Abnormal Expression Research Articles

Aberrant Expression of Small Nucleolar RNA SNORA63 and Its Clinical Significance in Patients with Acute Leukemia

To investigate the expression level of small nucleolar RNA (snoRNA) SNORA63 in bone marrow of patients with acute leukemia (AL) and its significance in the clinical diagnosis, treatment and prognosis of AL patients. Bone marrow samples of 53 newly diagnosed AL patients and 29 healthy subjects in the Affiliated Hospital of Guangdong Medical University from March 2018 to December 2021 were collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression level of SNORA63 in bone marrow mononuclear cells of the two groups. The median expression level of SNORA63 in AL patients was used as the boundary value to divide the patients into SNORA63 high and low expression groups, and the relationship between the expression level of SNORA63 and the clinical characteristics, clinical indicators and prognosis of AL patients was analyzed and discussed. The relative expression level of SNORA63 in AL patients was significantly lower than that in healthy control group [0.3018 (0.0244-1.2792) vs 1.0882 (0.2797-1.9889)] (P < 0.01). The expression level of SNORA63 in AL patients without remission after initial treatment was significantly lower than that in healthy controls and the patients who received complete remission (CR) (P < 0.01), while there was no statistical difference in the expression level of SNORA63 between AML and ALL groups (P >0.05). The abnormal low expression of SNORA63 was closely related to fever, hemorrage, poor prognosis, efficacy, platelets (PLT), lactate dehydrogenase (LDH), albumin (ALB), and molecular biological abnormalities of AL patients (P < 0.05), but not significantly correlated with sex, age, AL subtype, pallor, fatigue, extramedullary infiltration, white blood cell count (WBC), hemoglobin (HGB), C-reactive protein (CRP), procalcitonin (PCT), fibrinogen (FIB) or chromosome karyotype (P >0.05). Meanwhile, overall survival (OS) and event-free survival (EFS) of AL patients in SNORA63 high-expression group were significantly higher than those in SNORA63 low-expression group (P < 0.05). Univariate Cox regression analysis showed that SNORA63, molecular biological abnormalities, fever, PLT and LDH were the factors influencing OS and EFS in AL patients (P < 0.05). Multivariate Cox regression analysis indicated that fever, molecular biological abnormalities and LDH were independent factors associated with OS and EFS in AL patients (P < 0.05). SNORA63 is significantly down-expressed in AL patients, which is a molecular marker of great clinical value for disease monitoring and prognosis evaluation in AL patients.

Single-cell analysis identified PDIA3 as regulator of malignant characteristics and macrophage function in human cancers.

Protein disulfide isomerase A3 (PDIA3) is an endoplasmic reticulum (ER) protein. It has different functions including glycoprotein folding in the ER. The unfavorable prognosis of cancer patients was related to the abnormal PDIA3 expression level. However, it is unclear how PDIA3 correlates with the malignant characteristics of different tumors and its impact on tumor immunity. Pan-cancer data were downloaded from several databases for large-scale bioinformatics analysis. The immunological functions of PDIA3 were systematically explored at the single-cell sequencing level, including cell communication, cell metabolism, cell evolution and epigenetic modification. We performed immunofluorescence staining to visualize PDIA3 expression and infiltration of macrophages in pan-cancer samples. Further, we performed a loss-of-function assay of PDIA3 in vitro. The CCK8 assay, clone formation assay, and transwell assay were performed. M2 macrophages were co-cultured with different cell lines before the transwell assay was performed. The immunofluorescence staining of pan-cancer samples presented a higher expression of PDIA3 than those of the paired normal tissues. According to single-cell sequencing analysis, expression of PDIA3 was closely associated with cell communication, cell metabolism, cell evolution and epigenetic modification. The knockdown of PDIA3 in tumor cells inhibited cell proliferation and invasion, and restrained cocultured M2 macrophage migration. Furthermore, PDIA3 displayed predictive value in immunotherapy response in human cancer cohorts, indicating a potential therapeutic target. Our study showed that PDIA3 was associated with tumor malignant characteristics and could mediate the migration of M2 macrophages in various tumor types. PDIA3 could be a promising target to achieve tumor control and improve the immune response on a pan-cancer scale.

An Inherited Allele Confers Prostate Cancer Progression and Drug Resistance via RFX6/HOXA10-Orchestrated TGFβ Signaling.

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFβ/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

FOXA2 Activates RND1 to Regulate Arachidonic Acid Metabolism Pathway and Suppress Cisplatin Resistance in Lung Squamous Cell Carcinoma.

The primary cause of cancer-related fatalities globally is lung cancer. Although the chemotherapy drug cisplatin (DDP) has brought certain benefits to patients, the rapid development of drug resistance has greatly hindered treatment success. We used the lung squamous cell carcinoma (LUSC) mRNA data set to explore the differentially expressed gene (RND1) in LUSC and detected RND1 expression in LUSC cells and DDP-resistant cells by qRT-PCR. Meanwhile, we performed abnormal expression treatment on RND1 and conducted CCK8, colony formation, and flow cytometry to evaluate the impact of RND1 expression on cell proliferation, apoptosis, and DDP resistance. In addition, we analyzed metabolism pathways involving RND1 using GSEA. We also used online tools such as hTFtarget and JASPAR to screen for the upstream transcription factor FOXA2 of RND1 and verified their relationship through CHIP and dual luciferase experiments. Finally, we validated the role of FOXA2-RND1 in DDP resistance in LUSC through the above experiments. RND1 was downregulated in LUSC, and overexpression of RND1 repressed proliferation and DDP resistance of LUSC cells and facilitated cell apoptosis. RND1 modulated the arachidonic acid (AA) metabolism pathway, and FOXA2 positively manipulated RND1 expression. By activating FOXA2, stabilizing RND1, and regulating AA levels, the sensitivity of LUSC cells to DDP could be enhanced. Our study suggested that FOXA2 positively modulated the RND1-AA pathway, which repressed the resistance of LUSC cells to DDP.

Epigenomic landscapes during prefrontal cortex development and aging in rhesus.

The prefrontal cortex (PFC) is essential for higher-level cognitive functions. How epigenetic dynamics participates in PFC development and aging is largely unknown. Here, we profiled epigenomic landscapes of rhesus monkey PFCs from prenatal to aging stages. The dynamics of chromatin states, including higher-order chromatin structure, chromatin interaction and histone modifications are coordinated to regulate stage-specific gene transcription, participating in distinct processes of neurodevelopment. Dramatic changes of epigenetic signals occur around the birth stage. Notably, genes involved in neuronal cell differentiation and layer specification are pre-configured by bivalent promoters. We identified a cis-regulatory module and the transcription factors (TFs) associated with basal radial glia development, which was associated with large brain size in primates. These TFs include GLI3, CREB5 and SOX9. Interestingly, the genes associated with the basal radial glia (bRG)-associated cis-element module, such as SRY and SOX9, are enriched in sex differentiation. Schizophrenia-associated single nucleotide polymorphisms are more enriched in super enhancers (SEs) than typical enhancers, suggesting that SEs play an important role in neural network wiring. A cis-regulatory element of DBN1 is identified, which is critical for neuronal cell proliferation and synaptic neuron differentiation. Notably, the loss of distal chromatin interaction and H3K27me3 signal are hallmarks of PFC aging, which are associated with abnormal expression of aging-related genes and transposon activation, respectively. Collectively, our findings shed light on epigenetic mechanisms underlying primate brain development and aging.

Dysregulated T-cell homeostasis and decreased CD30+ Treg proliferating in aplastic anemia

Aplastic anemia (AA) is an autoimmune hematopoietic disease mediated by autoreactive T cells leading to bone marrow failure. However, the precise role of autoreactive T cells in the development of AA is not fully understood, hindering the advancement of therapeutic and diagnostic strategies. In this study, we conducted a single-cell transcriptome analysis of CD8+ T cells, conventional CD4+ T (CD4+ Tconv) cells, and Treg cells, to elucidate the potential disruption of T cell homeostasis in patients with AA. We identified changes in CD4+ Tconv cells, including loss of homeostasis in naïve and memory cells and increased differentiation potential in T helper type 1 (TH1), T helper type 2 (TH2), and T helper type 17 (TH17) cells. Additionally, we identified naïve and memory CD8+ T cells that were enforced into an effector state. CD127 is an ideal surface marker for assessing the immune state of CD8+ T cells，as identified by flow cytometry. Abnormal expression of TNFSF8 has been observed in AA and other autoimmune diseases. Flow cytometry analysis revealed that TNFRSF8 (CD30), a receptor for TNFSF8, was predominantly present in human Treg cells. Importantly, patients with AA have a decreased CD30+ Treg subset. RNA-sequencing analysis revealed, that the CD30+ Treg cells are characterized by high proliferation and a remarkable immunosuppressive phenotype. Taken, together, we propose that abnormal TNFSF8/TNFRSF8 signaling is involved in dysfunctional T cell immunity by increasing the destruction of CD30+ Treg cells.

In vitro study of ATP1A3 p.Ala275Pro mutant causing alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism.

We previously reported that ATP1A3 c.823G>C (p.Ala275Pro) mutant causes varying phenotypes of alternative hemiplegia of childhood and rapid-onset dystonia-parkinsonism in the same family. This study aims to investigate the function of ATP1A3 c.823G>C (p.Ala275Pro) mutant at the cellular and zebrafish models. ATP1A3 wild-type and mutant Hela cell lines were constructed, and ATP1A3 mRNA expression, ATP1A3 protein expression and localization, and Na+-K+-ATPase activity in each group of cells were detected. Additionally, we also constructed zebrafish models with ATP1A3 wild-type overexpression (WT) and p.Ala275Pro mutant overexpression (MUT). Subsequently, we detected the mRNA expression of dopamine signaling pathway-associated genes, Parkinson's disease-associated genes, and apoptosisassociated genes in each group of zebrafish, and observed the growth, development, and movement behavior of zebrafish. Cells carrying the p.Ala275Pro mutation exhibited lower levels of ATP1A3 mRNA, reduced ATP1A3 protein expression, and decreased Na+-K+-ATPase activity compared to wild-type cells. Immunofluorescence analysis revealed that ATP1A3 was primarily localized in the cytoplasm, but there was no significant difference in ATP1A3 protein localization before and after the mutation. In the zebrafish model, both WT and MUT groups showed lower brain and body length, dopamine neuron fluorescence intensity, escape ability, swimming distance, and average swimming speed compared to the control group. Moreover, overexpression of both wild-type and mutant ATP1A3 led to abnormal mRNA expression of genes associated with the dopamine signaling pathway and Parkinson's disease in zebrafish, and significantly upregulated transcription levels of bad and caspase-3 in the apoptosis signaling pathway, while reducing the transcriptional level of bcl-2 and the bcl-2/bax ratio. This study reveals that the p.Ala275Pro mutant decreases ATP1A3 protein expression and Na+/K+-ATPase activity. Abnormal expression of either wild-type or mutant ATP1A3 genes impairs growth, development, and movement behavior in zebrafish.

YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells.

Highly metastatic and heterogeneous breast cancer affects the health of women worldwide. Abnormal expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB), also known as 14-3-3β, is associated with the tumorigenesis and progression of bladder cancer, lung cancer and hepatocellular carcinoma; however, to the best of our knowledge, the role of YWHAB in breast cancer remains unknown. In the present study, a dual luciferase assay demonstrated that the transcription factor iroquois homeobox 5 may regulate YWHAB expression by affecting the promoter sequence upstream of its transcription start site. Subsequently, it was demonstrated that overexpression of YWHAB did not affect proliferation, but did reduce the migration and invasion of MDA-MB-231 cells. Furthermore, knockdown of YWHAB promoted the migration and invasion of MCF7 cells. Transcriptomics analysis demonstrated that when YWHAB was overexpressed, 61 genes were differentially expressed, of which 43 genes were upregulated and 18 genes were downregulated. These differentially expressed genes (DEGs) were enriched in cancer-related pathways, such as 'TNF signaling pathway' [Kyoto Encyclopedia of Genes and Genomes (KEGG): map04688]. The pathway with the largest number of DEGs was 'Rheumatoid arthritis' (KEGG: map05323). Notably, YWHAB downregulated vimentin, which is a mesenchymal marker, thus suggesting that it may weaken the mesenchymal properties of cells. These findings indicate that YWHAB may be a potential therapeutic target in breast cancer and further work should be performed to assess its actions as a potential tumor suppressor.

Integrated multi-omics profiling landscape of organising pneumonia.

Organising pneumonia (OP) is one of the most common and lethal diseases in the category of interstitial pneumonia, along with lung cancer. Reprogramming of lipid metabolism is a newly recognized hallmark of many diseases including cancer, cardiovascular disorders, as well as liver fibrosis and sclerosis. Increased levels of ceramides composed of sphingosine and fatty acid, are implicated in the development of both acute and chronic lung diseases. However, their pathophysiological significance in OP is unclear. The aim of this study was to investigate the role of lipid metabolism reprogramming in OP, focusing on inflammation and fibrosis. Comprehensive multi-omics profiling approaches, including single-cell RNA sequencing, Visium CytAssist spatial transcriptomics, proteomics, metabolomics and mass spectrometry, were employed to analyze the tissues. OP mice model was utilized and molecular mechanisms were investigated in macrophages. The results revealed a significant association between OP and lipid metabolism reprogramming, characterized by an abnormal expression of several genes related to lipid metabolism, including CD36, SCD1, and CES1 mainly in macrophages. CD36 deficiency in alveolar macrophages, led to an increased expression of C16/24 ceramides that accumulated in mitochondria, resulting in mitophagy or mitochondrial dysfunction. The number of alveolar macrophages in OP was significantly reduced, which was probably due to the ferroptosis signaling pathway involving GSH/SLC3A2/GPX4 through CD36 downregulation in OP. Furthermore, macrophage secretion of DPP7 and FABP4 influenced epithelial cell fibrosis. CD36 inhibited the ferroptosis pathway involving SLC3A2/GPX4 in alveolar macrophages of OP tissue by regulating lipid metabolism, thus representing a new anti-ferroptosis and anti-fibrosis effect of CD36 mediated, at least in part, by ceramides. Our findings reveal a significant association between organising pneumonia and lipid metabolism reprogramming and will make a substantial contribution to the understanding of the mechanism of organising pneumonia in patients.

Arsenic induces hepatotoxicity in chickens via PANoptosis pathway

Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people's mining and smelting of arsenic compounds. In addition, the widespread use of arsenic compounds, such as the use and production of arsenic-containing pesticides, is also a source of arsenic contamination. Arsenic contamination leads to an increased risk of arsenic exposure, and the multi-organ toxicity induced by arsenic exposure is a global health problem. As a non-mammalian vertebrate with high nutrient levels, chickens readily absorb and accumulate arsenic from their food. Relevant studies have shown that arsenic exposure induces hepatotoxicity in chickens, and there has been a steady stream of research into the specific mechanisms involved. PANoptosis, a newly discovered and unique mode of programmed cell death (PCD) characterized by both apoptosis, cellular pyroptosis, and necroptosis. There are no studies to indicate whether chicken liver toxicity due to arsenic is associated with PANoptosis. Therefore, we established chicken animal models and chicken primary hepatocyte models exposed to different arsenic concentrations to dissect the role and mechanism of PANoptosis in arsenic exposure-induced hepatotoxicity in chickens. Our histopathological results showed that arsenic treatment caused dose-dependent damage to chicken liver structure. Meanwhile, different doses of arsenic treatment groups caused significant up-regulation of the protein level of ZBP1, a key factor of PANoptosis. And then consequently triggered the abnormal gene and protein expression levels of apoptosis-associated factors (Caspase-8, Caspase-7, Caspase-3), cellular pyroptosis-associated factors (NLRP3, ASC, GSDMD) and necroptosis-associated factors (RIPK1, RIPK3, MLKL). In conclusion, our study revealed that PANoptosis is involved in arsenic-induced chicken hepatotoxicity. Our findings provide a new perspective on the pathogenesis of arsenic exposure-induced hepatotoxicity in chickens.

An Emerging Role of Long Noncoding RNAs as Novel Biomarkers for Breast Cancer Metastasis

Breast cancer is a leading cause of cancer-related deaths among women both worldwide and in Poland. Consequently, ensuring equitable access to diagnostic tests for all populations is crucial, alongside the urgent need to develop new, minimally invasive methods for early cancer detection with a particular focus on metastasis. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cancer metastasis. This review aims to investigate the potential of lncRNAs as novel biomarkers for breast cancer, focusing on their mechanisms, clinical relevance, and therapeutic implications. A comprehensive literature search was conducted using PubMed and Google Scholar databases, targeting publications from 2013 to 2024. Keywords included “lncRNA”, “biomarker”, “breast cancer”, “metastasis”, “prognosis”, and “diagnosis”. A total of 111 articles were selected based on their relevance and quality. Recent studies have identified numerous lncRNAs such as HOTAIR, MALAT1, BANCR, NEAT1, H19, and GAS5 as key regulators of various metastatic processes in breast cancer. They can be both upregulated and downregulated. Clinical studies have shown that abnormal lncRNA expression correlates with poor prognosis, higher metastatic potential, and therapy resistance in breast cancer patients. LncRNAs have significant potential as novel biomarkers for breast cancer metastasis because of their regulatory roles in metastasis-related processes and detectability in body fluids. Further research is essential to validate these findings in larger clinical studies and to develop lncRNA-based diagnostic and therapeutic tools, ultimately improving patient outcomes in breast cancer.

Influence of Varied Dietary Cholesterol Levels on Lipid Metabolism in Hamsters.

Syrian hamsters are valuable models for studying lipid metabolism due to their sensitivity to dietary cholesterol, yet the precise impact of varying cholesterol levels has not been comprehensively assessed. This study examined the impact of varying dietary cholesterol levels on lipid metabolism in Syrian hamsters. Diets ranging from 0% to 1% cholesterol were administered to assess lipid profiles and oxidative stress markers. Key findings indicate specific cholesterol thresholds for inducing distinct lipid profiles: below 0.13% for normal lipids, 0.97% for elevated LDL-C, 0.43% for increased VLDL-C, and above 0.85% for heightened hepatic lipid accumulation. A cholesterol supplementation of 0.43% induced hypercholesterolemia without adverse liver effects or abnormal lipoprotein expression. Furthermore, cholesterol supplementation significantly increased liver weight, plasma total cholesterol, LDL-C, and VLDL-C levels while reducing the HDL-C/LDL-C ratio. Fecal cholesterol excretion increased, with stable bile acid levels. High cholesterol diets correlated with elevated plasma ALT activities, reduced hepatic lipid peroxidation, and altered leptin and CETP levels. These findings underscore Syrian hamsters as robust models for hyperlipidemia research, offering insights into experimental methodologies. The identified cholesterol thresholds facilitate precise lipid profile manipulation, enhancing the hamster's utility in lipid metabolism studies and potentially informing clinical approaches to managing lipid disorders.

Comprehensive analysis of shared risk genes and immunity-metabolisms between non-alcoholic fatty liver disease and atherosclerosis via bulk and single-cell transcriptome analyses

Objectiveand design: Considering the clinical link between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (AS), we performed bioinformatics analysis to uncover their pathogenic interrelationship. Methods and resultsData from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999–2018 were included. Among 4851 participants in NHANES, NAFLD was significantly associated with atherosclerotic cardiovascular disease risk (ASCVD risk) (OR = 2.32, 95%CI: 2.04–2.65, P < 0.0001). We conducted WGCNA analysis for NAFLD (GSE130970) and AS (GSE28829) and identified three modules positively related to NAFLD severity and two modules accelerating atherosclerosis plaque progression. 198 key-modules genes were obtained via overlapping these modules. Next, we mined the disease-controlled differentially expressed genes (DEGs) from NAFLD (GSE89632) and AS (GSE100927), respectively. The final common risk genes (ACP5, TP53I3, RPS6KA1, TYMS, TREM2, CA12, and IFI27) were defined by intersecting the upregulated DEGs with 198 genes and validated in new datasets (GSE48452 and GSE43292). Importantly, they showed good diagnostic ability for NAFLD and AS. Immune infiltration analysis showed both illnesses have dysregulated immunity. Analysis of single-cell sequencing datasets NAFLD (GSE179886) and AS (GSE159677) uncovered different abnormal expressions of seven common genes in different immune cells while highlighting metabolic disturbances including upregulation of fatty acid biosynthesis, downregulation of fatty acid degradation and elongation. ConclusionWe found 7 shared hub genes with good diagnostic ability and depicted the landscapes of immune and metabolism involved in NAFLD and AS. Our results provided a comprehensive association between them and may contribute to developing potential intervention strategies for targeting both disorders based on these risk factors.

Melatonin reverses EGFR-TKI therapeutic resistance by modulating crosstalk between circadian-related gene signature and immune infiltration patterns in patients with COVID-19 and lung adenocarcinoma

BackgroundPatients with lung cancer exhibit the poorest outcomes when infected with coronavirus disease 2019 (COVID-19). However, the potential impact of COVID-19 on the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains unknown. MethodsExpression data and clinical information were sourced from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Prognostic, differentially expressed circadian-related genes (CRGs) were identified using multivariate Cox regression and LASSO regression analyses to establish an immune-related gene signature. The clinical value, immune landscape, somatic mutations, and drug sensitivity of high- and low-risk groups were assessed using Kaplan-Meier curves and immunotherapy cohorts. Finally, in vitro and in vivo experiments were conducted to elucidate the molecular function of melatonin in regulating the immune microenvironment and therapeutic resistance. ResultsThree circadian-related patterns and distinct CRGs clusters were identified based on the abnormal expression of 13 CRGs. Circadian genomic phenotypes were identified based on 13 circadian phenotype-related differentially expressed genes (DEGs). A CRGs risk signature was constructed; the high CRGs risk group displayed an immunosuppressive TME, poor survival, and therapy resistance. Melatonin reversed EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance by regulating immune cell infiltration into the TME, both in vitro and in vivo. ConclusionsThe investigation revealed crosstalk between CRGs signatures and immune infiltration patterns in LUAD and COVID-19. Melatonin acted as a promising agent to suppress the malignant features of lung cancer and enhance treatment sensitivity by modulating the TME.

ST3GAL1 Promotes Malignant Phenotypes in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis, and elucidation of the molecular mechanisms underlying iCCA malignancy is of great significance. Glycosylation, an important post-translational modification, is closely associated with tumor progression. Altered glycosylation, including aberrant sialylation resulting from abnormal expression of sialyltransferases (STs) and neuraminidases (NEUs), is a significant feature of cancer cells. However, there is limited information on the roles of STs and NEUs in iCCA malignancy. Here, utilizing our proteogenomic resources from a cohort of 262 patients with iCCA, we identified ST3GAL1 as a prognostically relevant molecule in iCCA. Moreover, overexpression of ST3GAL1 promoted proliferation, migration, and invasion and inhibited apoptosis of iCCA cells invitro. Through proteomic analyses, we identified the downstream pathway potentially regulated by ST3GAL1, which was the NF-κB signaling pathway, and further demonstrated that this pathway was positively correlated with malignancy in iCCA cells. Notably, glycoproteomics showed that O-glycosylation was changed in iCCA cells with high ST3GAL1 expression. Importantly, the altered O-glycopeptides underscored the potential utility of O-glycosylation profiling as a discriminatory marker for iCCA cells with ST3GAL1 overexpression. Additionally, miR-320b was identified as a post-transcriptional regulator of ST3GAL1, capable of suppressing ST3GAL1 expression and then reducing the proliferation, migration, and invasion abilities of iCCA cell lines. Taken together, these results suggest ST3GAL1 could serve as a promising therapeutic target for iCCA.

Functions and mechanisms of RNA m6A regulators in breast cancer (Review).

Breast cancer (BC) is a major malignant tumor in females and the incidence rate of BC has increased worldwide in recent years. N6‑methyladenosine (m6A) is a methylation modification that occurs extensively in eukaryotic RNA. The abnormal expression of m6A and related regulatory proteins can activate or inhibit certain signal pathways or oncogenes, thus affecting the proliferation, metastasis and prognosis of BC. Numerous studies have shown that m6A regulator disorder exists in BC, and this disorder can be reversed. Therefore, m6A is predicted as a potential therapeutic target for BC. However, the molecular mechanism of m6A RNA methylation regulating the occurrence and development of BC has not been comprehensively elucidated. In this review article, the functions of various m6A regulators and the specific mechanisms of certain regulators of the progress of BC were summarized. Furthermore, the dual role of RNA methylation in tumor progression was discussed, concluding that RNA methylation can not only lead to tumorigenesis but at times give rise to inhibition of tumor formation. In addition, further comprehensive analysis on mechanisms of m6A regulators in BC is conducive to screening effective potential targets and formulating targeted treatment strategies, which will provide new methods for the prevention and treatment of BC.

Interventional Effect of Donkey Bone Collagen Peptide Iron Chelate on Cyclophosphamide Induced Immunosuppressive Mice.

Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.

The odyssey of the TR(i)P journey to the cellular membrane.

Ion channels are integral membrane proteins mediating ion flow in response to changes in their environment. Among the different types of ion channels reported to date, the super-family of TRP channels stands out since its members have been linked to many pathophysiological processes. The family comprises 6 subfamilies and 28 members in mammals, which are widely distributed throughout most tissues and organs and have an important role in several aspects of cellular physiology. It has been evidenced that abnormal expression, post-translational modifications, and channel trafficking are associated with several pathologies, such as cancer, cardiovascular disease, diabetes, and brain disorders, among others. In this review, we present an updated summary of the mechanisms involved in the subcellular trafficking of TRP channels, with a special emphasis on whether different post-translational modifications and naturally occurring mutagenesis affect both expression and trafficking. Additionally, we describe how such changes have been associated with the development and progress of diverse pathologies associated with the gain or loss of functional phenotypes. The study of these processes will not only contribute to a better understanding the role of TRP channels in the different tissues but will also present novel possible therapeutic targets in diseases where their activity is dysregulated.

Signals from intestinal microbiota mediate the crosstalk between the lung-gut axis in an influenza infection mouse model.

Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear. Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry. Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity. Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma.

This study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis. Bioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC). Significantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which "mutation" was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyl-transferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models. This study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC.