Immune and Genetic Mechanisms in COPD: Possible Targets for Therapeutic Interventions

Epigenetics is the study of heritable changes in gene function that do not involve changes in the DNA sequence. Epigenetic changes, consisting principally of DNA methylation, histone modifications and non-coding RNAs, maintain and modulate the initial impact of regulatory factors that recognize and associate with particular genomic sequences. This book’s primary goal is to establish a framework that can be used to understand the basis of epigenetic regulation and to appreciate both its derivation from genetics and its interdependence with genetic mechanisms. A further aim is to highlight the role played by the three-dimensional organization of the genetic material itself (the complex of DNA, histones and non-histone proteins referred to as chromatin) and its distribution within a functionally compartmentalized nucleus. Dysfunctions at any level of genetic regulation have the potential to result in an increased susceptibility to disease or actually give rise to overt pathologies. As illustrated in this book, research is continuously uncovering the role of epigenetics in a variety of human disorders, providing new avenues for therapeutic interventions and advances in regenerative medicine.

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Quantitative Association Tests of Immune Responses to Antigens ofMycobacterium Tuberculosis: A Study of Twins in West Africa

Twin Research ◽

10.1375/twin.7.6.578 ◽

2004 ◽

Vol 7 (6) ◽

pp. 578-588 ◽

Cited By ~ 3

Author(s):

Amanda Wiart ◽

Annette Jepson ◽

Winston Banya ◽

Steve Bennett ◽

Hilton Whittle ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Therapeutic Interventions ◽

In Vitro Assays ◽

Peptide Antigens ◽

Tnf Α ◽

Genetic Mechanisms ◽

Host Genetic

AbstractThere is now considerable evidence that host genetic factors are important in determining the outcome of infection withMycobacterium tuberculosis(MTB). The aim of this study was to assess the role of several candidate genes in the variation observed in the immune responses to MTB antigens. In-vitro assays of T-cell proliferation, an in-vivo intradermal delayed hypersensitivity response; cytokine and antibody secretions to several mycobacterial peptide antigens were assessed in healthy, but exposed, West African twins. Candidate gene polymorphisms were typed in theNRAMP1,Vitamin D receptor,IL10,IL4,IL4 receptorandCTLA-4genes. Variants of the lociIL10(−1082 G/A),CTLA-4(49 A/G) and theIL4 receptor(128 A/G) showed significant associations with immune responses to several antigens. T-cell proliferative responses and antibody responses were reduced, TNF-α responses were increased for subjects with theCTLA-4G allele. The T-cell proliferative responses of subjects withIL10GA and GG genotypes differed significantly.IL4 receptorAG and GG genotypes also showed significant differences in their T-cell proliferative responses to MTB antigens. These results yield a greater understanding of the genetic mechanisms that underlie the immune responses in tuberculosis and have implications for the design of therapeutic interventions.

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Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors

Biochemical Society Symposium ◽

10.1042/bss0700201 ◽

2003 ◽

Vol 70 ◽

pp. 201-212 ◽

Cited By ~ 51

Author(s):

Hideaki Nagase ◽

Keith Brew

Keyword(s):

Three Dimensional ◽

Therapeutic Interventions ◽

Tissue Inhibitors Of Metalloproteinases ◽

Structural Basis ◽

Structural Elements ◽

Ridge Structure ◽

Extracellular Matrix Components ◽

Metalloproteinase Inhibitors ◽

The Matrix ◽

A Disintegrin And Metalloproteinase

The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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Novel Genetic Mechanisms in Development

Developmental Biology ◽

10.1016/j.ydbio.2006.04.005 ◽

2006 ◽

Author(s):

I CHOW

Keyword(s):

Genetic Mechanisms

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Emotion-Oriented Coping Style Predicts Self-Harm in Response to Acute Psychiatric Hospitalization

Crisis ◽

10.1027/0227-5910/a000713 ◽

2020 ◽

pp. 1-7

Author(s):

Jacqueline M. Frei ◽

Vladimir Sazhin ◽

Melissa Fick ◽

Keong Yap

Keyword(s):

Borderline Personality Disorder ◽

Personality Disorder ◽

Psychiatric Hospitalization ◽

Coping Styles ◽

Psychiatric Inpatients ◽

Borderline Personality ◽

Self Report ◽

Therapeutic Interventions ◽

Coping Behaviors ◽

Self Harm

Abstract. Psychiatric hospitalization can cause significant distress for patients. Research has shown that to cope with the stress, patients sometimes resort to self-harm. Given the paucity of research on self-harm among psychiatric inpatients, a better understanding of transdiagnostic processes as predictors of self-harm during psychiatric hospitalization is needed. The current study examined whether coping styles predicted self-harm after controlling for commonly associated factors, such as age, gender, and borderline personality disorder. Participants were 72 patients (mean age = 39.32 years, SD = 12.29, 64% male) admitted for inpatient treatment at a public psychiatric hospital in Sydney, Australia. Participants completed self-report measures of coping styles and ward-specific coping behaviors, including self-harm, in relation to coping with the stress of acute hospitalization. Results showed that younger age, diagnosis of borderline personality disorder, and higher emotion-oriented coping were associated with self-harm. After controlling for age and borderline personality disorder, higher levels of emotion-oriented coping were found to be a significant predictor of self-harm. Findings were partially consistent with hypotheses; emotion-oriented but not avoidance-oriented coping significantly predicted self-harm. This finding may help to identify and provide psychiatric inpatients who are at risk of self-harm with appropriate therapeutic interventions.

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