Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a ...Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.展开更多
BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory...BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.展开更多
Fibroblast growth factor 21(FGF21)has been identified as an important regulator of carbohydrate and lipid metabolism,which plays an important role for metabolic regulation,particularly under conditions of energy depri...Fibroblast growth factor 21(FGF21)has been identified as an important regulator of carbohydrate and lipid metabolism,which plays an important role for metabolic regulation,particularly under conditions of energy deprivation or stress conditions.Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation.It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation.This finding suggests that FGF21 might exert similar functions in dairy cows than in other species,such as mice or humans.However,the role of FGF21 in dairy cows has been less investigated so far.Following a brief summary of the previous findings about the function of FGF21 in humans and mice,the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows.The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows.In the second part,the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed.In the third part,findings of exogenous FGF21 application on metabolism in dairy cows are reported.Finally,the potential relevance of FGF21 in dairy cows is discussed.It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows.However,further studies are needed for a better understanding of the functions of FGF21 in dairy cows.展开更多
BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures.Leukocyte cellderived chemotaxin-2(LECT2)has been widely st...BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures.Leukocyte cellderived chemotaxin-2(LECT2)has been widely studied to determine its usefulness in monitoring the course of non-alcoholic fatty liver disease but not for alcoholic liver cirrhosis(ALC).AIM To determine the concentration of LECT2 in the blood serum of patients in relation to progressive stages of ALC,its relation to fibroblast growth factor 1(FGF-1)and FGF-21,and to examine the possible wider use of LECT2 in diagnosing ALC.METHODS A retrospective case-control study was conducted with 69 ALC cases and 17 controls with no ALC.Subjects were recruited from the region of Lublin(eastern Poland).Liver cirrhosis was diagnosed based on clinical features,history of heavy alcohol consumption,laboratory tests,and abdominal ultrasonography.The degree of ALC was evaluated according to Pugh-Child criteria(the Pugh-Child score).Blood was drawn and,after centrifugation,serum was collected for analysis.LECT2,FGF-1,and FGF-21 were determined using enzyme-linked immunosorbent assay kits.RESULTS The LECT2 Levels in the control group were 18.99±5.36 ng/mL.In the study groups,they declined with the progression of cirrhosis to 11.06±6.47 ng/mL in one group and to 8.06±5.74 ng/mL in the other(P<0.0001).Multiple comparison tests confirmed the statistically significant differences in LECT2 Levels between the control group and both test groups(P=0.006 and P<0.0001).FGF-21 Levels were 44.27±64.19 pg/mL in the first test group,45.4±51.69 pg/mL in the second(P=0.008),and 13.52±7.51 pg/mL in the control group.The difference between the control group and the second test group was statistically significant(P=0.007).CONCLUSION We suggest that LECT2 may be a non-invasive diagnostic factor for alcoholinduced liver cirrhosis.The usefulness of LECT2 for non-invasive monitoring of alcohol-induced liver cirrhosis was indirectly confirmed by the multiple regression model developed on the basis of our statistical analysis.展开更多
[ Objective] This study aimed to investigate the expression of recombinant protein of fibroblast growth factor 21 （ FGF21 ） in Escherichia coli induced by lactose and explore the possibility of engineering productio...[ Objective] This study aimed to investigate the expression of recombinant protein of fibroblast growth factor 21 （ FGF21 ） in Escherichia coli induced by lactose and explore the possibility of engineering production. [ Method ] The effects of lactose concentration, induction duration, induction starting time, and induc- tion temperature on expression of the recombinant product were compared, and the optimal condition for lactose induction was determined with IPTG induction as a control. [ Result] As an induction agent, lactose plays an ideal rele in the production of recombinant FGF21. In addition, the expression level of lactose induction product is consistent with that of IPTG induction product. Induction in a 250 rrd flask containing 50 ml of medium at A600 0.8 - 1.0 using 0.5 g/L lactose at 35 ℃ for 6 h are the optimal condition. [ Conclusion] Lactose can induce the expression of FGF21 gene and achieve ideal results. This study provides experimental basis and reference for the industrial production of FGF21.展开更多
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...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 1light 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 FGF21may 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 FGF21and 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.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approxim...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approximately 100 billion dollars.Unfortunately,there is no Federal Drug Administration(FDA)-approved medication for its treatment.However,various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD.It is valuable to have a compilation of the data available on their efficacy.AIM To assess the efficacy of cyclophilin inhibitors,fibroblast growth factor 21 analogs(FGF21),and dual and pan peroxisome proliferator-activated receptor(PPAR)agonists for treating NAFLD.METHODS A comprehensive literature search using keywords including cyclophilin inhibitor,FGF agonist,pan-PPAR agonists,dual-PPAR agonist,NAFLD,nonalcoholic steatohepatitis,and fatty liver was conducted on October 29,2022,in PubMed,EMBASE,Cochrane Library,Scopus and Web of Science.Animal and human research,case reports,and published articles in English from all countries with patients aged 18 and above were included.Only articles with a National Institutes of Health(NIH)Quality Assessment score of five or higher out of eight points were included.Articles that were narrative or systematic reviews,abstracts,not in English,focused on patients under 18 years old,did not measure outcomes of interest,were inaccessible,or had a low NIH Quality Assessment score were excluded.Each article was screened by two independent researchers evaluating relevance and quality.Resources were scored based on the NIH Quality Assessment Score;then,pertinent data was extracted in a spreadsheet and descriptively analyzed.RESULTS Of the 681 records screened,29 met the necessary criteria and were included in this review.These records included 12 human studies and 17 animal studies.Specifically,there were four studies on cyclophilin inhibitors,four on FGF agonists/analogs,eleven on pan-PPAR agonists,and ten on dual-PPAR agonists.Different investigational products were assessed:The most common cyclophilin inhibitor was NV556;FGF agonists and analogs was Efruxifermin;pan-PPAR agonists was Lanifibranor;and dual-PPAR agonists was Saroglitazar.All classes were found to be statistically efficacious for the treatment of NAFLD,with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan(P<0.05).CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes,as well as good safety profiles(P<0.05).We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.展开更多
Background Fibroblast growth factor 21 （FGF21） is a new member of FGF super family that is an important endogenous regulator for systemic glucose and lipid metabolism. This study aimed to explore whether FGF21 reduc...Background Fibroblast growth factor 21 （FGF21） is a new member of FGF super family that is an important endogenous regulator for systemic glucose and lipid metabolism. This study aimed to explore whether FGF21 reduces atherosclerotic injury and prevents endothelial dysfunction as an independent protection factor.Methods The present study was designed to investigate the changes of FGF21 levels induced by oxidized-low density lipoprotein （ox-LDL）, and the changes of apoptosis affected by regulating FGF21 expression. The FGF21 mRNA levels of cultured cardiac microvascular endothelial cells （CMECs） were determined by real time-PCR and the protein concentration in culture media was detected by enzyme-linked immunosorbent assay. We analyzed the different expression levels of untreated controls and CMFCs incubated with ox-LDL, and the changes of CMECs apoptosis initiated by the enhancement or suppression of FGF21 levels.Results The secretion levels of FGF21 mRNA and protein were significantly upregulated in CMECs incubated with ox-LDL. Furthermore, FGF21 levels increased by 200 μmol/L bezafibrate could reduce CMECs apoptosis, and inhibit FGF21 expression by shRNA induced apoptosis （P ＜0.05）.Conclusions FGF21 may be a signal of injured target tissue, and may play physiological roles in improving the endothelial function at an early stage of atherosclerosis and in stopping the development of coronary heart disease.展开更多
Background： Chronic kidney disease （CKD） is closely related to the cardiovascular events in vascular calcification （VC）. However, little has known about the characteristics of kidney injury caused by VC. Fibrobla...Background： Chronic kidney disease （CKD） is closely related to the cardiovascular events in vascular calcification （VC）. However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 （FGF21 ） is an endocrine thctor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases, Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats. Methods： The male Sprague-Dawley rats were divided into three groups： （ 1 ） control group, （2） Vitamin D3 plus nicotine （VDN）-induced VC group, （3） FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases （ALPs） activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 （FGFR1） protein were measured by enzyme-linked immunosorbent assay （EL1SA）. The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining. Results： The renal lhnction impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% （34.750 ± 4.334 pmol/L vs. 27.630± 2.387pamol/L） and 4.0% （7.038 ± 0.590 mmol/L vs. 6.763 ±0.374 mmol/L; P 〈 0.01 ）, respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% （P 〈 0.01 ） and 11.7% （P 〈 0.05） as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. EL1SA assays showed that the expression of [3-Klotho, a component of FGF21 receptor system was increased in VDN-treated VC rats by 37.4% （6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P 〈 0.01）, indicating an FGF2 l-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% （9.054 ± 0.963 pg/mg vs. 7.544± 1.362 pg/mg, P 〈 0.05）. However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration （0.191 ± 0.0376 rig/rag vs. 0.189 ± 0.032 ng/mg rs. 0.181± 0.034 mg/mg; P 〉 0.05）. Conclusions： In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting offthe vicious circle between VC and kidney injury.展开更多
The liver,the largest solid visceral organ of the body,has numerous endocrine functions,such as direct hormone and hepatokine production,hormone metabolism,synthesis of binding proteins,and processing and redistributi...The liver,the largest solid visceral organ of the body,has numerous endocrine functions,such as direct hormone and hepatokine production,hormone metabolism,synthesis of binding proteins,and processing and redistribution of metabolic fuels.In the last 10 years,many new endocrine functions of the liver have been discovered.Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones[including 25-hydroxyvitamin D,insulin-like growth factor 1(IGF-1),and angiotensinogen],hepatic metabolism of hormones(including thyroid hormones,glucagon-like peptide-1,and steroid hormones),and actions of specific binding proteins to glucocorticoids,sex steroids,and thyroid hormones.These studies have furthered insight into cirrhosis-associated endocrinopathies,such as hypogonadism,osteoporosis,IGF-1 deficiency,vitamin D deficiency,alterations in glucose and lipid homeostasis,and controversially relative adrenal insufficiency.Several novel endocrine functions of the liver have also been unraveled,elucidating the liver’s key negative feedback regulatory role in the pancreaticαcell-liver axis,which regulates pancreaticαcell mass,glucagon secretion,and circulating amino acid levels.Betatrophin and other hepatokines,such as fetuin-A and fibroblast growth factor 21,have also been discovered to play important endocrine roles in modulating insulin sensitivity,lipid metabolism,and body weight.It is expected that more endocrine functions of the liver will be revealed in the near future.展开更多
Objective:To determine the relationship between human fibroblast growth factor 21(FGF21)and thyroid stimulating hormone(TSH)by testing the level of FGF21,lipid metabolism,and car-bohydrate metabolism-related indices,a...Objective:To determine the relationship between human fibroblast growth factor 21(FGF21)and thyroid stimulating hormone(TSH)by testing the level of FGF21,lipid metabolism,and car-bohydrate metabolism-related indices,as well as the level of TSH,among metabolic syndrome-free patients with normal physical examination results.Methods:An enzyme-linked immunosorbent assay(ELISA)was used to test the levels of serum FGF21 and free fatty acids(FFA)in metabolic syndrome-free patients with normal physi-cal examination results,and electrochemiluminescence(ECLIA)was used to measure TSH,thy-roglobulin antibodies(TGAbs),and thyroid peroxidase antibody(TPOAb)levels.Results:Three hundred fifty-six metabolic syndrome-free patients(116 males and 240 females;average age,43±13 years)with normal physical examination results were enrolled.Among the pa-tients with normal physical examination results,FGF21 had a weak relationship with obesity indices,such as the waist circumference(r=0.110,P=0.038),the waist-to-hip ratio(r=0.119,P=0.025),and the triglycerides level(TG;r=0.302,P=0.000),and a weak relationship with blood lipid levels,such as total cholesterol(TCHO;r=0.113,P=0.012)and low-density lipoprotein-cholesterol(LDL-C;r=0.175,P=0.001),but no relationship with TSH(r=-0.023,P=0.666).In addition,the FGF21 levels in thyroid autoantibody-positive and-negative groups were not significantly different.Conclusion:Among the metabolic syndrome-free patients with normal physical examina-tion results,FGF21 has no apparent relationship with TSH or thyroid autoimmunity.展开更多
Dietary interventions include the change of dietary styles,such as fasting and dietary or nutrient restrictions;or the addition of plant-derived compounds(such as polyphenols known as curcumin,resveratrol,or anthocyan...Dietary interventions include the change of dietary styles,such as fasting and dietary or nutrient restrictions;or the addition of plant-derived compounds(such as polyphenols known as curcumin,resveratrol,or anthocyanin,or other nutraceuticals)into the diet.During the past a few decades,large number of studies have demonstrated therapeutic activities of these dietary interventions on metabolic and other diseases in human subjects or various animal models.Mechanisms underlying those versatile therapeutic activities,however,remain largely unclear.Interestingly,recent studies have shown that fibroblast growth factor 21(FGF21),a liver-derived hormone or hepatokine,mediates metabolic beneficial effects of certain dietary polyphenols as well as protein restriction.Here I have briefly summarized functions of FGF21,highlighted related dietary interventions,and presented literature discussions on role of FGF21 in mediating function of dietary polyphenol intervention and protein restriction.This is followed by presenting my perspective view,with the involvement of gut microbiota.It is anticipated that further breakthroughs in this field in the near future will facilitate conceptual merge of classical medicine and modern medicine.展开更多
Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential ro...Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver diseases.Once the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain homeostasis.In recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much attention.FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress.Also,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role.This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.展开更多
Nonalcoholic steatohepatitis(NASH)is a chronic liver disease affecting a large population worldwide.No clinically approved drugs are available.In this minireview,we discuss the heterogeneous nature of NASH and lack of...Nonalcoholic steatohepatitis(NASH)is a chronic liver disease affecting a large population worldwide.No clinically approved drugs are available.In this minireview,we discuss the heterogeneous nature of NASH and lack of consensus in outcome measures among clinical trials.We summarize NASH therapeutic targets and candidate drugs.We compare the efficacy of 33 published clinical trials that evaluated noninvasive biomarkers and liver biopsy.Currently,phase Ⅱ trial results of fibroblast growth factor 21(FGF21)and phase Ⅲ trial results of resmetirom and pioglitazone are encouraging.展开更多
基金supported by grants from Jiangsu Commission of Health,No.Z2021086(to XL)Science and Technology Program of Suzhou,Nos.SYSD2020008(to XL),SKYD2022012(to XL)+1 种基金Suzhou Municipal Health Commission,No.KJXW2020058(to XL)Science and Technology Program of Zhangjiagang,No.ZKS2018(to XL)。
文摘Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.
基金the 2022 Zhejiang Provincial Health Science and Technology Plan,No.2022KY1216.
文摘BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.
文摘Fibroblast growth factor 21(FGF21)has been identified as an important regulator of carbohydrate and lipid metabolism,which plays an important role for metabolic regulation,particularly under conditions of energy deprivation or stress conditions.Dairy cows are subjected to a negative energy balance and various kinds of stress particularly during the periparturient phase and during early lactation.It has been shown that the plasma concentration of FGF21 in dairy cows is dramatically increased at parturition and remains high during the first weeks of lactation.This finding suggests that FGF21 might exert similar functions in dairy cows than in other species,such as mice or humans.However,the role of FGF21 in dairy cows has been less investigated so far.Following a brief summary of the previous findings about the function of FGF21 in humans and mice,the present review aims to present the current state of knowledge about the role of FGF21 in dairy cows.The first part of the review deals with the tissue localization of FGF21 and with conditions leading to an upregulation of FGF21 expression in the liver of dairy cows.In the second part,the influence of nutrition on FGF21 expression and the role of FGF21 for metabolic diseases in dairy cows is addressed.In the third part,findings of exogenous FGF21 application on metabolism in dairy cows are reported.Finally,the potential relevance of FGF21 in dairy cows is discussed.It is concluded that FGF21 might be of great importance for metabolic adaptation to negative energy balance and stress conditions in dairy cows.However,further studies are needed for a better understanding of the functions of FGF21 in dairy cows.
基金Supported by the Grant from the Medical University of Lublin,No. DS 507/2013–2015
文摘BACKGROUND The importance of early diagnosis of alcoholic liver disease underscores the need to seek better and especially non-invasive diagnostic procedures.Leukocyte cellderived chemotaxin-2(LECT2)has been widely studied to determine its usefulness in monitoring the course of non-alcoholic fatty liver disease but not for alcoholic liver cirrhosis(ALC).AIM To determine the concentration of LECT2 in the blood serum of patients in relation to progressive stages of ALC,its relation to fibroblast growth factor 1(FGF-1)and FGF-21,and to examine the possible wider use of LECT2 in diagnosing ALC.METHODS A retrospective case-control study was conducted with 69 ALC cases and 17 controls with no ALC.Subjects were recruited from the region of Lublin(eastern Poland).Liver cirrhosis was diagnosed based on clinical features,history of heavy alcohol consumption,laboratory tests,and abdominal ultrasonography.The degree of ALC was evaluated according to Pugh-Child criteria(the Pugh-Child score).Blood was drawn and,after centrifugation,serum was collected for analysis.LECT2,FGF-1,and FGF-21 were determined using enzyme-linked immunosorbent assay kits.RESULTS The LECT2 Levels in the control group were 18.99±5.36 ng/mL.In the study groups,they declined with the progression of cirrhosis to 11.06±6.47 ng/mL in one group and to 8.06±5.74 ng/mL in the other(P<0.0001).Multiple comparison tests confirmed the statistically significant differences in LECT2 Levels between the control group and both test groups(P=0.006 and P<0.0001).FGF-21 Levels were 44.27±64.19 pg/mL in the first test group,45.4±51.69 pg/mL in the second(P=0.008),and 13.52±7.51 pg/mL in the control group.The difference between the control group and the second test group was statistically significant(P=0.007).CONCLUSION We suggest that LECT2 may be a non-invasive diagnostic factor for alcoholinduced liver cirrhosis.The usefulness of LECT2 for non-invasive monitoring of alcohol-induced liver cirrhosis was indirectly confirmed by the multiple regression model developed on the basis of our statistical analysis.
基金Supported by Science and Technology Development Fund of Jilin Province(20090949,20116044)Student Research Fund from Jilin Medical College([2010]No.09)
文摘[ Objective] This study aimed to investigate the expression of recombinant protein of fibroblast growth factor 21 （ FGF21 ） in Escherichia coli induced by lactose and explore the possibility of engineering production. [ Method ] The effects of lactose concentration, induction duration, induction starting time, and induc- tion temperature on expression of the recombinant product were compared, and the optimal condition for lactose induction was determined with IPTG induction as a control. [ Result] As an induction agent, lactose plays an ideal rele in the production of recombinant FGF21. In addition, the expression level of lactose induction product is consistent with that of IPTG induction product. Induction in a 250 rrd flask containing 50 ml of medium at A600 0.8 - 1.0 using 0.5 g/L lactose at 35 ℃ for 6 h are the optimal condition. [ Conclusion] Lactose can induce the expression of FGF21 gene and achieve ideal results. This study provides experimental basis and reference for the industrial production of FGF21.
基金supported by the National Key Research and Development Program of China(No.2021YFA1100500)the National Natural Science Foundation of China(Nos.92159202,81930016,and 82102910)+3 种基金the Key Research&Development Plan of Zhejiang Province(No.2019C03050)the Construction Fund of Key Medical Disciplines of Hangzhou(No.0020200093)the Postdoctoral Science Foundation(No.2020M671762)the Medical and Health Technology Program in Zhejiang Province(No.WKJ-ZJ-2120),China.
文摘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 1light 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 FGF21may 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 FGF21and 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.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approximately 100 billion dollars.Unfortunately,there is no Federal Drug Administration(FDA)-approved medication for its treatment.However,various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD.It is valuable to have a compilation of the data available on their efficacy.AIM To assess the efficacy of cyclophilin inhibitors,fibroblast growth factor 21 analogs(FGF21),and dual and pan peroxisome proliferator-activated receptor(PPAR)agonists for treating NAFLD.METHODS A comprehensive literature search using keywords including cyclophilin inhibitor,FGF agonist,pan-PPAR agonists,dual-PPAR agonist,NAFLD,nonalcoholic steatohepatitis,and fatty liver was conducted on October 29,2022,in PubMed,EMBASE,Cochrane Library,Scopus and Web of Science.Animal and human research,case reports,and published articles in English from all countries with patients aged 18 and above were included.Only articles with a National Institutes of Health(NIH)Quality Assessment score of five or higher out of eight points were included.Articles that were narrative or systematic reviews,abstracts,not in English,focused on patients under 18 years old,did not measure outcomes of interest,were inaccessible,or had a low NIH Quality Assessment score were excluded.Each article was screened by two independent researchers evaluating relevance and quality.Resources were scored based on the NIH Quality Assessment Score;then,pertinent data was extracted in a spreadsheet and descriptively analyzed.RESULTS Of the 681 records screened,29 met the necessary criteria and were included in this review.These records included 12 human studies and 17 animal studies.Specifically,there were four studies on cyclophilin inhibitors,four on FGF agonists/analogs,eleven on pan-PPAR agonists,and ten on dual-PPAR agonists.Different investigational products were assessed:The most common cyclophilin inhibitor was NV556;FGF agonists and analogs was Efruxifermin;pan-PPAR agonists was Lanifibranor;and dual-PPAR agonists was Saroglitazar.All classes were found to be statistically efficacious for the treatment of NAFLD,with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan(P<0.05).CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes,as well as good safety profiles(P<0.05).We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.
基金This study was supported by a grant from National Natural Science Foundation of China （No. 81070227）.
文摘Background Fibroblast growth factor 21 （FGF21） is a new member of FGF super family that is an important endogenous regulator for systemic glucose and lipid metabolism. This study aimed to explore whether FGF21 reduces atherosclerotic injury and prevents endothelial dysfunction as an independent protection factor.Methods The present study was designed to investigate the changes of FGF21 levels induced by oxidized-low density lipoprotein （ox-LDL）, and the changes of apoptosis affected by regulating FGF21 expression. The FGF21 mRNA levels of cultured cardiac microvascular endothelial cells （CMECs） were determined by real time-PCR and the protein concentration in culture media was detected by enzyme-linked immunosorbent assay. We analyzed the different expression levels of untreated controls and CMFCs incubated with ox-LDL, and the changes of CMECs apoptosis initiated by the enhancement or suppression of FGF21 levels.Results The secretion levels of FGF21 mRNA and protein were significantly upregulated in CMECs incubated with ox-LDL. Furthermore, FGF21 levels increased by 200 μmol/L bezafibrate could reduce CMECs apoptosis, and inhibit FGF21 expression by shRNA induced apoptosis （P ＜0.05）.Conclusions FGF21 may be a signal of injured target tissue, and may play physiological roles in improving the endothelial function at an early stage of atherosclerosis and in stopping the development of coronary heart disease.
基金This study was funded by grants from National Natural Science Fund of China （No. 81570388）, Beijing Natural Science Foundation （No. 7142048）, and the Major State Basic Research Development Program of China （973 Program, No. 2015CB554404）.
文摘Background： Chronic kidney disease （CKD） is closely related to the cardiovascular events in vascular calcification （VC）. However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 （FGF21 ） is an endocrine thctor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases, Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats. Methods： The male Sprague-Dawley rats were divided into three groups： （ 1 ） control group, （2） Vitamin D3 plus nicotine （VDN）-induced VC group, （3） FGF21-treated VDN group. After 4 weeks, the rats were killed and the blood was collected for serum creatinine, urea nitrogen, calcium, and phosphate measurement. Moreover, the renal tissues were homogenized for alkaline phosphatases （ALPs） activity and calcium content. The levels of FGF21 protein were measured by radioimmunoassay. The levels of β-Klotho and FGF receptor 1 （FGFR1） protein were measured by enzyme-linked immunosorbent assay （EL1SA）. The structural damage and calcifications in aortas were stained by Alizarin-red S. Moreover, the structure of kidney was observed by hematoxylin and eosin staining. Results： The renal lhnction impairment caused by VDN modeling was ameliorated by FGF21 treatment, inhibited the elevated serum creatinine and urea level by 20.5% （34.750 ± 4.334 pmol/L vs. 27.630± 2.387pamol/L） and 4.0% （7.038 ± 0.590 mmol/L vs. 6.763 ±0.374 mmol/L; P 〈 0.01 ）, respectively, together with the structural damages of glomerular atrophy and renal interstitial fibrosis. FGF21 treatment downregulated the ALP activity, calcium content in the kidney of VC rats by 42.1% （P 〈 0.01 ） and 11.7% （P 〈 0.05） as well as ameliorated the aortic injury and calcification as compared with VDN treatment alone group, indicating an ameliorative effect on VC. EL1SA assays showed that the expression of [3-Klotho, a component of FGF21 receptor system was increased in VDN-treated VC rats by 37.4% （6.588 ± 0.957 pg/mg vs. 9.054 ± 0.963 pg/mg; P 〈 0.01）, indicating an FGF2 l-resistant state. Moreover, FGF21 treatment downregulated the level of β-Klotho in renal tissue by 16.7% （9.054 ± 0.963 pg/mg vs. 7.544± 1.362 pg/mg, P 〈 0.05）. However, the level of FGFR1, the receptor of FGF21, kept unchanged under VDN and VDN plus FGF21 administration （0.191 ± 0.0376 rig/rag vs. 0.189 ± 0.032 ng/mg rs. 0.181± 0.034 mg/mg; P 〉 0.05）. Conclusions： In the present study, FGF21 was observed to ameliorate the kidney injury in VDN-induced VC rats. FGF21 might be a potential therapeutic factor in CKD by cutting offthe vicious circle between VC and kidney injury.
文摘The liver,the largest solid visceral organ of the body,has numerous endocrine functions,such as direct hormone and hepatokine production,hormone metabolism,synthesis of binding proteins,and processing and redistribution of metabolic fuels.In the last 10 years,many new endocrine functions of the liver have been discovered.Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones[including 25-hydroxyvitamin D,insulin-like growth factor 1(IGF-1),and angiotensinogen],hepatic metabolism of hormones(including thyroid hormones,glucagon-like peptide-1,and steroid hormones),and actions of specific binding proteins to glucocorticoids,sex steroids,and thyroid hormones.These studies have furthered insight into cirrhosis-associated endocrinopathies,such as hypogonadism,osteoporosis,IGF-1 deficiency,vitamin D deficiency,alterations in glucose and lipid homeostasis,and controversially relative adrenal insufficiency.Several novel endocrine functions of the liver have also been unraveled,elucidating the liver’s key negative feedback regulatory role in the pancreaticαcell-liver axis,which regulates pancreaticαcell mass,glucagon secretion,and circulating amino acid levels.Betatrophin and other hepatokines,such as fetuin-A and fibroblast growth factor 21,have also been discovered to play important endocrine roles in modulating insulin sensitivity,lipid metabolism,and body weight.It is expected that more endocrine functions of the liver will be revealed in the near future.
文摘Objective:To determine the relationship between human fibroblast growth factor 21(FGF21)and thyroid stimulating hormone(TSH)by testing the level of FGF21,lipid metabolism,and car-bohydrate metabolism-related indices,as well as the level of TSH,among metabolic syndrome-free patients with normal physical examination results.Methods:An enzyme-linked immunosorbent assay(ELISA)was used to test the levels of serum FGF21 and free fatty acids(FFA)in metabolic syndrome-free patients with normal physi-cal examination results,and electrochemiluminescence(ECLIA)was used to measure TSH,thy-roglobulin antibodies(TGAbs),and thyroid peroxidase antibody(TPOAb)levels.Results:Three hundred fifty-six metabolic syndrome-free patients(116 males and 240 females;average age,43±13 years)with normal physical examination results were enrolled.Among the pa-tients with normal physical examination results,FGF21 had a weak relationship with obesity indices,such as the waist circumference(r=0.110,P=0.038),the waist-to-hip ratio(r=0.119,P=0.025),and the triglycerides level(TG;r=0.302,P=0.000),and a weak relationship with blood lipid levels,such as total cholesterol(TCHO;r=0.113,P=0.012)and low-density lipoprotein-cholesterol(LDL-C;r=0.175,P=0.001),but no relationship with TSH(r=-0.023,P=0.666).In addition,the FGF21 levels in thyroid autoantibody-positive and-negative groups were not significantly different.Conclusion:Among the metabolic syndrome-free patients with normal physical examina-tion results,FGF21 has no apparent relationship with TSH or thyroid autoimmunity.
基金funding support from Canadian Institutes of Health Research(CIHR)and Banting and Best Diabetes Centre(BBDC)in the past decade on conducting our dietary polyphenol intervention and FGF21 related bench work research.Jin’s lab is current supported by CIHR on FGF21 studies(PJT159735)Financial support from CIHR,BBDC,University of Toronto and elsewhere for trainees in my lab is also highly appreciated.
文摘Dietary interventions include the change of dietary styles,such as fasting and dietary or nutrient restrictions;or the addition of plant-derived compounds(such as polyphenols known as curcumin,resveratrol,or anthocyanin,or other nutraceuticals)into the diet.During the past a few decades,large number of studies have demonstrated therapeutic activities of these dietary interventions on metabolic and other diseases in human subjects or various animal models.Mechanisms underlying those versatile therapeutic activities,however,remain largely unclear.Interestingly,recent studies have shown that fibroblast growth factor 21(FGF21),a liver-derived hormone or hepatokine,mediates metabolic beneficial effects of certain dietary polyphenols as well as protein restriction.Here I have briefly summarized functions of FGF21,highlighted related dietary interventions,and presented literature discussions on role of FGF21 in mediating function of dietary polyphenol intervention and protein restriction.This is followed by presenting my perspective view,with the involvement of gut microbiota.It is anticipated that further breakthroughs in this field in the near future will facilitate conceptual merge of classical medicine and modern medicine.
基金supported by the National Key Research and Development Program of China(No.2021YFA1100500)the Major Research Plan of the National Natural Science Foundation of China(No.92159202)+2 种基金the Key Program,National Natural Science Foundation of China(No.81930016)the Young Program of National Natural Science Funds(China)(No.82000617)A Project Supported by Scientific Research Fund of Zhejiang Provincial Education Department(China)(No.Y202250784).
文摘Liver diseases are worldwide problems closely associated with various stresses,such as endoplasmic reticulum stress.The exact interplay between stress and liver diseases remains unclear.Autophagy plays an essential role in maintaining homeostasis,and recent studies indicate tight crosstalk between stress and autophagy in liver diseases.Once the bal-ance between damage and autophagy is broken,autophagy can no longer resist injury or main-tain homeostasis.In recent years,FGF21(fibroblast growth factor 21)-induced autophagy has attracted much attention.FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress.Also,increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role.This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.
文摘Nonalcoholic steatohepatitis(NASH)is a chronic liver disease affecting a large population worldwide.No clinically approved drugs are available.In this minireview,we discuss the heterogeneous nature of NASH and lack of consensus in outcome measures among clinical trials.We summarize NASH therapeutic targets and candidate drugs.We compare the efficacy of 33 published clinical trials that evaluated noninvasive biomarkers and liver biopsy.Currently,phase Ⅱ trial results of fibroblast growth factor 21(FGF21)and phase Ⅲ trial results of resmetirom and pioglitazone are encouraging.
