Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperative. N6-methyladenosine (m6A) is an important modification of eukaryotic RNAs. It is a critical regulator of gene expression that is involved in different cellular functions and physiological processes. Many studies have indicated that m6A modification regulates the development of many metabolic processes and metabolic diseases. In this review, we summarized recent studies on the role of m6A modification in different metabolic processes and metabolic diseases. Additionally, we highlighted the potential m6A-targeted therapy for metabolic diseases, expecting to facilitate m6A-targeted strategies in the treatment of metabolic diseases.

The Inhibitory Effects of Propofol on Colorectal Cancer Progression through the NF-κB/HIF-1α Signaling Pathway.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is a neoplastic disease that gradually develops due to genetic variations and epigenetic changes. Surgical excision is the first-line treatment for CRC. Accumulating evidence has shown that total intravenous anesthesia has beneficial effects for CRC patients as it decreases the probability of tumor recurrence and metastasis. Propofol is one of the most frequently used intravenous anesthetics in clinical practice. However, it remains unknown whether it can reduce recurrence and metastasis after surgery in cancer patients. METHODS: CRC cell lines (HCT116 and SW480) were cultured in vitro, and different concentrations of propofol were added to the cell culture medium. The proliferation effect of propofol on CRC cell lines was evaluated by CCK-8 assay. The effect of propofol on the migration and invasion of CRC cells was evaluated by scratch healing and Transwell experiments. The inhibitory effects of propofol on NF-κB and HIF-1α expressions in CRC cell lines were determined by Western blotting and immunofluorescence assays to further clarify the regulatory effects of propofol on NF-κB and HIF-1α. RESULTS: Compared to the control, propofol significantly inhibited the proliferation, migration, and invasion abilities of CRC cells (HCT116 and SW480) (P < 0.0001). The expression levels of NF-κB and HIF-1α gradually decreased with increasing propofol concentration in both cell lines. After activation and inhibition of NF-κB, the expression of HIF-1α changed. Further studies showed that propofol inhibited LPS-activated NF-κB-induced expression of HIF-1α, similar to the NF-κB inhibitor Bay17083 (P < 0.0001). CONCLUSION: In vitro, propofol inhibited the proliferation, migration, and invasion of CRC cells (HCT116 and SW480) in a dose-dependent manner, possibly by participating in the regulation of the NF-κB/HIF-1α signaling pathway.

Hepatic transcriptome discloses the potential targets of Xuefu Zhuyu Decoction ameliorating non-alcoholic fatty liver disease induced by high-fat diet.

Background and Aim: Xuefu Zhuyu decoction (XZD), a traditional Chinese medicinal formula, was firstly recorded in the Qing dynasty of ancient China and previously demonstrated to ameliorate hepatic steatosis. In the present study, the effects of XZD on non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) were evaluated in mice and the hepatic transcriptome was detected to disclose the potential mechanisms of XZD. Experimental procedure: The effects of XZD (low- and high-dosage) on NAFLD induced by HFD for 16 weeks were evaluated. Obeticholic acid was used as control drug. Body weight, food intake and index of homeostatic model assessment for insulin resistance (HOMA-IR) were analyzed. Hepatic histology were observed in haematoxylin and eosin stained sections and quantified with NAFLD activity score (NAS). Lipid in hepatocytes was visualized by Oil red staining. Alanine aminotransferase (ALT) and hepatic triglyceride (TG) was measured. The hepatic transcriptom was detected with RNA-sequencing and validated with real-time polymerase chain reaction, western-blotting and hepatic quantitative metabolomics. Results: XZD ameliorated hepatic histology of NAFLD mice, accompanied with decreasing fasting insulin, HOMA-IR, NAS, ALT and hepatic TG. The hepatic transcriptom of NAFLD was significantly reversed by XZD treatment, especially the genes enriched in the pathways of arachidonic acid metabolism, fatty acid degradation, cytokine-cytokine receptor interaction and extracellular matrix (ECM) -receptor interaction. The hepatic quantitative metabolomics analysis confirmed fatty acid degradation as the key targeting pathway of XZD. Conclusions: XZD ameliorated NAFLD induced by HFD, which probably correlated closely to the pathways of fatty acid degradation.

Meta-analysis: Efficacy and safety of fibroblast growth factor 21 analogues for the treatment of non-alcoholic steatohepatitis and non-alcoholic steatohepatitis-related fibrosis.

BACKGROUND: Fibroblast growth factor 21 (FGF21) analogues have emerged as promising therapeutic targets for non-alcoholic steatohepatitis (NASH). However, the effects and safety of these analogues on NASH and NASH-related fibrosis remain unexplored. AIMS: To estimate the efficacy and safety of FGF21 analogues for treating NASH and NASH-related fibrosis. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies up to 11 October 2023. Primary outcomes were defined as the fibrosis improvement ≥1 stage without worsening of NASH and NASH resolution without worsening fibrosis. Secondary outcomes included biomarkers of fibrosis, liver injury, and metabolism. Treatment-related adverse events were also analysed. RESULTS: Nine studies, including 1054 patients with biopsy-proven NASH and stage F1-F4 fibrosis, were identified. Seven studies reported histological outcomes. The relative risk (RR) for obtaining fibrosis improvement ≥1 stage efficacy was 1.79 (95% CI 1.29-2.48, I2 = 37%, p < 0.001) with FGF21 analogues relative to placebo. Although no statistically significant difference was observed between FGF21 analogues in NASH resolution, sensitivity analyses and fragility index suggest that this result is unstable. The drugs improved hepatic fat fraction (HFF), along with other biomarkers of fibrosis, liver injury, and metabolism (MRE, LSM, Pro-C3, ELF, ALT, AST, TG, HDL-C, and LDL-C). Additionally, no significant difference in serious adverse event incidence rate was observed (RR = 1.26, 95% CI 0.82-1.94, I2 = 24%, p = 0.3). CONCLUSIONS: FGF21 analogues appear as promising agents for the treatment of NASH and NASH-related fibrosis, and they generally seem to be safe and well tolerated.

Global acute-on-chronic liver failure trends during 2012-2022: A bibliometric study.

Introduction: Acute-on-chronic liver failure (ACLF) is a clinical syndrome with high short-term mortality. ACLF has been increasingly studied in recent years; however, a bibliometric analysis of the entire ACLF field has not been conducted. This study assesses current global trends and hotspots in ACLF research. Materials and methods: The core Web of Science database was searched for all ACLF-related publications conducted during 2012-2022. The data included information on the author, country, author keywords, publication year, citation frequency, and references. Microsoft Excel was used to collate the data and calculate percentages. VOSviewer software was used for citation and density visualization analysis. Histogram rendering was performed using GraphPad Prism Version 8.0 and R software was used to supplement the analysis. Result: A total of 1609 ACLF-related articles from 67 different countries were identified. China contributed the most literature, followed by the United States. However, Chinese literature only had the 4th highest number of citations, indicating that cooperation with other countries needs to be strengthened. The Journal of Hepatology had the highest number of ACLF-related citations. Prognosis was one of the most common author keywords, which may highlight current research hotspots. Bacterial infection was a common keyword and was closely related to prognosis. Conclusion: This bibliometric analysis suggests that future research hotspots will focus on the interplay among bacterial infection, organ failure, and prognosis.

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors.

M6A is essential for tumor occurrence and progression. The expression patterns of m6A regulators differ in various kinds of tumors. Transcriptomic expression statistics together with clinical data from a database were analyzed to distinguish patients with digestive tract tumors. Based on the expression patterns of diverse m6A regulators, patients were divided into several clusters. Survival analysis suggested significant differences in patient prognosis among the m6A clusters. The results showed overlapping of m6A expression patterns with energy metabolism and nucleotide metabolism. Functional analyses imply that m6A modifications in tumor cells probably drive metabolic reprogramming to sustain rapid proliferation of cancer cells. Our analysis highlights the m6A risk characterizes various kinds of metabolic features and predicts chemotherapy sensitivity in digestive tract tumors, providing evidence for m6A regulators as markers to predict patient outcomes.

A Novel Score Based on Controlled Attenuation Parameter Accurately Predicts Hepatic Steatosis in Individuals With Metabolic Dysfunction Associated Steatotic Liver Disease: A Derivation and Independent Validation Study.

INTRODUCTION: In metabolic dysfunction-associated steatotic liver disease, the diagnostic efficacy of controlled attenuation parameter (CAP) was not very accurate in evaluating liver fat content. The aim of this study was to develop a score, based on CAP and conventional clinical parameters, to improve the diagnostic performance of CAP regarding liver fat content. METHODS: A total of 373 participants from 2 independent Chinese cohorts were included and divided into derivation (n = 191), internal validation (n = 75), and external validation (n = 107) cohorts. Based on the significant difference index between the 2 groups defined by the magnetic resonance imaging-proton density fat fraction (MRI-PDFF) in derivation cohort, the optimal model (CAP-BMI-AST score [CBST]) was screened by the number of parameters and the area under the receiver operating characteristic curve (AUROC). In the internal and external validation cohorts, the AUROC and corresponding 95% confidence intervals (CIs) were used to compare the diagnostic performance of CBST with that of CAP. RESULTS: We constructed the CBST = -14.27962 + 0.05431 × CAP - 0.14266 × body mass index + 0.01715 × aspartate aminotransferase. When MRI-PDFF was ≥20%, ≥10%, and ≥5%, the AUROC for CBST was 0.77 (95% CI 0.70-0.83), 0.89 (95% CI 0.83-0.94), and 0.93 (95% CI 0.88-0.98), which was higher than that for CAP respectively. In the internal validation cohort, the AUROC for CBST was 0.80 (95% CI 0.70-0.90), 0.95 (95% CI 0.91-1.00), and 0.98 (95% CI 0.94-1.00). The optimal thresholds of CBST were -0.5345, -1.7404, and -1.9959 for detecting MRI-PDFF ≥20%, ≥10%, and ≥5%, respectively. DISCUSSION: The CBST score can accurately evaluate liver steatosis and is superior to the CAP.

USP5: Comprehensive insights into structure, function, biological and disease-related implications, and emerging therapeutic opportunities.

Ubiquitin specific protease 5 (USP5) is a vital deubiquitinating enzyme that regulates various physiological functions by removing ubiquitin chains from target proteins. This review provides an overview of the structural and functional characteristics of USP5. Additionally, we discuss the role of USP5 in regulating diverse cellular processes, including cell proliferation, apoptosis, DNA double-strand damage, methylation, heat stress, and protein quality control, by targeting different substrates. Furthermore, we describe the involvement of USP5 in several pathological conditions such as tumors, pathological pain, developmental abnormalities, inflammatory diseases, and virus infection. Finally, we introduce newly developed inhibitors of USP5. In conclusion, investigating the novel functions and substrates of USP5, elucidating the underlying mechanisms of USP5-substrate interactions, intensifying the development of inhibitors, and exploring the upstream regulatory mechanisms of USP5 in detail can provide a new theoretical basis for the treatment of various diseases, including cancer, which is a promising research direction with considerable potential. Overall, USP5 plays a critical role in regulating various physiological and pathological processes, and investigating its novel functions and regulatory mechanisms may have significant implications for the development of therapeutic strategies for cancer and other diseases.

Myeloid-specific blockade of notch signaling alleviates dopaminergic neurodegeneration in Parkinson's disease by dominantly regulating resident microglia activation through NF-κB signaling.

Yolk sac-derived microglia and peripheral monocyte-derived macrophages play a key role during Parkinson's disease (PD) progression. However, the regulatory mechanism of microglia/macrophage activation and function in PD pathogenesis remains unclear. Recombination signal-binding protein Jκ (RBP-J)-mediated Notch signaling regulates macrophage development and activation. In this study, with an 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) hydrochloride-induced acute murine PD model, we found that Notch signaling was activated in amoeboid microglia accompanied by a decrease in tyrosine hydroxylase (TH)-positive neurons. Furthermore, using myeloid-specific RBP-J knockout (RBP-JcKO) mice combined with a PD model, our results showed that myeloid-specific disruption of RBP-J alleviated dopaminergic neurodegeneration and improved locomotor activity. Fluorescence-activated cell sorting (FACS) analysis showed that the number of infiltrated inflammatory macrophages and activated major histocompatibility complex (MHC) II+ microglia decreased in RBP-JcKO mice compared with control mice. Moreover, to block monocyte recruitment by using chemokine (C-C motif) receptor 2 (CCR2) knockout mice, the effect of RBP-J deficiency on dopaminergic neurodegeneration was not affected, indicating that Notch signaling might regulate neuroinflammation independent of CCR2+ monocyte infiltration. Notably, when microglia were depleted with the PLX5622 formulated diet, we found that myeloid-specific RBP-J knockout resulted in more TH+ neurons and fewer activated microglia. Ex vitro experiments demonstrated that RBP-J deficiency in microglia might reduce inflammatory factor secretion, TH+ neuron apoptosis, and p65 nuclear translocation. Collectively, our study first revealed that RBP-J-mediated Notch signaling might participate in PD progression by mainly regulating microglia activation through nuclear factor kappa-B (NF-κB) signaling.

Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Multimodal Local Resonators for Low-Frequency Amelioration of Acoustic Black Holes.

Acoustic black holes (ABHs) are effective at suppressing vibrations at high frequencies, but their performance at low frequencies is limited. This paper aims to improve the low-frequency performance of ABH plates through the design of a metamaterial acoustic black hole (MMABH) plate. The MMABH plate consists of a double-layer ABH plate with a set of periodic local resonators installed between the layers. The resonators are tuned to the low-frequency peak points of the ABH plate, which are identified using finite element analysis. To dissipate vibration energy, the beams of the resonators are covered with damping layers. A modal analysis of the MMABH plate is performed, confirming its damping effect over a wide frequency band, especially at low frequencies.

A high-trans fat, high-carbohydrate, high-cholesterol, high-cholate diet-induced nonalcoholic steatohepatitis mouse model and its hepatic immune response.

Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive disease that can progress to non-alcoholic steatohepatitis (NASH). Animal models are important tools for basic NASH research. Immune activation plays a key role in liver inflammation in patients with NASH. We established a high-trans fat, high-carbohydrate, and high-cholesterol, high-cholate diet-induced (HFHCCC) mouse model. C57BL/6 mice were fed a normal or HFHCCC diet for 24 weeks, and the immune response characteristics of this model were evaluated. The proportion of immune cells in mouse liver tissues was detected by immunohistochemistry and flow cytometry, Multiplex bead immunoassay and Luminex technology was used to detecte the expression of cytokines in mouse liver tissues. The results showed that mice treated with HFHCCC diet exhibited remarkably increased hepatic triglycerides (TG) content, and the increase in plasma transaminases resulted in hepatocyte injury. Biochemical results showed that HFHCCC induced elevated hepatic lipids, blood glucose, insulin; marked hepatocyte steatosis, ballooning, inflammation, and fibrosis. The proportion of innate immunity-related cells, including Kupffer cells (KCs), neutrophils, dendritic cells (DCs), natural killer T cells (NKT), and adaptive immunity-related CD3+ T cells increased; interleukin-1α (IL-1α), IL-1ß, IL-2, IL-6, IL-9, and chemokines, including CCL2, CCL3, and macrophage colony stimulating factor (G-CSF) increased. The constructed model closely approximated the characteristics of human NASH and evaluation of its immune response signature, showed that the innate immune response was more pronounced than adaptive immunity. Its use as an experimental tool for understanding innate immune responses in NASH is recommended.

Safety and efficacy of robotic-assisted versus laparoscopic distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer.

BACKGROUND: Robot-assisted distal gastrectomy (RADG) has been used in the minimally invasive surgical treatment of gastric cancer, but the research on advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC) has not been reported. This study aimed to analyze the outcomes of RADG versus laparoscopic distal gastrectomy (LDG) after NAC for AGC. METHODS: This was a retrospective propensity score-matched analysis from February 2020 and March 2022. Patients who underwent RADG or LDG for AGC (cT3-4a/N +) following NAC were enrolled and a propensity score-matched analysis was performed in a 1:1 manner. The patients were divided into RADG group and LDG group. The clinicopathological characteristics and short-term outcomes were observed. RESULTS: After propensity score matching, 67 patients each in the RADG and LDG groups. RADG was associated with a lower intraoperative blood loss (35.6 vs. 118.8 ml, P = 0.014) and more retrieved lymph nodes (LNs) (50.7 vs. 39.5, P < 0.001), more extraperigastric (18.3 vs. 10.4, P < 0.001), and suprapancreatic LNs (16.33 vs. 13.70, P = 0.042). The RADG group showed lower VAS scores at postoperative 24 h (2.2 vs 3.3, P = 0.034), earlier ambulation (1.3 vs. 2.6, P = 0.011), aerofluxus time (2.2 vs. 3.6, P = 0.025), and shorter postoperative hospital stay (8.3 vs. 9.8, P = 0.004). There were no significant differences in the operative time (216.7 vs.194.7 min, P = 0.204) and postoperative complications between the two groups. CONCLUSION: RADG may be a potential therapeutic option for patients with AGC after NAC considering its advantages in perioperative period compared with LDG.

Geniposide plus chlorogenic acid reverses non-alcoholic steatohepatitis via regulation of gut microbiota and bile acid signaling in a mouse model in vivo.

Background: Geniposide and chlorogenic acid are the major active ingredients in Yinchenhao Decoction and are widely used as herbal medicines in Asia. This study further assessed their effects on improvement of non-alcoholic steatohepatitis (NASH) in a mouse model and explored the underlying molecular events in vivo. Methods: Male C57BL/6 and farnesoid X receptor knockout (FXR-/-) mice were used to establish the NASH model and were treated with or without geniposide, chlorogenic acid, obeticholic acid (OCA), and antibiotics for assessment of the serum and tissue levels of various biochemical parameters, bile acid, DNA sequencing of bacterial 16S amplicon, protein expression, and histology. Results: The data showed that the combination of geniposide and chlorogenic acid (GC) reduced the levels of blood and liver lipids, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the liver tissue index in NASH mice. In addition, GC treatment improved the intestinal microbial disorders in the NASH mice as well as the intestinal and serum bile acid metabolism. At the gene level, GC induced FXR signaling, i.e., increased the expression of FXR, small heterodimer partner (SHP), and bile salt export pump (BSEP) in liver tissues and fibroblast growth factor 15 (FGF15) expression in the ileal tissues of NASH mice. However, antibiotics (ampicillin, neomycin, vancomycin, and tinidazole) in drinking water (ADW) reversed the effect of GC on NASH and altered the gut microbiota in NASH mice in vivo. Furthermore, GC treatment failed to improve NASH in the FXR-/- mouse NASH model in vivo, indicating that the effectiveness of GC treatment might be through FXR signaling activation. Conclusion: GC was able to alleviate NASH by improving the gut microbiome and activating FXR signaling; its effect was better than each individual agent alone.

Effectiveness and safety analysis of Danggui Shaoyao Powder for the treatment of non-alcoholic fatty liver disease: study protocol for a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD) has been on the rise in recent years, and there are no effective drugs to treat NAFLD; therefore, effective prevention and treatment of NAFLD have become a new challenge. Danggui Shaoyao Powder (DGSY) is a classic prescription commonly used in clinical practice and has been shown to reduce hepatic steatosis in patients with NAFLD. In addition, previous studies have shown that DGSY can alleviate hepatic steatosis and inflammation in NAFLD mice. Although clinical practice and basic studies have shown that DGSY is effective in NAFLD, high levels of clinical evidence are lacking. Therefore, a standardized RCT study protocol is required to evaluate its clinical efficacy and safety. METHODS AND ANALYSIS: This study will be a randomized, double-blind, placebo-controlled, and single-center trial. According to the random number table, NAFLD participants will be randomly divided into the DGSY or placebo group for 24 weeks. The follow-up period will be 6 weeks after drug withdrawal. The primary outcome is the relative change in MRI-proton density fat fraction (MRI-PDFF) from baseline to 24 weeks. Absolute changes in serum alanine aminotransferase (ALT), liver stiffness measurement (LSM), body mass index (BMI), blood lipid, blood glucose, and insulin resistance index will be selected as secondary outcomes to comprehensively evaluate the clinical efficacy of DGSY in the treatment of NAFLD. The safety of DGSY will be evaluated by renal function, routine blood and urine tests, and electrocardiogram. DISCUSSION: This study will provide evidence-based medical corroboration for the clinical application of DGSY and promote the development and application of this classic prescription. TRIAL REGISTRATION: http://www.chictr.org.cn . TRIAL NUMBER: ChiCTR2000029144. Registered on 15 Jan 2020.

New insights into the role of dietary triglyceride absorption in obesity and metabolic diseases.

The incidence of obesity and associated metabolic diseases is increasing globally, adversely affecting human health. Dietary fats, especially triglycerides, are an important source of energy for the body, and the intestine absorbs lipids through a series of orderly and complex steps. A long-term high-fat diet leads to intestinal dysfunction, inducing obesity and metabolic disorders. Therefore, regulating dietary triglycerides absorption is a promising therapeutic strategy. In this review, we will discuss diverse aspects of the dietary triglycerides hydrolysis, fatty acid uptake, triglycerides resynthesis, chylomicron assembly, trafficking, and secretion processes in intestinal epithelial cells, as well as potential targets in this process that may influence dietary fat-induced obesity and metabolic diseases. We also mention the possible shortcomings and deficiencies in modulating dietary lipid absorption targets to provide a better understanding of their administrability as drugs in obesity and related metabolic disorders.

The role of FOXA family transcription factors in glucolipid metabolism and NAFLD.

Abnormal glucose metabolism and lipid metabolism are common pathological processes in many metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Many studies have shown that the forkhead box (FOX) protein subfamily FOXA has a role in regulating glucolipid metabolism and is closely related to hepatic steatosis and NAFLD. FOXA exhibits a wide range of functions ranging from the initiation steps of metabolism such as the development of the corresponding metabolic organs and the differentiation of cells, to multiple pathways of glucolipid metabolism, to end-of-life problems of metabolism such as age-related obesity. The purpose of this article is to review and discuss the currently known targets and signal transduction pathways of FOXA in glucolipid metabolism. To provide more experimental evidence and basis for further research and clinical application of FOXA in the regulation of glucolipid metabolism and the prevention and treatment of NAFLD.

Potential therapeutic action of tauroursodeoxycholic acid against cholestatic liver injury via hepatic Fxr/Nrf2 and CHOP-DR5-caspase-8 pathway.

Cholestasis is a pathophysiologic syndrome with limited therapeutic options. Tauroursodeoxycholic acid (TUDCA) has been employed to treat hepatobiliary disorders and is as effective as UDCA in alleviating cholestatic liver disease in clinical trials. Until now, TUDCA's mechanism of action toward cholestasis remains unclear. In the present study, cholestasis was induced with a cholic acid (CA)-supplemented diet or α-naphthyl isothiocyanate (ANIT) gavage in wild-type and Farnesoid X Receptor (FXR) deficient mice, using obeticholic acid (OCA) as control. The effects of TUDCA on liver histological changes, transaminase level, bile acid composition, hepatocyte death, expression of Fxr and nuclear factor erythroid 2-related factor 2 (Nrf2) and target genes, as well as apoptotic signaling pathways, were investigated. Treating CA-fed mice with TUDCA markedly alleviated liver injury, attenuated bile acids retention in liver and plasma, increased Fxr and Nrf2 nuclear levels and modulated the expression of targets regulating synthesis and transportation of bile acids, including BSEP, MRP2, NTCP and CYP7A1. TUDCA, but not OCA, activated Nrf2 signaling and exerted protective effects against cholestatic liver injury in Fxr-/- mice fed with CA. Furthermore, in both mice with CA- and ANIT-induced cholestasis, TUDCA decreased expression of GRP78 and CCAAT/enhancer-binding protein homologous protein (CHOP), reduced death receptor 5 (DR5) transcription, caspase-8 activation, and BID cleavage, and subsequently inhibited activation of executioner caspases and apoptosis in liver. We confirmed that TUDCA protected against cholestatic liver injury by alleviating BAs burden of dually activating hepatic Fxr and Nrf2. Moreover, inhibiting CHOP-DR5-caspase-8 pathway contributed to the anti-apoptotic effect of TUDCA in cholestasis.

Whole-Exome Sequencing Revealed the Mutational Profiles of Primary Central Nervous System Lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma. METHODS: Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples. RESULTS: We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression. CONCLUSIONS: WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.

In Vivo Anchoring Bis-Pyrene Probe for Molecular Imaging of Early Gastric Cancer by Endoscopic Techniques.

With the development of blue laser endoscopy (BLE) technique, it's often used to diagnose early gastric cancer (EGC) by the morphological changes of blood vessels through BLE. However, EGC is still not obvious to identify, resulting in a high rate of missed diagnosis. Molecular imaging can show the changes in early tumors at molecular level, which provides a possibility for diagnosing EGC. Therefore, developing a probe that visually monitors blood vessels of EGC under BLE is particularly necessary. Herein, a bis-pyrene (BP) based nanoprobe (BP-FFVLK-(PEG)-RGD, M1 ) is designed, which can target angiogenesis and self-assemble into fibers in situ, resulting in stable and long-term retention in tumor. Moreover, M1 probe can emit yellow-green fluorescence for imaging under BLE. M1 probe is confirmed to steadily remain in tumor for up to 96 hours in mice transplanted subcutaneously. In addition, the M1 probe is able to target angiogenesis for molecular imaging of isolated human gastric cancer tissue under BLE. Finally, M1 probe i.v. injected into primary gastric cancer model rabbits successfully highlighted the tumor site under BLE, which is confirmed by pathological analysis. It's the first time to develop a probe for diagnosing EGC by visualizing angiogenesis under BLE, showing great clinical significance.