Exploring the Impact of Different Inflammatory Cytokines on Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infection is a global health concern affecting millions worldwide. Chronic HCV infection often leads to liver inflammation and can progress to cirrhosis and hepatocellular carcinoma. Inflammatory cytokines are crucial in modulating the immune response during HCV infection. This review aims to investigate the impact of different inflammatory cytokines on HCV infection and associated immune responses. This review was conducted to identify relevant studies on the interplay between inflammatory cytokines and HCV infection. The analysis focused on the effects of key inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), and interferon-gamma (IFN-γ), on HCV replication, immune cell activation, and liver inflammation. The findings reveal that these inflammatory cytokines can significantly influence HCV infection and the subsequent immune response. TNF-α, IL-6, and IL-1 have been shown to enhance HCV replication, while IFN-γ exerts antiviral effects by inhibiting viral replication and promoting immune cell-mediated clearance of infected hepatocytes. Moreover, these cytokines contribute to the recruitment and activation of immune cells, such as natural killer cells, T cells, and macrophages, which play critical roles in controlling HCV infection. Understanding the precise mechanisms by which inflammatory cytokines impact HCV infection is crucial for developing more targeted therapeutic strategies. Modulating the levels or activity of specific cytokines may provide opportunities to attenuate HCV replication, reduce liver inflammation, and improve treatment outcomes. In conclusion, this review highlights the significance of inflammatory cytokines in influencing HCV infection and associated immune responses.

Overexpression of miRNA 26a and 26b with MMP-9 are valuable diagnostic biomarkers for colorectal cancer patients.

Background: The key role of miRNA expression in incidence and progression of colorectal cancer (CLC) have been developed over the last decade. Materials & methods: A total of 153 subjects were enrolled into two phases: 14 selected miRNAs were first evaluated in 50 subjects, then miR-26a and miR-26b relative expression were further evaluated in 103 subjects and their target protein MMP-9 was measured. Results: miR-26a and -26b showed highly significant overexpression. Both miR-26a and -26b (p < 0.001) had high diagnostic efficacy for CRC. There was a significant increase in serum MMP-9 protein in CRC patients with positive correlation with miR-26a and -26b expression levels (p < 0.001). Conclusion: miRNA 26a and 26b with MMP-9 can be used as diagnostic biomarker for CRC patients.

Molecules called miRNAs, found in blood, have a key role in colon cancer progression. This evidence highlights the importance of studying the role of some miRNAs in colorectal cancer (CRC) patients. miRNAs are one of the most recent targets for CRC screening and prognosis. miR-26a and -26b showed high overexpression in CRC patients. Results showed that both miR-26a and -26b had high diagnostic efficacy for CRC.

The impact of genetic variations in sofosbuvir metabolizing enzymes and innate immunity mediators on treatment outcome in HCV-infected patients.

Hepatitis C virus (HCV) is the leading cause of liver diseases worldwide. At present, combinations of different classes of direct-acting antiviral agents (DAAs) are used as treatment options for HCV, in which sofosbuvir (SOF) is the common DAA among different therapeutic regimes. In Egypt, SOF plus daclatasvir (DCV) is the widely used anti-HCV treatment protocol. Herein, we aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) at the genes coding for 2 SOF metabolizing enzymes: histidine triad nucleotide-binding protein 1 (HINT1) rs4696/rs7728773 and nucleoside diphosphate kinase 1 (NME1) rs3760468, together with the most potent anti-HCV innate molecule, i.e., interferon lambda 3 (IFNL3) rs12979860 and the response to SOF/DCV in Egyptian patients chronically infected with genotype 4 (GT4). SNPs were genotyped using real-time PCR in DNA from patients who achieved sustained virological response (SVR) at 12 weeks post-SOF/DCV treatment (i.e., responders; n = 188), patients who failed to achieve SVR12 (i.e., non-responders; n = 109), and healthy controls (n = 62). Our results demonstrated that patients bearing HINT1 rs7728773 CT/TT (odds ratio 2.119, 95% CI 1.263-3.559, p = 0.005) and IFNL3 rs12979860 CC (odds ratio 3.995, 95% CI 2.126-7.740, p = 0.0001) were more likely to achieve SVR12. However, neither HINT1 rs4696 nor NME1 rs3760468 seems to contribute to the responsiveness to SOF/DCV. Binary regression analysis defined 5 predictor factors independently associated with SVR12: age, bilirubin, hemoglobin, early stages of fibrosis, and combined HINT1 rs7728773 and IFNL3 rs12979860 favorable and mixed genotypes (odds ratio 3.134, 95% CI 1.518-6.47, p = 0.002), and that was confirmed by the combined ROC curve for the 5 predictor factors (AUC = 0.91, 95% CI 0.869-0.95, P = 0.0001). In conclusion, these data suggest that the two SNPs have the potential in predicting the response rate to SOF/DCV treatment in patients infected with HCV GT4. This study is the first to investigate the pharmacogenetics of SOF metabolizing enzyme and introduce HINT1 rs7728773 as a novel SNP that predicts the treatment efficacy.

The potential value of miRNA-223 as a diagnostic biomarker for Egyptian colorectal patients.

OBJECTIVES: Colorectal cancer (CRC) is the third lethal malignancy worldwide. Dysregulation of microRNAs (miRNAs) mediates several growth factors signaling pathways and induces abnormal genes expression, which leads to colorectal carcinogenesis. We aimed to comprehensively assess the expression of miRNA-200c, miRNA-203a, miRNA-223 in Egyptian CRC tissue and their corresponding serum samples and to explore if they have any potential prognostic or diagnostic value for CRC patients. METHODS: A total of 195 subjects (120 CRC patients and 75 healthy controls) participated in exploration and validation sets. The relative expression of miRNA-200c, miRNA-203a, and miRNA-223 was measured in both CRC tissue and serum samples, and the expressed miRNAs were compared in different CRC grades and types and the prognostic value was evaluated. RESULTS: The expression levels of miRNA-200c and miRNA-203a were reduced in CRC tissue samples than adjacent noncancerous tissues. miRNA-223 level was significantly upregulated in both CRC tissue and serum samples with a positive association between them (r = 0.85, P = 0.001). The miRNA-223 can effectively discriminate CRC patients from controls and can significantly differentiate between colon and rectal cancer patients. The association between serum miRNA-223 expression and CRC development was validated in the second set and the ROC curve showed highly significant prognostic value with 90.1% sensitivity, 87% specificity, and area under the curve of 0.914 (95% confidence interval: 0.830-0.978, P = 0.0001). These results showed the association between miRNA-223 upregulation and the CRC carcinogenesis. CONCLUSION: Circulating miRNA-223 can be a potential noninvasive prognostic biomarker for Egyptian CRC patients.

Differential Expression of miR-21, miR-23a, and miR-27a, and Their Diagnostic Significance in Egyptian Colorectal Cancer Patients.

Background: Colorectal cancer (CRC) rates are affected by genetics, ethnicity, and environmental factors; it is considered one of the most aggressive human malignancies with high mortality and morbidity rates worldwide due, in part, to its asymptomatic nature during the early stages of disease. Objective: Owing to the impact of microRNA (miRNA) dysregulation on CRC development and progression, this study was conducted to explore the expression levels of mir-21, -23a, and -27a in the sera and tissues of Egyptian CRC patients and to evaluate their diagnostic efficacy based on circulating levels. Methods: In the test phase, the relative expression levels of the studied miRNAs were evaluated in the sera of 70 participants (35 CRC patients and 35 healthy controls) using quantitative real-time-polymerase chain reaction and to verify their diagnostic value. The exploratory phase was designed to validate the tumor-derived trait by comparing the miRNA levels in the cancerous and adjacent noncancerous tissues. Results: The relative expression levels of the studied miRNAs were significantly upregulated in both serum and tumor tissues of the patients compared to their corresponding controls. In addition, significant positive correlations were found between the relative expression levels of the studied miRNAs in serum samples and their levels in the matched CRC tissues. The serum expression levels of mir-21 and -23a were more predictive of CRC than mir-27a. Conclusion: Circulating mir-21, -23a, and -27a expression levels appear to be valuable diagnostic biomarkers for CRC, especially when combined.

MicroRNAs expression profiling in Egyptian colorectal cancer patients.

Egypt has increased incidence and high rate of early onset colorectal cancer (CRC). This study aimed to profile the expression levels of 84 circulating microRNAs (miRNAs) in Egyptian CRC patients and to evaluate the diagnostic accuracy of some selected miRNAs as diagnostic biomarkers for CRC patients. A total of 129 subjects (84 CRC patients and 45 healthy controls) were enrolled in two independent sample sets: the screening set (39 subjects) and the validation set (90 subjects). The expression profiles of 84 miRNAs were studied by miRNA PCR array in the screening set. Then four miRNAs (let-7c, 21, 26a, 146a) were selected to be studied by quantitative real-time PCR in the validation set. The PCR array results revealed significant up regulation of 20 miRNAs and downregulation of two miRNAs in CRC patients compared to the healthy subjects. Moreover, the expression levels of the four selected miRNAs were significantly higher in CRC serum samples than controls. The ROC analysis revealed that miRNAs (let-7c, 21, 26a and 146a) can effectively discriminate between CRC patients and the controls. The combination of the four miRNAs showed AUC of 0.950 (95% CI [0.898-1.002], p = .001). However, the combination of miR-21 and miR-26a showed the best diagnostic accuracy with AUC of 0.953 (95% CI [0.908-0.999], p = .001). The current data suggest that miRNAs (let-7c, 21, 26a, 146a) could play an important role in CRC development and they can be used as diagnostic biomarkers for CRC.

The Synergistic Effect of TNFα -308 G/A and TGFß1 -509 C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients.

Tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta (TGFß1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNFα -308 G/A and TGFß1 -509 C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNFα -308 G/A and TGFß1 -509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNFα and TGFß1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n = 36) and late (F2-F4, n = 36) HCV fibrosis patients showed that late fibrosis patients had higher TNFα -308 AA genotype and TGFß1 -509 TT genotype than early fibrosis patients (p = 0.016, 0.028, respectively). Moreover, the TNFα and TGFß1 serum levels were significantly higher in HCV patients with TNFα A containing genotypes (GA+AA) (p = 0.004) and patients with TGFß1 T containing genotypes (CT+TT) (p = 0.001), respectively. The combined unfavorable TNFα (GA/AA) and TGFß1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p = 0.023, 0.029). The multivariate analysis results confirmed that the combined TNFα-308 (AA) and TGFß1 -509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p = 0.013). In conclusion, both TNFα -308 G/A and TGFß1 -509 C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.

Tumor necrosis factor-α -G308A polymorphism is associated with liver pathological changes in hepatitis C virus patients.

AIM: To investigate the association of tumor necrosis factor alpha (TNFα) -G308A polymorphism with different liver pathological changes in treatment-naïve Egyptian patients infected with hepatitis C virus (HCV) genotype 4. METHODS: This study included 180 subjects, composed of 120 treatment-naïve chronic HCV patients with different fibrosis grades (F0-F4) and 60 healthy controls. The TNFα -G308A region was amplified by PCR and the different genotypes were detected by restriction fragment length polymorphism analysis. The TNFα protein was detected by enzyme-linked immunosorbent assay. The influence of different TNFα -G308A genotypes on TNFα expression and liver disease progression were statistically analyzed. The OR and 95%CI were calculated to assess the relative risk confidence. RESULTS: Current data showed that the TNFα -G308A SNP frequency was significantly different between controls and HCV infected patients (P = 0.001). Both the AA genotype and A allele were significantly higher in late fibrosis patients (F2-F4, n = 60) than in early fibrosis patients (F0-F1, n = 60) (P = 0.05, 0.04 respectively). Moreover, the GA or AA genotypes increased the TNFα serum level greater than the GG genotype (P = 0.002). The results showed a clear association between severe liver pathological conditions (inflammation, steatosis and fibrosis) and (GA + AA) genotypes (P = 0.035, 0.03, 0.04 respectively). The stepwise logistic regression analysis showed that the TNFα genotypes (GA + AA) were significantly associated with liver inflammation (OR = 3.776, 95%CI: 1.399-10.194, P = 0.009), severe steatosis (OR = 4.49, 95%CI: 1.441-14.0, P = 0.010) and fibrosis progression (OR = 2.84, 95%CI: 1.080-7.472, P = 0.034). Also, the A allele was an independent risk factor for liver inflammation (P = 0.003), steatosis (P = 0.003) and fibrosis (P = 0.014). CONCLUSION: TNFα SNP at nucleotide -308 represents an important genetic marker that can be used for the prognosis of different liver pathological changes in HCV infected patients.