Abstract Atherosclerotic cardiovascular disease continues to pose a major threat to human health. It has been shown that Chinese herbal medicines rich in palmatine(PAL) exert significant beneficial effects on atherosclerosis(AS). However, the specific biological functions and mechanisms of PAL in AS remain unclear. In this study, we investigated the effects of PAL on the core pathological changes in macrophage foam cell formation, a key process in the development of AS. The results demonstrated that PAL significantly reduced the formation of lipid droplets and accumulation of cholesterol ester in oxidized low-density lipoprotein (OX-LDL)-induced macrophage foam cells. RNA-sequencing was used to comprehensively analyze the effect of PAL. The findings revealed that the peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway is the primary target of PAL in suppressing foam cell formation. Real-time fluorescence quantitative polymerase chain reaction and western blotting results confirmed that PAL substantially upregulated the transcription and expression levels of lipid metabolism-related proteins, such as PPAR-γ and liver X receptor-α (LXR-α), whereas it inhibited the transcription of inflammatory factors TNF-α, interleukin-1β (IL-1β), and IL-6. These biological changes were reversed by treatment with the PPAR-γ inhibitor T0070907. Molecular docking analysis showed that the binding sites of PAL with PPAR-γ (325THR) is close to the reported PPAR-γ agonist rosiglitazone（323HIS）, suggesting that PAL may act as a PPAR-γ partial agonist to improve atherosclerosis. Collectively, the results of this study suggest that PAL promotes cholesterol efflux and inhibits inflammatory responses mainly by regulating the PPAR-γ signaling pathway, thus ameliorating macrophage foam cell formation. Our findings may provide a foundation for further research on the pharmacological activity and potential value of PAL in the treatment of AS.

JinQi Jiangtang tablet (JQJTT) is a Chinese patent medicine that has been shown to be beneficial for patients with diabetes both preclinically and clinically; however, the molecular mechanism underlying the effects of JQJTT remains unclear. In this study, surface plasmon resonance fishing was employed to identify JQJTT constituent molecules that can specifically bind to fibroblast growth factor receptor 1 (FGFR1), leading to the retrieval of palmatine (PAL), a key active ingredient of JQJTT. In vivo and in vitro experiments demonstrated that PAL can significantly stimulate FGFR1 phosphorylation and upregulate glucose transporter type 1 (GLUT-1) expression, thereby facilitating glucose uptake in insulin resistance (IR) HepG2 cells as well as alleviating hyperglycemia in diabetic mice. Our results revealed that PAL functions as an FGFR1 activator and that the hypoglycemic effect of JQJTT is partially dependent on the PAL-induced activation of the FGFR1 pathway. In addition, this study contributed to the understanding the pharmacodynamic basis and mechanism of action of JQJTT and provided a novel concept for future research on PAL.

The aim of this study was to investigate the therapeutic effect of JQ-R on metabolic hypertension and its correlation with Fibroblast growth factor 21/Fibroblast growth factor receptors 1(FGF21/FGFR1) pathway. In this study, fructose-induced metabolic hypertension rats were used as hypertension models to detect the regulation effect of JQ-R on hypertension. The effects of JQ-R on blood glucose, blood lipids, serum insulin levels and other metabolic indicators of rats were also measured. The effects of JQ-R on FGF21/FGFR1 signaling pathway in model animals were detected by Real-time quantitative PCR and Western blotting. The results showed that JQ-R significantly reduce the blood pressure of model rats in a dose-dependent manner. Meanwhile, fasting insulin, fasting blood glucose, insulin resistance index, total cholesterol and triglyceride levels were significantly decreased, and glucose and lipid metabolism abnormalities were also significantly improved. JQ-R induces these changes along with FGFR1 phosphorylation, which was also detected in JQ-R treated FGF21 knockout mice. These results suggest that JQ-R can reduce blood pressure and improve glucose and lipid metabolism in fructose-induced hypertension rats. Activation of FGF21/FGFR1 signaling pathway to regulate downstream blood pressure and glucolipid metabolism-related pathways may be one of the important mechanisms of JQ-R in regulating blood pressure.

Age-related macular degeneration (AMD) is the main cause of blindness in elderly individuals. As a metabolic regulator, fibroblast growth factor 21 (FGF-21) has been proven indicated to have an effect on wet AMD, but whether this cytokine has a therapeutic effect on dry AMD is unclear. The current study aimed to evaluate the preventive effects of FGF-21 against retinal degeneration in mice and provide mechanistic insights. FGF-21-/- mice were raised to 10 months of age. Then, the morphological changes in the retinal pigment epithelium (RPE)/choroid of the mice were observed by transmission electron microscopy (TEM), and iTRAQ was used to detect the variations in the protein profile. Next, FGF-21-/- and wild-type mice of the same age were fed hydroquinone to generate a dry AMD mouse model to examine whether exogenous FGF-21 can interfere with the occurrence and development of dry AMD. In vivo studies revealed that following FGF-21 knockout, there was an increase in the expression of complement in the RPE/choroid concomitant with the occurrence of dry AMD-like pathological changes. Furthermore, exogenous FGF-21 administration effectively reversed this phenomenon. FGF-21 also demonstrated strong anti-inflammatory effects in the RPE/choroid by inhibiting the NF-κB pathway. In conclusion, the present study demonstrates that FGF-21 treatment presents a novel therapeutic approach for the prevention and development of dry AMD by reducing complement.

Context Genistein (Gen) has shown protective effects against ageing process. Objective To explore the role of Gen on the senescence of H2O2-induced human umbilical vein endothelial cells (HUVECs) and investigate the possible mechanism. Materials and methods HUVECs were treated with different concentrations of H2O2 (50, 100, 200 and 400 mu mol/L) for 1 h or Gen administration (20, 40, 80 and 160 mu g/mL) for 24 h. Functional experiments (cell counting kit-8, beta-galactosidase staining and flow cytometry) were used to detect the effect of Gen on H2O2-induced HUVECs. After HUVECs were transfected with TXNIP overexpression plasmids, the expression of p16, p21, thioredoxin-interacting protein (TXNIP), nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3), cleaved caspase-3 and cleaved caspase-1 in HUVECs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results H2O2 (200 and 400 mu mol/L) inhibited the proliferation of HUVECs. At concentrations of >50 mu mol/L, H2O2 induced the cell cycle progression arrests in G1 phase and promoted cell senescence of HUVECs. Gen had no obvious cytotoxicity to HUVECs below 160 mu g/mL. H2O2-induced HUVEC senescence and the expression of TXNIP and NLRP3 in HUVECs were down-regulated by Gen (40 and 80 mu g/mL). Expressions of TXNIP and NLRP3 in HUVECs were up-regulated by H2O2 but down-regulated by Gen. Overexpressed TXNIP partially reversed the suppressive effect of Gen on H2O2-induced senescence and apoptosis of HUVECs. Expressions of p16, p21, TXNIP, NLRP3, cleaved caspase-3 and cleaved caspase-1 in H2O2-treated HUVECs were inhibited by Gen, while the inhibition as such was partially reversed by overexpressed TXNIP. Discussion and conclusions H2O2-induced HUVEC senescence was alleviated by Gen via suppressing the TXNIP/NLRP3 axis, which may offer a potential therapeutic approach for improving HUVEC senescence and provide a new direction for the treatment of cardiovascular disease.

Chronic pancreatitis (CP) is a progressive, irreversible inflammatory and fibrotic disease. The characteristics of this disease are progressive inflammation, acinar atrophy and fibrosis. Numerous factors are involved in CP such as inflammation, and oxidative stress. Recently, it has been noted that fibroblast growth factor 21 (FGF-21) reduced the severity of acute pancreatitis in mice. However, whether FGF-21 has effects on CP remains unclear. Thus, the present study was undertaken to detect the effects of FGF-21 on l-arginine induced chronic pancreatitis/islet fibrosis in mice. We used l-arginine to create a CP model in C57BL/6 mice and treated these mice with FGF-21. Compared to normal mice, blood glucose and intra-peritoneal glucose tolerance test (IPGTT) revealed significant impairment in CP animal model. CP mice also had acinar atrophy, loss of pancreas morphology, inflammatory cells infiltration, extensive deposition of collagen, elevated -SMA expression, collagen I expression, serum amylase activity, MPO activity and MDA level. All these pathological changes were significantly improved by FGF-21 treatment. Moreover, FGF-21 ameliorated inflammatory state in the serum, pancreas and peritoneal macrophages of CP mice. Furthermore, we also found that FGF-21 could regulate differentiation of macrophages so as to improve pancreatic fibrogenesis in CP mice. Taken together, our study identifies the beneficial role of FGF-21 in CP and suggests that FGF-21 improves pancreatic fibrogenesis in CP via the mTOR pathway.

Objective Obesity‐related, chronic, low‐grade inflammation has been identified as a key factor in the development of many metabolic diseases, such as type 2 diabetes and cardiovascular diseases. Adipocytes, preadipocytes, and macrophages have been implicated in initiating inflammation in adipose tissue. This study aims to investigate the effects of fibroblast growth factor‐21 (FGF‐21) on obesity‐related inflammation and its mechanisms in vivo and in vitro. Methods Monosodium glutamate (MSG) was used to induce obesity in mice and subsequently treated the mice with or without FGF‐21. Primary adipocytes and stromal vascular fraction cells were isolated from MSG‐obesity mice for additional experiments. Results Results obtained by ELISA and real‐time polymerase chain reaction showed that FGF‐21 efficiently ameliorated obesity‐related inflammation in MSG‐obesity mice. This study demonstrated that preadipocytes and adipocytes responded to anti‐inflammatory effects of FGF‐21. In vitro, 3 T3‐L1 preadipocytes lacking β‐klotho did not respond to FGF‐21 under glucose uptake. Interestingly, the treatment of 3 T3‐L1 preadipocytes with FGF‐21 significantly attenuated lipopolysaccharide‐induced inflammatory response. Conclusions Our study showed that FGF‐21–induced glucose uptake and FGF‐21–related anti‐inflammatory effects are mediated by different signaling pathways. Moreover, FGF‐21 showed anti‐inflammatory effects on preadipocytes; these effects are mediated by the fibroblast growth factor receptor substrate 2/ERK1/2 signaling pathway.

Type 2 diabetes mellitus (T2DM) is accompanied by abnormal glucose metabolism and low-grade chronic inflammation. Fibroblast growth factor 21 (FGF-21) is a novel metabolic regulator and can function as an endocrine hormone to regulate glucose and lipid metabolism. Recently, FGF-21 was found to have anti-inflammatory effect, to our knowledge, the effect of FGF-21 on inflammatory state in diabetes has not been elucidated. Here, we use db/db mice as a Type 2 diabetes model to determine whether FGF-21 alleviates inflammatory state while improves hyperglycemia. Our results demonstrated that FGF-21 not only showed potent long lasting hypoglycemic effect, but also demonstrated strong anti-inflammatory effect in the serum and white adipose tissue. Besides, in vitro experiments, insulin resistance (IR) was induced in 3T3-L1 adipocytes by treating with TNF-α. Our results showed that TNF-α impaired glucose metabolism of 3T3-L1 adipocytes but FGF-21 repressed gene expression of inflammatory factors caused by IR and consequently improved the glucose metabolism in 3T3-L1 adipocytes. Furthermore, FGF-21 ameliorated glucose uptake of TNF-α-induced IR in 3T3-L1 adipocytes by inhibiting NF-κB signaling pathway.

Monocytes display a gradual change in metabolism during inflammation. When activated, the increase in glucose utilization is important for monocytes to participate in immune and inflammatory responses. Further studies on the mechanism underlying this biological phenomenon may provide a new understanding of the relationship between immune response and metabolism. The THP-1 cells were used as a monocyte model. The cells were activated with lipopolysaccharide (LPS). Glucose uptake was measured using flow cytometry. The expression of fibroblast growth factor 21 (FGF-21), glucose transporter 1 (GLUT-1), and other FGF-21 signaling pathway-related factor mRNAs was determined by real-time polymerase chain reaction. Further, the relationship between FGF-21 expression in monocytes and phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling pathway was determined by Western blotting. LPS elevated FGF-21 expression in monocytic THP-1 cells in vitro. Functional assays showed that the phenomenon in which LPS and FGF-21 stimulated glucose uptake in monocytic THP-1 cells could be inhibited by FGFR inhibitor. The mechanism of elevation of FGF-21 was found to involve the PI3K/Akt signaling pathway. This study indicated that FGF-21 could regulate the immune response indirectly by influencing the glucose uptake of activated monocytes cells.

目的 研究成纤维细胞生长因子-21(fibroblast growth factor-21,FGF-21)抑制脂多糖(LPS)诱导的急性炎症的作用及机制.方法 构建LPS诱导的小鼠急性炎症模型,FGF-21高、中、低剂量进行处理后,HE染色法观察肺部组织病理学变化,ELISA法检测血清中肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6、IL-17含量,实时荧光定量聚合酶链反应(PCR)法检测TNF-α、IL-1β、IL-6、IL-17表达量,激光共聚焦和Western blot法检测腹腔巨噬细胞核因子(NF)-κB蛋白向细胞核内转移情况.结果 FGF-21干预后,模型小鼠肺部损伤明显减轻,炎性浸润细胞减少.血清和腹腔巨噬细胞中TNF-α、IL-1β、IL-6、IL-17含量均显著降低且成剂量依赖性趋势.激光共聚焦和Western-blot结果均显示,FGF-21能够抑制NF-κB向细胞核内转移.结论 FGF-21能够作用于巨噬细胞调控机体免疫系统,通过NF-κB信号通路缓解小鼠炎症反应状态可能是FGF-21调节免疫系统的机制之一.

Our previous report has shown that FGF21 has anti-inflammatory properties in a collagen-induced arthritis (CIA) model. In this study, the underlying molecular mechanisms of action were also investigated using RAW 264.7 cells, a murine monocyte-macrophage. RAW 264.7 cells were pre-incubated with various concentrations (2000, 500, 100ng/ml) of FGF21 and stimulated with LPS to induce oxidative stress and inflammation. The result of flow cytometry showed that β-Klotho, FGF21 specific receptor, was expressed in murine splenic macrophages and RAW 264.7. In vitro, FGF21 reduced the expression of TNF-α, IL-1β, IL-6 and IFN-γ and increased the level of IL-10 in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages. FGF21 also suppressed profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level, and restored the activities of antioxidant enzymes SOD and GSH-Px in LPS-stimulated RAW 264.7 macrophages. Moreover, FGF21 inhibited LPS-induced nuclear factor-κB (NF-κB) activation, including degradation of I-κB and nuclear translocation of p65. In addition, the result of Western blot and real-time PCR showed that FGF21 induced heme oxygenase-1 (HO-1) expression and increased the nuclear transcription factor-E2-related factor 2 (Nrf2) levels in a dose-dependent manner in LPS-stimulated RAW 264.7 macrophages. In conclusion, the results suggest that macrophages are the targets for the anti-inflammatory effects of FGF21, and FGF21 exerted an anti-inflammatory effect mainly via enhancing Nrf2-mediated anti-oxidant capacity and suppressing NF-κB signaling pathway.

Recently, FGF21 was reported to play an important role in anti-inflammation. The aim of the study is to explore the mechanism for FGF21 alleviating inflammation of CIA. CIA mice were injected with FGF21 once a day for 28 days after first booster immunization. The results showed that FGF21 alleviates arthritis severity and decreases serum anti-CII antibodies levels in CIA mice. Compared with CIA model, the number of the splenic TH17 cells was significantly decreased in FGF21-treated mice. FGF21 treatment reduced the mRNA expression of IL-17, TNF-α, IL-1β, IL-6, IL-8, and MMP3 and increased level of IL-10 in the spleen tissue. The expression of STAT3 and phosphorylated STAT3 was suppressed in FGF21-treated group. The mRNA expression of RORγt and IL-23 also decreased. In conclusion, these findings suggest that the beneficial effects of FGF21 on CIA mice were achieved by down-regulating Th17-IL-17 axis through STAT3/RORγt pathway. Modulating of Th17-mediated inflammatory response may be one of the mechanisms for FGF21 attenuating inflammation in CIA.

Recombinant Newcastle Disease Virus (rNDV) has shown oncolytic therapeutic effect in preclinical studies. Previous data indicate that rNDV carrying IL2 has shown promise in cancer therapy. Due to the significant side effects of IL2, IL15 has been introduced into cancer therapy. A number of studies have suggested that IL15 efficiently enhances the activities of CTL and NK cells and inhibits the tumor recurrence and metastasis. Furthermore, IL15 is less toxic than IL2. Therefore, we hypothesize that a recombinant NDV expressing IL15 would be a promising agent for the treatment of malignant tumors. The human IL15 gene or IL2 gene was incorporated into the genome of lentogenic LaSota strain at the position between the HN and L genes (namely rNDV-IL15 or rNDV-IL2). The two viruses efficiently infected tumor cells and expressed IL15 or IL2 protein. Melanoma tumor-bearing mice were treated by intra-tumoral (i.t.) injection of rNDV-IL15 or rNDV-IL2. Both rNDV-IL15 and rNDV-IL2 effectively suppressed tumor growth compared with rNDV. The 120-day survival rate of rNDV-IL15- treated group was 12.5% higher than that of rNDV-IL2 group, although the difference was not statistically significant, both recombinant viruses had strong abilities to induce CD41 T cell and CTL cell responses. However, rNDV-IL15 significantly induced more IFN-γ release and stimulated more CD81 T cells infiltration in the tumor sites compared with rNDV-IL2. In the tumor re-challenged experiment, the survival rates of rNDV-IL15 group and rNDV-IL2 group were statistically higher than that of PBS group. The survival rate of rNDV-IL15 group was 26.67% higher than that of rNDV-IL2 group although the difference was not statistically significant. In conclusion, rNDV-IL15 is a promising antitumor agent against melanoma.

It has been demonstrated that circulating FGF21 levels are elevated in the serum and synovial fluid of patients with rheumatoid arthritis (RA). The aim of this study is to investigate efficacy of FGF21 for treatment of RA and the molecular mechanisms of the therapeutic effect on collagen-induced arthritis (CIA). Mice with CIA were subcutaneously administered with FGF21 (5, 2 or 1mg·kg(-1)·d(-1)), IL-1β antibody (5mg·kg(-1)·d(-1)), IL-17A antibody (5mg·kg(-1)·d(-1)) and dexamethasone (DEX) (1mg·kg(-1)·d(-1)), respectively. The effects of treatment were determined by arthritis severity score, histological damage and cytokine production. The activation of NF-κB was analyzed by Western blotting. We also detected the levels of oxidative stress parameters. Our results showed that FGF21 had beneficial effects on clinical symptom and histological lesion of CIA mice. Similar to antibody and DEX, FGF21 treatment alleviated the severity of arthritis by reducing humoral and cellular immune responses and down-regulating the expression of pro-inflammatory cytokines. FGF21 treatment also reduced the expression of TNF-α, IL-1β, IL-6, IFN-γ and MMP-3 and increased level of IL-10 in the spleen tissue or the plasma of CIA mice in a dose-dependent manner. Furthermore, FGF21 inhibited IκBα degradation and NF-κB p65 nuclear translocation and induced significant changes of oxidative stress parameters (MDA, SOD, CAT, GSH-PX and GSH) in the plasma. FGF21 exerts therapeutic efficacy for RA through antioxidant reaction and inhibiting NF-κB inflammatory pathway. This study provides evidence that FGF21 may be a promising therapeutic agent for RA patients.

The aim of this study is to investigate the role of FGF21 in obesity-related inflammation in livers of monosodium glutamate (MSG)-induced obesity rats. The MSG rats were injected with recombinant murine fibroblast growth factor 21(FGF21) or equal volumes of vehicle. Metabolic parameters including body weight, Lee’s index, food intake, visceral fat and liver weight, intraperitoneal glucose tolerance, glucose, and lipid levels were dynamically measured at specific time points. Liver function and routine blood test were also analyzed. Further, systemic inflammatory cytokines such as glucose transporter 1 (GLUT-1), leptin, TNF-α, and IL-6 mRNAs were determined by real-time PCR. FGF21 independently decreased body weight and whole-body fat mass without reducing food intake in the MSG rats. FGF21 reduced blood glucose level, Lee’s index, visceral fat, and liver weight, and improved glucose tolerance, lipid metabolic spectrum, and hepatic steatosis in the MSG-obesity rats. Liver function parameters including AST, ALT, ALP, TP, T.Bili, and D.Bili levels significantly reduced in the FGF21-treated obesity rats compared to the controls. Further, FGF21 ameliorated the total and differential white blood cell (WBC) count, serum C-reactive protein (CRP), IL-6, and TNF-α levels in adipose tissues of the obesity rats, suggesting inflammation amelioration in the in the obesity rats by FGF21. FGF21 improves multiple metabolic disorders and ameliorates obesity-related inflammation in the MSG-induced obesity rats.

FGF21 is recently discovered with pleiotropic effects on glucose and lipid metabolism. However, the potential protective effect of FGF21 against D-gal-induced injury in the liver has not been demonstrated. The aim of this study is to investigate the pathophysiological role of FGF21 on hepatic oxidative injury and apoptosis in mice induced by D-gal. The 3-month-old Kunming mice were subcutaneously injected with D-gal (180 mg kg(-1) d(-1)) for 8 weeks and administered simultaneously with FGF21 (5 or 1 mg kg(-1) d(-1)). Our results showed that the administration of FGF21 significantly alleviated histological lesion including structure damage, degeneration, and necrosis of hepatocytes induced by D-gal, and attenuated the elevation of liver injury markers, serum AST, and ALP in a dose-dependent manner. FGF21 treatment also suppressed D-gal-induced profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level in the liver, and restored the activities of antioxidant enzymes SOD, CAT, GSH-Px, and T-AOC. Moreover, FGF21 treatment increased the nuclear abundance of Nrf2 and subsequent up regulation of several antioxidant genes. Furthermore, a TUNEL assay showed that D-gal-induced apoptosis in the mouse liver was significantly inhibited by FGF21. The expression of caspase-3 was markedly inhibited by the treatment of FGF21 in the liver of D-gal-treated mice. The levels of PI3K and PBK/Akt were also largely enhanced, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 and Bax proteins in the liver of D-gal-treated mice. In conclusion, these results suggest that FGF21 protects the mouse liver against D-gal-induced hepatocyte oxidative stress via enhancing Nrf2-mediated antioxidant capacity and apoptosis via activating PI3K/Akt pathway.

Fibroblast growth factor 21 (FGF21) is a hormone secreted predominantly in the liver, pancreas and adipose tissue. Recently, it has been reported that FGF21-Transgenic mice can extend their lifespan compared with wild type counterparts. Thus, we hypothesize that FGF21 may play some roles in aging of organisms. In this study d-galactose (d-gal)-induced aging mice were used to study the mechanism that FGF21 protects mice from aging. The three-month-old Kunming mice were subcutaneously injected with d-gal (180mg·kg−1·d−1) for 8weeks and administered simultaneously with FGF21 (1, 2 or 5mg·kg−1·d−1). Our results showed that administration of FGF21 significantly improved behavioral performance of d-gal-treated mice in water maze task and step-down test, reduced brain cell damage in the hippocampus, and attenuated the d-gal-induced production of MDA, ROS and advanced glycation end products (AGEs). At the same time, FGF21 also markedly renewed the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total anti-oxidation capability (T-AOC), and decreased the enhanced total cholinesterase (TChE) activity in the brain of d-gal-treated mice. The expression of aldose reductase (AR), sorbitol dehydrogenase (SDH) and member-anchored receptor for AGEs (RAGE) declined significantly after FGF21 treatment. Furthermore, FGF21 suppressed inflamm-aging by inhibiting IκBα degradation and NF-κB p65 nuclear translocation. The expression levels of pro-inflammatory cytokines, such as TNF-α and IL-6, decreased significantly. In conclusion, these results suggest that FGF21 protects the aging mice brain from d-gal-induced injury by attenuating oxidative stress damage and decreasing AGE formation.

Fibroblast growth factor 21 (FGF21), a recently discovered regulatory factor, plays an important role in glucose and lipid metabolism. In this study, we firstly found the FGF21 expression in white blood cells (WBCs). Then, we enrolled 51 women with gestational diabetes mellitus (GDM) and 50 pregnant women with normal blood glucose levels to determine the FGF21 levels in the WBCs and the sera at the 28th week of pregnancy, and tracked the dynamic changes of FGF21 in these women until the 7th day postpartum. Repeated Measures analysis of variance (ANOVA) revealed that there was a significant interaction effect between group and time on FGF21 levels (P < 0.05). FGF21 levels were significantly higher in the GDM patients than those in the controls at the 28th week of pregnancy. The 7th day after the delivery, the FGF21 levels decreased in the WBCs and the sera in both groups. The D values (the difference between pregnancy and postpartum) for FGF21 levels were significantly higher in the GDM group (P < 0.05). Serum FGF21 level during gestation positively correlated with leptin, triglyceride, and HDL-cholesterol, and FGF21 may act as a glucose and lipid metabolism compensatory regulatory factor to improve glucose and lipid metabolism during the period of pregnancy. Further, FGF21 level in the WBCs (during pregnancy and the D values for FGF21) was chiefly influenced by GDM.

To investigate the cell-killing effect and its possible mechanism of rClone30-hDR5 in combination with TRAIL on human hepatic carcinoma (HCC) cell line, first of all, recombinant plasmid pee12.4-hDR5 was introduced into HepG2 cells by liposome transfection. After five rounds of screening by flow cytometry, HepG2 cells expressing high levels of DR5 on cell surface were isolated. The cytotoxicity of TRAIL to selected cells was higher than that of TRAIL to HepG2 cells by MTT method (P < 0.01). The result suggested that the cloned hDR5 gene had biological activity. MTT assay showed that, rClone30- hDR5 in combination with TRAIL more efficiently inhibited the tumor growth of HepG2 cells compared to rClone30-hDR5 or TRAIL in vitro. The results of Annexin V-FITC/PI staining and Quantitative Real-time PCR indicated that rClone30-hDR5 in combination with TRAIL significantly increased the mRNA levels of caspase 3 and caspase 8, and induced the apoptosis of tumor cells. HepG2 cells were infected with rClone30-hDR5 or rClone30 at MOI of 1. The expression of hDR5 on tumor surface increased significantly by rClone30-hDR5 compared to that by rClone30, which contributed to the sensitivity to TRAIL. In conclusion, rClone30-hDR5 in combination with TRAIL has potential application value in cancer treatment.

Newcastle disease virus (NDV) is an intrinsically tumor-specific virus, several clinical trials have reported that mesogenic NDV is a safe and effective agent for human cancer therapy. Interleukin 2 (IL2) is a cytokine that stimulates T cell propagation to trigger innate and adaptive immunity. IL2 has been used for cancer therapy and has achieved curative effects. In this study, a recombinant NDV LaSota strain expressing human interleukin 2 (rLaSota/IL2) was generated. The ability of rLaSota/IL2 to express human IL2 was detected in the infected tumor cells. In addition, the activity of IL2 was analyzed. The antitumor potential of rLaSota/IL2 was studied by xenograph mice carrying H22 and B16-F10 cells. Tumor-specific CD4(+) and CD8(+) T cells and MHC II were also analyzed in the two tumor-bearing models. Our study showed that rLaSota/IL2 significantly stimulated tumor-specific cytotoxic T-lymphocyte (CTL) responses and increased regulatory CD4(+) and cytotoxic CD8(+) T cells proliferation. The treatment with rLaSota/IL2 led to tumor regression in tumor-bearing mice and prolonged the survival of tumor-bearing mice. Furthermore, tumor challenging experiments demonstrated that rLaSota/IL2 invoked mice a unique capacity to remember a pathogen through the generation of memory T cells, which protect the host in the event of reinfection and form adaptive immune system. The result indicates that tumor-infiltrating CD4(+) T regulatory cells may denote the effective regression of tumors. Taken together, rLaSota/IL2 has potential for immunotherapy and oncolytic therapy of cancers and may be an ideal candidate for clinical application in future cancer therapy.