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1.
Expert Opin Investig Drugs ; 30(10): 1037-1046, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34449288

RESUMO

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.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Desenvolvimento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Fármacos Gastrointestinais/administração & dosagem , Humanos , Integrinas/antagonistas & inibidores
2.
Front Immunol ; 12: 656452, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017333

RESUMO

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-α4ß7 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.


Assuntos
Movimento Celular/imunologia , Doenças Inflamatórias Intestinais/imunologia , Animais , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Quimiocinas/antagonistas & inibidores , Quimiocinas/metabolismo , Suscetibilidade a Doenças/imunologia , Desenvolvimento de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Terapia de Alvo Molecular , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
3.
Sci Rep ; 11(1): 9010, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33907256

RESUMO

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 (UC100) that distinctly separated UC inflamed from uninflamed transcriptomes. Several UC100 DEGs, with unidentified roles in UC, were validated in primary tissue. Additionally, non-responders to anti-TNFα and anti-α4ß7 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.


Assuntos
Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Regulação da Expressão Gênica , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Terapia Biológica , Estudos de Coortes , Colite Ulcerativa/terapia , Conjuntos de Dados como Assunto , Humanos , Integrinas/antagonistas & inibidores , Integrinas/imunologia , Leucócitos/imunologia , Transdução de Sinais , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
4.
Eur J Pharmacol ; 899: 174022, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33727054

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Desintegrinas/uso terapêutico , Integrinas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Venenos de Serpentes/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/isolamento & purificação , Desintegrinas/efeitos adversos , Desintegrinas/isolamento & purificação , Humanos , Integrinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais
5.
Cancer Cell ; 39(1): 54-67.e9, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33385331

RESUMO

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 αvß6 receptor on the surface of tumor cells, which activates TGFß from a latent precursor. An integrin αvß6/8-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 αvß6-TGFß-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos de Neoplasias/genética , Antineoplásicos Imunológicos/uso terapêutico , Integrinas/genética , Fatores de Transcrição SOXC/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Evasão Tumoral , Animais , Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Camundongos , Transplante de Neoplasias , Fatores de Transcrição SOXC/metabolismo , Análise de Sequência de RNA , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/metabolismo , Fator de Crescimento Transformador beta/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
FASEB J ; 35(2): e21282, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33484474

RESUMO

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 (α4ß7 antibody or α4ß7/α4ß1 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 α4ß7/α4ß1 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.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Animais , Anticorpos Neutralizantes/imunologia , Integrinas/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Fenilalanina/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral
7.
Expert Opin Drug Discov ; 16(2): 197-211, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32921156

RESUMO

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.


Assuntos
Descoberta de Drogas/métodos , Integrinas/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Desenvolvimento de Medicamentos/métodos , Indústria Farmacêutica , Humanos , Integrinas/metabolismo , Terapia de Alvo Molecular , Peptídeos Cíclicos/farmacologia , Peptidomiméticos/farmacologia
8.
J Crohns Colitis ; 15(5): 860-863, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33232456

RESUMO

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.


Assuntos
COVID-19/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Doenças Inflamatórias Intestinais/epidemiologia , Integrinas/antagonistas & inibidores , Masculino , Sistema de Registros , Inibidores do Fator de Necrose Tumoral/uso terapêutico
9.
Biol Pharm Bull ; 44(3): 416-421, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33328427

RESUMO

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 ß (TGF-ß) 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-ß did not show additional HSC activation after stiffness stimulation, the TGF-ß 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.


Assuntos
Células Estreladas do Fígado/fisiologia , Mecanotransdução Celular , Actinas/genética , Trifosfato de Adenosina/metabolismo , Animais , Benzamidas/farmacologia , Células Cultivadas , Colchicina/farmacologia , Colágeno Tipo I/genética , Células Estreladas do Fígado/efeitos dos fármacos , Imidazóis/farmacologia , Integrinas/antagonistas & inibidores , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Paclitaxel/farmacologia , Piperazinas/farmacologia , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Ratos Sprague-Dawley , Roscovitina/farmacologia , Sulfonamidas/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Moduladores de Tubulina/farmacologia
10.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333756

RESUMO

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.


Assuntos
Fibroblastos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mecanotransdução Celular , Ligamento Periodontal/metabolismo , Adolescente , Adulto , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Quinase 1 de Adesão Focal/antagonistas & inibidores , Genisteína/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Glicosaminoglicanos/antagonistas & inibidores , Humanos , Indazóis/farmacologia , Integrinas/antagonistas & inibidores , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Mecanotransdução Celular/genética , Ligamento Periodontal/citologia , Ligamento Periodontal/efeitos dos fármacos , Fosforilação , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/biossíntese , Prostaglandinas/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Técnicas de Movimentação Dentária , Ureia/análogos & derivados , Ureia/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Biomed Res Int ; 2020: 2905634, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134374

RESUMO

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 ανß3 receptor in the expression of hyaluronic acid (HA) in OA chondrocytes. Overexpression of OPN significantly increased the expression of integrin ανß3 and hyaluronic acid synthases (HAS) and synthesis of HA. Depleting OPN in OA chondrocytes showed the opposite trend for integrin alpha;νß3, HAS, and HA. Nonspecifically and specifically blocking integrin receptor using GRGDSP and integrin ανß3 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 ανß3. Taken together, we have delineated the importance of the OPN/integrin ανß3/HAS/HA axis in OA and identified OPN as a promising candidate for molecular therapy for use in patients with OA.


Assuntos
Hialuronan Sintases/genética , Ácido Hialurônico/metabolismo , Integrina beta3/genética , Integrinas/genética , Osteoartrite do Joelho/genética , Osteopontina/genética , Anticorpos Neutralizantes/farmacologia , Artroplastia do Joelho/métodos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Cartilagem Articular/cirurgia , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica , Humanos , Hialuronan Sintases/metabolismo , Integrina beta3/metabolismo , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Oligopeptídeos/farmacologia , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Osteoartrite do Joelho/cirurgia , Osteopontina/metabolismo , Cultura Primária de Células , Ligação Proteica , Transdução de Sinais
12.
Drug Discov Today ; 25(12): 2317-2325, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33035665

RESUMO

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.


Assuntos
Infecções Bacterianas/tratamento farmacológico , Integrinas/antagonistas & inibidores , Micoses/tratamento farmacológico , Oligopeptídeos/antagonistas & inibidores , Sepse/tratamento farmacológico , Viroses/tratamento farmacológico , Humanos
14.
Cochrane Database Syst Rev ; 10: CD013256, 2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33098570

RESUMO

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.


Assuntos
Infecções/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Complicações Pós-Operatórias/induzido quimicamente , Corticosteroides/efeitos adversos , Adulto , Ácidos Aminossalicílicos/efeitos adversos , Viés , Colite Ulcerativa/tratamento farmacológico , Intervalos de Confiança , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Infecções/epidemiologia , Integrinas/antagonistas & inibidores , Masculino , Estudos Observacionais como Assunto/estatística & dados numéricos , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Deiscência da Ferida Operatória/induzido quimicamente , Deiscência da Ferida Operatória/epidemiologia , Infecção da Ferida Cirúrgica/induzido quimicamente , Infecção da Ferida Cirúrgica/epidemiologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
15.
Nat Commun ; 11(1): 4659, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938936

RESUMO

The αvß6 integrin plays a key role in the activation of transforming growth factor-ß (TGFß), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvß6 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 αvß6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFß signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvß6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvß6, induces prolonged inhibition of TGFß 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.


Assuntos
Butiratos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Pirazóis/farmacologia , Pirrolidinas/farmacologia , Administração por Inalação , Animais , Antígenos de Neoplasias/metabolismo , Bleomicina/toxicidade , Butiratos/administração & dosagem , Butiratos/metabolismo , Butiratos/farmacocinética , Colágeno/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Integrinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Naftiridinas/administração & dosagem , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/metabolismo , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Tomografia Computadorizada de Emissão de Fóton Único , Fator de Crescimento Transformador beta/metabolismo , Pesquisa Médica Translacional
16.
Front Immunol ; 11: 1275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765488

RESUMO

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections compromise gut immunological barriers, inducing high levels of inflammation and a severe depletion of intestinal CD4+ T cells. Expression of α4ß7 integrin promotes homing of activated T cells to intestinal sites where they become preferentially infected; blockade of α4ß7 with an anti-α4ß7 monoclonal antibody (mAb) prior to infection has been reported to reduce gut SIV viremia in rhesus macaques (RMs). Interleukin-21 (IL-21) administration in antiretroviral therapy-treated, SIV-infected RMs reduces gut inflammation and improves gut integrity. We therefore hypothesized that the combination of IL-21 and anti-α4ß7 mAb therapies could synergize to reduce inflammation and HIV persistence. We co-administered two intravenous doses of rhesus anti-α4ß7 mAb (50 mg/kg) combined with seven weekly subcutaneous infusions of IL-21-IgFc (100 µg/kg) in four healthy, SIV-uninfected RMs to evaluate the safety and immunological profiles of this intervention in blood and gut. Co-administration of IL-21 and anti-α4ß7 mAb showed no toxicity at the given dosages as assessed by multiple hematological and chemical parameters and did not alter the bioavailability of the therapeutics or result in the generation of antibodies against the anti-α4ß7 mAb or IL-21-IgFc. Upon treatment, the frequency of CD4 memory T cells expressing ß7 increased in blood and decreased in gut, consistent with an inhibition of activated CD4 T-cell homing to the gut. Furthermore, the frequency of T cells expressing proliferation and immune activation markers decreased in blood and, more profoundly, in gut. The combined IL-21 plus anti-α4ß7 mAb therapy is well-tolerated in SIV-uninfected RMs and reduces the gut homing of α4ß7+ CD4 T cells as well as the levels of gut immune activation.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunidade/efeitos dos fármacos , Integrinas/antagonistas & inibidores , Interleucinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Disponibilidade Biológica , Biomarcadores , Quimioterapia Combinada , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Interleucinas/administração & dosagem , Interleucinas/efeitos adversos , Interleucinas/farmacocinética , Isoanticorpos/sangue , Isoanticorpos/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macaca mulatta
17.
Expert Opin Investig Drugs ; 29(9): 935-945, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657172

RESUMO

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.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Integrinas/antagonistas & inibidores , Doenças Retinianas/tratamento farmacológico , Animais , Neovascularização de Coroide/fisiopatologia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/fisiopatologia , Edema Macular/tratamento farmacológico , Edema Macular/fisiopatologia , Doenças Retinianas/fisiopatologia
18.
Molecules ; 25(14)2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32708610

RESUMO

Matricellular proteins, which exist in association with the extracellular matrix (ECM) and ECM protein molecules, harbor functional sites within their molecular structures. These functional sites are released through proteolytic cleavage by inflammatory proteinases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the peptides containing these functional sites have unique biological activities that are often not detected in the parent molecules. We previously showed that tenascin-C (TNC) and plasma fibronectin (pFN), examples of matricellular proteins, have cryptic bioactive sites that have opposite effects on cell adhesion to the ECM. A peptide containing the bioactive site of TNC, termed TNIIIA2, which is highly released at sites of inflammation and in the tumor microenvironment (TME), has the ability to potently and persistently activate ß1-integrins. In the opposite manner, the peptide FNIII14 containing the bioactive site of pFN has the ability to inactivate ß1-integrins. This review highlights that peptide TNIIIA2 can act as a procancer factor and peptide FNIII14 can act as an anticancer agent, based on the regulation on ß1-integrin activation. Notably, the detrimental effects of TNIIIA2 can be inhibited by FNIII14. These findings open the possibility for new therapeutic strategies based on the inactivation of ß1-integrin by FNIII14.


Assuntos
Integrinas/genética , Neoplasias/tratamento farmacológico , Peptídeos/uso terapêutico , Tenascina/genética , Antineoplásicos/uso terapêutico , Fibronectinas/genética , Fibronectinas/uso terapêutico , Humanos , Integrinas/antagonistas & inibidores , Neoplasias/patologia , Peptídeos/genética
19.
Cell ; 182(3): 545-562.e23, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32621799

RESUMO

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.


Assuntos
Cicatriz/metabolismo , Colágeno Tipo V/deficiência , Colágeno Tipo V/metabolismo , Traumatismos Cardíacos/metabolismo , Contração Miocárdica/genética , Miofibroblastos/metabolismo , Animais , Cicatriz/genética , Cicatriz/fisiopatologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Colágeno Tipo V/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Feminino , Fibrose/genética , Fibrose/metabolismo , Regulação da Expressão Gênica/genética , Integrinas/antagonistas & inibidores , Integrinas/genética , Integrinas/metabolismo , Isoproterenol/farmacologia , Masculino , Mecanotransdução Celular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Força Atômica/instrumentação , Microscopia Eletrônica de Transmissão , Contração Miocárdica/efeitos dos fármacos , Miofibroblastos/citologia , Miofibroblastos/patologia , Miofibroblastos/ultraestrutura , Análise de Componente Principal , Proteômica , RNA-Seq , Análise de Célula Única
20.
J Hepatol ; 73(5): 1013-1022, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32540177

RESUMO

BACKGROUND & AIMS: The heterodimeric integrin receptor α4ß7 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 α4ß7-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 α4ß7+ CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in α4ß7+ CD4 T cells was associated with markedly higher expression of the α4ß7 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. α4ß7 blockade in WD-fed knockout mice significantly decreased α4ß7+ 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 α4 and ß7 integrins. CONCLUSIONS: These findings establish α4ß7/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 α4ß7-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 α4ß7 antibody in the treatment of human NASH.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Dieta Ocidental/efeitos adversos , Integrinas/metabolismo , Mucosa Intestinal/imunologia , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/metabolismo , Moléculas de Adesão Celular/antagonistas & inibidores , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Humanos , Integrinas/antagonistas & inibidores , Integrinas/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Mucoproteínas/antagonistas & inibidores , Mucoproteínas/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Ribossômico 16S/genética , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética
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