5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

<b><i>Introduction:</i></b> Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease. Dysregulation of circulating miRNAs has been reported, suggesting their pathological roles in DKD. This study aimed to investigate differentially expressed miRNAs in the sera of type 2 diabetes mellitus (T2DM) patients with and without albuminuria in a selected Malaysian population. <b><i>Method:</i></b> Forty-one T2DM patients on follow-up at a community clinic were divided into normo-(NA), micro-(MIC), and macroalbuminuria (MAC) groups. Differential levels of miRNAs in 12 samples were determined using the pathway-focused (human fibrosis) miScript miRNA qPCR array and was validated in 33 samples, using the miScript custom qPCR array (CMIHS02742) (Qiagen GmbH, Hilden, Germany). <b><i>Results:</i></b> Trends of upregulation of 3 miRNAs in the serum, namely, miR-874-3p, miR-101-3p, and miR-145-5p of T2DM patients with MAC compared to those with NA. Statistically significant upregulation of miR-874-3p (<i>p</i> = 0.04) and miR-101-3p (<i>p</i> = 0.01) was seen in validation cohort. Significant negative correlations between the estimated glomerular filtration rate (eGFR) and miR-874-3p (<i>p</i> = 0.05), miR-101-3p (<i>p</i> = 0.03), and miR-145-5p (<i>p</i> = 0.05) as well as positive correlation between miR-874-3p and age (<i>p</i> = 0.03) were shown by Pearson’s correlation coefficient analysis. <b><i>Conclusion:</i></b> Upregulation of previously known miRNA, namely, miR-145-5p, and possibly novel ones, namely, miR-874-3p and miR-101-3p in the serum of T2DM patients, was found in this study. There was a significant correlation between the eGFR and these miRNAs. The findings of this study have provided encouraging evidence to further investigate the putative roles of these differentially expressed miRNAs in DKD.

Long non-coding RNAs (lncRNAs) are non-coding RNAs consisting of more than 200 nucleotides in length. LncRNAs present in exosomes may play a critical role in the cellular processes involved in cancer pathogenesis and progression including proliferation, invasion, and migration of tumor cells. This paper aims to identify the differential expression of exosomal lncRNAs derived from the sera of non-cancer individuals and patients diagnosed with colorectal carcinoma. These differentially-expressed exosomal serum lncRNAs may provide an insight into the pathogenesis and progression of colorectal cancer (CRC). Serum exosomes and exosomes from SW480-7 cell culture supernatants were isolated and viewed by transmission electron microscope (TEM). The particle size distribution and protein markers of exosomes derived from SW480-7 were further analyzed using the Zetasizer Nano S instrument and western blotting technique. TEM showed that exosomes derived from serum and SW480-7 cells were round vesicles with sizes ranging from 50–200 nm. The exosomes derived from SW480-7 had an average diameter of 274.6 nm and contained the exosomal protein, ALIX/PDCD6IP. In our clinical studies, six lncRNAs, namely GAS5, H19, LINC00152, SNHG16, RMRP, and ZFAS1 were detected in the exosomes from sera of 18 CRC patients. Among these six lncRNAs, the expression level of LINC00152 was found to be significantly lower in CRC patients as compared to non-cancer individuals (p = 0.04) while lncRNA H19 was significantly up-regulated in advanced-stages (stage III and IV) of CRC (p = 0.04) as compared to early-stages (stage I and II). In conclusion, the detection of lower LINC00152 in exosomes of sera from CRC patients versus non-cancer individuals and H19 upregulation in advanced stages suggests that they may play important roles in pathogenesis and progression of CRC.

Introduction: Diabetic kidney disease (DKD) is a major global cause of end-stage-kidney disease. In view of its ongoing risk of disease progression, the search for a better biomarkers and treatment led to the discovery of microRNAs which regulate gene expression post-translationally. Recently, we reported a trend of upregulation of miR-145-5p in sera of type 2 diabetic patients with macroalbuminuria in a selected Malaysian population, which concurred with previous in vivo and in vitro studies of DKD. In addition, miR-145 has been implicated as a tumour suppressor in various cancers. Methods: In this study, bioinformatics tools were utilized to predict the mRNA targets of miR-145-5p. Results: A total of 683 and 224 experimentally-validated mRNA targets of miR-145-5p were identified by Tarbase and miRTarbase, respectively. Eighty-six (86) commonly identified targets were submitted to Metascape and Enrichr for enrichment analysis. Bioinformatics analysis and literature search suggested that insulin receptor substrate 1 (IRS1) was the most promising target of miR-145-5p. Its associated Gene Ontology terms and pathways included insulin-like growth factor receptor signalling and Forkhead transcription factors (FOXO), respectively. Based on these analyses, the roles of IRS1 in DKD were proposed. Conclusion: As the kidneys are heterogenous in cell types and the mechanism of miRNA is cell-type-dependent, target prediction of miR-145-5p by bioinformatics analysis is particularly important in DKD, to improve the likelihood of a successful in vitro experimental verification in specific renal cell types. In addition, this study attempts to utilize bioinformatics studies, which is not widely done in DKD, as recently reported.

Introduction: Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. Current biomarkers and treatment still fall short at preventing its progression. In search for a better diagnostic or therapeutic target, much interest in microRNAs, which act as post-translational regulators of gene expression has emerged. An upregulation of miR-101-3p was identified in the sera of type 2 diabetic patients with macroalbuminuria in a selected Malaysian population by profiler RT-PCR array. Using bioinformatics tools, this study aimed to predict the mRNA targets of miR-101-3p. Given the scarcity of bioinformatics studies in DKD, this study also attempted to fill the gap. Methods: The mRNA targets were identified from two experimentally validated databases, namely Tarbase and MirTarBase. The commonly identified mRNA targets were submitted to Metascape and Enrichr bioinformatic tools. Results: A total of 2630 and 342 mRNA targets of miR-101-3p were identified by Tarbase and miRTarbase, respectively. One-hundred ninety-seven (197) mRNA targets were submitted for functional enrichment analysis. Our bioinformatics and bibliographical analyses suggested that ras-related C3 botulinum toxin substrate 1 (RAC1) and Ras-associated protein-1 b (RAP1b) were the most promising putative mRNA targets of miR-101-3p. The most enriched Gene Ontology term and pathway associated with these putative mRNA targets included Ras protein signal transduction and focal adhesion, respectively. Based on these analyses, their molecular mechanisms were proposed. Conclusion: Given the structural heterogeneity of the kidneys and cell type-dependent miRNA modulation, an in-silico target prediction of miR-101-3p increases the probability of a successful future in-vitro experimental verification.