Comprehensive investigation of malignant epithelial cell-related genes in clear cell renal cell carcinoma: development of a prognostic signature and exploration of tumor microenvironment interactions.

Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy with complex heterogeneity within epithelial cells, which plays a crucial role in tumor progression and immune regulation. Yet, the clinical importance of the malignant epithelial cell-related genes (MECRGs) in ccRCC remains insufficiently understood. This research aims to undertake a comprehensive investigation into the functions and clinical relevance of malignant epithelial cell-related genes in ccRCC, providing valuable understanding of the molecular mechanisms and offering potential targets for treatment strategies. Using data from single-cell sequencing, we successfully identified 219 MECRGs and established a prognostic model MECRGS (MECRGs' signature) by synergistically analyzing 101 machine-learning models using 10 different algorithms. Remarkably, the MECRGS demonstrated superior predictive performance compared to traditional clinical features and 92 previously published signatures across six cohorts, showcasing its independence and accuracy. Upon stratifying patients into high- and low-MECRGS subgroups using the specified cut-off threshold, we noted that patients with elevated MECRGS scores displayed characteristics of an immune suppressive tumor microenvironment (TME) and showed worse outcomes after immunotherapy. Additionally, we discovered a distinct ccRCC tumor cell subtype characterized by the high expressions of PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) and SAA1 (Serum Amyloid A1), which we further validated in the Renji tissue microarray (TMA) cohort. Lastly, 'Cellchat' revealed potential crosstalk patterns between these cells and other cell types, indicating their potential role in recruiting CD163 + macrophages and regulatory T cells (Tregs), thereby establishing an immunosuppressive TME. PLOD2 + SAA1 + cancer cells with intricate crosstalk patterns indeed show promise for potential therapeutic interventions.

Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy.

There are estimated 300 million people afflicted with chronic hepatitis B (CHB) worldwide. The risk of liver cirrhosis and hepatocellular carcinoma (HCC) increases considerably with chronic hepatitis B infection. While current therapeutics are effective in controlling hepatitis B virus (HBV) infection and disease progression, a cure for HBV infection remains unattainable due to an intranuclear replicative intermediate known as covalently closed circular DNA (cccDNA). It has recently been shown that serum HBV RNA is a non-invasive biomarker that reflects cccDNA transcriptional activity. This review provides a comprehensive overview and the latest updates on the molecular characteristics and clinical significance of serum HBV RNA, such as species of serum HBV RNA, forms of serum HBV RNA carriers and predictive value for relapses in CHB patients after nucleos(t)ide analogues (NAs) discontinuation and development of liver fibrosis and HCC. Furthermore, we summarize standardized assays for testing serum HBV RNA, the dynamic changes of serum HBV RNA levels in treatment-naïve CHB patients and those under NAs therapy, as well as the host and viral influencing factors of serum HBV RNA levels. Finally, we discuss the future perspectives in studies of serum HBV RNA.

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling.

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

Enhancer dependence of cell-type-specific gene expression increases with developmental age.

How overall principles of cell-type-specific gene regulation (the "logic") may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type-specific regulation employs different cis elements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer-promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type-specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.

Neddylation inhibitor MLN4924 has anti-HBV activity via modulating the ERK-HNF1α-C/EBPα-HNF4α axis.

Hepatitis B virus (HBV) infection is a major public health problem. The high levels of HBV DNA and HBsAg are positively associated with the development of secondary liver diseases, including hepatocellular carcinoma (HCC). Current treatment with nucleos(t)ide analogues mainly reduces viral DNA, but has minimal, if any, inhibitory effect on the viral antigen. Although IFN reduces both HBV DNA and HBsAg, the serious associated side effects limit its use in clinic. Thus, there is an urgent demanding for novel anti-HBV therapy. In our study, viral parameters were determined in the supernatant of HepG2.2.15 cells, HBV-expressing Huh7 and HepG2 cells which transfected with HBV plasmids and in the serum of HBV mouse models with hydrodynamic injection of pAAV-HBV1.2 plasmid. RT-qPCR and Southern blot were performed to detect 35kb mRNA and cccDNA. RT-qPCR, Luciferase assay and Western blot were used to determine anti-HBV effects of MLN4924 and the underlying mechanisms. We found that treatment with MLN4924, the first-in-class neddylation inhibitor currently in several phase II clinical trials for anti-cancer application, effectively suppressed production of HBV DNA, HBsAg, 3.5kb HBV RNA as well as cccDNA. Mechanistically, MLN4924 blocks cullin neddylation and activates ERK to suppress the expression of several transcription factors required for HBV replication, including HNF1α, C/EBPα and HNF4α, leading to an effective blockage in the production of cccDNA and HBV antigen. Our study revealed that neddylation inhibitor MLN4924 has impressive anti-HBV activity by inhibiting HBV replication, thus providing sound rationale for future MLN4924 clinical trial as a novel anti-HBV therapy.

Adolescent exposure to environmental level of PCBs (Aroclor 1254) induces non-alcoholic fatty liver disease in male mice.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants found in various environmental media, and there is growing evidence that PCBs may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The purposes of this study were to investigate whether environmental level of Aroclor 1254 (a commercial mixture of PCBs) exposure to adolescent male mice could induce the development of NAFLD and the mechanisms involved. Twenty-one-day-old male C57BL/6 mice were exposed to Aroclor 1254 (0.5-500 µg/kg body weight) by oral gavage once every third day for 60 days. The results showed that exposure to Aroclor 1254 increased body weight and decreased the liver-somatic index in a dose-dependent manner. Aroclor 1254 administration increased lipid accumulation in the liver and induced the mRNA expression of genes associated with lipogenesis, including acetyl-CoA carboxylase 1 (Acc1), acetyl-CoA carboxylase 2 (Acc2) and fatty acid synthase (Fasn). Moreover, Aroclor 1254 decreased peroxisome proliferator-activated receptor alpha (PPARα) signaling and lipid oxidation. In addition, we found that Aroclor 1254 administration induced oxidative stress in mouse liver and elevated the protein level of cyclooxygenase 2 (COX-2), an inflammatory molecule, possibly via the endoplasmic reticulum (ER) stress inositol-requiring enzyme 1α-X-box-binding protein-1 (IRE1α-XBP1) pathway, but not the nuclear factor-κB (NF-κB) pathway. In summary, adolescent exposure to environmental level of PCBs stimulated oxidative stress, ER stress and the inflammatory response and caused NAFLD in male mice. This work provides new insight into the idea that adolescent exposure to environmental level of PCBs might induce the development of NAFLD under the regulation of ER stress in males.

MicroRNA-141 Targets Sirt1 and Inhibits Autophagy to Reduce HBV Replication.

BACKGROUND/AIMS: About 400 million individuals are chronically infected with hepatitis B virus, at high risk of developing liver cirrhosis and hepatocellular carcinoma. Recent studies have demonstrated an interaction between hepatitis B virus replication and autophagy activity of hepatocytes. In the present study, we aimed to investigate the role of miR-141 in regulating autophagy and hepatitis B virus replication. METHODS: The expression of HBV-DNA, miR-141 and Sirt1 mRNA was determined by quantitative real-time PCR analysis. The expression of HBsAg and HBeAg was determined by ELISA. Western blotting was performed to detect protein expression. The LC3 puncta was determined by immunofluorescence. To test whether miR-141 directly regulate the expression level of Sirt1 mRNA, dual-luciferase reporter gene assay was performed. RESULTS: In vitro studies showed that miR-141 mimic inhibited the autophagic response, hepatitis B virus and the expression of Sirt1 in hepatocytes. And transfection with miR-141 inhibitor enhanced autophagic response and Sirt1 expression. The autophagy induced by overexpression of Sirt1 was inhibited by miR-141 mimic. In addition, miR-141 mimic also decreased the expression of Sirt1 mRNA. Sirt1 was predicted as a potential miR-141 target by bioinformatic analysis of its 3'-UTR, and confirmed by luciferase reporter assays which analyzing the interaction of miR-141 with the wild- type or the mutated Sirt1 3'-UTR. CONCLUSION: We have therefore demonstrated a role of miR-141 in regulating autophagy-mediated hepatitis B virus inhibition by targeting Sirt1, and may provide potential targets for drug development.

5-FU promotes HBV replication through oxidative stress-induced autophagy dysfunction.

BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation is a major problem that must be overcome during chemotherapy for HBV-related hepatocellular carcinoma (HCC). However, the mechanism underlying chemotherapy-associated HBV reactivation is still not fully understood, hindering the development of improved HBV-related HCC treatments. METHODS: A meta-analysis was performed to assess the HBV reactivation risk during transcatheter arterial chemoembolization (TACE). To investigate the regulatory effects and mechanisms of 5-FU on HBV replication, an HBV mouse model was established by pAAV-HBV1.2 hydrodynamic injection followed by intraperitoneal 5-FU injection, and different in vitro models (HepG2.2.15 or Huh7 cells) were established. Realtime RT‒qPCR, western blotting, luciferase assays, and immunofluorescence were used to determine viral parameters. We also explored the underlying mechanisms by RNA-seq, oxidative stress evaluation and autophagy assessment. RESULTS: The pooled estimated rate of HBV reactivation in patients receiving TACE was 30.3 % (95 % CI, 23.1%-37.4 %). 5-FU, which is a chemotherapeutic agent commonly used in TACE, promoted HBV replication in vitro and in vivo. Mechanistically, 5-FU treatment obviously increased autophagosome formation, as shown by increased LC3-II levels. Additionally, 5-FU impaired autophagic degradation, as shown by marked p62 and mCherry-GFP-LC3 upregulation, ultimately promoting HBV replication and secretion. Autophagy inhibition by 3-methyladenine or chloroquine significantly altered 5-FU-induced HBV replication. Furthermore, 5-FU-induced autophagy and HBV replication were markedly attenuated with a reactive oxygen species (ROS) scavenger. CONCLUSIONS: Together, our results indicate that ROS-induced autophagosome formation and autophagic degradation play a critical role in 5-FU-induced HBV reactivation.

Recent progress in the synthesis of transition metal nitride catalysts and their applications in electrocatalysis.

Transition metal nitrides (TMNs) have become excellent substitutes for precious metals such as Pt and Ir in the field of electrocatalysis because of their excellent electrocatalytic performance, high conductivity, good corrosion resistance and stability. As we all know, the commonly utilized carbon-based materials corrode easily during electrocatalysis, which will lead to catalyst falling off and agglomeration. Compared with carbon-based materials, TMNs have stronger corrosion resistance and higher stability. In the metal nitrides, a variety of chemical bonds (metal bond, ionic bond and covalent bond) coexist, among which the ionic bond between metal atoms and nitrogen atoms can make the d-band shrink and narrow, which leads to TMNs having characteristics similar to precious metals in the electrocatalytic process; thus, they can be used as a substitute for precious metal catalysts. In this paper, the synthesis method and catalytic principle of transition metal nitrides and their applications in the fields of hydrogen evolution reaction (HER), oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) are discussed, and the shortcomings of TMNs as a catalyst, the challenges faced in catalyst research and the developments and prospects for the future are pointed out.

Hyperoside prevents high-fat diet-induced obesity by increasing white fat browning and lipophagy via CDK6-TFEB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum perforatum L. (genus Hypericum, family Hypericaceae) is a flowering plant native to Europe, North Africa and Asia, which can be used in the treatment of psychiatric disorder, cardiothoracic depression and diabetes. Crataegus pinnatifida Bunge (genus Crataegus pinnatifida Bunge, family Rosaceae) was another traditional Chinese medicine for treating hyperlipidemia. Hyperoside (Hype), a major flavonoid glycoside component of Hypericum perforatum L. and Crataegus pinnatifida Bunge, possesses multiple physiological activities, such as anti-inflammatory and antioxidant effects. However, the role of Hype on obesity and related metabolic diseases still needs to be further investigated. AIM OF THE STUDY: We explored the effect of Hype on high-fat diet (HFD)-induced obesity and its metabolic regulation on white fat tissues. MATERIALS AND METHODS: In vivo four-week-old male C57BL/6J mice were randomly assigned to vehicle (0.5% methycellulose) and Hype (80 mg/kg/day by gavage) group under a normal chow diet (NCD) or HFD for 8 weeks. In vitro, 3T3-L1 preadipocyte cell line and primary stromal vascular fraction (SVF) cells from inguinal white adipose tissue (iWAT) of mice were used to investigate the molecular mechanisms of Hype regulation on adipocyte energy metabolism. RESULTS: Hype treatment in vivo promotes UCP1-dependent white to beige fat transition, increases glucose and lipid metabolism, and resists HFD-induced obesity. Meanwhile, Hype induces lipophagy, a specific autophagy that facilitates the breakdown of lipid droplets, and blocking autophagy partially reduces UCP1 expression. Mechanistically, Hype inhibited CDK6, leading to the increased nuclear translocation of TFEB, while overexpression of CDK6 partially reversed the enhancement of UCP1 by Hype. CONCLUSIONS: Hype protects mice from HFD-induced obesity by increasing energy expenditure of white fat tissue via CDK6-TFEB pathway.

Acteoside improves adipocyte browning by CDK6-mediated mTORC1-TFEB pathway.

Adipocyte browning increases energy expenditure by thermogenesis, which has been considered a potential strategy against obesity and its related metabolic diseases. Phytochemicals derived from natural products with the ability to improve adipocyte thermogenesis have aroused extensive attention. Acteoside (Act), a phenylethanoid glycoside, exists in various medicinal or edible plants and has been shown to regulate metabolic disorders. Here, the browning effect of Act was evaluated by stimulating beige cell differentiation from the stromal vascular fraction (SVF) in the inguinal white adipose tissue (iWAT) and 3T3-L1 preadipocytes, and by converting the iWAT-SVF derived mature white adipocytes. Act improves adipocyte browning by differentiation of the stem/progenitors into beige cells and by direct conversion of mature white adipocytes into beige cells. Mechanistically, Act inhibited CDK6 and mTOR, and consequently relieved phosphorylation of the transcription factor EB (TFEB) and increased its nuclear retention, leading to induction of PGC-1α, a driver of mitochondrial biogenesis, and UCP1-dependent browning. These data thus unveil a CDK6-mTORC1-TFEB pathway that regulates Act-induced adipocyte browning.

Comparison of partial nephrectomy and radical nephrectomy for cystic renal cell carcinoma: a SEER-based and retrospective study.

Cystic renal cell carcinoma (cRCC) is uncommon and surgical indication remains controversial. We compared radical nephrectomy (RN) with partial nephrectomy (PN) in patients with cRCC using data from the Surveillance, Epidemiology and End Results (SEER) database and a retrospective cohort including 106 cRCC patients hospitalized in Ruijin and Renji Hospitals from 2013 to 2022. The baseline characteristics between RN and PN groups in both cohorts were adjusted by propensity score-matching (PSM). A total of 640 patients were included in the SEER cohort. Before PSM, PN group in the SEER cohort had a lower level of T stage (p < 0.001) and comprised more Caucasians (p < 0.001). After PSM, RN was associated with worse overall survival (p < 0.001) and cancer-specific survival (p = 0.006) in contrast to PN. In the Chinese cohort, 86 patients who underwent PN and 20 patients who underwent RN were finally included. The mean proportions of estimated glomerular filtration rate preserved after RN were worse than PN. Therefore, PN should be preferred in cRCC patients.

Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1.

In this study, we aim to determine cellular mechanisms linking nutrient metabolism to the regulation of inflammation and insulin resistance. The nutrient sensors AMP-activated protein kinase (AMPK) and SIRT1 show striking similarities in nutrient sensing and regulation of metabolic pathways. We find that the expression, activity, and signaling of the major isoform alpha1AMPK in adipose tissue and macrophages are substantially down-regulated by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), and diet-induced obesity. Activating AMPK signaling in macrophages by 5-aminoimidazole-4-carboxamide-1-beta4-ribofuranoside or constitutively active alpha1AMPK (CA-alpha1) significantly inhibits; although inhibiting alpha1AMPK by short hairpin RNA knock-down or dominant-negative alpha1AMPK (DN-alpha1) increases LPS- and FFA-induced tumor necrosis factor alpha expression. Chromatin immunoprecipitation and luciferase reporter assays show that activation of AMPK by CA-alpha1 in macrophages significantly inhibits LPS- or FFA-induced NF-kappaB signaling. More importantly, in a macrophage-adipocyte co-culture system, we find that inactivation of macrophage AMPK signaling inhibits adipocyte insulin signaling and glucose uptake. Activation of AMPK by CA-alpha1 increases the SIRT1 activator NAD(+) content and SIRT1 expression in macrophages. Furthermore, alpha1AMPK activation mimics the effect of SIRT1 on deacetylating NF-kappaB, and the full capacity of AMPK to deacetylate NF-kappaB and inhibit its signaling requires SIRT1. In conclusion, AMPK negatively regulates lipid-induced inflammation, which acts through SIRT1, thereby contributing to the protection against obesity, inflammation, and insulin resistance. Our study defines a novel role for AMPK in bridging the signaling between nutrient metabolism and inflammation.

Distinct Bile Acid Profiles in Patients With Chronic Hepatitis B Virus Infection Reveal Metabolic Interplay Between Host, Virus and Gut Microbiome.

Hepatitis B virus (HBV) can hijack the host bile acids (BAs) metabolic pathway during infection in cell and animal models. Additionally, microbiome was known to play critical role in the enterohepatic cycle of BAs. However, the impact of HBV infection and associated gut microbiota on the BA metabolism in chronic hepatitis B (CHB) patients is unknown. This study aimed to unveil the distinct BA profiles in chronic HBV infection (CHB) patients with no or mild hepatic injury, and to explore the relationship between HBV, microbiome and BA metabolism with clinical implications. Methods: Serum BA profiles were compared between CHB patients with normal ALT (CHB-NALT, n = 92), with abnormal ALT (CHB-AALT, n = 34) and healthy controls (HCs, n = 28) using UPLC-MS measurement. Hepatic gene expression in CHB patients were explored using previously published transcriptomic data. Fecal microbiome was compared between 30 CHB-NALT and 30 HCs using 16S rRNA sequencing, and key microbial function was predicted by PICRUSt analysis. Results: Significant higher percentage of conjugated BAs and primary BAs was found in CHB patients even without apparent liver injury. Combinatory BA features can discriminate CHB patients and HCs with high accuracy (AUC = 0.838). Up-regulation of BA importer Na+ taurocholate co-transporting peptide (NTCP) and down-regulation of bile salt export pump (BSEP) was found in CHB-NALT patients. The microbial diversity and abundance of Lactobacillus, Clostridium, Bifidobacterium were lower in CHB-NALT patients compared to healthy controls. Suppressed microbial bile salt hydrolases (BSH), 7-alpha-hydroxysteroid dehydrogenase (hdhA) and 3-dehydro-bile acid Delta 4, 6-reductase (BaiN) activity were found in CHB-NALT patients. Conclusion: This study provides new insight into the BA metabolism influenced both by HBV infection and associated gut microbiome modulations, and may lead to novel strategy for clinical management for chronic HBV infection.

Emerging relationship between RNA helicases and autophagy.

RNA helicases, the largest family of proteins that participate in RNA metabolism, stabilize the intracellular environment through various processes, such as translation and pre-RNA splicing. These proteins are also involved in some diseases, such as cancers and viral diseases. Autophagy, a self-digestive and cytoprotective trafficking process in which superfluous organelles and cellular garbage are degraded to stabilize the internal environment or maintain basic cellular survival, is associated with human diseases. Interestingly, similar to autophagy, RNA helicases play important roles in maintaining cellular homeostasis and are related to many types of diseases. According to recent studies, RNA helicases are closely related to autophagy, participate in regulating autophagy, or serve as a bridge between autophagy and other cellular activities that widely regulate some pathophysiological processes or the development and progression of diseases. Here, we summarize the most recent studies to understand how RNA helicases function as regulatory proteins and determine their association with autophagy in various diseases.

Methods for Establishment and Maintenance of Germ-Free Rat Models.

Numerous studies have demonstrated that the gut microbiota plays a vital role in human health and disease development. Although the number of studies on host-microbiota interactions have increased in recent years, the underlying pathogenesis of dysbiosis-related diseases are still largely unknown. Germ-free (GF) rodent models, with the animals housed in sterile isolators and completely free of microbiota, are useful tools to advance our understanding of host-microbiota relationship in vivo. Although protocols concerning the establishment and maintenance of GF mouse models have previously been reported, the establishment, maintenance and monitoring of GF rodents are labor-intensive, tedious and take experience and skills. The aim of our study was to establish a GF rat model for the following microbiota-related researches and provide an easy-to-use protocol for the establishment and maintenance of GF rat model in detail, including steps to set up the isolator, sterilize the flexible isolator bubble, import food, water and other supplies, and methods to acquire newborn GF rats, hand rearing of suckling GF rats and reproduction of GF offspring. During the hand feeding period, the body weight of suckling GF rats was weighed once a day to ascertain the amount of artificial milk was given. Based on our results, the body weight of suckling GF rats decreased 1 week after birth and then began to increase. Methods for verifying the quality of the model like assessing the sterile status of the rat colony are also described. Moreover, possible difficulties and challenges, especially during gavage, and suggestions to avoid contamination will be discussed. The protocol presented will facilitate the establishment of GF rat models and downstream microbiota-related researches.

DHX15 Inhibits Autophagy and the Proliferation of Hepatoma Cells.

Autophagy is a highly conserved process by which superfluous or harmful components in eukaryotic cells are degraded by autophagosomes. This cytoprotective mechanism is strongly related to various human diseases, such as cancer, autoimmune diseases, and diabetes. DEAH-box helicase 15 (DHX15), a member of the DEAH box family, is mainly involved in RNA splicing and ribosome maturation. Recently, DHX15 was identified as a tumor-related factor. Although both autophagy and DHX15 are involved in cellular metabolism and cancer progression, their exact relationship and mechanism remain elusive. In this study, we discovered a non-classic function of DHX15 and identified DHX15 as a suppressive protein in autophagy for the first time. We further found that mTORC1 is involved in DHX15-mediated regulation of autophagy and that DHX15 inhibits proliferation of hepatocellular carcinoma (HCC) cells by suppressing autophagy. In conclusion, our study demonstrates a non-classical function of DHX15 as a negative regulator of autophagy related to the mTORC1 pathway and reveals that DHX15-related autophagy dysfunction promotes HCC cell proliferation, indicating that DHX15 may be a target for liver cancer treatment.

The protective effects of Nile tilapia (Oreochromis niloticus) scale collagen hydrolysate against oxidative stress induced by tributyltin in HepG2 cells.

Oxidative stress is regarded as one of the most important factors associated with many diseases, such as atherosclerosis, cancer, and diabetes. Various chemicals are released into the environment, causing environmental pollution. Importantly, many of them may cause damage to organisms through oxidative stress. In this work, we investigated the possible protective effects of Nile tilapia (Oreochromis niloticus) scale collagen hydrolysate (TSCH) (molecular weight approximately 4 kDa) against tributyltin (TBT)-induced oxidative stress in vitro. The results showed that pretreatment with TSCH protected against decreases in cell viability and changes in cell morphology in HepG2 cells exposed to TBT. Treatment with TSCH reduced the TBT-induced elevation in malondialdehyde (MDA) levels in HepG2 cells in a dose-dependent manner. Pretreatment with TSCH increased glutathione reductase (GR) and superoxide dismutase (SOD) activity. Moreover, TSCH decreased the expression of the proapoptotic protein Bax, reducing apoptosis. These results suggest that the protective mechanism of TSCH may be associated with its ability to scavenge MDA, increase antioxidant enzyme activity and downregulate the expression of Bax.

The role of HBV-induced autophagy in HBV replication and HBV related-HCC.

Hepatitis B virus (HBV) is infecting about 364 million people around the world. It can cause various diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, the present anti-viral treatment in clinics is limited; studies for new therapies are highly desired. Autophagy is a crucial and major catabolic process in the maintenance of normal intracellular homeostasis in host cells. Host cells use this unique process to degrade and recycle long-lived proteins, damaged organelles, and various pathogens for keeping the normal physiological functions. Recently, published studies indicated that HBV can induce autophagy in host cells; this autophagic response is involved in viral replication and pathogenesis. Several viral proteins, such as surface and X proteins, are assumed to be responsible for inducing autophagy in HBV infection. This review briefly summarizes some important mechanisms involved in HBV-induced autophagy and provides a novel perspective on therapies of HBV infection and HBV-related HCC.

Protective effects of fucoxanthin and fucoxanthinol against tributyltin-induced oxidative stress in HepG2 cells.

Tributyltin (TBT) is a biocide extremely toxic to a wide range of organisms, which has been used for decades for industrial purposes. Fucoxanthin is a natural carotenoid that is isolated from seaweed, and fucoxanthinol is a major primary metabolite of fucoxanthin. Although fucoxanthin and fucoxanthinol have been reported to possess anti-oxidant activities in vitro, little is known as to whether they protect against TBT-induced oxidative stress in cultured cells. In the present study, the protective effect of fucoxanthin and fucoxanthinol against oxidative stress induced by TBT was investigated. The data showed that incubation of HepG2 cells with 0.2 µM TBT significantly increased cell apoptosis, whereas treatment with fucoxanthin or fucoxanthinol (3 µM) significantly recovered cell viability. In addition, fucoxanthinol treatment significantly decreased the intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) in HepG2 cells incubated with TBT. Moreover, fucoxanthin and fucoxanthinol markedly increased the expression level of Bcl-2/Bax. These results demonstrated that both fucoxanthin and fucoxanthinol effectively prevented cytotoxicity in HepG2 cells treated with TBT, and the protective effect was likely associated with decreased intracellular ROS and MDA and increased Bcl-2/Bax levels.