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The main function of transfer RNAs (tRNAs) is to carry amino acids into the ribosome and synthesize proteins under the guidance of messenger RNAs (mRNAs). In addition to this, it has been observed that tRNAs undergo precise cleavage at specific loci, giving rise to an extensive array of distinct small RNAs, termed tRNA-derived small RNAs (tsRNAs). Existing studies have shown that tsRNAs are widely present across various organisms and comprehensively regulate gene expression, aberrant expression of tsRNAs is inextricably linked to tumorigenesis and development, thus, a systematic understanding of tsRNAs is necessary. This review aims to comprehensively delineate the genesis and expression patterns of tsRNAs, elucidate their diverse functions and emphasize their prospective clinical application as biomarkers and targets for therapy. It is noteworthy that we innovatively address the roles played by tsRNAs in human cancers at the level of the hallmarks of tumorigenesis proposed by Hanahan in anticipation of a broad understanding of tsRNAs and to guide the treatment of tumors. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukemia (CML) relapse and progression after discontinuation of tyrosine kinase inhibitors (TKI) therapy in the chronic phase (CP) are attributed to primitive quiescent leukemic progenitor cells (LPCs). This study aimed to identify key differentially expressed genes (DEGs) involved in molecular pathways alternative to BCR-ABL, which could lead to the eradication of leukemic stem/progenitor cells. Methods: mRNA expression profiling dataset comprising newly diagnosed untreated CP CML leukemic progenitor cell samples n = 5 and normal hematopoietic progenitor cell samples n = 5 were selected for DEGs identification. A weighted gene co-expression network was constructed to identify significant hub modules. Protein–protein interaction (PPI) network construction and pathway enrichment analysis provided additional information on the biological pathways involved. The genes involved in the resultant PPI network were subjected to a gene transcriptional regulatory network based on transcription factors (TFs) and microRNAs (miRNAs) involved in the target genes. Results: A total of 709 genes that were differentially expressed among those corresponding to p < 0.05 and log 2 FC > 0.5 . The WGCNA showed a significant hub module comprising 267 DEGs. The major pathways of the hub genes involved in the PPI network at the highest confidence score > 0.9 were related to mitochondrial translational elongation. The integrated gene transcriptional regulatory network revealed a TF (ETS1), two miRNAs (miR-34a-5p and miR-205-5p) targeting a hub gene (GFM1) as the highest-order motif or subnetwork in the three-node miRNA feed-forward loop. Conclusions: The study suggests that the regulatory feed-forward loop may provide a potential therapeutic target in CML. Consequently, the mitochondrial translation pathway may be explored as an alternative to BCR-ABL pathways, which could aid in eliminating or increasing sensitization of CML progenitor/stem cells to TKI treatment. [ABSTRACT FROM AUTHOR]

Nephrolithiasis is one of the most common diseases in urology, characterized by notable incidence and recurrence rates, leading to significant morbidity and financial burden. Despite its prevalence, the precise mechanisms underlying stone formation remain incompletely understood, thus hindering significant advancements in kidney stone management over the past three decades. Investigating the pivotal biological molecules that govern stone formation has consistently been a challenging and high-priority task. A significant portion of mammalian genomes are transcribed into noncoding RNAs (ncRNAs), which have the ability to modulate gene expression and disease progression. They are thus emerging as a novel target class for diagnostics and pharmaceutical exploration. In recent years, the role of ncRNAs in stone formation has attracted burgeoning attention. They have been found to influence stone formation by regulating ion transportation, oxidative stress injury, inflammation, osteoblastic transformation, autophagy, and pyroptosis. These findings contributes new perspectives on the pathogenesis of nephrolithiasis. To enhance our understanding of the diagnostic and therapeutic potential of nephrolithiasis-associated ncRNAs, we summarized the expression profiles, biological functions, and clinical significance of these ncRNAs in the current review. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) can lead to right ventricular hypertrophy, significantly increasing mortality rates. This study aims to clarify PH-specific metabolites and their impact on genomic and post-translational modifications (PTMs) in cancer, evaluating DHA and EPA's therapeutic potential to mitigate oxidative stress and inflammation. Methods: Data from 289,365 individuals were analyzed using Mendelian randomization to examine 1,400 metabolites' causal roles in PH. Anti-inflammatory and antioxidative effects of DHA and EPA were tested in RAW 264.7 macrophages and cancer cell lines (A549, HCT116, HepG2, LNCaP). Genomic features like CNVs, DNA methylation, tumor mutation burden (TMB), and PTMs were analyzed. DHA and EPA's effects on ROS production and cancer cell proliferation were assessed. Results: We identified 57 metabolites associated with PH risk and examined key tumor-related pathways through promoter methylation analysis. DHA and EPA significantly reduced ROS levels and inflammatory markers in macrophages, inhibited the proliferation of various cancer cell lines, and decreased nuclear translocation of SUMOylated proteins during oxidative stress and inflammatory responses. These findings suggest a potential anticancer role through the modulation of stress-related nuclear signaling, as well as a regulatory function on cellular PTMs. Conclusion: This study elucidates metabolic and PTM changes in PH and cancer, indicating DHA and EPA's role in reducing oxidative stress and inflammation. These findings support targeting these pathways for early biomarkers and therapies, potentially improving disease management and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the potential therapeutic targets of anlotinib using the patient‐derived xenografts (PDX) and evaluate the efficacy of the combination of chemotherapy and anlotinib in osteosarcoma patients before surgery. Methods: Forty‐three osteosarcoma specimens were used to establish the PDX model in mice, resulting in Twenty‐one PDX successful models. Eventually, six models were randomly selected for the pharmacodynamic experiment. The tumor‐bearing mice were randomly divided into the anlotinib (3 mg/kg) and placebo groups (n = 5 each). After treatment, the tumors were harvested and analyzed by immunohistochemistry (IHC) and western blotting. Results: In PDX model establishment, the tumors from donors with relapse, metastasis or chemoresistance demonstrated higher engraftment capacity. Histology results suggested that anlotinib significantly inhibited the growth of osteosarcoma by inducing mitotic arrest, necrosis and apoptosis, and selective against tumors with high expression of VEGFR2, PDGFRβ and CD31. Based on these results, five osteosarcoma patients who had progressed during NAC were treated with the combination of anlotinib and chemotherapy before surgery, which led to tumor regression in four patients. Next‐generation sequencing showed that most patients with tumor reduction expressed medium or high levels of VEGFR2 and PDGFRβ mRNA. The toxicities were tolerable. Conclusions: In conclusion, osteosarcoma with high expression of VEGFR2, PDGFRβ and CD31 is more sensitive to anlotinib. However, the potential of synergistic effect of anlotinib and chemotherapy in osteosarcoma patients needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Previous studies have implicated the involvement of FAM3C in cancerous development and progression. Herein, we aimed to further investigate the oncological mechanism of FAM3C, specifically in glioma. Methods: We utilized open‐source bioinformatics tools and platforms to analyze the transcriptional expression levels, prognosis, and correlation with clinical variables of FAM3C in gliomas, and subsequently, to hypothesize its potential molecular functions and possibly associated signaling pathways. Following this, glioma tissues were obtained from resected specimens of patients to assess the expression of FAM3C and molecular markers related to epithelial–mesenchymal transition (EMT) and Notch signaling pathways. Furthermore, glioma cell lines were subjected to treatments including FAM3C siRNA knockdown, lentiviral overexpression, and Notch signaling pathway blockade, enabling the investigation of molecular functions of FAM3C in vitro, particularly in EMT and Notch signaling pathways, as well as its effects on cancer cell proliferation, cell cycle progression, apoptosis, and invasion, using assays such as MMT cell proliferation assay, transwell migration, and flow cytometry analysis. Finally, a mouse subcutaneous xenograft model was established to explore the integrative function of FAM3C in glioma growth in vivo. Results: The expression level of FAM3C correlated with the progression of glioma grade and served as a prognostic indicator for poor patient outcomes. Subsequent experiments conducted on glioma cell lines, tumor tissues, and mouse models reinforced the close association of FAM3C with processes including glioma cell proliferation, cell cycle progression, apoptosis, and invasion. Additionally, it was observed that FAM3C is involved in the regulation of the Notch signaling pathway. Conclusions: FAM3C emerges as a potential candidate for clinical detection and prognostic biomarker application. Its regulatory role in glioma cell proliferation, cell cycle progression, and modulation of epithelial–mesenchymal transition‐driven invasion and migration via the Notch signaling pathway implies its potential to unveil novel therapeutic targets for glioma treatment. [ABSTRACT FROM AUTHOR]

Gastrointestinal cancers pose a significant global health challenge. N-glycosylation modulates various cellular processes, including key cancer-related mechanisms. Elucidating its involvement in the onset and advancement of these cancers can offer critical insights for enhancing diagnostic and therapeutic approaches. This review outlines the core process of protein N-glycosylation and highlights its contribution to the progression of gastrointestinal cancers, encompassing cell proliferation, survival, invasion, metastasis, and immune evasion, mainly through its impact on critical signaling pathways. Notably, aberrant N-glycosylation patterns have emerged as crucial biomarkers for the diagnosis and prognosis of various gastrointestinal cancers, providing the foundation for more personalized therapeutic approaches. Therapeutic strategies targeting N-glycosylation, such as glycosyltransferase inhibitors and glycoengineering, show significant promise in mitigating tumor aggressiveness and enhancing immune recognition. However, the clinical implementation of N-glycosylation biomarkers requires the standardization of glycosylation analysis techniques and solutions to challenges in sample processing and data interpretation. Future research efforts should concentrate on overcoming these obstacles to unlock the full potential of N-glycosylation in enhancing cancer management and advancing patient outcomes. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a pregnancy complication that is often diagnosed due to elevated blood pressure and proteinuria. Though current research focuses on the identification of novel biomarkers and therapeutic targets, still, there is a lack of clinical validation for the use of biomarkers and therapeutic targets for early diagnosis and treatment of PE. Several molecules are being studied for their potential role in PE. Among them, microRNAs are studied vastly for their role in the diagnosis, prognosis, and treatment of PE. But only a few studies are focused on the therapeutic efficacy of miRNAs in PE. Thus, the relevant articles were identified and discussed in this review. These studies provide evidence that miRNAs are indeed important molecules in PE that have the role of both therapeutic targets and therapeutic molecules. However, the studies are limited to in vivo an in vitro models, hence further studies are required to validate the complete potential of miRNA therapeutics. Long non-coding RNA (lncRNA) sponges, miRNA mimics, miRNA inhibitors, exosome-associated miRNAs, and several other molecules have been studied as miRNA-based therapeutics in PE. Thus, miRNAs are postulated to be potential therapeutic targets and miRNA-based therapeutics might pave the way for novel therapeutic approaches for PE. • MiRNAs in PE sheds light on the disease's underlying mechanisms. • MiRNA help in research on diagnostic markers, potential treatment strategies for PE. • MiRNA-based therapeutics are studied for their potential role in treatment of PE. • LncRNA sponges, mimics, inhibitors, exosomal miRNAs are few crucial research in PE. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) dysregulation is implicated in osteoarthritis (OA), but the mechanisms underlying this dysregulation remain unclear. We investigated the role of cereblon, a substrate-recognition protein within the E3-ligase ubiquitin complex, in AMPK dysregulation and OA pathogenesis. Cereblon expression was examined in human (n = 5) and mouse (n = 10) OA cartilage. The role of cereblon was investigated through its adenoviral overexpression (n = 10) or knockout (KO, n = 15) in the destabilization of the medial meniscus (DMM)-operated mice. The therapeutic potentials of the chemical cereblon degrader, TD-165, and the AMPK activator, metformin, were assessed through intra-articular (IA) injection to mice (n = 15). Immunostaining revealed that cereblon is upregulated in human and mouse OA cartilage. In DMM model mice, cartilage destruction was exacerbated by overexpression of cereblon in mouse joint tissues (OARSI grade; 1.11 [95% CI: 0.50 to 2.75]), but inhibited in global (−2.50 [95% CI: −3.00 to −1.17]) and chondrocyte-specific (−2.17 [95% CI: −3.14 to −1.06]) cereblon KO mice. The inhibitory effects were more pronounced in mice fed a high-fat diet compared to a regular diet. The degradation of cereblon through IA injection of TD-165 inhibited OA cartilage destruction (−2.47 [95% CI: −3.22 to −1.56]). Mechanistically, cereblon exerts its catabolic effects by negatively modulating AMPK activity within chondrocytes. Consistently, activation of AMPK by IA injection of metformin inhibited posttraumatic OA cartilage destruction (−1.20 ([95% CI: −1.89 to −0.45]). The cereblon-AMPK axis acts as a catabolic regulator of OA pathogenesis and seems to be a promising therapeutic target in animal models of OA. [ABSTRACT FROM AUTHOR]

Background: Postmenopausal women (post-MW) are at a heightened risk of cardiovascular diseases, including hypercholesterolemia. This study aimed to investigate metabolomic variations to identify potential markers and targets for postmenopausal hypercholesterolemia. Methods: Sixty-two female volunteers aged 40–65 were recruited for this study. Metabolomic analysis using the Ultra-Performance Liquid Chromatography Quadrupole Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap MS) platform was conducted to investigate changes in endogenous substances in premenopause (n = 25) and postmenopause (n = 37) women. Following ovariectomy surgery, menopausal mice were monitored for changes in their biomarker levels, and the integrity of the large artery walls in each treatment group was observed through hematoxylin and eosin staining. In vitro cellular models were utilized to assess variations in lipid metabolism, reactive oxygen species (ROS) levels, and changes in the levels of superoxide dismutase and glutathione peroxidase enzymes in different cell groups postintervention using Western blot analysis. Results: Treatment with carnitine in postmenopausal mouse models led to increased plasma cholesterol and carnitine levels, as well as indicators of arterial sclerosis. In HepG2 cells, carnitine treatment resulted in heightened lipid levels, elevated ROS production, and decreased antioxidant enzyme levels. Conclusions: The findings suggest that carnitine may serve as a potential risk marker or therapeutic target for postmenopausal hypercholesterolemia. This study provides valuable insights into cardiovascular conditions in post-MW and offers new avenues for therapeutic interventions. Continued research in this area is crucial to enhance our understanding of cardiovascular diseases in post-MW and to explore additional treatment options. [ABSTRACT FROM AUTHOR]

Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb., two nootropics, are recognized in Indian Ayurvedic texts. Studies have attempted to understand their action as memory enhancers and neuroprotectants, but many molecular aspects remain unknown. We propose that Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb. share common neuroprotective mechanisms. Mass spectrometry–based untargeted metabolomics and network pharmacology approach were used to identify potential protein targets for the metabolites from each extract. Phytochemical analyses and cell culture validation studies were also used to assess apoptosis and ROS activity using aqueous extracts prepared from both herbal powders. Further, docking studies were also performed using the LibDock protocol. Untargeted metabolomics and network pharmacology approach unveiled 2751 shared metabolites and 3439 and 2928 non-redundant metabolites from Bacopa monnieri and Centella asiatica extracts, respectively, suggesting a potential common neuroprotective mechanism among these extracts. Protein-target prediction highlighted 92.4% similarity among the proteins interacting with metabolites for these extracts. Among them, kinases mapped to MAPK, mTOR, and PI3K-AKT signaling pathways represented a predominant population. Our results highlight a significant similarity in the metabolome of Bacopa monnieri (L.) Wettst and Centella asiatica (L.) Urb., and their potential protein targets may be attributed to their common neuroprotective functions. Workflow employed for phytochemical assays, mass spectrometry-based metabolomics, protein-target identification, cell culture validations, and docking studies. Comparison of Bacopa monnieri and Centella asiatica non-redundant metabolite identification at MS level,as well as at MS/MS level [ABSTRACT FROM AUTHOR]

The mitochondrion is an essential cell organelle known as the powerhouse of the cell. Mitochondrial ribosomal proteins (MRPs) are nuclear encoded, synthesised in the cytoplasm but perform their main functions in the mitochondria, which includes translation, transcription, cell death and maintenance. However, MRPs have also been implicated in cancer, particularly advanced disease and metastasis across a broad range of cancer types, where they play a central role in cell survival and progression. For some, their altered expression has been investigated as potential prognostic markers, and/or therapeutic targets, which is the focus of this review. Several therapies targeting MRPs are currently approved by the Food and Drug Administration and the European Medicines Agency for use in other diseases, revealing the opportunity for repurposing their use in advanced and metastatic cancer. Herein, we review the evidence supporting key MRPs as molecular drivers of advanced disease in multiple cancer types. We also highlight promising avenues for future use of MRPs as precision targets in the treatment of late-stage cancers for which there are currently very limited effective treatment options. [ABSTRACT FROM AUTHOR]

Cervical cancer ranks as the fourth most common and fatal cancer among women worldwide. Studies have demonstrated a strong association between purinergic platelet signaling and tumor progression in this type of cancer. The literature shows that neoplastic cells, when in the bloodstream, secrete adenosine triphosphate (ATP) and adenosine nucleotide diphosphate (ADP) that act on their corresponding platelet P2Y and P2X receptors. The interaction of these nucleotides with their receptors results in platelet activation and degranulation, ensuing several consequences, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, ADP, and ATP. These molecules play essential roles in angiogenesis and tumor metastasis in cervical cancer. Several purinergic receptors are found in endothelial cells. Their activation, especially P2Y2, by the nucleotides released by platelets can induce relaxation of the endothelial barrier and consequent extravasation of tumor cells, promoting the development of metastases. Cancer cells that enter the bloodstream during the metastatic process are also subject to high shear stress and immune surveillance. In this context, activated platelets bind to circulating tumor cells and protect them against shear stress and the host's immune system, especially against natural killer cells, facilitating their spread throughout the body. Furthermore, activation of the P2Y12 receptor present on the platelet surface promotes the release of VEGF, the main inducer of angiogenesis in cervical cancer, in addition to increasing the concentration of several other pro-angiogenic molecules. Therefore, this review will address the role of platelet purinergic signaling in tumor progression of cervical cancer and propose possible therapeutic targets. [ABSTRACT FROM AUTHOR]

Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study of tumor energy metabolism has gradually become an emerging field of tumor treatment. Recent studies have shown that epigenetic regulation is closely linked to tumor energy metabolism, influencing the metabolic remodeling and biological traits of tumor cells. This review focuses on the primary pathways of tumor energy metabolism and explores therapeutic strategies to target these pathways. It covers key areas such as glycolysis, the Warburg effect, mitochondrial function, oxidative phosphorylation, and the metabolic adaptability of tumors. Additionally, this article examines the role of the epigenetic regulator SWI/SNF complex in tumor metabolism, specifically its interactions with glucose, lipids, and amino acids. Summarizing therapeutic strategies aimed at these metabolic pathways, including inhibitors of glycolysis, mitochondrial-targeted drugs, exploitation of metabolic vulnerabilities, and recent developments related to SWI/SNF complexes as potential targets. The clinical significance, challenges, and future directions of tumor metabolism research are discussed, including strategies to overcome drug resistance, the potential of combination therapy, and the application of new technologies. [ABSTRACT FROM AUTHOR]

Background: Therapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between genetic variants and phenotypic variation; however, identifying the genes driving associations identified in GWAS remains challenging. Integration of molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) and colocalization analyses can help with the identification of causal genes. Careful interpretation remains warranted because eQTL can affect the expression of multiple genes within the same locus. Methods: We used a combination of genomic features that include variant annotation, activity-by-contact maps, MR, and colocalization with molQTL to prioritize causal genes across 4,611 disease GWAS and meta-analyses from biobank studies, namely FinnGen, Estonian Biobank and UK Biobank. Results: Genes identified using this approach are enriched for gold standard causal genes and capture known biological links between disease genetics and biology. In addition, we find that eQTL colocalizing with GWAS are statistically enriched for corresponding disease-relevant tissues. We show that predicted directionality from MR is generally consistent with matched drug mechanism of actions (> 85% for approved drugs). Compared to the nearest gene mapping method, genes supported by multi-omics evidences displayed higher enrichment in approved therapeutic targets (risk ratio 1.75 vs. 2.58 for genes with the highest level of support). Finally, using this approach, we detected anassociation between the IL6 receptor signal transduction gene IL6ST and polymyalgia rheumatica, an indication for which sarilumab, a monoclonal antibody against IL-6, has been recently approved. Conclusions: Combining variant annotation, activity-by-contact maps, and molQTL increases performance to identify causal genes, while informing on directionality which can be translated to successful target identification and drug development. [ABSTRACT FROM AUTHOR]

Oral cancer, the most prevalent cancer worldwide, is far more likely to occur after the age of forty-five, according to the World Health Organization. Although many biomarkers have been discovered over the years using non-invasive saliva samples, biopsies, and human blood, these biomarkers have not been incorporated into standard clinical practice. Investigating the function of microRNAs (miRNAs) in the diagnosis, aetiology, prognosis, and treatment of oral cancer has drawn more attention in recent years. Though salivary microRNA can act as a window into the molecular environment of the tumour, there are challenges due to the heterogeneity of oral squamous cell carcinoma (OSCC), diversity in sample collection, processing techniques, and storage conditions. The up and downregulation of miRNAs has been found to have a profound role in OSCC as it regulates tumour stages by targeting many genes. As a result, the regulatory functions of miRNAs in OSCC underscore their significance in the field of cancer biology. Salivary miRNAs are useful diagnostic and prognostic indicators because their abnormal expression profiles shed light on tumour behaviour and patient prognosis. In addition to their diagnostic and prognostic value, miRNAs hold promise as therapeutic targets for oral cancer intervention. The current review sheds light on the challenges and potentials of microRNA studies that could lead to a better understanding of oral cancer prognosis, diagnosis, and therapeutic intervention. Furthermore, the clinical translation of OSCC biomarkers requires cooperation between investigators, physicians, regulatory bodies, and business partners. There is much potential for improving early identification, tracking therapy response, and forecasting outcomes in OSCC patients by including saliva-based miRNAs as biomarkers. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b+Ly6G−Ly6C− myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. [ABSTRACT FROM AUTHOR]

Background: Hypersensitivity to odorants like perfumes can induce or promote asthma with non-type 2 inflammation for which therapeutic options are limited. Cell death of primary bronchial epithelial cells (PBECs) and the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 are key in the pathogenesis. Extra-nasal olfactory receptors (ORs) can influence cellular processes involved in asthma. This study investigated the utility of ORs in epithelial cells as potential drug targets in this context. Methods: We used the A549 cell line and primary bronchial epithelial cells using air–liquid interface culture system (ALI-PBECs). OR expression was investigated by RT-PCR, Western blot, and Immunofluorescence. Effects of OR activation by specific ligands on intracellular calcium concentration, cAMP, Phospholipase C (PLC), cell viability, and IL-6 and IL-8 secretion were analyzed by calcium imaging, enzyme immunoassays, Annexin V/ propidium iodide -based fluorescence-activated cell staining or by ELISA, respectively. Results: By screening A549 cells, the OR51B5 agonists Farnesol and Isononyl Alcohol and the OR1G1 agonist Nonanal increased intracellular Ca2 +. OR51B5 and OR1G1 mRNAs and proteins were detected. Both receptors showed a preferential intracellular localization. OR51B5- but not OR1G1-induced Ca2 + dependent on both cAMP and PLC signaling. Farnesol, Isononyl Alcohol, and Nonanal, all reduced cell viability and induced IL-8 and IL-6 release. The data were verified in ALI-PBECs. Conclusion: ORs in the lung epithelium might be involved in airway-sensitivity to odorants. Their antagonism could represent a promising strategy in treatment of odorant-induced asthma with non-type 2 inflammation. [ABSTRACT FROM AUTHOR]

Metabolism reprogramming (MR) is one of the top ten hallmarks of malignant tumors. The aberrant activation of MR has been recognized as a critical contributory factor to the malignant progression of solid tumors. Moreover, various long non-coding RNAs (lncRNAs) are implicated in the aberrant activation of MR in solid tumor cells. Therefore, in this review, we mainly focus on summarizing the functional relevance and molecular mechanistic underpinnings of lncRNAs in modulating MR of solid tumors by targeting glucose metabolism, lipid metabolism, affecting mitochondrial function, and regulating interactions between tumor and non-tumor cells in tumor microenvironment. Besides, we also underscore the potential for constructing lncRNAs-centered tumor metabolic regulation networks and developing novel anti-tumor strategies by targeting lncRNAs and abnormal MR. Ultimately, this review seeks to offer new targets and avenues for the clinical treatment of solid tumors in the future. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and gradual tissue destruction. New research has shown how important noncoding RNAs (ncRNAs) are for changing immune and inflammatory pathways, such as the WNT signaling pathway, which is important for activating synovial fibroblasts and osteoblasts to work. This article examines the current understanding of several ncRNAs, such as miRNAs, lncRNAs, and circRNAs, that influence NF-κB signaling in the pathogenesis of RA. We investigate how these ncRNAs impact NF-κB signaling components, altering cell proliferation, differentiation, and death in joint tissues. The paper also looks at how ncRNAs can be used as potential early detection markers and therapeutic targets in RA because they can change important pathogenic pathways. This study highlights the therapeutic potential of targeting ncRNAs in RA therapy techniques, with the goal of reducing inflammation and stopping disease progression. This thorough analysis opens up new possibilities for understanding the molecular foundations of RA and designing novel ncRNA-based treatments. [ABSTRACT FROM AUTHOR]

Objective: This study elucidated the mechanistic role of Cyathulae Radix (CR) in type 2 diabetes mellitus (T2DM) through bioinformatics analysis and experimental validation. Methods: Components and targets of CR were retrieved from the traditional Chinese medical systems pharmacology, while potential T2DM targets were obtained from GeneCards and Online Mendelian Inheritance in Man databases. Intersecting these datasets yielded target genes between CR and T2DM. Differential genes were used for constructing a protein–protein interaction network, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and dynamics simulations were performed using AutoDock and GROMACS, respectively, and in vitro experiments validated the results. Experiments evaluated the effect of CR on T2DM pancreatic β‐cells. Results: Bioinformatics analysis identified four active compounds of CR, 157 related genes, and 5431 T2DM target genes, with 141 shared targets. Key targets such as JUN, MAPK1, and MAPK14 were identified through topological analysis of the PPI network. GO analysis presented 2663 entries, while KEGG analysis identified 161 pathways. The molecular docking results demonstrated favorable binding energy between the core components and the core proteins. Among them, JUN‐rubrosterone, MAPK1‐rubrosterone, and MAPK14‐rubrosterone deserved further investigation. Molecular dynamics results indicated that all of them can form stable binding interactions. CR could inhibit the expression of JUN, MAPK1, and MAPK14, promote insulin secretion, alleviate apoptosis, and regulate autophagy in INS‐1 cells. Conclusion: This study suggests CR approach to T2DM management by multitarget and multipathway provides a scientific basis for further research on the hypoglycemic effect of CR. [ABSTRACT FROM AUTHOR]

Lactylation, a novel discovered posttranslational modification, is a vital component of lactate function and is prevalent in a wide range of cells, interacting with both histone and non-histone proteins. Recent studies have confirmed that lactylation as a new contributor to epigenetic landscape is involved in multiple pathological processes. Accumulating evidence reveals that lactylation exists in different pathophysiological states and leads to inflammation and cancer; however, few mechanisms of lactylation have been elaborated. This review summarizes the biological processes and pathophysiological roles of lactylation in cancer, as well as discusses the relevant mechanisms and potential therapeutic targets, aiming to provide new insights for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) presents as an intricate mental health issue often associated with Anxiety. In this study, we used data from Gene Expression Omnibus (GEO) to investigate how anxiety acts as a comorbidity to MDD at the molecular level. We used NCBI GEO Accession ID: GSE98793 for this study. This microarray dataset examines the gene expression profiles associated with MDD both with and without anxiety. As the outcome of the study, a total of 15 significantly upregulated Differential Expressed Genes (DEGs), 4 significantly down regulated Differential Expressed Genes (DEGs) were found in MDD with anxiety data’s and 5 significantly upregulated Differential Expressed Genes (DEGs), 18 significantly down regulated Differential Expressed Genes (DEGs) were found in MDD without anxiety data were obtained from the dataset. After protein-protein interaction networks were generated using STRING DB, the molecular associations for MDD were visualised using Cytohubba, a Cytoscape plugin. We performed a functional enrichment analysis using the DAVID Functional Annotation tool to identify the biological processes and pathways associated with the up-regulated and down-regulated genes in the anxiety and nonanxiety groups. ARG1, CRISP3, DEFA4, LCN2, BPI, and LTF were discovered in the anxiety group, while HLA-DQB1, FAM3B, GATB, and HLA-DQA1 were discovered in the non-anxiety group. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) were used to analyse differentially expressed genes (DEGs). Interestingly, factors like Staphylococcus aureus infection, the intestinal immune network's role in producing IgA, the steps involved in processing and presenting antigens, and the development of Th1 and Th2 cells are all processes that play a role in the illness and its comorbidity. [ABSTRACT FROM AUTHOR]

Background: Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage‐mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. Aims: This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. Methods: We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. Results: The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. Conclusion: Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro‐inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA‐associated macrophages. [ABSTRACT FROM AUTHOR]

Background: Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Methods: Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Results: Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. Conclusions: The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathway in cancer biology. This review delves into the epigenetic mechanisms that modulate ferroptosis in cancer cells, focusing on how DNA methylation, histone modifications, and non-coding RNAs influence the expression and function of essential genes involved in this process. By unraveling the complex interplay between these epigenetic mechanisms and ferroptosis, the article sheds light on novel gene targets and functional insights that could pave the way for innovative cancer treatments to enhance therapeutic efficacy and overcome resistance in cancer therapy. [ABSTRACT FROM AUTHOR]

Breast implant surgery has evolved significantly, yet challenges such as capsular contracture remain a persistent concern. This review presents an in-depth analysis of recent advancements in understanding the immune mechanisms and clinical implications associated with silicone mammary implants (SMIs). The article systematically examines the complex interplay between immune responses and capsular fibrosis, emphasizing the pathophysiological mechanisms of inflammation in the etiology of this fibrotic response. It discusses innovations in biomaterial science, including the development of novel anti-biofilm coatings and immunomodulatory surfaces designed to enhance implant integration and minimize complications. Emphasis is placed on personalized risk assessment strategies, leveraging molecular insights to tailor interventions and improve patient outcomes. Emerging therapeutic targets, advancements in surgical techniques, and the refinement of post-operative care are also explored. Despite notable progress, challenges such as the variability in immune responses, the long-term efficacy of new interventions, and ethical considerations remain. Future research directions are identified, focusing on personalized medicine, advanced biomaterials, and bridging preclinical findings with clinical applications. As we advance from bench to bedside, this review illuminates the path forward, where interdisciplinary collaboration and continued inquiry weave together to enhance the art and science of breast implant surgery, transforming patient care into a realm of precision and excellence. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory reaction caused by infection, and severe sepsis can develop into septic shock, eventually leading to multiorgan dysfunction and even death. In recent years, studies have shown that mitochondrial damage is closely related to the occurrence and development of sepsis. Recent years have seen a surge in concern over mitochondrial DNA (mtDNA), as anomalies in this material can lead to cellular dysfunction, disruption of aerobic respiration, and even death of the cell. In this review, we discuss the latest findings on the mechanisms of mitochondrial damage and the molecular mechanisms controlling mitochondrial mtDNA release. We also explored the connection between mtDNA misplacement and inflammatory activation. Additionally, we propose potential therapeutic targets of mtDNA for sepsis treatment. [ABSTRACT FROM AUTHOR]

Objective: Association between mitochondrial dysfunction and osteoarthritis (OA) has been consistently investigated, yet their genetic association remains obscure. In this study, mitochondrial-related genes were used as instrumental variables to proxy for mitochondrial dysfunction, and summary data of knee OA (KOA) were used as outcome to examine their genetic association. Methods: We obtained 1136 mitochondrial-related genes from the human MitoCarta3.0 database. Genetic proxy instruments for mitochondrial-related genes from studies of corresponding gene expression (n = 31,684) and protein (n = 35,559) quantitative trait locus (eQTLs and pQTLs), respectively. Aggregated data for KOA (62,497 KOA cases and 333,557 controls) were extracted from the largest OA genome-wide association study (GWAS). We integrated QTL data with KOA GWAS data to estimate their genetic association using summary data-based Mendelian randomization analysis (SMR). Additionally, we implemented Bayesian colocalization analysis to reveal whether suggestive mitochondrial-related genes and KOA were driven by a same genetic variant. Finally, to validate the primary findings, replication study (24,955 cases and 378,169 controls) and multi-SNP-based SMR (SMR-multi) test was performed. Results: Through SMR analysis, we found that the expression levels of 2 mitochondrial-related genes were associated with KOA risk. Specifically, elevated gene expression levels of the IMMP2L (odds ratio [OR] = 1.056; 95% confidence interval [CI] = 1.030–1.082; P-FDR = 0.004) increased the risk of KOA. Conversely, increased gene expression levels of AKAP10 decreased the risk of KOA (OR = 0.955; 95% CI, 0.934–0.977; P-FDR = 0.019). Colocalization analysis demonstrated that AKAP10 (PP.H4 = 0.84) and IMMP2L (PP.H4 = 0.91) shared the same genetic variant with KOA. In addition, consistent results were found in replication study and SMR-multi test, further demonstrating the reliability of our findings. Conclusions: In summary, our analyses revealed the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA, providing new insight into potential pathogenesis of KOA. Furthermore, these identified candidate genes offer the possibility of clinical drug target development for KOA. Key points • This is the first SMR study to explore the genetic association between mitochondrial dysfunction proxied by mitochondrial-related genes and KOA. • Sufficient evidence to support genetic association between the expression levels of AKAP10 and IMMP2L, and KOA • Our MR analysis may provide novel new insight into potential pathogenesis of KOA. • These identified candidate genes offer the possibility of clinical drug target development for KOA [ABSTRACT FROM AUTHOR]

The mutual regulation between hydrogen sulfide (H 2 S) and microRNA (miRNA) is involved in the development of many diseases, including cancer, cardiovascular disease, inflammatory disease, and high-risk pregnancy. Abnormal expressions of endogenous H 2 S-producing enzyme and miRNA in tissues and cells often indicate the occurrence of diseases, so the maintenance of their normal levels in the body can mitigate damages caused by various factors. Many studies have found that H 2 S can promote the migration, invasion, and proliferation of cancer cells by regulating the expression of miRNA, while many H 2 S donors can inhibit cancer progression by interfering with the proliferation, apoptosis, cell cycle, metastasis, and angiogenesis of cancer cells. Furthermore, the mutual regulation between H 2 S and miRNA can also prevent cell injury in cardiovascular disease and inflammatory disease through anti-inflammation, anti-oxidation, anti-apoptosis, and pro-autophagy. In addition, H 2 S can promote angiogenesis and relieve vasoconstriction by regulating the expression of miRNA, thereby improving fetal growth in high-risk pregnancy. In this review, we discuss the mechanism of mutual regulation between H 2 S and miRNA in various diseases, which may provide reliable therapeutic targets for these diseases. • H 2 S promotes the progression of cancer cells by regulating the miRNA expression. • H 2 S donors inhibit cancer growth via the mutual regulation between H 2 S and miRNA. • The mutual regulation between H 2 S and miRNA plays a protective role in diseases. • H 2 S plays a double-edged sword role in inflammation via interaction with miRNA. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is a genetically complex multifactorial trait. Over the past decade, population-based genome-wide association studies (GWAS) have identified more than 30 IgAN risk loci, providing novel perspectives on both the epidemiology of the disease and its underlying molecular mechanisms. In addition, the association between IgAN and galactose-deficient IgA1 (Gd-IgA1) presented another avenue for genetic exploration due to the heritability of the elevated serum Gd-IgA1 levels. These endeavors also yielded and enabled refinement of polygenic risk scores, which may help identify specific groups of individuals at significantly increased risks, leading to stratifications of medical treatments. In this review, we aim to explore the existing evidence for genetic causation in IgAN. We summarize the state of genetic research in IgAN and how it has led to the reformulation of the new pathogenesis model and novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a common autoimmune disease characterized primarily by persistent synovial inflammation and joint destruction. In recent years, ferroptosis, as a novel form of cell death, has garnered widespread attention due to its critical role in various diseases. This review explores the potential mechanisms of ferroptosis in RA and its relationship with the pathogenesis of RA, systematically analyzing the regulatory role of ferroptosis in synovial cells, chondrocytes, and immune cells. We emphasize the evaluation of ferroptosis-related pathways and their potential as therapeutic targets, including the development and application of inhibitors and activators. Although ferroptosis shows some promise in RA treatment, its dual role and safety issues in clinical application still require in-depth study. Future research should focus on elucidating the specific mechanisms of ferroptosis in RA pathology and developing more effective and safer therapeutic strategies to provide new treatment options for RA patients. [ABSTRACT FROM AUTHOR]

This study aimed to address the challenges of treating advanced stages of colon cancer (CRC) by exploring potential therapeutic options. The research focused on the genetic aspects of CRC, specifically the mutation rate of the KRAS gene, along with other genes like TTN, APC, MUC16, and TP53, using the TCGA dataset. Additionally, the study investigated the efficacy of Oleuropein, a polyphenolic compound found in olives, in combating CRC by using iron oxide nanoparticles coated with glucose and conjugated with Oleuropein. The study characterized the physicochemical properties of the nanoparticles, and the cytotoxic effects of the nanoparticles were evaluated on CRC and normal fibroblast cell lines, demonstrating significantly higher cytotoxicity against CRC cells compared to normal cells. Furthermore, the study analyzed gene expression changes using the GSE124627 dataset to understand the influence of KRAS alterations. It identified numerous upregulated and downregulated genes in KRAS-overexpressing samples, suggesting their involvement in critical cancer-related pathways. These findings suggest that KRAS-influenced genes could serve as potential therapeutic targets for CRC treatment. The study also examined the expression levels of identified genes in CRC samples compared to normal samples. Among the upregulated genes, 22 showed significant increases in cancer samples, while 14 downregulated genes exhibited decreased expression in both KRAS-influenced and cancer samples. Cox regression analysis identified specific upregulated genes, including ANKZF1, SNAI1, PPFIA4, SIX4, and NOTUM, associated with poor prognosis. Kaplan-Meier analysis further confirmed the correlation between increased expression of these genes and higher patient mortality rates. In conclusion, this study provided valuable insights into the genetic aspects of CRC and potential therapeutic strategies. The use of Oleuropein-conjugated iron oxide nanoparticles showed promising cytotoxic effects on colon cancer cells. These findings contribute to advancing our understanding of CRC and offer potential targets for further investigation and the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic ketoacidosis (DKA) is a severe and potentially fatal acute complication in diabetic patients, commonly occurring in type 1 diabetes (T1D) but also seen in type 2 diabetes (T2D). The pathogenesis of DKA involves complex physiological processes that are not fully understood, especially the role of mitochondria. Mitochondria, known as the powerhouse of cells, plays a crucial role in oxidative phosphorylation and ATP production, which is vital in various metabolic diseases, including diabetes. However, the exact causal relationship between mitochondrial dysfunction and DKA remains unclear. Methods: This study employed Mendelian randomization (MR) analysis and protein-protein interaction (PPI) networks to systematically explore the causal relationships between mitochondrial DNA copy number (mtDNA-CN) and specific mitochondrial proteins with DKA. We used bidirectional MR analysis and genome-wide association study (GWAS) data from openGWAS database to investigate the causal effects of mtDNA-CN and 64 mitochondrial-related proteins on DKA and its subtypes (T1DKA, T2DKA, unspecified-DKA). Results: The study revealed that increased mtDNA-CN significantly reduces the risk of DKA, whereas the effect of DKA onmtDNA-CNwas not significant. Mitochondrial related proteins such as MRPL32, MRPL33, COX5B, DNAJC19, and NDUFB8 showed a negative causal relationship with DKA, indicating their potential protective roles. Conversely, ATP5F1B and COX4I2 have a positive causal relationship with DKA, indicating that excessive ATP production in diabetic patients may be detrimental to health and increase the risk of severe complications such as DKA. Discussion: The results emphasize the necessity of protecting mitochondrial function in order to reduce the risk of DKA. The study offers novel perspectives on the molecular pathways involved in DKA, emphasizing the critical functions of mt-DNA and distinct proteins. These evidences not only enhance our comprehension of the implications of mitochondrial dysfunction in diabetesrelated complications but also identify potential therapeutic targets for individualized treatment approaches, thereby making a substantial contribution to clinical care and public health initiatives. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)—with antioxidant and anti-cancer properties—downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a β-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies. [ABSTRACT FROM AUTHOR]

Background We aimed to pinpoint biomarkers, create a diagnostic model for ulcerative colitis (UC), and delve into its immune features to better understand this autoimmune condition. Methods The sequencing data for both the UC and the control groups were obtained from GEO, including both bulk and single-cell data. Using GSE87466 as training group, we applied differential analysis, WGCNA, PPI, LASSO, RF, and SVM-RFE for biomarker selection. A neural network shaped our diagnostic model, corroborated by GSE92415 as the validation cohort with ROC assessment. Immune cell profiling was conducted using CIBERSORT. Results 53 disease-associated genes were screened. Enrichment analysis highlighted roles in complement cascades and cell adhesion. Eight biomarkers were finally identified through multiple machine learning and PPI: B4GALNT2, PDZK1IP1, FAM195A, REG4, MTMR11, FLJ35024, CD55, and CD44. The diagnostic model had AUCs of 0.984 (training group) and 0.957 (validation group). UC tissues revealed heightened plasma cells, CD8 T cells, and other immune cells. Two unique UC immune patterns emerged, with certain T and NK cells central to immune modulation. Conclusion We identified eight biomarkers of UC by various methods, constructed a diagnostic model through neural networks, and explored the immune complexity of the disease, which contributes to the diagnosis and treatment of UC. [ABSTRACT FROM AUTHOR]

Aims: Previous proteomics studies in dysferlinopathy muscle have been limited in scope, often utilizing 2D‐electrophoresis and yielding only a small number of differential expression calls. To address this gap, this study aimed to employ high‐resolution proteomics to explore the proteomic landscapes of dysferlinopathy and analyze the correlation between muscle pathological changes and alterations in protein expression in muscle biopsies. Methods: We conducted a comprehensive approach to investigate the proteomic profile and disease‐associated changes in the muscle tissue proteome from 15 patients with dysferlinopathy, exhibiting varying degrees of dystrophic pathology, alongside age‐matched controls. Our methodology encompasses tandem mass tag (TMT)‐labeled liquid chromatography‐mass spectrometry (LC–MS/MS)‐based proteomics, protein–protein interaction (PPI) network analysis, weighted gene co‐expression network analysis, and differential expression analysis. Subsequently, we examined the correlation between the expression of key proteins and the clinical characteristics of the patients to identify pathogenic targets associated with DYSF mutations in dysferlinopathy. Results: A total of 1600 differentially expressed proteins were identified, with 1321 showing high expression levels and 279 expressed at lower levels. Our investigation yields a molecular profile delineating the altered protein networks in dysferlinopathy‐afflicted skeletal muscle, uncovering dysregulation across numerous cellular pathways and molecular processes, including mRNA metabolic processes, regulated exocytosis, immune response, muscle system processes, energy metabolic processes, and calcium transmembrane transport. Moreover, we observe significant associations between the protein expression of ANXA1, ANXA2, ANXA4, ANXA5, LMNA, PYGM, and the extent of histopathologic changes in muscle biopsies from patients with dysferlinopathy, validated through immunoblotting and immunofluorescence assays. Conclusions: Through the aggregation of expression data from dysferlinopathy‐impacted muscles exhibiting a range of pathological alterations, we identified multiple key proteins associated with the dystrophic pathology of patients with dysferlinopathy. These findings provide novel insights into the pathogenesis of dysferlinopathy and propose promising targets for future therapeutic endeavors. [ABSTRACT FROM AUTHOR]

Objective To explore the role of MAPK4 in cervical squamous cell carcinoma (CSCC) for the identification of candidate prognostic prediction biomarkers and molecular therapeutic targets. Methods The TCGA cohort was subjected to Kaplan-Meier survival analysis. Immunohistochemistry experiments were conducted on clinical samples to explore the correlation between MAPK4 and patient prognosis. A nomogram was constructed based on MAPK4 mRNA levels. Western blot, CCK-8, colony formation, and Transwell cell function experiments were performed to clarify the abnormal expression and role of MAPK4 in CSCC. DIA proteome sequencing was used to identify effector molecules regulated by MAPK4. Combined with the above cell function experiments, the knockdown of MAPK4 and the overexpression of effector molecules revealed that MAPK4 regulated effector molecules to mediate tumor progression. Results CSCC patients with elevated MAPK4 mRNA levels and high protein expression have a worse prognosis. The constructed nomogram based on MAPK4 can accurately predict the 1-, 3-, and 5-year survival rates of patients. Compared with that in normal cervical tissues, MAPK4 protein expression was up-regulated in tumors. MAPK4 knockdown substantially inhibited the proliferation, colony formation, migration, and invasion of CSCC ME180 and SiHa cells. SLC3A2 is a downstream effector molecule of MAPK4 Overexpression SLC3A2 can weaken the inhibitory effect of MAPK4 knockdown on cell proliferation, colony formation, migration, and invasion. Conclusion MAPK4 is a candidate prognostic biomarker for patients with CSCC. MAPK4 positively regulates SLC3A2 protein expression and accelerates tumor progression, making it a potential molecular therapeutic target for patients with CSCC [ABSTRACT FROM AUTHOR]

Mutations in LRRK2 are the most common causes of Parkinson's disease (PD). Dysfunction in LRRK2 enzymatic activities and elevated protein levels are associated with the disease. Higher-order dimerization/oligomerization and membrane recruitment appear to be required for LRRK2 activation. Rab29/12/38/32/8/10 and VPS35 are emerging upstream activators of LRRK2. A unique feature of LRRK2 is that it possesses two enzymatic functions: kinase and GTPase. It phosphorylates a group of proteins including Rabs and its autophosphorylation site S1292. LRRK2 GTPase regulation and contribution to PD is understudied. LRRK2 plays a diverse role in multiple cellular pathways. LRRK2 could be targeted on enzymatic activities, protein levels, crucial cellular interactors, and dimerization. Targeting LRRK2 kinase activity and protein levels has shown promise, and some approaches are advancing to clinical trials. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of Parkinson's disease (PD) to date. Dysfunction in LRRK2 enzymatic activities and elevated protein levels are associated with the disease. How is LRRK2 activated, and what downstream molecular and cellular processes does LRRK2 regulate? Addressing these questions is crucial to decipher the disease mechanisms. In this review we focus on the upstream regulations and briefly discuss downstream substrates of LRRK2 as well as the cellular consequences caused by these regulations. Building on these basic findings, we discuss therapeutic strategies targeting LRRK2 and highlight the challenges in clinical trials. We further highlight the important questions that remains to be answered in the LRRK2 field. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy has garnered considerable attention, emerging as a new standard of care in cancer treatment. The conventional targets, such as VEGF and EGFR, have been extended to others including BRAF and PD-1/PD-L1, which have shown significant potential in recent cancer treatments. This review aims to succinctly overview the impact and mechanisms of therapies that modulate PD-1/PD-L1 expression by targeting VEGF, EGFR, LAG-3, CTLA-4 and BRAF. We investigated how modulation of PD-1/PD-L1 expression impacts growth factor signaling, shedding light on the interplay between immunomodulatory pathways and growth factor networks within the tumor microenvironment. By elucidating these interactions, we aim to provide insights into novel potential synergistic therapeutic strategies for cancer immunotherapy. [Display omitted] • PD-1/PD-L1 inhibitors enhance immune responses, significantly improving cancer treatment outcomes. • Combining PD-1/PD-L1 inhibitors with anti-EGFR treatments shows promise for better survival rates. • Biomarkers like PD1, EGFR, VEGF, and BRAF predict therapy responses and optimize precision medicine. • Future research should refine biomarker strategies, understand resistance, and integrate genomic profiling. [ABSTRACT FROM AUTHOR]

The aims of this narrative review were to summarize the current literature on the beneficial effects of exercise interventions on individuals with comorbid depression and cardiovascular disease, and to review the current evidence that advances our understanding of the pathophysiological mechanisms underlying these effects. Ninety relevant articles were included and analyzed through a systematic search of PubMed and Web of Science. The analyses indicated that exercise interventions could modulate regulatory pathways to prevent depressive symptoms and reduce adverse cardiovascular events through five mechanisms: promoting immunosuppression, improving mitochondrial function, balancing the autonomic nervous system, up-regulating serum brain-derived neurotrophic factor, and improving vascular endothelial function; and the critical role of integrating the key principles of exercise prescription (frequency, intensity, type, time, volume, and progression) to identify novel therapeutic targets and optimize interventions. In conclusion, this study emphasizes not only the significance of exercise interventions but also the critical role of optimizing exercise prescriptions in managing comorbid depression and cardiovascular disorders. The approach holds important theoretical and clinical practice implications for enhancing both mental and cardiovascular health. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) poses a global health threat, with the oral microbiome increasingly implicated in its pathogenesis. This study leverages Mendelian Randomization (MR) to explore causal links between oral microbiota and CRC using data from the China National GeneBank and Biobank Japan. By integrating multi-omics approaches, we aim to uncover mechanisms by which the microbiome influences cellular metabolism and cancer development. Methods: We analyzed microbiome profiles from 2017 tongue and 1915 saliva samples, and GWAS data for 6692 CRC cases and 27178 controls. Significant bacterial taxa were identified via MR analysis. Single-cell RNA sequencing and enrichment analyses elucidated underlying pathways, and drug predictions identified potential therapeutics. Results: MR identified 19 bacterial taxa significantly associated with CRC. Protective effects were observed in taxa like RUG343 and Streptococcus_umgs_2425, while HOT-345_umgs_976 and W5053_sp000467935_mgs_712 increased CRC risk. Single-cell RNA sequencing revealed key pathways, including JAK-STAT signaling and tyrosine metabolism. Drug prediction highlighted potential therapeutics like Menadione Sodium Bisulfite and Raloxifene. Conclusion: This study establishes the critical role of the oral microbiome in colorectal cancer development, identifying specific microbial taxa linked to CRC risk. Single-cell RNA sequencing and drug prediction analyses further elucidate key pathways and potential therapeutics, providing novel insights and personalized treatment strategies for CRC. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression. [ABSTRACT FROM AUTHOR]

(1) Background: Small ubiquitin-like modifiers (SUMOs) are pivotal in post-translational modifications, influencing various cellular processes, such as protein localization, stability, and genome integrity. (2) Methods: This review explores the SUMO family, including its isoforms and catalytic cycle, highlighting their significance in regulating key biological functions in thyroid cancer. We discuss the multifaceted roles of SUMOylation in DNA repair mechanisms, protein stability, and the modulation of receptor activities, particularly in the context of thyroid cancer. (3) Results: The aberrant SUMOylation machinery contributes to tumorigenesis through altered gene expression and immune evasion mechanisms. Furthermore, we examine the therapeutic potential of targeting SUMOylation pathways in thyroid cancer treatment, emphasizing the need for further research to develop effective SUMOylation inhibitors. (4) Conclusions: By understanding the intricate roles of SUMOylation in cancer biology, we can pave the way for innovative therapeutic strategies to improve outcomes for patients with advanced tumors. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogenous malignant hemopathy, and although new drugs have emerged recently, current treatment options still show limited efficacy. Therapy resistance remains a major concern due to its contribution to treatment failure, disease relapse, and increased mortality among patients. The underlying mechanisms of resistance to therapy are not fully understood, and it is crucial to address this challenge to improve therapy. Macrophages are immune cells found within the bone marrow microenvironment (BMME), of critical importance for leukemia development and progression. One defining feature of macrophages is their plasticity, which allows them to adapt to the variations in the microenvironment. While this adaptability is advantageous during wound healing, it can also be exploited in cancer scenarios. Thus, clinical and preclinical investigations that target macrophages as a therapeutic strategy appear promising. Existing research indicates that targeting macrophages could enhance the effectiveness of current AML treatments. This review addresses the importance of macrophages as therapeutic targets including relevant drugs investigated in clinical trials such as pexidartinib, magrolimab or bexmarilimab, but also provides new insights into lesser-known therapies, like macrophage receptor with a collagenous structure (MACRO) inhibitors and Toll-like receptor (TLR) agonists. [ABSTRACT FROM AUTHOR]

Since prostate cancer is one of the leading causes of cancer-related death, a better understanding of the molecular pathways guiding its development is imperative. A key factor in prostate cancer is autophagy, a cellular mechanism that affects both cell survival and death. Autophagy is essential in maintaining cellular homeostasis. Autophagy is a physiological mechanism wherein redundant or malfunctioning cellular constituents are broken down and recycled. It is essential for preserving cellular homeostasis and is implicated in several physiological and pathological conditions, including cancer. Autophagy has been linked to metastasis, tumor development, and treatment resistance in prostate cancer. The deregulation of miRNAs related to autophagy appears to be a crucial element in the etiology of prostate cancer. These miRNAs influence the destiny of cancer cells by finely regulating autophagic mechanisms. Numerous investigations have emphasized the dual function of specific miRNAs in prostate cancer, which alter autophagy-related pathways to function as either tumor suppressors or oncogenes. Notably, miRNAs have been linked to the control of autophagy and the proliferation, apoptosis, and migration of prostate cancer cells. To create customized therapy approaches, it is imperative to comprehend the dynamic interplay between autophagy and miRNAs in prostate cancer. The identification of key miRNAs provides potential diagnostic and prognostic markers. Unraveling the complex network of lncRNAs, like PCA3, also expands the repertoire of molecular targets for therapeutic interventions. This review explores the intricate interplay between autophagy and miRNAs in prostate cancer, focusing on their regulatory roles in cellular processes ranging from survival to programmed cell death. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic myeloid leukemia (CML) relapse and progression after discontinuation of tyrosine kinase inhibitors (TKI) therapy in the chronic phase (CP) are attributed to primitive quiescent leukemic progenitor cells (LPCs). This study aimed to identify key differentially expressed genes (DEGs) involved in molecular pathways alternative to BCR-ABL, which could lead to the eradication of leukemic stem/progenitor cells. Methods mRNA expression profiling dataset comprising newly diagnosed untreated CP CML leukemic progenitor cell samples $$\left( {n = 5} \right)$$ n = 5 and normal hematopoietic progenitor cell samples $$\left( {n = 5} \right)$$ n = 5 were selected for DEGs identification. A weighted gene co-expression network was constructed to identify significant hub modules. Protein–protein interaction (PPI) network construction and pathway enrichment analysis provided additional information on the biological pathways involved. The genes involved in the resultant PPI network were subjected to a gene transcriptional regulatory network based on transcription factors (TFs) and microRNAs (miRNAs) involved in the target genes. Results A total of 709 genes that were differentially expressed among those corresponding to $$p < 0.05$$ p < 0.05 and $$\left| {\log_{2} \left( {FC} \right)} \right| > 0.5$$ log 2 FC > 0.5 . The WGCNA showed a significant hub module comprising 267 DEGs. The major pathways of the hub genes involved in the PPI network at the highest confidence score $$> 0.9$$ > 0.9 were related to mitochondrial translational elongation. The integrated gene transcriptional regulatory network revealed a TF (ETS1), two miRNAs (miR-34a-5p and miR-205-5p) targeting a hub gene (GFM1) as the highest-order motif or subnetwork in the three-node miRNA feed-forward loop. Conclusions The study suggests that the regulatory feed-forward loop may provide a potential therapeutic target in CML. Consequently, the mitochondrial translation pathway may be explored as an alternative to BCR-ABL pathways, which could aid in eliminating or increasing sensitization of CML progenitor/stem cells to TKI treatment.

As the deadliest type of primary brain tumor, gliomas represent a significant worldwide health concern. Circular RNA (circRNA), a unique non-coding RNA molecule, seems to be one of the most alluring target molecules involved in the pathophysiology of many kinds of cancers. CircRNAs have been identified as prospective targets and biomarkers for the diagnosis and treatment of numerous disorders, particularly malignancies. Recent research has established a clinical link between temozolomide (TMZ) resistance and certain circRNA dysregulations in glioma tumors. CircRNAs may play a therapeutic role in controlling or overcoming TMZ resistance in gliomas and may provide guidance for a novel kind of individualized glioma therapy. To address the biological characteristics of circRNAs and their potential to induce resistance to TMZ, this review has highlighted and summarized the possible roles that circRNAs may play in molecular pathways of drug resistance, including the Ras/Raf/ERK PI3K/Akt signaling pathway and metabolic processes in gliomas.

The aims of this narrative review were to summarize the current literature on the beneficial effects of exercise interventions on individuals with comorbid depression and cardiovascular disease, and to review the current evidence that advances our understanding of the pathophysiological mechanisms underlying these effects. Ninety relevant articles were included and analyzed through a systematic search of PubMed and Web of Science. The analyses indicated that exercise interventions could modulate regulatory pathways to prevent depressive symptoms and reduce adverse cardiovascular events through five mechanisms: promoting immunosuppression, improving mitochondrial function, balancing the autonomic nervous system, up-regulating serum brain-derived neurotrophic factor, and improving vascular endothelial function; and the critical role of integrating the key principles of exercise prescription (frequency, intensity, type, time, volume, and progression) to identify novel therapeutic targets and optimize interventions. In conclusion, this study emphasizes not only the significance of exercise interventions but also the critical role of optimizing exercise prescriptions in managing comorbid depression and cardiovascular disorders. The approach holds important theoretical and clinical practice implications for enhancing both mental and cardiovascular health.