MicroRNA signature in patients with hepatocellular carcinoma associated with type 2 diabetes

BACKGROUND Nonalcoholic steatohepatitis-related cirrhosis is one of the liver complications in type 2 diabetes mellitus(T2DM)and reported to be a risk factor for developing hepatocellular carcinoma(HCC).A reliable screening biomarker of liver cirrhosis(LC)and HCC among T2DM patients is important to reduce the morbidity and mortality of this disease.MicroRNA(miRNA)is considered a key player in HCC and T2DM,and it might be a hidden culprit in diabetes-associated HCC,making it a promising reliable prognostic tool.AIM To investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients.METHODS Expression profiles of miRNAs in serum samples of diabetic LC and diabetic HCC patients were assessed using Illumina sequencing;then,RT-qPCR was used to validate significantly altered miRNAs between the two groups.Candidate miRNAs were tested in serum samples of 200 T2DM patients,270 LC patients,200 HCC patients,and 225 healthy control subjects.Additionally,receiver operating characteristic(ROC)analysis,with area under the curve(AUC),was performed to assess the diagnostic performance of the screened miRNAs for discriminating HCC from LC and nonmalignant patients(LC+T2DM).RESULTS Expression of the sequenced miRNAs in serum was different in HCC vs LCpositive T2DM patients.Two miRNAs(miR-34a,miR-221)were significantly upregulated and five miRNAs(miR-16,miR-23-3p,miR-122-5p,miR-198,miR-199a-3p)were significantly down-regulated in HCC compared to LC patients.Analysis of ROC curve demonstrated that the combination of these seven miRNAs can be used as a reliable biomarker for detection of HCC in diabetic patients,as it could identify HCC with high diagnostic accuracy in diabetic LC patients(AUC=0.993)and in diabetic nonmalignant patients(AUC=0.961).CONCLUSION This study validates a panel of serum miRNAs that can be used as a reliable noninvasive screening biomarker of HCC among T2DM cirrhotic and noncirrhotic patients.The study recommends further research to shed light on a possible role of c-Met in T2DM-associated HCC via the miRNA regulatory pathway.

Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites

Background:Transmembrane 4 L six family member 5(TM4SF5)translocates subcellularly and functions metabolically,although it is unclear how intracellu-lar TM4SF5 translocation is linked to metabolic contexts.It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.Methods:Here,we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites(MLCSs),using in vitro cells and in vivo animal systems,via approaches by immunofluorescence,proximity labelling based proteomics analysis,organelle reconstitution etc.Results:Upon extracellular glucose repletion following depletion,TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8(FKBP8)and lysosomal TM4SF5.Proximity labeling showed molecular clustering of phospho-dynamic-related protein I(DRP1)and certain mitophagy receptors at TM4SF5-enriched MLCSs,leading to mitochondrial fis-sion and autophagy.TM4SF5 bound NPC intracellular cholesterol transporter 1(NPC1)and free cholesterol,and mediated export of lysosomal cholesterol to mitochondria,leading to impaired oxidative phosphorylation but intact tri-carboxylic acid(TCA)cycle andβ-oxidation.In mouse models,hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria,both with positive relations to liver malignancy.Conclusions:Our findings suggested that TM4SF5-enriched MLCSs regu-late glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming,presumably while hepatocellular carcinogenesis,recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial repro-gramming to support biomolecule synthesis in addition to glycolytic energetics.

Plant-derived nanovesicles: Current understanding and applications for cancer therapy

Plant-derived vesicles(PDVs)are membranous structures that originate from plant cells and are responsible for multiple physiological and pathological functions.In the last decade,PDVs have gained much attention for their involvement in different biological processes,including intercellular communication and defense response,and recent scientific evidence has opened a new avenue for their applications in cancer treatment.Nevertheless,much remains unknown about these vesicles,and current research remains inconsistent.This review aims to provide a comprehensive introduction to PDVs,from their biological characteristics to purification methods,and to summarize the status of their potential development for cancer therapy.

Emerging nanoformulation strategies for phytocompounds and applications from drug delivery to phototherapy to imaging

Over thousands of years,natural bioactive compounds derived from plants(bioactive phytocompounds,BPCs)have been used worldwide to address human health issues.Today,they are a significant resource for drug discovery in the development of modern medicines.Although many BPCs have promising biological activities,most of them cannot be effectively utilized in drugs for therapeutic applications because of their inherent limitations of low solubility,structural instability,short half-life,poor bioavailability,and non-specific distribution to organs.Researchers have utilized emerging nanoformulation(NF)technologies to overcome these limitations as they have demonstrated great potential to improve the solubility,stability,and pharmacokinetic and pharmacodynamic characteristics of BPCs.This review exemplifies NF strategies for resolving the issues associated with BPCs and summarizes recent advances in their preclinical and clinical applications for imaging and therapy.This review also highlights how innovative NF technologies play a leading role in next-generation BPC-based drug development for extended therapeutic applications.Finally,this review discusses the opportunities to take BPCs with meaningful clinical impact from bench to bedside and extend the patent life of BPC-based medicines with new formulations or application to new adjacent diseases beyond the primary drug indications.