Search Results (1,242)

One of the critical requirements for the production of artificial meat is to mimic the flavor of the original meat. Therefore, incorporation of heme has been proposed, but it is toxic when added at high concentrations in cell culture systems. Additionally, obtaining heme can be costly depending on the source. In this study, we aimed to support the growth of normal bovine muscle cells (BRMC-F2401, BRMCs) by introducing a bacterial extract obtained from a safe, high-heme-containing Corynebacterium species. The BRMCs exhibited heme toxicity when the bacterial heme level was >20 μM; however, they were adapted to stably proliferate with a 3 on–3 off culture scheme. RNA sequencing of the heme-adapted BRMCs showed gene expression changes, including upregulation of detoxification genes, CYP1A1, CYP26B1, and SERPINB2. The knockdown of these three genes increased heme sensitivity and reversed heme tolerance of the heme-adapted BRMCs. Additionally, ROS levels increased upon heme treatment, suggesting that ROS is an important factor in heme adaptation processes. Collectively, our study presents an affordable strategy to incorporate heme in cultured meat production and the mechanism underlying this process. Full article

A novel series of Schiff bases (3a–3k), incorporating tranexamic acid (TXA) and phenol-derived aldehydes via imine linkers, was synthesized and structurally characterized. The antimicrobial activity of the compounds was evaluated against a range of clinically and environmentally relevant bacterial and fungal strains. Among them, derivatives 3i and 3k, bearing bromine and chlorine substituents on the phenol ring, exhibited the most potent antimicrobial effects, particularly against Penicillium italicum and Proteus mirabilis (MIC as low as 0.014 mg/mL). To elucidate the underlying mechanism of action, in silico molecular docking studies were conducted, revealing strong binding affinities of 3i and 3k toward fungal sterol 14α-demethylase (CYP51B), with predicted binding energies surpassing those of the reference antifungal ketoconazole. Additionally, UV-Vis and fluorescence spectroscopy assays demonstrated good stability of compound 3k in PBS and its effective binding to human serum albumin (HSA), respectively. ADMET and ProTox-II predictions further supported the drug-likeness, low toxicity (Class 4), and favorable pharmacokinetic profile of compound 3k. Collectively, these findings highlight TXA–phenol imine derivatives as promising scaffolds for the development of next-generation antimicrobial agents, particularly targeting resistant fungal pathogens. Full article

With the improvement of living standards, people’s awareness of health care is becoming stronger and stronger. Rabbit meat is a very high-quality and healthy meat, but its consumption is low due to its poor flavor. To explore the regulatory mechanism of nutrition on the meat quality of rabbits, twenty-four rabbits were fed a control diet or a high-fat (5 percent lard) diet over 15 days. The contents and tissues of the jejunum were subjected to 16S sequencing and mRNA transcriptome sequencing, respectively. The results indicated that there were significant differences in species diversity through beta diversity analysis (p < 0.05). The diversity of alpha in the experimental group was also significantly reduced (p < 0.05). Based on gene function annotation, 8 bacteria at the phylum level and 11 bacteria at the genus level that are related to the metabolism of adipose tissue showed significant differences between the two groups (p < 0.05). The transcriptome results of the jejunum showed significant differences in 135 genes between the experimental group and control group (p < 0.05). Gene annotation revealed 10 differentially expressed genes related to fat metabolism, which regulate 36 signaling pathways. We speculated that Alloprevotella may influence drip loss and cooked meat rate by changing the expression of PHGDH through correlation analysis. In addition, Coprococcus may influence IMF by changing the expression of NEDD4, ANGPTL3, and CYP8B1. These results indicated that a high-fat diet changed the species and composition of bacteria in the rabbit jejunum. Alloprevotella and Coprococcus may influence rabbit meat quality and flavor by changing PHGDH, NEDD4, ANGPTL3, and CYP8B1 gene expression in the host. This study laid a molecular foundation for the improvement of rabbit meat quality through nutritional diets. Full article

To investigate the effect of epigenetic modifications on sex determination and differentiation in northern pike (Esox lucius), we employed Whole-Genome Bisulfite Sequencing (WGBS) to analyze the DNA methylation patterns in gonadal tissues of females, males, and neomales. First, we obtained high-quality sequencing data, including a total of 410.16 Gb of raw reads and 361.48 Gb of clean reads, with an 86% unique mapping rate, and a bisulfite conversion efficiency of 99.6%. Subsequently, comparative analysis revealed that 66,581 differentially methylated CG regions (i.e., DNA regions with a high frequency of CG dinucleotides), 1215 differentially methylated CHG regions (i.e., DNA regions where CG is followed by another nucleotide), and 3185 differentially methylated CHH regions (i.e., regions where cytosine is methylated in a CHH sequence, with ‘H’ representing A, T, or C) were identified among the three groups. Furthermore, we identified four key differentially methylated candidate genes (Rspo1, hsd11b2, CYP27A1 and smad3) associated with sex determination and differentiation processes in E. lucius. Finally, by integrating GO and KEGG enrichment analyses, we explored the role of epigenetic modification regulatory networks in the sex determination and differentiation of E. lucius and identified multiple metabolic pathways related to sex determination and differentiation processes (Notch signaling pathway, Wnt signaling pathway and Ovarian steroidogenesis). This study thereby lays a foundation for subsequent functional verification. Full article

Cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) is a widely expressed enzyme involved in the hydroxylation of sterols. Generated by transposon technology in zygotes, male rats lacking Cyp7b1 expression in homozygosis showed an absence of Cyp7b1 mRNA expression in the liver, small intestine, adipose tissue, and muscle. Elevated levels of 25-hydroxycholesterol were found in the liver of mutant rats. After overnight fasting, plasma triglyceride (TG) levels were increased in the homozygous rats. In agreement with this, increased hepatic secretion of very-low-density lipoprotein-TG (VLDL) in fasting rats treated with tyloxapol and decreased low-density receptor protein (LDLr) on the hepatocyte plasma membranes were observed. The decrease in LDLr was not due to decreased mRNA expression but to increased expressions of its proteases (Psck9 and Mylip). RNA sequencing identified Fasn, Igfbp2, and Pcsk9 as targets of the Cyp7b1 absence. However, the hepatic protein contents of IGFBP2 were increased in Cyp7b1-deficient rats, accompanied by a normal glucose tolerance test. HepG2 cells lacking CYP7B1 showed increased expressions of FASN and IGFBP2. These results suggest a role of CYP7B1 in the control of hepatic IGFBP2 and VLDL-TG secretion as a prediabetes sign exerted through 25-hydroxycholesterol and transcriptional or translational mechanisms depending on the species. Full article

Personalizing therapy using medical marijuana (MM) is based on understanding the pharmacogenomics (PGx) and drug–drug interactions (DDIs) involved, as well as identifying potential epigenetic risk markers. In this work, the evidence regarding the role of variants in phase I (CYP2C9, CYP2C19, CYP3A4/5) and II (UGT1A9/UGT2B7) genes, transporters (ABCB1), and selected neurobiological factors (AKT1/COMT) in differentiating responses to Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been reviewed. Data indicating enzyme inhibition by CBD and the possibility of phenoconversion were also considered, which highlights the importance of a dynamic interpretation of PGx in the context of current pharmacotherapy. Simultaneously, the results of epigenetic studies (DNA methylation, histone modifications, and ncRNA) in various tissues and developmental windows were summarized, including the reversibility of some signatures in sperm after a period of abstinence and the persistence of imprints in blood. Based on this, practical frameworks for personalization are proposed: the integration of PGx testing, DDI monitoring, and phenotype correction into clinical decision support systems (CDS), supplemented by cautious dose titration and safety monitoring. The culmination is a proposal of tables and diagrams that organize the most important PGx–DDI–epigenetics relationships and facilitate the elimination of content repetition in the text. The paper identifies areas of implementation maturity (e.g., CYP2C9/THC, CBD-CYP2C19/clobazam, AKT1, and acute psychotomimetic effects) and those requiring replication (e.g., multigenic analgesic signals), indicating directions for future research. Full article

Rapid methadone metabolism in patients with opioid use disorder could complicate methadone treatment. Toxicology screenings to monitor methadone levels may show negative for methadone, even with regular adherence to a regimen. A patient receiving treatment for opioid use disorder tested negative for methadone in 11 out of 22 toxicology screenings (50.0%). We hypothesized that the patient was a rapid methadone metabolizer. After tapering doses to a maintenance level and using supervised urine collection, the patient was negative for methadone in seven out of seven tests (100.0%), but positive for cocaine in five out of seven tests (71.4%) near the end of the maintenance period. Chronic cocaine use and genetic factors, particularly CYP2B6 polymorphisms, have been found to cause rapid methadone metabolism. Clinicians should be vigilant for unusual metabolic reactions and modify dose and monitoring schedules accordingly. More investigation into the physiological and genetic aspects of methadone metabolism is needed. Full article

Sodium butyrate (NaBu), a common feed additive, has been shown to enhance reproductive performance in livestock and poultry. However, whether NaBu exerts this effect by directly regulating follicular development remains unclear. In this study, a three-dimensional (3D) in vitro culture system of mouse preantral follicles was used to investigate the effects of NaBu on follicular growth, hormone secretion, maturation of oocytes, and subsequent embryonic development. Preantral follicles were treated with different doses of NaBu on the fourth day of culture. Subsequently, the mature oocytes (MII stage) were released from the follicles on the ninth day and subjected to parthenogenetic activation for developmental assessment. The results showed that 0.10 mM NaBu treatment could significantly promote follicular growth, antral formation, and oocyte maturation. Furthermore, NaBu also significantly increased estradiol (E₂) secretion, improved follicular structure, and maintained cellular viability. qPCR analysis revealed that NaBu significantly increased the mRNA levels of STAR, CYP11A1, and CYP1B1. In addition, it significantly enhanced the distribution and organization of F-actin, with increases in the mRNA levels of GDF9, BMP15, and CX37. NaBu treatment significantly reduced intracellular ROS levels and increased the mRNA levels of NRF2 and SOD1, while SOD2 and GSR showed increasing trends without significant differences. NaBu significantly improved oocyte cytoskeletal organization and the morphology of the spindle, but it did not lead to a significant increase in the rates of cleavage and blastocyst formation after parthenogenetic activation. Collectively, these findings indicate that NaBu promotes follicular development and improves oocyte quality, at least partly, by enhancing steroidogenesis, alleviating oxidative stress, and maintaining cytoskeletal integrity, providing insight into its potential application for improving reproductive performance in livestock and poultry. Full article

The development of new approach methodologies that include human cells differentiated into organotypic formats is of high interest due to their structural and functional similarities to tissues in vivo, enabling mechanistic understanding and translation to adverse health outcomes in humans. However, these systems often fail to capture complex intercellular signaling required for processes such as pulmonary inflammation induced by polycyclic aromatic hydrocarbons (PAHs). To investigate airway epithelial–macrophage interactions in response to benzo[a]pyrene and a PAH mixture (Tox Mix), co-culture models utilizing primary human bronchial epithelial cells (HBECs) differentiated at the air–liquid interface were cultured with THP-1 macrophages either directly or indirectly, alongside HBECs alone. After 24 h of exposure, cytokine expression (IL1B, IL6, CXCL8, TNF) as well as PAH biomarkers previously identified for chemical metabolism (CYP1A1, CYP1B1), oxidative stress (ALDH3A1, HMOX1, NQO1), and barrier integrity (TJP2) were evaluated. Cytotoxicity and barrier integrity were also assessed. HBECs alone and direct co-cultures exhibited similar responses after PAH treatment, while indirect co-cultures showed lower sensitivity to induction of inflammatory cytokines and CYP1A1 and CYP1B1 biomarker expression following exposure to PAHs. The expression of other biomarkers, including ALDH3A1, HMOX1, and NQO1, remained largely consistent across all models after treatment. Overall, these findings suggest that direct co-culture systems may provide a more physiologically relevant platform for studies of PAH-induced toxicity and demonstrate that the configuration of co-culture systems can influence cellular responses to chemical exposure. Full article

Persistent postoperative opioid use (PPOU) is an emerging challenge in pediatric perioperative care, with rates as high as 4.7% in opioid-naive adolescents. Despite advances in multimodal analgesia, current protocols often fail to prevent long-term opioid exposure, particularly after high-risk surgeries such as spinal fusions. While multiple strategies exist to reduce PPOU in children, including regional anesthesia and non-opioid analgesics, this review specifically focuses on methadone and pharmacogenomic-guided opioid prescribing as promising approaches. Methadone, a long-acting opioid with mu-opioid agonism, NMDA antagonism, and monoamine reuptake inhibition, has shown encouraging outcomes in adult and emerging pediatric studies but remains underutilized due to concerns over safety, variability, and familiarity. This narrative review explores the intersection of methadone pharmacology, pharmacogenomic (PGx)-guided opioid prescribing, and their potential to reduce PPOU and optimize perioperative pain control in children. We examine methadone’s unique pharmacokinetic profile, extended half-life, and ability to reduce central sensitization and opioid tolerance. Data from pediatric trials in cardiac, spinal, and major abdominal surgeries are reviewed, highlighting methadone’s potential to lower total opioid use, stabilize postoperative pain trajectories, and improve recovery. The review also discusses the role of PGx testing, particularly CYP2D6, CYP3A4, UGT2B7, and OPRM1 variants, in tailoring methadone dosing to individual metabolic profiles, reducing adverse effects, and improving analgesic efficacy. There are no well accepted generalizable perioperative methadone dose, number of doses and dosing intervals due to limited large multicenter studies in children. We outline challenges, including QTc prolongation, dosing variability, lack of pediatric-specific PGx guidelines, and ethical considerations around genetic testing in minors. The review calls for multidisciplinary perioperative teams, expanded PGx implementation, and real-world data from registries and AI-integrated models to support precision opioid strategies. Preventing PPOU in children is critical. Integration of methadone-based multimodal analgesia in high-risk painful in-patient procedures and future integration of PGx represent positive steps toward personalized, effective, and safer pain management in pediatric surgical patients, an urgent need as opioid stewardship becomes a clinical and public health imperative. Full article

Lipid accumulation disrupts mitochondrial dynamics, leading to dysfunctional energy metabolism and increased oxidative stress. However, the relationship between mitochondrial dynamics and ovarian function in therapeutic contexts is still not fully elucidated. Therefore, the objective of this study was to demonstrate whether increased carnitine palmitoyltransferase 1A (CPT1A) expression induced by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in ovaries of a lipid toxicity-induced rat model by regulating lipid metabolism and mitochondrial dynamics. A rat model of injury was induced through intraperitoneal administration of thioacetamide (TAA) for 12 weeks. During the 8th week of induction, PD-MSCs (2 × 10⁶ cells) were transplanted via the tail vein. Initially, we examined the engraftment of PD-MSCs. The inflammatory response (e.g., IL-6, TNFα) and apoptosis (e.g., LDH levels, TUNEL assay) were significantly increased in the non-transplanted (NTx) group compared to the normal group; however, they were significantly decreased in the transplanted (Tx) group compared to the NTx group (* p < 0.05). Additionally, oxidative stress was attenuated through the regulation of mitochondrial dynamics, including the expression of DRP1, ATP5B, and PGC1α, in the Tx group compared to the NTx group (* p < 0.05). In the NTx group, abnormally accumulated lipid droplets were observed due to dysfunctional mitochondria, whereas in the Tx group, the accumulation of lipid droplets and the expression of CPT1A were significantly comparable to those in the normal group (* p < 0.05). The levels of the steroidogenesis markers (e.g., CYP11A1 and HSD3β1) were decreased in the NTx group compared to the normal group and increased in the Tx group compared to the NTx group (* p < 0.05). The levels of sex hormone and follicular development were protected in the Tx group compared to the NTx group. Furthermore, cocultivation of PD-MSCs with etomoxir (CPT1A inhibitor)-treated primary theca cells increased the expression of steroidogenesis. In conclusion, PD-MSCs improve ovarian function in TAA-induced injury by reducing lipid accumulation and oxidative stress through the regulation of lipid metabolism and mitochondrial dynamics. The upregulation of CPT1A and related mitochondrial proteins contributes to enhanced steroidogenesis and restoration of ovarian homeostasis. These findings offer new insights into the application of stem cell therapies for reproductive medicine. Full article

Background/Objectives: Silver nanoparticles (AgNPs), used in industry and medicine, can have a negative impact on the human organism, particularly on the reproductive system, while polyphenolic supplementation may reduce oxidative stress (OS) and enhance male reproductive potential. The aim of this study was to investigate the effects of anthocyanin-rich blackcurrant pomace (BC) on sex steroid hormone metabolism and the OS indicator in the testes of rats following exposure to AgNPs. Methods: Adult rats were fed with a control feed (CTR) or diet supplemented with a 2% BC (BC group). The rats from AgNano and AgNano+BC groups were treated with 20 nm AgNPs (30 mg/kg/day for 28 days by gavage). Results: The plasma testosterone (T) and plasma dihydrotestosterone (DHT) concentrations were decreased in all experimental groups compared to the control (CTR) animals. The co-treatment of animals with AgNPs and BC resulted in decreased oestrogen receptor (ESR2) levels in the testes as compared to rats fed with a diet with BC alone, and the up-regulation of mRNA level of genes involved in T synthesis and metabolism (StAr, Cyp11a1, Hsd17b3, Hsd3b3, Cyp19a1, and Srd5a1), and steroid hormone signalling (AR, ESR1, and ESR2) compared to the Ctr group. The addition of BC to the diet of rats treated with AgNPs resulted in decreased protein carbonyls in the testes as compared to AgNPs-treated animals. Conclusions: The study demonstrated that relatively low AgNPs administration to rats was associated with increased oxidative stress in the gonads. Incorporating BC into the animals’ feed mitigated AgNPs-induced oxidative stress and stimulated the expression of genes involved in steroid synthesis and metabolism in testes. The bioactive compounds in blackcurrant pomace have plausible mechanisms to influence reproductive health. Full article

Brassica juncea (L.) Coss. var. foliosa Bailey contains high glucosinolate (GSL) levels that define its flavor and defense properties. However, the regulatory mechanisms controlling GSL biosynthesis in Brassica crops remain unclear. Here, four MYB29 homologs were identified in allotetraploid Brassica juncea. These BjuMYB29 proteins localize to the nucleus and possess transcriptional activation activity. Evolutionary analysis suggests polyploidization-driven expansion of MYB genes contributed to GLS diversification in Brassica species. Expression profiling showed distinct spatiotemporal and herbivory-responsive patterns among BjuMYB29 homologs. Heterologous expression of BjuA03.MYB29 and BjuA10.MYB29 in Arabidopsis enhanced insect resistance via GSL accumulation. Although both homologs upregulate aliphatic GSL biosynthetic genes, they differentially regulate indolic GSLs, with BjuA03.MYB29 suppressing and BjuA10.MYB29 enhancing their accumulation, potentially through differential control of CYP79B2. These results reveal subfunctionalization among MYB29 homologs in GSL regulation. This functional diversification of MYB29 homologs offers novel targets for precision breeding of Brassica crops with customized GSL profiles to optimize pest resistance and nutritional quality. Full article

Di(2-ethylhexyl) phthalate (DEHP) is known to adversely affect reproduction. Our previous study demonstrated that DEHP exposure during embryogenesis impaired fertility in adult female zebrafish. The objective of this study was to investigate developmental events underlying this effect. Embryos were exposed to DEHP 5 h post-fertilization (hpf), and the distribution of primordial germ cells (PGCs), along with the expression of genes involved in PGC migration, maintenance, and neuroendocrine regulation, was assessed. Molecular docking simulations were performed to evaluate whether DEHP’s main metabolite, mono(2-ethylhexyl) phthalate (MEHP), is able to bind to zebrafish estrogen receptors (Esr). Our results show that DEHP reduced the expression of cxcr4b, cxcr7b, esr1, and esr2a at 24 hpf. Using vasa:egfp transgenic embryos, we found that DEHP altered the distribution of PGCs. In addition, DEHP inhibited the expression of PGC-specific dazl. DEHP also induced the expression of lhb and cyp19a1 and reduced the expression of esr2a in 120 hpf larvae, consistent with disruption of the neuroendocrine reproductive axis. Molecular docking indicates that MEHP can bind to the ligand-binding domains of Esr1, Esr2a, and Esr2b. Collectively, the results show that DEHP disrupts both PGC distribution and early neuroendocrine signaling pathways, providing mechanistic insight into reduced fertility in adult female zebrafish following embryonic DEHP exposure. Full article

Background: There are important gaps in describing the associations between variants found by GWAS and various phenotypes. Prior reports suggest that SNPs in regulatory regions should be further investigated to uncover these associations. Thus, this study involved a novel approach, along with Pharmacoepigenomics, prompting a new coined term “CpG-PGx SNP”. Methods: The rationale behind our analysis strategy was based on the impact of SNPs playing dual roles both in the CpG site disruption/formation and having PGx associations. Thus, we employed GeneCards (relevance score), PharmGKB (significant p-value), and GWAS catalog data for each gene (p < 5 × 10⁻⁸). Following the obtainment of the 25 best-scored genes of four major epigenetic processes (methylation, demethylation, acetylation, and deacetylation), we generated two lists of candidate genes, including potential CpG-PGx SNPs and possible CpG-PGx SNPs. Results: Among 2900 significant PGx annotations, we found 99 potential CpG-PGx SNPs related to 16 genes. CYP2B6, CYP2C19, CYP2D6, and COMT genes were the top genes. Additionally, we found 1230 significant GWAS-based SNPs, among them 329 CpG-SNPs related to 48 genes with at least one CpG site disruption/formation. The top gene with the highest CpG-SNPs was TET2, followed by JMJD1C and HDAC9. Importantly, we detected some synonymous variants in the Epigenetically Modifiable Accessible Region (EMAR), which can provide insights into undiscovered roles of these SNPs. We identified 173 CpG-Disruptive SNPs, 155 CpG-Forming SNPs, and just 1 CpG SNP with both impacts. Conclusions: In conclusion, here we introduce CpG-PGx SNP for the first time and suggest three major genes playing crucial roles in Pharmacoepigenomics (PEpGx), CYP2D6 as the heart of PEpGx, and TET2 with the highest possibility of having CPG-PGx SNPs. We believe that this approach will help the scientific community to utilize “CpG-PGx SNP” to unravel complex disease-driven genetic and epigenetic interactions, yielding therapeutic opportunities. Full article