Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

Trentini, Alessandro; Castellazzi, Massimiliano; Cervellati, Carlo; Manfrinato, Maria Cristina; Tamborino, Carmine; Hanau, Stefania; Volta, Carlo Alberto; Baldi, Eleonora; Kostić, Vladimir; Drulović, Jelena; Granieri, Enrico; Dallocchio, Franco; Bellini, Tiziana; Dujmović, Irena; Fainardi, Enrico

doi:10.1155/2016/3672353

Cited by 27 publications

(20 citation statements)

References 43 publications

(51 reference statements)

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“…There are numerous indications for the role of MMP-9, and perhaps MMP-2, in MS 66,67. MMP-9 levels are elevated in MS serum and cerebrospinal fluid, particularly in patients with active disease 32,68–70. Injection of MMP-9 into the brain causes disruption of the basement membrane and is associated with breakdown of the BBB 71,72.…”

Section: Discussionmentioning

confidence: 99%

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

et al. 2017

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The design of selective matrix metalloproteinase (MMP) inhibitors that also possess favorable solubility properties has proved to be especially challenging. A prior approach using collagen-model templates combined with transition state analogs produced a first generation of triple-helical peptide inhibitors (THPIs) that were effective in vitro against discrete members of the MMP family. These THPI constructs were also highly water-soluble. The present study sought improvements in the first generation THPIs by enhancing thermal stability and selectivity. A THPI selective for MMP-2 and MMP-9 was redesigned to incorporate non-native amino acids (Flp and mep), resulting in an increase of 18 °C in thermal stability. This THPI was effective in vivo in a mouse model of multiple sclerosis, reducing clinical severity and weight loss. Two other THPIs were developed to be more selective within the collagenolytic members of the MMP family. One of these THPIs was serendipitously more effective against MMP-8 than MT1-MMP and was utilized successfully in a mouse model of sepsis. The THPI targeting MMP-8 minimized lung damage, increased production of the anti-inflammatory cytokine IL-10, and vastly improved mouse survival.

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Section: Discussionmentioning

confidence: 99%

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

et al. 2017

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“…Indeed, immune cells mediate both neuro-inflammation and partly axonal damage, the two main disease hallmarks leading to disease progression and increased patients' disability. Basically, MS patients exhibit an impaired Blood Brain Barrier (BBB), which indicates infiltration of leukocyte into the CNS, reflecting in increased circulating levels of active Matrix Metalloproteinases (MMPs) [109][110][111]. The same is true for pro-inflammatory cytokines, which are found to be deranged and increased both in blood and cerebrospinal fluid (CSF) of MS patients compared to controls [112,113].…”

Section: Sex Disparity In Multiple Sclerosismentioning

confidence: 99%

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

Gemmati

Varani

Bramanti

et al. 2019

IJMS

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Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

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“…However, MMP9 is also up-regulated in inflamed intestine of IBD patients and has been recently suggested as a predictor marker of disease exacerbation in CD (82,83). Moreover, high levels of MMP9 were also found in the serum and cerebrospinal fluid of MS patients and increase during relapses (84,85). Thus, anti-inflammatory compounds able to dampen excessive production of MMPs might represent potential therapeutic strategies for inflammatory diseases.…”

Section: Cd28-associated Class 1a Pi3k Regulates Il-22 Expression Andmentioning

confidence: 99%

CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes

et al. 2020

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IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4 + T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-kB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22-dependent epithelial cell barrier functions.

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Interplay between Matrix Metalloproteinase-9, Matrix Metalloproteinase-2, and Interleukins in Multiple Sclerosis Patients

Cited by 27 publications

References 43 publications

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

Second Generation Triple-Helical Peptide Inhibitors of Matrix Metalloproteinases

“Bridging the Gap” Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era

CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes

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