Altered Profile Research Articles

Lipidomics analysis reveals the effects of Schizochytrium sp. supplementation on the lipid composition of Tan sheep meat

Schizochytrium sp. (SZ) can potentially be employed in nutritional strategies for producing high-quality sheep meat. However, the effects of SZ on the lipid composition of sheep meat are insufficiently understood. In this study, the effects of SZ supplementation on the lipid profile of Tan sheep meat were evaluated using non-targeted lipidomic techniques. Lipidomics analysis revealed 383 differential lipids (DLs) between the SZ and control groups, and there were six metabolic pathways associated with lipids, including glycerophospholipid metabolism, glycerolipid metabolism, α-linolenic acid metabolism, linoleic acid metabolism, glycine, serine and threonine metabolism, and arachidonic acid metabolism (P < 0.05). Glycerophospholipid metabolism was the core pathway of DLs; we found that phosphatidylcholine, phosphatidylserine, and lysophosphatidylcholine were the crucial lipid metabolites of this pathway. Dietary supplementation with SZ increased n-3 polyunsaturated fatty acid (PUFA), C22:6n-3, and C20:5n-3 (P < 0.05), while it decreased C18:0, saturated fatty acid (SFA), and SFA/PUFA (P < 0.05). These results indicate that SZ supplementation induces positive alterations in the lipid profile of Tan sheep meat, which is beneficial to meat quality and sheds valuable insights into the future development of functional lipids in sheep meat.

Bile Acids and Liver Cancer: Molecular Mechanism and Therapeutic Prospects.

Hepatocellular carcinoma (HCC) is a highly aggressive liver malignancy and one of the most lethal cancers globally, with limited effective therapeutic options. Bile acids (BAs), as primary metabolites of hepatic cholesterol, undergo enterohepatic circulation involving secretion into the intestine and reabsorption into the liver, and their composition is modulated in this process. Recent clinical observations have revealed a correlation between alteration in the BAs profile and HCC incidence, and the effect of various species of BAs on HCC development has been investigated. The regulatory effect of different BA species on cell proliferation, migration, and apoptosis in tumor cells, as well as their interaction with gut microbiota, inflammation, and immunity have been identified to be involved in HCC progression. In this review, we summarize the current understanding of the diverse functions of BAs in HCC pathogenesis and therapy, from elucidating the fundamental mechanisms underlying both tumor-promoting and tumor-suppressive consequences of various BA species to exploring potential strategies for leveraging BAs for HCC therapy. We also discuss ongoing efforts to target specific BA species in HCC treatment while highlighting new frontiers in BA biology that may inspire further exploration regarding their connection to HCC.

Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities in adnp/adnp2 Mutant Zebrafish.

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

Impact of labially inclined implant axes on immediate implant placement and provisionalization in anterior maxilla: A prospective cohort study.

To investigate whether a labially inclined implant axis compromises the clinical outcomes of immediate implant placement and provisionalization (IIPP) in the anterior maxilla. Patients with unsalvageable central or lateral maxillary incisors were enrolled. IIPP with simultaneous connective tissue graft (CTG) was performed in all participants. In the control group, the alveolar ridge had a long axis aligned with the tooth, which ensured that the immediate implant was aimed at the incisor edge or the cingulum of future restoration. The test group had a large angle between the axes of the ridge and tooth. To avoid bone fenestration, the implants were placed labially inclined and emerged from the labial side of future restoration. Intra-oral scanning and cone-beam computed tomography were performed to record soft and hard tissue profiles at baseline and 1 year later. Soft tissue stability, bone remodeling, and pink esthetic score (PES) were evaluated and compared between two groups. Thirty-nine participants (19 tests and 20 controls) completed the study. At 1-year post-surgery, the mid-facial gingival margin migrations were 0.85 ± 0.37 mm (test) and 0.81 ± 0.33 mm (control), without significant differences. No differences were identified in buccal profile alteration, linear ridge reduction, buccal bone thickness, or PES scores. The test group demonstrated thinner buccal soft tissue at the crestal level than the control group. When large tooth-ridge angulation presented, labially inclined implant, avoiding buccal ridge fenestration in IIPP with CTG, did not compromise the clinical outcome in short term.

Deciphering DNA Methylation in Gestational Diabetes Mellitus: Epigenetic Regulation and Potential Clinical Applications.

Gestational diabetes mellitus (GDM) represents a prevalent complication during pregnancy, exerting both short-term and long-term impacts on maternal and offspring health. This review offers a comprehensive outline of DNA methylation modifications observed in various maternal and offspring tissues affected by GDM, emphasizing the intricate interplay between DNA methylation dynamics, gene expression, and the pathogenesis of GDM. Furthermore, it explores the influence of environmental pollutants, maternal nutritional supplementation, and prenatal gut microbiota on GDM development through alterations in DNA methylation profiles. Additionally, this review summarizes recent advancements in DNA methylation-based diagnostics and predictive models in early GDM detection and risk assessment for subsequent type 2 diabetes. These insights contribute significantly to our understanding of the epigenetic mechanisms underlying GDM development, thereby enhancing maternal and fetal health outcomes and advocating further efforts in this field.

Altered coagulation profile of patients with high-grade glioma: clinical study with control group.

Background Activation of coagulation is a common phenomenon in patients with high-grade glioma, a primary malignant brain tumor. Objective Identify if there is an alteration in the coagulation profile in patients with high-grade glioma compared to other patients with benign brain tumors. Methods Sociodemographic and clinical characteristics, ECOG at admission, prothrombin time, activated partial thromboplastin time, international normalized ratio, platelet count, and blood panel results of 21 high-grade glioma patients (cases) and 42 meningioma patients (controls) from northern Peru were reviewed. Bivariate and multivariate analysis with logistic regression were performed to determine which factors are associated with glioma. Results Both groups had high proportions of high blood pressure (29%) and diabetes mellitus (14%). According to multivariate analysis, altered values for prothrombin time, platelet count, and ECOG score were associated with glioma (p=0.01). Furthermore, alterations in the blood panel were observed in both cases and controls but failed to reach statistical significance. Conclusion Patients with high-grade glioma seem to suffer more from hypercoagulable states than other patients with benign brain tumors, suggesting careful vigilance and anticoagulant treatment for these patients.

Multiplex Profiling of miR-122 for Preclinical and Clinical Evaluation of Drug-Induced Liver Injury by a Full-Scale Platform.

Diagnostic and monitoring for drug-induced liver injury (DILI) predominantly rely on serum aminotransferases. However, owing to their widespread expression across multiple organs, a significant challenge emerges from the absence of reliable biomarkers for DILI diagnosis. Herein, we introduce a concept for DILI detection, circumventing the nonspecific elevation and delayed release of aminotransferases and then straightforwardly focusing on the core feature of DILI, abnormal gene expression caused by drug overdose. The developed full-scale platform integrates the properties of spherical nucleic acids with elaborately designed fluorescence in situ hybridization sequences, enabling the sensitive and specific profiling of drug-overdosed miR-122 expression alterations across molecular, cellular, organismal, and clinical scales and effectively bypassing the phenotypic features of disease. Furthermore, the diagnostic efficacies of serum and total RNA extracted from both mouse and human blood samples for DILI diagnosis were analyzed using the receiver operating characteristic curve and principal component analysis. We anticipate that this universal platform holds potential in facilitating DILI diagnosis, therapeutic evaluation, and prognosis.

Liquid Biopsy-Based Accurate Diagnosis and Genomic Profiling of Hard-to-Biopsy Tumors via Parallel Single-Cell Genomic Sequencing of Exfoliated Tumor Cells.

Liquid biopsy provides a convenient and safer procedure for the diagnosis and genomic profiling of tumors that are inaccessible to biopsy by analyzing exfoliated tumor cells (ETCs) or tumor-derived cell-free DNA (cfDNA). However, its primary challenge lies in its limited accuracy in comparison to tissue-based approaches. We report a parallel single-ETC genomic sequencing (Past-Seq) method for the accurate diagnosis and genomic profiling of hard-to-biopsy tumors such as cholangiocarcinoma (CCA) and upper tract urothelial carcinoma (UTUC). For CCA, a prospective cohort of patients with suspicious biliary strictures (n = 36) was studied. Parallel single-cell whole genome sequencing and whole exome sequencing were performed on bile ETCs for CCA diagnosis and resolving mutational profiles, respectively, along with bile cfDNA sequenced for comparison. Concordant single-cell copy number alteration (CNA) profiles in multiple ETCs provided compelling evidence for generating a malignant diagnosis. Past-Seq yielded bile-based accurate CCA diagnosis (96% sensitivity, 100% specificity, and positive predictive value), surpassing pathological evaluation (56% sensitivity) and bile cfDNA CNA analysis (13% sensitivity), and generated the best performance in the retrieval tissue mutations. To further explore the applicability of Past-Seq, 10 suspicious UTUC patients were investigated with urine specimens, and Past-Seq exhibited 90% sensitivity in diagnosing UTUC, demonstrating its broad applicability across various liquid biopsies and cancer types.

Optimization and Detection of Freshness Biomarkers of Atlantic Salmon Subjected to Different Vacuum Packaging Conditions during Storage at 0 °C by Metabolomics and Molecular Docking.

The freshness of Atlantic salmon is influenced mainly by tissue metabolism, which in turn is affected by storage time and conditions. The alterations in taste profiles and nutritional values of salmon when packaged using vacuum methods have not been fully understood, and the factors contributing to these changes require further research. In this work, the extraction method for flavor nutrients from salmon was optimized via the Plackett-Burman (PB) test. A sensitive and rapid targeted metabolomics method for the simultaneous determination of 34 nutrients was successfully established via ultra-performance liquid chromatography-triple quadrupole/linear ion trap composite mass spectrometry (UHPLC-QTRAP/MS), and various nutritional compositions during storage at 0 °C under different vacuum conditions (0 kPa or -90 kPa) for 4 and 8 days were analyzed. Results showed that storage time had a significant effect on salmon metabolism. The total amino acids decreased by 62.95% and 65.89% at 0 kPa and -90 kPa, respectively. Notably, a marked reduction in histidine after 8 days at -90 kPa may have diminished bitterness, while decreased levels of umami-tasting amino acids like glutamine and aspartic acid affected the overall flavor profile. Overall, the packaging conditions at 0 °C and 0 kPa were more suitable for the preservation of most nutrients in salmon. Pathway enrichment analysis revealed that the reduction in substances was mainly related to the alanine, aspartate, and glutamate metabolism pathways. Alanine, inosine, and histidine, whose levels changed significantly, can bind to the typical umami taste receptor TIR1/TIR3 and can be biomarkers to monitor and determine the freshness or spoilage of salmon after 4-8 days of storage. This study revealed the changes in small-molecule nutrients in salmon during storage under different packaging conditions, which provides a reference for the packaging preservation technology of fresh salmon and new ideas for the evaluation of salmon quality and determination of freshness.

Gut microbiota-derived indole-3-acetic acid suppresses high myopia progression by promoting type I collagen synthesis

High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM’s gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.

Feeding sows milk biofortified with n-6 and n-3 modulates immune status of sows and drives positive transgenerational effects.

The risk of chronic diseases such as cardiovascular disease, cancer, inflammation, obesity, and autoimmune disease is linked to the quality of dietary fats, with lower intake of saturated and higher intake of n-6 and n-3 polyunsaturated fatty acids (PUFA) considered beneficial to health. This study investigated the effect of supplementing sows' diets with cow's milk biofortified with n-6 or n-3 PUFA, at varying n-6/n-3 ratios (8.26, 7.92, and 2.72) during their growing phase and throughout gestation and lactation on their reproductive performance and immune-inflammatory status. Specifically, we analyzed circulating cholesterol and fatty acid profiles of serum, colostrum and milk, sow body weight, and neonate colostrum intake, Apgar scores, muscle composition, and embryo viability. Analysis of circulating immunoglobulins (Ig), interleukins, and eicosanoids and complement system hemolytic activity were used to evaluate inflammatory and immune responses of sows and piglets. Expression of lipolysis and lipogenic genes in the liver were investigated in sows and piglets, with additional investigation of hypothalamus genes regulating appetite in sows. Feeding sows milk biofortified with n-6 and n-3 PUFA altered serum fatty acid profiles, reduced triglycerides (TG), increased embryo total number, increased early gestation backfat, and reduced colostrum IgG. Piglets of biofortified sow had higher circulating IgA, IgM and TNF-α, and lower IL-10. Sows fed n-3 biofortified milk had higher very low-density lipoproteins (VLDL) and TNF-α in circulation. Offspring from sows fed n-6 versus n-3 biofortified milk had lower IL-10 and expression levels of SREBP-1. N-3 versus n-6 also lowered arachidonic acid (ARA) levels in sow's milk and piglet viability 1. Findings offer insights into the potential health benefits of dietary supplementation with biofortified milk in swine, which serve as good model of diet-nutrition studies of humans, and therefore can potentially be considered in dietary recommendations both human and animal populations.

Vitamin D levels and lipid profiles in patients with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine disorder among women. Dyslipidemia is a prevalent metabolic abnormality in individuals with PCOS. Moreover, vitamin D deficiency is widespread across all societal strata, with a particularly heightened prevalence observed in patients afflicted with PCOS. The present study aimed to investigate the level of vitamin D and its correlation with lipid profiles in Iranian women diagnosed with PCOS.MethodsThis cross-sectional study was carried out at the PCOS and infertility clinic of Arash Women’s Hospital in Tehran. The study encompassed the medical records of PCOS patients who attended the clinic from March 2021 to December 2023. All patients underwent blood tests, which included assessments of fasting blood sugar levels, lipid profiles, and 25-hydroxyvitamin D (25(OH)D) levels. The investigation focused on evaluating the relationship between vitamin D levels and lipid profiles. Statistical analyses, including the chi-square test and Spearman’s correlation coefficient, were employed to analyze the data.ResultsA total of 1004 women diagnosed with PCOS were included in the study. The age range of the participants was 14 to 46 years. The majority of the participants had a body mass index (BMI) within the normal range (n = 555, 55.3%). The median vitamin D level among the participants was 26.00 (IQR: 19.00–34.00). The relationship between vitamin D levels and lipid profile parameters was assessed, revealing no significant correlation between vitamin D levels and low-density lipoprotein (LDL) (r = 0.021, p = 0.505), high-density lipoprotein (HDL) (r = 0.011, p = 0.719), or triglyceride (TG) (r = -0.026, p = 0.417) levels, both in non-adjusted and age-adjusted analyses.ConclusionAccording to the present study, there was no significant correlation between serum 25(OH)D deficiency and elevated TG or LDL levels or decreased HDL levels in PCOS patients. Nevertheless, further prospective studies are needed to determine whether there is a causal relationship between vitamin D deficiency and lipid profile alterations, specifically among PCOS patients.

Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency

BackgroundAlthough WD repeat domain 45 (WDR45) mutations have been linked to β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\upbeta$$\\end{document}-propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.MethodsTo investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.ResultsOur study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.ConclusionsIn this study, we uncovered the molecular mechanisms underlying the contribution of WDR45 deficiency to axonal degeneration, which involves complex relationships between phospholipid metabolism, autophagy, and tubular ER. These findings greatly advance our understanding of the fundamental molecular mechanisms driving axonal degeneration and may provide a foundation for developing novel mechanistically based therapeutic interventions for BPAN and other neurodegenerative diseases.

Altered individual-level morphological similarity network in children with growth hormone deficiency

BackgroundAccumulating evidences indicate regional grey matter (GM) morphology alterations in pediatric growth hormone deficiency (GHD); however, large-scale morphological brain networks (MBNs) undergo these patients remains unclear.ObjectiveTo investigate the topological organization of individual-level MBNs in pediatric GHD.MethodsSixty-one GHD and 42 typically developing controls (TDs) were enrolled. Inter-regional morphological similarity of GM was taken to construct individual-level MBNs. Between-group differences of topological parameters and network-based statistics analysis were compared. Finally, association relationship between network properties and clinical variables was analyzed.ResultsCompared to TDs, GHD indicated a disturbance in the normal small-world organization, reflected by increased Lp, γ, λ, σ and decreased Cp, Eglob (all PFDR < 0.017). Regarding nodal properties, GHD exhibited increased nodal profiles at cerebellum 4-5, central executive network-related left inferior frontal gyrus, limbic regions-related right posterior cingulate gyrus, left hippocampus, and bilateral pallidum, thalamus (all PFDR < 0.05). Meanwhile, GHD exhibited decreased nodal profiles at sensorimotor network -related bilateral paracentral lobule, default-mode network-related left superior frontal gyrus, visual network -related right lingual gyrus, auditory network-related right superior temporal gyrus and bilateral amygdala, right cerebellum 3, bilateral cerebellum 10, vermis 1-2, 3, 4-5, 6 (all PFDR < 0.05). Furthermore, serum markers and behavior scores in GHD group were correlated with altered nodal profiles (P ≤ 0.046, uncorrected).ConclusionGHD undergo an extensive reorganization in large-scale individual-level MBNs, probably due to abnormal cortico-striatal-thalamo-cerebellum loops, cortico-limbic-cerebellum, dorsal visual-sensorimotor-striatal, and auditory-cerebellum circuitry. This study highlights the crucial role of abnormal morphological connectivity underlying GHD, which might result in their relatively slower development in motor, cognitive, and linguistic functional within behavior problem performance.

Effects of Dietary Bio-Fermented Selenium Supplementation on Growth, Immune Performance, and Intestinal Microflora of Chinese Mitten Crabs, Eriocheir sinensis.

Selenium is a vital trace mineral that is crucial for maintaining regular biological processes in aquatic animals. In this study, a four-week dietary trial was carried out to assess the impact of bio-fermented selenium (Bio-Se) on the growth and immune response of Chinese mitten crabs, Eriocheir sinensis. The crabs were randomly allocated to five dietary treatment groups, each receiving a different dose of Bio-Se. The doses included 0, 0.3, 0.6, 1.5, and 3.0 mg/kg and were accurately measured in basal diet formulations. The results showed the weight gain rate (WGR), specific growth rate (SGR), and survival rate (SR) in the 1.5 mg/kg Bio-Se group were the highest, and 3.0 mg/kg of Bio-Se has an inhibitory effect on the WGR, SGR, and SR. The activities of the immune enzymes, including glutathione peroxidase (GPX), superoxide dismutase (SOD), and acid phosphatase (ACP), of the hepatopancreas were significantly (p < 0.05) increased in the 1.5 mg/kg Bio-Se group, while they decreased (p < 0.05) in the 3.0 mg/kg feeding group compared to the 0 mg/kg feeding group. The concentration of maleic dialdehyde (MDA) exhibited the opposite pattern. Similarly, the mRNA expression levels of antimicrobial peptides (ALF-1, Crus-1, and LYS), ERK, and Relish genes were also observed to be the highest in the 1.5 mg/kg Bio-Se group compared with the other groups. Furthermore, the administration of 1.5 mg/kg of Bio-Se resulted in an increase in the thickness of the intestinal plica and mucosal layer, as well as in alterations in the intestinal microbial profile and bacterial diversity compared to the dose of 0 mg/kg of Bio-Se. Notably, the population of the beneficial bacterial phylum Fusobacteria was increased after crabs were fed the 1.5 mg/kg Bio-Se diet. In conclusion, the oral administration of 1.5 mg/kg of Bio-Se improved the growth efficiency, antioxidant capabilities, immunity, and intestinal health of E. sinensis. Through a broken-line analysis of the WGR against dietary Bio-Se levels, optimal dietary Bio-Se levels were determined to be 1.1 mg/kg. These findings contribute valuable insights to the understanding of crab cultivation and nutrition.

Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption

BackgroundDiesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. Methods and resultsUtilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 μg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/β-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and β-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression. ConclusionsOur study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ β-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability.

Differences in Bone Metabolism between Children with Prader-Willi Syndrome during Growth Hormone Treatment and Healthy Subjects: A Pilot Study.

Despite therapy with growth hormone (GH) in children with Prader-Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research.

Bioinformatics analysis of the role of RNA modification regulators in polycystic ovary syndrome

PurposePolycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder affecting women of reproductive age. The pathogenesis of PCOS is influenced by factors such as race, genetics, environment, hyperandrogenemia, hyperinsulinemia, and obesity. However, the molecular mechanisms linking RNA modification and PCOS remain underexplored. This study aims to investigate the potential genetic and molecular pathways connecting RNA modification with PCOS through bioinformatics analyses. MethodsThe GSE34526, GSE5850, and GSE98421 datasets were obtained from the National Center for Biotechnology Information Gene Expression Omnibus database. We identified intersecting differentially expressed genes (DEGs) and RNA modification-related genes within the GSE34526 dataset and visualized the overlaps using a Venn diagram. Subsequent analyses included Gene Ontology (GO), pathway enrichment (Kyoto Encyclopedia of Genes and Genomes), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis. Additionally, we constructed a protein-protein interaction network as well as mRNA-miRNA, mRNA-RNA binding protein, and mRNA-transcription factor (TF) regulatory networks. The expression and receiver operating characteristic curves of hub genes were also identified. ResultsThe expression of several RNA modification-related DEGs (RMRDEGs) (ALYREF, NUDT1, AGO2, TET2, YTHDF2, and TRMT61B) showed significant differences in PCOS patients. GSEA and GSVA indicated that RMRDEGs were enriched in the hedgehog, MAPK, JAK STAT, and Notch pathways. Key transcription factors, including SP7, KLF8, HCFC1, IRF1, and MLLT1, were identified in the TF regulatory networks. ConclusionsThese findings suggest that there are gene and miRNA profile alterations exist in PCOS patients and highlight immune-related differences. This knowledge could pave the way for new research directions in the diagnosis and treatment of PCOS.

Impact of Exogenous dsRNA on miRNA Composition in Arabidopsis thaliana.

The application of double-stranded RNAs (dsRNAs) to plant surfaces has emerged as a promising tool for manipulating gene expression in plants and pathogens, offering new opportunities for crop improvement. While research has shown the capability of exogenous dsRNAs to silence genes, the full spectrum of their impact, particularly on the intricate network of microRNAs (miRNAs), remains largely unexplored. Here, we show that the exogenous application of chalcone synthase (CHS)-encoding dsRNA to the rosette leaves of Arabidopsis thaliana induced extensive alterations in the miRNA profile, while non-specific bacterial neomycin phosphotransferase II (NPTII) dsRNA had a minimal effect. Two days after treatment, we detected 60 differentially expressed miRNAs among the 428 miRNAs found in the A. thaliana genome. A total of 59 miRNAs were significantly changed after AtCHS-dsRNA treatment compared with water and NPTII-dsRNA, and 1 miRNA was significantly changed after AtCHS-dsRNA and NPTII-dsRNA compared with the water control. A comprehensive functional enrichment analysis revealed 17 major GO categories enriched among the genes potentially targeted by the up- and downregulated miRNAs. These categories included processes such as aromatic compound biosynthesis (a pathway directly related to CHS activity), heterocycle biosynthesis, RNA metabolism and biosynthesis, DNA transcription, and plant development. Several predicted targets of upregulated and downregulated miRNAs, including APETALA2, SCL27, SOD1, GRF1, AGO2, PHB, and PHV, were verified by qRT-PCR. The analysis showed a negative correlation between the expression of miRNAs and the expression of their predicted targets. Thus, exogenous plant gene-specific dsRNAs induce substantial changes in the plant miRNA composition, ultimately affecting the expression of a wide range of genes. These findings have profound implications for our understanding of the effects of exogenously induced RNA interference, which can have broader effects beyond targeted mRNA degradation, affecting the expression of other genes through miRNA regulation.

Discovery of Potent Isoquinolinequinone N-Oxides to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.