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Diseases Etiology and Management: Towards a Precision Medicine Approach

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A special issue of International Journal of Environmental Research and Public Health (ISSN 1660-4601).

Deadline for manuscript submissions: closed (20 September 2022) | Viewed by 13226

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Dr. Romina Combi

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School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: cell biology; genetics; neurogenetics; molecular bases of neurological diseases; epilepsy; neurodegenerative disorders; exome sequencing; autism; ion channels and diseases

Special Issue Information

Dear Colleagues,

In recent decades, the development of new technologies has modified our perspective of both the study of etiology and the management of diseases, driving us towards precision medicine. This is an emerging approach for disease treatment and prevention that takes into account variability in the genes, environments, and lifestyles of individuals. This new approach is based on molecular and bioinformatics developments, the use of new models of biomedical research, and the empowerment of patients and citizens as partners in healthcare research and organization. To date, this approach has led several researchers to identify new biomarkers of disease or of new targets for drug discovery and delivery. However, some barriers are still present in the application of precision medicine. In particular, the costs for individual studies and therapies are still too high, and some doctors and stakeholders are not yet prepared for this new approach.

In this Special Issue, current knowledge, as well as new discoveries and future perspectives of the etiology and management of diseases with regard to precision medicine, will be discussed.

Prof. Romina Combi
Guest Editor

Manuscript Submission Information

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Keywords

etiology
disease management
precision medicine
genes
biomarkers
therapy
disease models
drug delivery

Published Papers (6 papers)

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Research

11 pages, 934 KiB

Open AccessArticle

Exome Sequencing in an ADSHE Family: VUS Identification and Limits

by Chiara Villa, Federica Arrigoni, Eleonora Rivellini, Marialuisa Lavitrano, Luca De Gioia, Luigi Ferini-Strambi and Romina Combi

Int. J. Environ. Res. Public Health 2022, 19(19), 12548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph191912548 - 01 Oct 2022

Viewed by 1368

Abstract

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is the familial form of a focal epilepsy characterized by hyperkinetic focal seizures, mainly arising during non-rapid eye movements (NREM) sleep. Mutations associated with ADSHE account for a small proportion of the genetically determined cases, suggesting the existence of other disease-causing genes. Here, we reported the results obtained by performing trio-based whole-exome sequencing (WES) in an Italian family showing ADSHE and investigated the structural impact of putative variants by in silico modeling analysis. We identified a p.(Trp276Gly) variant in MOXD1 gene encoding the monooxigenase DBH like 1 protein, cosegregating with the disease and annotated as VUS under the ACMG recommendations. Structural bioinformatic analysis predicted a high destabilizing effect of this variant, due to the loss of important hydrophilic bonds and an expansion of cavity volume in the protein hydrophobic core. Although our data support a functional effect of the p.(Trp276Gly) variant, we highlight the need to identify additional families carrying MOXD1 mutations or functional analyses in suitable models to clarify its role in ADSHE pathogenesis. Moreover, we discuss the importance of VUS reporting due to the low rate of pathogenic variant identification by NGS in epilepsy and for future reinterpretation studies. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

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9 pages, 336 KiB

Open AccessArticle

Cardiac Structure and Function in Adults with Down Syndrome

by Fadi M. Azar, Victor D. Y. Beck, Alice M. Matthews, Daniel E. Forsha and Thessa I. M. Hilgenkamp

Int. J. Environ. Res. Public Health 2022, 19(19), 12310; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph191912310 - 28 Sep 2022

Cited by 1 | Viewed by 1294

Abstract

Various factors may alter the risk for cardiovascular disease in adults with Down syndrome (Ds), yet few studies have examined differences in cardiac physiology in this population. Previous research suggested lower systolic and diastolic function, but inconsistent methodologies and younger samples warrant research in adults with Ds. Our aim is to compare the cardiac structure and function of adults with Ds to age- and sex-matched adults without Ds. Echocardiography was used to assess systolic function, diastolic function, and cardiac structure in n = 19 adults (Ds n = 9, control n = 10). Regarding cardiac structure, adults with Ds had increased left ventricular posterior wall thickness at end-systole compared to adults without Ds (p = 0.007). Regarding systolic and diastolic function, adults with Ds were found to have lower septal peak systolic annular velocity (S’) (p = 0.026), lower lateral and septal mitral annular early diastolic velocity (E’) (p = 0.007 and p = 0.025, respectively), lower lateral peak mitral annular late diastolic velocity (A’) (p = 0.027), and higher lateral and septal mitral annular early systolic velocity to diastolic velocity ratios (E/e’) (p = 0.001 and p = 0.001, respectively). Differences in both cardiac structure and function were found when comparing adults with Ds to matched adults without Ds. Most of the differences were indicative of worse diastolic function. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

21 pages, 4776 KiB

Open AccessArticle

Counteractive Effects of IL-33 and IL-37 on Inflammation in Osteoarthritis

by Vikrant Rai, Matthew F. Dilisio, Farial Samadi and Devendra K. Agrawal

Int. J. Environ. Res. Public Health 2022, 19(9), 5690; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph19095690 - 07 May 2022

Cited by 8 | Viewed by 2292

Abstract

Osteoarthritis (OA) is a chronic inflammatory disease where pro-inflammatory cytokines, damage-associated molecular patterns (DAMPs), and macrophages play a crucial role. However, the interactive role of these mediators, the exact cause precipitating OA and definitive treatment for OA are not known yet. Moreover, the interactive role of interleukin (IL)-33 and IL-37 with other factors in the pathogenesis of OA has not been discussed elaborately. In this study, we analyzed the expression of IL-33 and IL-37 in human OA knee and hip joint cartilage tissues. The effect of increased DAMPs, IL-33, and IL-37 on IL-6, tumor necrosis factor (TNF)-α, toll-like receptors (TLRs), and matrix metalloproteinases (MMPs) expression was delineated using human normal and osteoarthritic chondrocytes. The effect of anti-inflammatory cytokine IL-37 on various mediators of inflammation in the presence of IL-33, rHMGB-1, and LPS was investigated to delineate the effects of IL-37. Further, the effects of blocking IL-33 downstream signaling and the effects of IL-33 and IL-37 on macrophage polarization were assessed along with examining the macrophage phenotypes in human OA cartilage tissues. The results of this study revealed increased expression of IL-33 in OA cartilage and that IL-33 increases IL-6, TNF-α, TLRs, and MMPs expression and favors phenotypic conversion towards the M1 phenotype, while IL-37 and blocking IL-33 receptor ST2 have opposite effects. Overall, the results suggest that blocking IL-33 and increasing IL-37 act synergistically to attenuate inflammation and might serve as potential therapeutics in OA. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

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14 pages, 3740 KiB

Open AccessArticle

Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations of Mycobacterium tuberculosis Inducing Resistance to Pyrazinamide

by Eid A. Alatawi and Fahad M. Alshabrmi

Int. J. Environ. Res. Public Health 2022, 19(3), 1615; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph19031615 - 30 Jan 2022

Cited by 2 | Viewed by 2443

Abstract

Tuberculosis (TB), the most frequent bacterium-mediated infectious disease caused by Mycobacterium tuberculosis, has been known to infect humans since ancient times. Although TB is common worldwide, the most recent report by the WHO (World Health Organization) listed the three countries of India, China, and Russia with 27%, 14%, and 8% of the global burden of TB, respectively. It has been reported that resistance to TB drugs, particularly by the pncA gene to the pyrazinamide drug due to mutations, significantly affects the effective treatment of TB. Understanding the mechanism of drug resistance using computational methods is of great interest to design effective TB treatment, exploring the structural features with these tools. Thus, keeping in view the importance of these methods, we employed state-of-the-art computational methods to study the mechanism of resistance caused by the W68L, L85P, and T87A mutations recently reported in 2021. We employed a molecular docking approach to predict the binding conformation and studied the dynamic properties of each complex using molecular dynamics simulation approaches. Our analysis revealed that compared to the wildtype, these three mutations altered the binding pattern and reduced the binding affinity. Moreover, the structural dynamic features also showed that these mutations significantly reduced the structural stability and packing, particularly by the W68L and L85P mutations. Moreover, principal component analysis, free energy landscape, and the binding free energy results revealed variation in the protein’s motion and the binding energy. The total binding free energy was for the wildtype −9.61 kcal/mol, W68L −7.57 kcal/mol, L85P −6.99 kcal/mol, and T87A −7.77 kcal/mol. Our findings can help to design a structure-based drug against the MDR (multiple drug-resistant) TB. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

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13 pages, 6881 KiB

Open AccessArticle

Rescuing the Host Immune System by Targeting the Immune Evasion Complex ORF8-IRF3 in SARS-CoV-2 Infection with Natural Products Using Molecular Modeling Approaches

by Aqel Albutti

Int. J. Environ. Res. Public Health 2022, 19(1), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph19010112 - 23 Dec 2021

Cited by 5 | Viewed by 2465

Abstract

The perennial emergence of SARS-CoV-2 and its new variants causing upper respiratory complexities since December 2019 has aggravated the pandemic situation around the world. SARS-CoV-2 encodes several proteins among which ORF8 is a novel factor that is unique to SARS-CoV-2 only and is reported to help the virus in disease severity and immune evasion. ORF8-IRF3 complex induces endoplasmic reticulum stress, thus helps in the evasion of immune response. Consequently, targeting the ORF8-IRF3 complex is considered as a prime target for the discovery of novel drugs against SARS-CoV-2. In this regard, computational methods are of great interest to fast track the identification and development of novel drugs. Virtual screening of South African Natural Compounds Database (SANCDB), followed by docking and molecular dynamics (MD) simulation analysis, were performed to determine novel natural compounds. Computational molecular search and rescoring of the SANCDB database followed by induced-fit docking (IFD) protocol identified Quercetin 3-O-(6″-galloyl)-beta-D-galactopyranoside (SANC00850), Tribuloside (SANC01050), and Rutin (SANC00867) are the best scoring compounds. Structural-dynamic properties assessment revealed that these three compounds have stable dynamics, compactness, and a higher number of hydrogen bonds. For validation, we used MM/GBSA, in silico bioactivity estimation and dissociation constant (K_D) approaches, which revealed that these compounds are the more potent inhibitors of the ORF8-IRF3 complex and would rescue the host immune system potentially. These compounds need further in vitro and in vivo validations to be used as therapeutics against SARS-CoV-2 to rescue the host immune system during COVID-19 infection. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

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17 pages, 3206 KiB

Open AccessArticle

Determination of Novel Anti-Cancer Agents by Targeting OGG1 Enzyme Using Integrated Bioinformatics Methods

by Ziyad Tariq Muhseen, Mustafa Hussein Ali, Nawar Rushdi Jaber, Dheyaa Shakir Mashrea, Ali Mamoon Alfalki and Guanglin Li

Int. J. Environ. Res. Public Health 2021, 18(24), 13290; https://0-doi-org.brum.beds.ac.uk/10.3390/ijerph182413290 - 16 Dec 2021

Cited by 1 | Viewed by 2429

Abstract

The 8-oxoguanine DNA glycosylase (OGG1) enzyme is a key DNA glycosylase mediating the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA molecule to the start base excision repair pathway. The OGG1 glycosylase function depletion has been seen to obstruct pathological conditions such as inflammation, A3 T-cell lymphoblastic acute leukemia growth, and neurodegenerative diseases, thus warranting OGG1 as an attractive anti-cancer enzyme. Herein, we employed several drug libraries intending to screen non-toxic inhibitory molecules against the active pocket of the enzyme that achieved stable binding mode in dynamics. Two anti-cancer compounds ([O-]C1=C(CC2=CC=CC=C2)SC(=[N+]1CC(=O)NC3=NC=C(CC4=CC=CC=C4)S3)S and CCCN(CCC)[S]-(=O)(=O)C1=CC=C(C=C1)C(=O)NNC2=NC3=CC=C(Br)C=C3C(=N2)C4=CC=CC=C4) from Selleckchem.com were identified to occupy the active pocket of OGG1 and bind with greater affinity than Control TH5487. The binding affinity of Top-1 is −11.6 kcal/mol while that of Top-2 is −10.7 kcal/mol in contrast to TH5487 Control (−9 kcal/mol). During molecular dynamic simulations versus time, the said compounds are tightly held by the enzyme with no minor structural deviations reported except flexible loops in particular those present at the N and C-terminal. Both the compounds produced extensive hydrophobic interactions with the enzyme along with stable hydrogen bonding. The docking and molecular dynamics simulations predictions were further validated by molecular mechanics with generalized Born and surface area solvation (MM/GBSA) and Poisson Boltzmann surface area (MM/PBSA), and WaterSwap binding energies that validated strong binding of the compounds to the enzyme. The MM/GBSA binding free energy for Top-1 complex is −28.10 kcal/mol, Top-2 complex is −50.14 kcal/mol) and Control is −46.91 kcal/mol while MM/PBSA value for Top-1, Top-2 and Control is −23.38 kcal/mol, −35.29 kcal/mol and −38.20 kcal/mol, respectively. Computational pharmacokinetics support good druglike candidacy of the compounds with acceptable profile of pharmacokinetics and very little toxicity. All these findings support the notion that the compounds can be used in experiments to test their anti-cancer activities. Full article

(This article belongs to the Special Issue Diseases Etiology and Management: Towards a Precision Medicine Approach)

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