Search Results (234)

Acyl-CoA dehydrogenase 9 deficiency is considered as a rare neuromuscular syndrome with an autosomal recessive transmission. The ACAD9 protein presents two essential functions, i.e., the limiting step enzyme of the fatty acid β-oxidation pathway and one of the complex’s compounds involved in the respiratory chain complex I assembly. Thus, loss-of-function mutations are known to convey mitochondrial cytopathologies. A patient with a mild and late-onset phenotype, suffering from exercise intolerance and hypertrophic cardiomyopathy, was diagnosed as a compound heterozygote of the ACAD9 gene. The first c.1240C> T p.Arg414Cys variant has been previously reported and is known to be responsible for ACAD9 deficiency. However, the second c.1636G> A p.Val546Met variant has never been described. The goal was to investigate the eventual pathogenicity of this new genetic variant. For this purpose, molecular cloning was generated to express the ACAD9 gene with the V546M variant in a cell line (ACAD9mut) and compared to cells expressing the wild-type ACAD9. Then, the mitochondrial respiration, ATP production, the mitochondrial network, and the oxidative phosphorylation’s composition were investigated to reveal the effects of the V546M variant. While avoiding to affect the amount of the respiratory chain’s complexes, the new ACAD9 variant was entirely responsible for reducing over 50% of the mitochondrial complex I activity. Full article

Dysregulated inflammatory processes contribute to depression, and gene–environment interactions may influence an individual’s risk and resilience. Reduced brain-derived neurotrophic factor (BDNF) expression increases susceptibility for developing depressive symptoms, and the Val66Met (rs6265) single-nucleotide polymorphism (SNP) on the BDNF gene is linked to mood disorders. However, whether Val66Met confers increased vulnerability to inflammation-induced depressive tendencies is unknown. Here, we tested the hypothesis that the Val66Met SNP increases vulnerability to inflammation-induced depressive symptoms in a mouse model of lipopolysaccharide (LPS)-induced depression-like behavior. Behavior and neuroinflammation, following a 24 h LPS challenge, were measured in mice expressing the human BDNF Val66Met gene variant or Val66Val littermates (control). The Val66Met genotype did not affect the peripheral inflammatory response, acute neuroinflammation, or the acute sickness behavior response. Val66Met mice exhibited anhedonia-like behavioral responses following LPS challenge, and we found increased mRNA expression of IL-1β and TNFα in the cerebrum compared to controls. The mRNA expression of IL-1β and TNFα in the hippocampus and the nucleus accumbens of Val66Met mice was increased following LPS, and a significant genotype × LPS interaction was detected for CD68 expression in the nucleus accumbens. In summary, these data suggest that immune activation in Val66Met mice increased susceptibility to anhedonic behavior and dysregulated negative regulation of inflammation. Full article

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID. Full article

Background: In this study, molecular mechanisms contributing to delafloxacin resistance in Pseudomonas aeruginosa strains were investigated. Delafloxacin is a recently approved fluoroquinolone currently introduced to clinical applications. Methods: A total of 52 P. aeruginosa strains were collected from clinical isolates. Antimicrobial susceptibility testing was performed via broth microdilution, and the minimum inhibitory concentration (MIC) values for ciprofloxacin, levofloxacin, delafloxacin, ceftazidime and imipenem were determined. Five delafloxacin-resistant P. aeruginosa strains were selected for whole-genome sequencing (WGS). Results: MIC50 values were determined, and the following results were obtained: ciprofloxacin 0.25 mg/L, levofloxacin 0.25 mg/L and delafloxacin 1 mg/L. All five selected strains showed both extended-spectrum beta-lactamase and carbapenemase production. WGS analysis of these strains determined the sequence types (STs), namely, ST235 (two strains), ST316 (two strains) and ST395. Several mutations in quinolone-resistance-determining regions (QRDRs) were detected in all five delafloxacin-resistant P. aeruginosa strains as follows: gyrA Thr83Ile and parC Ser87Leu mutations were present in all five strains, while parE Thr223Ala in ST235, Glu459Val in ST316 and Val200Met in ST395 were detected. MexAB-OprM and MexCD-OprJ efflux pumps were uniformly present in all delafloxacin-resistant P. aeruginosa strains. All strains of ST235 and ST316 carried bla_NDM-1 in combination with other beta-lactamases. In our study, the in vitro efficacy of delafloxacin is inferior compared to previous fluoroquinolones based on MIC50 values; however, MIC values of delafloxacin ranged between 0.125 and 128 mg/L in our P. aeruginosa collection, and 21 out of 52 strains showed susceptibility to delafloxacin. Conclusions: Multiple QRDR mutations combined with several efflux pumps confer delafloxacin resistance in P. aeruginosa. Among the different detected multidrug-resistant P. aeruginosa strains in this study, we also report on an NDM-1 producing P. aeruginosa ST316 in Hungary. Full article

Background/Objectives: Chronic pancreatitis (CP) is a progressive inflammatory condition of the pancreas that leads to irreversible changes in pancreatic structure. The pancreatic α and β cells secrete hormones such as insulin and glucagon into the bloodstream. The pancreatic acinar cells secrete digestive enzymes that break down macromolecules. When these digestive enzymes do not function properly, maldigestion, malabsorption, and malnutrition may result. Presented here is a case study of an individual newly diagnosed with chronic pancreatitis, along with a genetic analysis of his son and an in-silico analysis of two of the variant proteins. Methods: This study was conducted using human subjects, namely, the proband (father) and his son. Medical genetic testing of the proband (father) identified the presence of two variants in the cystic fibrosis transmembrane receptor gene (CFTR): variant rs213950, resulting in a single amino acid change (p. Val470Met), and variant rs74767530, a nonsense variant (Arg1162Ter) with known pathogenicity for cystic fibrosis. Medical testing also revealed an additional missense variant, rs515726209 (Ala73Thr), in the CTRC gene. Cheek cell DNA was collected from both the proband and his son to determine the inheritance pattern and identify any additional variants. A variant in the human leukocyte antigen (rs7454108), which results in the HLA-DQ8 haplotype, was examined in both the proband and his son due to its known association with autoimmune disease, a condition also linked to chronic pancreatitis. In silico tools were subsequently used to examine the impact of the identified variants on protein function. Results: Heterozygosity for all variants originally identified through medical genetic testing was confirmed in the proband and was absent in the son. Both the proband and his son were found to have the DRB1*0301 (common) haplotype for the HLA locus. However, the proband was also found to carry a linked noncoding variant, rs2647088, which was absent in the son. In silico analysis of variant rs213950 (Val470Met) in CFTR and rs515726209 (Ala73Thr) in CTRC revealed distinct changes in predicted ligand binding for both proteins, which may affect protein function and contribute to the development of CP. Conclusions: This case study of a proband and his son provides additional evidence for a polygenic inheritance pattern in CP. The results also highlight new information on the role of the variants on protein function, suggesting additional testing of ligand binding for these variants should be done to confirm the functional impairments. Full article

This study aimed to assess the nutritional value of whole corn germ (WCG) in the diet of chickens. Amino acid digestibility, fatty acid digestibility, and metabolizable energy were evaluated. A metabolism assay was conducted using the precise feeding method on roosters. A completely randomized design was used, with two treatments and ten replications per rooster in each experimental unit. The treatments were as follows: WCG1, precise feeding with WCG; and WCG2, fasting birds to determine metabolic and endogenous losses in energy and fat. The variables analyzed were coefficients for amino acids in corn germ meal and fatty acid digestibility. The results showed that the standardized digestibility coefficients for amino acids in corn germ meal were (in g/kg) as follows: Lys, 920; Thr, 780; Met + Cys, 800; Arg, 910; His, 890; Ile, 950; Leu, 970; Phe + Tyr, 870; Val, 980; Gly + Ser, 740; Ala, 960; Asp, 870; and Glu, 930. The average fatty acid digestibility and AMEn were 850 g/kg and 4934 kcal/kg, respectively. Corn germ meal, which showed high digestibility of nutrients and energy, is considered an interesting ingredient for diets requiring high energy concentration. Full article

Background/Objectives: Genetic variants, such as the µ-opioid receptor 1 (OPRM1) rs1799971 and the catechol-O-methyltransferase (COMT) rs4680, have been considered among the potential causes in the development of some chronic pain conditions. In this regard, there are controversial results regarding their roles in fibromyalgia (FM). We aimed to investigate whether the OPRM1 rs1799971 and COMT rs4680 polymorphisms are associated with the development of or susceptibility to FM, as well as their potential association with syndrome characteristic variables, in a sample of the Spanish population with and without FM. Methods: The present study analysed COMT Val158Met and OPRM1 Asn40Asp genetic variants in 311 FM patients (301 women and 10 men) and 135 non-FM participants (120 women and 15 men). In addition to clinical variables, widespread pain index (WPI), symptom severity scale (SSS) (fatigue, rest quality, and cognitive symptoms), pain, stress episodes, and Borg scale were collected. Results: The main results indicate that women carrying the Val/Val genotype (i.e., high COMT activity) exhibited significantly lower levels of fatigue, cognitive impairment, and total SSS than heterozygote carriers. In addition, Met allele carriers (i.e., lower COMT activity) showed higher probabilities of suffering a stress episode and higher levels of exertion during daily activities. Conclusions: The present research suggests a link between dopaminergic dysfunction and exacerbated, frequently described symptoms in female FM patients. Although further research with wider genetic variants and recruited patients is needed, these results point out the necessity of considering gender as a separate category in chronic pain studies. Full article

Mesothelioma is a rare and aggressive cancer linked to asbestos exposure and characterized by rapid metastasis and poor prognosis. Inhibition of adenosine deaminase acting on dsRNA 2 (ADAR2) RNA binding but not ADAR2 editing has shown antitumor effects in mesothelioma. Natural compounds from the Traditional Chinese Medicine (TCM) database were docked to the RNA-binding interface of ADAR2’s second dsRNA binding domain (dsRBD2), and their drug-likeness and predicted safety were assessed. Eight ligands (ZINC000085597263, ZINC000085633079, ZINC000014649947, ZINC000034512861, ZINC000070454124, ZINC000085594944, ZINC000085633008, and ZINC000095909822) showed high binding affinity to dsRBD2 from molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) calculations. Protein–ligand interactions were analyzed to identify key residues contributing to these binding affinities. Molecular dynamics (MD) simulations of dsRBD–ligand–RNA complexes revealed that four compounds (ZINC000085597263, ZINC000085633079, ZINC000014649947, and ZINC000034512861) had negative binding affinities to dsRBD2 in the presence of the RNA substrate GluR-2. Key residues, including Val164, Met165, Lys209, and Lys212, were crucial for ligand binding, even with RNA present, suggesting these compounds could inhibit dsRBD2’s RNA-binding function. The predicted biological activities of these compounds indicate potential anticancer properties, particularly for the treatment of mesothelioma. These compounds are structurally similar to known anti-mesothelioma agents or anticancer drugs, highlighting their therapeutic potential. Current mesothelioma treatments are limited. Optimization of these compounds, alone or in combination with current therapeutics, has potential for mesothelioma treatment. Additionally, five high-quality full-length ADAR2 models were developed. These models provide insights into ADAR2 function, mutation impacts, and potential areas for protein engineering to enhance stability, RNA-binding specificity, or protein interactions, particularly concerning dimerization or complex formation with other proteins and RNAs. Full article

Background: The metabolome of COVID-19 patients has been studied sparsely, with most research focusing on a limited number of plasma metabolites or small cohorts. This is the first study to test saliva metabolites in COVID-19 patients in a comprehensive way, revealing patterns significantly linked to disease and severity, highlighting saliva’s potential as a non-invasive tool for pathogenesis or diagnostic studies. Methods: We included 30 asymptomatic subjects with no prior COVID-19 infection or vaccination, 102 patients with mild SARS-CoV-2 infection, and 61 hospitalized patients with confirmed SARS-CoV-2 status. Saliva samples were analyzed using hydrophilic interaction liquid chromatography–mass spectrometry (HILIC-MS/MS) in positive and negative ionization modes. Results: Significant differences in metabolites were identified in COVID-19 patients, with distinct patterns associated with disease severity. Dipeptides such as Val-Glu and Met-Gln were highly elevated in moderate cases, suggesting specific protease activity related to SARS-CoV-2. Acetylated amino acids like N-acetylserine and N-acetylhistidine increased in severe cases. Bacterial metabolites, including muramic acid and indole-3-carboxaldehyde, were higher in mild–moderate cases, indicating that oral microbiota differs according to disease severity. In severe cases, polyamines and organ-damage-related metabolites, such as N-acetylspermine and 3-methylcytidine, were significantly increased. Interestingly, most metabolites that were reduced in moderate cases were elevated in severe cases. Conclusions: Saliva metabolomics offers insightful information that is potentially useful in studying COVID-19 severity and for diagnosis. Full article

Background: Adequate levels of leisure-time exercise (LTE) are associated with mental health benefits. Despite increased research in recent years through randomized controlled trials (RCTs), a systematic literature review summarizing these findings is lacking. Here, we examined publication trends, impact, and research gaps regarding LTE’s effects on mental health in the form of a bibliometric analysis. Methods: Five electronic databases (PubMed, EMBASE, Web of Science, Ovid Medline, and the Cumulative Index for Nursing and Allied Health Literature) were searched from their inception until 20 November 2024. Citations were independently screened by two authors and included based on pre-determined eligibility criteria. Bibliometric analysis was conducted using SciVal and VOSviewer under five themes: (1) descriptive analysis, (2) network analysis, (3) thematic mapping, (4) co-citation and co-occurrence analysis, and (5) bibliometric coupling. Results: The systematic search identified 5792 citations, of which 78 RCTs met the inclusion criteria. Only one study was conducted in a low- or middle-income country. Sixty-four percent of studies were published in quartile-one journals. Most studies were conducted in the United States, followed by Australia, Canada, and the United Kingdom. National collaborations yielded the highest citation rates, reflecting the influence of cultural and social norms on exercise and mental health. Research gaps were identified with regards to the validity of mental health measures, the paucity of data from low- and middle-income countries, and emerging research sources. Conclusions: This bibliometric analysis highlights the existing evidence on LTE’s impact on mental health and identifies areas for future research and policy. Trials exploring valid mental health outcomes, biomarkers such as mood and oxidative stress, and collaborative research are needed, particularly in underrepresented regions of the world. Full article

Background: Sweet almond expeller is an abundant protein resource, but there are few studies on multifunctional peptides. The purpose of this study is to improve its application in food and medical industries. Methods: This study investigated the identification, screening, and action mechanisms of antihypertensive peptides with antioxidant and ferrous binding activities derived from sweet almond globulin hydrolysates using intergrade in vitro and in silico methods and an animal model. Results: Eight novel oligopeptides were identified in sweet almond globulin hydrolysates subfraction D; of them, Pro-Met-Tyr-Gly-Gly-Gly-Met-Val (PMYGGGMV) exhibited ACE inhibitory activity (IC₅₀: 121.16 μmol/L), ferrous binding ability (11.01 mg/g), and quenching capacities on hydroxyl (93.06%) and ABTS radicals (83.67%). The phenolic hydroxyl, amino, and carboxyl groups of PMYGGGMV were linked to Lys511, Tyr520, and Tyr523 in ACE’s substrate binding center through four short hydrogen bonds. PMYGGGMV can inhibit the Kelch-like ECH-Associated Protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) interaction by binding to seven residues of Keap1 (including a key residue, Arg415). The ACE inhibitory and antioxidant activities of PMYGGMY were stable during gastrointestinal digestion. Ferrous chelation did not alter the ACE inhibitory and antihypertensive effects of PMYGGMY, but it reduced its ABTS and hydroxyl radical scavenging ability (p < 0.05). Additionally, PMYGGGMV reduced blood pressure of spontaneous hypertension rates and improved iron absorption across Caco-2 cells (p < 0.05). Conclusions: PMYGGGMV has the potential to prevent oxidative stress, hypertension, and iron deficiency. Full article

Multiple sclerosis (MS) is a chronic, autoimmune pathology that affects the nervous system. It is characterized by inflammatory lesions that cause axonal damage with neurodegeneration. The signs and symptoms present in this pathology include among others, psychiatric disorders. In MS, depression is the most frequent psychiatric disorder, with prevalence levels of 40 to 60%; to date, the cause is unknown. The brain-derived neurotrophic factor (BDNF) is a neurotrophin related to neuroplasticity. The single-nucleotide polymorphism Val66Met, encoded by the BDNF gene, has been associated with various effects, including the presence of neuropsychiatric disorders. The purpose of our study was to evaluate the association between the BDNF Val66Met polymorphism and depression in MS patients. Methods: Study design, cases, and controls: Mexican mestizo MS patients. Cases: Patients diagnosed with depression. Controls: Patients without depression diagnosis. Measurements: For depression, the Beck Depression Inventory; for polymorphism, real-time PCR. Results: No statistically significant differences were found in sociodemographic and disease variables between the case and control groups. qPCR analysis showed that 68% of the participants were Val/Val wild-type homozygotes, 29% were Val/Met polymorphism heterozygotes, and 3% were Met/Met polymorphism homozygotes. The presence of the BDNF gene rs6265 polymorphism was associated with a 5.6-fold increase in the probability of depression in the cases compared to the controls. Conclusions: The BDNF Val66Met Polymorphism is associated with depression in Mexican mestizo patients diagnosed with MS. Full article

Obesity represents a complex interplay between genetics, nutrition, and lifestyle. This study aimed to elucidate the intricate relationship between genetic variants, energy intake, and bioactive compounds in influencing obesity risk, particularly in low energy intake, to reveal how dietary intake modulates molecular-level interactions. We analyzed 53,117 participants stratified by obesity status and energy intake levels. Genome-wide association studies explored the genetic variants associated with obesity risk in low-energy- and high-energy-intake subgroups. Advanced computational approaches, including molecular docking, k-means clustering, and uniform manifold approximation and projection (UMAP), were employed to analyze interactions between missense variants and natural compounds. Ten genetic variants were significantly associated with obesity, particularly in participants with low energy intake. The most prominent variants included brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265). Molecular docking identified 152 bioactive compounds with strong binding affinity to BDNF Val66Met, including 107 compounds binding to both wild and mutant types. Citrus fruits and green vegetables showed selective binding to the mutant type. Antioxidant nutrient intake (anthocyanins, isoflavonoids, vitamins C and E, selenium) was higher in lean versus obese individuals in the high-energy-intake group. Alcohol consumption and selenium intake modulated polygenic risk scores’ influence on obesity risk in high-energy-intake individuals. Notably, citrus fruit intake correlated with lower BMI across all BDNF rs6265 genotypes. In conclusion, energy intake-specific genetic associations with obesity and identifies potential bioactive compounds for targeted interventions. The findings suggest that antioxidant nutrient intake, particularly from citrus fruits, may help manage obesity risk, especially in individuals with specific genetic variants. Full article

Background/Objectives: Lactic acid bacteria (LAB) produce several diverse metabolites during fermentation that play key roles in enhancing health and food quality. These metabolites include peptides, organic acids, exopolysaccharides, and antimicrobial compounds, which contribute to gut health, immune system modulation, and pathogen inhibition. This study analyzed the intracellular (Met-Int) and extracellular metabolites (Met-Ext-CFS; cell-free supernatant) of Lactiplantibacillus plantarum UTNGt2, a probiotic strain isolated from Theobroma grandiflorum. Methods: The assessment was performed using capillary LC-MS/MS metabolomics with a SWATH-based data-independent acquisition approach to identify molecules associated with antimicrobial activity. Results: The integration of metabolomic data with whole-genome annotation enabled the identification of several key metabolites, including amino acids, nucleotides, organic acids, oligopeptides, terpenes, and flavonoids, many of which were associated with the antimicrobial activity of UTNGt2. Pathway analysis reveals critical processes such as secondary metabolite biosynthesis, nucleotide and galactose metabolism, and cofactor biosynthesis. By integrating RiPP (ribosomally synthesized and post-translationally modified peptide) cluster gene predictions with LC-MS data, this study validates the production of specific RiPPs and uncovers novel bioactive compounds encoded within the UTNGt2 genome. The oligopeptide val-leu-pro-val-pro-gln found in both Met-Int (ESI+) and Met-Ext-CFS (ESI+) may contribute to the strain’s antimicrobial strength. It could also enhance probiotic and fermentation-related functions. Conclusions: While genome-based predictions highlight the strain’s biosynthetic potential, the actual metabolite profile is influenced by factors like transcriptional regulation, post-transcriptional and post-translational modifications, and environmental conditions. These findings emphasize the value of multi-omics approaches in providing a holistic understanding of metabolite production and its role in antimicrobial activity. Full article

This study investigated the impacts of light spectra on oxidative stress and nutrient quality of the fish Plectropomus leopardus in indoor recirculating aquaculture systems. The fish (100 g ± 0.45 g [wet weight]) were cultures in five different light spectra (full-spectrum (400–800 nm), blue (450 nm), green (530 nm), red (630 nm), and dark) for 60 days. After experimentation, blood and muscle tissue were collected and analyzed for biochemical variables and nutritional quality. We demonstrated that the total cholesterol, triglycerides activities of P. leopardus in the dark groups were substantially elevated, relative to other groups (p < 0.05). Glutathione and glutathione peroxidase activities were elevated in the green light group versus other red groups, and cortisol was drastically reduced in the red group relative to other groups (p < 0.05). The crude ash concentration in the blue and full-spectrum group was substantially more elevated than in other groups (p < 0.05). Thr, Glu, Cys, Val, Met, Ile, Leu, Phe, Lys, His, Arg were markedly higher in the blue light versus the red light group (p < 0.05). The muscle of P. leopardus was rich in lysine and its essential AA index was in the order of blue light, full-spectrum, green light, dark and red group. The content of total saturated fatty acids in the blue light group was drastically lower relative to the dark, green and red groups (p < 0.05), and the total polyunsaturated fatty acids and DHA + EPA contents in the blue light group were substantially elevated relative to the other groups (p < 0.05). These results revealed that different light environments had certain effects on blood biochemical, antioxidant capacity, nutrient composition and proportion of P. leopardus. A comprehensive evaluation found that the blue light environment had more positive effects on the physiological, biochemical and nutritional quality of P. leopardus. This result provides a theoretical reference for the lighting strategy of an indoor recirculating aquaculture system. Full article