scholarly journals KCNN4 Expression Is Elevated in Inflammatory Bowel Disease: This Might Be a Novel Marker and Therapeutic Option Targeting Potassium Channels

2020 ◽  
Vol 29 (4) ◽  
pp. 539-547
Author(s):  
Christoph Süss ◽  
Lucile Broncy ◽  
Kirstin Pollinger ◽  
Claudia Kunst ◽  
Karsten Gülow ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cell Monolayer ◽  
Secretory Diarrhea ◽  
K Channel ◽  
Epithelial Barrier ◽  
Mrna Levels ◽  
Inflammatory Bowel

Background and Aims: The K + channel KCNN4 is involved in many inflammatory diseases. Previous work has shown that this channel is involved in epithelial ion transport and intestinal restitution. In inflammatory bowel diseases (IBD) a defective epithelial barrier can lead to typical symptoms like secretory diarrhea and the formation of intestinal ulcers. We compared surgical samples from patients with IBD, diverticulitis and controls without inflammation to determine the potential role of KCNN4 as a diagnostic marker and/or therapeutic target. Methods: mRNA-levels of KCNN4 and a control K + channel were determined in intestinal epithelial cells (IEC) from patients with IBD, diverticulitis and controls. In addition, we performed a Western blot analysis of KCNN4 and a respective control K + channel in IEC from patients with IBD. Furthermore, we determined epithelial barrier integrity by measuring the flux of fluorescent-labeled dextran beads across a cell monolayer upon incubation with interferon-γ. Results: KCNN4 mRNA and protein levels were elevated in IEC from patients with Crohn`s disease (CD) and ulcerative colitis (UC). Of note, KCNN4 was not elevated in non-IBD intestinal inflammatory conditions e.g. diverticulitis. Of clinical relevance, pharmacological KCNN4 channel openers stabilized epithelial barrier function in vitro. Thus, KCNN4 may have a protective role in IBD and constitute a therapeutic target. Conclusions: Our data demonstrate elevated KCNN4 both at mRNA and protein level in IEC specifically from patients with IBD. Therefore, we conclude that KCNN4 could be used as a novel marker for IBD, especially for the establishment of initial diagnosis. Of therapeutic consequence, we show that pharmacological KCNN4 openers stabilize the epithelial barrier. Thus, KCNN4 might be a novel target to diagnose and treat IBD.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

scholarly journals Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

2021 ◽  
Vol 22 (14) ◽  
pp. 7311
Author(s):  
Mateusz Wawro ◽  
Jakub Kochan ◽  
Weronika Sowinska ◽  
Aleksandra Solecka ◽  
Karolina Wawro ◽  
...  
Keyword(s):  
Family Member ◽  
Cellular Localization ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Psoriasis Patient ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

scholarly journals NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1861
Author(s):  
Tyler Sheetz ◽  
Joseph Mills ◽  
Anna Tessari ◽  
Megan Pawlikowski ◽  
Ashley E. Braddom ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Therapeutic Option ◽  
The United States ◽  
Mrna Levels ◽  
Advanced Stage ◽  
Castration Resistant Prostate Cancer ◽  
Single Chain

Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.

The therapeutic use of the zonulin inhibitor AT-1001 (Larazotide) for a variety of acute and chronic inflammatory diseases

2021 ◽  
Vol 28 ◽  
Author(s):  
Jacopo Troisi ◽  
Giorgia Venutolo ◽  
Concetta Terracciano ◽  
Matteo Delli Carri ◽  
Simone Di Micco ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Inflammatory Diseases ◽  
Endothelial Permeability ◽  
Careful Examination ◽  
Subsequent Increase ◽  
Inflammatory Bowel

Background: The involvement of intercellular tight junctions and, in particular, the modulation of their competency by the zonulin pathway with a subsequent increase in epithelial and endothelial permeability, has been described in several chronic and acute inflammatory diseases. In this scenario, Larazotide, a zonulin antagonist, could be employed as a viable therapeutic strategy. Objective: The present review aims to describe recent research and current observations about zonulin involvement in several diseases and the use of its inhibitor Larazotide for their treatment. Methods: A systematic search was conducted on PubMed and Google Scholar, resulting in 209 publications obtained with the following search query: “Larazotide,” “Larazotide acetate,” “AT-1001,” “FZI/0” and “INN-202.” After careful examination, some publications were removed from consideration because they were either not in English or were not directly related to Larazotide. Results: The obtained publications were subdivided according to Larazotide’s mechanism of action and different diseases: celiac disease, type 1 diabetes, other autoimmune diseases, inflammatory bowel disease, Kawasaki disease, respiratory (infective and/or non-infective) diseases, and other. Conclusions: A substantial role of zonulin in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro, indicating the possible efficacy of a Larazotide treatment. Moreover, new possible molecular targets for this molecule have also been demonstrated.

Phytochemical Analysis and In-vitro Anti-Diabetic and Anti- Inflammatory study of root extract of Apama siliquosa LAMK.

2021 ◽  
pp. 5838-5842
Author(s):  
Manu Jose ◽  
Stephin Baby ◽  
Dona Mathew ◽  
Naurin Muhammed ◽  
Jayalakshmi P M
Keyword(s):  
Inflammatory Diseases ◽  
Herbal Medicines ◽  
Alpha Amylase ◽  
Phytochemical Analysis ◽  
Root Extract ◽  
Inhibition Assay ◽  
Ic50 Value ◽  
Inflammatory Bowel ◽  
Anti Inflammatory

The demand for herbal medicines in many pharmaceutical sectors is growing at a drastic rate due to their improved pharmacological actions, minimal side effects and cost-effectiveness. Anti-inflammatory phytochemicals are found to be efficacious against the treatment of inflammatory diseases like rheumatoid arthritis, glomerulonephritis, hepatitis, inflammatory bowel disease, etc. Anti-diabetic phytochemicals are found to treat the increasing incidence of diabetes prevalent globally. This work aims to perform the phytochemical screening and to evaluate the antidiabetic and anti-inflammatory activity of crude extract of Apama siliquosa Lamk. The method employed for obtaining the active principles includes soxhlation technique with methanol as solvent. The anti-inflammatory property was studied in vitro using inhibition of albumin denaturation technique as well as heat-induced hemolysis and IC50 value was found to be 39.5μg/ml and 36.30μg/ml respectively. The anti-diabetic activity was estimated using the alpha-amylase inhibition assay and Glucose diffusion inhibitory study. The IC50 value for alpha-amylase inhibition assay was found to be 15.75μg/ml. It also shows a strong inhibition of glucose across the dialysis membrane.

scholarly journals Barrier Protection and Recovery Effects of Gut Commensal Bacteria on Differentiated Intestinal Epithelial Cells In Vitro

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2251
Author(s):  
Nooshin Mohebali ◽  
Katharina Ekat ◽  
Bernd Kreikemeyer ◽  
Anne Breitrück
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Bacterial Species ◽  
Cell Monolayer ◽  
Commensal Bacteria ◽  
Epithelial Barrier ◽  
Inflammatory Stimulus ◽  
Monocyte Chemoattractant Protein 1

Alterations in the gut microbiota composition play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) as specific commensal bacterial species are underrepresented in the microbiota of IBD patients. In this study, we examined the therapeutic potential of three commensal bacterial species, Faecalibacterium prausnitzii (F. prausnitzii), Roseburia intestinalis (R. intestinalis) and Bacteroides faecis (B. faecis) in an in vitro model of intestinal inflammation, by using differentiated Caco-2 and HT29-MTX cells, stimulated with a pro-inflammatory cocktail consisting of interleukin-1β (IL-1β), tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), and lipopolysaccharide (LPS). Results obtained in this work demonstrated that all three bacterial species are able to recover the impairment of the epithelial barrier function induced by the inflammatory stimulus, as determined by an amelioration of the transepithelial electrical resistance (TEER) and the paracellular permeability of the cell monolayer. Moreover, inflammatory stimulus increased claudin-2 expression and decreased occludin expression were improved in the cells treated with commensal bacteria. Furthermore, the commensals were able to counteract the increased release of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) induced by the inflammatory stimulus. These findings indicated that F. prausnitzii, R. intestinalis and B. faecis improve the epithelial barrier integrity and limit inflammatory responses.

scholarly journals α4β7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis

2021 ◽  
Vol 14 ◽  
pp. 175628482110547
Author(s):  
Michaela Melde ◽  
Tanja M. Müller ◽  
Ines Schneider ◽  
Carol-Immanuel Geppert ◽  
Laura Mühl ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion Molecule ◽  
Ileal Pouch ◽  
Therapeutic Option ◽  
Clinical Effects ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Inflammatory Bowel ◽  
And Function

Background: The anti-α4β7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far. Methods: We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis. Results: T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4β7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1. Conclusion: Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.

scholarly journals Itaconate and its derivatives repress C2C12 myogenesis via succinate dehydrogenase inhibition

2021 ◽  
Author(s):  
Tae Seok Oh ◽  
Damian C. Hutchins ◽  
Rabina Mainali ◽  
Kevin Goslen ◽  
Joshua Hayes ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Krebs Cycle ◽  
Muscle Differentiation ◽  
Protein Markers ◽  
Dimethyl Malonate ◽  
Disease Treatment

AbstractA Krebs cycle intermediate metabolite, itaconate, has gained attention as a potential antimicrobial and autoimmune disease treatment due to its anti-inflammatory effects. While itaconate and its derivatives pose an attractive therapeutic option for the treatment of inflammatory diseases, the effects outside the immune system still remain limited, particularly in the muscle. Therefore, we endeavored to determine if itaconate signaling impacts muscle differentiation. Utilizing the well-established C2C12 model of in vitro myogenesis, we evaluated the effects of itaconate and its derivatives on transcriptional and protein markers of muscle differentiation as well as mitochondrial function. We found itaconate and the derivatives dimethyl itaconate and 4-octyl itaconate disrupt differentiation media-induced myogenesis. A primary biological effect of itaconate is a succinate dehydrogenase (SDH) inhibitor. We find the SDH inhibitors dimethyl malonate and harzianopyridone phenocopies the anti-myogenic effects of itaconate. Furthermore, we find treatment with exogenous succinate results in blunted myogenesis. Together our data indicate itaconate and its derivatives interfere with in vitro myogenesis, potentially through inhibition of SDH and subsequent succinate accumulation. More importantly, our findings suggest the therapeutic potential of itaconate and its derivatives could be limited due to deleterious effects on myogenesis.

scholarly journals MiR-143-5p Deficiency Triggers EMT and Metastasis by Targeting HIF-1α in Gallbladder Cancer

2017 ◽  
Vol 42 (5) ◽  
pp. 2078-2092 ◽  
Author(s):  
Min He ◽  
Ming Zhan ◽  
Wei Chen ◽  
Sunwang Xu ◽  
Manmei Long ◽  
...  
Keyword(s):  
Gallbladder Cancer ◽  
Therapeutic Target ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Regulation Mechanism ◽  
Mrna Levels ◽  
Mesenchymal Transition

Background/Aims: Early metastasis plays a pivotal role in tumor-caused death in gallbladder cancer (GBC) patients. Increasing evidence suggest that miR-143-5p is an active player involved in cancer metastasis and a potential therapeutic target. However, its role in the development of GBC cells remains unclear. The aim of this study is to reveal the inhibiting effects of miR-143-5p on the proliferation and metastasis in GBC. Methods: Quantitative real-time PCR were used to investigate miR-143-5p and its target HIF-1α mRNA levels. Protein expression was measured by immunohistochemistry and western blot. The function and regulation mechanism of miR-143-5p was confirmed by MTS, colony formation, wound healing, transwell, and luciferase reporter assays. Results: miR-143-5p was first found significantly reduced in GBC tissues compared with corresponding noncancerous gallbladder tissues. In addition, miR-143-5p deficiency correlated well with larger tumor size, advanced TNM stage, and poorer survival rate. In vitro, miR-143-5p addition dramatically suppressed GBC cells proliferation, migration and invasion, whereas miR-143-5p antisense led the opposite effects. Further elucidating the molecular mechanism inside, we found miR-143-5p exerted its inhibitory function through downregulating the expression of HIF-1α, which further reduced Twist1 and impeded epithelial-mesenchymal transition (EMT). Conclusions: Altogether, our studies identified a novel regulator, miR-143-5p, implicated in GBC prognosis through targeting HIF-1α/EMT related signaling pathway, which could serve as a biomarker and therapeutic target for GBC.

scholarly journals Acyclic Triterpenoid Isolated from Alpinia katsumadai Alleviates Formalin-Induced Chronic Mouse Paw Inflammation by Inhibiting the Phosphorylation of ERK and NF-κB

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3345 ◽  
Author(s):  
Hyung Jin Lim ◽  
Seon Gyeong Bak ◽  
Hee Ju Lim ◽  
Seung Woong Lee ◽  
Soyoung Lee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Diseases ◽  
Extracellular Signal ◽  
Tnf Α ◽  
J774 Cells ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Necrosis Factor

Chronic and excessive inflammation can destroy host organs and cause inflammatory diseases such as inflammatory bowel disease, asthma, and rheumatoid arthritis. In this study, we investigated the anti-inflammatory effects of Alpinia katsumadai seed-derived 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (PHT) using lipopolysaccharide (LPS)-stimulated J774 cells and a formalin-induced chronic paw inflammation mouse model. The in vitro results showed that PHT exhibited no cytotoxicity and decreased LPS-induced NO secretion. Additionally, PHT inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. The quantitative real-time PCR results showed that PHT downregulated the gene expression of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). PHT inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB). In a mouse model, oral administration of 50 mg/kg PHT significantly alleviated both mouse paw thickness and volume. These results indicate that PHT has potential anti-inflammatory effects and should be considered a possible functional material.

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