Specific Pathways Research Articles

The effect of anti‐imbalance on glycolipid metabolic homeostasis via the liver–gut axis intervened by 3′‐sialyllactose in obese mice

AbstractSialic acid could ameliorate disorders associated with glycolipid metabolism. 3′‐Sialyllactose (3′‐SL), a type of oligosaccharide, contains sialic acid. We examined the effects of 3′‐SL on glycolipid metabolism in obese mice with high fat diet and explore the underlying mechanisms. A total of 160 male C57BL/6J mice were fed with high‐fat diet for 8 weeks to construct obese mice model. Sixty successfully constructed obese mice were randomly divided three 3′‐SL dosage‐dependent groups, one free sialic acid N‐acetylneuraminic acid (Neu5Ac) group, and one blank control group. Each group of obese mice (n = 12) was continuously supplemented by 3′‐SL or Neu5Ac for 10 weeks. Ten‐week 3′‐SL supplementation and Neu5Ac supplementation both yielded remarkedly lower body weight, reduced fat content, increased energy expenditure and active daily exercises with improved glycolipid biomarkers, and attenuated proinflammation. 3′‐SL increased the colonic abundances of Akkermansia, Lactobacillus, and Solibacillus and reduced those of Enterobacter and Enterococcus. Changes were also observed in colonic and liver transcript and metabolites, which were mainly enriched in glycolipid metabolism, ameliorated immune function, and mitigated inflammatory signals, autophagy, bile acid metabolism, and insulin resistance. Akkermansia and Solibacillus were significantly associated with changes in colonic metabolites and transcriptome genes. The liver bile component and glucose metabolites were significantly correlated with transcriptional gene expression in the aforementioned differential pathways. Therefore, 3′‐SL can enhance the gut microbiota, regulate intestinal immunity and bile acid metabolism, reduce liver oxidative stress and autophagy processes, alleviate chronic inflammation levels, and improve islet function and lower blood sugar levels by acting through the gut–liver axis.

Vertebrate endocrine disruptors induce sex-reversal in blue mussels

Mollusks are the second most diverse animal phylum, yet little is known about their endocrinology or how they respond to endocrine disrupting compound (EDC) pollution. Characteristic effects of endocrine disruption are reproductive impairment, skewed sex ratios, development of opposite sex characteristics, and population decline. However, whether classical vertebrate EDCs, such as steroid hormone-like chemicals and inhibitors of steroidogenesis, exert effects on mollusks is controversial. In the blue mussel, Mytilus edulis, EDC exposure is correlated with feminized sex ratios in wild and laboratory mussels, but sex reversal has not been confirmed. Here, we describe a non-destructive qPCR assay to identify the sex of M. edulis allowing identification of males and females prior to experimentation. We exposed male mussels to 17α-ethinylestradiol and female mussels to ketoconazole, EDCs that mimic vertebrate steroid hormones or inhibit their biosynthesis. Both chemicals changed the sex of individual mussels, interfered with gonadal development, and disrupted gene expression of the sex differentiation pathway. Impacts from ketoconazole treatment, including changes in steroid levels, confirmed a role for steroidogenesis and steroid-like hormones in mollusk endocrinology. The present study expands the possibilities for laboratory and field monitoring of mollusk species and provides key insights into endocrine disruption and sexual differentiation in bivalves.

Genetic architectures of the human hippocampus and those involved in neuropsychiatric traits

BackgroundThe hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus’s high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential.MethodsWe analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits.ResultsOur analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10−9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson’s disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson’s disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18–1.43, P = 6.15 × 10⁻⁸) for right hippocampal volume.ConclusionsThese findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages.

SnRNA-seq reveals differential functional transcriptional pathway alterations in three mutant types of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, characterized by ventricular dilation, thinning of the ventricular walls, and systolic dysfunction in either the left or both ventricles, often accompanied by fibrosis. Human cardiac tissue is composed of various cell types, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), macrophages, lymphocytes and so on. In DCM patients, these cells frequently undergo functional and phenotypic changes, contributing to contractile dysfunction, inflammation, fibrosis, and cell death, thereby increasing the risk of heart failure. This study focuses on DCM patients with mutations (LMNA, RBM20, and TTN) and analyzes functional changes in subpopulations of four cardiac cell types. The study involves functional annotation of subpopulations within each cell type and explores the association between gene mutations and specific functions and pathways. Additionally, the SCENIC method is employed of a particular cell subpopulation with significant functional importance, aiming to identify key transcriptional regulators in specific cell states. By analyzing the expression levels of ligand-receptor pairs in vCM4, vFB2, EC5.0, T cells, and NK cells across the DCM mutant genotypes, we predicted their signaling pathways and communications. This research provides insights into the molecular mechanisms of DCM and potential therapeutic targets.

Decoding the role of HIF-1α in immunoregulation in Litopenaeus vannamei under hypoxic stress

Hypoxia poses a significant challenge to aquatic organisms, especially Litopenaeus vannamei (L. vannamei), which play a vital role in the global aquaculture industry. Hypoxia-inducible factor 1α (HIF-1α) is a pivotal regulator of the organism's adaptation to hypoxic conditions. To understand of how HIF-1α affects the immunity of L. vannamei under hypoxic conditions, we conducted a thorough study involving various approaches. These included observing tissue morphology, analyzing the expression of immune-related genes, assessing the activities of immune-related enzymes, and exploring immune-related pathways. Our study revealed that RNA interference (RNAi)-mediated knockdown of HIF-1α markedly reduced HIF-1α expression in the gill (75–95 %), whereas the reduction ranged from 2 to 43 % in the hepatopancreas. Knockdown of HIF-1α resulted in increased damage to both gill and hepatopancreatic tissues in hypoxic conditions. Additionally, immune-related genes, including Astakine (AST), Hemocyanin (HC), and Ferritin (FT), as well as immune-related enzymes such as Acid Phosphatase (ACP), Alkaline Phosphatase (AKP), and Phenoloxidase (PO), exhibited intricate regulatory patterns in response to hypoxia stress following the knockdown of HIF-1α. Transcriptome analysis revealed that HIF-1α knockdown significantly impacts multiple signaling pathways, including the JAK-STAT signaling pathway, Th17 cell differentiation pathways, PI3K-Akt signaling pathway, ErbB signaling pathway, MAPK signaling pathway, chemokine signaling pathway, ribosomal pathways, apoptosis, lysosomes and arachidonic acid metabolism. These alterations disrupt the organism's immune balance and interfere with normal metabolic processes, potentially leading to various immune-related diseases. We speculate that the weakened immune response resulting from HIF-1 inhibition is due to the reduced metabolic capacity, and the existence of a direct regulatory relationship between them requires further exploration. This study greatly advances our understanding of the vital role that HIF-1α plays in regulating immune responses in shrimp under hypoxic conditions, thereby deepening our comprehension of this critical biological mechanism.

Metabolic profiling of blood plasma in depression in pregnant women during early pregnancy.

The study aimed to perform metabolic profiling of serum samples using liquid chromatography with mass spectroscopy (LC-MS) and to explore potential biomarkers of early trimester depression. Using the Edinburgh Postnatal Depression Scale (EPDS), participants were randomly divided into study and control groups. Serum metabolic profiles of the two groups were analysed by using LC-MS. Differential metabolite and pathway analysis were identified by using orthogonal projections to latent structure-discriminant analysis (OPLS-DA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Additionally, least absolute shrinkage and selection operator (LASSO) logistic and receiver operating characteristic (ROC) curve analyses were also conducted to explore potential biomarkers of antenatal depression (AD). The study included 41 participants, consisting of 16 subjects with AD and 25 controls. A total of 22 different metabolites were identified (p < .005), mainly affecting glycerophospholipid metabolism, linoleic acid metabolism, synthesis and degradation of ketone bodies, phenylalanine metabolism, and butanoate metabolism. The area under the ROC curve (AUC) for the LysoPC (24:0) was 0.858. This suggests that LysoPC (24:0) may be a potentially effective predictor of risk factors for AD. The study suggests that LysoPC (24:0) may be an effective and specific lipid biomarker for early trimester depression.

Screening core genes for minimal change disease based on bioinformatics and machine learning approaches.

Based on bioinformatics and machine learning methods, we conducted a study to screen the core genes of minimal change disease (MCD) and further explore its pathogenesis. First, we obtained the chip data sets GSE108113 and GSE200828 from the Gene Expression Comprehensive Database (GEO), which contained MCD information. We then used R software to analyze the gene chip data and performed functional enrichment analysis. Subsequently, we employed Cytoscape to screen the core genes and utilized machine learning algorithms (random forest and LASSO regression) to accurately identify them. To validate and analyze the core genes, we conducted immunohistochemistry (IHC) and gene set enrichment analysis (GSEA). Our results revealed a total of 394 highly expressed differential genes. Enrichment analysis indicated that these genes are primarily involved in T cell differentiation and p13k-akt signaling pathway of immune response. We identified NOTCH1, TP53, GATA3, and TGF-β1 as the core genes. IHC staining demonstrated significant differences in the expression of these four core genes between the normal group and the MCD group. Furthermore, GSEA suggested that their up-regulation may be closely associated with the pathological changes in MCD kidneys, particularly in the glycosaminoglycans signaling pathway. In conclusion, our study highlights NOTCH1, TP53, GATA3, and TGF-β1 as the core genes in MCD and emphasizes the close relationship between glycosaminoglycans and pathogenesis of MCD.

Spatial Transcriptomics Unravel the Tissue Complexity of Oral Pathogenesis.

Spatial transcriptomics (ST) is a cutting-edge methodology that enables the simultaneous profiling of global gene expression and spatial information within histological tissue sections. Traditional transcriptomic methods lack the spatial resolution required to sufficiently examine the complex interrelationships between cellular regions in diseased and healthy tissue states. We review the general workflows for ST, from specimen processing to ST data analysis and interpretations of the ST dataset using visualizations and cell deconvolution approaches. We show how recent studies used ST to explore the development or pathogenesis of specific craniofacial regions, including the cranium, palate, salivary glands, tongue, floor of mouth, oropharynx, and periodontium. Analyses of cranial suture patency and palatal fusion during development using ST identified spatial patterns of bone morphogenetic protein in sutures and osteogenic differentiation pathways in the palate, in addition to the discovery of several genes expressed at critical locations during craniofacial development. ST of salivary glands from patients with Sjögren's disease revealed co-localization of autoimmune antigens with ductal cells and a subpopulation of acinar cells that was specifically depleted by the dysregulated autoimmune response. ST of head and neck lesions, such as premalignant leukoplakia progressing to established oral squamous cell carcinomas, oral cancers with perineural invasions, and oropharyngeal lesions associated with HPV infection spatially profiled the complex tumor microenvironment, showing functionally important gene signatures of tumor cell differentiation, invasion, and nontumor cell dysregulation within patient biopsies. ST also enabled the localization of periodontal disease-associated gene expression signatures within gingival tissues, including genes involved in inflammation, and the discovery of a fibroblast subtype mediating the transition between innate and adaptive immune responses in periodontitis. The increased use of ST, especially in conjunction with single-cell analyses, promises to improve our understandings of craniofacial development and pathogenesis at unprecedented tissue-level resolution in both space and time.

The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency

BackgroundThe epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs.MethodsWe investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs.ResultsWe found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML.ConclusionOur study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

12353 Differential Gene Expression And Pathway Analysis In Growth Hormone Secreting Pituitary Tumors According To Granulation Pattern

Abstract Disclosure: H. Shin: None. Differential gene expression and pathway analysis in growth hormone-secreting pituitary tumors according to granulation pattern. Hye Ju Shin [1], Kyung Won Kim[2], Chan Woo Kang[2], Eun Jig Lee[2], Cheol Ryong Ku[2]. [1]Department of Clinical Drug Discovery &amp; Development, Yonsei University College of Medicine, Seoul, Republic of Korea, [2]Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea Objective: The purpose of this research is to explain clinical variations in patients with acromegaly by exploring gene expression differences according to granulation patterns in growth hormone (GH)-secreting pituitary tumors. Materials &amp; methods: Transcriptome analysis was conducted on 6 normal pituitary tissues and 15 GH-secreting pituitary tumors, including 9 densely granulated somatotroph tumors (DGSTs) and 6 sparsely granulated somatotroph tumors (SGSTs). Results: The median age at diagnosis was 50 years, with a predominance of female patients (60%). We identified 3111 differentially expressed genes (DEGs) in tumors compared to normal pituitaries, with 1117 DEGs unique to a specific granulation within tumors. SGST showed enriched the pathways involved in neuronal development (axon development, axonogenesis, axon guidance, synapse and presynapse organization, gliogenesis, glial cell differentiation, nerve development, synaptic membrane adhesion, semaphorin-plexin signaling pathway involved in neuron projection guidance) and acute inflammatory response. No pathways were significantly downregulated in SGST compared with those in DGST. Three signaling pathways (JAK-STAT, phosphatidylinositol 3-kinase, and MAP cascade) and three neuronal development processes (generation of neurons, nerve development, and neurogenesis) were significantly enriched in both GO and GSEA analysis. The PPI networks constructed with the up- and downregulated DEGs consisted of 128 and 132 PPI pairs, respectively. There were 10 hub proteins, top highly connected DEGs: ANLN, TLE3, TLE2, DMD, ADRA1A, RBFOX1, MMP2, LMO1, RUNX1T1, and NPPA. Conclusion: The results indicate that granulation-specific gene expression may underpin diverse clinical characteristics in acromegaly. Overall, this study emphasizes the potential for further investigation into these transcriptomic variations and their roles in disease pathology, particularly the involvement of genes linked to neuronal development, inflammatory response, and JAK-STAT signaling in SGST. Presentation: 6/3/2024

New generalized metric based on branch length distance to compare B cell lineage trees

The B cell lineage tree encapsulates the successive phases of B cell differentiation and maturation, transitioning from hematopoietic stem cells to mature, antibody-secreting cells within the immune system. Mathematically, this lineage can be conceptualized as an evolutionary tree, where each node represents a distinct stage in B cell development, and the edges reflect the differentiation pathways. To compare these lineage trees, a rigorous mathematical metric is essential. Analyzing B cell lineage trees mathematically and quantifying changes in lineage attributes over time necessitates a comparison methodology capable of accurately assessing and measuring these changes. Addressing the intricacies of multiple B cell lineage tree comparisons, this study introduces a novel metric that enhances the precision of comparative analysis. This metric is formulated on principles of metric theory and evolutionary biology, quantifying the dissimilarities between lineage trees by measuring branch length distance and weight. By providing a framework for systematically classifying lineage trees, this metric facilitates the development of predictive models that are crucial for the creation of targeted immunotherapy and vaccines. To validate the effectiveness of this new metric, synthetic datasets that mimic the complexity and variability of real B cell lineage structures are employed. We demonstrated the ability of the new metric method to accurately capture the evolutionary nuances of B cell lineages.

Bioinformatic analysis of molecular characteristics and oncogenic features of CARD14 in human cancer

Aberrant caspase recruitment domain family member 14 (CARD14) signaling has been strongly associated with inflammatory skin conditions. CARD14 acts as a scaffold protein, ultimately activating the transcription factor NF-KB. Although primarily studied in the context of inflammation, recent research has suggested its potential implications in tumorigenesis. In this study, we gathered The Cancer Genome Atlas (TCGA) tumor data to gauge the involvement of CARD14 in cancer, including genetic alterations, expression patterns, survival correlations, immune cell infiltration and functional interactions across diverse cancer types. We found heightened CARD14 expression in most tumors and there was a significant correlation between CARD14 expression and the prognosis of patients for certain tumors. For instance, patients with higher CARD14 expression had a better prognosis in sarcoma, lung, cervix and head and neck cancers. Moreover, CARD14 expression positively correlated with neutrophil infiltration in most of the cancer types analyzed. Finally, enrichment analysis showed that epithelial development and differentiation pathways were involved in the functional mechanism of CARD14. Our results show that CARD14 may have the potential to become a prognostic biomarker in several cancers, hence, further prospective studies will be required for its validation.

NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways.

Neural cell adhesion molecule (NCAM), a common mammalian cell surface glycoprotein, is the major substrate of polysialic acid (polySia). Polysialylated NCAM occurs in many types of cancer, but rarely in normal adult tissues. The functional role of NCAM hypersialylation in the epithelial-mesenchymal transition (EMT) process remains unclear. The present study indicates that NCAM and attached polysialic acid affect behaviors of breast epithelial cells through differential signaling pathways. NCAM and polysialylated NCAM are aberrantly regulated in breast cancer cells. They are both upregulated in normal breast epithelial cells undergoing EMT. Western blot analysis demonstrates that NCAM-140 overexpression induces EMT in breast epithelial cells and promotes cell proliferation and migration through activation of the β-catenin/slug signaling pathway. Modification of polySia attached to NCAM modulates cell adhesion and promotes cell motility through activation of the EGFR/STAT3 pathway. These observations contribute to clarifying the molecular mechanisms by which polysialic acid and its major substrate, NCAM, modulate cell behaviors, and highlight the significance of increased polysialylated expression on NCAM during EMT and tumor development.

ERBB2 is a potential diagnostic and prognostic biomarker in renal clear cell carcinoma

Renal clear cell carcinoma (ccRCC) is a common parenchymal tumor of the kidney, and the discovery of biomarkers for early and effective diagnosis of ccRCC can improve the early diagnosis of patients and thus improve long-term survival. Erb-b2 receptor tyrosine kinase 2 (ERBB2) mediates the processes of cell proliferation, differentiation, and apoptosis inhibition. The purpose of this study was to investigate the diagnostic and prognostic role of ERBB2 in ccRCC. We analyzed the expression levels of ERBB2 in various cancers from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. RNA-seq data were analyzed using R packages to identify differentially expressed genes between the high and low ERBB2 expression groups in the TCGA-KIRC dataset. Spearman correlation analysis was performed to determine the correlation between ERBB2 expression and immune cell infiltration, immune checkpoint expression, and PTEN expression. DNA methylation changes and genetic alterations in ERBB2 were assessed using the MethSurv and cBioPortal databases. Logistic regression analysis was performed to determine the correlation between ERBB2 expression and the clinicopathological characteristics of ccRCC patients. The diagnostic and prognostic value of ERBB2 was assessed using Kaplan‒Meier (K‒M) survival curves, diagnostic ROC curves, time-dependent ROC curves, nomogram models, and Cox regression models. The expression level of ERBB2 is lower in tumor tissues of ccRCC patients than in the corresponding control tissues. Differentially expressed genes associated with ERBB2 were significantly enriched in the pathways “BMP2WNT4FOXO1 pathway in primary endometrial stromal cell differentiation” and “AMAN pathway”. In ccRCC tissues, ERBB2 expression levels were associated with immune cell infiltration, immune checkpoints, and PTEN. The DNA methylation status of 10 CpG islands in the ERBB2 gene was associated with the prognosis of ccRCC. ERBB2 expression levels in ccRCC tissues were associated with race, sex, T stage, M stage, histological grade, and pathological stage. Cox regression analysis showed that ERBB2 was a potential independent predictor of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in ccRCC patients. ROC curve analysis showed that the expression level of ERBB2 could accurately distinguish between ccRCC tissue and adjacent normal renal tissue. Our study showed that ERBB2 expression in ccRCC tissues can be of clinical importance as a potential diagnostic and prognostic biomarker.

Differential Gene Expression and Signal Pathways Activation Lead to Differences in Cell Proliferation and Migration of Venous and Arterial Pig Smooth Muscle Cells

Differential Gene Expression and Signal Pathways Activation Lead to Differences in Cell Proliferation and Migration of Venous and Arterial Pig Smooth Muscle Cells

Uremia, Angioplasty Injury, and Vessel Type (Artery vs. Vein) Activate Differential Gene Expression and Pathway Profiles

Uremia, Angioplasty Injury, and Vessel Type (Artery vs. Vein) Activate Differential Gene Expression and Pathway Profiles

Cancer Pathways Targeted by Berberine: Role of microRNAs.

Cancer is a complex and heterogeneous malignant disease. Due to its multifactorial nature, including progressive changes in genetic, epigenetic, transcript, and protein levels, conventional therapeutics fail to save cancer patients. Evidence indicates that dysregulation of microRNA (miRNA) expression plays a crucial role in tumorigenesis, metastasis, cell proliferation, differentiation, metabolism, and signaling pathways. Moreover, miRNAs can be used as diagnostic and prognostic markers and therapeutic targets in cancer. Berberine, a naturally occurring plant alkaloid, has a wide spectrum of biological activities in different types of cancers. Inhibition of cell proliferation, metastasis, migration, invasion, and angiogenesis, as well as induction of cell cycle arrest and apoptosis in cancer cells, is reported by berberine. Recent studies suggested that berberine regulates many oncogenic and tumor suppressor miRNAs implicated in different phases of cancer. This review discussed how berberine inhibits cancer growth and propagation and regulates miRNAs in cancer cells. And how berberine-mediated miRNA regulation changes the landscape of transcripts and proteins that promote or suppress cancer progression. Overall, the underlying molecular pathways altered by berberine and miRNA influencing the tumor pathophysiology will enhance our understanding to combat the malignancy.

Plasma levels of progranulin, a tumorigenic protein, are persistently elevated during the first month after minimally invasive colorectal cancer resection.

Progranulin (PGRN), also identified as Precursor cell-derived growth factor (PCDGF), is a glycoprotein that is expressed and released ubiquitously. PGRN is plays a crucial role in regulating cell proliferation, differentiation, and pathological pathways. PGRN overexpression has been noted in many cancers and plays an important role in wound healing. Surgery's impact on PGRN levels is unknown. The aim of this study was to assess the levels of plasma PGRN before during the first month after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC) resection. CRC patients who were enrolled in a data/plasma bank approved by an Institutional Review Board and underwent MICR for whom adequate plasma samples were available were studied. Blood samples were obtained before surgery and at different time intervals after the operation and late samples were grouped into 7-day blocks and considered as single time points. PGRN levels (pg/mL) were determined in duplicate via ELISA and reported as median and 95% confidence interval (95% CI) values. The paired t-test was used for statistical analysis. Preoperative and 1 or more late postoperative plasma sample were available for 93 MICR CRC patients. The distribution of cancer stages in the final analysis was: stage I accounted for 37% of cases, stage II for 27%, stage III for 32%, and stage IV for 4%. The median preoperative PGRN level was 50.69 pg/mL, 95% CI: 47.71-56.30, n=93. When compared to preoperative levels, significantly elevated (P<0.001) median levels (pg/mL) were noted on postoperative day (POD) 1 (64.78, 95% CI: 60.86-68.83, n=92), POD 3 (69.15, 95% CI: 66.43-74.32, n=85), POD 7-13 (63.93, 95% CI: 59.62-68.35, n=68), and POD 14-20 (68.19, 95% CI: 60.12-73.37, n=26), POD 21-27 (67.38, 95% CI: 60.30-76.65, n=20) and on POD 28-41 (75.13, 95% CI: 54.02-83.16, n=22; P<0.01). Following surgery for CRC, plasma PGRN levels showed a significant increase compared to baseline levels, persisting for a duration of one month. This initial surge post-operation could potentially be attributed to the transient acute inflammatory response. The elevation observed in weeks 2 and 4 could potentially be attributed to the process of wound healing, as PGRN has been shown to enhance the accumulation of fibroblasts and facilitate angiogenesis within wounds. Additional investigation is warranted.

Over Activation of IL-6/STAT3 Signaling Pathway in Juvenile Dermatomyositis.

Juvenile dermatomyositis (JDM) is characterized by persistent non-purulent inflammation in the muscle and skin. The underlying mechanisms still remain uncertain. This study aims to elucidate the mechanism of interleukin-6 (IL-6) activation of Janus kinase/signal transducer and activator of transcription 3 pathway (JAK/STAT3), contributing to the pathogenesis of JDM. Serum IL-6 levels were compared between 72 newly diagnosed patients with JDM and the same patient cohort in treatment remission. Single-cell RNA sequencing (scRNA-seq) was employed to identify differential signaling pathway expression in muscle biopsy samples from two patients with JDM and healthy controls. Immunohistochemistry was used to examine differences in STAT3 phosphorylation between JDM and control muscle tissues. In vitro, skeletal muscle cell lines were stimulated with IL-6, and the transcription levels of genes related to mitochondrial calcium channels were quantified via reverse transcription-polymerase chain reaction (RT-PCR). Reactive oxygen species (ROS) production was measured in both IL-6 treated and untreated groups. ROS levels were then compared between IL-6 receptor antagonist pre-treated skeletal muscle cells and untreated cells. IL-6 levels in newly onset patients with JDM were significantly higher compared to the same patient cohort in remission states (p < 0.0001). Serum IL-6 was significantly increased in patients with negative myositis specific antibody (MSA), positive melanoma differentiation associated protein 5 (MDA5) and positive nuclear matrix protein 2 (NXP2), yet not for JDM with positive transcriptional intermediary factor γ(TIF1γ), based on subgroup analysis. ScRNA-seq analysis of muscle biopsies from patients with MDA5-positive JDM and patients with MSA negative JDM revealed abnormal activation of the JAK/STAT3 pathway in skeletal myocytes, macrophages, and vascular endothelial cells. The phosphorylation levels of STAT3 were elevated in active JDM cases. Transcription of the calcium channel modulation gene sarcolipin (SLN) was significantly higher in JDM primary skeletal muscle cells compared to normal cells. In vitro, IL-6 enhanced SLN transcription and induced ROS production, and blocking the IL-6 receptor resulted in decreased ROS generation in skeletal muscle cells. IL-6/JAK/STAT3 signaling pathway was abnormally activated in patients with JDM. IL-6 may be involved in the pathogenesis of muscle damage by triggering the development of calcium overload and production of ROS. Blockade of the IL-6/JAK/STAT3 pathway can be a potential treatment option for JDM, especially MDA5-positive patients and those who are negative for MSA.

Molecular correlates of social adversity in breast cancer.

48 Background: Neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa) survival independent of individual, tumor, and treatment factors, suggesting more aggressive tumor biology in women from disadvantaged neighborhoods. This study evaluates how differential DNA methylation (DNAm), gene expression, and biologic pathways are wired with each other to delineate the regulatory landscape of ND on BCa. Methods: We leveraged 55 geocoded ER+/HER2- BCa samples from Hispanic White women enrolled in a prospective genomic-epidemiologic cohort study. Objective ND was evaluated using the Area Deprivation Index (ADI) and subjective ND was evaluated using the patient-reported Neighborhood Social Environment Adversity Survey and the Everyday Expanded Discrimination Survey. We analyzed the association between ND and (1) DNAm, (2) RNA transcription and miRNAs, and (3) blood concentration levels of DNAm co-factors (B12 and folate) from the same patient. To evaluate how the DNAm/expressed pathways are wired with each other to delineate the regulatory landscape of ND in these tumors, we performed correlation analyses among CpGs, genes, and miRNAs in the same topologically associated domain (TAD). We used Spearman correlation as our metric and adjusted the resulting p-values to FDR values. Results: The cohort was divided into low ND (ADI&lt;5; 31%) and a high ND (ADI&gt;=5; 69%). There were no significant differences between groups by age, race/ethnicity, genetic ancestry, BMI, smoking/alcohol, subtype, stage, or OncotypeDX scores. We discovered that high ND exhibits epigenetic deregulation of immune pathways, consistent with our findings of lower circulating B12 in high ND, suggesting activation of immune pathways through reduced systemic availability of methyl donors. RNA-seq identified higher tumor infiltration of immune cells in patients from high ND (e.g., Interferon alpha and gamma responses and inflammatory responses) consistent with aggressive biology. Estrogen response genes were downregulated suggesting that patients from high ND may develop estrogen-resistant tumors. Higher subjective ND scores discovered epigenetic changes on cell adhesion and calcium signaling genes, along with gene expression of E2F targets and cell cycle’s G2M checkpoint, indicative of a more proliferative/stemness signature. TAD analysis discovered significant developmental, immune, and signaling pathways when correlating DNAm with gene expression (e.g., estrogen response and EMT). Conclusions: In this multi-omic matched cohort, we discovered differentially methylated/expressed pathways, consistent with aggressive biology, wired with each other to identify a novel regulatory landscape of ND on BCa. These findings can inform interventions such as improved access to healthy nutrition (B12) in ND/food deserts or targeted stress-reduction interventions based on our survey findings to ultimately reverse aggressive tumor biology and reduce BCa disparities by ND.