Public Health Responses and Therapeutic Interventions

The current coronavirus outbreak represents a severe threat to public health worldwide. Finding measures to properly manage and prevent the epidemic is ongoing, right now practitioners and public health authorities need immediate, actionable information. Basic science and medical scientific disciplines have quickly produced a quantity of publications never seen with other emergencies, with a risk of exaggerated information and non-evidence-based measures. This rapid literature review of PubMed®/MEDLINE publications from January 20 to April 20, 2020 using COVID-19 as main key-word resulted in over 6.000 articles, with around 600 reviews. The contributions were subsequently clustered in subgroups according to journal sources and preselected areas of reference. Results were aggregated into 4 categories: supported, promising controversial and critical data. This Review has revealed a major criticality: only seven pathology articles were based on post-mortem material (minimally invasive autopsies/biopsies) . Dealing with an unknown disease, autopsies are indispensable to understand pathogenetic mechanisms, in order to rationalize therapeutic interventions. Even more important is to adopt a dedicated protocol aimed at correlating pathological findings with disease duration, patient location (home, hospital ward, ICU), and, for each period, symptoms, and treatment. Autopsy reports should not be released before a multidisciplinary discussion by hospital Root Cause Analysis or Morbidity/Mortality conferences. Telepathology is not a suitable means for such studies.

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Need for evidence-based early intervention programmes: a public health perspective

Evidence-Based Mental Health ◽

10.1136/ebmental-2018-300030 ◽

2018 ◽

Vol 21 (4) ◽

pp. 128-130 ◽

Cited By ~ 10

Author(s):

Sinan Guloksuz ◽

Jim van Os

Keyword(s):

Public Health ◽

Early Intervention ◽

High Risk ◽

Help Seeking ◽

Health Impact ◽

Assessment Tools ◽

Therapeutic Interventions ◽

Psychotic Symptoms ◽

Public Health Perspective ◽

Prognostic Accuracy

This paper attempts to discuss why the early intervention agenda based on the current convention of ‘ultra-high risk’ (UHR) or ‘clinical high risk’ (CHR) for ‘transition’ to psychosis framework has been destined to fall short of generating a measurable and economically feasible public health impact. To summarise: (1) the primary determinant of the ‘transition’ rate is not the predictive value of the UHR/CHR but the degree of the risk-enrichment; (2) even with a significant pre-test risk enrichment, the prognostic accuracy of the assessment tools in help-seeking population is mediocre, failing to meet the bare minimum thresholds; (3) therapeutic interventions arguably prolong the time-to-onset of psychotic symptoms instead of preventing ‘transition’, given that the UHR/CHR and ‘transition’ lie on the same unidimensional scale of positive psychotic symptoms; (4) meta-analytical evidence confirms that specific effective treatment for preventing ‘transition’ (the goal—primary outcome—of the UHR/CHR framework) is not available; (5) the UHR/CHR-‘transition’ is a precarious target for research given the unpredictability driven by the sampling strategies and the natural ebb and flow of psychotic symptoms within and between individuals, leading to false positives; (6) only a negligible portion of those who develop psychosis benefits from UHR/CHR services (see prevention paradox); (7) limited data on the cost-effectiveness of these services exist. Given the pitfalls of the narrow focus of the UHR/CHR framework, a broader prevention strategy embracing pluripotency of early psychopathology seems to serve as a better alternative. Nevertheless, there is a need for economic evaluation of these extended transdiagnostic early intervention programmes.

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Environmental Epigenetics: Crossroad between Public Health, Lifestyle, and Cancer Prevention

BioMed Research International ◽

10.1155/2015/587983 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 31

Author(s):

Massimo Romani ◽

Maria Pia Pistillo ◽

Barbara Banelli

Keyword(s):

Public Health ◽

Chromatin Remodeling ◽

Genetic Information ◽

Therapeutic Interventions ◽

Disease Development ◽

Health Lifestyle ◽

Environmental Epigenetics ◽

Epigenetic Modifiers ◽

Psychological Influence ◽

Potential Use

Epigenetics provides the key to transform the genetic information into phenotype and because of its reversibility it is considered an ideal target for therapeutic interventions. This paper reviews the basic mechanisms of epigenetic control: DNA methylation, histone modifications, chromatin remodeling, and ncRNA expression and their role in disease development. We describe also the influence of the environment, lifestyle, nutritional habits, and the psychological influence on epigenetic marks and how these factors are related to cancer and other diseases development. Finally we discuss the potential use of natural epigenetic modifiers in the chemoprevention of cancer to link together public health, environment, and lifestyle.

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Role of inflammasomes in pathogenesis of diseases with a high impact on public health

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2018.01.77-89 ◽

2018 ◽

pp. 77-89

Author(s):

С.В. Пирожков ◽

П.Ф. Литвицкий

Keyword(s):

Public Health ◽

Inflammatory Diseases ◽

Animal Experiments ◽

High Impact ◽

Therapeutic Interventions ◽

Mouse Strains ◽

Pathogenic Microorganisms ◽

Inflammatory Damage ◽

Decay Products

Инфламмасома - важный компонент нативного иммунитета. Она представляет собой макромолекулярный комплекс, включающий сенсорные элементы, адапторные белки и зимоген каспазы-1. Под действием продуктов распада тканей и патогенных микроорганизмов инфламмасома активируется и превращает про-IL-1b и про-IL-18 в активные интерлейкины. Активация инфламмасом отмечена при многих воспалительных заболеваниях и служит мишенью для терапевтических воздействий. В настоящем обзоре обсуждается вклад инфламмасом в патогенез социально-значимых заболеваний человека, таких, как атеросклероз, ишемическая болезнь сердца, сахарный диабет, артриты, болезни легких, печени и почек. Результаты клинических исследований и модельных экспериментов на линиях мышей с нокаутированными генами компонентов инфламмасомы говорят о существенной роли этих структур в прогрессировании патологии, связанной с воспалительным повреждением тканей. An inflammasome becomes activated under the action of tissue decay products or pathogenic microorganisms and converts pro-IL-1 and pro-IL-18 to their active forms. Activation of inflammasomes has been reported in many inflammatory diseases and serves as a target for therapeutic interventions. The present review discusses the contribution of inflammasomes to pathogenesis of diseases with a high impact on public health, such as atherosclerosis, ischemic heart disease, diabetes mellitus, arthritis, diseases of lungs and kidneys. Results of clinical studies and animal experiments on knockout mouse strains with a deficit of inflammasome components suggest a significant role of these structures in progression of pathology associated with inflammatory damage to tissues.

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Mechanisms and Therapeutic Implications of GSK-3 in Treating Neurodegeneration

Cells ◽

10.3390/cells10020262 ◽

2021 ◽

Vol 10 (2) ◽

pp. 262

Author(s):

Ido Rippin ◽

Hagit Eldar-Finkelman

Keyword(s):

Public Health ◽

Neurodegenerative Disorders ◽

Glycogen Synthase ◽

Mammalian Target Of Rapamycin ◽

Therapeutic Interventions ◽

Glycogen Synthase Kinase 3 ◽

Disease Pathogenesis ◽

Therapeutic Implications ◽

Cytoskeleton Organization ◽

Challenges And Opportunities

Neurodegenerative disorders are spreading worldwide and are one of the greatest threats to public health. There is currently no adequate therapy for these disorders, and therefore there is an urgent need to accelerate the discovery and development of effective treatments. Although neurodegenerative disorders are broad ranging and highly complex, they may share overlapping mechanisms, and thus potentially manifest common targets for therapeutic interventions. Glycogen synthase kinase-3 (GSK-3) is now acknowledged to be a central player in regulating mood behavior, cognitive functions, and neuron viability. Indeed, many targets controlled by GSK-3 are critically involved in progressing neuron deterioration and disease pathogenesis. In this review, we focus on three pathways that represent prominent mechanisms linking GSK-3 with neurodegenerative disorders: cytoskeleton organization, the mammalian target of rapamycin (mTOR)/autophagy axis, and mitochondria. We also consider the challenges and opportunities in the development of GSK-3 inhibitors for treating neurodegeneration.

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Digital Therapeutics: Exploring the Possibilities of Digital Intervention for Myopia

Frontiers in Digital Health ◽

10.3389/fdgth.2021.710644 ◽

2021 ◽

Vol 3 ◽

Author(s):

Yong Sun Lee ◽

Seung Eun Choi ◽

Jarang Hahm ◽

Myoung Joon Kim ◽

Hyo Sook Bae ◽

...

Keyword(s):

Public Health ◽

Clinical Studies ◽

Conventional Treatment ◽

Treatment Strategies ◽

Therapeutic Interventions ◽

Public Health Issue ◽

Evidence Based ◽

Humoral Factors ◽

Major Public Health Issue ◽

Theoretical Hypothesis

Pediatric myopia is increasing globally and has become a major public health issue. However, the mechanism of pediatric myopia is still poorly understood, and there is no effective treatment to prevent its progression. Based on results from animal and clinical studies, certain neuronal–humoral factors (NHFs), such as IGF-1, dopamine, and cortisol may be involved in the progression of pediatric myopia. Digital therapeutics uses evidence-based software as therapeutic interventions and it has the potential to offer innovative treatment strategies for pediatric myopia beyond conventional treatment methods. In this perspective article, we introduce digital therapeutics SAT-001, a software algorithm that modulates the level of NHFs to reduce the progression of pediatric myopia. The proposed mechanism is based on a theoretical hypothesis derived from scientific research and clinical studies and will be further confirmed by evidence generated from clinical studies involving pediatric myopia.

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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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