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Chronic kidney disease (CKD) is a global public health problem, involving about 10% of the global population. Unfortunately, there are currently no effective drugs. Kidney fibrosis is the main pathology of CKD, where integrins play crucial roles in renal fibrogenesis. Recently, Bexotegrast (PLN-74809) as a dual integrin αvβ1/αvβ6 inhibitor could reduce the degree of lung fibrosis in patients with idiopathic pulmonary fibrosis. However, the role of PLN-74809 remains unclear in fibrotic kidney disease. Here, we have revealed that PLN-74809 administration dose-dependently delayed the progression of renal fibrosis in both adenine diet- and unilateral ureteral obstruction (UUO)-induced mice. Mechanistically, PLN-74809 targeted integrin αvβ1/αvβ6 to inhibit FAK/Src/Akt/β-catenin cascade in fibrotic kidneys. In summary, our results for the first time highlighted the αvβ1/αvβ6 inhibitor PLN-74809 exerted potential therapeutic against kidney fibrosis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

The α v β 6 integrin has been identified as a target for the treatment of fibrotic diseases, based on the role it has in activating TGF-β 1 , a protein implicated in the pathogenesis of fibrosis. However, the development of orally bioavailable α v β 6 inhibitors has proven challenging due to the zwitterionic pharmacophore required to bind to the RGD binding site. This work describes the design and development of a novel, orally bioavailable series of α v β 6 inhibitors, developing on two previously published α v β 6 inhibitors, GSK3008348 and GSK3335103. Strategies to reduce the basicity of the central ring nitrogen present in GSK3008348 were employed, while avoiding the synthetic complexity of the chiral, fluorine-containing quaternary carbon center contained in GSK3335103. Following initial PK studies, this series was optimized, aided by analysis of the physicochemical and in vitro PK properties, to deliver lead molecules ( S )- 20 and 28 as potent and orally bioavailable α v β 6 inhibitors with improved synthetic tractability.

A series of 3-aryl(( S )-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable α v β 6 integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and p K a of the central cyclic amine is described. ( S )-4-(( S )-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities, high α v β 6 integrin potency of pIC50 of 8.0, and high solubility in physiological media (>2 mg/mL). Equating to the estimated human dose range of 10-75 mg b.i.d. to achieve 90% α v β 6 target engagement at C min , it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

Competing Interests: The authors declare no conflict of interest.

Integrin proteins have received a significant increase in attention in recent scientific endeavors. The current trend uses the pre-established knowledge that the arginyl-glycyl-aspartic acid (RGD) structural motif present in the A20FMDV2 peptide is highly selective for the integrin class αvβ6 which is overexpressed in many cancer types. This review will provide an extensive overview of the existing literature research to date to the best of our knowledge, highlighting significant improvements and drawbacks of structure-activity relationships (SAR) work undertaken, aiding future research to identify established SAR for an informed design of future A20FMDV2 mimetic inhibitors. Herein, the review aims to collate the existing structural chemical modifications present on A20FMDV2 in the literature to highlight key structural analogues that display more potent biological activity., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5 , ITGB3 , PAI1 , and p21 , may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.

Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleavable or non-cleavable linker in peptide-drug conjugates (PDCs) or small molecule-drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody-drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small-molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin α V β 3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin-addressing PDCs and SMDCs while highlighting points of great interest., (© 2024 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown cause with a dismal prognosis. Nintedanib and Pirfenidone are approved worldwide for the treatment of IPF, but they only slow the rate of functional decline and disease progression. Therefore, there is an urgent need for more efficacious and better tolerated drugs., Areas Covered: αvβ6 and αvβ1 are two integrins overexpressed in fibrotic tissue, which play a critical role in the development of lung fibrosis. They act by converting transforming growth factor (TGF)-β, one of the most important profibrotic cytokine, in its active form. Here, we summarize and critically discuss the potential of a dual αvβ6/αvβ1 integrin inhibitor for the treatment of IPF., Expert Opinion: Bexotegrast, a dual αvβ6/αvβ1 integrin inhibitor, has the potential to slow or even halt disease progression in IPF. Indeed, the strong pre-clinical rationale and promising early phase clinical trial data have raised expectations.

Crohn's disease (CD) is a chronic and debilitating inflammatory bowel disease that affects millions of individuals worldwide. Despite the availability of various treatment options, a significant number of patients do not achieve remission or experience adverse effects with conventional therapies. Vedolizumab, a novel therapeutic agent, has emerged as a promising approach in the management of CD. Despite improvements in treatment choices, there is still a demand for medicines that are efficient and well-tolerated. Vedolizumab, a monoclonal antibody targeting α4β7 integrin, has emerged as a promising therapeutic approach for the treatment of CD. The review aims to provide a summary of vedolizumab, current treatment options, impact of vedolizumab on the patient's quality of life, mechanism of action, clinical effectiveness, safety and efficacy of vedolizumab, potential side effects or risks associated with vedolizumab therapy, and potential predictors. Furthermore, we investigate limitations and challenges associated with vedolizumab and possible future developments and medical implications. This review provides a comprehensive examination of the present data supporting vedolizumab as a possible treatment option for CD, highlighting its benefits and outlining prospective directions for future study and clinical practice improvement., (© 2024 Wiley Periodicals LLC.)

Background: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvβ6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis., Methods: Serum anti-integrin αvβ6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvβ6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients., Results: Anti-integrin αvβ6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvβ6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvβ6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvβ6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvβ6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC., Conclusions: Anti-integrin αvβ6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis., (© 2024. The Author(s).)

Background: Closing mucosal defects to reach mucosal healing is an important goal of therapy in inflammatory bowel disease (IBD). Among other cells, monocyte-derived macrophages are centrally involved in such intestinal wound healing. We had previously demonstrated that the anti-α4β7 integrin antibody vedolizumab blocks the recruitment of non-classical monocytes as biased progenitors of wound healing macrophages to the gut and delays wound healing. However, although important for the interpretation of disappointing results in recent phase III trials in IBD, the effects of the anti-β7 antibody etrolizumab on wound healing are unclear so far., Methods: We analyzed the expression of etrolizumab targets on human and mouse monocyte subsets by flow cytometry and assessed their function in adhesion and homing assays. We explored wound-associated monocyte recruitment dynamics with multi-photon microscopy and compared the effects of etrolizumab and vedolizumab surrogate (-s) antibodies on experimental wound healing and wound-associated macrophage abundance. Finally, we investigated wound healing macrophage signatures in the large intestinal transcriptome of patients with Crohn's disease treated with etrolizumab., Results: Human and mouse non-classical monocytes expressed more αEβ7 integrin than classical monocytes and were a target of etrolizumab-s, which blocked non-classical monocyte adhesion to MAdCAM-1 and E-Cadherin as well as gut homing in vivo. Intestinal wound healing was delayed on treatment with etrolizumab-s along with a reduction of peri-lesional wound healing macrophages. Wound healing macrophage signatures in the colon of patients with Crohn's disease were substantially down-regulated on treatment with etrolizumab, but not with placebo., Conclusions: Combined blockade of αEβ7 and α4β7 with etrolizumab seems to exceed the effect of anti-α4β7 treatment on intestinal wound healing, which might help to inform further investigations to understand the recent observations in the etrolizumab phase III trial program., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Integrins are a group of heterodimers consisting of α and β subunits that mediate a variety of physiological activities of immune cells, including cell migration, adhesion, proliferation, survival, and immunotolerance. Multiple types of integrins act differently on the same immune cells, while the same integrin may exert various effects on different immune cells. In the development of cancer, integrins are involved in the regulation of cancer cell proliferation, invasion, migration, and angiogenesis; conversely, integrins promote immune cell aggregation to mediate the elimination of tumors. The important roles of integrins in cancer progression have provided valuable clues for the diagnosis and targeted treatment of cancer. Furthermore, many integrin inhibitors have been investigated in clinical trials to explore effective regimens and reduce side effects. Due to the complexity of the mechanism of integrin-mediated cancer progression, challenges remain in the research and development of cancer immunotherapies (CITs). This review enumerates the effects of integrins on four types of immune cells and the potential mechanisms involved in the progression of cancer, which will provide ideas for more optimal CIT in the future.

Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvβ6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvβ6 is intended to locally and selectively block transforming growth factor beta (TGF-β) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvβ6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-β. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvβ6 or TGF-β receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvβ6 inhibition and decreased TGF-β signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Background and Objectives: To evaluate the safety, tolerability, and biological activity of a topical selective integrin inhibitor (OTT166) eyedrop administered BID for diabetic retinopathy (DR) and diabetic macular edema (DME)., Study Design/materials and Methods: A prospective, multicenter, randomized, double-masked Phase 1b study. Subjects with nonproliferative DR and DME with central subfield thickness (CST) &gt; 325 microns were randomized to OTT166 eyedrops (2.5% or 5%) BID for 28 days. Subjects were followed for an additional 28 days after treatment cessation., Results: Forty-four subjects were enrolled. No drug-related serious adverse events (SAEs) and two drug-related adverse events (AEs) were reported. OTT166 was well-tolerated with no evidence of ocular toxicity. Best-corrected visual acuity (BCVA) remained stable. Mean central retinal thickness (CRT) overall was variable: +12.8/+1.8 microns at Day 28 (end of treatment) and -50.3/+5.5 microns at Day 56 (end of study) for the 2.5% and 5% groups, respectively. Median CRT overall demonstrated consistent reduction by end of study: -39.0/-16.5 microns for the 2.5% and 5% groups, respectively. Median responses were greater in the treatment-naïve group (-41.5/-26.0 microns for the 2.5% and 5% groups, respectively). Thirty-seven percent of 'responder' subjects exhibited a mean reduction in CRT of 46.6 microns on optical coherence tomography (OCT) at end of treatment (Day 28) which persisted to end of the study (Day 56) - mean reduction of 67.4 microns, suggesting a durable effect., Conclusion: OTT166 eyedrops were safe, well-tolerated, and demonstrated biological activity in 37% of responders. These results warrant further evaluation of OTT166 eyedrops. &lt;b&gt;[&lt;i&gt;Ophthalmic Surg Lasers Imaging Retina&lt;/i&gt; 2022;53:553-560.]&lt;/b&gt;.

223 Ra is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity toward PCa cells near the bone interface, whereas cells positioned in the core respond poorly because of short α-particle penetrance. β1 integrin (β1I) interference has been shown to increase radiosensitivity and significantly enhance external-beam radiation efficiency. We hypothesized that targeting β1I would improve 223 Ra outcome. Methods: We tested the effect of combining 223 Ra and anti-β1I antibody treatment in PC3 and C4-2B PCa cell models expressing high and low β1I levels, respectively. In vivo tumor growth was evaluated through bioluminescence. Cellular and molecular determinants of response were analyzed by ex vivo 3-dimensional imaging of bone lesions and by proteomic analysis and were further confirmed by computational modeling and in vitro functional analysis in tissue-engineered bone mimetic systems. Results: Interference with β1I combined with 223 Ra reduced PC3 cell growth in bone and significantly improved overall mouse survival, whereas no change was achieved in C4-2B tumors. Anti-β1I treatment decreased the PC3 tumor cell mitosis index and spatially expanded 223 Ra lethal effects 2-fold, in vivo and in silico. Regression was paralleled by decreased expression of radioresistance mediators. Conclusion: Targeting β1I significantly improves 223 Ra outcome and points toward combinatorial application in PCa tumors with high β1I expression., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbβ3, α4β7/α4β1 and αLβ2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvβ3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvβ6 and αvβ1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins., (© 2021. Springer Nature Limited.)

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvβ6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvβ6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvβ6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvβ6 integrin and inhibit the activation of TGFβ in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvβ6 engagement, TGFβ signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvβ6 inhibitor that attenuates TGFβ signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC)., Methods: In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks., Results: PTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood., Conclusions: PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, "disease specificity" has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, "disease specific" integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather "pathology specific" nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.

Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson's trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-β (TGF-β) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism.

PN-943 is an orally stable, gastrointestinal-restricted peptide that binds specifically to α4ß7 integrin on leukocytes, blocking leukocyte trafficking to and activation in the gut, inhibiting colon inflammation and reducing signs and symptoms of active ulcerative colitis. Two pharmacokinetic/pharmacodynamic studies were conducted in healthy volunteers. Study 1 was a first-in-human study with 40 male subjects receiving PN-943, 100 to 1400 mg or placebo, as single doses and 57 male subjects receiving PN-943, 100 to 1000 mg or placebo, as multiple doses. Study 2 was a randomized, crossover study comparing multiple doses of 450-mg PN-943 twice daily as a liquid solution and as an immediate-release tablet in 10 subjects. No subjects discontinued due to treatment-emergent adverse events. Consistent with the gastrointestinal-restricted nature of the peptide, systemic exposure was minimal; there was an approximate dose-proportional increase in area under the plasma concentration-time curve. There was minimal accumulation with once-daily dosing and an absence of time-dependent changes in pharmacokinetics. Administration of PN-943 after a high-fat meal reduced peak plasma concentration and area under the plasma concentration-time curve. There was minimal (<0.1%) urinary excretion of intact drug, and there was a dose-related increase in fecal excretion of intact PN-943. Dose-dependent increases in blood receptor occupancy and reduction in blood receptor expression were observed, supporting target engagement. Twice-daily dosing resulted in sustained receptor occupancy with low plasma fluctuations (143%). PN-943 was generally well tolerated following single and multiple oral doses with low systemic exposure. Twice-daily dosing resulted in sustained pharmacokinetics and pharmacodynamics, supporting further investigation in efficacy studies., (© 2021 Protagonist Therapeutics Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Introduction: Despite huge and increasing developments in the treatment of inflammatory bowel disease (IBD), a significant percentage of patients with Crohn's disease (CD) and ulcerative colitis (UC) is still in need of an effective and safe therapeutic option. Tackling the trafficking of leukocytes specifically within or directed to the inflamed gut appears to be a particularly promising strategy, and several new anti-integrin agents are currently under investigation in clinical trials., Areas Covered: This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). It also discusses the future perspectives for the treatment of IBD patients with this class of agents., Expert Opinion: The pipeline of anti-integrin agents is well assorted, and it is reasonable to expect that some will be introduced in the market soon. Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way.

Snake venoms are a potential source of various enzymatic and non-enzymatic compounds with a defensive role for the host. Various peptides with significant medicinal properties have been isolated and characterized from these venoms. Few of these are FDA approved. They inhibit tumor cells adhesion, migration, angiogenesis and metastasis by inhibiting integrins on transmembrane cellular surfaces. This plays important role in delaying tumor growth, neovascularization and development. Tumor targeting and smaller size make them ideal candidates as novel therapeutic agents for cancer treatment. This review is based on sources of these disintegrins, their targeting modality, classification and underlying anti-cancer potential., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We aimed to describe physician practice patterns in holding or continuing IBD therapy in the setting of COVID-19 infection, using the Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease [SECURE-IBD] registry., Methods: IBD medications that were stopped due to COVID-19 were recorded in the SECURE-IBD registry in addition to demographic and clinical data. We conducted descriptive analyses to understand characteristics associated with stopping IBD medications in response to active COVID-19 infection., Results: Of 1499 patients, IBD medications were stopped in 518 [34.6%] patients. On bivariate and multivariable analyses, a diagnosis of ulcerative colitis or IBD-unspecified was associated with a lower odds of stopping medication compared with Crohn's disease (adjusted odds ratio [aOR] 0.6, 95% confidence interval [CI] 0.48, 0.75). When evaluating specific medications, 5-aminosalicylic acid was more likely to be continued [p <0.001] whereas anti-tumour necrosis factor therapy and immunomodulator therapy were more likely to be stopped [global p <0.001]. Other demographic and clinical characteristics did not affect prescription patterns., Conclusions: IBD medications other than immunomodulators were continued in the majority of IBD patients with COVID-19, in the international SECURE-IBD registry. Future studies are needed to understand the impact of stopping or continuing IBD medications on IBD- and COVID-19 related outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wiendl, Becker, Müller, Voskens, Neurath and Zundler.)

The heterogeneous pathobiology underlying Ulcerative Colitis (UC) is not fully understood. Using publicly available transcriptomes from adult UC patients, we identified the immune cell landscape, molecular pathways, and differentially expressed genes (DEGs) across patient cohorts and their association with treatment outcomes. The global immune cell landscape of UC tissue included increased neutrophils, T CD4 memory activated cells, active dendritic cells (DC), and M0 macrophages, as well as reduced trends in T CD8, Tregs, B memory, resting DC, and M2 macrophages. Pathway analysis of DEGs across UC cohorts demonstrated activated bacterial, inflammatory, growth, and cellular signaling. We identified a specific transcriptional signature of one hundred DEGs (UC 100 ) that distinctly separated UC inflamed from uninflamed transcriptomes. Several UC 100 DEGs, with unidentified roles in UC, were validated in primary tissue. Additionally, non-responders to anti-TNFα and anti-α4β7 therapy displayed distinct profiles of immune cells and pathways pertaining to inflammation, growth, and metabolism. We identified twenty resistant DEGs in UC non-responders to both therapies of which four had significant predictive power to treatment outcome. We demonstrated the global immune landscape and pathways in UC tissue, highlighting a unique UC signature across cohorts and a UC resistant signature with predictive performance to biologic therapy outcome.

In hepatitis, activated hepatic stellate cells (HSCs) produce collagens, causing liver fibrosis. Microenvironmental stiffness is a known trigger of HSC activation and is communicated through mechanotransduction. Cell proliferation, alpha smooth muscle actin (α-SMA) and collagen type Iα (Col1α) are indicative of activated HSCs. We hypothesized that certain compounds could interfere with the HSC's recognition of microenvironmental stiffness by blocking cell adhesion signaling. To verify the potential of mechanotransduction, and in particular of focal adhesion proteins, as liver fibrosis drug targets, we evaluated existing drugs. We examined the effects of the integrin antagonist, BS-1417; the focal adhesion kinase (FAK) inhibitor, defactinib; the cyclin-dependent kinase (CDK) inhibitor, roscovitine; and two microtubule modulators, paclitaxel and colchicine, on stiffness-induced HSC activation. To determine the extent of transforming growth factor β (TGF-β) participation in mechanotransduction, we measured gene expression levels of α-SMA and Col1α. We also measured ATP levels to determine cell number. Results revealed that interestingly, although TGF-β did not show additional HSC activation after stiffness stimulation, the TGF-β receptor inhibitor, SB525334, markedly suppressed stiffness-induced α-SMA and Col1α mRNA expression. BS-1417, roscovitine, defactinib and colchicine suppressed α-SMA and Col1α mRNA expression as well as the number of HSCs. Paclitaxel also suppressed stiffness-induced α-SMA mRNA expression and the number of HSCs, but mildly reduced that of Col1α mRNA. Together, these results show that an integrin antagonist and mechanotransduction-targeting drugs reduced stiffness-induced HSC activation in a dose-dependent fashion. The targeting of focal adhesion proteins involved in mechanotransduction is promising in liver fibrosis drug development.

Introduction: Integrins are a family of 24 cell adhesion receptors that play a role in the biggest unmet needs in medicine - cardiovascular disease, immunology and cancer. Their discovery promised huge potential for the pharmaceutical industry. Areas covered. Over 35-years since their discovery, there is little to show for the hundreds of billions of dollars of investment in anti-integrin drug discovery programmes. In this review the author discusses the reasons for the failure of this promising class of drugs and the future for this class of drugs. Expert opinion. Within 10-years, there was a plethora of potent, specific anti-integrin molecules and since their discovery, many of these agents have entered clinical trials. The success in discovering these agents was due to recently discovered monoclonal antibody technology. The integrin-recognition domain Arg-Gly-Asp (RGD) provided the basis for discovering small molecule inhibitors to integrins - both cyclic peptides and peptidomimetics. Most agents failed in the Phase III clinical trials and those agents that did make it to the market were plagued with issues of toxicity and limited efficacy and were soon replaced with non-integrin targeting agents. Their failure was due to a combination of poor pharmacokinetics and pharmacodynamics, complicated by the complex pathophysiology of integrins.

Cellular viral reservoirs are rapidly established in tissues upon HIV-1/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut-associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV-1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4β7 antibody or α4β7/α4β1 dual antagonist TR-14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post-SIV inoculation. The results showed that blockade of α4β7/α4β1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell-associated SIV RNA/DNA to controls. Surprisingly, TR-14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV-1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation., (© 2021 Federation of American Societies for Experimental Biology.)

Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano-bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management., (Copyright © 2019. Published by Elsevier Ltd.)

Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin., Competing Interests: Declaration of Interests K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, and Nextechinvest, and he receives sponsored research funding from Novartis. He is a co-founder of Immunitas Therapeutics, a biotech company. D.D. consults for Novartis and is on the advisory board for Oncology Analytics, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cancer Stem Cells (CSCs) play an important role in various stages of cancer development, advancement, and therapy resistance. Ketoprofen-RGD has been revealed to act as an anti-cancer agent against some tumors., Objective: We aimed to explore the effects of a novel Ketoprofen-RGD compound on the suppression of Breast Cancer Stem-like Cells (BCSCs) and their parental cells., Methods: Mammospheres were developed from MCF-7 cells and assessed by CSC surface markers through flowcytometry. The anti-proliferative and pro-apoptotic activities of Ketoprofen-RGD were measured by MTS assay and flowcytometry. The expression levels of stemness markers and JAK2/STAT proteins were measured by quantitative Real Time-PCR (qRT-PCR) and western blotting, respectively. Intracellular Reactive Oxygen Species (ROS) was measured using a cell permeable, oxidant-sensitive fluorescence probe (carboxy-H2DCFDA)., Results: Ketoprofen-RGD significantly reduced the mammosphere formation rate and the expression of three out of six stemness markers and remarkably decreased viability and induced apoptosis of spheroidal and parental cells compared to controls. Further experiments using CD95L, as a death ligand, and ZB4 antibody, as an extrinsic apoptotic pathway blocker, showed that Ketoprofen-RGD induced intrinsic pathway, suggesting a mechanism by which Ketoprofen-RGD triggers apoptosis. ROS production was also another way to induce apoptosis. Results of western blot analysis also revealed a marked diminish in the phosphorylation of JAK2 and STAT proteins., Conclusion: Our study, for the first time, elucidated an anti-BCSC activity for Ketoprofen-RGD via declining stemness markers, inducing toxicity, and apoptosis in these cells and parental cells. These findings may suggest this compound as a promising anti-breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Orthodontic tooth movement (OTM) creates compressive and tensile strain in the periodontal ligament, causing circulation disorders. Hypoxia-inducible factor 1α (HIF-1α) has been shown to be primarily stabilised by compression, but not hypoxia in periodontal ligament fibroblasts (PDLF) during mechanical strain, which are key regulators of OTM. This study aimed to elucidate the role of heparan sulfate integrin interaction and downstream kinase phosphorylation for HIF-1α stabilisation under compressive and tensile strain and to which extent downstream synthesis of VEGF and prostaglandins is HIF-1α-dependent in a model of simulated OTM in PDLF. PDLF were subjected to compressive or tensile strain for 48 h. In various setups HIF-1α was experimentally stabilised (DMOG) or destabilised (YC-1) and mechanotransduction was inhibited by surfen and genistein. We found that HIF-1α was not stabilised by tensile, but rather by compressive strain. HIF-1α stabilisation had an inductive effect on prostaglandin and VEGF synthesis. As expected, HIF-1α destabilisation reduced VEGF expression, whereas prostaglandin synthesis was increased. Inhibition of integrin mechanotransduction via surfen or genistein prevented stabilisation of HIF-1α. A decrease in VEGF expression was observed, but not in prostaglandin synthesis. Stabilisation of HIF-1α via integrin mechanotransduction and downstream phosphorylation of kinases seems to be essential for the induction of VEGF, but not prostaglandin synthesis by PDLF during compressive (but not tensile) orthodontic strain.

Sepsis is a life-threatening condition caused by the response of the body to an infection, and has recently been regarded as a global health priority because of the lack of effective treatments available. Vascular endothelial cells have a crucial role in sepsis and are believed to be a major target of pathogens during the early stages of infection. Accumulating evidence suggests that common sepsis pathogens, including bacteria, fungi, and viruses, all contain a critical integrin recognition motif, Arg-Gly-Asp (RGD), in their major cell wall-exposed proteins that might act as ligands to crosslink to vascular endothelial cells, triggering systemic dysregulation resulting in sepsis. In this review, we discuss the potential of anti-integrin therapy in the treatment of sepsis and septic shock., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pro-TGF-β1, show the persistence over time of a bidentate Arg-Asp ligand-receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg 2+ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential αvβ6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-π interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol -1 , on average, of experiments.

Objective: To assess the impact of inflammatory bowel disease (IBD) medications on postoperative infection risk within 30 days of surgery., Methods: We searched multiple electronic databases and reference lists of articles dating up to August 2018 for prospective and retrospective studies comparing postoperative infection risk in patients treated with an IBD medication perioperatively with the risk in patients who were not taking that medication. Outcomes were overall infectious complications and intra-abdominal infections within 30 days of surgery., Results: Sixty-three studies were included. Overall infectious complications were increased in patients who received anti-tumor necrosis factor (TNF) agents (odds ratio [OR] 1.26; 95% confidence interval [CI], 1.07-1.50) and corticosteroids (OR 1.34; 95% CI, 1.25-1.44) and decreased in those who received 5-aminosalicylic acid (OR 0.63; 95% CI, 0.46-0.87). No difference was observed in those treated with immunomodulators (OR 1.08; 95% CI, 0.94-1.25) or anti-integrin agents (OR 1.06; 95% CI, 0.67-1.69). Both corticosteroids and anti-TNF agents were associated with increased intra-abdominal infection risk (OR 1.63; 95% CI, 1.33-2.00 and OR 1.46; 95% CI, 1.08-1.97, respectively), whereas no impact was observed with 5-aminosalicylates, immunomodulators, or anti-integrin therapy. Twenty-two studies had low risk of bias while the remaining studies had very high risk., Conclusions: Corticosteroids and anti-TNF agents were associated with increased overall postoperative infection risk as well as intra-abdominal infection in IBD patients, whereas no increased risk was observed for immunomodulators or anti-integrin therapy. Although these results may result from residual confounding rather than from a true biological effect, prospective studies that control for potential confounding factors are required to generate higher-quality evidence., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: The heterodimeric integrin receptor α 4 β 7 regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown. Herein, we examined the role of α 4 β 7 -mediated recruitment of CD4 T cells to the intestine and liver in NASH., Methods: Male littermate F11r +/+ (control) and junctional adhesion molecule A knockout F11r -/- mice were fed a normal diet or a western diet (WD) for 8 weeks. Liver and intestinal tissues were analyzed by histology, quantitative reverse transcription PCR (qRT-PCR), 16s rRNA sequencing and flow cytometry. Colonic mucosa-associated microbiota were analyzed using 16s rRNA sequencing. Liver biopsies from patients with NASH were analyzed by confocal imaging and qRT-PCR., Results: WD-fed knockout mice developed NASH and had increased hepatic and intestinal α 4 β 7 + CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in α 4 β 7 + CD4 T cells was associated with markedly higher expression of the α 4 β 7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the colonic mucosa and livers of WD-fed knockout mice. Elevated MAdCAM-1 expression correlated with increased mucosa-associated Proteobacteria in the WD-fed knockout mice. Antibiotics reduced MAdCAM-1 expression indicating that the diet-altered microbiota promoted colonic and hepatic MAdCAM-1 expression. α 4 β 7 blockade in WD-fed knockout mice significantly decreased α 4 β 7 + CD4 T cell recruitment to the intestine and liver, attenuated hepatic inflammation and fibrosis, and improved metabolic indices. MAdCAM-1 blockade also reduced hepatic inflammation and fibrosis in WD-fed knockout mice. Hepatic MAdCAM-1 expression was elevated in patients with NASH and correlated with higher expression of α 4 and β 7 integrins., Conclusions: These findings establish α 4 β 7 /MAdCAM-1 as a critical axis regulating NASH development through colonic and hepatic CD4 T cell recruitment., Lay Summary: Non-alcoholic steatohepatitis (NASH) is an advanced and progressive form of non-alcoholic fatty liver disease (NAFLD), and despite its growing incidence no therapies currently exist to halt NAFLD progression. Herein, we show that blocking integrin receptor α 4 β 7 -mediated recruitment of CD4 T cells to the intestine and liver not only attenuates hepatic inflammation and fibrosis, but also improves metabolic derangements associated with NASH. These findings provide evidence for the potential therapeutic application of α 4 β 7 antibody in the treatment of human NASH., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Medications used to treat inflammatory bowel disease (IBD) have significantly improved patient outcomes and delayed time to surgery. However, some of these therapies are recognized to increase the general risk of infection and have an unclear impact on postoperative infection risk., Objectives: To assess the impact of perioperative IBD medications on the risk of postoperative infections within 30 days of surgery., Search Methods: We searched the Cochrane IBD Group's Specialized Register (29 October 2019), MEDLINE (January 1966 to October 2019), Embase (January 1985 to October 2019), the Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform from inception up to October 2019, and reference lists of articles., Selection Criteria: Randomized controlled trials, quasi-randomized controlled trials, non-randomized controlled trials, prospective cohort studies, retrospective cohort studies, case-control studies and cross-sectional studies comparing participants treated with an IBD medication preoperatively or within 30 days postoperatively to those who were not taking that medication (either another active medication, placebo, or no treatment). We included published study reports and abstracts., Data Collection and Analysis: Two review authors independently screened titles and abstracts and extracted data. The primary outcome was postoperative infection within 30 days of surgery. Secondary outcomes included incisional infections and wound dehiscence, intra-abdominal infectious complications and extra-abdominal infections. Three review authors assessed risks of bias using the Newcastle-Ottawa Scale. We contacted authors for additional information when data were missing. For the primary and secondary outcomes, we calculated odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) using the generic inverse variance method. When applicable, we analyzed adjusted and unadjusted data separately. We evaluated the certainty of the evidence using GRADE., Main Results: We included 68 observational cohort studies (total number of participants unknown because some studies did not report the number of participants). Of these, 48 studies reported including participants with Crohn's disease, 36 reported including participants with ulcerative colitis and five reported including participants with indeterminate colitis. All 42 studies that reported urgency of surgery included elective surgeries, with 31 (74%) of those also including emergency surgeries. Twenty-four studies had low risk of bias while the rest had very high risk. Based on pooling of adjusted data, we calculated ORs for postoperative total infection rates in participants who received corticosteroids (OR 1.70, 95% CI 1.38 to 2.09; low-certainty evidence), immunomodulators (OR 1.29, 95% CI 0.95 to 1.76; low-certainty evidence), anti-TNF agents (OR 1.60, 95% CI 1.20 to 2.13; very low-certainty evidence) and anti-integrin agents (OR 1.04, 95% CI 0.79 to 1.36; low-certainty evidence). We pooled unadjusted data to assess postoperative total infection rates for the use of aminosalicylates (5-ASA) (OR 0.76, 95% CI 0.51 to 1.14; very low-certainty evidence). One secondary outcome examined was wound-related complications in participants using: corticosteroids (OR 1.41, 95% CI 0.72 to 2.74; very low-certainty evidence), immunomodulators (OR 1.35, 95% CI 0.96 to 1.89; very low-certainty evidence), anti-TNF agents (OR 1.18, 95% CI 0.83 to 1.68; very low-certainty evidence) and anti-integrin agents (OR 1.64, 95% CI 0.77 to 3.50; very low-certainty evidence) compared to controls. Another secondary outcome examined the odds of postoperative intra-abdominal infections in participants using: corticosteroids (OR 1.53, 95% CI 1.28 to 1.84; very low-certainty evidence), 5-ASA (OR 0.77, 95% CI 0.45 to 1.33; very low-certainty evidence), immunomodulators (OR 0.86, 95% CI 0.66 to 1.12; very low-certainty evidence), anti-TNF agents (OR 1.38, 95% CI 1.04 to 1.82; very low-certainty evidence) and anti-integrin agents (OR 0.40, 95% CI 0.14 to 1.20; very low-certainty evidence) compared to controls. Lastly we checked the odds for extra-abdominal infections in participants using: corticosteroids (OR 1.23, 95% CI 0.97 to 1.55; very low-certainty evidence), immunomodulators (OR 1.17, 95% CI 0.80 to 1.71; very low-certainty evidence), anti-TNF agents (OR 1.34, 95% CI 0.96 to 1.87; very low-certainty evidence) and anti-integrin agents (OR 1.15, 95% CI 0.43 to 3.08; very low-certainty evidence) compared to controls., Authors' Conclusions: The evidence for corticosteroids, 5-ASA, immunomodulators, anti-TNF medications and anti-integrin medications was of low or very low certainty. The impact of these medications on postoperative infectious complications is uncertain and we can draw no firm conclusions about their safety in the perioperative period. Decisions on preoperative IBD medications should be tailored to each person's unique circumstances. Future studies should focus on controlling for potential confounding factors to generate higher-quality evidence., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Osteoarthritis (OA) is a joint disease characterized by cartilage degeneration. Osteopontin (OPN) is involved in the initiation, repair, and maintenance of metabolic homeostasis in normal articular cartilage. This study investigated the role of OPN and its interaction with the integrin ανβ 3 receptor in the expression of hyaluronic acid (HA) in OA chondrocytes. Overexpression of OPN significantly increased the expression of integrin ανβ 3 and hyaluronic acid synthases (HAS) and synthesis of HA. Depleting OPN in OA chondrocytes showed the opposite trend for integrin alpha;νβ 3, HAS, and HA. Nonspecifically and specifically blocking integrin receptor using GRGDSP and integrin ανβ 3 antibody downregulated HAS and HA; both were inhibited to similar extents. The expression of HAS and HA was predominantly regulated by the interaction between OPN and integrin ανβ 3. Taken together, we have delineated the importance of the OPN/integrin ανβ 3/HAS/HA axis in OA and identified OPN as a promising candidate for molecular therapy for use in patients with OA., Competing Interests: No conflict of interest to declare., (Copyright © 2020 Yuhao Yuan et al.)

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.

Background and Aims: Vedolizumab [VDZ] is a monoclonal antibody directed against the α4β7 integrin heterodimer, approved for patients with inflammatory bowel diseases [IBD]. This study aimed at identifying immunological variables associated with response to vedolizumab in patients with ulcerative colitis [UC] and Crohn's disease [CD]., Methods: This is a phase IV explorative prospective interventional trial. IBD patients received open-label VDZ at Weeks 0, 2, 6, and 14. Patients with a clinical response at Week 14 were maintained with VDZ up to Week 54. At Weeks 0 and 14, their peripheral blood was obtained and endoscopy with biopsies was performed. The Week 14 clinical response and remission, Week 54 clinical remission, and Week 14 endoscopic response were evaluated as endpoints of the study. The expression of surface markers, chemokine receptors, and α4β7 heterodimer in peripheral blood and lamina propria lymphocytes was assessed by flow cytometry. A panel of soluble mediators was assessed in sera at baseline and at Week 14 by 45-plex., Results: A total of 38 IBD patients [20 UC, 18 CD] were included in the study. At Week 14, the clinical response and remission rates were 87% and 66%, respectively. Higher baseline levels of circulating memory Th1 cells were strongly associated with clinical response at Week 14 [p = 0.0001], whereas reduced baseline levels of lamina propria memory Th17 and Th1/17 cells were associated with endoscopic response. Immunological clusters were found to be independently associated with vedolizumab outcomes at multivariable analysis. A panel of soluble markers, including IL17A, TNF, CXCL1, CCL19 for CD and G-CSF and IL7 for UC, associated with vedolizumab-induced Week 54 clinical remission., Conclusions: The results of this exploratory study uncovered a panel of circulating and mucosal immunological variables associated with response to treatment with vedolizumab., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Vedolizumab was shown to be safe and effective for the treatment of Crohn's disease [CD] and ulcerative colitis [UC] in the GEMINI Long-Term Safety [LTS] study. The vedolizumab Extended Access Program [XAP] provides patients with continued treatment. This XAP pharmacokinetics [PK] sub-study investigated vedolizumab efficacy, safety, and PK., Methods: Vedolizumab dosing frequency was reduced from every 4 weeks [Q4W] to every 8 weeks [Q8W] at XAP enrolment, and patients were followed for 56 weeks. Outcomes included: efficacy, loss of clinical benefit, and re-escalation to Q4W dosing; and vedolizumab PK, immunogenicity, and adverse events., Results: Among 167 enrolled patients [CD = 88, UC = 79], 80 [91%] with CD and 73 [92%] with UC completed 56 weeks; 76 [86%] and 71 [90%] with CD and UC, respectively, remained on Q8W dosing for 56 weeks. Clinical remission, corticosteroid-free clinical remission, and C-reactive protein levels were stable among patients remaining on Q8W through Week 56. Four patients with CD and two with UC resumed Q4W dosing [three with CD regained clinical response]. Patients with CD who completed Week 56 on Q8W dosing had median trough vedolizumab concentrations of 43.6 µg/mL at enrolment and 10.4 µg/mL at Week 56; concentrations were 42.4 µg/mL and 13.3 µg/mL, respectively, in patients with UC. Treatment-related adverse events were infrequent; no new or serious adverse events related to vedolizumab were reported., Conclusions: In the XAP-PK sub-study, adherence to Q8W dosing was high, with no loss of efficacy; very few patients required re-escalation to Q4W. There were no new safety signals., (© European Crohn’s and Colitis Organisation (ECCO) 2020.)

Introduction: Integrins are a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix (ECM) to actin cytoskeleton in the cell cortex, thus regulating cellular adhesion, migration, proliferation, invasion, survival, and apoptosis. Consequently, integrins play a role in inflammation, angiogenesis and fibrosis., Areas Covered: This review examines individual anti-integrin agents in terms of their chemical nature, route of administration, and anti-integrin action. It also provides a summary of preclinical and clinical studies. Current clinical candidates include risuteganib, THR-687, and SF-0166, which have shown promise in treating diabetic macular edema (DME) and/or age-related macular degeneration (AMD) in early clinical studies. Preclinical candidates include SB-267268, AXT-107, JNJ-26076713, Cilengitide and Lebecetin, which exhibit a decrease in retinal permeability, angiogenesis and/or choroidal neovascularization (CNV)., Expert Opinion: Anti-integrin therapies show potential in treating retinal diseases. Anti-integrin agents tackle the multi-factorial nature of diabetic retinopathy (DR) and AMD and show promise as injectable and topical agents in preclinical and early clinical studies. Integrin inhibition has potential to serve as primary therapy, adjunctive therapy to anti-vascular endothelial growth factor agents, or secondary therapy in refractory cases.

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner., Competing Interests: Declaration of Interests The authors declare no competing interests. Based on this work, patent no: 63/002,828 “Compositions and methods for treating dysregulated wound healing” has been filed and assigned to the Regents of the University of California., (Copyright © 2020 Elsevier Inc. All rights reserved.)