Bosnian Journal of Basic Medical Sciences (BJBMS)
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miR-145-5p regulates hepatocellular carcinoma malignant advancement and immune escape via down-regulation of AcylCoA synthase ACSL4
Get PDFHepatocellular carcinoma (HCC) exhibits a subtle onset, high incidence rates, and low survival rates, becoming a substantial threat to human health. Hence, it is crucial to discover fresh biomarkers and treatment targets for the early detection and management of HCC. CCK-8, scratch-wound, and transwell assays were used to evaluate the biological properties of HCC cell lines (Huh-7 and Hep3B). Bioinformatics analysis identified the downstream target mRNA of miR-145-5p as acyl-CoA synthetase long-chain family member 4 (ACSL4). RT-qPCR was used to test miR-145-5p and ACSL4 levels. Transwell chambers were used to co-incubate purified CD8+ T cells and HCC cells for 48 h, and the effect of CD8+ T cells on apoptosis in HCC cells was detected by flow cytometry. A subcutaneous graft tumor model was constructed, and ELISA kits were used to assess cytokine levels and CD8+ T cell activation markers. HCC cells showed a decline in miR-145-5p levels and a rise in ACSL4 levels. Overexpression of miR-145-5p hindered HCC cell proliferation, migration, and invasion, while stimulating CD8+ T cell activation. Conversely, overexpression of ACSL4 enhanced the malignant biological properties of HCC cells and reduced the effect of CD8+ T cells, while silencing ACSL4 had the opposite effect. miR-145-5p targeted and downregulated ACSL4, while overexpression of miR-145-5p weakened the promotion of HCC malignant progression caused by ACSL4 overexpression. Additionally, overexpression of miR-145-5p and silencing ACSL4 were effective in inhibiting tumor growth in vivo. In conclusion, miR-145-5p targets and downregulates ACSL4, leading to the inhibition of HCC malignant progression and preventing immune escape in HCC cells
The gut microbiota modulates airway inflammation in allergic asthma through the gut-lung axis related immune modulation: A review
Get PDFThe human gut microbiota is a vast and complex microbial community. According to statistics, the number of bacteria residing in the human intestinal tract is approximately ten times that of total human cells, with over 1000 different species. The interaction between the gut microbiota and various organ tissues plays a crucial role in the pathogenesis of local and systemic diseases, exerting a significant influence on disease progression. The relationship between the gut microbiota and intestinal diseases, along with its connection to the pulmonary immune environment and the development of lung diseases, is commonly referred to as the “gut–lung axis.” The incidence of bronchial asthma is rising globally. With ongoing research on gut microbiota, it is widely believed that intestinal microorganisms and their metabolic products directly or indirectly participate in the occurrence and development of asthma. Based on the gut–lung axis, this review examines recent research suggesting that the intestinal microbiota can influence the occurrence and progression of allergic asthma through the modulation of cytokine immune balance and mucosal integrity. Though the precise immune pathways or microbial species influencing asthma through the gut–lung axis are still under exploration, summarizing the immune modulation through the gut–lung axis in allergic asthma may provide insights for the clinical management of the condition
Therapeutic effects of chlorogenic acid on allergic rhinitis through TLR4/MAPK/NF-κB pathway modulation
Get PDFChlorogenic acid (CGA) exhibits promising anti-inflammatory properties, making it a potential therapeutic agent for inflammatory conditions and allergic rhinitis (AR). This study aimed to evaluate the therapeutic effects of CGA on inflammation in RAW264.7 macrophage cells and on AR in mice. RAW264.7 cells were treated with lipopolysaccharide (LPS) to induce inflammation and cultured with varying concentrations of CGA, a Tlr4-silenced gene (shTlr4) transfection, and the MAPK/NF-κB pathway activator diprovocim. Cell viability was assessed using the CCK8 assay, while levels of nitric oxide (NO), TNF-α, and IL-6 were measured by Griess colorimetry, immunofluorescence, and ELISA. Expression and phosphorylation levels of the MAPK/NF-κB pathway were evaluated using qPCR and western blotting. Additionally, ovalbumin (OVA)-induced AR mice received different doses of CGA, and Toll-like receptor-4 (Tlr4) overexpression was induced. In vitro, CGA treatment significantly reduced LPS-induced cell activity, NO, TNF-α, and IL-6 secretion, and downregulated Tlr4, p-p38, p-p65, and p-IκB expression. Tlr4 inhibition suppressed cell activity and inflammation by blocking MAPK/NF-κB pathway activation. Conversely, Tlr4 overexpression counteracted the effects of CGA, increasing cell activity and inflammatory factor concentration. In OVA-induced AR mice, CGA effectively alleviated allergic symptoms, reduced inflammatory factor secretion, and inhibited TLR4/MAPK/NF-κB pathway activity. These findings suggest CGA’s potential as an anti-inflammatory agent in RAW264.7 cells and AR models through modulation of the TLR4/MAPK/NF-κB pathway
Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus
Get PDFWhite adipose tissue (WAT) plays a pivotal role in the onset of type 2 diabetes mellitus (T2DM) and obesity. Despite its significance the underlying pathogenesis and key genes associated with it remain elusive. In our study, we screened the differentially expressed genes (DEGs) in intra-abdominal WAT of T2DM patients with obesity, as well as those with simple obesity, aiming to lay a foundational theory for an in-depth investigation of T2DM pathogenesis and the identification of novel therapeutic targets. Gene expression datasets (GSE16415 and GSE71416) were retrieved from the Gene Expression Omnibus (GEO) database. We employed R for screening DEGs and conducted a functional enrichment analysis using the Metascape database. Combined Lasso regression and Boruta feature selection algorithms were used to identify key DEGs. Subsequently, these were cross-verified using the GSE29231 dataset. Samples and medical records were collected from clinical study participants. The mRNA and protein expressions of the key DEGs were verified using qRT-PCR and western blotting, respectively. We discerned a total of 130 DEGs, with 40 being upregulated and 90 downregulated. Functional and pathway enrichment analyses illuminated that these genes are instrumental in mediating metabolite and energy production, neutrophil-mediated immunity, and other associated biological processes. This includes their involvement in the tricarboxylic acid cycle, glycolysis/gluconeogenesis, peroxisome proliferator-activated receptors, and other signalling pathways. Two genes, CIDEA and FSCN1 emerged as key DEGs. The low expression of CIDEA and high expression of FSCN1 in the T2DM and obesity group were verified in clinical samples (P < 0.05). We established that CIDEA and FSCN1 manifest significant differential expression in T2DM patients who are obese. This suggests their potential as risk assessment markers and therapeutic targets for T2DM
Silencing METTL14 alleviates liver injury in non-alcoholic fatty liver disease by regulating mitochondrial homeostasis
Get PDFMitochondrial dysfunction is an important pathogenic factor in non-alcoholic fatty liver disease (NAFLD). Methyltransferase-like 14 (METTL14) has been implicated in mitochondrial fission processes. This research aimed to investigate the mechanism of METTL14 in the mitochondrial function of NAFLD. We first established NAFLD mouse models and cell models, recording body and liver weights and examining pathological changes in liver tissues. Subsequently, serum levels of liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total cholesterol [TC], and triglycerides [TG]), inflammatory markers (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6, and IL-1β), and mitochondrial dysfunction indicators (fission 1 protein [Fis1], dynamin-related protein 1 [Drp1], mitofusin 2 [Mfn2], SID1 transmembrane family member 2 [SIDT2], and mitochondrial membrane potential [MMP]) in the liver and cells were evaluated. The N6-methyladenosine (m6A) modification level of primary microRNA (pri-miRNA) and m6A enrichment on pri-miR-34a were quantified. Co-immunoprecipitation and dual-luciferase reporter gene assays were utilized to validate gene interactions. Our findings revealed highly elevated METTL14 expression in NAFLD mouse and cell models. Silencing METTL14 reduced weight gain and mitigated adverse liver function indices, inflammation, hepatic steatosis, and structural damage in NAFLD mice. It also led to a decrease in Fis1/Drp1 levels and an increase in MMP/Mfn2 in the liver and cells. Moreover, METTL14 increased the m6A level, promoting the binding of DiGeorge syndrome critical region 8 (DGCR8) to pri-miR-34a, which enhanced miR-34a-5p expression. Databases and dual-luciferase reporter gene assays indicated that miR-34a-5p could suppress SIDT2 expression. The overexpression of miR-34a-5p or inhibition of SIDT2 expression negated the alleviative effects of METTL14 silencing on mitochondrial homeostasis imbalance. In conclusion, METTL14, through m6A modification, modulates the miR-34a-5p/SIDT2 axis, impairing mitochondrial homeostasis in NAFLD
Parathyroid hormone-related protein as a potential prostate cancer biomarker: Promoting prostate cancer progression through upregulation of c-Met expression
Get PDFParathyroid hormone-related protein (PTHrP) plays a significant role in various tumor types, including prostate cancer. However, its specific role and underlying mechanisms in prostate cancer remain unclear. This study investigates the role of PTHrP and its interaction with the c-Met in prostate cancer. PTHrP was overexpressed and knocked down in prostate cancer cell lines to determine its effect on cell functions. Xenograft tumor models were employed to assess the impact of PTHrP overexpression on tumor growth. To delve into the interaction between PTHrP and c-Met, rescue experiments were conducted. Clinical data and tissue samples from prostate cancer patients were gathered and analyzed for PTHrP and c-Met expression. PTHrP overexpression in prostate cancer cells upregulates c-Met expression and augments cell functions. In contrast, PTHrP-knockdown diminishes c-Met expression and inhibits cell functions. In vivo experiments further demonstrated that PTHrP overexpression promoted tumor growth in xenograft models.Moreover, modulating c-Met expression in rescue experiments led to concurrent alterations in prostate cancer cell functions. Immunohistochemical analysis of clinical samples displayed a significant positive correlation between PTHrP and c-Met expression. Additionally, PTHrP expression correlated with clinical parameters like prostate-specific antigen (PSA) levels, tumor stage, lymph node involvement, distant metastasis, and Gleason score. PTHrP plays a crucial role in prostate cancer progression by upregulating c-Met expression. These insights point to PTHrP as a promising potential biomarker for prostate cancer
Skeletal muscle myosin heavy chain expression and 3D capillary network changes in streptozotocin-induced diabetic female mice
Get PDFIt is not well-understood how type 1 diabetes (T1DM) affects skeletal muscle histological phenotype, particularly capillarisation. This study aimed to analyze skeletal muscle myosin heavy chain (MyHC) fibre type changes and 3D capillary network characteristics in experimental T1DM mice. Female C57BL/6J-OlaHsd mice were categorized into streptozotocin (STZ)-induced diabetic (n = 12) and age-matched non-diabetic controls (n =12). The muscle fibre phenotype of the soleus, gluteus maximus, and gastrocnemius muscles were characterized based on the expression of MyHC isoforms, while capillaries of the gluteus maximus were assessed with immunofluorescence staining, confocal laser microscopy and 3D image analysis. STZ-induced diabetic mice exhibited elevated glucose levels, reduced body weight, and prolonged thermal latency, verifying the T1DM phenotype. In both T1DM and non-diabetic mice, the gluteus maximus and gastrocnemius muscles predominantly expressed fast-twitch type 2b fibers, with no significant differences noted. However, the soleus muscle in non-diabetic mice had a greater proportion of type 2a fibers and comparable type 1 fiber densities (26.2 ± 14.6% vs 21.9 ± 13.5%) relative to diabetic mice. T1DM mice showed reduced fiber diameters (P = 0.026), and the 3D capillary network analysis indicated a higher capillary length per muscle volume in the gluteus maximus of diabetic mice compared to controls (P < 0.05). Overall, T1DM induced significant changes in the skeletal muscle, including shifts in MyHC fibre types, decreased fibre diameters, and increased relative capillarisation, possibly due to muscle fibre atrophy. Our findings emphasize the superior detail provided by the 3D analytical method for characterizing skeletal muscle capillary architecture, highlighting caution in interpreting 2D data for capillary changes in T1DM
The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status
Get PDFIn the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER−/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/−, AR+/−). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%–50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC. The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody–drug conjugates (ADCs) for HER2-low breast cancers
Metabolic score tool for personalized acute pancreatitis prognosis: A multicenter analysis
Get PDFIncreasing evidence suggests that body composition is associated with the development of acute pancreatitis (AP). This study aimed to investigate the applicability of body composition in predicting AP severity. Data of 213 patients with AP from Affiliated Hospital of Putian University (AHOPTU) were included in this study, whilst data of 173 patients with AP from Fujian Medical University Union Hospital (FMUUH) were used for external validation. Patients were classified into the non-severe and severe groups according to AP severity. After seven days of treatment, in patients from AHOPTU, the difference in skeletal muscle index before and after treatment (ΔSMI) was significantly higher (P = 0.002), while the skeletal muscle radiodensity before treatment (PreSMR) was significantly lower (P = 0.042) in the non-severe group than in the severe group. The multivariate logistic regression model also revealed that the ΔSMI and PreSMR were independent risk factors for AP severity. The optimal cut-off values of ΔSMI and PreSMR were 1.0 and 43.7, respectively. The following metabolic score (SMS) was established to predict AP severity: 0: ΔSMI < 1.0 and PreSMR < 43.7; 1: ΔSMI ≥ 1.0 and PreSMR < 43.7 or ΔSMI < 1.0 and PreSMR ≥ 43.7; 3: ΔSMI ≥ 1.0 and PreSMR ≥ 43.7. In patients from AHOPTU and FMUUH, the areas under the curves (AUC) for this model were 0.764 and 0.741, respectively. ΔSMI and PreSMR can accurately predict AP severity. It is recommended to routinely evaluate the statuses of patients with AP using the predictive model presented in this study for individualized treatment
Identifying key inflammatory genes in psoriasis via weighted gene co-expression network analysis: Potential targets for therapy
Get PDFPsoriasis is a globally prevalent chronic inflammatory skin disease. This study aimed to scrutinize the hub genes related to inflammation and potential molecular mechanisms in psoriasis. Utilizing mRNA expression profiles from public datasets GSE13355, GSE78097, and GSE14905, we set up a comprehensive analysis. Initially, we selected differentially expressed genes (DEGs) from psoriasis and control samples in GSE13355, followed by calculating inflammatory indices using genomic set variation analysis (GSVA). Weighted gene co-expression network analysis (WGCNA) was then applied to link significant modules with the inflammatory index. This process helped us identify differentially expressed inflammation-related genes (DE-IRGs). A protein-protein interaction (PPI) network was established, with the molecular complex detection (MCODE) plug-in pinpointing six chemokine genes (CCR7, CCL2, CCL19, CXCL8, CXCL1, and CXCL2) as central hub genes. These genes demonstrated pronounced immunohistochemical staining in psoriatic tissues compared to normal skin. Notably, the CCR7 gene exhibited the highest potential for m6A modification sites. Furthermore, we constructed transcription factor-microRNA-mRNA networks, identifying 139 microRNAs and 52 transcription factors associated with the hub genes. For the LASSO logistic regression model, the area under the curve (AUC) in the training set was 1, and in the two validation cohorts GSE78097 and GSE14905 were 1 and 0.872, respectively. In conclusion, our study highlights six chemokine genes (CCR7, CCL2, CCL19, CXCL8, CXCL1, and CXCL2) as potential biomarkers in psoriasis, providing insights into the immune and inflammatory responses as pivotal instances in disease pathogenesis. These findings pave the way for exploring new therapeutic targets, particularly focusing on chemokine-associated pathways in psoriasis treatment