International Journal of Molecular Sciences

Research

30 pages, 11533 KiB

Open AccessArticle

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

by Olga V. Anatskaya, Andrey L. Runov, Sergey V. Ponomartsev, Maxim S. Vonsky, Artem U. Elmuratov and Alexander E. Vinogradov

Int. J. Mol. Sci. 2023, 24(8), 7063; https://doi.org/10.3390/ijms24087063 - 11 Apr 2023

Cited by 3 | Viewed by 3567

Abstract

Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic [...] Read more.

Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., “negative regulation of chromosome organization”, “transcription” and “ribosome biogenesis”. These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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16 pages, 1503 KiB

Open AccessArticle

Genetic Obesity in Pregnant A^y Mice Does Not Affect Susceptibility to Obesity and Food Choice in Offspring

by Elena Makarova, Anastasia Dubinina, Elena Denisova and Antonina Kazantseva

Int. J. Mol. Sci. 2023, 24(6), 5610; https://doi.org/10.3390/ijms24065610 - 15 Mar 2023

Viewed by 1490

Abstract

Maternal diet and obesity (MO) may influence taste preferences and increase the susceptibility to obesity in offspring, but the impact of MO per se to these influences is poorly understood. We evaluated the influence of MO on food choice and susceptibility to obesity [...] Read more.

Maternal diet and obesity (MO) may influence taste preferences and increase the susceptibility to obesity in offspring, but the impact of MO per se to these influences is poorly understood. We evaluated the influence of MO on food choice and susceptibility to obesity in offspring when mothers consumed a standard diet (SD). Mice with the Lethal yellow mutation (A^y/a) develop obesity consuming an SD. Metabolic parameters were assessed in pregnant and lactating A^y/a (obesity) and a/a (control) mothers. Metabolic response to the consumption of a sweet–fat diet (SFD: SD, lard, and sweet biscuits) and the choice of components of this diet were evaluated in their male and female offspring. Compared to control mothers, pregnant obese mothers had higher levels of insulin, leptin, and FGF21. MO increased food intake and liver expression of lipogenesis genes in male offspring consuming the SD. SFD consumption caused obesity development and insulin resistance, increased liver expression of glycolytic and lipogenesis genes, and affected hypothalamic expression of anorexigenic and orexigenic genes. In offspring of both sexes, MO had no effect on food choice and metabolic response to SFD intake. Therefore, when obese mothers consume a balanced diet, MO does not affect food choice and development of diet-induced obesity in offspring. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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11 pages, 1219 KiB

Open AccessArticle

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

by Elin Barnekow, Johan Hasslow, Wen Liu, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin and Annika Lindblom

Int. J. Mol. Sci. 2023, 24(5), 4468; https://doi.org/10.3390/ijms24054468 - 24 Feb 2023

Cited by 1 | Viewed by 1622

Abstract

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide [...] Read more.

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10⁻¹¹), 11q22.3 (OR 2.4; p 5.2 × 10⁻⁹), 15q11.2 (OR 3.6; p 2.3 × 10⁻⁸), 16q24.1 (OR 3; p 3 × 10⁻⁸) and Xq21.31 (OR 3.3; p 1.7 × 10⁻⁸) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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31 pages, 14371 KiB

Open AccessArticle

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

by Svetlana Shikhevich, Irina Chadaeva, Bato Khandaev, Rimma Kozhemyakina, Karina Zolotareva, Anna Kazachek, Dmitry Oshchepkov, Anton Bogomolov, Natalya V. Klimova, Vladimir A. Ivanisenko, Pavel Demenkov, Zakhar Mustafin, Arcady Markel, Ludmila Savinkova, Nikolay A. Kolchanov, Vladimir Kozlov and Mikhail Ponomarenko

Int. J. Mol. Sci. 2023, 24(4), 3996; https://doi.org/10.3390/ijms24043996 - 16 Feb 2023

Cited by 4 | Viewed by 2491

Abstract

Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what [...] Read more.

Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what ARDs one can develop depending on their genetic background. Within this mainstream paradigm, we wanted to find out whether the known ARD-linked DEGs available in PubMed can reveal a molecular marker that will serve the purpose in anyone’s any tissue at any time. We sequenced the periaqueductal gray (PAG) transcriptome of tame versus aggressive rats, identified rat-behavior-related DEGs, and compared them with their known homologous animal ARD-linked DEGs. This analysis yielded statistically significant correlations between behavior-related and ARD-susceptibility-related fold changes (log₂ values) in the expression of these DEG homologs. We found principal components, PC1 and PC2, corresponding to the half-sum and the half-difference of these log₂ values, respectively. With the DEGs linked to ARD susceptibility and ARD resistance in humans used as controls, we verified these principal components. This yielded only one statistically significant common molecular marker for ARDs: an excess of Fcγ receptor IIb suppressing immune cell hyperactivation. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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14 pages, 1424 KiB

Open AccessArticle

Biochemical, Clinical, and Genetic Characteristics of Mexican Patients with Primary Hypertriglyceridemia, Including the First Case of Hyperchylomicronemia Syndrome Due to GPIHBP1 Deficiency

by Perla Graciela Rodríguez-Gutiérrez, Ana Gabriela Colima-Fausto, Paola Montserrat Zepeda-Olmos, Teresita de Jesús Hernández-Flores, Juan Ramón González-García and María Teresa Magaña-Torres

Int. J. Mol. Sci. 2023, 24(1), 465; https://doi.org/10.3390/ijms24010465 - 27 Dec 2022

Viewed by 1576

Abstract

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was [...] Read more.

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was to describe biochemical–clinical characteristics and variants in the APOA5, GPIHBP1, LMF1, and LPL genes in patients with primary hypertriglyceridemia. Thirty DNA fragments were analyzed using PCR and Sanger sequencing in 58 unrelated patients. The patients’ main clinical–biochemical features were hypoalphalipoproteinemia (77.6%), pancreatitis (18.1%), and a TG median value of 773.9 mg/dL. A total of 74 variants were found (10 in APOA5, 16 in GPIHBP1, 34 in LMF1, and 14 in LPL), of which 15 could be involved in the development of PHTG: 3 common variants with significative odds and 12 heterozygous rare pathogenic variants distributed in 12 patients. We report on the first Mexican patient with hyperchylomicronemia syndrome due to GPIHBP1 deficiency caused by three variants: p.R145*, p.A154_G155insK, and p.A154Rfs*152. Moreover, eleven patients were heterozygous for the rare variants described as causing PHTG and also presented common variants of risk, which could partially explain their phenotype. In terms of findings, two novel genetic variants, c.-40_-22del LMF1 and p.G242Dfs*10 LPL, were identified. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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15 pages, 1807 KiB

Open AccessArticle

Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism

by Maria Becker, Karin Abaev, Elena Shmerkin, Liza Weinstein-Fudim, Albert Pinhasov and Asher Ornoy

Int. J. Mol. Sci. 2022, 23(19), 11898; https://doi.org/10.3390/ijms231911898 - 7 Oct 2022

Cited by 4 | Viewed by 1508

Abstract

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found [...] Read more.

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12–15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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15 pages, 792 KiB

Open AccessArticle

Genetic Variants of ABC and SLC Transporter Genes and Chronic Myeloid Leukaemia: Impact on Susceptibility and Prognosis

by Raquel Alves, Ana Cristina Gonçalves, Joana Jorge, Gilberto Marques, André B. Ribeiro, Rita Tenreiro, Margarida Coucelo, Joana Diamond, Bárbara Oliveiros, Amélia Pereira, Paulo Freitas-Tavares, António M. Almeida and Ana Bela Sarmento-Ribeiro

Int. J. Mol. Sci. 2022, 23(17), 9815; https://doi.org/10.3390/ijms23179815 - 29 Aug 2022

Cited by 3 | Viewed by 1936

Abstract

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and [...] Read more.

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters comprise a variety of proteins expressed on cell membranes responsible for intrusion or extrusion of substrates, respectively, including nutrients, xenobiotics, and chemotherapeutic agents. These transporters mediate the cellular disposition of tyrosine kinase inhibitors (TKIs), and their genetic variants could affect its function, potentially predisposing patients to chronic myeloid leukaemia (CML) and modulating treatment response. We explored the impact of genetic variability (single nucleotide variants—SNVs) of drug transporter genes (ABCB1, ABCG2, SLC22A1, and SLC22A5) on CML susceptibility, drug response, and BCR-ABL1 mutation status. We genotyped 10 SNVs by tetra-primers-AMRS-PCR in 198 CML patients and 404 controls, and assessed their role in CML susceptibility and prognosis. We identified five SNVs associated with CML predisposition, with some variants increasing disease risk, including TT genotype ABCB1 (rs1045642), and others showing a protective effect (GG genotype SLC22A5 rs274558). We also observed different haplotypes and genotypic profiles associated with CML predisposition. Relating to drug response impact, we found that CML patients with the CC genotype (rs2231142 ABCG2) had an increased risk of TKI resistance (six-fold). Additionally, CML patients carrying the CG genotype (rs683369 SLC22A1) presented a 4.54-fold higher risk of BCR-ABL1 mutations. Our results suggest that drug transporters’ SNVs might be involved in CML susceptibility and TKI response, and predict the risk of BCR-ABL1 mutations, highlighting the impact that SNVs could have in therapeutic selection. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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Review

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29 pages, 2336 KiB

Open AccessReview

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

by Yozo Mitsui, Fumito Yamabe, Shunsuke Hori, Masato Uetani, Hideyuki Kobayashi, Koichi Nagao and Koichi Nakajima

Int. J. Mol. Sci. 2023, 24(12), 10133; https://doi.org/10.3390/ijms241210133 - 14 Jun 2023

Cited by 3 | Viewed by 1736

Abstract

Peyronie’s disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into [...] Read more.

Peyronie’s disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, research into understanding of the detailed mechanisms and risk factors involved in the development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including the genes involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide a better understanding regarding the involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as to provide insight into disease prevention and novel therapeutic interventions. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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18 pages, 1386 KiB

Open AccessReview

Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis

by Elisa Duranti and Chiara Villa

Int. J. Mol. Sci. 2023, 24(1), 704; https://doi.org/10.3390/ijms24010704 - 31 Dec 2022

Cited by 9 | Viewed by 3904

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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8 pages, 586 KiB

Open AccessCase Report

Disclosing an In-Frame Deletion of the Titin Gene as the Possible Predisposing Factor of Anthracycline-Induced Cardiomyopathy: A Case Report

by Yu-Wei Chang, Hui-Ying Weng, Shih-Feng Tsai and Frank Sheng Fan

Int. J. Mol. Sci. 2022, 23(16), 9261; https://doi.org/10.3390/ijms23169261 - 17 Aug 2022

Cited by 2 | Viewed by 1533

Abstract

Anthracycline-induced cardiomyopathy has been noted as a non-neglectable issue in the field of clinical oncology. Remarkable progress has been achieved in searching for inherited susceptible genetic deficits underlying anthracycline cardiotoxicity in the past several years. In this case report, we present the preliminary [...] Read more.

Anthracycline-induced cardiomyopathy has been noted as a non-neglectable issue in the field of clinical oncology. Remarkable progress has been achieved in searching for inherited susceptible genetic deficits underlying anthracycline cardiotoxicity in the past several years. In this case report, we present the preliminary results of a genetic study in a young male patient who was treated with standard dose anthracycline-based chemotherapy for his acute myeloid leukemia and attacked by acute congestive heart failure after just two courses of therapy. After a survey of 76 target genes, an in-frame deletion of the titin gene was recognized as the most possible genetic defect responsible for his cardiomyopathy caused by anthracycline. This defect proved to pass down from the patient′s mother and did not exist in seven unrelated chemotherapy-treated cancer patients without chemotherapy-induced cardiomyopathy and four other healthy volunteer DNA donors. Full article

(This article belongs to the Special Issue Genetic and Molecular Susceptibility in Human Diseases)

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