Alteration of cognitive function in overweight and obese adolescents and its relationship with serum FGF21 levels / 上海交通大学学报（医学版）

Objective·To evaluate the changes in cognitive function in overweight and obese adolescents,and explore the association between cognitive function and fibroblast growth factor 21(FGF21).Methods·A total of 175 adolescents from a senior high school in Shanghai were divided into normal weight group(n=50),overweight group(n=50)and obese group(n=75)based on their body mass index(BMI).General information,anthropometric data and laboratory testing indicators of the adolescents were collected and compared.The cognitive function of the three groups of adolescents was assessed by using the accuracy(ACC)and reaction time of Flanker task and n-back task.Enzyme-linked immunosorbent assay(ELISA)was used to detect the serum FGF21 level of the three groups of adolescents.Partial correlation analysis and multiple linear regression model were used to evaluate the correlation between cognitive task performance and anthropometric data and laboratory testing indicators.Results·Compared with the normal weight group,systolic blood pressure,diastolic blood pressure,and the levels of fasting plasma glucose,glycosylated hemoglobin and triacylglycerol in the obese group were higher(all P<0.05).Under congruent or incongruent stimulus conditions in the Flanker task,there was no significant difference in ACC between any two groups;compared with the normal weight and overweight groups,the reaction time of the adolescents in the obese group was prolonged(all P<0.05).In the n-back task,there were no significant differences in ACC between any two groups,while the obese group had longer reaction time in the 1-back and 2-back tasks compared to the normal weight and overweight groups(all P<0.05).Compared with the normal weight group,serum FGF21 levels of the adolescents in the obese group were higher(P=0.000).Partial correlation analysis showed that the reaction time of the adolescents in Flanker and n-back tasks was correlated with their BMI,body fat mass,waist circumference,waist-to-hip ratio and FGF21 level(all P<0.05).Multiple linear regression analysis further confirmed that BMI was associated with prolonged reaction time in cognitive-related behavioral tasks in the adolescents(all P<0.05),and FGF21 level was associated with ACC in the 2-back task(P=0.000)and reaction time in the incongruent stimulus condition(P=0.048).Conclusion·Overweight and obese adolescents have cognitive impairments,and BMI and serum FGF21 levels are associated with changes in their cognitive function.

FGF21 regulates liver cell lipid metabolism through the SOCS3/JAK/STAT pathway / 中国现代医生

@#Objective By knocking down the expression of fibroblast growth factors 21(FGF21)in adipose liver cells,to observe lipid metabolism and to explore the molecular mechanism of FGF21 regulating lipid metabolism in liver cells.Methods By interfering with lentivirus transfection through FGF21,the expression of FGF21 was reduced in HepG2 cells.HepG2 cells were transfected with an empty vector as a control,and were respectively referred to as interference group and control group.Both groups were stimulated with palmitic acid oleic acid to construct non-alcoholic fatty liver disease(NAFLD)cell model.The expression of FGF21 was interfered by lentivirus vector,oil red O staining and spectrophotometric value were measured to observe the lipid deposition in cells.Use Western blot method to detect the changes of suppressor of cytokine signaling 3(SOCS3),JAK2,and STAT3 proteins in fatty liver cells.Results Oil red O staining and absorbance values showed that compared with control group,interference group significantly reduced the lipid droplet content in liver cells;Western blot results showed that the expression levels of suppressor of cytokine signaling 3(SOCS3),Janus kinase 2(JAK2),signal transducer and activator of transcription 3(STAT3),and STAT3 protein were significantly increased in interference group of liver cells.Conclusion In the fatty liver cell model,knocking down FGF21 can improve lipid deposition through liver cells.The mechanism may be through increasing the SOCS3/JAK/STAT pathway,but the specific mechanism of action needs further in-depth research in the future.

FGF1-based Drugs for The Treatment of Obesity-related Complications / 生物化学与生物物理进展

At present, the incidence of overweight and obesity has reached epidemic levels worldwide, which call a challenge to the prevention and control of chronic metabolic diseases. Because obesity is a major risk factor for a range of metabolic diseases, including type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular and neurodegenerative diseases, sleep apnea, and some types of cancer. However, the drugs remain limited. Therefore, there is an urgent need to develop effective long-term treatments to address obesity-related complications. Fibroblast growth factor 1 (FGF1) is an important regulator of systemic energy homeostasis, glycolipid metabolism and insulin sensitivity. FGF1 is a non-glycosylated polypeptide consisting of 155 amino acids, consisting of 12 inverted parallel β chains with amino and carboxyl terminus, and N-terminus extending freely without the typical secretory signaling sequence, closely related to its own biological activity. Thus, FGF1 mutants or derivatives with different activities can be designed by substitution or splicing modification at theN-terminal. FGF1 plays an irreplaceable role in the development, deposition and function of fat. High-fat diet can regulate available FGF1 through two independent mechanisms of nutritional perception and mechanical perception, and influence the function of fat cells. FGF1 controls blood glucose through peripheral and central effects, enhances insulin sensitivity, improves insulin resistance, and plays a role in diabetic complications, which is expected to become a new target for the treatment of T2DM in the future. FGF1 may be involved in the regulation of NAFLD from mild steatosis to severe non-alcoholic steatohepatitis. FGF1 is closely related to the occurrence and development of a variety of cancers, improve the efficacy of anti-cancer drugs, and play a direct and indirect anti-cancer role. In addition, FGF1 plays an important role in the occurrence and development of the cardiovascular system and the improvement of cardiovascular diseases such as ischemia/reperfusion injury, myocardial infarction, pathological cardiac remodeling, cardiotoxicity. Therefore, FGF1 shows a number of therapeutic benefits in the treatment of obesity and obesity-related complications. But because FGF1 has strong mitotic activity and long-term use has been associated with an increased risk of tumorigenesis, its use in vivo has been limited and enthusiasm for developing it to treat obesity-related complications has been dampened. However, FGF1 was found to induce cell proliferation primarily through FGFR3 and FGFR4, but its metabolic activity was mainly mediated by FGFR1. That is, FGF1 activity that promotes mitosis and anti-obesity-related complications appears to be separable. Currently, many engineered FGF1 variants have been developed, such as FGF1ΔHBS, MT-FGF1ΔHBS, FGF1∆NT, ∆nFGF1, FGF1R50E. Although the effect of FGF1 or its analogues on obesity-related complications has been demonstrated in many rodent studies, there are no relevant clinical results. This may be due to the unknown safety and therapeutic efficacy of FGF1 in large animals and humans, as well as concerns about tumorigenesis that hinder its development into a lifelong therapeutic agent. This review summarizes recent advances in the development of FGF1-based biologic drugs for the treatment of obesity-related complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these obstacles.

Use of FGF21 analogs for the treatment of metabolic disorders: a systematic review and meta-analysis

ABSTRACT FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.

Refractory Rickets

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets. In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets

Highly Expressed hsa_circRNA_103124 Inhibits Macrophage M2 Polarization by Down-regulating FGF18 in Crohn's Disease / 胃肠病学

Background:Crohn's disease(CD)was a kind of inflammatory bowel disease,whichwas chronic and recurrent attacked,seriously affect the quality of life of patients.Its pathogenesis is not clear.Aims:To study the effect of hsa_circRNA_103124 which was highly expressed in CD on its downstream gene expression,and the expression level of hsa_circRNA_103124 and its downstream genes in Crohn's disease.The mechanism of hsa_circRNA_103124 in the occurrence and development of CD was discussed in this study.Methods:Transcriptome sequencing revealed differentially expressed genes inhsa_circRNA_103124 overexpressed THP1 cells which was induced macrophage-like differentiation with PMA.IL4 was used to induce macrophage M2 differentiation in hsa_circRNA_103124 overexpressed THP1 cells.The expression levels of M2 differentiation markers CD206 and CD163 were detected by flow cytometry.The expression levels of hsa_circRNA_103124 and its downstream genes were analyzed by qPCR.The levels of hsa_circRNA_103124 and mRNA of its downstream genes in peripheral blood mononuclear cells of 30 patients with CD and 30 healthy controls were analyzed by qPCR.Results:Hsa_circRNA_103124 overexpressed and PMA-induced THP1 cells showed low expression of FGF18(P<0.01).Hsa_circRNA_103124 inhibited macrophage M2 differentiation and down-regulated the expression of CD206(P<0.05)and CD163(P<0.01).The expression of FGF18(P<0.05)and CCL2(P<0.05)was down-regulated in M2-polarized THP1 cells with hsa_circRNA_103124 overexpressed.The expression of hsa_circRNA_103124(P<0.05)in peripheral blood mononuclear cells of CD patients was up-regulated,and the expression of FGF18(P<0.01)and CCL2(P<0.05)was down-regulated.Conclusions:The high expression of hsa_circRNA_103124 in peripheral blood of patients with CD inhibits the M2 polarization of macrophages by down-regulating the expression levels of FGF18 and CCL2,which may play a role in promoting inflammation in the occurrence and development of CD.

Research progress on pathogenesis and potential therapeutic target of sarcopenia obesity / 中国临床药理学与治疗学

Sarcopenia obesity (SO), a specific disease with co-occurrence of obesity and sarcopenia, is shown clinically as abnormal accumulation of fat, decreased mass and strength of muscle, and increased risk of incidence and mortality of other chronic diseases. Currently, there exist various definitions and diagnoses about SO in the various regions of the world. Its prevalence in populations elevates in an age-dependent manner. This article summarized the possible pathogenesis of SO from the view of chronic inflammation, oxidative stress, insulin resistance, and Hippo pathway, subsequently listed and analyzed potential pharmacological targets (fibroblast growth factor, CD44, adiponectin, etc) involved in treating SO, in order to provide new ideas for clinical diagnosis, treatment of SO patients and research and development of innovative drugs.

Research Progress of β-Klotho in Energy Metabolism and Tumor Development / 中国生物化学与分子生物学报

β-Klotho (KLB) is a member of the Klotho protein family, which is mainly distributed in organs and tissues such as the liver, fat, pancreas, and brain. KLB is a single-pass transmembrane protein whose structural characteristics determine that KLB acts as a co-receptor for fibroblast growth factor (FGF) 19/21 targeting the activation of fibroblast growth factor receptor (FGFRs). KLB is involved in the regulation of blood glucose, lipids, body weight, bile acid circulation, and hepatocyte proliferation in the FGF21/19-KLB-FGFRs pathway. This paperwill review the structural characteristics and distribution of KLB, as well as the regulatory mechanism of material energy and its role in tumor formation in the FGF19/21-KLB-FGFRs pathways.

Fgf8P2A-3×GFP/+: A New Genetic Mouse Model for Specifically Labeling and Sorting Cochlear Inner Hair Cells / 神经科学通报·英文版

The cochlear auditory epithelium contains two types of sound receptors, inner hair cells (IHCs) and outer hair cells (OHCs). Mouse models for labelling juvenile and adult IHCs or OHCs exist; however, labelling for embryonic and perinatal IHCs or OHCs are lacking. Here, we generated a new knock-in Fgf8P2A-3×GFP/+ (Fgf8GFP/+) strain, in which the expression of a series of three GFP fragments is controlled by endogenous Fgf8 cis-regulatory elements. After confirming that GFP expression accurately reflects the expression of Fgf8, we successfully obtained both embryonic and neonatal IHCs with high purity, highlighting the power of Fgf8GFP/+. Furthermore, our fate-mapping analysis revealed, unexpectedly, that IHCs are also derived from inner ear progenitors expressing Insm1, which is currently regarded as an OHC marker. Thus, besides serving as a highly favorable tool for sorting early IHCs, Fgf8GFP/+ will facilitate the isolation of pure early OHCs by excluding IHCs from the entire hair cell pool.

Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.

Research progress in the application of anti-fibroblast growth factor and its receptor signaling pathway drugs in tumor therapy / 中国肿瘤生物治疗杂志

@#[摘 要] 成纤维细胞生长因子受体（FGFR）是一种受体酪氨酸激酶（RTK），与其配体成纤维细胞生长因子（FGF）相结合，激活下游的信号转导通路，参与调控细胞的正常生理活动。当FGFR基因发生扩增、突变或者融合等异常改变时，就会导致下游细胞信号通路的异常激活，促进细胞的增殖、迁移、侵袭及上皮-间质转化，进而促进肿瘤的发展。同时，FGFR在多种肿瘤中均呈高表达，因此FGF/FGFR可作为肿瘤治疗的重要靶点。根据药物作用机制，可以将抗FGFR信号通路药物分为两大类，分别为FGFR-酪氨酸激酶抑制剂（TKI）和阻断FGF/FGFR的单克隆抗体。目前，已有多种针对FGF/FGFR的靶向药物进入临床试验阶段，在肿瘤治疗中取得较好的临床效果，有的靶向药物获批用于临床肿瘤的治疗，为肿瘤的精准治疗带来了新的曙光。

Traditional Chinese Medicine Intervenes in Signaling Pathways Associated with CKD-MBD： A Review / 中国实验方剂学杂志

Traditional Chinese medicine （TCM） has certain advantages in the treatment of chronic kidney disease-mineral and bone disorder （CKD-MBD）. In recent years， there have been many studies on the treatment of CKD-MBD by Chinese medicinal compounds and monomers. As revealed by literature retrieval， the research on the mechanism of Chinese medicine in intervening in signaling pathways related to CKD-MBD was mainly based on self-made Chinese medicinal compounds， and the action pathways involved fibroblast growth factor 23/Klotho （FGF23/Klotho） signaling pathway， Wnt/β-catenin signaling pathway， receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin （RANK/RANKL/OPG） system， and other signaling pathways. TCM can improve calcium and phosphorus metabolism and bone metabolism disorder， and regulate inflammatory reaction， oxidative stress， apoptosis， and autophagy by regulating this series of signaling pathways for the treatment of CKD-MBD. This paper introduced the research results of these signaling pathways and the mechanism of TCM in the treatment of CKD-MBD in order to provide ideas and references for the related research of Chinese medicine in the treatment of CKD-MBD.

Temporal pattern of Fos and Jun families expression after mitogenic stimulation with FGF-2 in rat neural stem cells and fibroblasts

Intense stimulation of most living cells triggers the activation of immediate early genes, such as Fos and Jun families. These genes are important in cellular and biochemical processes, such as mitosis and cell death. The present study focused on determining the temporal expression pattern of Fos and Jun families in fibroblasts and neural stem cells of cerebellum, hippocampus, and subventricular zone (SVZ) of rats of different ages at 0, 0.5, 1, 3, and 6 h after stimulation with fibroblast growth factor (FGF)-2. In neonates, a similar expression pattern was observed in all cells analyzed, with lower expression in basal condition, peak expression at 0.5 h after stimulation, returning to baseline values between 1 and 3 h after stimulation. On the other hand, cells from adult animals only showed Fra1 and JunD expression after stimulation. In fibroblasts and hippocampus, Fra1 reached peak expression at 0.5 h after stimulation, while in the SVZ, peak level was observed at 6 h after stimulation. JunD in fibroblasts presented two peak expressions, at 0.5 and 6 h after stimulation. Between these periods, the expression observed was at a basal level. Nevertheless, JunD expression in SVZ and hippocampus was low and without significant changes after stimulation. Differences in mRNA expression in neonate and adult animals characterize the significant differences in neurogenesis and cell response to stimulation at different stages of development. Characterizing these differences might be important for the development of cell cultures, replacement therapy, and the understanding of the physiological response profile of different cell types.

New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia

Abstract Phosphorus is one of the most abundant minerals in the human body; it is required to maintain bone integrity and mineralization, in addition to other biological processes. Phosphorus is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and fibroblast growth factor 23 (FGF-23) in a complex set of processes that occur in the gut, skeleton, and kidneys. Different molecular mechanisms - overproduction of FGF-23 by tumors responsible for oncogenic osteomalacia, generation of an FGF-23 mutant that is resistant to cleavage by enzymes, and impaired FGF-23 degradation due to a reduction in or loss of the PHEX gene - can lead to FGF-23-stimulating activity and the consequent waste of urinary phosphate and low levels of 1,25(OH)2D3. Conventional treatment consists of multiple daily doses of oral phosphate salts and vitamin D analogs, which may improve radiographic rickets but do not normalize growth. Complications of the conventional long-term treatment consist of hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired renal function, and potentially chronic kidney disease. Recently, burosumab, an antibody against FGF-23, was approved as a novel therapy for children and adults with X-linked hypophosphatemia and patients with tumor-induced osteomalacia. Burosumab showed good performance in different trials in children and adults. It increased and sustained the serum phosphorus levels, decreased the rickets severity and pain scores, and improved mineralization. It offers a new perspective on the treatment of chronic and disabling diseases. Arch Endocrinol Metab. 2022;66(5):658-65

Phosphaturic mesenchymal tumor: An underdiagnosed rare entity

Tumor-induced osteomalacia is a paraneoplastic syndrome resulting in renal phosphate wasting and decreased bone mineralization. Phosphaturic mesenchymal tumors represent a rare etiology of tumor-induced osteomalacia. They are exceptionally rare, probably accounting for < 0.01% of all soft tissue tumors. Most PMTs present as small inapparent lesions that require very careful clinical examination and radionucleotide scan for localization. Here we describe a case in a 65 years old woman with recurrent multiple bone fractures and subsequent detection of a tumor involving right femur and adjacent soft tissue, low phosphate level and elevated serum Fibroblast growth factor-23 (FGF-23).

Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β 3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

Effect of Modified Da Chaihutang on FXR/FGF15/FGFR4 Signaling Pathway in Mice with Cholesterol Gallstone Differentiated into Damp-Heat Syndrome / 中国实验方剂学杂志

ObjectiveTo observe the effect of modified Da Chaihutang on cholesterol gallstone （CS） in mice due to damp-heat based on the farnesoid X receptor （FXR）/fibroblast growth factor 15 （FGF15）/fibroblast growth factor receptor 4 （FGFR4） pathway and explore the molecular biological mechanisms of CS differentiated into damp-heat syndrome from the perspective of correspondence between prescription and syndrome. MethodForty-eight six-week-old mice were randomly divided into the blank group， model group， modified Da Chaihutang （23.4 g·kg-1） group， and ursodeoxycholic acid （0.12 g·kg-1） group， with 12 mice in each group. The ones in the latter three groups were exposed to "internal dampness + external dampness + high-cholesterol diet" for 12 weeks for inducing CS due to damp-heat. Mice in the modified Da Chaihutang group and ursodeoxycholic acid group were gavaged with the corresponding drugs， while those in the model and blank groups with the same amount of normal saline for a total of four weeks. Before and after modeling， mice in each group were subjected to open field tests for determining their activities and mental states. Such general conditions as body mass， food intake， fur， and urine and stool of mice in each group were observed and recorded weekly for judging the damp-heat syndrome. After the intervention， the sampled liver and gallbladder tissues of mice in each group were stained with hematoxylin-eosin （HE） staining， and the serum γ-glutamyltransferase （GGT）， alkaline phosphatase （ALP）， and total bilirubin （TBIL） were determined. The total cholesterol （TC） and total bile acid （TBA） contents in bile were measured by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of FXR， FGF15， FGFR4， and cholesterol 7α-hydroxylase gene （CYP7A1） were assayed by real-time fluorescence quantitative polynucleotide chain reaction （Real-time PCR） and Western blot. ResultCompared with the blank group， the model group exhibited enlarged gallbladder， brown turbid bile with flocculent precipitation visible to the naked eye， obvious damp-heat syndrome， lipoid degeneration in the liver tissue， rough and thickened gallbladder wall， elevated ALP， GGT， and TBIL in serum （P<0.01） and TC in bile （P<0.01）， reduced TBA （P<0.01）， up-regulated FXR， FGF15， and FGFR4 mRNA and protein expression in ileum （P<0.05， P<0.01）， and down-regulated CYP7A1 mRNA and protein expression （P<0.01）. Compared with the model group， the two medication groups displayed improved bile turbidity， and the bile in the modified Da Chaihutang group became clearer. After intervention， the damp-heat syndrome of mice in the modified Da Chaihutang group was significantly alleviated. The liver and gallbladder lesions of mice in the two medication groups were significantly relieved， manifested as reduced serum ALP， GGT， and TBIL （P<0.01）. The reduction in ALP and TBIL of the modified Da Chaihutang group was more significant （P<0.01）. The TC contents in the bile of mice from the two medication groups were significantly lowered， whereas the TBA contents were elevated （P<0.01）， with more significant changes present in the modified Da Chaihutang group （P<0.01）. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the modified Da Chaihutang group were down-regulated （P<0.05， P<0.01）， while the mRNA and protein expression levels of CYP7A1 rose （P<0.05）， except that the elevation in FGF15 and FGFR4 protein expression and reduction in CYP7A1 protein expression were not significant. The mRNA and protein expression levels of FXR， FGF15， and FGFR4 in the ursodeoxycholic acid group all decreased， among which the reduction in FXR was remarkable （P<0.05）， and the mRNA and protein expression levels of CYP7A1 were significantly up-regulated （P<0.05）. ConclusionModified Da Chaihutang significantly improves the stone， liver function， bile composition， abnormal cholesterol-bile acid metabolism， and damp-heat syndrome in the model mice of CS differentiated into damp-heat syndrome， which may be related to its regulation of key factors FXR， FGF15， FGFR4， and CYP7A1 mRNA and protein expression in the cholesterol-bile acid metabolism pathway.

Recent Advances in Tumor Therapy Targeting FGFR / 肿瘤防治研究

Abnormal FGFR signaling has been found in a variety of cancers. The abnormal FGFR signaling is involved in several processes of tumorigenesis which include cell survival, proliferation, inflammation, migration, angiogenesis, epithelial-mesenchymal transformation and drug resistance. Therefore, FGFR is a very promising target for the treatment of tumors. More and more FGFR inhibitors have been developed for preclinical and clinical trials, and some FGFR inhibitors have been used in clinical applications. However, the problems such as acquired resistance and systemic toxicity have hindered the application of FGFR inhibitors. This paper reviews the clinical application of common FGFR inhibitors and summarizes the problems and solutions in their application.

Research progress of virus-mediated gene therapy in type 2 diabetes mellitu / 中国临床药理学与治疗学

Type 2 diabetes mellitus results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. At present, there are many drawbacks in the clinical treatment of T2DM, so there is an urgent need for a new treatment method for improvement. In recent years, gene therapy has been proved to reverse T2DM related symptoms such as insulin resistance at the animal level, and no obvious side effects such as hypoglycemia have been found. Therefore, gene therapy may be the main development direction of T2DM therapy in the future. This article reviews the role of fibroblast growth factor related genes such as fibroblast growth factor 21, glucagon like peptide-1, peroxisome proliferator activated receptor and insulin in glucose and lipid metabolism and the development of T2DM, and summarized the application of various viral vectors in gene therapy of T2DM. The significance and existing problems of gene therapy in T2DM are discussed, and the possible development direction of gene therapy T2DM in the future is prospected.