A gain-of-function mutation in micro-RNA-142 is sufficient to cause the development of T-cell leukemia in mice.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. miRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there are no reports of carcinogenic point mutations in miRNAs. MicroRNA-142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Thereafter, bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8+ T-cell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8+ T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt-mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.

Exosomal ZFPM2-AS1 contributes to tumorigenesis, metastasis, stemness, macrophage polarization, and infiltration in hepatocellular carcinoma through PKM mediated glycolysis.

BACKGROUND: With high morbidity and mortality, hepatocellular carcinoma (HCC) deserves further exploration in its pathogenesis mechanisms for promising prognostic and therapeutic markers. This research was conducted to dig out roles of exosomal ZFPM2-AS1 in HCC. METHODS: The level of exosomal ZFPM2-AS1 in HCC tissue and cells was determined by Real-time fluorescence quantitative PCR. Pull-down assay and dual-luciferase reporter assay were performed to identify interactions between ZFPM2-AS1 and miRNA-18b-5p, as well as miRNA-18b-5p and PKM. Western blotting was employed to explore the potential regulatory mechanism. Several in vitro assays were conducted in mice xenograft and orthotopic transplantation models to investigate impacts of exosomal ZFPM2-AS1 on HCC development, metastasis, and macrophage infiltration. RESULTS: ZFPM2-AS1 was activated in HCC tissue and cells, with high enrichment in HCC-derived exosomes. Exosomal ZFPM2-AS1 enhances the cell abilities and stemness of HCC. MiRNA-18b-5p was directly targeted by ZFPM2-AS1 which triggered PKM expression via sponging miR-18b-5p. Exosomal ZFPM2-AS1 modulated glycolysis via PKM in an HIF-1α dependent way in HCC, promoting M2 polarization, and macrophage recruitment. Furthermore, exosomal ZFPM2-AS1 enhanced HCC cell growth, metastasis, and M2 infiltration in vivo. CONCLUSIONS: Exosomal ZFPM2-AS1 exerted regulatory function on the progression of HCC via miR-18b-5p/PKM axis. ZFPM2-AS1 could be promising biomarker for the diagnosis and therapies of HCC.

The value of serum Sema4D level in reflecting the inflammatory state of acute ST-segment elevation myocardial infarction.

Background: This study sought to investigate the expression of soluble semaphorin 4D (sSema4D) in acute ST-segment elevation myocardial infarction (STEMI) and to explore its value in evaluating the inflammatory status of acute myocardial infarction (AMI). Methods: From October 2020 to June 2021, 100 patients with STEMI diagnosed at the Department of Cardiology of our hospital were selected as the STEMI group, 83 patients with unstable angina (UA) were selected as the UA group, and 78 patients with negative coronary angiography (CAG) were selected as the control group. The baseline data of the 3 groups of patients were recorded, the sSema4D levels were determined, the expression of sSema4D levels in AMI was analyzed, and the value of sSema4D levels in reflecting inflammatory state of AMI was explored. Results: Compared with UA group and control group, the expression of sSema4D in peripheral blood of STEMI group was significantly increased (P<0.001), which could better reflect the inflammatory status of patients with STEMI than traditional inflammatory indicators [hypersensitive c-reactive protein (hs-CRP)] (P<0.05). The receiver operating characteristic (ROC) curve showed that sSema4D (AUC =0.780, cut-off =19.62, 95% CI: 0.629, 0.837, P<0.001) was more specific than hs-CRP (AUC =0.697, cut-off =3.39, 95% CI: 0.629, 0.765, P<0.001) in reflecting the inflammatory status of STEMI patients. Conclusions: sSema4D levels have certain value in reflecting the inflammatory state of STEMI.

Association between pre-stroke sarcopenia risk and stroke-associated infection in older people with acute ischemic stroke.

Background: Stroke-associated infection (SAI) is a common complication after a stroke. The incidence of infection was higher in people with sarcopenia than in the general population. However, the relationship between pre-stroke sarcopenia risk and SAI in older patients has not been confirmed. This study aimed to investigate the association between pre-stroke sarcopenia risk and SAI in older patients with acute ischemic stroke (AIS). Methods: This retrospective study was conducted by the Peking University People's Hospital. We evaluated the pre-stroke sarcopenia risk by applying the SARC-F questionnaire. Multivariate logistic regression was applied to explore the association between pre-stroke sarcopenia risk and SAI. Results: A total of 1,002 elder patients with AIS (592 men; 72.9 ± 8.6 years) were enrolled in our study. Pre-stroke sarcopenia risk was found in 29.1% of the cohort. The proportion of patients with pre-stroke sarcopenia risk was larger in the SAI group than in the non-SAI group (43.2 vs. 25.3%, p < 0.001). In multivariate logistic analysis, pre-stroke sarcopenia risk was shown to be independently associated with SAI (OR = 1.454, 95% CI: 1.008-2.097, p = 0.045) after adjusting for potential factors. This association remained consistent across the subgroups based on age, sex, body mass index, smoking status, drinking status, diabetes, hypertension, and dyslipidemia. Conclusion: Pre-stroke sarcopenia risk was independently associated with SAI in older patients with AIS. Our findings highlight the significance of pre-stroke sarcopenia identification in the prevention and management of SAI in this population.

Inhibition of Astrocytic Carbohydrate Sulfotransferase 15 Promotes Nerve Repair After Spinal Cord Injury via Mitigation of CSPG Mediated Axonal Inhibition.

Nerve tissue regeneration is a significant problem. After neural diseases and damage such as spinal cord injury (SCI), the accumulation of chondroitin sulfate proteoglycans (CSPG) comprising axonal inhibitory glycosaminoglycan chains in the microenvironment is a major barrier that obstructs nerve repair. Interfering with the production of glycosaminoglycans, especially the critical inhibitory chains, could be a potential therapeutic strategy for SCI, which is, however, poorly defined. This study identifies Chst15, the chondroitin sulfotransferase controlling the generation of axonal inhibitory chondroitin sulfate-E, as a therapeutic target of SCI. Using a recently reported small molecular Chst15 inhibitor, this study investigates the effects of Chst15 inhibition on astrocyte behaviors and the associated consequences of in vivo disruption of the inhibitory microenvironment. Deposition of CSPGs in the extracellular matrix and migration of astrocytes are both significantly impaired by Chst15 inhibition. Administration of the inhibitor in transected spinal cord tissues of rats effectively promotes motor functional restoration and nerve tissue regeneration by a mechanism related to the attenuation of inhibitory CSPGs, glial scar formation and inflammatory responses. This study highlights the role of Chst15 in the CSPG-mediated inhibition of neural recovery after SCI and proposes an effective neuroregenerative therapeutic strategy that uses Chst15 as a potential target.

The function of Golgi apparatus in LRRK2-associated Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disease associated with the intracellular organelles. Leucine-rich repeat kinase 2 (LRRK2) is a large multi-structural domain protein, and mutation in LRRK2 is associated with PD. LRRK2 regulates intracellular vesicle transport and function of organelles, including Golgi and lysosome. LRRK2 phosphorylates a group of Rab GTPases, including Rab29, Rab8, and Rab10. Rab29 acts in a common pathway with LRRK2. Rab29 has been shown to recruit LRRK2 to the Golgi complex (GC) to stimulate LRRK2 activity and alter the Golgi apparatus (GA). Interaction between LRRK2 and Vacuolar protein sorting protein 52 (VPS52), a subunit of the Golgi-associated retrograde protein (GARP) complex, mediates the function of intracellular soma trans-Golgi network (TGN) transport. VPS52 also interacts with Rab29. Knockdown of VPS52 leads to the loss of LRRK2/Rab29 transported to the TGN. Rab29, LRRK2, and VPS52 work together to regulate functions of the GA, which is associated with PD. We highlight recent advances in the roles of LRRK2, Rabs, VPS52, and other molecules, such as Cyclin-dependent kinase 5 (CDK5) and protein kinase C (PKC) in the GA, and discuss their possible association with the pathological mechanisms of PD.

Reveal key genes and factors affecting athletes performance in endurance sports using bioinformatic technologies.

Medium-intensity activities comprise the major proportion of many sorts of sports. The energy consumption of athletes has been a research emphasis for the purpose of improving both training efficiency and competition performance. However, the evidence based on large-scale gene screen has been rarely performed. This is a bioinformatic study revealing the key factors contributed to the metabolic difference between subjects with different endurance activity capacities. A dataset comprised of high- (HCR) and low-capacity running (LCR) rats was used. Differentially expressed genes (DEGs) were identified and analysed. The Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment was obtained. The DEGs' protein-protein interaction (PPI) network was built, and the enriched terms of the PPI network were also analysed. Our findings showed that the GO terms were enriched in lipid metabolism-related terms. The KEGG signalling pathway analysis enriched in the ether lipid metabolism. Plb1, Acad1, Cd2bp2, and Pla2g7 were identified as the hub genes. This study provides a theoretical foundation showing lipid metabolism plays an important role in the performance of endurance activities. Plb1, Acad1, and Pla2g7 may be the key genes involved. The training plan and diet for athletes can be designed based on above results and expecting a better competitive performance.

Metabolic interaction between biflavonoids in Ginkgo biloba leaves and tacrolimus.

The aim of this study was to investigate the effect of biflavonoids in Ginkgo biloba leaves on tacrolimus metabolism. First, the inhibitory effects of five main biflavonoids (amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, bilobetin) in G. biloba leaves on tacrolimus metabolism were investigated in vitro in human liver microsomes (HLM), and the concentration-dependent inhibition was further calculated. Then the time-dependent inhibition activities of five biflavonoids were studied and the drug interaction was studied in Sprague-Dawley (SD) rats. Finally, the molecular mechanism of inhibition was explored by molecular docking. The results of in vitro incubation in HLM showed tacrolimus metabolism was strongly inhibited by amentoflavone, ginkgetin, and bilobetin, whose IC50 value was 5.57, 3.16, and 5.03 µM, respectively. The time-dependent inhibition of the three above biflavonoids at 50 µM was 33.47%-50.89%. In the in vivo study in rats, the AUC0-t and Cmax of tacrolimus increased 3.8-fold and 2.5-fold after oral preadministration with amentoflavone. The molecular docking results showed that the inhibitory effect may be related to the formation of hydrogen bonds. The results showed that long-term combination of G. biloba leaves and tacrolimus may cause drug-drug interactions. This study provided theoretical and experimental basis for rational drug use in clinical practice.

Interaction mechanism of Cu+/Cu2+ on bovine serum albumin: Vitro simulation experiments by spectroscopic methods.

Copper (Cu) is an essential trace element for organisms, while excessive concentration of Cu is toxic. In order to assess the toxicity risk of copper in different valences, FTIR, fluorescence, and UV-vis absorption techniques were conducted to study the interactions between either Cu+ or Cu2+ and bovine serum albumin (BSA) under vitro simulated physiological condition. The spectroscopic analysis demonstrated that the intrinsic fluorescence emitted by BSA could be quenched by Cu+/Cu2+ via static quenching with binding sites 0.88 and 1.12 for Cu+ and Cu2+, respectively. On the other hand, the constants of Cu+ and Cu2+ are 1.14 × 103 L/mol and 2.08 × 104 L/mol respectively. ΔH is negative whereas ΔS is positive, showing that the interaction between BSA and Cu+/Cu2+ was mainly driven by electrostatic force. In accordance with Föster's energy transfer theory, the binding distance r showed that the transition of energy from BSA to Cu+/Cu2+ is highly likely to happen. BSA conformation analyses indicated that the interactions between Cu+/Cu2+ and BSA could alter the secondary structure of proteins. Current study provides more information of the interaction between Cu+/Cu2+ and BSA, and reveals the potential toxicological effect of different speciation of copper at molecular level.

Inhibitory effect and mechanism of a compound essential oils on Cladophora glomerata.

Cladophora glomerata (C. glomerata) is a typical macroalgae inducing green tide and affecting economic benefits in aquaculture. A high-efficiency, environment friendly compound essential oils (CEOs) was provided to control C. glomerata blooms. The inhibition effect of CEOs against C. glomerata was assessed through the growth, cellular morphology and the physiological and biochemical indexes of C. glomerata. Results of the Chl-a content indicated that 300 µL/L CEOs could significantly inhibited the growth (85 % ± 2 %) of C. glomerata on the 11th day; the damage degree of algal thallus can be observed based on the results of cell morphology; the results of the physiological and biochemical indicators presented the decreased photosynthetic capacity, the dysfunction of antioxidant system and the algal apoptosis gene caspase- 8, 9, 3 activated when C. glomerata exposed to CEOs. This study elucidated the effect and mechanism of CEOs control the green tide induced by C. glomerata.

A Comprehensive Review of Health-Benefiting Components in Rapeseed Oil.

Rapeseed oil is the third most consumed culinary oil in the world. It is well-known for its high content of unsaturated fatty acids, especially polyunsaturated fatty acids, which make it of great nutritional value. There is increasing evidence that a diet rich in unsaturated fatty acids offers health benefits. Although the consumption of rapeseed oil cuts across many areas around the world, the nutritional elements of rapeseed oil and the exact efficacy of the nutrients remain unclear. In this review, we systematically summarized the latest studies on functional rapeseed components to ascertain which component of canola oil contributes to its function. Apart from unsaturated fatty acids, there are nine functional components in rapeseed oil that contribute to its anti-microbial, anti-inflammatory, anti-obesity, anti-diabetic, anti-cancer, neuroprotective, and cardioprotective, among others. These nine functional components are vitamin E, flavonoids, squalene, carotenoids, glucoraphanin, indole-3-Carbinol, sterols, phospholipids, and ferulic acid, which themselves or their derivatives have health-benefiting properties. This review sheds light on the health-benefiting effects of rapeseed oil in the hope of further development of functional foods from rapeseed.

Incidence and risk factors for second malignancies among patients with myeloproliferative neoplasms.

OBJECTIVE: The clinical characteristics and survival of patients with myeloproliferative neoplasms (MPNs) with secondary cancer were analyzed to explore the possible risk factors for secondary cancer in MPN patients. METHODS: The clinical characteristics of 1060 Chinese patients with MPN were retrospectively analyzed. The Kaplan-Meier method was used to analyze the survival. The Cox multivariate regression model was used to analyze the risk factors for developing secondary cancer in patients with MPNs. RESULTS: The 1060 patients with MPN had a median follow-up of 10 years (range 1-50) and a median age of 55 years (range 21-86), and 497 (45.2%) were male. The proportion of PV, ET, and PMF was 52.2%, 33.5%, and 14.3%, respectively. About 28.1% (298/1060) of 1060 MPN patients died. The median survival times of the PV, ET, and PMF groups were 20, 24, and 12 years, respectively (p < 0.0001). In age- and sex-matched healthy Chinese patients, the standardized incidence ratio (SIR) value of developing secondary cancer in MPN patients was 6.41 (95% CI: 4.90-9.48). The median survival time was 14 years in the MPN with secondary cancer group. The Cox multivariate analysis showed that age ≥ 65 years (p < 0.0001, HR = 5.027, 95% CI [2.823, 8.952]), MF-1 (p = 0.001, HR = 2.887, 95% CI [1.503, 5.545]) were risk factors for developing secondary cancer. CONCLUSIONS: The survival of MPN patients with secondary cancer was significantly worse than that of patients without secondary cancer. Compared with normal subjects, MPN patients had a 6.41-fold increased risk of developing secondary cancer, and age ≥ 65 years and MF-1 were risk factors for developing secondary cancer in MPN patients.

CD11b mediates hypertensive cardiac remodeling by regulating macrophage infiltration and polarization.

INTRODUCTION: Leukocyte infiltration is an early event during cardiac remodeling frequently leading to heart failure (HF). Integrins mediate leukocyte infiltration during inflammation. However, the importance of specific integrins in hypertensive cardiac remodeling is still unclear. OBJECTIVES: To elucidate the significance of CD11b in hypertensive cardiac remodeling. METHODS: Angiotensin (Ang II) or deoxycorticosterone acetate (DOCA)-salt was used to induce cardiac remodeling in mice of gene knockout (KO), bone marrow (BM) chimera, and the CD11b neutralizing antibody or agonist leukadherin-1 (LA1) treatment. RESULTS: Our microarray data showed that integrin subunits Itgam (CD11b) and Itgb2 (CD18) were the most highly upregulated in Ang II-infused hearts. CD11b expression and CD11b/CD18+ myelomonocytes were also time-dependently increased. KO or pharmacological blockade of CD11b greatly attenuated cardiac remodeling and macrophage infiltration and M1 polarization induced by Ang II or DOCA-salt. This protection was verified in wild-type mice transplanted with CD11b-deficient BM cells. Conversely, administration of CD11b agonist LA1 showed the opposite effects. Further, CD11b KO reduced Ang II-induced macrophage adhesion and M1 polarization, leading to reduction of cardiomyocyte enlargement and fibroblast differentiation in vitro. The numbers of CD14+CD11b+CD18+ monocytes and CD15+CD11b+CD18+ granulocytes were obviously higher in HF patients than in normal controls. CONCLUSION: Our data demonstrate an important role of CD11b+ myeloid cells in hypertensive cardiac remodeling, and suggest that HF may benefit from targeting CD11b.

Multiomics analysis revealed miRNAs as potential regulators of the immune response in Carassius auratus gills to Aeromonas hydrophila infection.

The gill of fish is an important immune organ for pathogen defense, but its microRNA (miRNA) expression and regulatory mechanism remain unclear. In this study, we report on the histopathological and immunohistochemical features of the gills of the crucian carp Carassius auratus challenged with Aeromonas hydrophila. Small RNA libraries of the gills were constructed and sequenced on the Illumina HiSeq 2000 platform. A total of 1,165 differentially expressed miRNAs (DEMs) were identified in gills, of which 539 known and 7 unknown DEMs were significantly screened (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the potential target genes/proteins were primarily involved in 33 immune-related pathways, in which the inflammatory responses were focused on the Toll-like receptor (TLR), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathways. Moreover, the expression levels of 14 key miRNAs (e.g., miR-10, miR-17, miR-26a, miR-144, miR-145, and miR-146a) and their target genes (e.g., TNFα, TLR4, NF-κB, TAB1, PI3K, and IRAK1) were verified. In addition, the protein levels based on isobaric tags for relative and absolute quantification (iTRAQ) were significantly associated with the results of the quantitative real-time PCR (qRT-PCR) analysis (p < 0.01). miR-17/pre-miR-17 were identified in the regulation expression of the NF-κB target gene, and the phylogenetic tree analysis showed that the pre-miR-17 of C. auratus with the closest similarity to the zebrafish Danio rerio is highly conserved in teleosts. This is the first report of the multi-omics analysis of the miRNAs and proteins in the gills of C. auratus infected with A. hydrophila, thus enriching knowledge on the regulation mechanism of the local immune response in Cyprinidae fish.

Study of the permeation-promoting effect and mechanism of solid microneedles on different properties of drugs.

In transdermal drug delivery systems, the physicochemical properties of the drug affect its percutaneous permeability. However, whether the physicochemical properties of drugs change their transdermal permeability in the presence of pores in the presence of solid microneedles (MNs) has been less studied in this area. In this project, cinnamaldehyde, curcumin, ferulic acid and geniposide were selected as model drugs for the study of their transdermal permeability under the action of MNs, and a combination of classical experiments and visualization means such as scanning electron microscopy and laser confocal was used to investigate the permeation-promoting mechanism of MNs. The results showed that the MNs had significant permeation-promoting effects on different properties of drugs, with the permeation-promoting effects on cinnamaldehyde, curcumin, ferulic acid and geniposide being 6.36, 17.43, 29.54 and 8.91 times, respectively, and the permeation-promoting effects were more pronounced for lipid-soluble and amphiphilic drugs. Using scanning electron microscopy, transmission electron microscopy and other means to confirm that MNs can promote the penetration by acting on the skin to produce pores, and their effect on skin structure is greater than that of drugs. In addition, the existence of pores increases the amount of drug transdermal, which may enhance the diffusion of drug on the skin, and has no effect on lipid exchange and transdermal route. Through the research, it has been found that MNs is equivalent to direct peeling of the stratum corneum (SC), but it is simpler and safer for the patient.

ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via ß-catenin signaling and enhances mitomycin C sensitivity.

The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and ß-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of ß-catenin and strongly influences the chemosensitivity of BC cells.

Differences in in vivo absorption of flavone glycosides, flavone aglycones and terpene lactones under different dosage forms and physiological conditions.

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. extract (GBE) oral preparations have been used for many years in the prevention and treatment of cardiovascular and cerebrovascular diseases, and the main active ingredients are flavonoids and terpene lactones. Among them, the oral absorption of the prototype components of flavonoid glycosides into the blood needs to be further clarified, and the differences in the oral absorption of different components in GBE by different dosage forms and physiological conditions are not clear yet. AIM OF THE STUDY: To clarify the oral absorption of the prototype flavonoid glycosides in vivo, and to further explore the differences in the oral absorption of various active compounds under different oral dosage forms and dietary conditions. MATERIALS AND METHODS: Firstly, the target compounds were selected based on the characteristic chromatogram of GBE and literature. Then, the content differences of three different oral GBE preparations were studied, and their pharmacokinetics (PK) were compared. Finally, the PK differences of the preparations with better oral absorption under different dietary conditions were studied. RESULTS: Five flavonoid glycosides, three aglycones and four terpene lactones were selected as the research objects. The content determination results of GBE tablets, guttate pills and tinctures showed that the content of several components especially flavonoid glycosides in the tincture was higher than that of the other two preparations. After oral administration of these three preparations, the PK study showed different results from previous studies. The PK behavior of flavonoid glycosides was also determined at the same time as flavonoid glycosides and terpene lactones. and the bioavailability of flavonoid glycosides in the tincture was higher than that of the other two preparations. PK results of fasting and non-fasting showed that taking GBE tincture on an empty stomach increased the absorption of various compounds, especially flavonoid glycosides. However, due to the existence of food residues in the gastrointestinal tract, the oral bioavailability of flavonoid glycosides was significantly improved. CONCLUSIONS: This study discussed the differences in the content and oral absorption of active compounds in different oral preparations of GBE, clarified the in vivo absorption of flavonoid glycosides prototype, as well as the influence of diet on the PK of active compounds, which has certain guiding significance for the clinical application of GBE oral preparations.

Targeting soluble epoxide hydrolase promotes osteogenic-angiogenic coupling via activating SLIT3/HIF-1α signalling pathway.

Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross-talk between co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co-cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31hi EMCNhi endothelial cells (ECs) and SLIT3 and HIF-1α expression levels in co-cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif-1α in HUVECs impaired the formation of CD31hi EMCNhi ECs and reversed TPPU-induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs-derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF-1α signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair.

Emerging evidence on the effects of plant-derived microRNAs in colorectal cancer: a review.

Food nutrition and human health are still interesting international issues. Early detection, risk assessment and diet are vital to mitigate the load of intestinal diseases and enhance the quality of life. Plant-derived microRNAs could be transferred to mammalian organisms by cross-kingdom regulation which adjusts relevant target genes for their participation in the process of carcinogenesis. But the mechanism of plant-derived microRNAs in colorectal cancer is still unclear. This review aims to summarize the current pathways of plant-derived microRNAs in colorectal cancer including intestinal bacteria, the tumor microenvironment, plant active substances and protein, discuss the direct or indirect effects of plant-derived microRNAs on the occurrence and/or progression of colorectal cancer and explain why plant-derived microRNAs can be used as a potential anti-cancer agent. Moreover, the drawbacks of plant-derived microRNAs are also discussed in terms of both edible plants and synthetic delivery vectors for RNAi interference technology for human disease treatment. This review will provide a potential way for plant-derived microRNAs to target colorectal cancer.

USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells.

Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6-8 weeks old) were intraperitoneally injected with 10% CCl4 in olive oil (5 µl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 µl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-ß1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis.