FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease.

BACKGROUND AND PURPOSE: Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation. METHODS: The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber-DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH-DA staining was adopted to visualize reactive oxidative species (ROS). RESULTS: FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite. CONCLUSIONS: FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Effect of modified okara insoluble dietary fibre on the quality of yoghurt.

The aim of this study was to investigate the potential of adding soya bean dregs insoluble dietary fibre (IDF) modified by jet cavitation combined with cellulase to yoghurt to improve its functional properties (Yoghurt was prepared by adding 10 µL of yoghurt fermenter to 100 mL of milk, fermented to pH 4.5 in a constant temperature incubator at 42 °C, and then stored in a refrigerator at 4 °C after adding IDF separately). The results showed that the modified IDF had a rough structure with high water-holding capacity and sodium cholate adsorption capacity. The addition of modified IDF improved the pH, hardness, and elasticity of the yoghurt. During the entire storage period, the titratable acidity and whey precipitation rate of the modified IDF yoghurt gradually increased, and antioxidant activity gradually decreased, and its titratable acidity, whey precipitation rate, and antioxidant activity had a significant advantage compared with those of the blank group yoghurt. In conclusion, the modified soya bean dregs IDF-added yoghurt prepared by jet cavitation combined with the cellulase method has the potential for sodium cholate adsorption capacity and antioxidant activity, which can confer unique functional properties and improve the pH, texture, and reduce whey precipitation of yoghurt. This study provides a scientific basis for the application of soya bean dregs IDF as a fibre fortifier in yoghurt production and suggests innovative ideas for the design of functional dairy products.

Logistic analysis of the recurrence of laparoscopic percutaneous extraperitoneal repair of pediatric inguinal hernia: A report of 486 cases.

BACKGROUND: Although the laparoscopic treatment of pediatric inguinal hernia (PIH) has more benefits than traditional surgery, it is difficult to completely avoid the problem of recurrence. The aim of this study was to use a logistic regression model to investigate the causes of recurrence after laparoscopic percutaneous extraperitoneal repair (LPER) of PIH. PATIENTS AND METHODS: From June 2017 to December 2021, 486 cases of PIH were performed using LPER in our department. We utilized a two-port approach to implement LPER for PIH. All cases were followed up and the recurrent cases were recorded in detail. We used a logistic regression model to analyze the clinical data in order to find the reasons for recurrence. RESULTS: We completed 486 cases with an internal inguinal ostium high ligation using laparoscopic surgery without conversion. Patients were followed for 10-29 months with an average of 18.2 months and 8 cases had recurrent ipsilateral hernia, including 4 recurrent cases in 89 cases (4.49%) using absorbable suture, 1 in 7 cases (14.29%) with internal inguinal ostium larger than 25 mm, 2 in 26 cases (7.69%) with BMI greater than 21, 2 in 41 cases (4.88%) with postoperative chronic constipation. The total recurrence rate was 1.65%. A foreign body reaction occurred in 2 cases, there were no complications such as scrotal hematoma, trocar umbilical hernia and testicular atrophy, and no deaths in this study. Univariate logistic regression analysis showed that patient BMI, ligation suture, diameter of the internal inguinal ostium and postoperative chronic constipation were significant variables (P values 0.093, 0.027, 0.060 and 0.081). The multivariate logistic regression analysis showed that the ligation suture and the diameter of the internal inguinal ostium were the main risk factors for postoperative recurrence, the odds ratio (OR) value were 5.374 and 2.801, the P values 0.018 and 0.046, and the 95% CI were 2.513-11.642 and 1.134-9.125. The area under ROC curve (AUC) for the logistic regression model was 0.735 (the 95% CI 0.677-0.801, P < 0.01). CONCLUSION: An LPER for PIH is a safe and effective operation, but there still remains a small probability of recurrence. In order to reduce the recurrence rate of LPER, we should improve surgical skills, choose an appropriate ligature and avoid using LPER for a huge internal inguinal ostium (especially over 25 mm). It is appropriate to be converted to open surgery for the patients with a very wide internal inguinal ostium.

Farnesoid X receptor overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in nonalcoholic fatty liver disease.

Oxidative stress-mediated activation of inflammasome has a significant effect on the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Farnesoid X receptor (NR1H4, FXR) has been implicated in biological function and many diseases, including NAFLD. The regulatory effect of FXR on oxidative stress and whether this process is related with the activation of absent melanoma 2 (AIM2) inflammasome in NAFLD remain unclear. In the present research, we confirmed that FXR in the livers of steatosis patients is significantly reduced compared with normal liver tissue by using the Gene Expression Omnibus (GEO) database and a palmitic acid (PA) - mediated steatosis model in AML-12 cells. Under the premise of ensuring the same food intake as the control group, overexpression of FXR in mice attenuated HFD-mediated weight gain and liver steatosis, facilitated lipid metabolism, improved fatty acid ß-oxidation, lipolysis, and reduced fatty acid synthesis and intake, which also inhibited the activation of AIM2 inflammasome. Overexpression of FXR alleviated PA-induced triglyceride (TG) accumulation, imbalance of lipid homeostasis, and the activation of AIM2 inflammasome in hepatic steatosis cells, while FXR knockdown appeared the opposite effects. FXR overexpression suppressed PA- and HFD-induced oxidative stress, but FXR siRNA demonstrated the opposite influence. The decreased ROS generation may be the reason why FXR weakens AIM2 activation when a fatty acid overload occurs. In conclusion, our results confirm that other than regulating lipid homeostasis and blocking NLRP3 inflammasome activation, FXR improves hepatic steatosis by a novel mechanism that inhibits oxidative stress and AIM2 inflammasome activation.

Epigenetic modification of TWIST1 in macrophages promotes hypertension-induced atherosclerotic plaque instability.

It is accepted that hypertension is a major, independent risk factor for atherosclerotic cardiovascular ischemic events, which are mainly attributed to the formation of unstable, vulnerable atherosclerotic lesions. But the mechanisms by which hypertension aggravates atherosclerosis (AS) through increased macrophage recruitment are unknown. It has been reported that TWIST1 can regulate the shear stress of blood flow in endothelial cells to promote the development of atherosclerosis, but the function of TWIST1 in macrophage recruitment during hypertension remains undefined. Here, the roles of TWIST1 in macrophage activation during N w -nitro-l-arginine-methyl ester (L-NAME; NO-synthase (NOS) inhibitor)-induced hypertension were investigated in ApoE-/- mice fed a high-fat diet (HFD) and RAW264.7 cells treated with oxidized low-density lipoprotein(ox-LDL). Oil Red O staining and hematoxylin and eosin staining were adopted to analyze atherosclerotic lesions and plaque instability. Chromatin immunoprecipitation (ChIP)-PCR was used to explore whether Lysine-specific histone demethylase 1A (LSD1/KDM1A) and Variegated suppressor 3-9 homolog 1 (SUV39H1) could regulate histone modification of the TWIST1 promoter. We reported that L-NAME increased the expression of TWIST1 in the aortic tissues of ApoE-/- mice fed a high-fat diet (HFD) and RAW264.7 cells treated with ox-LDL. TWIST1 accelerated the development of an unstable atherosclerotic phenotype by promoting macrophage activation, inflammatory factor secretion, macrophage polarization, and lipid phagocytosis. Moreover, we found that H3K9me2 and H3K9me3 in the TWIST1 promoter could be coregulated by LSD1 and SUV39H1, and this process was modulated by CK2α. Taken together, these results revealed that TWIST1 in macrophages is a critical factor that mediates foam cell formation and enhances atherosclerotic plaque vulnerability during hypertension, and targeting TWIST1 may be a promising new therapeutic approach for delaying the progression of AS in hypertension.

Catalpol ameliorates dexamethasone-induced osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via the activation of PKD1 promoter.

OBJECTIVE: To investigate the effects of CA on glucocorticoid-induced osteoporosis (GIOP) and lucubrate the underlying mechanism of CA via the activation of polycystic kidney disease-1(PKD1) in bone marrow mesenchymal stem cells (BMSCs). METHODS: In vivo, a GIOP model in mice treated with dexamethasone (Dex) was established. Biomechanical, micro-CT, immunofluorescence staining of OCN, ALP and PKD1 and others were severally determined. qRT-PCR and Western blot methods were adopted to elucidate the particular mechanisms of CA on GIOP. In addition, BMSCs cultured in vitro were also induced by Dex to verify the effects of CA. Finally, siRNA and luciferase activity assays were performed to confirm the mechanisms. RESULTS: We found that CA could restore the destroyed bone microarchitecture and increase the bone mass in GIOP mice. CA could also upregulate PKD1 protein expression, reduce oxidative stress, and promote mRNA expression of bone formation-associated markers in GIOP mice. Furthermore, it was also observed that CA reduced oxidative stress and promoted osteogenic differentiation in Dex-induced BMSCs. Mechanically, CA could promote protein expression via increasing the activity of PKD1 promoter. CONCLUSION: This study provides important evidences for CA in the further clinical treatment of GIOP, reveals the activation of PKD1 promoter as the underlying mechanism.

Restoration and preservation effects of mung bean antioxidant peptides on H2O2-induced WRL-68 cells via Keap1-Nrf2 pathway.

Mung bean antioxidant peptides (MBAPs) were prepared from mung bean protein hydrolysate, and four peptide sequences including Ser-Asp-Arg-Thr-Gln-Ala-Pro-His (~953 Da), Ser-His-Pro-Gly-Asp-Phe-Thr-Pro-Val (~956 Da), Ser-Asp-Arg-Trp-Phe (~710 Da), and Leu-Asp-Arg-Gln-Leu (~644 Da) were identified. The effects of MBAPs on the oxidation-induced normal human liver cell line WRL-68 were analyzed to determine the mechanism protecting the oxidation-induced injury. The results showed that the cells were subjected to certain oxidative damage by H2O2 induction, as evidenced by decreased cell number and viability, overproduction of intracellular ROS, and decreased mitochondrial membrane potential. Compared with the H2O2-induced group, the MBAP-treated oxidation-induced group exhibited significantly higher cell number and viability, and the intracellular ROS was similar to that of the control group, suggesting that MBAP scavenges excessive intracellular free radicals after acting on the oxidation-induced cells. Combined with Western blotting results, it was concluded that the MBAP-treated oxidation-induced group also significantly promoted the expression of proteins related to the kelch-like ech-related protein 1 (Keap1)/ nuclear factor e2-related factor 2 (Nrf2) signaling pathway, which resulted in an approximately 2-fold increase in antioxidant enzymes, and a decrease in malondialdehyde content of approximately 55% compared to oxidatively-induced cells, leading to the recovery of both cell morphology and viability. These results suggest that MBAPs scavenge intracellular free radicals and improve oxidative stress in hepatocytes through the expression of Keap1/Nrf2 pathway-related protein, thereby reducing oxidative attack on the liver. Therefore, MBAP is applied as a nutritional ingredient in the functional food field, and this study provides a theoretical basis for the high utilization of mung bean proteins.

The efficacy and safety assessment of oncolytic virotherapies in the treatment of advanced melanoma: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of oncolytic virotherapies in the treatment of advanced melanoma still remains controversal. It is necessary to conduct quantitative evaluation on the basis of preclinical trial reports. METHODS: Publicly available databases (PubMed, Embase, Medline, Web of Science and Cochrane Library.) and register (Clinicaltrials.gov) were searched to collect treatment outcomes of oncolytic virotherapies (including herpes simplex virus type 1 (HSV), coxsackievirus A21 (CVA21), adenovirus, poxvirus and reovirus) for advanced/unresectable melanoma. Comparisons of treatment response, adverse events (AEs) and survival analyses for different virotherapies were performed by R software based on the extracted data from eligible studies. RESULTS: Finally, thirty-four eligible studies were analysed and HSV virotherapy had the highest average complete response (CR, 24.8%) and HSV had a slightly higher average overall response rate (ORR) than CVA21 (43.8% vs 42.6%). In the pooled results of comparing talimogene laherparepve (T-VEC) with or without GM-CSF/ICIs (immune checkpoint inhibitors) to GM-CSF/ICIs monotherapy suggested virotherapy was more efficient in subgroups CR (RR = 1.80, 95% CI [1.30; 2.51], P < 0.01), ORR (RR = 1.17, 95% CI [1.02; 1.34], P < 0.05), and DCR (RR = 1.27, 95% CI [1.15; 1.40], P < 0.01). In patients treated with T-VEC+ICIs, 2-year overall survival (12.1 ± 6.9 months) and progression-free survival (9.9 ± 6.9) were significantly longer than those treated with T-VEC alone. Furthermore, we found that AEs occurred frequently in virotherapy but decreased in a large cohort of enrolled patients, some of which, such as abdominal distension/pain, injection site pain and pruritus, were found to be positively associated with disease progression in patients treated with T-VEC monotherapy. CONCLUSION: Given the relative safety and tolerability of oncolytic viruses, and the lack of reports of dose-limiting-dependent toxicities, more patients treated with T-VEC with or without ICIs should be added to future assessment analyses. There is still a long way to go before it can be used as a first-line therapy for patients with advanced or unresectable melanoma.

Ganoderma lucidum polysaccharide peptide (GLPP) attenuates rheumatic arthritis in rats through inactivating NF-κB and MAPK signaling pathways.

BACKGROUND: Not many drugs with fewer side effects are available for the treatment of rheumatoid arthritis (RA). Ganoderma lucidum polysaccharide peptide (GLPP) has good immunomodulatory effects, but whether it is effective in managing RA is not clear. PURPOSE: This study was conducted to examine the anti-RA activity and possible mechanisms of GLPP in collagen-induced arthritis (CIA) rats. METHODS: Male Wistar rats were intradermally injected with bovine type II collagen in the tail base to establish the CIA model and were orally administered 100 or 200 mg/kg GLPP for 35 days. Paw thickness, clinical arthritis scores, gait analysis, organ index determination, blood cell counts, micro-CT imaging and pathological staining were performed on the rats. Liver and kidney function were measured by commercial kits, and antibody levels were measured by ELISA kits. RA-related protein levels were detected by Western blotting. RESULTS: GLPP effectively alleviated CIA symptoms and reduced immune organ indexes, antibody levels and systemic organ injury. GLPP decreased the protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, matrix metalloproteinase (MMP)2, MMP9, MMP13, BCL-2, OPN, ß-Catenin, and hypoxia inducible factor (HIF)-1α and increased the protein expression of BAX in the joint tissues of CIA rats. Moreover, GLPP decreased the phosphorylation levels of p65, IκB-α and ERK1/2. CONCLUSION: GLPP effectively alleviated RA symptoms in CIA rats by inhibiting the NF-κB and MAPK pathways. This study suggests a promising therapeutic effect of mushroom-derived polysaccharide peptides on RA.

Recent advances in exploring and exploiting soybean functional peptides-a review.

Soybeans are rich in proteins and phytochemicals such as isoflavones and phenolic compounds. It is an excellent source of peptides with numerous biological functions, including anti-inflammatory, anticancer, and antidiabetic activities. Soy bioactive peptides are small building blocks of proteins that are released after fermentation or gastrointestinal digestion as well as by food processing through enzymatic hydrolysis, often in combination with novel food processing techniques (i.e., microwave, ultrasound, and high-pressure homogenization), which are associated with numerous health benefits. Various studies have reported the potential health benefits of soybean-derived functional peptides, which have made them a great substitute for many chemical-based functional elements in foods and pharmaceutical products for a healthy lifestyle. This review provides unprecedented and up-to-date insights into the role of soybean peptides in various diseases and metabolic disorders, ranging from diabetes and hypertension to neurodegenerative disorders and viral infections with mechanisms were discussed. In addition, we discuss all the known techniques, including conventional and emerging approaches, for the prediction of active soybean peptides. Finally, real-life applications of soybean peptides as functional entities in food and pharmaceutical products are discussed.

The role of cancer-associated fibroblasts in breast cancer metastasis.

Breast cancer deaths are primarily caused by metastasis. There are several treatment options that can be used to treat breast cancer. There are, however, a limited number of treatments that can either prevent or inhibit the spread of breast tumor metastases. Thus, novel therapeutic strategies are needed. Studies have increasingly focused on the importance of the tumor microenvironment (TME) in metastasis of breast cancer. As the most abundant cells in the TME, cancer-associated fibroblasts (CAFs) play important roles in cancer pathogenesis. They can remodel the structure of the extracellular matrix (ECM) and engage in crosstalk with cancer cells or other stroma cells by secreting growth factors, cytokines, and chemokines, as well as components of the ECM, which assist the tumor cells to invade through the TME and cause distant metastasis. Clinically, CAFs not only foster the initiation, growth, angiogenesis, invasion, and metastasis of breast cancer but also serve as biomarkers for diagnosis, therapy, and prediction of prognosis. In this review, we summarize the biological characteristics and subtypes of CAFs and their functions in breast cancer metastasis, focusing on their important roles in the diagnosis, prognosis, and treatment of breast cancer. Recent studies suggest that CAFs are vital partners of breast cancer cells that assist metastasis and may represent ideal targets for prevention and treatment of breast cancer metastasis.

Modification of the Structural and Functional Characteristics of Mung Bean Globin Polyphenol Complexes: Exploration under Heat Treatment Conditions.

During the storage and processing of mung beans, proteins and polyphenols are highly susceptible to interactions with each other. Using globulin extracted from mung beans as the raw material, the study combined it with ferulic acid (FA; phenolic acid) and vitexin (flavonoid). Physical and chemical indicators were combined with spectroscopy and kinetic methods, relying on SPSS and peak fit data to statistically analyze the conformational and antioxidant activity changes of mung bean globulin and two polyphenol complexes before and after heat treatment and clarify the differences and the interaction mechanism between globulin and the two polyphenols. The results showed that, with the increase in polyphenol concentration, the antioxidant activity of the two compounds increased significantly. In addition, the antioxidant activity of the mung bean globulin-FA complex was stronger. However, after heat treatment, the antioxidant activity of the two compounds decreased significantly. The interaction mechanism of the mung bean globulin-FA/vitexin complex was static quenching, and heat treatment accelerated the occurrence of the quenching phenomenon. Mung bean globulin and two polyphenols were combined through a hydrophobic interaction. However, after heat treatment, the binding mode with vitexin changed to an electrostatic interaction. The infrared characteristic absorption peaks of the two compounds shifted to different degrees, and new peaks appeared in the areas of 827 cm-1, 1332 cm-1, and 812 cm-1. Following the interaction between mung bean globulin and FA/vitexin, the particle size decreased, the absolute value of zeta potential increased, and the surface hydrophobicity decreased. After heat treatment, the particle size and zeta potential of the two composites decreased significantly, and the surface hydrophobicity and stability increased significantly. The antioxidation and thermal stability of the mung bean globulin-FA were better than those of the mung bean globulin-vitexin complex. This study aimed to provide a theoretical reference for the protein-polyphenol interaction mechanism and a theoretical basis for the research and development of mung bean functional foods.

Effects of cavitation-jet technology combined with enzyme treatment on the structure properties and functional properties of OKARA insoluble dietary fiber.

In this study, a new composite modification method utilizing a cavitation jet combined with a composite enzyme (cellulase and xylanase) was developed to modify the insoluble dietary fibre (IDF) of okara (IDF was first treated with the cavitation jet at 0.3 MPa for 10 min, and then 6% of the enzyme was added, the composite enzyme with a 1:1 enzyme activity was hydrolysed for 1.5 h to obtain the modified IDF), and explored the structure-activity relationship between the structural properties, physicochemical properties and biological activities of IDF before and after modification. Under the action of cavitation jet and double enzyme hydrolysis, the modified IDF had a wrinkled and loose porous structure, which improved the thermal stability. Its water holding capacity (10.81 ± 0.17 g/g), oil holding capacity (4.83 ± 0.03 g/g) and swelling capacity (18.60 ± 0.60 mL/g) were significantly higher than those of unmodified IDF. In addition, compared with other IDFs, the combined modified IDF had greater advantages in nitrite adsorption (13.75 ± 0.14 µg/g), glucose adsorption (6.46 ± 0.28 mmol/g) and cholesterol adsorption (16.86 ± 0.83 mg/g), and improved in vitro probiotic activity and in vitro anti-digestion rate. The results show that the cavitation jet combined with compound enzyme modification method can effectively improve the economic value of okara.

Protective Effect of Polyphenols, Protein, Peptides, and Polysaccharides on Alcoholic Liver Disease: A Review of Research Status and Molecular Mechanisms.

Alcoholic liver disease (ALD) has emerged as an important public health problem in the world. The polyphenols, protein, peptides, and polysaccharides have attracted attention for prevention or treatment of ALD. Therefore, this paper reviews the pathogenesis of ALD, the relationship between polyphenols, peptides, polysaccharides, and ALD, and expounds the mechanism of gut microbiota on protecting ALD. It is mainly found that the hydroxyl group of polyphenols endows it with antioxidation to protect ALD. The ALD protection of bioactive peptides is related to amino acid composition. The ALD protection of polysaccharides is related to the primary structure. Meanwhile, polyphenols, protein, peptides, and polysaccharides prevent or treat ALD by antioxidation, anti-inflammatory, antiapoptosis, lipid metabolism, and gut microbiota regulation. This contribution provides updated information on polyphenols, protein, peptides, and polysaccharides in response to ALD, which will not only facilitate the development of novel bioactive components but also the future application of functional food raw materials will be promoted.

Effect of ultrasound combined with exogenous GABA treatment on polyphenolic metabolites and antioxidant activity of mung bean during germination.

Mung bean seeds were treated by a combination of ultrasound and γ-aminobutyric acid (GABA). Effect of these treatments on the free polyphenols content, antioxidant activity, and digestibility of mung bean sprouts was evaluated. Additionally, phenolic compounds were analyzed and identified using a metabolomics approach. The combined ultrasound and GABA treatments significantly enhanced the free polyphenols and flavonoids content (P < 0.05) of mung bean sprouts depending on sprouting duration. Besides, a positive correlation (P < 0.05) was found between the polyphenols content and in vitro antioxidant activity of mung bean sprouts. Moreover, a total number of 608 metabolites were detected, and 55 polyphenol compounds were identified, including flavonoids, isoflavones, phenols, and coumarins. Also, the KEGG metabolic pathway analysis revealed 10 metabolic pathways of phenols, including flavonoid, isoflavone, and phenylpropanoid biosynthesis. Powder of 48 h sprouted mung bean released polyphenols during simulated gastric digestion and possessed antioxidant activity.

Carboxylated superparamagnetic Fe3O4 nanoparticles modified with 3-amino propanol and their application in magnetic resonance tumor imaging.

BACKGROUND: Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are of potential magnetic resonance imaging (MRI) contrast agents for tumor diagnosis. However, ultrasmall particle size or negative surface charge lead to relative short half-life which limit the utilization of USPIO for in vivo MRI contrast agents. METHODS: Superparamagnetic Fe3O4 nanoparticles coated with polyacrylic acid (PAA)were synthetized, and modified by 3-amino propanol and 3-diethyl amino propyl amine. The characteristics of superparamagnetic Fe3O4 nanoparticles were investigated through transmission electron microscopy, X-ray diffraction analysis, Zata potential analysis, thermogravimetric analysis, and relaxation properties analysis. Magnetic resonance imaging animal experiment was performed. RESULTS: The synthetized nanoparticles were irregular spherical, with small particle size, few agglomeration, and good dispersion in water. After modification, the potential fluctuation of nanoparticles was small, and the isoelectric point of nanoparticles changed to high pH. After 3-amino propanol modification, the weight loss of the curve from 820 to 940 °C was attributed to the decomposition of 3-amino propanol molecules on the surface. The T1 relaxation rate of nanoparticles changed little before and after modification, which proved that the modification didn't change the relaxation time. Brighter vascular images were observed after 3-amino propanol modification through measurement of magnetic resonance tumor imaging. CONCLUSION: These data indicated the Fe3O4 nanoparticles modified by 3-amino propanol should be a better contrast agent in the field of magnetic resonance tumor imaging.

Comparative Inhibitory Effects of Natural Biflavones from Ginkgo against Human CYP1B1 in Recombinant Enzymes and MCF-7 Cells.

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.

Novel Potent EGFR-JAK3 Dual-Target Inhibitor that Overcomes KRAS Mutation Resistance in Colorectal Cancer.

BACKGROUND: In-depth and clear mechanistic study is a prerequisite for new drugs to enter clinical research. METHODS: New chemical entity BY4008 was identified by our lab as a novel and highly potent EGFR and JAK3 dualtarget inhibitor. A cell-based test exhibited strong antiproliferative activities against SW620 and HCT116 colon cancer cells harboring KRAS mutation with IC50 of nanomolar potency. Furthermore, acridine orange/ethidium bromide (AO/EB), Hematoxylin-Eosin (H&E) and DAPI staining assays and flow cytometry analyses indicated that BY4008 has the function of pro-apoptosis and arresting the cell cycle. In addition, BY4008 inhibited the autophosphorylation of EGFR and blocked the activation of downstream signaling and the JAK-STAT3 pathway. RESULTS: Meanwhile, a decreased level of reactive oxygen species (ROS) and an increased level of malondialdehyde (MDA) in SW620 and HCT116 cells were observed after exposure to BY4008. CONCLUSION: In summary, this study provides an important structural basis and mechanistic study for future effective treatment of colorectal cancer.

Anti-Postmenopausal osteoporosis effects of Isopsoralen: A bioinformatics-integrated experimental study.

Isopsoralen (IPRN), which comes from the fruit of Psoralea corylifolia, has been identified as a kind of phytoestrogen and has been proven to be effective for the treatment of osteoporosis (OP). However, the mechanisms underlying IPRN's anti-OP effects, especially the anti-postmenopausal osteoporosis (PMOP) effects, remain indistinct. Thus, this study aimed to investigate the effects and mechanisms of IPRN's anti-PMOP activity. In this study, the bioinformatics results predicted that IPRN could resist PMOP by targeting EGFR, AKT1, SRC, CCND1, ESR1 (ER-α), AR, PGR, BRCA1, PTGS2, and IGF1R. An ovariectomized (OVX) mice model and a H2 O2 -induced bone marrow mesenchyml stem cells (BMSCs) model confirmed that IPRN could inhibit the bone loss induced by OVX in mice and promote the osteogenic differentiation in H2 O2 -induced BMSCs by inhibiting oxidative stress and apoptosis. Moreover, IPRN could significantly produce the above effects by upregulating ESR1. IPRN might be a therapeutic agent for PMOP by acting as an estrogen replacement agent and a natural antioxidant.