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ABSTRACT: Inosine monophosphate (IMP) plays a significant role in meat taste, yet the molecular mechanisms controlling IMP deposition in muscle tissues still require elucidation. The present study systematically and comprehensively explores the molecular network governing IMP deposition in different regions of Jingyuan chicken muscle. Two muscle groups, the breast and leg, were examined as test materials. Using nontargeted metabolomic sequencing, we screened and identified 20 metabolites that regulate IMP-specific deposition. We maintained regular author and institution formatting, used clear, objective, and value-neutral language, and avoided biased or emotional language. We followed a consistent footnote style and formatting features and used precise word choice with technical terms where appropriate. Out of these, 5 were identified as significant contributors to the regulation of IMP deposition. We explained technical term abbreviations when first used and ensured a logical flow of information with causal connections between statements. The results indicate that PGM1, a key enzyme involved in synthesis, is higher in the breast muscle compared to the leg muscle, which may provide an explanation for the increased deposition of IMP in the breast muscle. We aimed for a clear structure with logical progression, avoided filler words, and ensured grammatical correctness. The activity of key enzymes (PKM2, AK1, AMPD1) involved in this process was higher in the breast muscle than in the leg muscle. In the case of IMP degradation metabolism, the activity of its participating enzyme (PurH) was lower in the breast muscle than in the leg muscle. These findings suggest that the increased deposition of IMP in Jingyuan chickens' breast muscle may result from elevated metabolism and reduced catabolism of key metabolites. In summary, a metaomic strategy was utilized to assess the molecular network regulation mechanism of IMP-specific deposition in various segments of Jingyuan chicken. These findings provide insight into genetic improvement and molecular breeding of meat quality traits for top-notch broilers.

ABSTRACT: Intramuscular fat (IMF) has a pivotal influence on meat quality, with its deposition being a multifaceted physiological interaction of several regulatory factors. N6-methyladenosine (m6A), the preeminent epigenetic alteration among eukaryotic RNA modifications, holds a crucial role in moderating post-transcriptional gene expression. However, there is a dearth of comprehensive understanding regarding the functional machinery of m6A modification in the context of IMF deposition in poultry. Our current study entails an analysis of the disparities in IMF within the breast and leg of 180-day-old Jingyuan chickens. We implemented methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to delve into the distribution of m6A and its putative regulatory frameworks on IMF deposition in chickens. The findings demonstrated a markedly higher IMF content in leg relative to breast (P < 0.01). Furthermore, the expression of METTL14, WTAP, FTO, and ALKBH5 was significantly diminished in comparison to that of breast (P < 0.01). The m6A peaks in the breast and leg primarily populated 3′untranslated regions (3′UTR) and coding sequence (CDS) regions. The leg, when juxtaposed with the breast, manifested 176 differentially methylated genes (DMGs), including 151 hyper-methylated DMGs and 25 hypo-methylated DMGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed a pronounced enrichment of DMGs in the biosynthesis of amino acids, peroxisome, Fatty acid biosynthesis, fatty acid elongation, and cell adhesion molecules (CAMs) pathways. Key DMGs, namely ECH1, BCAT1, and CYP1B1 were implicated in the regulation of muscle lipid anabolism. Our study offers substantial insight and forms a robust foundation for further exploration of the functional mechanisms of m6A modification in modulating IMF deposition. This holds profound theoretical importance for improving and leveraging meat quality in indigenous chicken breeds.

ABSTRACT: Intramuscular fat (IMF) is an important indicator for determining meat quality, and IMF deposition during muscle development is regulated by a complex molecular network involving multiple genes. The N6-methyladenosine (m6A) modification of mRNA plays an important regulatory role in muscle adipogenesis. However, the distribution of m6A and its role in IMF metabolism in poultry has not been reported. In the present study, a transcriptome-wide m6A profile was constructed using methylated RNA immunoprecipitation sequence (MeRIP-seq) and RNA sequence (RNA-seq) to explore the potential mechanism of regulating IMF deposition in the breast muscle based on the comparative analysis of IMF differences in the breast muscles of 42 (group G), 126 (group S), and 180-days old (group M) Jingyuan chickens. The findings revealed that the IMF content in the breast muscle increased significantly with the increase in the growth days of the Jingyuan chickens (P < 0.05). The m6A peak in the breast muscles of the 3 groups was highly enriched in the coding sequence (CDS) and 3′ untranslated regions (3′ UTR), which corresponded to the consensus motif RRACH. Moreover, we identified 129, 103, and 162 differentially methylated genes (DMGs) in the breast muscle samples of the G, S, and M groups, respectively. Functional enrichment analyses revealed that DMGs are involved in many physiological activities of muscle fat anabolism. The m6A-induced ferroptosis pathway was identified in breast muscle tissue as a new target for regulating IMF metabolism. In addition, association analysis demonstrated that LMOD2 and its multiple m6A negatively regulated DMGs are potential regulators of IMF differential deposition in muscle. The findings of the present study provide a solid foundation for further investigation into the potential role of m6A modification in regulating chicken fat metabolism.

Inosine monophosphate (IMP) is an indicator of meat taste, and the molecular mechanism underlying IMP deposition in muscle tissues is important to developing superior poultry breeds. The aim of this study was to identify the key proteins regulating IMP deposition in different muscle groups of 180-day-old Jingyuan chickens (Hen) using a proteomics-based approach. We identified 1,300 proteins in the muscle tissues of Jingyuan chickens, of which 322 were differentially expressed between the breast and leg muscles (129 proteins were highly expressed in breast muscles and 193 proteins were highly expressed in leg muscles). PGM1, PKM2, AK1, AMPD1, and PurH/ATIC were among the differentially expressed proteins (DEPs) involved in the purine metabolism pathway, of which purH was highly expressed in leg muscles, while the others were highly expressed in breast muscles. The proteomics screening results were verified by PRM, qPCR, and western blotting, showing consistency with the proteomics results. Our findings are not only significant in terms of protecting the Jingyuan chicken germplasm resources, but also provide the molecular basis for generating high-quality broiler chicken breeds.

Diacetylmorphine (DA) abuse can result in severe arrhythmias and even sudden death. Although previous research has connected ion channel proteins to arrhythmia occurrences, the precise mechanism underlying DA-induced arrhythmias remains poorly understood. This study conducted a comprehensive analysis of the myocardial toxicity of DA by applying proteomic and histopathological approaches and investigated the underlying mechanisms using in vitro experiments. In vivo experiments confirmed that DA induces cardiac arrhythmias, as evidenced by electrocardiographic analyses of rats. Additionally, Masson staining, wheat germ agglutinin staining (WGA) staining, and western blotting of myocardial tissues revealed significant myocardial damage. Tandem mass tag proteomics analysis identified syntrophin alpha 1 (SNTA1) as a pivotal target molecule linked to myocardial toxicity. Ex vivo experiments showed specific upregulation of SNTA1 in rat cardiomyocytes following DA exposure. Furthermore, in vitro experiments indicated that DA caused disruption of potassium channels and activated the arrhythmia-related PI3K/AKT signaling pathway. Silencing and overexpression studies of SNTA1 highlighted its role in ion channel abnormalities and that of the PI3K/AKT signaling pathway expression in cardiomyocytes, underscoring the crucial role of mitochondrial function in cardiac arrhythmias. This research indicates that SNTA1 is integral to arrhythmia development by influencing the PI3K/AKT signaling pathway, leading to mitochondrial dysfunction and ion channel irregularities. SNTA1 is a potential therapeutic target for DA-induced arrhythmias. This study enhances our understanding of DA-induced myocardial toxicity and offers valuable insights for assessing the risks of DA exposure in humans.

Ten percent of non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations harbor uncommon variants. These mutations are mainly involved in lung adenocarcinomas but are rare in lung squamous cell carcinoma (LSCC). In 2018, the Food and Drug Administration-approved afatinib for this specific patient population. However, there is limited information regarding the effectiveness of afatinib for LSCC with EGFR mutations. This case report documented a unique case of a patient with LSCC, which had a rare compound EGFR mutation (G719C and S768I) and showed significant response to afatinib treatment, with 10 months of progression-free survival. New NTRK1 and RET gene mutations may play a potential role in the development of acquired resistance to afatinib following clinical progression. This case highlights the importance of genetic profiling in patients with LSCC. Although these patients have a low positive rate of EGFR mutations, searching for EGFR mutations in these patients might broaden their treatment options.

Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1β and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.