Papers by Ramón Cacabelos
Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into pot... more Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2, CYP2C9, CYP4F2, GSTP1, and NAT2 that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolize...
Expert Opinion on Drug Discovery, 2016
Pharmaceutics
Alzheimer’s disease (AD), the most common cause of dementia, causes irreversible memory loss and ... more Alzheimer’s disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related (NOS3 and COX-2) gene expression in 3–4-month-old mice only, global (5mC)- and de novo DNA methylation (DNMT3a), HDAC3 expression and HDAC activity in 3–4-month-old mice; and SIRT1 expression and acetyla...
Neuropsychiatric Disease and Treatment, 2008
A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs) an... more A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs) and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H +) and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or defi ciency of different growth factors (GFs) in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases. Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The "trophic factor withdrawal syndrome" is described for the fi rst time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specifi c and nonspecifi c aspects of cell biology.
Life
The main health problems in developed countries are cardiovascular diseases (25–30%), cancer (20–... more The main health problems in developed countries are cardiovascular diseases (25–30%), cancer (20–25%) and nervous system disorders (10–15%), which globally account for more than 80% of the morbidity and mortality in the general population [...]
Epigenetics of Brain Aging
Conn's Handbook of Models for Human Aging
Abstract The complexity of human aging and longevity results from a combination of genetic, epige... more Abstract The complexity of human aging and longevity results from a combination of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation, chromatin structure, and RNA interference, regulate gene expression and control the main metabolic pathways throughout life. This strict epigenetic management becomes progressively defective with age, which increases the risk for the onset of age-related pathologies. This chapter reviews the main alterations of the epigenetic machinery throughout life, with special focus on those affecting the aging brain, as well as the epigenetic control of life span by regulating telomere length and mitochondrial function, with special emphasis on the epigenetic interplay between nuclear and mitochondrial DNA. The last section summarizes the main epigenetic aberrations involving the most prevalent form of pathologic brain deterioration in elderly individuals, Alzheimer's disease, and novel potential epigenetic-based treatments.
Life, 2022
Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large con... more Alzheimer’s disease (AD) is a priority health problem with a high cost to society and a large consumption of medical and social resources. The management of AD patients is complex and multidisciplinary. Over 90% of patients suffer from concomitant diseases and require personalized therapeutic regimens to reduce adverse drug reactions (ADRs), drug–drug interactions (DDIs), and unnecessary costs. Men and women show substantial differences in their AD-related phenotypes. Genomic, epigenetic, neuroimaging, and biochemical biomarkers are useful for predictive and differential diagnosis. The most frequent concomitant diseases include hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60–90%), neuropsychiatric disorders (60–90%), and cancer (10%). Over 90%...
International Journal of Molecular Sciences, 2021
Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in de... more Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and ins...
International Journal of Molecular Sciences, 2021
Epigenetics is the study of heritable changes in gene expression that occur without alterations t... more Epigenetics is the study of heritable changes in gene expression that occur without alterations to the DNA sequence, linking the genome to its surroundings. The accumulation of epigenetic alterations over the lifespan may contribute to neurodegeneration. The aim of the present study was to identify epigenetic biomarkers for improving diagnostic efficacy in patients with neurodegenerative diseases. We analyzed global DNA methylation, chromatin remodeling/histone modifications, sirtuin (SIRT) expression and activity, and the expression of several important neurodegeneration-related genes. DNA methylation, SIRT expression and activity and neuregulin 1 (NRG1), microtubule-associated protein tau (MAPT) and brain-derived neurotrophic factor (BDNF) expression were reduced in buffy coat samples from patients with neurodegenerative disorders. Our data suggest that these epigenetic biomarkers may be useful in clinical practical for the diagnosis, surveillance, and prognosis of disease activit...
Life, 2022
Novel and effective chemotherapeutic agents are needed to improve cancer treatment. Epidrugs are ... more Novel and effective chemotherapeutic agents are needed to improve cancer treatment. Epidrugs are currently used for cancer therapy but also exhibit toxicity. Targeting the epigenetic apparatus with bioproducts may aid cancer prevention and treatment. To determine whether the lipoprotein marine extract AntiGan shows epigenetic and antitumor effects, cultured HepG2 (hepatocellular carcinoma) and HCT116 (colorectal carcinoma) cell lines were treated with AntiGan (10, 50, 100, and to 500 µg/mL) for 24 h, 48 h, and 72 h. AntiGan (10 µg/mL) reduced cell viability after 48 h and increased Bax expression; AntiGan (10 and 50 µg/mL) increased caspase-3 immunoreactivity in HepG2 and HCT116 cells. AntiGan (10 and 50 µg/mL) attenuated COX-2 and IL-17 expression in both cell lines. AntiGan (10 µg/mL) increased 5mC levels in both cell types and reduced DNMT1 and DNMT3a expression in these cells. AntiGan (10 and 50 µg/mL) promoted DNMT3a immunoreactivity and reduced SIRT1 mRNA expression in both ce...
Journal of Clinical Epigenetics, 2017
Central nervous system (CNS) disorders represent polygenic/ multifactorial phenotypes with a grea... more Central nervous system (CNS) disorders represent polygenic/ multifactorial phenotypes with a great impact in our society due to the psychological burden, cost and disability that they may cause. Most CNS disorders are clinical entities which, in many instances, share some common features: (i) pathogenically, they are complex disorders in which a plethora of plural events (genomic defects, epigenetic aberrations, mitochondrial dysfunction, environmental factors) is potentially involved; (ii) many of them, especially those with a late onset, are characterized by intracellular and/or extracellular deposits of abnormal proteins; (iii) their diagnosis is difficult because they lack specific biomarkers (and their prediction is almost impossible); (iv) their treatment is symptomatic (not anti-pathogenic) and not costeffective; and (v) the vast majority represent chronic ailments with progressive deterioration and bad prognosis [1,2].
Pharmacoepigenetics: A Long Way Ahead
Pharmacoepigenetics, 2019
Journal of Clinical Epigenetics, 2017
Nutrients, 2020
The investigation of new alternatives for disease prevention through the application of findings ... more The investigation of new alternatives for disease prevention through the application of findings from dietary and food biotechnology is an ongoing challenge for the scientific community. New nutritional trends and the need to meet social and health demands have inspired the concept of functional foods and nutraceuticals which, in addition to their overall nutritional value, present certain properties for the maintenance of health. However, these effects are not universal. Nutrigenetics describes how the genetic profile has an impact on the response of the body to bioactive food components by influencing their absorption, metabolism, and site of action. The EbioSea Program, for biomarine prospection, and the Blue Butterfly Program, for the screening of vegetable-derived bioproducts, have identified a new series of nutraceuticals, devoid of side effects at conventional doses, with genotype-dependent preventive and therapeutic activity. Nutrigenomics and nutrigenetics provide the oppor...
Journal of Exploratory Research in Pharmacology, 2018
Many clinical conditions exist in which it is desirable to stimulate or suppress the immune syste... more Many clinical conditions exist in which it is desirable to stimulate or suppress the immune system, and many different drugs are able to do this. It is also well known that nutrition may affect human health and immune responses. Nutritional factors are crucial components of the diet, essential for the normal growth and development of both vertebrate and invertebrate organisms. Many of these components have been shown to play different roles in the immune response, and under different circumstances they can significantly modulate the immune system to create an effective response. The aim of the present review was to show the effect of a biomarine lipofishin (E-JUR-94013) obtained from the species T. trachurus, present on the Galician coast of the Atlantic Ocean, in the improvement of immune system function. In humans, the results obtained under different clinical conditions clearly demonstrated the ability of E-JUR-94013 to improve the host innate and acquired immune responses. In three different clinical studies, 56, 205 and 1,500 patients were included, respectively. All patients were supplemented with 750 mg/day of E-JUR-94013. In the first study, significant increases in IgA (p = 0.033) and IgG (p = 0.016), and a reduction in IgE were observed. In the second study, a normalization in leukocyte cell counts after treatment was observed (p < 0.05). The main objective of the last study was to correlate inflammatory genotypes with response to E-JUR-94013. The results obtained indicated that high ultrasensitive C-reactive protein was down-regulated. In addition, both IL-6-C573G and IL1β-T3954C genotypes clearly correlated with response to E-JUR-94013 treatment. Taken together, these results suggest that supplementation of diets with E-JUR-94013 can be employed to improve, enhance and regulate certain immune responses and lead to increased resistance to disease.
Clinical & Medical Biochemistry Open Access, 2016
Diagnostic Pathology: Open Access, 2016
Pharmacogenomics of Antidepressant Drugs
Melatonin, Neuroprotective Agents and Antidepressant Therapy, 2016
Antidepressants are among the most prescribed drugs in developed countries. Pharmacogenomics acco... more Antidepressants are among the most prescribed drugs in developed countries. Pharmacogenomics accounts for over 60 % variability in the pharmacodynamics and pharmacokinetics of antidepressants (selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic and tetracyclic compounds, monoamine oxidase inhibitors, and noradrenergic and serotonergic modulators). The genes involved in the pharmacogenomic response to antidepressant drugs fall into five major categories: (i) genes associated with the pathogenesis of depression (disease-specific genes, pathogenic genes), (ii) genes associated with the mechanism of action of drugs (mechanistic genes), (iii) genes associated with drug metabolism (metabolic genes), (iv) genes associated with drug transporters, and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions. About 24 % of antidepressants are major substrates of CYP1A2 enzymes, 5 % of CYP2B6, 38 % of CYP2C19, 85 % of CYP2D6, and 38 % of CYP3A4. Among Caucasians, approximately one-quarter of the population is deficient in the enzymatic activity of the CYP2D6-CYP2C19-CYP2C9 cluster responsible for the metabolism of over 60 % of current drugs. The implementation of pharmacogenomic procedures in the clinical setting would help to optimize the use of antidepressants in psychiatric patients.
Journal of Alzheimer's Disease & Parkinsonism, 2016
Over 80% of brain disorders are associated with multiple genomic defects in conjunction with envi... more Over 80% of brain disorders are associated with multiple genomic defects in conjunction with environmental factors and epigenetic phenomena. Classical epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs (miRNAs) regulation, are among the major regulatory elements that control metabolic pathways at the molecular level, with epigenetic modifications controlling gene expression transcriptionally and miRNAs suppressing gene expression post-transcriptionally. Epigenetic modifications are related to disease development, environmental exposure, drug treatment and aging. Epigenetic changes are reversible and can be potentially targeted by pharmacological intervention. Both hypermethylation and hypomethylation of DNA, chomatin changes and miRNA dysregulation are common in age-related disorders and in many neuropsychiatric, neurodevelopmental and neurodegenerative disorders. Major epigenetic mechanisms may contribute to Alzheimer's disease (AD) pathology. Several pathogenic genes and many other AD-related susceptibility genes contain methylated CpG sites. AD brains exhibit a genome-wide decrease in DNA methylation. Pathogenic histone modifications are present in AD. Alterations in epigentically regulated miRNAs may contribute to the abnormal expression of pathogenic genes in AD. Epigenetic drugs can reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Individual differences in drug response are associated with genetic and epigenetic variability and disease determinants. Pharmacoepigenomics deals with the influence that epigenetic alterations may exert on genes involved in the pharmacogenomic network (pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes) responsible for the pharmacokinetics and pharmacodynamics of drugs (efficacy and safety), as well as the effects that drugs may have on the epigenetic machinery.
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Papers by Ramón Cacabelos