[Chemical composition analysis of Ganoderma lucidum based on UPLC-Orbitrap-HRMS and virtual screening of FXR activators for treatment of liver fibrosis].

The chemical composition of Ganoderma lucidum ethanol extracts was systematically analyzed and identified by ultra-high performance liquid chromatography-quadrupole electrostatic field orbitrap high-resolution mass spectrometry(UPLC-Orbitrap-HRMS). The fragmentation pattern of the representative chemical compounds was summarized, and the potential anti-liver fibrosis active compounds of G. lucidum acting on the farnesoid X receptor(FXR) target were studied to elucidate its pharmacodynamic substance basis. Preliminarily, 95 chemical constituents of G. lucidum ethanol extracts were identified, including 24 ganoderic acids, 9 ganoderenic acids, 13 lucidenic acids, 3 ganolucidic acids, 1 ganoderma lactone, 40 other triterpenoids, 4 fatty acids, and 1 other constituent. In addition, the fragmentation patterns of the representative compounds were also analyzed. The structural characteristics of ganoderic acids and ganoderenic acids were the C30 skeleton, containing free-COOH and-OH groups, which could easily lose H_2O and CO_2 to form fragment ions. The D-ring was mostly a five-membered ring, which was prone to breakage. Lucidenic acids were the lanosterolane-type of the C27 skeleton, and the side-chain structure became shorter and contained the same free-COOH and-OH compared with ganoderic acids, which had been reduced from 8 to 5 cartons and prone to lose H_2O and CO_2. Then, six reported FXR receptor agonists were selected to form a training set for establishing a pharmacophore model based on FXR ligands. The 95 identified chemical constituents of G. lucidum were matched with the pharmacophore, and the optimal pharmacophore model 02(sensitivity=0.750 00, specificity=0.555 56, ROC=0.750) was selected for the virtual screening of the G. lucidum compound library through the validation of the test set. Finally, 31 potential G. lucidum active constituents were screened and chosen to activate the FXRs. The ADMET results showed that ganoderic acid H and lucidenic acid J had less than 90% plasma protein binding rate and no hepatotoxicity, which could be used as FXR activators for developing clinical drugs for the treatment of liver fibrosis, either alone or in combination.

Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Chinese herbal decoction, Yi-Qi-Jian-Pi formula exerts anti-hepatic fibrosis effects in mouse models of CCl4-induced liver fibrosis.

Background: Yi-Qi-Jian-Pi Formula (YQJPF) is a herbal medicine that is used to treat patients with liver failure. However, scientific evidence supporting the treatment of hepatic fibrosis with YQJPF has not been forthcoming. The present study aimed to determine the mechanisms underlying the anti-fibrotic effects of YQJPF in mouse models of hepatic fibrosis. Methods: Mice were randomly assigned to control, hepatic fibrosis model, silymarin (positive treated), and low-, medium- and high-dose YQJPF (7.5, 15, and 30 g/kg, respectively) groups. Liver function, inflammatory cytokines, and oxygen stress were analyzed using ELISA kits. Sections were histopathologically stained with hematoxylin-eosin, Masson trichrome, and Sirius red. Macrophage polarization was measured by flow cytometry and immunofluorescence. Potential targets of YQJPF against hepatic fibrosis were analyzed by network pharmacology of Chinese herbal compound and the effects of YQJPF on the transforming growth factor-beta (TGF-ß)/Suppressor of Mothers against Decapentaplegic family member 3 (Smad3) signaling pathway were assessed using qRT-PCR and immunohistochemical staining. Finally, metagenomics and LC-MS/MS were used to detect the intestinal flora and metabolites of the mice, and an in-depth correlation analysis was performed by spearman correlation analysis. The data were compared by one-way ANOVA and least significant differences (LSDs) or ANOVA-Dunnett's T3 method used when no homogeneity was detected. Results: We induced hepatic fibrosis using CCl4 to establish mouse models and found that YQJPF dose-dependently increased body weight, improved liver function, and reversed hepatic fibrosis. Elevated levels of the pro-inflammatory factors IL-1ß, IL-6, and TNF-α in the model mice were substantially decreased by YQJPF, particularly at the highest dose. Levels of serum malondialdehyde and superoxide dismutase (SOD) activity were elevated and reduced, respectively. The malondialdehyde concentration decreased and SOD activity increased in the high-dose group. M1 polarized macrophages (CD86) in the mouse models were significantly decreased and M2 polarization was mildly decreased without significance. However, high-dose YQJPF increased the numbers of M2 macrophages and inhibited TGF-ß/Smad3 signaling. Metagenomic and non-targeted metabolomics detection results showed that YQJPF could regulate intestinal homeostasis, and Spearman correlation analysis showed that the abundance of Calditerrivibrio_nitroreducens was significantly negatively correlated with 18ß-glycyrrhetinic acid. It is suggested that Calditerrivibrio_nitroreducens may reduce the anti-fibrosis effect of licorice and other Chinese herbs by digesting 18ß-glycyrrhetinic acid. Conclusions: YQJPF can reverse liver fibrosis by inhibiting inflammation, suppressing oxidative stress, regulating the immunological response initiated by macrophages, inhibiting TGF-ß/Smad3 signaling and regulating intestinal flora homeostasis. Therefore, YQJPF may be included in clinical regimens to treat hepatic fibrosis.

Comprehensive pan-cancer investigation: unraveling the oncogenic, prognostic, and immunological significance of Abelson interactor family member 3 gene in human malignancies.

Background: Abelson interactor Family Member 3 (ABI3) encodes protein that not only suppresses the ectopic metastasis of tumor cells but also hinders their migration. Although ABI3 had been found to modulate the advancement of diverse neoplasms, there is no comprehensive pan-cancer analysis of its effects. Methods: The transcriptomics data of neoplasm and normal tissues were retrieved from the Genomic Data Commons (GDC) data portal, and UCSC XENA database. To gather protein information for ABI3, Human Protein Atlas (HPA) and GeneMANIA websites were utilized. Additionally, Tumor Immune Single-cell Hub (TISCH) database was consulted to determine the primary cell types expressing ABI3 in cancer microenvironments. Univariate Cox regression approach was leveraged to evaluate ABI3's prognostic role across cancers. The Cbioportal and Gene Set Cancer Analysis (GSCA) website were leveraged to scrutinize the genomic landscape information across cancers. TIMER2.0 was leveraged to probe the immune cell infiltrations associated with ABI3 across cancers. The associations of ABI3 with immune-related genes were analyzed through Spearman correlation method. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were utilized to search associated biological pathways. The CellMiner database and molecular docking were implemented to identify potential interactions between the ABI3 protein and specific anticarcinogen. Findings: ABI3 expression and its ability to predict prognosis varied distinct tumor, with particularly high expression observed in Tprolif cells and monocytes/macrophages. Copy number variation (CNV) and methylation negatively correlated with ABI3 expression in the majority of malignancies. Corresponding mutation survival analysis indicated that the mutation status of ABI3 was strongly connected to the prognosis of LGG patients. ABI3 expression was linked to immunotherapeutic biomarkers and response in cancers. ESTIMATE and immune infiltrations analyses presented ABI3 association with immunosuppression. ABI3 was significantly correlated with immunoregulators and immune-related pathways. Lastly, prospective ABI3-targeted drugs were filtered and docked to ABI3 protein. Interpretation: Our study reveals that ABI3 acts as a robust tumor biomarker. Its functions are vital that could inhibit ectopic metastasis of tumor cells and modulate cellular adhesion and migration. The discoveries presented here may have noteworthy consequences for the creation of fresh anticancer suppressors, especially those targeting BRCA.

Therapeutic mechanism exploration of polysaccharides from Dendrobium officinale on unilateral ureteral obstruction operation-induced renal fibrosis based on improving oxidative stress injury mediated by AhR/NOX4 pathway.

Dendrobium officinale polysaccharides (DOP) has been reported to possess remarkable effects on improving renal function, oxidative stress damage and fibrotic diseases. However, the role and mechanism of DOP in preventing and treating renal fibrosis remain unclear. The purpose of this paper was to explore the therapeutic effects and underlying mechanisms of DOP on renal fibrosis. Firstly, renal fibrosis model was induced by unilateral ureteral obstruction operation (UUO) in male BALB/c mice. Subsequently, the anti-renal fibrosis effect of DOP was evaluated. It turned out that DOP significantly attenuated UUO induced renal fibrosis. The beneficial effects of DOP on renal fibrosis were concretely manifested in the relief of clinical symptoms, improvement of renal function, reduction of extracellular matrix collagen aggregation, attenuation of structural damage and inflammation, and decrement of profibrotic factors secretion. Meanwhile, DOP could also alleviate oxidative stress injury and inhibit the AhR/NOX4 pathway proteins expression. Furthermore, multivariate statistical analysis, AhR interference and overexpression experiments showed that the effect of DOP on alleviating renal fibrosis was closely related to the improvement of oxidative stress injury mediated by the AhR/NOX4 pathway. Overall, the data in the present paper indicated that DOP could alleviate renal fibrosis through improving AhR/NOX4 mediated oxidative stress injury.

Application of protein/polysaccharide aerogels in drug delivery system: A review.

Drug delivery systems have emerged as a prominent research focus in the field of drug development, offering enhanced stability and improved bioavailability. Among them, protein (silk, gelatin and whey) or polysaccharide (alginate, chitosan, cellulose, starch, pectin and carrageenan) aerogels derived from natural sources have gained increasing popularity due to their unique advantages, such as cost-effectiveness, flexible preparation, bioactivity, biocompatibility, and biodegradability. However, despite their growing significance, there remains a lack of comprehensive information and ongoing confusion regarding the application of protein/polysaccharide aerogels in drug delivery system. Hence, the objective of this review was to provide a comprehensive review of the research progress in protein/polysaccharide aerogels for drug delivery systems from the perspective of aerogels category, synthesis strategy, drug-loading method, performance characteristic and release mechanism. Furthermore, by consolidating the existing information, we aimed to present our own perspectives and insights on the future development of protein/polysaccharide aerogels in drug delivery system. In conclusion, this comprehensive review served as a valuable resource for researchers and scholars, addressing the current gaps in knowledge and clarifying the complex landscape of protein/polysaccharide aerogels in drug delivery system.

Extraction and characterization of polysaccharide from fermented mycelia of Coriolus versicolor and its efficacy for treating nonalcoholic fatty liver disease.

Coriolus versicolor, a popular traditional Chinese medicinal herb, is widely used in China to treat spleen and liver diseases; however, the beneficial effects of C. versicolor polysaccharides (CVPs) on nonalcoholic fatty liver disease (NAFLD) remain elusive. Herein we isolated and purified a novel CVP (molecular weight, 17,478 Da) from fermented mycelium powder. This CVP was composed of mannose, galacturonic acid, glucose, galactose, xylose, and fucose at a molar ratio of 22:1:8:15:10:3. Methylation, gas chromatography-mass spectrometry, and nuclear magnetic resonance analyses indicated that the CVP backbone consisted of →1)-ß-D-Man-(6,4→1)-α-D-Gal-(3→1)-α-D-Man-(4→1)-α-D-Gal-(6→, with branches of →1)-α-D-Glc-(6→1)-α-D-Man-(4,3→1)-ß-D-Xyl-(2→1)-ß-D-Glc on the O-6 position of →1)-ß-D-Man-(6,4→ of the main chain. The secondary branches linked to the O-4 position of →1)-α-D-Man-(4,3→ with the chain of →1)-α-D-Fuc-(4→1)-α-D-Man. Further, CVP treatment alleviated the symptoms of NAFLD in an HFD-induced mice model. CVP altered gut microbiota, predominantly suppressing microbes associated with bile acids both in the serum and cecal contents. In vitro data showed that CVP reduced HFD-induced hyperlipidemia via farnesoid X receptor. Our results improve our understanding of the mechanisms underlying the cholesterol- and lipid-lowering effects of CVP and indicate that CVP is a promising candidate for NAFLD therapy.

Human TRMT1 catalyzes m2G or m22G formation on tRNAs in a substrate-dependent manner.

TRMT1 is an N2-methylguanosine (m2G) and N2,N2-methylguanosine (m22G) methyltransferase that targets G26 of both cytoplasmic and mitochondrial tRNAs. In higher eukaryotes, most cytoplasmic tRNAs with G26 carry m22G26, although the majority of mitochondrial G26-containing tRNAs carry m2G26 or G26, suggesting differences in the mechanisms by which TRMT1 catalyzes modification of these tRNAs. Loss-of-function mutations of human TRMT1 result in neurological disorders and completely abrogate tRNA:m22G26 formation. However, the mechanism underlying the independent catalytic activity of human TRMT1 and identity of its specific substrate remain elusive, hindering a comprehensive understanding of the pathogenesis of neurological disorders caused by TRMT1 mutations. Here, we showed that human TRMT1 independently catalyzes formation of the tRNA:m2G26 or m22G26 modification in a substrate-dependent manner, which explains the distinct distribution of m2G26 and m22G26 on cytoplasmic and mitochondrial tRNAs. For human TRMT1-mediated tRNA:m22G26 formation, the semi-conserved C11:G24 serves as the determinant, and the U10:A25 or G10:C25 base pair is also required, while the size of the variable loop has no effect. We defined the requirements of this recognition mechanism as the "m22G26 criteria". We found that the m22G26 modification occurred in almost all the higher eukaryotic tRNAs conforming to these criteria, suggesting the "m22G26 criteria" are applicable to other higher eukaryotic tRNAs.

Mechanism exploration of 6-Gingerol in the treatment of atherosclerosis based on network pharmacology, molecular docking and experimental validation.

BACKGROUND: The 6-Gingerol has significant anti-inflammatory, anti-oxidative and hypolipidemic activities and is widely used for treating cardiac-cerebral vascular diseases. However, the multi-target mechanism of 6-Gingerol in the treatment of atherosclerosis remains to be elucidated. METHODS: Firstly, the therapeutic actions of 6-Gingerol anti-atherosclerosis were researched based on an atherosclerotic ApoE-deficient mice model induced by high-fat feed. Then, network pharmacology and molecular docking were employed to reveal the anti-atherogenic mechanism of 6-Gingerol. Finally, the target for these predictions was validated by target protein expression assay in vitro and in vivo experiments and further correlation analysis. RESULTS: Firstly, 6-Gingerol possessed obvious anti-atherogenic activity, which was manifested by a significant reduction in the plaque area, decrease in the atherosclerosis index and vulnerability index. Secondly, based on network pharmacology, 14 predicted intersection target genes between the targets of 6-Gingerol and atherogenic-related targets were identified. The key core targets of 6-Gingerol anti-atherosclerosis were found to be TP53, RELA, BAX, BCL2, and CASP3. Lipid and atherosclerosis pathways might play a critical role in 6-Gingerol anti-atherosclerosis. Molecular docking results also further revealed that the 6-Gingerol bound well and stable to key core targets from network pharmacological predictions. Then, the experimental results in vivo and in vitro verified that the up-regulation of TP53, RELA, BAX, CASP3, and down-regulation of BCL2 from atherosclerotic ApoE-deficient mice model can be improved by 6-Gingerol intervention. Meanwhile, the correlation analysis further confirmed that 6-Gingerol anti-atherosclerosis was closely related to these targets. CONCLUSION: The 6-Gingerol can markedly improve atherosclerosis by modulating key multi-targets TP53, RELA, BAX, CASP3, and BCL2 in lipid and atherosclerosis pathways. These novel findings shed light on the anti-atherosclerosis mechanism of 6-Gingerol from the perspective of multiple targets and pathways.

Danggui Buxue Tang: A Review of its Major Components.

Context: Danggui Buxue Tang (DBT) is a classical Chinese medicine that practitioners have used for thousands of years. Historically, those practitioners have used 16 prescriptions of DBT but currently are using only three prescriptions. Objective: The review intended to summarize pharmacological profiles of DBT and also clarify the major active chemicals found within it to provide a better understanding of the significance of DBT clinically. Design: The research team performed a narrative review by searching Pubmed databases. The search used the keywords Danggui Buxue Tang, bioactive chemcials, pharmacological functions. Setting: The databases setting were done by Gong Guowei and Zhou Xuan in the Zunyi Medical University, Zhuhai campus. Results: There are multiple results related to the crude fractions isolated from Danggui Buxue Tang, and also included the clinical trails. Conclusions: Thousands of years of clinical experience have ensured the efficacy of TCM treatments, which can determine the direction of basic research. That research can modify formulas at the molecular level to improve targeting and specificity in the treatment of specific diseases. As a result, the discovery and identification of new compounds within the herbal complex can provide useful research ideas and ensure the viability of new drug development.

Resveratrol protects against postmenopausal atherosclerosis progression through reducing PCSK9 expression via the regulation of the ERα-mediated signaling pathway.

Elevated circulating proprotein convertase subtilisin/kexin 9 (PCSK9) levels are an important contributor to postmenopausal atherosclerosis (AS). We have previously reported that resveratrol (RSV), as a phytoestrogen, reduces hepatocyte steatosis and PCSK9 expression in L02 cells. This study aimed to investigate how RSV reduces PCSK9 expression to inhibit postmenopausal AS progression. Here, we found that treatment of Ovx/ApoE -/- mice with RSV significantly reduced dyslipidemia, plasma PCSK9 concentration and aortic plaque area. In addition, RSV significantly inhibited liver fat accumulation and improved the hepatocyte ultrastructure. Further studies showed that RSV upregulated estrogen receptor α (ERα) expression, while reduced the liver X receptor α (LXRα) expression and sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity. In vitro, RSV inhibited insulin-induced elevated intracellular/extracellular PCSK9 levels, enhanced receptor-mediated uptake of low-density lipoproteins in HepG2 cells. Furthermore, RSV attenuated the activity of the SRE-dependent PCSK9 promoter. However, these effects can be partially reversed by the antiestrogen ICI 182,780. Attenuation of these changes with ERα inhibition suggest that RSV may prevent the progression of postmenopausal AS by reducing PCSK9 expression in hepatocytes through ERα-mediated signaling.

Anti-Invasive and Anti-Migratory Effects of Ononin on Human Osteosarcoma Cells by Limiting the MMP2/9 and EGFR-Erk1/2 Pathway.

Osteosarcoma is a common malignancy of the bone. Due to its high metastatic properties, osteosarcoma becomes the leading cause of cancer death worldwide. Ononin is an isoflavone glycoside known to have various pharmacological properties, including antioxidant and anti-inflammatory activities. In the present study, we aimed to investigate the efficacy of ononin on osteosarcoma cell migration, invasion, and the underlying mechanisms. The in vitro anti-tumorigenic and anti-migratory properties of ononin were determined by MTT, colony formation, invasion, and migration in MG-63 and U2OS osteosarcoma cell lines. The results were compared with the standard chemotherapeutic drug, doxorubicin (DOX), as a positive control. The dose-dependent manners of ononin treatment increased the expression of apoptosis and inhibition of cell proliferation through the EGFR-Erk1/2 signaling pathways. Additionally, ononin significantly inhibited the invasion and migration of human osteosarcoma cells. For consistency, we used the MG-63-xenograft mice model to confirm the in vivo anti-tumorigenic and anti-migratory efficacy of ononin by inhibiting the protein expressions of EGFR-Erk1/2 and MMP2/9. According to the histological study, ononin had no adverse effect on the liver and kidney. Overall, our findings suggested that ononin could be a potentially effective agent against the development and metastasis of osteosarcoma.

Danggui Buxue Tang potentiates the cytotoxicity of 5-fluorouracil on colorectal adenocarcinoma cells: A signaling mediated by c-Jun N-terminal kinase.

Danggui Buxue Tang (DBT) is a well-known Chinese herbal recipe often prescribed in clinical treatment for menopausal and cardiovascular symptoms. 5-Fluorouracil (5-FU) is a chemotherapy drug that treats several cancers; however, it causes severe adverse effects and multidrug resistance. Combining natural medications can reduce the side effects of 5-FU use. Hence, we aimed to determine the role of DBT in strengthening the anticancer capabilities of 5-FU in a cultured colorectal adenocarcinoma cell line (HT-29 cell) and xenograft nude mice. HT-29 cells cultured with DBT did not exhibit cytotoxicity. However, co-administration of DBT with 5-FU significantly increased apoptosis and the expression of apoptotic markers. The inhibition of proliferation induced by DBT and 5-FU was shown to be mediated by c-Jun N-terminal kinase signaling. In addition, the potentiation effect of 5-FU and DBT was demonstrated in reducing tumor size, expressions of Ki67 and CD34 in HT-29 xenograft mice. This finding suggests that DBT can work with 5-FU as a novel chemotherapeutic strategy for treating colon cancer.

Chitosan oligosaccharide alleviates renal fibrosis through reducing oxidative stress damage and regulating TGF-ß1/Smads pathway.

Renal fibrosis (RF) is the common pathway for a variety of chronic kidney diseases that progress to end-stage renal disease. Chitosan oligosaccharide (COS) has been identified as possessing many health functions. However, it is not clear whether COS can prevent RF. The purpose of this paper was to explore the action and mechanism of COS in alleviating RF. First, an acute unilateral ureteral obstruction operation (UUO) in male BALB/c mice was performed to induce RF, and COS or fosinopril (positive control drug) were administered for 7 consecutive days. Data from our experiments indicated that COS treatment can significantly alleviate kidney injury and decrease the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) in the UUO mouse model. More importantly, our results show that COS can reduce collagen deposition and decrease the expression of fibrosis proteins, such as collagen IV, fibronectin, collagen I, α-smooth muscle actin (α-SMA) and E-cadherin, ameliorating experimental renal fibrosis in vivo. In addition, we also found that COS suppressed oxidative stress and inflammation in RF model mice. Further studies indicated that the mechanism by which COS alleviates renal fibrosis is closely related to the regulation of the TGF-ß1/Smad pathway. COS has a therapeutic effect on ameliorating renal fibrosis similar to that of the positive control drug fosinopril. Taken together, COS can alleviate renal fibrosis induced by UUO by reducing oxidative stress damage and regulating the TGF-ß1/Smad pathway.

Effects of Broussonetia papyrifera (L.) L'Hér. ex Vent. fruits water extract on hippocampal neurogenesis in the treatment of APP/PS1 transgenic mice.

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6 weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/ß-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3ß and ß-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/ß-catenin signaling pathway.

Vitexin Protects against Dextran Sodium Sulfate-Induced Colitis in Mice and Its Potential Mechanisms.

Vitexin, one of the major active components in hawthorn, has been shown to possess multiple pharmacological activities. Here, we sought to investigate the effect of vitexin on an ameliorating dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mouse model and further explored its potential mechanism. The results indicated that vitexin administration could significantly alleviate the signs of colitis via suppressing body weight loss, reducing disease activity index (DAI) score, and mitigating colonic damage. Also, vitexin treatment in colitis mice markedly inhibited the production of pro-inflammation cytokines (such as IL-1ß, IL-6, and TNF-α). Meanwhile, vitexin also could markedly down-regulate the phosphorylation levels of p65, IκB, and STAT1. Moreover, vitexin also dose-dependently increased the expressions of muc-2, ZO-1, and occludin proteins in colonic tissues of colitis mice. Further studies revealed that vitexin dramatically modulated the disturbed intestinal flora in colitis mice. Vitexin is beneficial for regulating abundances of some certain bacteria, such as Bacteroides, Helicobacter, Alistipes, Lachnospiraceae_NK4A136_group, and Lachnospiraceae_UCG-006. Interestingly, the correlation analysis indicated that key microbes were strongly correlated with colitis features, such as pro-inflammatory cytokines and gut barrier. Collectively, these results demonstrated that vitexin treatment alleviated inflammation, intestinal barrier dysfunction, and intestinal flora dysbiosis in colitis mice. Vitexin is expected to be a promising compound for UC treatment.

Synthesis of Star 6-Arm Polyethylene Glycol-Heparin Copolymer to Construct Anticorrosive and Biocompatible Coating on Magnesium Alloy Surface.

Magnesium alloy has become a research hotspot of the degradable vascular stent materials due to its biodegradability and excellent mechanical properties. However, its rapid degradation rate after implantation and the limited biocompatibility restrict its application in clinic. Constructing a multifunctional bioactive polymer coating on the magnesium alloys represents one of the popular and effective approaches to simultaneously improve the corrosion resistance and biocompatibility. In the present study, the copolymer of 6-arm polyethylene glycol and heparin (PEG-Hep) was successfully synthesized and then immobilized on the surface of chitosan (Chi)-modified magnesium alloy surface through electrostatic interaction to improve the corrosion resistance and biocompatibility. The results of attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy showed that a dense and compact coating was created on the magnesium alloy surface. The coating displayed excellent hydrophilicity. At the same time, the as-prepared coating can significantly not only improve the corrosion potential, reduce the corrosion current and the pH changes of the immersion solution, but also keep a relatively intact surface morphology after immersing in simulated body fluid solution for 14 days, demonstrating that the coating can significantly improve the corrosion resistance of the magnesium alloy. Moreover, the magnesium alloy with PEG-Hep coating exhibited excellent hemocompatibility according to the results of the hemolysis rate and platelet adhesion and activation. In addition, the modified magnesium alloy had a good ability to promote the endothelial cell adhesion and proliferation. Therefore, the PEG-Hep multifunctional coating can be applied in the surface modification of the biodegradable magnesium alloy stent to simultaneously improve the corrosion resistance and biocompatibility.

A dual role of human tRNA methyltransferase hTrmt13 in regulating translation and transcription.

Since numerous RNAs and RBPs prevalently localize to active chromatin regions, many RNA-binding proteins (RBPs) may be potential transcriptional regulators. RBPs are generally thought to regulate transcription via noncoding RNAs. Here, we describe a distinct, dual mechanism of transcriptional regulation by the previously uncharacterized tRNA-modifying enzyme, hTrmt13. On one hand, hTrmt13 acts in the cytoplasm to catalyze 2'-O-methylation of tRNAs, thus regulating translation in a manner depending on its tRNA-modification activity. On the other hand, nucleus-localized hTrmt13 directly binds DNA as a transcriptional co-activator of key epithelial-mesenchymal transition factors, thereby promoting cell migration independent of tRNA-modification activity. These dual functions of hTrmt13 are mutually exclusive, as it can bind either DNA or tRNA through its CHHC zinc finger domain. Finally, we find that hTrmt13 expression is tightly associated with poor prognosis and survival in diverse cancer patients. Our discovery of the noncatalytic roles of an RNA-modifying enzyme provides a new perspective for understanding epitranscriptomic regulation.

Antitumor Effects of Ononin by Modulation of Apoptosis in Non-Small-Cell Lung Cancer through Inhibiting PI3K/Akt/mTOR Pathway.

Lung cancer is a leading global cause of cancer-related death in both males and females. Non-small-cell lung cancer (NSCLC) is the most commonly diagnosed cancer type that can be difficult to control with conventional chemotherapeutic and surgical approaches resulting in a poor prognosis. Paclitaxel (PTX) is a commonly used chemotherapeutic drug for NSCLC, which can cause tissue injury in healthy cells and affect the quality of life in patients with cancer. In order to treat NSCLC, alternative medications with minimal or no side effects are highly needed. Ononin is an isoflavone glycoside extracted from Astragali Radix (AR) that has various pharmacological activities. Therefore, this study investigated whether ononin inhibits NSCLC progression and promotes apoptosis synergistically with PTX both in vitro and in vivo. Antitumorigenic properties of ononin were determined by MTT assay, colony formation assay, migratory capacity, and apoptotic marker expression in A549 and HCC827 cells. The combination of ononin with PTX increased the expression of apoptotic markers and ROS generation and inhibited cell proliferation through the PI3K/Akt/mTOR signaling pathways. Furthermore, ononin prevented the translocation of NF-κB from cytosol to the nucleus. Also, we used the xenograft NSCLC mice model to confirm the in vivo antitumorigenic efficacies of ononin by reduction of CD34 and Ki67 expressions. Based on the histological analysis, the cotreatment of PTX and ononin reduced PTX-induced liver and kidney damage. Overall, our findings suggested that the therapeutic index of PTX-based chemotherapy could be improved by reducing toxicity with increasing antitumor capabilities when combined with ononin.

Position 34 of tRNA is a discriminative element for m5C38 modification by human DNMT2.

Dnmt2, a member of the DNA methyltransferase superfamily, catalyzes the formation of 5-methylcytosine at position 38 in the anticodon loop of tRNAs. Dnmt2 regulates many cellular biological processes, especially the production of tRNA-derived fragments and intergenerational transmission of paternal metabolic disorders to offspring. Moreover, Dnmt2 is closely related to human cancers. The tRNA substrates of mammalian Dnmt2s are mainly detected using bisulfite sequencing; however, we lack supporting biochemical data concerning their substrate specificity or recognition mechanism. Here, we deciphered the tRNA substrates of human DNMT2 (hDNMT2) as tRNAAsp(GUC), tRNAGly(GCC) and tRNAVal(AAC). Intriguingly, for tRNAAsp(GUC) and tRNAGly(GCC), G34 is the discriminator element; whereas for tRNAVal(AAC), the inosine modification at position 34 (I34), which is formed by the ADAT2/3 complex, is the prerequisite for hDNMT2 recognition. We showed that the C32U33(G/I)34N35 (C/U)36A37C38 motif in the anticodon loop, U11:A24 in the D stem, and the correct size of the variable loop are required for Dnmt2 recognition of substrate tRNAs. Furthermore, mammalian Dnmt2s possess a conserved tRNA recognition mechanism.