scholarly journals Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis

2019 ◽  
Vol 11 (515) ◽  
pp. eaax2945 ◽  
Author(s):  
Yi-Ling Chen ◽  
Danuta Gutowska-Owsiak ◽  
Clare S. Hardman ◽  
Melanie Westmoreland ◽  
Teena MacKenzie ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Therapeutic Potential ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Severity Index ◽  
Fundamental Biology ◽  
Targeted Inhibition

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

scholarly journals Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiyuan Yan ◽  
Yingchi Zhang ◽  
Gaohong Sheng ◽  
Bowei Ni ◽  
Yifan Xiao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Therapeutic Effects ◽  
Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

Anti-angiogenic role of microRNA-23b in melanoma by disturbing NF-κB signaling pathway via targeted inhibition of NAMPT

2020 ◽  
Vol 16 (10) ◽  
pp. 541-458 ◽  
Author(s):  
Renrong Lv ◽  
Jing Yu ◽  
Qian Sun
Keyword(s):  
Signaling Pathway ◽  
Tumor Tissues ◽  
Melanoma Treatment ◽  
Melanoma Patients ◽  
Targeted Inhibition ◽  
Nicotinamide Phosphoribosyl Transferase ◽  
Poor Patient Survival

Aim: Melanoma is the major cause of death in patients inflicting skin cancer. We identify miR-23b plays an anti-angiogenic role in melanoma. Materials & methods: We collected tumor tissues from melanoma patients. Experiments in vivo and in vitro were designed to evaluate the role of miR-23b in melanoma. Results & conclusion: miR-23b was found to be downregulated in melanoma tissues, and associated with poor patient survival. Elevating miR-23b inhibited cell viability and colony formation, reduced pro-angiogenetic ability, and accelerated apoptosis in SK-MEL-28 cells. miR-23b targeted NAMPT. Disturbing NF-κB signaling pathway with ammonium pyrrolidinedithiocarbamate (an inhibitor of NF-kB signaling pathway) impeded acquired pro-angiogenetic ability of nicotinamide phosphoribosyl transferase-overexpressed SK-MEL-28 cells. MiR-23b is a prognostic factor in melanoma. This study provides an enhanced understanding of microRNA-based targets for melanoma treatment.

scholarly journals Metformin Ameliorates Ethanol-Induced Liver Triglyceride Accumulation by LKB1/AMPK/ACC Pathway

2021 ◽  
Author(s):  
Fotian Xie ◽  
Dongmei Wang ◽  
Kwok Fai So ◽  
Jia Xiao ◽  
Yi Lv
Keyword(s):  
Lipid Accumulation ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Liver Triglyceride ◽  
Hepatic Lipid Accumulation ◽  
Triglyceride Accumulation ◽  
Lipid Formation

Abstract Background: Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease. Metformin is an AMPK activator that has been shown to have lipid lowering effects. The purpose of this study was to investigate whether metformin had a beneficial effect on lipid accumulation in the pathogenesis of ALD.Methods: AML12 cells and male C57BL/6 mice were used to establish ALD models in vitro and in vivo, respectively. The effects of metformin on hepatocyte lipid accumulation and ALD progression in mice were detected. The role of LKB1/AMPK/ACC axis in metformin against ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference.Results: Metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK/ACC and SREBP1c and inhibiting PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver adipose accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo.Conclusion: Metformin protects against lipid formation in ALD by activating LKB1/AMPK/ACC axis. Thus, metformin has therapeutic potential for the prevention of ALD.

scholarly journals Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar ◽  
Kumari Sunita Prajapati ◽  
Mohd Shuaib ◽  
Prem Prakash Kushwaha ◽  
Hardeep Singh Tuli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Xenograft Models ◽  
Inhibitory Potential ◽  
Pharmacological Potential

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.

scholarly journals Therapeutic potential of KIOM‐62 extract for atopic dermatitis in vitro and in vivo

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Hye‐Sun Lim ◽  
Hyekyung Ha ◽  
Mee‐Young Lee ◽  
Soo‐Jin Jeong ◽  
Seong Eun Jin ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Therapeutic Potential

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195 ◽  
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

Abstract The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

scholarly journals Metoprolol exerts a non-class effect against ischaemia–reperfusion injury by abrogating exacerbated inflammation

2020 ◽  
Vol 41 (46) ◽  
pp. 4425-4440 ◽  
Author(s):  
Agustín Clemente-Moragón ◽  
Mónica Gómez ◽  
Rocío Villena-Gutiérrez ◽  
Doménica V Lalama ◽  
Jaime García-Prieto ◽  
...  
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Adrenergic Receptor ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Β Blockers

Abstract Aims Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous β-blockers. Methods and results Mice undergoing 45 min/24 h ischaemia–reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of β-blockers on the conformation of the β1 adrenergic receptor was studied in silico. Of the tested β-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular β1 adrenergic receptor conformational changes when bound to metoprolol than to the other two β-blockers. Conclusions Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of β-blockers may be related to distinct conformational changes in the β1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous β-blocker of choice for patients with ongoing infarction.

Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Lin Zhao ◽  
Guangming Cheng ◽  
Yanjuan Yang ◽  
Anweshan Samanta ◽  
Rizwan R Afzal ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Ang Ii ◽  
Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

The RHO GTPASE CDC42 Regulator CDC42GAP Plays a Critical Role in Neutrophil Migration Via Podosome-Like Formation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 651-651 ◽  
Author(s):  
Marie-Dominique Filippi ◽  
Haiming Xu ◽  
Jason Towe ◽  
Chad E. Harris ◽  
Kathleen Szczur ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Rho Gtpase ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Cell Movement ◽  
Directed Migration ◽  
Mutant Cells

Abstract Neutrophils (PMN) are a critical cell in inflammatory processes. In response to environmental stimuli, they activate various signal transduction pathways allowing them to move rapidly to a site of microbial invasion and to perform phagocytosis, cytokine and oxygen substrate release. Rho GTPase proteins, Rac1, Rac2, CDC42 and Rho, are central regulators of cell movement via actin rearrangement. We have demonstrated the specific role of Rac1 and Rac2 in PMN functions (Gu and Filippi et al, Science 2003; Filippi et al. Nat Immuol., 2004) which raises the question of the specificity of the other Rho GTPases. CDC42 primarily regulates the formation of filopodia. CDC42 controls cell polarity and migration in hematopoietic cell lines. Most of previous studies have utilized dominant active or negative mutants which lack specificity and cannot be easily used to define in vivo cell biology. Here, we used mice genetically deficient in the CDC42 negative regulator CDC42 GTPase Activating Protein (GAP) to study the role of CDC42 in neutrophil functions in vitro and in vivo. Heterozygote (CDC42GAP+/−) or homozygote (CDC42GAP−/−) mutant mice displayed normal neutrophil differentiation in vitro and in vivo. PMN deficient in CDC42GAP displayed 2-fold increased in CDC42 activity. In vivo recruitment of PMN in peritoneal cavities after thioglycollate exposure was significantly impaired in CDC42GAP+/− mice compared with wild type (WT) mice (25.5±0.76 x 105 vs 35.7±0.38 x 105, p<0.05). Both CDC42GAP+/− and CDC42GAP−/− PMN demonstrated defective directed migration in vitro in response to fMLP in a Boyden chamber assay compared with WT (248±31 and 199±20 versus 314±29 migrated cells, p<0.05), suggesting that CDC42 plays a critical role in neutrophil migration in vitro and in vivo. To further understand the role of CDC42GAP in neutrophil migration, single-cell analysis by time-lapse videomicroscopy was performed. Surprisingly, CDC42GAP+/− PMN demonstrated higher migration velocity compared with WT cells in response to fMLP, but this increased speed was associated with an abnormal shape. Upon beta-2 integrin ligation, CDC42GAP+/− PMN demonstrated abnormal elongated trailing tail associated with increased tail filopodia. Importantly, the podosome-like structures identified by a vinculin ring surrounding F-actin at the ventral plasma membrane that are present in the leading edge of WT PMN was absent in the mutant cells. CDC42GAP−/− PMN demonstrated more dramatic F-actin impairment upon integrin ligation compared with CDC42GAP+/− and WT cells and remarkably showed complete loss of cell polarity, consistent with the known role of CDC42 in cell polarity. We hypothesize that the lack of podosome formation in mutant cells could account for the increased speed observed in CDC42GAP+/− cells and therefore result in ineffective directed migration in vivo. Altogether, this suggests that regulation of CDC42 activity plays a pivotal role in neutrophil migration likely via integrin-dependent podosome-like formation. This reinforces the importance of turnover of attachment structures during cell movement and suggests a new role for CDC42 in actin-based attachment structure in neutrophils.

Biological and Therapeutic Potential of Mir-155, 585 and Let-7f in Myeloma in Vitro and In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 833-833
Author(s):  
Sophia Adamia ◽  
Mariateresa Fulciniti ◽  
Herve Avet-Loiseau ◽  
Samir B Amin ◽  
Parantu Shah ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Tumor Size ◽  
Therapeutic Potential ◽  
Mrna Translation ◽  
Biological Role ◽  
Loss Of Function

Abstract Abstract 833 A growing body of evidence suggests that the genome of a many organisms, particularly mammals is controlled not only by transcription factors but also by post-transcriptional programs that are modulated by the family of small RNA molecules including microRNAs (miRs). miRs can block mRNA translation and affect mRNA stability. We have evaluated profiles of 384 human miRs in CD138+ cells from 79 patients with multiple myeloma (MM), 11 MM cell lines and 9 healthy donors (HD) using qRT-PCR based microRNA array. This analysis has identified a MM specific miRNA signature that significantly correlates with OS (p=0.05) and EFS (p=0.017) of patients. Based on this signature one group of patients clustered with HD suggesting indolent disease while other with cell lines indicating aggressive disease. We identified significant modulation of expression of 61 microRNAs in MM cells compared to normal plasma cells. Specific miRs with established oncogenic and tumor suppressor functions such as miR-155, miR-585 and Let7-f were significantly dysregulated in MM (p<0.001). Modulation of miRs-155, -585 and Let7 were observed most frequently in the group of patients with poor OS and EFS suggesting their crucial role in MM. However biological role of these miRs have not yet been defined. To further evaluate biological function of these most recurrent miRs in MM, we evaluated role of miR-155, let-7f and mir-585 in MM cell lines by gain- and loss- of function experiments. We used locked nucleic acid (LNA) anti-miR probes for loss of function and pre-miR-155 for gain of function studies using them alone or in combination. Although manipulation of all 3 miRs induced 20-25% change in MM cell proliferation and/or induction of apoptosis, combination of anti-miR-let7f with pre-miR-155, and anti-miR-585 in combination with miR-155 had dramatic effects on MM cell proliferation and over 60% cells undergoing apoptosis. To evaluate the targets of these miRs, we have determined effects of these anti-miRs and pre-miR on global gene and miR expression profile in MM alone and in combinations. This analysis identified modulation of cluster of miRs as well as genes critical for cell growth and survival. Next, we have tested efficacy of these miRs in vivo in murine Xenograft model to evaluate their therapeutic potential. Tumor-bearing mice were treated intraperitoneal for four consecutively days with the LNA anti-miR-585 and Let-7 and pre-miR-155 probes and respective controls alone and in combination. We observed that the single LNA anti-miR-585 and let 7 and pre miR-155 treatment reduced tumor size by 36%, 31% and 155% in animal 7 days after treatment. However, significant tumor size reductions were achieved when animals were treated with combinations; anti-miR-Let 7f plus pre-miR-155 (58 %); LNA anti-miR-Let 7f plus LNA anti-miR-585 (56 %); LNA-anti-miR-585 plus pre-miR-155 (74 %).We did not observe any significant systemic toxicity in the animals. In conclusion our results suggest significant biological role for miR-585, let 7f and miR-155 in myeloma, both in vitro and in vivo; it highlights for the first time a concerted activity of combination of miRs and holds a great promise for developing novel therapeutic approach for myeloma. Disclosures: No relevant conflicts of interest to declare.

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