PGC-1α loss promotes mitochondrial protein lactylation in acetaminophen-induced liver injury via the LDHB-lactate axis.

Coronavirus disease 2019 (COVID-19) affected people worldwide, and fever is one of the major symptoms of this disease. Although Acetaminophen (APAP) is a common fever-reducing medication, it can also mediate liver injury. However, the role of PGC-1α in regulating mitochondrial quality control by lactate dehydrogenase B (LDHB), a vital enzyme catalyzing the conversion of lactate to pyruvate, in APAP-induced hepatotoxicity, is unclear. Here, gene expression omnibus data of patients with APAP-induced liver injury were used to explore gene expression profiles. AML12 cells and C57/BL6 mice were used to establish models of APAP-induced acute liver injury. SIRT1 and PGC-1α were overexpressed in vitro via lentiviral transfection to establish stable cell lines. The results showed that APAP treatment decreased SIRT1/PGC-1α/LDHB expression and increased protein lactylation, mitochondrial lactate levels, and pathological damage in liver mitochondria. PGC-1α upregulation or activation ameliorated APAP-induced damage in the cells and liver. Furthermore, PGC-1α overexpression increased LDHB synthesis, reduced lactylation, and induced a switch from lactate to pyruvate production. These results suggest that PGC-1α and LDHB play a role in APAP-induced liver injury by regulating mitochondrial quality control and lactate metabolic reprogramming. Therefore, the PGC-1α/LDHB axis is a potential therapeutic target for APAP-induced liver injury.

FXR/ASS1 axis attenuates the TAA-induced liver injury through arginine metabolism.

Previous studies demonstrated that arginine biosynthesis was frequently impaired in acute liver injury. However, the underlying mechanisms remain elusive. In this study, we found that Argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine metabolism, was downregulated in the TAA-induced liver injury model. Single-cell RNA-seq data found that ASS1 was highly enriched in the hepatocytes. The reduction of ASS1 was attributed to the decreased expression of Farnesoid X receptor (FXR), which is a bile acid-activated nuclear hormone receptor with high expression in the liver. Subsequent studies demonstrated that activation of FXR by its agonist obeticholic acid (OCA) directly promoted ASS1 transcription and enhanced arginine synthesis, leading to the alleviation of TAA-mediated liver injury. Further experiments found that OCA, ASS1, and arginine supplement can rescue TAA-mediated hepatocytes apoptosis by decreasing the protein levels of Cyto C, PARP, and Caspase 3. Taken together, our study illustrated a protective role of the FXR/ASS1 axis in TAA-induced liver injury by targeting arginine metabolism, which might shed light on the development of novel therapeutic approaches for acute liver injury.

A synthesized olean-28,13ß-lactam targets YTHDF1-GLS1 axis to induce ROS-dependent metabolic crisis and cell death in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a severe malignant with a 5-year survival rate of approximately 9%. Oleanolic acid is a well-known natural triterpenoid which exhibits pharmacological activities. We previously synthesized a series of oleanolic acid derivatives and evaluated the tumor-suppressive activity of olean-28,13ß-lactam (B28) in prostate cancer. However, the detailed mechanism remains to be understood. METHODS: The anti-tumor activity of B28 in PAAD was confirmed by RTCA, colony formation assay and flow cytometry. GO and KEGG enrichment analyses were performed to analyze the differentially expressed genes (DEGs) obtained by RNA sequencing. The effects of B28 on cell bioenergetics were evaluated by seahorse analyzer. Lenti-virus packaged plasmids were performed to knockdown or overexpress target genes. Alteration of mitochondrial membrane potential, ROS and GSH/GSSG were measured by corresponding detection kits according to the manufacturer's protocol. RESULTS: We evaluated and confirmed the promising anti-tumor activity of B28 in vitro. RNA-seq profile indicated that multiple metabolic pathways were interrupted in B28 treated PAAD cells. Next, we demonstrated that B28 induces cellular bioenergetics crisis to inhibit PAAD cells growth and induce cell death. We further validated that cell cycle arrest, inhibition of cell growth, cell apoptosis and cell bioenergetics disruption were functionally rescued by ROS scavenger NAC. Mechanistically, we found glutamine metabolism was inhibited due to B28 administration. Moreover, we validated that down-regulation of GLS1 contributes to ROS generation and bioenergetics interruption induced by B28. Furthermore, we elucidated that YTHDF1-GLS1 axis is the potential downstream target of B28 to induce PAAD cell metabolic crisis and cell death. Finally, we also confirmed the anti-tumor activity of B28 in vivo. CONCLUSIONS: Current study demonstrates B28 disrupts YTDFH1-GLS1 axis to induce ROS-dependent cell bioenergetics crisis and cell death which finally suppress PAAD cell growth, indicating that this synthesized olean-28,13ß-lactam maybe a potent agent for PAAD intervention.

The Mechanism of miR-222 Targets Matrix Metalloproteinase 1 in Regulating Fibroblast Proliferation in Hypertrophic Scars.

This study aimed to investigate the value of miR-222 in hypertrophic scars (HS). Specific mechanisms were used to measure the level of miR-222, while MTT assay, flow cytometry, western blot and qRT-PCR were employed to detect the relative proteins after fibroblasts were transfected with the miR-222 mimic/inhibitor. The direct target of miR-222 was determined by Dual-Luciferase Reporter assay. Furthermore, qRT-PCR and western blot were employed to detect the matrix metalloproteinase 1 (MMP1) RNA/protein after fibroblasts were transfected with the miR-222 mimic/inhibitor. These results revealed that miR-222 was significantly upregulated in HS fibroblasts. The overexpression of miR-222 enhanced the HS fibroblast proliferation, increased the cell population in the S phase, inhibited the cell apoptosis, enhanced the expression levels of Col1A1, Col3A1 mRNA/protein, proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin E1 and CDK1 and reduced the expression levels of cleaved caspase-3/9. However, the miR-222 suppression triggered opposite effects. Furthermore, miR-222 played a regulatory role in HS by negatively regulating its target gene MMP1 by binding with its 3'-untranslated region. The overexpression of MMP1 reduced the expression levels of PCNA and cyclin D1, but enhanced the expression levels of cleaved caspase-3. Therefore, MiR-222 and MMP1 have potential value for HS. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis.

BACKGROUND: Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. However, the role of Notch1 in the formation of myofibroblasts and fibrosis in kidneys following injury remains unknown. METHODS: The activity of Notch1 signalling was evaluated in fibrotic kidneys in CKD patients and in ureteral obstructive models in vivo and in cultured fibroblasts and TECs in vitro. In addition, the crosstalk of Notch1 with TGF-ß1/Smad2/3 signalling was also investigated. RESULTS: Notch1 activity was elevated in fibrotic kidneys of rat models and patients with chronic kidney disease (CKD). Further study revealed that epithelial and interstitial Notch1 activity correlated with an α-SMA-positive myofibroblastic phenotype. In vitro, injury stimulated epithelial Notch1 activation and epithelial-mesenchymal transition (EMT), resulting in matrix deposition in tubular epithelial cells (TECs). Additionally, interstitial Notch1 activation in association with fibroblast-myofibroblast differentiation (FMD) in fibroblasts mediated a myofibroblastic phenotype. These TGF-ß1/Smad2/3-dependent phenotypic transitions were abolished by Notch1 knockdown or a specific antagonist, DAPT, and were exacerbated by Notch1 overexpression or an activator Jagged-1-Fc chimaera protein. Interestingly, as a major driving force behind the EMT and FMD, TGF-ß1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-ß1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis. CONCLUSION: These findings suggest that epithelial and interstitial Notch1 activation in kidneys following injury contributes to the myofibroblastic phenotype and fibrosis through the EMT in TECs and to the FMD in fibroblasts by targeting downstream TGF-ß1/Smad2/3 signalling.

[microRNA-222 regulates proliferation and apoptosis of fibroblasts in hypertrophic scar via matrix metalloproteinase 1].

Objective: To explore the effect of microRNA(miR)-222 on cell proliferation and apoptosis of fibroblasts in hypertrophic scar (HS) and the underlying mechanisms. Methods: The expression of miR-222 in the HS and the normal skin tissues was detected by real-time RT-PCR. The HS fibroblasts were transfected with miR-222 mimic and miR-222 inhibitor respectively. The cell viability was tested with MTT assay, cell cycle distribution and apoptosis were detected with flow cytometry and the expression levels of proliferation, apoptosis and cell cycle related proteins were determined with Western blot. Direct target of miR-222 was evaluated by dual-luciferase reporter assay. Results: miR-222 was significantly up-regulated in HS tissues compared with normal skin tissues(P<0.05). Overexpression of miR-222 enhanced the cell viability of HS fibroblasts; increased mRNA and protein expressions of proliferating cell nuclear antigen (PCNA), collagen alpha-1 (Ⅰ) chain (Col1A1) and collagen alpha-1 (Ⅲ) chain (Col3A1); increased cell population in S phase and protein expressions of cyclin D1, cyclin E1 and cyclin-dependent kinases 1 (CDK1); inhibited cell apoptosis and reduced protein expressions of caspase-3/9. Overexpression of MMP1 attenuated the effects of miR-222 on the cell viability and apoptosis in fibroblasts, reduced expression levels of PCNA, cyclin D1 and the expression of caspase-3 was increased. Conclusion: miR-222 enhances cell proliferation and inhibits cell apoptosis of HS fibroblasts through negative regulation of MMP1, which suggests that miR-222 and MMP1 might be used as novel biomarkers and targets in diagnostic and therapeutic approaches for HS.

Inhibition of Macrophage Migration Inhibitory Factor Protects against Inflammation and Matrix Deposition in Kidney Tissues after Injury.

Background. Macrophage migration inhibitory factor (MIF) is an important immunoregulatory cytokine involved in inflammation, which may be one important reason resulting in matrix deposition in renal tissues after injury. However, the underlying mechanisms have not yet been elucidated. Methods and Results. We uncovered a crucial role of MIF in inflammation and collagen deposition in vivo and in vitro. In rats, ureteral obstruction induced tubular injury, matrix accumulation, and inflammatory cell infiltration. Additionally, enhanced MIF levels in the obstructed kidneys were closely related to the increasing numbers of CD68-positive macrophages. These obstruction-induced injuries can be relieved by recanalization, consequently resulting in downregulated expression of MIF and its receptor CD74. Similarly, ischemia reperfusion induced renal injury, and it was accompanied by elevated MIF levels and macrophages infiltration. In cultured tubular epithelial cells (TECs), aristolochic acid (AA) promoted matrix production and increased MIF expression, as well as the release of macrophage-related factors. Inhibition of MIF with an antagonist ISO-1 resulted in the abolishment of these genotypes in AA-treated TECs. Conclusion. MIF plays an important role in macrophage-related inflammation and matrix deposition in kidney tissues following injury. MIF as a specific inhibitor may have therapeutic potential for patients with inflammatory and fibrotic kidney diseases.

Targeting mitochondrial quality control: new therapeutic strategies for major diseases.

Mitochondria play a crucial role in maintaining the normal physiological state of cells. Hence, ensuring mitochondrial quality control is imperative for the prevention and treatment of numerous diseases. Previous reviews on this topic have however been inconsistencies and lack of systematic organization. Therefore, this review aims to provide a comprehensive and systematic overview of mitochondrial quality control and explore the possibility of targeting the same for the treatment of major diseases. This review systematically summarizes three fundamental characteristics of mitochondrial quality control, including mitochondrial morphology and dynamics, function and metabolism, and protein expression and regulation. It also extensively examines how imbalances in mitochondrial quality are linked to major diseases, such as ischemia-hypoxia, inflammatory disorders, viral infections, metabolic dysregulations, degenerative conditions, and tumors. Additionally, the review explores innovative approaches to target mitochondrial quality control, including using small molecule drugs that regulate critical steps in maintaining mitochondrial quality, nanomolecular materials designed for precise targeting of mitochondria, and novel cellular therapies, such as vesicle therapy and mitochondrial transplantation. This review offers a novel perspective on comprehending the shared mechanisms underlying the occurrence and progression of major diseases and provides theoretical support and practical guidance for the clinical implementation of innovative therapeutic strategies that target mitochondrial quality control for treating major diseases.

Decoding Organelle Interactions: Unveiling Molecular Mechanisms and Disease Therapies.

Organelles, substructures in the cytoplasm with specific morphological structures and functions, interact with each other via membrane fusion, membrane transport, and protein interactions, collectively termed organelle interaction. Organelle interaction is a complex biological process involving the interaction and regulation of several organelles, including the interaction between mitochondria-endoplasmic reticulum, endoplasmic reticulum-Golgi, mitochondria-lysosomes, and endoplasmic reticulum-peroxisomes. This interaction enables intracellular substance transport, metabolism, and signal transmission, and is closely related to the occurrence, development, and treatment of many diseases, such as cancer, neurodegenerative diseases, and metabolic diseases. Herein, the mechanisms and regulation of organelle interactions are reviewed, which are critical for understanding basic principles of cell biology and disease development mechanisms. The findings will help to facilitate the development of novel strategies for disease prevention, diagnosis, and treatment opportunities.

Versatile function of NF-ĸB in inflammation and cancer.

Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1ß, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.

Global longitudinal strain and the risk of major adverse cardiac events in post-myocardial infarction patients: A retrospective cohort study.

BACKGROUND: This study evaluates the relationship between global longitudinal strain (GLS) and late major adverse cardiovascular events (MACEs) in patients after acute myocardial infarction (AMI). METHODS: Data of newly diagnosed AMI patients between March 2010 and July 2014 were retrospectively evaluated. The patients underwent serial echocardiography at admission and at third and sixth months post-admission. We calculated GLS by averaging the strain from all myocardial segments using speckle-tracking echocardiography (STE). We used multivariate Cox regression analysis and receiver operating characteristic (ROC) curve analyses to assess the relationship between GLS at admission and late MACEs. RESULTS: Eighty-nine newly diagnosed AMI patients were enrolled. The average age at diagnosis was 61 ± 12.5 years, and approximately 89.9% of the patients were men. The average level of GLS was -17.5 ± 3.9%. The overall prevalence of MACEs was 23.6% (21/89), compared with 44% (11/25) in the group with GLS≥-15% and 17.9% (5/28) in the group with GLS<-20%. GLS was positively linked with MACEs in the fully adjusted Cox proportional hazard model (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.04-1.37; P=0.014) after adjusting potential confounders. The ROC curve analysis for one year MACEs between GLS at admission, with the most significant area under the curve(AUC) 78.1% (95% CI, 63.8% - 92.6%). CONCLUSIONS: Myocardial dysfunction, characterized by impaired GLS, is often observed in AMI patients, and a decrease in GLS levels at admission were associated with an increased risk of long-term MACEs in post-myocardial infarction patients.

Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis.

Non-alcoholic steatohepatitis (NASH), a progressive form of non-alcoholic fatty liver disease (NAFLD), is characterised by chronic liver inflammation, which can further progress into complications such as liver cirrhosis and NASH-associated hepatocellular carcinoma (HCC) and therefore has become a growing health problem worldwide. The type I interferon (IFN) signaling pathway plays a pivotal role in chronic inflammation; however, the molecular mechanisms underlying NAFLD/NASH from the perspective of innate immune response has not yet been fully explored. In this study, we elucidated the mechanisms of how innate immune response modulates NAFLD/NASH pathogenesis, and demonstrated that hepatocyte nuclear factor-1alpha (HNF1A) was suppressed and the type I IFN production pathway was activated in liver tissues of patients with NAFLD/NASH. Further experiments suggested that HNF1A negatively regulates the TBK1-IRF3 signaling pathway by promoting autophagic degradation of phosphorylated-TBK1, which constrains IFN production, thereby inhibiting the activation of type I IFN signaling. Mechanistically, HNF1A interacts with the phagophore membrane protein LC3 through its LIR-docking sites, and mutations of LIRs (LIR2, LIR3, LIR4, and LIRs) block the HNF1A-LC3 interaction. In addition, HNF1A was identified not only as a novel autophagic cargo receptor but also to specifically induce K33-linked ubiquitin chains on TBK1 at Lys670, thereby resulting in autophagic degradation of TBK1. Collectively, our study illustrates the crucial function of the HNF1A-TBK1 signaling axis in NAFLD/NASH pathogenesis via cross-talk between autophagy and innate immunity.

CASMART, a one-step CRISPR Cas12a-mediated isothermal amplification for rapid and high-resolution digital detection of rare mutant alleles.

Convenient, ultrasensitive, and accurate detection of rare variants is essential for early cancer diagnosis and precision medicine, however, despite years of efforts, tools that have all these qualities remain elusive. Here, we developed a one-step CRISPR/Cas12a-based digital diagnostic platform for accurately quantifying mutant alleles, referred to as the CRISPR ASsoaciated Mutation Allele Rapid Test (CASMART). The platform accurately quantifies the variant allele frequency of EGFR L858R within 1 h at 42 °C and can detect mutant targets as low as 0.3 copies/µL (0.498 aM) in mock multiplex cfDNA samples. We further investigated the applicability of CASMART using human genomic samples with confirmed EGFR L858R mutations previously measured variant allele frequency by next-generation sequencing. Comparison across platforms revealed equivalent detection performance (Pearson's correlation coefficient, R2 = 0.9208) and high quantification accuracy for mutation allele frequency (intraclass correlation coefficient = 0.959). Our one-step approach enables easy and accurate variant allele frequency measurement of rare mutant alleles without PCR instrumentation, while the assay time was reduced by approximately half compared to the digital PCR with the shortest turnaround. The CASMART is an alternative to conventional single nucleotide polymorphism detection methods with great potential as a next-generation biosensor for rapidly quantifying the variant allele fraction, especially in resource-limited settings.

[Corrigendum] Anti­fibrotic effect of Sedum sarmentosum Bunge extract in kidneys via the hedgehog signaling pathway.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that certain of the data featured in Fig. 1A on p. 740 had already appeared in another publication written by the same authors [Sedum sarmentosum Bunge extract exerts renal anti­fibrotic effects in vivo and in vitro. Bai Y, Lu H, Wu C, Lin C, Liang Y and Chen B. Life Sci: 105, 22­30, 2014]. The authors have been able to re­examine their original data, and realized that certain of the data were misplaced in Fig. 1 in the above paper on account of mishandling their data. The revised version of Fig. 1 in shown on the next page, featuring the corrected data in Fig. 1A for the HE staining SSBE- and Vehicle-UUO experiments, and the Masson staining/SSBE and Vehicle/Sham and UUO experiments (all four data panels), the TGF-ß1 experiments in Fig. 1C (all four data panels) and the four data panels in Fig. 1D. Note that the errors made during the assembly of this figure did not adversely affect the overall conclusions reported in the study. The authors are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and all authors agree to the publication of this corrigendum. Furthermore, they wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 16: 737­745, 2017; DOI: 10.3892/mmr.2017.6628].

A novel circular RNA (hsa_circ_0059930)-mediated miRNA-mRNA axis in the lipopolysaccharide-induced acute lung injury model of MRC-5 cells.

Circular RNA (circRNA) is a class of newly discovered endogenous non-coding RNA with closed circular structure. Some circRNAs have been reported to be closely associated with acute lung injury (ALI). While the expression profile of circRNAs in lipopolysaccharide (LPS)-induced ALI and the underlying roles are still not completely clear. The LPS-induced ALI model of MRC-5 cells was first established, and the expression profiles of circRNAs and mRNAs in LPS-induced MRC-5 cells were confirmed through RNA sequencing analysis. Gene Ontologyanalysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were also applied to predict the latent functions and pathways of the differential mRNAs. After hsa_circ_0059930 knockdown, the proliferation and apoptosis of MRC-5 cells were identified by CCK-8, flow cytometer, and western blot assays. And we predicted the network analysis of hsa_circ_0059930. We testified that LPS could markedly prevent proliferation and induce apoptosis of MRC-5 cells. We discovered a total of 820 differential circRNAs (560 upregulated and 260 downregulated circRNAs) and 484 differential mRNAs (240 upregulated and 244 downregulated mRNAs) in LPS-induced MRC-5 cells. Besides, hsa_circ_0059930 was identified to be significantly upregulated in LPS-induced MRC-5 cells, and knockdown of hsa_circ-0059930 could notably accelerate proliferation and suppress apoptosis of LPS-mediated MRC-5 cells. Moreover, through the network analysis of hsa_circ_0059930, we preliminarily screened the potential regulatory axis hsa_circ_0059930/hsa-miR-382-5p/Topoisomerase 1 (TOP1) in LPS-induced ALI. Our data contribute to understand the importance of circRNAs and mRNAs in LPS-induced ALI. We also provided many hsa_circ_0059930-mediated microRNA (miRNA)-mRNA axis, especially hsa_circ_0059930/hsa-miR-382-5p/TOP1 in LPS-induced ALI.

Long non-coding RNA review and implications in acute lung inflammation.

Acute lung inflammatory diseases severely affect the patients' recovery and outcomes worldwide. Unregulated acute inflammatory response is fundamentally central to acute lung inflammation including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To limit the potentially deleterious effects of acute lung inflammation, complex transcriptional and posttranscriptional regulatory networks have been explored, which often involves long noncoding RNAs (lncRNA). LncRNAs are RNAs that longer than 200 nucleotides, functioning as scaffolds or decoys in the cytoplasm or nucleus. By now, lncRNAs have been found to join in all major cellular processes including cell proliferation, metabolism, stress response or death. Extensive advance over the last decade furthermore indicated a fundamental role of lncRNAs in acute lung inflammation. This article reviews and summarizes the current knowledge on lncRNA in acute lung inflammatory response.

Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/ß-catenin pathway.

Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/ß-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/ß-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer.

A Novel Mechanism of Cannabidiol in Suppressing Hepatocellular Carcinoma by Inducing GSDME Dependent Pyroptosis.

Cannabidiol (CBD), a phytochemical derived from Cannabis sativa L., has been demonstrated to exhibit promising anti-tumor properties in multiple cancer types. However, the effects of CBD on hepatocellular carcinoma (HCC) cells remain unknown. We have shown that CBD effectively suppresses HCC cell growth in vivo and in vitro, and induced HCC cell pyroptosis in a caspase-3/GSDME-dependent manner. We further demonstrated that accumulation of integrative stress response (ISR) and mitochondrial stress may contribute to the initiation of pyroptotic signaling by CBD. Simultaneously, CBD can repress aerobic glycolysis through modulation of the ATF4-IGFBP1-Akt axis, due to the depletion of ATP and crucial intermediate metabolites. Collectively, these observations indicate that CBD could be considered as a potential compound for HCC therapy.

Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer.

Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-ß, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.

Long noncoding RNA X-inactive specific transcript promotes malignant melanoma progression and oxaliplatin resistance.

Long noncoding RNA X-inactive specific transcript (XIST) was confirmed to participate in the development of many cancers. However, the function of XIST in malignant melanoma (MM) remained largely unknown. In the current study, we found that the XIST expression level was upregulated in MM tissues and cell lines. In addition, the growth rate of MM cells transfected with silencing XIST was significantly decreased compared with that with silencing normal control. XIST knockdown inhibited proliferation and migration in MM cells and increased the oxaliplatin sensitivity of oxaliplatin-resistant MM cells. Bioinformatics analysis showed that XIST acts as a molecular sponge for miR-21 and miR-21 directly targets with 3'-UTR of PI3KR1. Furthermore, XIST knockdown inhibited PI3KRI and AKT expression, and promoted Bcl-2 and Bax expression. In short, the current study showed that XIST was a crucial regulator in progression and oxaliplatin resistance of MM, providing a novel insight into the pathogenesis and underlying therapeutic target for MM.