and disease progression are highly variable and unpredictable. IBD comprises several heterogeneous inflammatory conditions ranging from Ulcerative Colitis (UC) to Crohn’s Disease (CD). Importantly, a definite, well-established, and effective clinical treatment for these pathologies is still lacking. The urgent need for treatment is further supported by the notion that patients affected by UC or CD are also at risk of developing cancer. Therefore, a deeper understanding of the molecular mechanisms at the basis of IBD development and progression is strictly required to design new and efficient therapeutic regimens. Although the development of animal models has undoubtedly facilitated the study of IBD, such in vivo approaches are often expensive and time-consuming. Here we propose an organ ex vivo culture (Gut-Ex-Vivo system, GEVS) based on colon from Balb/c mice cultivated in a dynamic condition, able to model the biochemical and morphological features of the mouse models exposed to DNBS (5–12 days), in 5 h. Indeed, upon DNBS exposure, we observed a dose-dependent: (i) up-regulation of the stress-related protein transglutaminase 2 (TG2); (ii) increased intestinal permeability associated with deregulated tight junction protein expression; (iii) increased expression of pro-inflammatory cytokines, such as TNFα, IFNγ, IL1β, IL6, IL17A, and IL15; (iv) down-regulation of the anti-inflammatory IL10; and (v) induction of Endoplasmic Reticulum stress (ER stress), all markers of IBD. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of IBD, in a time- and cost-effective manner.
“…It is worthy of noting that Jonathan H. Lin et al demonstrated that human embryonic kidney (HEK) 293 cells pretreated with TM or thapsigargin (TG) (the SERCA ATPase sarco-endoplasmic reticulum Ca 2+ -ATPases inhibitor) exhibited ER stress with an evaluation of Xbp-1s mRNA level detected by reverse transcription-polymerase chain reaction (RT-PCR) and its protein levels tested by western bolting, which indicated IRE1 activation. To further assess the effect of IRE, through selectively upregulating IRE1 activity by treating HEK293 cells with adenosine triphosphate (ATP) analog 4-amino-1-tert-butyl-3-(1′-naphthylmethyl) pyrazolo ( Kim et al, 2020 ) pyrimidine (1NM-PP1), results indicated that the number of surviving cells is much higher ( Lin et al, 2007 ). Furthermore, normal human colon epithelial cell line (NCM-460) cell viability was significantly reduced upon IRE-1 RNA interference.…”
Section: Er Stress and Its Molecular Mechanism Of Signaling Pathwaymentioning
confidence: 99%
“…Colon-targeted prodrugs of 4-PBA were designed and synthesized, and their colon-targeting property was evaluated. Furthermore, the drug’s effectiveness was shown by regulating ER stress in a model of colitis in rats ( Kim et al, 2020 ).…”
Section: Treatment Of Intestinal Diseases Targeting Er Stressmentioning
The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.
“…Distribution coefficient of AS-DpS-AS was determined using water/1-octanol system as previously described [ 26 ]. The chemical stability of AS-DpS-AS was evaluated in pH 1.2 HCl-NaCl buffer and pH 6.8 isotonic phosphate buffer.…”
Dapsone (DpS) is an antimicrobial and antiprotozoal agent, especially used to treat leprosy. The drug shares a similar mode of action with sulfonamides. Additionally, it possesses anti-inflammatory activity, useful for treating autoimmune diseases. Here, we developed a “me-better” alternative to sulfasalazine (SSZ), a colon-specific prodrug of mesalazine (5-ASA) used as an anti-inflammatory bowel diseases drug; DpS azo-linked with two molecules of 5-ASA (AS-DpS-AS) was designed and synthesized, and its colon specificity and anti-colitic activity were evaluated. AS-DpS-AS was converted to DpS and the two molecules of 5-ASA (up to approximately 87% conversion) within 24 h after incubation in the cecal contents. Compared to SSZ, AS-DpS-AS showed greater efficiency in colonic drug delivery following oral gavage. Simultaneously, AS-DpS-AS substantially limited the systemic absorption of DpS. In a dinitrobenzene sulfonic acid-induced rat colitis model, oral AS-DpS-AS elicited better efficacy against rat colitis than oral SSZ. Moreover, intracolonic treatment with DpS and/or 5-ASA clearly showed that combined treatment with DpS and 5-ASA was more effective against rat colitis than the single treatment with either DpS or 5-ASA. These results suggest that AS-DpS-AS may be a “me-better” drug of SSZ with higher therapeutic efficacy, owing to the combined anti-colitic effects of 5-ASA and DpS.
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