Rapidly proliferating cancer cells exhibit a high energy demand. However, their utilization of the glycolytic pathway is inefficient, leading to a compensatory effect wherein cancer cells consume ten to twenty times more glucose than normal cells. In cases where glucose availability is limited due to a poorly perfused hypoxic microenvironment, cancer cells resort to alternative energy sources, including fructose. Certain tumors have been found to rely heavily on fructose, and fructose utilization contributes to pro-tumoral signaling and increased cancer risk. Over the past 70 years, dietary fructose intake has steadily increased, resulting in a rise in obesity and metabolic syndrome, both of which elevate cancer risk. In this paper, we present compelling evidence that highlights the role of fructose and the glucose transporter GLUT5 in promoting specific types of tumors. We summarize the existing evidence and pathways through which fructose contributes to cancer metabolism, particularly in cases where glucose availability is restricted. Furthermore, we propose a hypothesis that elucidates the regulation of the lipogenic phenotype by dietary fructose intake and cellular energy status. It is important to note that the effects of fructose are context-dependent, with its tumor-promoting effects varying based on the energy status of the cell. We comprehensively analyze why targeting fructose uptake and fructolysis should be important for the management of some tumors and cancer prevention. Full article

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed countries, contributing to ∼24% of cases worldwide and includes non-alcoholic steatohepatitis. NAFLD is characterized by lipid accumulation rather than alcohol consumption. There are several diagnostic/prognostic biomarkers for NAFLD including CK-18, ALT, AST, GGT, and haptoglobin, but with limited sensitivity and specificity. Therefore, high-throughput OMICS approaches have been used to characterize NAFLD conditions for the identification of potential molecular signatures or differentially regulated molecules (DEMs) and early detection of NAFLD. We analyzed the publically available data set (accession number: GSE63067) from the Gene Expression Omnibus (GEO) using the GEO2R program. The differentially expressed genes (DEGs) were filtered using the criteria where genes with p-value ≤0.05 and fold-change ≥2.0-fold (upregulated), and fold-change ≤0.5-fold (downregulated). We identified 264 differentially expressed genes (DEGs) between NAFLD and normal liver tissue samples, where 211 were upregulated and 53 were downregulated in NAFLD. Additionally, we identified novel genes SGMS2, and WNK3 that were not well understood in the molecular pathophysiology of NAFLD. Further gene ontology-based analysis revealed that among biological processes, cellular components, and molecular functions were also dysregulated in NAFLD. Collectively, this integration of a systemic-cum-meta-analysis approach suggests that an OMICS-based analysis may provide better solutions if microarray and other high-throughput study-based DEMs are to be cataloged systematically for sharing with the scientific community. This will allow potential candidates (DEMs) to be interrogated either alone or in combination with existing biomarkers for effective early detection and or diagnosis of NAFLD. Our study shows that meta-analysis of publicly available data could be a good source for identification of DEGs in NAFLD, and it can be easily extrapolated in other disease conditions. Full article

Radiotherapy is the most crucial nonsurgical therapeutic method in the multidisciplinary care of non-small cell lung cancer (NSCLC) patients. However, radiation resistance continues to be a significant clinical issue, negatively affecting cancer prognosis in patients. The small molecules that target these RNAs offer therapeutic modulation of multiple biological processes. The study aims to identify the genes and a long non-coding RNA (lncRNA) regulating their expression and binding potential of small volatile inhibitors to the lncRNA to overcome radioresistance in NSCLC. The non-coding RNA microarray dataset of NSCLC cells was analysed to identify the differentially expressed genes regulated by lncRNA driving radioresistance. The study comprises three volatile ligands due to their good pharmacokinetic profile to target the identified lncRNA. The analysis revealed the dysregulation of the cell cycle, evasion of apoptosis and cancer immune response. A co-expression analysis with a network pharmacology approach revealed a lncRNA ENST00000605056 regulating three highly ranked hub genes. The molecular interaction studies uncovered their high binding affinity to its binding pocket with a preponderance of non-covalent bond interactions between the ligand and the nucleotides. The molecular dynamics simulations revealed the binding stability of ligands to the lncRNA with a very low deviation compared to the control. This study demonstrated the ability of the small molecules to target lncRNA in overcoming the global concern of radioresistance among NSCLC patients and aid in future translational studies. Full article

With the improvement of living standards in recent years, up to 90% of obese patients have nonalcoholic fatty liver disease (NAFLD). The number of nonalcoholic steatohepatitis (NASH)-related deaths will gradually increase, and NASH is expected to be the most common cause of liver-related deaths in the future. Therefore, there is an urgent need to find effective and reliable serum biomarkers to distinguish simple hepatic steatosis (SS) from NASH. Liver cell regeneration, oxidative stress-induced DNA methylation, and biliary epithelial cell proliferation were reported to increase serum alpha-fetoprotein (AFP) levels. AFP has long been used as a tool to monitor liver cancer. However, the function of AFP in NAFLD, especially NASH, has not been clarified. Moreover, whether an elevated AFP level indicates the occurrence of NASH or serves as a serum biomarker remains to be elucidated. The miRNA-122 pathway, DNA methylation and DNA damage, and activation of resident stem cells and/or progenitor cells in the liver, as well as necrosis, regeneration, and repair of liver cells, may contribute to slight increases in AFP levels in the development of NASH in patients with NAFLD. Furthermore, mildly elevated AFP levels may indicate the development of NASH. This review explores the role of elevated AFP levels in the development of NASH, with a specific focus on the underlying molecular mechanisms and the clinical significance. Full article

Diabetes mellitus (DM) is an established risk for biliary tract cancer (BTC). Metformin, an anti-diabetes medication, has been reported for its association with a reduced risk of BTC. However, the controversy about metformin’s benefit among epidemiological studies is unresolved. This study is to investigate metformin’s effects on the development and progression of BTC. Literature searches were performed, without language restriction, in Pubmed, Embase, and Web of Science, from their respective inceptions to February 28, 2023. All studies were screened by two researchers using Covidence. Quality assessment was performed using the Newcastle-Ottawa Scale. Meta-analyses were performed by a fixed and random-effect model using RevMan version 5.4. Nine observational studies met the inclusion criteria and were included in the meta-analysis. With pooled samples of 24,743,526 individuals from 4 case-control and 2 cohort studies, metformin was not associated with a decreased risk of BTC (pooled RR: 0.82, 95% CI: 0.42–1.59, p = 0.56). Sub-group analyses in each study design also revealed a null effect of metformin. Meta-analysis of 3 cohort studies reporting the association between metformin and survival of patients with BTC with a pooled sample of 1,163 patients showed a marginally significant effect of metformin on survival outcome improvement in both fixed effect models (pooled RR: 0.83, 95% CI: 0.68–1.00, p = 0.05), and random-effect model (pooled RR: 0.83, 95% CI: 0.68–1.01, p = 0.07). Meta-analyses of available observational studies showed that metformin was neither significantly associated with decreased risk nor, survival improvement for BTC patients who had DM. Full article

Hepatocellular carcinoma (HCC) is one of the most lethal and widespread cancers in the human race. Despite its fatal attributes, there is only a limited understanding of the factors contributing to its pathogenesis at the cellular and molecular levels. Consequently, unraveling new facets involved in HCC progression is elemental for establishing novel targets and biomarkers for this disease. Over the last few years, emerging evidence signifies the role of RNA-induced silencing complex in mediating gene silencing and contributing to HCC. Recent studies also highlight the importance of human telomerase holoenzyme and its complex accessory proteins in the development of HCC. The current review encompasses the multifaceted roles of RNA-induced silencing complex and telomerase activity as well as their synergistic function in HCC. Full article

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the leading causes of hepatic fibrosis and liver-related mortality worldwide, despite efficient hepatitis B and C antiviral therapies that have dramatically lowered the disease load. Although significant efforts have been exerted to understand the molecular basis of disease pathogenesis, there are currently few therapeutic alternatives available for NAFLD-associated fibrosis. Thus, NAFLD prevention is critical before the development of disease-related complications. In this context, there is a tremendous substantial global burden on public health systems to actively search for effective preventive and therapeutic targets for NAFLD. In this review, we highlight the current strategies to prevent progression and poor outcomes of NAFLD and to avoid complications associated with disease fibrosis, notably cirrhosis, portal hypertension, and liver cancer. We discuss different nonpharmacological measures, such as lifestyle modifications (weight loss, exercise, healthy diet) and other pharmacological interventions that could prevent NAFLD. Full article

Today, medicinal plants and phytobiotics that contain flavonoids, alkaloids, and essential oils are widely used in animal feed. These additives have many benefits, including increasing liver function and preventing certain diseases. The liver is one of the organs that plays a key role in insulin-mediated regulation of metabolism as well as in glucose, whole-body, and lipid homeostasis. The aim of this study was to investigate the effect of fennel (Foeniculum vulgare) seed powder consumption on insulin-like growth factor 1 (IGF1) gene expression in the liver tissue of growing lambs. Three groups (including 0, 10, and 20 g/kg dry matter of fennel) of animals, with 10 animals in each group, were studied. The Pfaffl method was applied to assess the real-time polymerase chain reaction (qPCR) output. Mixing fennel into the feed of lambs increased the weights of their testis and gallbladder and decreased the weight of their liver in comparison to feed without fennel. It was also found that by increasing the fennel level in the feed, the expression level of IGF1 in the liver increased significantly (p < 0.05). Fennel had a useful effect on the expression of IGF1 in the liver tissue of sheep and may be applied to their diet to attain better liver function. Full article

The liver contributes substantially to the metabolic transformation and transport of lipids and lipoproteins. These bioactive substances represent a heterogeneous group of molecules with pivotal roles in diverse pathological processes as well as disease progression, the advent of complications, and the response to specific treatments in the context of cirrhosis. The present mini-review aims to summarize the underlying mechanisms regarding lipid changes across divergent circumstances. Recent evidence suggests the prognostic value of lipids/lipoproteins and their close relationship to an increased risk for morbidity and mortality among cirrhotic patients. However, more research regarding the development of risk stratification and therapeutic strategies based on altered lipid profiles in patients with cirrhosis is warranted. Full article