Circ-EIF3I Promotes Hepatocellular Carcinoma Progression Through Modulating miR-361-3p/DUSP2 Axis.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers globally. Circular RNAs (circRNAs) have been implicated in the development of HCC. Previous studies have confirmed that circ-EIF3I plays an important role in the progress of lung cancer. Nevertheless, the biological functions of circ-EIF3I and the underlying mechanisms by which they regulate HCC progression remain unclear. In this study, the regulatory mechanism and targets were studied with bioinformatics analysis, luciferase reporting analysis, transwell migration, Cell Counting Kit-8, and 5-Ethynyl-2'-deoxyuridine analysis. In addition, in vivo tumorigenesis and metastasis assays were employed to evaluate the roles of circ-EIF3I in HCC. The result shows that the circ-EIF3I expression was increased in HCC cell line, which means that circ-EIF3I plays a role in the progression of HCC. Downregulation of circ-EIF3I suppressed HCC cells' proliferation and migration in both in vivo and in vitro experiments. Bioinformatics and luciferase report analysis confirmed that both miR-361-3p and Dual-specificity phosphatase 2 (DUSP2) were the downstream target of circ-EIF3I. The overexpression of DUSP2 or inhibition of miR-361-3p restored HCC cells' proliferation and migration ability after silence circ-EIF3I. Taken together, our study found that downregulation of circ-EIF3I suppressed the progression of HCC through miR-361-3p/DUSP2 Axis.

Protein lipidation in health and disease: molecular basis, physiological function and pathological implication.

Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli and internal changes. Among these, protein lipidations which refer to lipid attachment to proteins are prominent, which primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor and cholesterylation. Lipid attachment to proteins plays an essential role in the regulation of protein trafficking, localisation, stability, conformation, interactions and signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, and biomedical studies has consistently shown that protein lipidation is pivotal in the regulation of broad physiological functions and is inextricably linked to a variety of diseases. Decades of dedicated research have driven the development of a wide range of drugs targeting protein lipidation, and several agents have been developed and tested in preclinical and clinical studies, some of which, such as asciminib and lonafarnib are FDA-approved for therapeutic use, indicating that targeting protein lipidations represents a promising therapeutic strategy. Here, we comprehensively review the known regulatory enzymes and catalytic mechanisms of various protein lipidation types, outline the impact of protein lipidations on physiology and disease, and highlight potential therapeutic targets and clinical research progress, aiming to provide a comprehensive reference for future protein lipidation research.

Comprehensive analyses of solute carrier family members identify SLC12A2 as a novel therapy target for colorectal cancer.

As the largest transporter family impacting on tumor genesis and development, the prognostic value of solute carrier (SLC) members has not been elucidated in colorectal cancer (CRC). We aimed to identify a prognostic signature from the SLC members and comprehensively analyze their roles in CRC. Firstly, we downloaded transcriptome data and clinical information of CRC samples from GEO (GSE39582) and TCGA as training and testing dataset, respectively. We extracted the expression matrix of SLC genes and established a prognostic model by univariate and multivariate Cox regression. Afterwards, the low-risk and high-risk group were identified. Then, the differences of prognosis traits, transcriptome features, clinical characteristics, immune infiltration and drug sensitivity between the two groups were explored. Furthermore, molecular subtyping was also implemented by non-negative matrix factorization (NMF). Finally, we studied the expression of the screened SLC genes in CRC tumor tissues and normal tissues as well as investigated the role of SLC12A2 by loss of function and gain of function. As a result, we developed a prognostic risk model based on the screened 6-SLC genes (SLC39A8, SLC2A3, SLC39A13, SLC35B1, SLC4A3, SLC12A2). Both in the training and testing sets, CRC patients in the high-risk group had the poorer prognosis and were in the more advanced pathological stage. What's more, the high-risk group were enriched with CRC progression signatures and immune infiltration. Two groups showed different drug sensitivity. On the other hand, two distinct subclasses (C1 and C2) were identified based on the 6 SLC genes. CRC patients in the high-risk group and C1 subtype had a worse prognosis. Furthermore, we found and validated that SLC12A2 was steadily upregulated in CRC. A loss-of-function study showed that knockdown of SLC12A2 expression restrained proliferation and stemness of CRC cells while a gain-of-function study showed the contrary results. Hence, we provided a 6-SLC gene signature for prognosis prediction of CRC patients. At the same time, we identified that SLC12A2 could promote tumor progression in CRC, which may serve as a potential therapeutic target.

Relationship between observation time and detection rate of focal lesions in Esophagogastroduodenoscopy: a single-center, retrospective study.

BACKGROUND: Current studies have shown that longer observation time can improve neoplastic detection rate. This study aimed to clarify whether endoscopists with longer observation times can detect more focal lesions. METHODS: Based on the mean examination time for Esophagogastroduodenoscopy (EGD) without biopsy, endoscopists were divided into fast and slow groups, and the detection rate of focal lesions was compared between the two groups. Univariate analysis, multivariate analysis and restricted cubic spline were used to explore the factors of focal lesion detection rate. RESULTS: Mean examination time of EGD without biopsy was 4.5 min. The cut-off times used were 5 min. 17 endoscopists were classified into the fast (4.7 ± 3.6 min), and 16 into the slow (7.11 ± 4.6 min) groups. Compared with fast endoscopists, slow endoscopists had a higher detection rate of focal lesions (47.2% vs. 51.4%, P < 0.001), especially in the detection of gastric lesions (29.7% vs. 35.9%, P < 0.001). In univariate and multivariate analyses, observation time, patient age and gender, expert, biopsy rate, and number of images were factors in FDR. There is a nonlinear relationship between observation time and FDR. CONCLUSION: Longer examination time improves the detection rate of focal lesions. Observation time is an important quality indicator of the EGD examination.

Absorbed Bioactive Compounds Replicate Guanxin II-Induced Endothelium-Associated in/ex vivo Vasodilation.

OBJECTIVE: To develop an interference-free and rapid method to elucidate Guanxin II (GX II)'s representative vasodilator absorbed bioactive compounds (ABCs) among enormous phytochemicals. METHODS: The contents of ferulic acid, tanshinol, and hydroxysafflor yellow A (FTA) in GX II/rat serum after the oral administration of GX II (30 g/kg) were detected using ultra-performance liquid chromatography-mass spectrometry. Totally 18 rats were randomly assigned to the control group (0.9% normal saline), GX II (30 g/kg) and FTA (5, 28 and 77 mg/kg) by random number table method. Diastolic coronary flow velocity-time integral (VTI), i.e., coronary flow or coronary flow-mediated dilation (CFMD), and endothelium-intact vascular tension of isolated aortic rings were measured. After 12 h of exposure to blank medium or 0.5 mmol/L H2O2, endothelial cells (ECs) were treated with post-dose GX II of supernatant from deproteinized serum (PGSDS, 300 µL PGSDS per 1 mL of culture medium) or FTA (237, 1539, and 1510 mg/mL) for 10 min as control, H2O2, PGSDS and FTA groups. Nitric oxide (NO), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), superoxide dismutase (SOD), malondialdehyde (MDA) and phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS) were analyzed. PGSDS was developed as a GX II proxy of ex vivo herbal crude extracts. RESULTS: PGSDS effectively eliminates false responses caused by crude GX II preparations. When doses equaled the contents in GX II/its post-dose serum, FTA accounted for 98.17% of GX II -added CFMD and 92.99% of PGSDS-reduced vascular tension. In ECs, FTA/PGSDS was found to have significant antioxidant (lower MDA and higher SOD, P<0.01) and endothelial function-protective (lower VEGF, ET-1, P<0.01) effects. The increases in aortic relaxation, endothelial NO levels and phosphorylated PI3K/Akt/eNOS protein induced by FTA/PGSDS were markedly abolished by NG-nitro-L-arginine methyl ester (L-NA, eNOS inhibitor) and wortmannin (PI3K/AKT inhibitor), respectively, indicating an endothelium-dependent vasodilation via the PI3K/AKT-eNOS pathway (P<0.01). CONCLUSION: This study provides a strategy for rapidly and precisely elucidating GX II's representative in/ex vivo cardioprotective absorbed bioactive compounds (ABCs)-FTA, suggesting its potential in advancing precision ethnomedicine.

Sirtuin2 suppresses the polarization of regulatory T cells toward T helper 17 cells through repressing the expression of signal transducer and activator of transcription 3 in a mouse colitis model.

INTRODUCTION: Regulatory T cells (Tregs) play an important role in inflammatory bowel diseases (IBDs) through modulating intestinal inflammation. However, the factors affecting Treg function and plasticity during IBD progression are not thoroughly disclosed. The current study aims to reveal new molecular mechanisms affecting Treg plasticity. METHODS: A mouse strain, in which tdTomato and enhanced green fluorescent protein were under the control of the Foxp3 promoter and Il17a promoter, was established and subjected to colitis induction with dextran sulfate sodium. The existence of Tregs and IL-17-expressing Tregs (i.e., Treg/T helper 17 [Th17] cells) were observed and sorted from the spleen, mesenteric lymph nodes, and lamina propria by flow cytometry, followed by measuring Sirtuin2 (Sirt2) expression using quantitative reverse transcription polymerase chain reaction and Immunoblotting. Lentivirus-induced Sirt2 silencing was applied to determine the impact of Sirt2 on Treg polarization to Treg/Th17 cells and even Th17 cells. The effect of Sirt2 on Stat3 was analyzed by flow cytometry and immunoblotting. RESULTS: Sirt2 was highly expressed in lamina propria Tregs and it moderately suppressed Foxp3 expression as well as the immunosuppressive function of Tregs. Surprisingly, lentivirus-mediated Sirt2 silencing promoted the generation of Treg/Th17 cells out of Tregs. Sirt2 silencing also enhanced the generation of Th17 cells out of Tregs under the Th17 induction condition. Furthermore, Sirt2 inhibited Th17 induction by suppressing the protein level of the signal transducer and activator of transcription 3. CONCLUSION: Sirt2 suppresses Treg function but also inhibits Treg polarization toward Treg/Th17 cells and Th17 cells. The ultimate effect of Sirt2 on colitis might depend on the balance among Tregs, Treg/Th17 cells, and Th17 cells.

YAP represses intestinal inflammation through epigenetic silencing of JMJD3.

BACKGROUND: Epigenetics plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Some studies have reported that YAP is involved in inflammatory response and can regulate target genes through epigenetic modifications. JMJD3, a histone H3K27me3 demethylase, is associated with some inflammatory diseases. In this study, we investigated the role of YAP in the development of IBD and the underlying epigenetic mechanisms. RESULTS: YAP expression was significantly increased in both in vitro and in vivo colitis models as well as in patients with IBD. Epithelial-specific knockout of YAP aggravates disease progression in dextran sodium sulfate (DSS)-induced murine colitis. In the TNF-α-activated cellular inflammation model, YAP knockdown significantly increased JMJD3 expression. Coimmunoprecipitation experiments showed that YAP and EZH2 bind to each other, and chromatin immunoprecipitation-PCR (ChIP-PCR) assay indicated that silencing of YAP or EZH2 decreases H3K27me3 enrichment on the promoter of JMJD3. Finally, administration of the JMJD3 pharmacological inhibitor GSK-J4 alleviated the progression of DSS-induced murine colitis. CONCLUSION: Our findings elucidate an epigenetic mechanism by which YAP inhibits the inflammatory response in colitis through epigenetic silencing of JMJD3 by recruiting EZH2.

The effect of vitamin K supplementation on cardiovascular risk factors: a systematic review and meta-analysis.

Cardiovascular disease (CVD) is one of the most important diseases which controlling its related risk factors, such as metabolic and inflammatory biomarkers, is necessary because of the increased mortality risk of that. The aim of our meta-analysis is to reveal the general effect of vitamin K supplementation on its related risk factors. Original databases were searched using standard keywords to identify all randomized clinical trials (RCTs) investigating the effects of vitamin K on CVD. Pooled weighted mean difference (WMD) and 95 % confidence intervals (95 % CI) were achieved by random-model effect analysis for the best estimation of outcomes. The statistical heterogeneity was determined using the Cochran's Q test and I2 statistics. Seventeen studies were included in this systematic review and meta-analysis. The pooled findings showed that vitamin K supplementation can reduce homeostatic model assessment insulin resistance (HOMA-IR) (WMD: -0⋅24, 95 % CI: -0⋅49, -0⋅02, P = 0⋅047) significantly compared to the placebo group. However, no significant effect was observed on other outcomes. Subgroup analysis showed a significant effect of vitamin K2 supplementation compared to vitamin K1 supplementation on HOMA-IR. However, no significant effect was observed on other variables. Also, subgroup analysis showed no potential effect of vitamin K supplementation on any outcome and omitting any articles did not affect the final results. We demonstrated that supplementation with vitamin K has no effect on anthropometrics indexes, CRP, glucose metabolism, and lipid profile factors except HOMA-IR.

Diversity of evolution in MDR monophasic S. Typhimurium among food animals and food products in Southern China from 2011 to 2018.

The monophasic variant of Salmonella enterica serovar Typhimurium with the antigenic formula 1,4,[5],12:i:- is one of the most common pathogenic bacteria causing global food-borne outbreaks. However, the research on molecular characteristics and evolution of monophasic S. typhimurium in China is still lacking. In the current study, 59 monophasic S. typhimurium strains were isolated from food animals and food products in South China between 2011 and 2018. A total of 87.5 % of monophasic S. typhimurium isolates were grouped into one independent clade with other monophasic S. typhimurium strains in China distinct from other countries by phylogenomic analysis. These isolates possess variable genotypes, including multiple ARGs on plasmid IncHI2, diverse evolutions at the fljAB locus, and virulence factors. Our results suggest that the monophasic S. typhimurium isolates currently circulating in China might be an independent epidemic subtype.

RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4.

Reprogramming of lipid metabolism during hepatocarcinogenesis is not well elucidated. Here, we aimed to explore pivotal RNA-binding motif proteins (RBMs) in lipid metabolism and their therapeutic potential in hepatocellular carcinoma (HCC). Through bioinformatic analysis, we identified RBM45 as a critical gene of interest among differentially expressed RBMs in HCC, with significant prognostic relevance. RBM45 influenced the malignant biological phenotype and lipid metabolism of HCC cells. Mechanically, RBM45 promotes de novo lipogenesis in HCC by directly targeting two key enzymes involved in long-chain fatty acid synthesis, ACSL1 and ACSL4. RBM45 also targets Rictor, which has been demonstrated to modulate lipid metabolism profoundly. RBM45 also aided lipid degradation through activating a key fatty acid ß oxidation enzyme, CPT1A. Thus, RBM45 boosted lipid synthesis and decomposition, indicating an enhanced utility of lipid fuels in HCC. Clinically, body mass index was positively correlated with RBM45 in human HCCs. The combination of a PI3K/AKT/mTOR pathway inhibitor in vitro or Sorafenib in orthotopic liver cancer mouse models with shRBM45 has a more significant therapeutic effect on liver cancer than the drug alone. In summary, our findings highlight the versatile roles of RBM45 in lipid metabolism reprogramming and its therapeutic potential in HCC. Lipids induced RBM45 expression. In turn, RBM45 promoted the utility of lipid in HCCs through accelerating both de novo lipogenesis and fatty acid ß oxidation, which required the participation of Rictor, a core component of mTORC2 that has been demonstrated to modulate lipid metabolism potently, as well as ACSL1/ACSL4, two key enzymes of long-chain fatty acid synthesis. When the first-line chemotherapy drug sorafenib is combined with a PI3K/AKT/mTOR pathway inhibitor (MK2206 is an AKT inhibitor, rapamycin is a mTOR inhibitor, and inhibiting RBM45 can significantly inhibit Rictor), cell cycle, proliferation, lipid metabolism reprogramming, and hepatocarcinogenesis can be significantly inhibited, while apoptosis can be significantly enhanced.

Synergistic antitumor efficacy of gemcitabine and cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via Sp1-SAT1-polyamine metabolism pathway.

PURPOSE: The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. METHODS: First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC-MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. RESULTS: Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. CONCLUSIONS: In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.

Risk factors for hypotension in patients with hemodialysis-associated superior vena cava syndrome.

OBJECTIVE: We analyzed the risk factors for hypotension in patients with hemodialysis-associated superior vena cava syndrome (SVCS) and effectiveness of endovascular intervention in hypotension related to SVCS. METHODS: This was a retrospective cohort study. A total of 194 maintenance hemodialysis patients diagnosed with SVCS who were admitted to the Department of Nephrology, West China Hospital of Sichuan University from January 2019 to December 2021 were selected and divided into a hypotension group and a nonhypotension group. Demographic and clinical data were compared. Hypotension simply refers to blood pressure levels of <90/60 mm Hg on a nondialysis day. All patients received endovascular intervention. RESULTS: Hypotension was found in 85 of the 194 patients. The following factors were significantly different between the hypotension and nonhypotension groups: body mass index, history of hypertension, tunneled-cuffed catheter as the means of dialysis access, azygos ectasis, SVC stenosis of >70% or occlusion, occlusion at the cavitary junction, serum calcium, diastolic left ventricular (LV) posterior wall thickness, LV end-diastolic volume, stroke output, and LV ejection fraction. Multivariate logistic regression analysis showed that hypertension history (OR, 0.314; P = .027), tunneled-cuffed catheter as vascular access (OR, 3.997; P < .001), SVC stenosis of >70% or occlusion (OR, 5.243; P < .001), LV posterior wall thickness (OR, 0.772; P = .044), and serum calcium (OR, 0.146; P = .005) were independent risk factors for hypotension. The mean values of systolic and diastolic blood pressure after intravascular treatment were significantly elevated from those before intervention (P < .001). The primary patency rates of SVC were 66.8%, 58.7%, and 50.0% at 3, 6, and 12 months after the procedure. CONCLUSIONS: The incidence of hypotension in patients with hemodialysis-associated SVCS is high. The identification of risk factors of hemodialysis-related hypotension provides insight into potential treatment strategies. Endovascular treatment is expected to improve hypotension related to SVCS in hemodialysis patients.

Dynamic regulation of EXO1 promotes the progression from liver fibrosis to HCC through TGF-ß1/Smad signaling feedback loop.

BACKGROUND: HSCs are the main stromal cells in the process of liver fibrosis and accelerate HCC progression. Previous studies determined that highly expressed exonuclease 1 (EXO1) increases the malignant behavior of HCC cells and is closely related to liver cirrhosis. This study aimed to explore the roles and mechanisms of EXO1 in the development of liver cirrhosis and HCC. METHODS: We fully demonstrated that EXO1 expression was positively correlated with liver fibrosis and cirrhotic HCC by combining bioinformatics, hepatic fibrosis mouse models, and human HCC tissues. The role of EXO1 in a murine HCC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated by employing an adeno-associated virus-mediated EXO1 knockdown technique. RESULTS: The knockdown of EXO1 promoted a regression of HCC in AKT/Ras mice and reduced the degree of liver fibrosis. Downregulated EXO1 inhibited LX-2 cell activation and inhibited the proliferation and migration of HCC cells. Moreover, conditioned medium of LX-2 cells with EXO1 overexpression increased the proliferation and migration of HCC cells, which was attenuated after EXO1 knockout in LX-2 cells. EXO1 knockdown attenuated the role of LX-2 in promoting HepG2 xenograft growth in vivo. Mechanistically, EXO1 promotes the activation of the downstream TGF-ß-smad2/3 signaling in LX-2 and HCC cells. Interestingly, increased TGF-ß-smad2/3 signaling had a feedback effect on EXO1, which sustains EXO1 expression and continuously stimulates the activation of HSCs. CONCLUSIONS: EXO1 forms a positive feedback circuit with TGF-ß-Smad2/3 signaling and promotes the activation of HSCs, which accelerates HCC progression. Those findings indicate EXO1 may be a promising target for the diagnosis and treatment of cirrhotic HCC.

Identification of Crucial Photosensitizing Factors to Promote CO2 -to-CO Conversion.

The sensitizing ability of a catalytic system is closely related to the visible-light absorption ability, excited-state lifetime, redox potential, and electron-transfer rate of photosensitizers (PSs), however it remains a great challenge to concurrently mediate these factors to boost CO2 photoreduction. Herein, a series of Ir(III)-based PSs (Ir-1-Ir-6) were prepared as molecular platforms to understand the interplay of these factors and identify the primary factors for efficient CO2 photoreduction. Among them, less efficient visible-light absorption capacity results in lower CO yields of Ir-1, Ir-2 or Ir-4. Ir-3 shows the most efficient photocatalytic activity among these mononuclear PSs due to some comprehensive parameters. Although the Kobs of Ir-3 is ≈10 times higher than that of Ir-5, the CO yield of Ir-3 is slightly higher than that of Ir-5 due to the compensation of Ir-5's strong visible-light-absorbing ability. Ir-6 exhibits excellent photocatalytic performance due to the strong visible-light absorption ability, comparable thermodynamic driving force, and electron transfer rate among these PSs. Remarkably, the CO2 photoreduction to CO with Ir-6 can achieve 91.5 µmol, over 54 times higher than Ir-1, and the optimized TONC-1 can reach up to 28160. Various photophysical properties of the PSs were concurrently adjusted by fine ligand modification to promote CO2 photoreduction.

miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor.

The activation of hepatic stellate cells (HSCs) is regarded as the primary driving factor of liver fibrosis. miR-192, a miRNA associated with hepatocellular carcinoma and enriched in HSCs, has an undisclosed role in HSC activation and liver fibrosis. In this study, a CCl4-induced rat liver fibrosis model and transforming growth factor-beta 1 (TGF-ß1)-treated HSC lines (LX-2 and HSC-T6) were used to detect miR-192 and Rictor levels in vivo and in vitro. Bioinformatic analysis and a dual luciferase assay were used to predict and confirm the interaction of Rictor with miR-192. Gain- and/or loss-of-function methods evaluated molecular changes and HSC activation phenotypes, detected by quantitative real-time PCR, western blotting, and immunofluorescence. We observed a gradual downregulation of miR-192 and upregulation of Rictor during CCl4-induced liver fibrosis/cirrhosis in rats. Enriched miR-192 was downregulated, while Rictor was upregulated in TGF-ß1-activated HSCs. miR-192 inhibited the activation of HSCs by directly targeting Rictor. High miR-192/low Rictor expression attenuated the fibrotic-related gene expression by AKT/mTORC2 signaling. In conclusion, miR-192 could inhibit the activation of HSCs by directly targeting Rictor in the AKT/mTORC2 signaling pathway. This study provides insights into potential therapeutic targets for liver fibrosis and cirrhosis.

Rictor mediates p53 deactivation to facilitate the malignant transformation of hepatocytes and promote hepatocarcinogenesis.

BACKGROUND: Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear. METHODS: Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. RESULTS: Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P < 0.05). In mice, xenograft tumors overexpressing miR-192 exhibited lower Rictor expression levels, leading to higher p53 activity, and these tumors displayed slower growth compared to untreated HCC cells. CONCLUSIONS: Rictor dynamically shuttles between the nucleus and cytoplasm during HCC development. Its pivotal oncogenic role involves binding and inhibiting p53wt activity within the nucleus in early hepatocarcinogenesis. Targeting Rictor presents a promising strategy for HCC based on p53 status.

DNA-Functionalized Porphyrinic Metal-Organic Framework-Based Drug Delivery System for Targeted Bimodal Cancer Therapy.

A DNA-functionalized porphyrinic MOF (porMOF) drug delivery system was successfully constructed. porMOF as a photosensitizer and drug delivery carrier can integrate photodynamic therapy (PDT) and chemotherapy. Via the strong coordination interaction between the zirconium cluster of porMOF and the terminal phosphate group of DNA, the stable modification of the DNA layer on the porMOF surface is achieved. Meanwhile, the introduction of C/G-rich base pairs into the DNA double-stranded structure provides more binding sites of chemotherapeutic drug doxorubicin (DOX). AS1411, an aptamer of nucleolin proteins that are overexpressed by cancer cells, is introduced in the double-stranded terminal, which can endow the nanosystem with the ability to selectively recognize cancer cells. C-rich sequences in DNA double strands form an i-motif structure under acidic conditions to promote the highly efficient release of DOX in cancer cells. In vitro and in vivo experiments demonstrate that the synergistic PDT/chemotherapy modality achieves highly efficient cancer cell killing and tumor ablation without undesirable side effects.

Indole produced during dysbiosis mediates host-microorganism chemical communication.

An imbalance of the gut microbiota, termed dysbiosis, has a substantial impact on host physiology. However, the mechanism by which host deals with gut dysbiosis to maintain fitness remains largely unknown. In Caenorhabditis elegans, Escherichia coli, which is its bacterial diet, proliferates in its intestinal lumen during aging. Here, we demonstrate that progressive intestinal proliferation of E. coli activates the transcription factor DAF-16, which is required for maintenance of longevity and organismal fitness in worms with age. DAF-16 up-regulates two lysozymes lys-7 and lys-8, thus limiting the bacterial accumulation in the gut of worms during aging. During dysbiosis, the levels of indole produced by E. coli are increased in worms. Indole is involved in the activation of DAF-16 by TRPA-1 in neurons of worms. Our finding demonstrates that indole functions as a microbial signal of gut dysbiosis to promote fitness of the host.