PubMed

Animals (Basel). 2024 Oct 19;14(20):3027. doi: 10.3390/ani14203027.ABSTRACTThis study investigated the effects of adding methionine (Met) in milk production and the milk and blood metabolites of lactating donkeys. Eighteen healthy multiparous donkeys in early-stage lactation were selected for this study. The donkeys were randomly divided into three groups and fed diets with different levels of Met: control group (C, Met 0 g/d), Met group I (M1, Met 5 g/d), and Met group II (M2, Met 15 g/d). The total duration of the experiment was 5 weeks. Donkey milk and blood samples were collected at the end of the experiment. The milk yield and composition, milk, and serum metabolites were analyzed. The results showed that the addition of 5 g of Met significantly increased milk yield as well as the milk composition contents of protein, fat, lactoferrin, polyunsaturated fatty acid (PFA), solids, and solids-not-fat (SNF) (p < 0.05). Significant differences in metabolites were detected among the different samples of milk (p < 0.05). The addition of Met increased the levels of milk metabolites, such as myristic acid, d-glutamine, l-aspartic acid, and LPS 16:0. A total of 753 metabolites were detected in the serum, including 17 differential metabolites between C and M1 and 48 differential metabolites between C and M2. The levels of serum metabolites, such as l-ascorbate, inositol, and l-lysine, were up-regulated by the addition of Met (p < 0.05). The above results indicated that Met increased donkey milk production and milk composition yield and improved milk metabolites by regulating serum metabolites. These results provide a foundation for improving the nutritional needs of lactating donkeys and the nutritional regulation of donkey milk synthesis.PMID:39457957 | DOI:10.3390/ani14203027

Animals (Basel). 2024 Oct 18;14(20):3016. doi: 10.3390/ani14203016.ABSTRACTHypoxia in the mammary gland epithelial cells of milk buffalo (BMECs) can affect milk yield and composition, and it can even cause metabolic diseases. Nitidine chloride (NC) is a natural alkaloid with antioxidant properties that can scavenge excessive reactive oxygen species (ROS). However, the effect of NC on the hypoxic injury of BMECs and its molecular mechanisms are still unknown. Here, an immunofluorescence assay, transmission electron microscopy (TEM), and flow cytometry, combined with untargeted metabolomics, were used to investigate the protective effect of NC on hypoxic stress injury in BMECs. It was found that NC can significantly reduce cell activity (p < 0.05) and inhibit cellular oxidative stress (p < 0.05) and cell apoptosis (p < 0.05). A significant decrease in mitophagy mediated by the PINK1-Parkin pathway was observed after NC pretreatment (p < 0.05). In addition, a metabolic pathway enrichment analysis demonstrated that the mechanisms of NC against hypoxic stress may be related to the downregulation of pathways involving aminoacyl tRNA biosynthesis; arginine and proline metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; and phenylalanine metabolism. Thus, NC has a protective effect on hypoxic mitochondria, and it can regulate amino acid metabolism in response to hypoxic stress. The present study provides a reference for the application of nitidine chloride to regulate the mammary lactation function of milk buffalo.PMID:39457946 | DOI:10.3390/ani14203016

Animals (Basel). 2024 Oct 11;14(20):2942. doi: 10.3390/ani14202942.ABSTRACTCastration is a prevalent and indispensable practice in sheep husbandry, aiding in enhancing meat quality, mitigating aggressive behavior, and managing unwanted reproduction. Nevertheless, the conventional surgical castration procedure poses several challenges, including heightened stress and pain, detrimental impacts on animal welfare, and diminished economic efficacy in farming operations. Consequently, immunocastration methods, serving as substitutes for surgical castration, are progressively finding application in livestock. The rumen, an essential and distinctive digestive and absorptive organ in ruminants, has been associated with enhanced meat quality and productive performance following castration in previous research studies, albeit fewer investigations have explored the potential impacts of GnRH immunization on the rumen's internal milieu in sheep post-de-escalation. Hence, the present study delved into evaluating the impact of GnRH immunocastration on the rumen microbiome and metabolomics in male Xizang sheep. This was achieved through the establishment of a GnRH immunocastration animal model and the collection of rumen fluid for microbiological and comprehensive metabolomics investigations. The outcomes of this investigation unveiled that the impact of GnRH immunocastration on body weight gain was more pronounced during the achievement of the castration objective. In addition, the Firmicutes-to-Bacteroidota ratio in the immune male (IM) group exceeded that of the control group (EM), suggesting that GnRH immunodeficiency may enhance the digestion and absorption of feed in male Xizang sheep. At the taxonomic level, the elevated presence of Prevotella and Quinella bacteria in the IM group compared to the EM group indicated that castration influenced a segment of the rumen microbiota in male Xizang sheep, thereby bolstering the digestive and metabolic efficacy of the rumen concerning nutrient utilization, particularly in the breakdown and absorption of proteins, carbohydrates, and lipids, ultimately expediting the fattening process and weight gain in male Xizang sheep following castration. Moreover, analysis of ruminal fluid metabolomics revealed that GnRH immunization had notable impacts on certain metabolites in the ruminal fluid of male Xizang sheep, with metabolites like 5-hydroxyindole acetic acid and 3-hydroxyindole acetic acid showing significant downregulation in the IM group compared to the EM group, while niacin and tyramine exhibited significant upregulation. These findings indicate a profound influence of GnRH immunization on the maintenance of ruminal equilibrium and ruminal health (including the health of ruminal epithelial cells). This study validates that GnRH immunocastration not only achieves the objectives of castration but also enhances ruminal health in male Xizang sheep, thus laying a foundational theoretical basis for the application and dissemination of GnRH immunocastration technology.PMID:39457871 | DOI:10.3390/ani14202942

Animals (Basel). 2024 Oct 11;14(20):2923. doi: 10.3390/ani14202923.ABSTRACTAnimal coloration offers a unique opportunity to explore the evolutionary mechanisms underlying phenotypic diversity. Conspicuous coloration caused by pigments plays a crucial role in social signaling across multiple species by conveying information about individual quality, social ranks, or reproductive condition. Nevertheless, most previous studies have focused predominantly on colors produced by the exogenous pigments-carotenoids. Pterins are another prevalent group of conspicuous pigments, which can be produced endogenously and have received comparatively little attention. Whether pterin-based colors represent reliable signals remains elusive. The remarkable red ventrolateral coloration exhibited by males of the Guinan toad-headed lizard (Phrynocephalus guinanensis) in the Mugetan Desert presents an ideal model for investigating pterin-based coloration. Through electron microscopy and metabolomic identification, we discovered three types of pterin pigments within xanthophores. Integrating a series of morphological measurements and behavioral experiments, we found that this red coloration was not correlated with body size, bite force, and testosterone level, nor did females show a preference bias toward it. However, the red intensity predicted male-male competition outcomes, with deeper red males being more likely to emerge as winners. Our results indicated that the pterin-based coloration could convey information about male quality, suggesting its potential role in honest signaling, given the vital importance of pterin metabolism in physiological processes. This study provides a novel case into the understanding of pterin-based colors in animals.PMID:39457853 | DOI:10.3390/ani14202923

Biomedicines. 2024 Oct 18;12(10):2389. doi: 10.3390/biomedicines12102389.ABSTRACTOsteoporosis (OP) is a prevalent skeletal disorder characterized by decreased bone mineral density (BMD) and increased fracture risk. The advancements in omics technologies-genomics, transcriptomics, proteomics, and metabolomics-have provided significant insights into the molecular mechanisms driving OP. These technologies offer critical perspectives on genetic predispositions, gene expression regulation, protein signatures, and metabolic alterations, enabling the identification of novel biomarkers for diagnosis and therapeutic targets. This review underscores the potential of these multi-omics approaches to bridge the gap between basic research and clinical applications, paving the way for precision medicine in OP management. By integrating these technologies, researchers can contribute to improved diagnostics, preventative strategies, and treatments for patients suffering from OP and related conditions.PMID:39457701 | DOI:10.3390/biomedicines12102389

Biomedicines. 2024 Sep 26;12(10):2196. doi: 10.3390/biomedicines12102196.ABSTRACTBackground/Objectives: The management of early breast cancer (BC) includes surgery, followed by adjuvant radiotherapy, chemotherapy, hormone therapy, or immunotherapy. However, the influence of these interventions in metabolic reprogramming remains unknown. This study explored alterations in the plasma metabolome of BC patients following distinct treatments to deepen our understanding of BC pathophysiology, outcomes, and the identification of potential biomarkers. Methods: We included 52 women diagnosed with BC and candidates for surgery as primary oncological treatment. Blood samples were collected at diagnosis, two weeks post-surgery, and one month post-radiotherapy. Plasma samples from 49 healthy women served as controls. Targeted metabolomics assessed 74 metabolites spanning carbohydrates, amino acids, lipids, nucleotide pathways, energy metabolism, and xenobiotic biodegradation. Results: Before treatment, the BC patients exhibited notable changes in carbohydrate, nucleotide, lipid, and amino acid metabolism. We noticed a gradual restoration of specific metabolite levels (hypoxanthine, 3-phosphoglyceric acid, xylonic acid, and maltose) throughout different treatments, suggesting a normalization of the nucleotide and carbohydrate metabolic pathways. Moreover, we observed increased dodecanoic acid concentrations, a metabolite associated with cancer protection. These variations distinguished patients from controls with high specificity and sensitivity. Conclusions: Our preliminary study suggests that oncological treatments modify the metabolism of patients towards a favorable profile with a decrease in the pathways that favor cell proliferation and an increase in the levels of anticancer molecules. These findings emphasize the pivotal role of metabolomics in recognizing the biological pathways influenced by each cancer treatment and the resulting metabolic consequences. Furthermore, it aids in identifying potential biomarkers for disease onset and progression.PMID:39457508 | DOI:10.3390/biomedicines12102196

Genes (Basel). 2024 Oct 19;15(10):1341. doi: 10.3390/genes15101341.ABSTRACTBACKGROUND: Goat milk has gained global attention for its unique nutritional properties and potential health benefits. Advancements in functional genomic technologies have significantly progressed genetic research on milk composition traits in dairy goats.RESULTS: This review summarizes various research methodologies applied in this field. Genome-wide association studies (GWAS) have identified genomic regions associated with major milk components, with the diacylglycerol acyltransferase 1 (DGAT1) gene and casein gene cluster consistently linked to milk composition traits. Transcriptomics has revealed gene expression patterns in mammary tissue across lactation stages, while the role of non-coding RNAs (such as miRNAs and circRNAs) in regulating milk composition has been confirmed. Proteomic and metabolomic studies have not only helped us gain a more comprehensive understanding of goat milk composition characteristics but have also provided crucial support for the functional validation of genes related to milk components. The integration of multi-omics data has emerged as an effective strategy for elucidating complex regulatory networks from a systems biology perspective.CONCLUSIONS: Despite progress, challenges remain, including refining reference genomes, collecting large-scale phenotypic data, and conducting functional validations. Future research should focus on improving reference genomes, expanding study populations, investigating functional milk components, exploring epigenetic regulation and non-coding RNAs, and studying microbiome-host genome interactions. These efforts will inform more precise genomic and marker-assisted selection strategies, advancing genetic improvements in milk composition traits in dairy goats.PMID:39457465 | DOI:10.3390/genes15101341

Genes (Basel). 2024 Oct 14;15(10):1319. doi: 10.3390/genes15101319.ABSTRACTBACKGROUND: Sweet potato (Ipomoea batatas (L.) Lam.) is widely cultivated as an important food crop. However, the molecular regulatory mechanisms affecting root tuber development are not well understood.METHODS: The aim of this study was to systematically reveal the regulatory network of sweet potato root enlargement through transcriptomic and metabolomic analysis in different early stages of sweet potato root development, combined with phenotypic and anatomical observations.RESULTS: Using RNA-seq, we found that the differential genes of the S1 vs. S2, S3 vs. S4, and S4 vs. S5 comparison groups were enriched in the phenylpropane biosynthesis pathway during five developmental stages and identified 67 differentially expressed transcription factors, including AP2, NAC, bHLH, MYB, and C2H2 families. Based on the metabolome, K-means cluster analysis showed that lipids, organic acids, organic oxides, and other substances accumulated differentially in different growth stages. Transcriptome, metabolome, and prophetypic data indicate that the S3-S4 stage is the key stage of root development of sweet potato. Weighted gene co-expression network analysis (WGCNA) showed that transcriptome differential genes were mainly enriched in fructose and mannose metabolism, pentose phosphate, selenium compound metabolism, glycolysis/gluconogenesis, carbon metabolism, and other pathways. The metabolites of different metabolites are mainly concentrated in amino sugar and nucleotide sugar metabolism, flavonoid biosynthesis, alkaloid biosynthesis, pantothenic acid, and coenzyme A biosynthesis. Based on WGCNA analysis of gene-metabolite correlation, 44 differential genes and 31 differential metabolites with high correlation were identified.CONCLUSIONS: This study revealed key gene and metabolite changes in early development of sweet potato root tuber and pointed out potential regulatory networks, providing new insights into sweet potato root tuber development and valuable reference for future genetic improvement.PMID:39457443 | DOI:10.3390/genes15101319

Genes (Basel). 2024 Sep 28;15(10):1275. doi: 10.3390/genes15101275.ABSTRACTBackgroud/Objectives: Ferula spp. is an essential crop in Central Asia with pronounced economic benefits governed by its flowering process. However, the mechanisms of the flowering phenotype remain unclear. Methods: In this study, using F. sinkiangensis as a model plant, we integrated transcriptome, proteome, and metabolome analyses to compare the multilayer differences in leaves and roots of plants with flowering and unflowering phenotypes. Results: We found that several variations in the transcriptome, proteome, and metabolome were closely associated with flowering. The Photosynthesis and Phenylpropanoid biosynthesis pathways in plants with the flowering phenotype were more active. Additionally, three flowering genes, named FL2-FL4, were upregulated in the leaves of flowering plants. Notably, six transcription factors were potentially responsible for regulating the expression of FL2-FL4 in the leaves to mediate flowering process of F. sinkiangensis. Moreover, genes relevant to Photosynthesis and Phenylpropanoid biosynthesis were also involved in regulating the expression of FL2-FL4 in flowering plants. Conclusions: The active regulation network together with Photosynthesis and Phenylpropanoid biosynthesis were essential for inducing the expression of flowering-related genes in leaves to promote the flowering process of F. sinkiangensis.PMID:39457399 | DOI:10.3390/genes15101275

Genes (Basel). 2024 Sep 27;15(10):1264. doi: 10.3390/genes15101264.ABSTRACTOBJECTIVE: The objective of this study was to assess serum chemistries and metabolomic parameters in cats with genetic variants of the alanine-glyoxylate aminotransferase 2 (AGXT2) gene to determine abnormalities associated with urolith formation and better understand effective approaches for the treatment of cats with uroliths.METHODS: AGXT2 genotypes of 445 cats in the colony at Hill's Pet Nutrition, Inc. (Topeka, KS, USA) were assessed in a genome-wide association study. Additionally, the serum chemistries and metabolic profiles of each cat were determined, along with their lifetime history of stone incidence. Factor analysis was used as a data-reduction method for metabolites in order to perform statistical hypothesis testing and to select significant metabolites from the more than 600 serum metabolites identified.RESULTS: Of the 82 cats forming stones in the colony (18.4%), the majority were calcium oxalate. Results showed that approximately one third of the cats with the AA variant of the AGXT2 gene have stones, that chronic kidney disease (CKD) is more common in cats with stones, and that having stones results in a shorter lifespan. A discriminant variable selection process was performed to determine the complete blood count, serum biochemistries, and serum metabolomic factors that best discriminated among the three genotypes (AA, AG, GG) and between cats forming stones and non-stone formers. Several of the highly ranked discriminating factors included metabolites related to decreased aminotransferase activity in cats with the AA variant of the AGXT2 gene. Another factor that ranked highly for discriminating between stone formers and non-stone formers contained lipid metabolites, consisting of multiple sphingomyelin species and cholesterol.CONCLUSIONS: These findings support the results of feeding studies in cats, whereby CKD cats fed food supplemented with betaine and prebiotics have experienced an increase in total body mass, reduced uremic toxins, and altered sphingomyelin concentrations.PMID:39457388 | DOI:10.3390/genes15101264

Genes (Basel). 2024 Sep 27;15(10):1263. doi: 10.3390/genes15101263.ABSTRACTBackground: A growing body of research supports the role of the microbial communities residing in the digestive system in the host's cognitive functioning. Most of these studies have been focused on the gut microbiome and its association with clinical phenotypes in middle-aged and older adults. There is an insufficiency of population-based research exploring the association of normative cognitive functioning with the microbiome particularly with the oral microbiota. Methods: In this study, using metagenomics and metabolomics, we characterized the salivary microbiome diversity in a sample of 51 males of Hispanic and African American origin aged 12-18 years and explored the associations between the microbiome and the youths' cognitive performance captured with the Kaufman Assessment Battery for Children II (KABC-II). Results: Several bacterial species of the oral microbiota and related metabolic pathways were associated with cognitive function. In particular, we found negative associations between indicators of general intelligence and the relative abundance of Bacteroidetes and Lachnospiraceae and positive associations with Bifidobacteriaceae and Prevotella histicola sp. Among metabolic pathways, the super pathways related to bacterial cell division and GABA metabolism were linked to cognitive function. Conclusions: The results of our work are consistent with the literature reporting on the association between microbiota and cognitive function and support further population work to elucidate the potential for a healthy oral microbiome to improve cognitive health.PMID:39457387 | DOI:10.3390/genes15101263

Genes (Basel). 2024 Sep 27;15(10):1261. doi: 10.3390/genes15101261.ABSTRACTBackground/Objectives: The gene-encoding farnesyl diphosphate O-methyltransferase 6 (FAMeT 6) is a member of the farnesyl diphosphate O-methyltransferase family. Our previous studies have demonstrated its influence on juvenile hormone levels in third instar silkworm larvae. Methods: we utilized transcriptomic and metabolomic techniques to investigate the changes in third instar larvae at 0, 12, and 24 h following BmFAMeT6 overexpression. Results: (1) The differentially expressed homologous genes were enriched in detoxification-related pathways at all three time points. (2) Transcription factor analysis of DEGs indicated a predominant presence of ZF-C2H2. (3) The metabolite-related network suggested that BmFAMeT6 may influence the metabolism of silkworm larvae through the ABC transporters, purine metabolism, and tyrosine metabolism pathways. (4) The differential gene count, differential metabolite count, and types of metabolites at the three time points indicated a shift in the regulatory focus within the larvae as time progresses, with the inflection point of regulation occurring at the third instar larval stage, 12 h. Conclusion: In summary, our research indicates that the regulatory role of BmFAMeT6 occurs within the context of the domestic silkworm's own growth and development regulation.PMID:39457386 | DOI:10.3390/genes15101261

Genes (Basel). 2024 Sep 26;15(10):1255. doi: 10.3390/genes15101255.ABSTRACTBackground:Gentiana crassicaulis Duthie ex Burk., a key species used in traditional Chinese medicine for treating rheumatic pain and stroke, contains iridoids as its primary active component. However, the biosynthetic mechanisms underlying iridoid production are not fully understood. Methods: This study focused on iridoid biosynthesis during the germination of G. crassicaulis seeds, integrating metabolomic and transcriptomic analyses to uncover the underlying pathways and key candidate genes. Results: 196,132 unigenes and 10 iridoid compounds were identified through RNA-seq and ultra performance liquid chromatography-quadrupole time of flight-mass spectrometer (UPLC-Q-TOF-MS), respectively. The intersection of results from Pearson correlation analysis and weighted gene co-expression network analysis (WGCNA) revealed a significant correlation between 26 genes and iridoid levels, suggesting their potential role in the iridoid metabolism. Notably, six highly expressed candidate genes (DL7H, SLS, CYP76, CYP72A2, CYP84A1, and 13-LOX3) and five iridoids (loganic acid, sweroside, swertiamarin, gentiopicroside, and 6'-O-β-D-glucosyl-gentiopicroside) responded to methyl jasmonate stimulation in G. crassicaulis seedlings. Conclusions: by combining the known functions of candidate gene families, It is hypothesized that the CYP716 and LOX families exert indirect influences on iridoid metabolism, while the CYP71, CYP81, CYP72, CYP76, CYP710 families, 2OG-FeII family, and the glucosyltransferase family are likely to play direct roles in the biosynthetic transformations of the five iridoids. This study provides a theoretical basis for further functional gene validation and metabolic engineering aimed at enhancing iridoid production. The insights gained could lead to improved iridoid production efficiency in medicinal plants, ultimately benefiting the quality and efficacy of medicinal materials.PMID:39457379 | DOI:10.3390/genes15101255

Int J Mol Sci. 2024 Oct 21;25(20):11309. doi: 10.3390/ijms252011309.ABSTRACTElevated CO2 can affect the synthesis and distribution of photosynthetic assimilates. However, the carbohydrate metabolism molecular mechanism of cucumber leaves in response to CO2 enrichment is unclear. Therefore, it is of great significance to investigate the key functional regulatory genes in cucumber. In this study, the growth of cucumber leaves under different CO2 conditions was compared. The results showed that under CO2 enrichment, leaf area increased, the number of mesophyll cells increased, stomata enlarged, and more starch grains accumulated in the chloroplasts. Compared with the control, the starch and soluble sugar content of leaves were maximally increased by 194.1% and 55.94%, respectively; the activities of fructose-1,6-bisphosphatase (FBPase), ADPG pyrophosphorylase (AGPase), starch synthase (SSS), sucrose phosphate synthase (SPS), sucrose synthase (SS) and invertase (Inv) were maximally increased by 36.91%, 66.13%, 33.18%, 21.7%, 54.11%, and 46.01%, respectively. Through transcriptome analysis, a total of 1,582 differential expressed genes (DEGs) were identified, in which the starch and sucrose metabolism pathway was significantly enriched, and 23 genes of carbon metabolism were screened. Through metabolome analysis, a total of 22 differential accumulation metabolites (DAMs) were identified. Moreover, D-glucose and D(+)-glucose were significantly accumulated, showing upregulation 2.4-fold and 2.6-fold, respectively. Through combined analysis of transcriptome and metabolome, it was revealed that seven genes were highly related to D-glucose, and Csa6G153460 (AGPase), Csa5G612840 (β-glucosidase), and Csa4G420150 (4-α-glucanotransferase) were significantly correlated to the carbohydrate regulatory network. Furthermore, the mechanism of CO2 enrichment that promotes carbohydrate metabolism in leaves at the molecular level was revealed. This mechanism advances the development of the cell wall and leaf morphology by activating the expression of key genes and improving enzyme activity.PMID:39457091 | DOI:10.3390/ijms252011309

Int J Mol Sci. 2024 Oct 20;25(20):11287. doi: 10.3390/ijms252011287.ABSTRACTOsteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms.PMID:39457070 | DOI:10.3390/ijms252011287

Int J Mol Sci. 2024 Oct 20;25(20):11283. doi: 10.3390/ijms252011283.ABSTRACTThe etiology of autism spectrum disorder (ASD) has not yet been completely elucidated. Through time, multiple attempts have been made to uncover the causes of ASD. Different theories have been proposed, such as being caused by alterations in the gut-brain axis with an emphasis on gut dysbiosis, post-vaccine complications, and genetic or even autoimmune causes. In this review, we present data covering the main streams that focus on ASD etiology. Data collection occurred in many countries covering ethnically diverse subjects. Moreover, we aimed to show how the progress in genetic techniques influences the explanation of medical White Papers in the ASD area. There is no single evidence-based pathway that results in symptoms of ASD. Patient management has constantly only been symptomatic, and there is no ASD screening apart from symptom-based diagnosis and parent-mediated interventions. Multigene sequencing or epigenetic alterations hold promise in solving the disjointed molecular puzzle. Further research is needed, especially in the field of biogenetics and metabolomic aspects, because young children constitute the patient group most affected by ASD. In summary, to date, molecular research has confirmed multigene dysfunction as the causative factor of ASD, the multigene model with metabolomic influence would explain the heterogeneity in ASD, and it is proposed that ion channel dysfunction could play a core role in ASD pathogenesis.PMID:39457068 | DOI:10.3390/ijms252011283

Int J Mol Sci. 2024 Oct 19;25(20):11265. doi: 10.3390/ijms252011265.ABSTRACTPropolis is a sticky substance produced by honeybees (Apis mellifera) through the collection of plant resins, which they mix with secretions from their palate and wax glands. Propolis can inhibit tumor invasion and metastasis, thereby reducing the proliferation of tumor cells and inducing cell apoptosis. Previous research has shown that propolis has an inhibitory effect on skin squamous cell carcinoma A431 cells. Nevertheless, its inhibitory mechanism is unclear because of many significantly different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the ethanol extract of the propolis (EEP) group and the control group of cells. In this study, the main components of EEP and the antitumor mechanism at an IC50 of 29.04 μg/mL EEP were determined via untargeted metabolomics determined using ultra high-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS), respectively. The results revealed 43 polyphenolic components in the EEP and 1052 metabolites, with 160 significantly upregulated and 143 significantly downregulated metabolites between cells treated with EEP and solvent. The KEGG enrichment results revealed that EEP significantly inhibited A431 cell proliferation via the steroid hormone biosynthesis and linoleic acid metabolism pathways. These findings may provide valuable insights for the development of targeted therapies for the treatment of cutaneous squamous cell carcinoma.PMID:39457046 | DOI:10.3390/ijms252011265

Int J Mol Sci. 2024 Oct 19;25(20):11259. doi: 10.3390/ijms252011259.ABSTRACTThe gut microbiome emerges as an integral component of precision medicine because of its signature variability among individuals and its plasticity, which enables personalized therapeutic interventions, especially when integrated with other multiomics data. This promise is further fueled by advances in next-generation sequencing and metabolomics, which allow in-depth high-precision profiling of microbiome communities, their genetic contents, and secreted chemistry. This knowledge has advanced our understanding of our microbial partners, their interaction with cellular targets, and their implication in human conditions such as inflammatory bowel disease (IBD). This explosion of microbiome data inspired the development of next-generation therapeutics for treating IBD that depend on manipulating the gut microbiome by diet modulation or using live products as therapeutics. The current landscape of artificial microbiome therapeutics is not limited to probiotics and fecal transplants but has expanded to include community consortia, engineered probiotics, and defined metabolites, bypassing several limitations that hindered rapid progress in this field such as safety and regulatory issues. More integrated research will reveal new therapeutic targets such as enzymes or receptors mediating interactions between microbiota-secreted molecules that drive or modulate diseases. With the shift toward precision medicine and the enhanced integration of host genetics and polymorphism in treatment regimes, the following key questions emerge: How can we effectively implement microbiomics to further personalize the treatment of diseases like IBD, leveraging proven and validated microbiome links? Can we modulate the microbiome to manage IBD by altering the host immune response? In this review, we discuss recent advances in understanding the mechanism underpinning the role of gut microbes in driving or preventing IBD. We highlight developed targeted approaches to reverse dysbiosis through precision editing of the microbiome. We analyze limitations and opportunities while defining the specific clinical niche for this innovative therapeutic modality for the treatment, prevention, and diagnosis of IBD and its potential implication in precision medicine.PMID:39457040 | DOI:10.3390/ijms252011259

Int J Mol Sci. 2024 Oct 19;25(20):11244. doi: 10.3390/ijms252011244.ABSTRACTFindings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by a deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130,000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.PMID:39457026 | DOI:10.3390/ijms252011244

Int J Mol Sci. 2024 Oct 18;25(20):11233. doi: 10.3390/ijms252011233.ABSTRACTAutoimmune hepatitis (AIH) is a chronic inflammatory liver disease treated by steroids and immunomodulator thiopurine drugs such as azathioprine (AZA). AZA is metabolized in the human body into bioactive forms such as 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP). Monitoring the levels of bioactive AZA metabolites is very important for proper treatment of patients. In this study, our aim was to develop and validate a fast and sensitive ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) method for the analysis of 6-TG and 6-MMP from blood samples of patients with AIH to monitor the level of these bioactive metabolites. The detection and quantification of the analytes was carried out by Selected Reaction Monitoring (SRM)-based targeted mass spectrometry. The method was validated according to the EMA guidelines. Blood samples from patients with AIH treated with AZA were analysed with the developed method. The method was successfully validated with appropriate accuracy and precision for the target biomolecules and their concentration in the samples from patients with AIH was determined. The developed and validated UHPLC-MS method enables the fast and precise analysis of AZA metabolites.PMID:39457015 | DOI:10.3390/ijms252011233