Search Results (25,221)

Liver fibrosis (LF) poses significant challenges in diagnosis and treatment. This study aimed to identify effective biomarkers for diagnosis and therapy, as well as to gain deeper insights into the immunological features associated with LF. LF-related datasets were retrieved from the Gene Expression Omnibus (GEO) database. Two datasets were merged to generate a metadata cohort for bioinformatics analysis and machine learning, while another dataset was reserved for external validation. Seventy-eight machine learning algorithms were employed to screen signature genes. The diagnostic performance of these genes was evaluated using receiver operating characteristic (ROC) curves, and their expression levels were validated via qRT-PCR experiments. The R language was utilized to delineate the immune landscape. Finally, correlation analysis was conducted to investigate the relationship between the signature genes and immune infiltration. Through the intersection of GEO datasets and Weighted Gene Co-expression Network Analysis (WGCNA), 42 genes were identified. Machine learning methods further narrowed down 13 signature genes (alpha-2-macroglobulin (A2M), ankyrin-3 (ANK3), complement component 7 (C7), cadherin 6 (CDH6), cysteine-rich motor neuron protein 1 (CRIM1), dihydropyrimidinase-like 3 (DPYSL3), F3, gamma-aminobutyric acid (GABA) receptor subunit epsilon (GABRE), membrane metalloendopeptidase (MME), solute carrier family 38 member 1 (SLC38A1), tropomyosin alpha-1 chain (TPM1), von Willebrand factor (VWF), and zinc finger protein 83 (ZNF83)), and qRT-PCR confirmed these genes’ expression patterns. Furthermore, these signature genes demonstrated strong correlations with multiple immune cell populations. In conclusion, the 13 genes (A2M, ANK3, C7, CDH6, CRIM1, DPYSL3, F3, GABRE, MME, SLC38A1, TPM1, VWF, and ZNF83) represent robust potential biomarkers for the diagnosis and treatment of LF. Among these genes, we first identified Gabre as related to LF and expressed in hepatocytes and cholangiocytes. The immune response mediated by these signature biomarkers plays a pivotal role in the pathogenesis and progression of LF through dynamic interactions between the biomarkers and immune-infiltrating cells. Full article

Schwann cells (SCs) are the primary glial cells of the Peripheral Nervous System (PNS), which insulate and provide protection and nutrients to the axons. Technological and experimental advances in neuroscience, focusing on the biology of SCs, their interactions with other cells, and their role in the pathogenesis of various diseases, have paved the way for exploring new treatment strategies that aim to harness the direct protective or causative properties of SCs in neurological disorders. SCs express cytokines, chemokines, neurotrophic growth factors, matrix metalloproteinases, extracellular matrix proteins, and extracellular vesicles, which promote the inherent potential of the injured neurons to survive and accelerate axonal elongation. The ability of SCs to support the development and functioning of neurons is lost in certain hereditary, autoimmune, metabolic, traumatic, and toxic conditions, suggesting their role in specific neurological diseases. Thus, targeting, modifying, and replacing SC strategies, as well as utilizing SC-derived factors and exosomes, have been considered novel therapeutic opportunities for neuropathological conditions. Preclinical and clinical data have demonstrated that SCs and SC-derived factors can serve as viable cell therapy for reconstructing the local tissue microenvironment and promoting nerve anatomical and functional recovery in both peripheral and central nerve injury repair, as well as in peripheral neuropathies. However, despite the promising successes of genetic engineering of SCs, which are now in preclinical and clinical trials, improving tactics to obtain ‘repair’ SCs and their products from different sources is the key goal for future clinical success. Finally, further development of innovative therapeutic approaches to target and modify SC survival and function in vivo is also urgently needed. Full article

The Mediator complex plays a key role in gene transcription. In particular, the interaction of the Mediator complex with nuclear receptors, the known transcription factors, regulates multiple nuclear receptor-mediated gene transcription pathways and associated cellular functions. Dysregulation of the interaction of the Mediator complex with nuclear receptors results in many pathological processes, such as cancer, metabolic and neuronal diseases. Thus, understanding of the mechanism by which the Mediator complex regulates the nuclear receptor-mediated transcriptional activity and biological function is crucial for therapy of both the Mediator complex- and nuclear receptor-associated diseases. In this review article, we attempt to summarize current research progress in the interaction of the Mediator complex with nuclear receptors and the associated nuclear receptor transcriptional signaling pathways, explore the clinical potential of the Mediator complex as a therapeutic target, and provide new perspectives for the treatment of diseases associated with the Mediator complex and nuclear receptors. Full article

This study investigated the effects of genotype and sex on carcass traits, myosin heavy chain (MyHC) isoforms, and meat quality in pigs raised under Thai commercial conditions. Fifty pigs (25 barrows and 25 gilts) from five genotypes—purebred Duroc (D), LWLR1 (Large White_old × Landrace_old), LWLR2 (Large White_new × Landrace_new), DLWLR1 (Duroc × LWLR1), and DLWLR2 (Duroc × LWLR2)—were slaughtered at ~110 kg body weight. LWLR1 is traditional maternal line, whereas LWLR2 is a newly selected line for higher intramuscular fat (IMF). Significant genotype × sex interactions were observed for dressing percentage, carcass length, bone percentage, purge loss, pH₂₄, and L* (lightness) (p < 0.05). The Longissimus lumborum (LL) muscle of Duroc pigs showed the lowest pH₄₅ and shear force but highest IMF, whereas LWLR1 pigs exhibited higher crude protein, polyunsaturated fatty acids, and flavor-enhancing nucleotides. The LL muscle of LWLR2 and DLWLR2 pigs showed greater expression of MyHC I and IIA, as well as calpain 1 (CAPN1), calpain 2 (CAPN2), and calpastatin (CAST) genes. In contrast, Duroc pigs had the highest MyHC IIX and lowest IIB expression, opposite to patterns in LWLR1 and DLWLR1. Principal component analysis revealed distinct genotype-based clustering, emphasizing the influence of maternal lineage on pork quality and offering valuable insights for genetic selection strategies. Full article

Background: Fat embolism frequently occurs as a result of trauma, such as long bone fractures and orthopedic surgeries, as well as in certain non-traumatic conditions. The formation can be attributed to mechanical or biochemical processes. According to Hullman’s biochemical hypothesis, elevated C-reactive protein levels facilitate the precipitation of very-low-density lipoproteins and chylomicrons, forming fat globules that may result in fat embolism. Based on the abovementioned hypothesis, this study aims to detect fat embolism in autopsy patients (postmortem) suffering from bronchopneumonia and determine its possible role as a cause of death. Methods: A group of autopsies of deceased individuals with bacterial purulent bronchopneumonia with confirmed or presumed elevated C-reactive protein levels was rigorously selected, excluding those with other potential causes of fat embolism such as cardiopulmonary resuscitation, hypothermia, and diabetes mellitus. Multiple organs were sampled for frozen section analysis using Oil Red O fat staining and assessed for the presence and extent of fat embolism. The Falzi score, as modified by Janssen, was employed for the lung tissue. Results: In 73% of the cases, predominantly sporadic, Grade 0 or Grade I fat embolism was observed; however, in none of the cases was fat embolism identified as the cause of death or as a significant contributing factor. Furthermore, neither fat embolism syndrome nor multiorgan fat embolism were detected. Conclusions: Although an elevated C-reactive protein level facilitates the formation of fat globules and fat embolism, its role as a direct cause of mortality remains uncertain. It may predispose individuals to such conditions and potentially interact with other factors, such as minor soft tissue trauma, to exacerbate the severity of fat embolism or its clinical manifestations. These findings underscore the necessity for further comprehensive investigations within the contexts of infection/inflammation, fat embolism, and dyslipidemia. Full article

Background: Hydroxycarboxylic acid receptor 3 (HCAR3) is a receptor that is mainly expressed in human adipose tissue. It can inhibit lipolysis through the inhibition of adenylyl cyclase; thus, it is closely related to the regulation of lipids in the human body. This makes HCAR3 a compelling target for developing drugs against dyslipidemia. Notably, the reported active compounds for HCAR3 are all carboxylic acids. This observation is in line with the fact that ARG111 has been reported as the key residue to anchor the active compound in a closely related homologous protein—HCAR2. Methods: In this study, we aim to discover new chemicals, through virtual screening, that may bind with HCAR3. As there are several choices for the receptor conformation, cross-docking was conducted and the root-mean-square deviation of the docking pose from the conformation of the crystal ligand was employed to determine the best receptor conformation for screening. Ligands from the ZINC20 database were screened through molecular docking, and 30 candidates were subjected to 100 ns MD simulations. Six stable complexes were further assessed by umbrella sampling to estimate binding affinity. Results: The homology model (HCAR3_homology) was selected as the receptor. Following the protocol determined by the retrospective docking process, prospective docking was conducted to screen the ligands from the ZINC20 database. Subsequently, the top 30 compounds with a good docking score and a good interaction with ARG111 were subjected to 100 ns molecular dynamics (MD) simulations, and their binding stability was analyzed based on the resulting trajectories. Finally, six compounds were chosen for binding free energy calculation using umbrella sampling; all showed negative binding affinities. Conclusions: All six compounds selected for umbrella sampling showed negative binding affinities, suggesting their potential as novel HCAR3 ligands for the development of drugs against dyslipidemia. Full article

Heat shock proteins (HSPs), a family of proteins including HSP27, HSP40, HSP60, HSP70, and HSP90, play critical roles in cellular processes and are often dysregulated in cancer. Heat Shock Factor 1 (HSF1) protein, the master regulator of HSP expression, is also a promising target for cancer therapy due to its involvement in tumorigenesis. This study is the first to investigate the potential of two novel curcumin analogs, MS13 (1,2-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) and MS17 (1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one), as modulators of these key targets. Employing molecular docking and molecular dynamics (MD) simulations, we investigated the interactions of MS13 and MS17 with HSF1 and the panel of HSPs. Both compounds demonstrated strong binding affinity for all the proteins, particularly for HSP70, exhibiting greater affinity compared to curcumin. Molecular docking revealed specific binding sites for both compounds on each target protein, which were further investigated using MD simulations. MS17 generally formed more stable complexes with HSP27, HSP40, HSP60, and HSP70, suggesting it might be a more potent modulator of these specific proteins. In contrast, MS13 displayed greater stability when bound to HSF1 and HSP90. These different variations could be attributed to variations in the chemical structures of MS13 and MS17, leading to distinct interactions with each protein’s binding site. MS13 and MS17 exhibit more advantageous ADMET profiles compared to curcumin, particularly in their predicted Blood–Brain Barrier (BBB) permeability and MS17’s superior passive membrane permeability and absorption. These findings highlight the potential of both MS13 and MS17 as promising leads for developing HSP modulators for cancer treatment. Full article

This study systematically investigated the decolorization efficacy and detoxification effect of crude laccase derived from Pleurotus ostreatus yang1 on azo and triphenylmethane dyes. This research encompassed decolorization efficiencies for 15 dyes (7 azo dyes and 8 triphenylmethane dyes), time course decolorization kinetics, and detoxification assessment using rice (Oryza sativa) and wheat (Triticum aestivum) seed germination as phytotoxicity indicators for both single-dye and mixed-dye systems. Molecular docking was employed to elucidate the laccase–dye interaction mechanisms. The results demonstrated that crude laccase from Pleurotus ostreatus yang1 exhibited significant decolorization efficiency and effective detoxification capacity toward both azo dyes and triphenylmethane dyes. It also displayed considerable decolorization efficiency for mixtures of azo and triphenylmethane dyes (mixture of two types of dyes), along with strong detoxification capability against the phytotoxicity of mixed dyes. Crude laccase showed robust continuous batch decolorization capability for azo dyes Alpha-naphthol Orange (α-NO) and Mordant Blue 13 (MB13). Similarly, it achieved high continuous batch decolorization efficiency for triphenylmethane dyes (e.g., Cresol Red, Acid Green 50) while maintaining stable laccase activity throughout the decolorization process. Crude laccase demonstrated excellent reusability and sustainable degradation performance during the continuous batch decolorization. The decolorization of crude laccase could significantly reduce or completely eliminate the phytotoxicity of both single dyes and mixtures of two dyes (pairwise mixtures of different types of dyes, totaling 18 different combinations). The results of molecular docking between the laccase protein and structurally diverse dyes further elucidated the underlying causes and potential mechanisms for variations in the catalytic ability of laccase toward different structural dyes. In summary, crude laccase from Pleurotus ostreatus yang1 possessed great application value and potential for efficiently degrading and detoxifying dye pollutants of different structural types. Full article

This study addresses the role of cytosine methylation in the fine-tuning of flowering time under water deficit in Arabidopsis thaliana. A drm1 drm2 cmt3 (ddc) triple methylation mutant was used together with the Col-0 wild type. The plants were grown under long-day conditions with water deficit induced by cessation of watering starting 12 days after seeding. Col-0 showed a 1-day delay in flowering as a result of the treatment. In contrast, ddc showed a 2-day delay regardless of the experimental conditions. We found that the two b-box domain proteins, BBX16/COL7 and BBX17/COL8, became overexpressed in the ddc background and in Col-0 under water deficit 24 days after seeding. Additionally, the NF-YA2 transcription factor became correspondingly down-regulated. Our results support a model where BBX16/COL7 and BBX17/COL8 interact with CONSTANS to delay the induction of FT under long-day conditions. NF-YA2, which is also recognized as a promoter of FT expression, with its down-regulation causes additional delay of FT-induced flowering. The plants overcome the BBX/NF-YA inhibition easily, resulting in a relatively small delay in flowering. The expression patterns of the three genes suggest the involvement of cytosine methylation in their regulation; however, no differential methylation could be found in cis that can explain these effects. The results therefore suggest a trans acting mechanism. Considering that the activities of BBX16/COL7 and BBX17/COL8 in different physiological conditions are not elucidated, this paper provides a background for future experiments targeting the role of these genes in the fine-tuning of flowering time in A. thaliana. Full article

The cytosolic pH (pH_i) of mammalian cells is tightly maintained at values ~7.2. Cytoplasmic acidosis (pH_i < 6.8) occurs when the intracellular proton concentration ([H⁺]_i) exceeds the buffering capacity of the cytosol and transport processes to extrude protons are exhausted. During intracellular acidosis, the contractility of cardiac and skeletal muscle cells is strongly reduced, often at sufficient Ca²⁺ levels. A contraction of striated muscle is achieved when the intracellular calcium (Ca²⁺) concentration rises above resting levels. The amplitude and kinetics of Ca²⁺ signals are controlled by Ca²⁺ handling proteins and force is generated if Ca²⁺ ions interact with contractile filaments of the sarcomere. Some aspects of this phenomenon, such as the biochemical origin of excessive protons in working muscle cells and molecular interactions of protons with Ca²⁺ handling proteins or contractile filaments, are not yet fully understood. This review summarizes our current understanding of how striated muscle cells handle Ca²⁺ and H⁺ and how a rise in [H⁺]_i may interfere with Ca²⁺ signaling in the working skeletal muscle (fatigue) or during ischemic events in cardiac muscle. Finally, we briefly address experimental strategies to measure Ca²⁺ signaling at different pH values with fluorescent probes and highlight their limitations. Full article

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a complex molecular landscape. Despite extensive research, our understanding of the molecular mechanisms remains incomplete, hindering the development of effective therapeutic strategies for this disease. Long non-coding RNAs (lncRNAs) have emerged as crucial factors in cancer biology, regulating key networks across various malignancies. These molecules exert their regulatory functions through interactions with nucleic acids or proteins, thereby influencing signaling pathways within tumor cells. Consequently, lncRNAs play a significant role in key processes like cell proliferation, metastasis, immune evasion, and treatment resistance. This review offers a comprehensive overview of current knowledge regarding lncRNA-mediated mechanisms in HNSCC. The first section explores how lncRNAs influence tumor processes through various modulation mechanisms, including transcriptional and post-transcriptional regulation, chromatin remodeling, and epigenetic modifications. We also highlight the impact of lncRNAs on specific signaling pathways that control essential cellular functions (e.g., proliferation, apoptosis, angiogenesis, invasion, metastasis). Ultimately, this underscores the promising potential of lncRNAs as diagnostic biomarkers and therapeutic targets capable of enhancing patient care in oncology. Gaining a deep understanding of how lncRNAs modulate carcinogenic mechanisms may yield innovative approaches for early detection, personalized treatment, and improved clinical outcomes for HNSCC patients. Full article

Intracerebral hemorrhage (ICH) remains the least treatable form of stroke, with inflammation implicated as a major pathophysiological feature. Hence, this study sought to associate serum proteins and hormones associated with inflammation and ICH outcomes. Patients presenting to Duke University Hospital with computed tomography-verified spontaneous, supratentorial, non-traumatic ICH within 24 h of symptom onset were prospectively recruited. In this pilot study, equal numbers of men and women and Black and White individuals were included and matched by a 6-month modified Rankin Score (mRS). The primary analyses were the correlation of L-ratios (LR; Log2(Day 2/Day 1 concentrations)) of serum gonadal hormones and neuroinflammatory proteins with mRS > 3 at 6 months. A total of 40 participants were included in this pilot study. LRs were significantly higher for C-reactive protein (CRP; p = 0.013) and lower for interleukin-6 (IL-6; p = 0.026) and surfactant protein-D (p = 0.036) in participants with unfavorable outcomes at 6 months after ICH. Further, higher CRP (p = 0.02) and lower IL-6 (p = 0.035) and surfactant protein-D (p = 0.041) LRs were associated with mRS > 3 at 6 months after ICH in multiple logistic regression analyses, adjusted for race and sex. The relationship amongst gonadal hormones, neuroinflammatory proteins, and ICH outcome is complex. In this pilot study, unfavorable outcomes after ICH may have been associated with selected inflammatory biomarkers. A larger scale study is warranted to define interactions between hormones, proteins, and their effects on ICH outcomes. Full article

Pseudomonas aeruginosa, a member of the “ESKAPE” group of bacterial pathogens, exhibits biofilm-forming capacity, a key factor contributing to its resistance to conventional antibiotics and posing significant challenges in clinical treatment. To develop more effective therapeutics against such infections, identifying potential drug targets through bioinformatics analysis is essential. Consequently, we utilized data from the GEO database to investigate differentially expressed genes between planktonic and biofilm groups, and identified drug targets through the construction of a protein–protein interaction (PPI) network and the cytoHubba algorithm. Inhibitors targeting this protein were identified through molecular docking screening of the FDA-approved drug library, and their anti-biofilm activity was validated in vitro. Through bioinformatics analysis, we identified GacS as the drug target in this study for treating biofilm-related infections. Virtual screening revealed that oxidized glutathione (GSSG) and arformoterol tartrate (ARF) are both capable of tightly binding to GacS and demonstrating good stability. In vitro experiments further confirmed that both GSSG and ARF demonstrated anti-biofilm activity, particularly when combined with azithromycin (AZM) or clarithromycin (CAM), significantly enhancing the biofilm inhibition effects of these antibiotics. This combination therapy offers a new and innovative strategy to combat biofilm-associated infections, showcasing the potential of GacS inhibitors in clinical applications. In conclusion, GSSG and ARF may serve as effective GacS inhibitors, and their combination with AZM or CAM could provide a novel approach for treating biofilm-related infections, paving the way for more effective treatment options. Full article

Background: The function and mechanism of N6-methyladenosine (m6A) methylation in pressure-overload cardiac fibrosis remains limited and unclear. This study aims to analyze and predict m6A modifications present in mouse hearts because of transverse aortic constriction (TAC). Materials and Methods: Twelve male C57BL/6 mice were randomly assigned to two groups, TAC group and sham group. The RNA Dot Blot assay was employed to evaluate the overall m6A methylation levels in both TAC and sham mice. The expression level of m6A-related enzymes were investigated through RT-PCR and Western blotting. MeRIP-seq and RNA-seq analyses were conducted to identify differentially modified m6A genes and mRNA expression genes. The protein–protein interaction (PPI) network was carried out to choose potential hub genes. Additionally, the transcription factor (TF)–microRNA (miRNA) coregulatory network and the drug–hub gene interaction network were built based on these hub genes. Furthermore, molecular docking simulations were also performed to analyze the interactions between drugs and hub genes. Results: Compared with the sham group, the TAC group demonstrated elevated levels of global m6A methylation. METTL3 and METTL14 were significantly upregulated, whereas FTO and ALKBH5 were significantly downregulated following TAC. MeRIP-seq analysis identified 17,806 m6A peaks associated with 9184 genes and 16,392 m6A peaks associated with 8550 genes in the TAC and sham groups, respectively. In conjunction with RNA-seq data, 66 genes were identified as exhibiting concurrent differences in both m6A methylation levels and mRNA expression. Six hub genes, Cd33, Irf4, Nr4a2, Hspa1b, Nr4a1, and Adcy1, were identified through the construction of a PPI network. The TF-miRNA coregulatory network contains six hub genes, 31 miRNAs, and 24 TFs. The drug–hub genes interaction network included five hub genes and 36 candidate drugs. Conclusions: The m6A modification is prevalent in TAC-induced cardiac fibrosis and significantly contributes to the fibrotic process by regulating critical genes. In the future, it may emerge as one of the potential cardiac fibrosis therapeutic targets. Full article

Biological-sequence representation methods are pivotal for advancing machine learning in computational biology, transforming nucleotide and protein sequences into formats that enhance predictive modeling and downstream task performance. This review categorizes these methods into three developmental stages: computational-based, word embedding-based, and large language model (LLM)-based, detailing their principles, applications, and limitations. Computational-based methods, such as k-mer counting and position-specific scoring matrices (PSSM), extract statistical and evolutionary patterns to support tasks like motif discovery and protein–protein interaction prediction. Word embedding-based approaches, including Word2Vec and GloVe, capture contextual relationships, enabling robust sequence classification and regulatory element identification. Advanced LLM-based methods, leveraging Transformer architectures like ESM3 and RNAErnie, model long-range dependencies for RNA structure prediction and cross-modal analysis, achieving superior accuracy. However, challenges persist, including computational complexity, sensitivity to data quality, and limited interpretability of high-dimensional embeddings. Future directions prioritize integrating multimodal data (e.g., sequences, structures, and functional annotations), employing sparse attention mechanisms to enhance efficiency, and leveraging explainable AI to bridge embeddings with biological insights. These advancements promise transformative applications in drug discovery, disease prediction, and genomics, empowering computational biology with robust, interpretable tools. Full article