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folic acid-induced animal model of kidney disease

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Animal Models and Experimental Medicine 2021年第4期4卷 329-342页

作者： Liang-Jun Yan Department of Pharmaceutical Sciences College of PharmacyUniversity of North Texas Health Science CenterFort WorthTexasUSA

The kidneys are a vital organ that is vulnerable to both acute kidney injury(AKI)and chronic kidney disease(CKD)which can be caused by numerous risk factors such as ischemia,sepsis,drug toxicity and drug overdose,exposure to heavy metals,and diabetes.In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD,there is still no available therapeutics that can be used to combat kidney disease effectively,highlighting an urgent need to further study the pathological mechanisms underlying AKI,CKD,and AKI progression to CKD.In this regard,animal models of kidney disease are indispensable.This article reviews a widely used animal model of kidney disease,which is induced by folic acid(FA).While a low dose of FA is nutritionally beneficial,a high dose of FA is very toxic to the kidneys.Following a brief description of the procedure for disease induction by FA,major mechanisms of FA-induced kidney injury are then reviewed,including oxidative stress,mitochondrial abnormalities such as impaired bioenergetics and mitophagy,ferroptosis,pyroptosis,and increased expression of fibroblast growth factor 23(FGF23).Finally,application of this FA-induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed.Given that this animal model is simple to create and is reproducible,it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.

关键词： acute kidney injury chronic kidney disease ferroptosis fibroblast growth factor 23 folic acid mitochondria mitophagy oxidative stress pyroptosis

Maternal dietary deficiencies in folic acid or choline worsen stroke outcomes in adult male and female mouse offspring

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Neural Regeneration Research 2023年第11期18卷 2443-2448页

作者： McCoy Clementson Lauren Hurley Sarah Coonrod Calli Bennett Purvaja Marella Agnes S.Pascual Kasey Pull Brandi Wasek Teodoro Bottiglieri Olga Malysheva Marie A.Caudill Nafisa M.Jadavji Department of Biomedical Sciences Midwestern UniversityGlendaleAZUSA College of Osteopathic Medicine Midwestern UniversityGlendaleAZUSA College of Veterinary Medicine Midwestern UniversityGlendaleAZUSA Center of Metabolomics Institute of Metabolic DiseaseBaylor Scott&White Research InstituteDallasTXUSA Division of Nutritional Sciences Cornell UniversityIthacaNYUSA Department of Neuroscience Carleton UniversityOttawaONCanada Department of Child Health College of Medicine–PhoenixUniversity of ArizonaPhoenixAZUSA

Maternal one-carbon metabolism plays an important role in early life programming.There is a well-established connection between the fetal environment and the health status of the offspring.Howeve r,there is a knowledge gap on how maternal nutrition impacts stro ke outcomes in offspring.The aim of our study was to investigate the role of maternal dietary deficiencies in folic acid or choline on stroke outcomes in 3-month-old offspring.Adult female mice were fed a folic acid-deficient diet,choline-deficient diet,or control diet 4 weeks before pregnancy.They we re continued on diets during pregnancy and la ctation.Male and female offspring were weaned onto a control diet and at 2 months of age were subjected to ischemic stroke within the sensorimotor cortex via photothrombotic damage.Mothers maintained on either a folic acid-deficient diet or choline-deficient diet had reduced levels of S-adenosylm ethionine in the liver and S-adenosylhomocysteine in the plasma.After ischemic stro ke,motor function was impaired in 3-month-old offspring from mothers receiving either a folic acid-deficient diet or choline-deficient diet compared to the animals receiving a control diet.In brain tissue,there was no difference in ischemic damage volume.When protein levels were assessed in ischemic brain tissue,there were lower levels of active caspase-3 and hypoxia-inducible factor 1α in males compared to females and betaine levels were reduced in offspring from the mothers receiving a choline-deficient diet.Our results demonstrate that a deficient maternal diet at critical time points in neurodevelopment results in worse stro ke outcomes.This study emphasizes the importance of maternal diet and the impact it can have on offspring health.

关键词： apoptosis choline metabolism folic acid ischemic stroke maternal diet motor function one-carbon metabolism stroke outcome

Dietary folic acid addition reduces abdominal fat deposition mediated by alterations in gut microbiota and SCFA production in broilers

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Animal Nutrition 2023年第1期12卷 54-62页

作者： Yanli Liu Jiantao Yang Xiaoying Liu Rui Liu Yibin Wang Xinhuo Huang Yingge Li Ruifang Liu Xiaojun Yang College of Animal Science and Technology Northwest A&F UniversityYangling 712100China Nano Vitamin Engineering Research Center of Shaanxi Province Xi'an 710000China Shaanxi Province Animal Husbandry Technology Extension Station Xi'an 710016China

Intensive selective breeding for high growth rate and body weight cause excess abdominal fat in broilers.Gut microbiota and folic acid were reported to regulate lipid metabolism.A total of 210 one-day-old broilers were divided into the control(folic acid at 1.3 mg/kg)and folic acid groups(folic acid at 13 mg/kg)to illustrate the effects of folic acid on growth performance,abdominal fat deposition,and gut microbiota,and the experiment lasted 28 d.Results revealed that dietary folic acid addition decreased abdominal fat percentage(Pfolic acid addition decreased caecal Firmicutes-to-Bacteroidetes ratio(Pacid,and propionic acid contents were found to be higher under folic acid treatment(Pacid content,and the same phenomenon was detected between propionic acid and Oscillospira and Ruminococcus(Pacid and Oscillospira were identified to be negatively associated with abdominal fat percentage(Pfolic acid reduced fat deposition in broilers by inhibiting abdominal adipocyte proliferation and differentiation,which might be mediated by changes in gut microbiota and short chain fatty acid production.

关键词： folic acid Caecal microbiota Abdominal adipocytes Short chain fatty acid Broilers

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1148-1162页

作者： Pearl Moharil Zhuoya Wan Apurva Pardeshi Jiang Li Haozhe Huang Zhangyi Luo Sanjay Rathod Ziqian Zhang Yuang Chen Bei Zhang Christian A.Fernandez Jingjing Sun Song Li Center for Pharmacogenetics Department of Pharmaceutical ScienceSchool of PharmacyUniversity of PittsburghPA 15261USA

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

关键词： folic acid Gemcitabine Polymeric micelles Breast cancer Dual targeting Tumor associated macrophages Ultrasmall nanocarrier Doxorubicin

Characterization of folic acid,5-methyltetrahydrofolate and synthetic folinic acid in the high-affinity folate transporters:impact on pregnancy and development

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Reproductive and Developmental Medicine 2023年第2期7卷 102-107页

作者： Ana M.Palacios Rachel A.Feiner Robert M.Cabrera Department of Nutritional Sciences Dell Pediatric Research InstituteUniversity of Texas at AustinAustinTexas Department of Health Policy and Community Health Jiann Ping Hsu College of Public HealthGeorgia Southern UniversitySavannahGeorgia Department of Behavioral Neuroscience College of ScienceNortheastern UniversityBostonMassachusetts Center for Precision Environmental Health Baylor College of MedicineHoustonTexas

Objectives:Folates are B vitamins that are essential for several molecular,cellular,and biological processes,including nucleotide synthesis,methylation,and methionine cycling.The physiological impacts of these processes on health also extend to cell proliferation,folate deficiency anemia,and reduction of the risk of birth defects during pregnancy.The primary objective of this study was to characterize the binding affinities of different folate forms,folic acid(FA),5-methyltetrahydrofolate(5MTHF),and folinic acid,to the folate receptorsαandβ,and to the bovine milk folate binding protein.These three dietary forms of folate are found in enriched grains(FA),various fruits and leafy vegetables(folinic acid),and red blood cells(5MTHF).Methods:The half maximal inhibitory concentration values and binding curves of each of these folates for each receptor were determined.Results:Our results indicated that FA had the highest affinity for all folate receptors,followed by 5MTHF,and lastly,by folinic acid,examined by several orders of magnitudes.Conclusion:These data are expected to provide new insights into the therapeutic applications of the different forms of folate in a variety of diseases.

关键词： 5-methyltetrahydrofolate folic acid folinic acid folate receptorα folate receptorβ affinity

folic acid Modified Electrospun Poly(vinyl alcohol)/Polyethyleneimine Nanofibers for Cancer Cell Capture Applications

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Chinese Journal of Polymer Science 2016年第6期34卷 755-765页

作者： Zhang-yu Fan Yi-li Zhao 朱晓玥 Yu Luo Ming-wu Shen 史向阳 College of Chemistry Chemical Engineering and BiotechnologyDonghua UniversityShanghai 201620China Key Laboratory of Textile Science&Technology Ministry of EducationCollege of TextilesDonghua UniversityShanghai 201620China

Capture and detection of metastatic cancer cells are crucial for diagnosis and treatment of malignant neoplasm. Here, we report the use of folic acid （FA） modified electrospun poly（vinyl alcohol）（PVA）/polyethyleneimine （PEI） nanofibers for cancer cell capture applications. Electrospun PVA/PEI nanofibers crosslinked by glutaraldehyde vapor were modified with FA via a poly（ethylene glycol）（PEG） spacer, followed by acetylation of the fiber surface PEI amines. The formed FA-modified nanofibers were well characterized. The morphology of the electrospun PVA/PEI nanofibers is smooth and uniform despite the surface modification. In addition, the FA-modified nanofibers display good hemocompatibility as confirmed by hemolysis assay. Importantly, the developed FA-modified nanofibers are able to specifically capture cancer cells overexpressing FA receptors, which were validated by quantitative cell counting assay and qualitative confocal microscopy analysis. The developed FA-modified PVA/PEI nanofibers may be used for capturing circulating tumor cells for cancer diagnosis applications.

关键词： Poly（vinyl alcohol） Polyethyleneimine Electrospun nanofibers folic acid Cancer cell capture.

folic acid Modified Polymeric Micelles for Intravesical Instilled Chemotherapy

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Chinese Journal of Polymer Science 2018年第4期36卷 479-487页

作者： Dan-Hua Zhou Guan Zhang Qing-Song Yu Zhi-Hua Gan National University of Singapore Environmental Research Institute(NERI) National University of SingaporeSingapore 117576Singapore Beijing Advanced Innovation Center for Soft Matter Science and Engineering State Key Laboratory of Organic-inorganic Composite MaterialsCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing 100029China Department of Urology China-Japan Friendship HospitalBeijing 100029China

In this study, a targeting micellar drug delivery system was developed for intravesical instilled chemotherapy of bladder cancer. The amphiphilic diblock copolymer poly（？-caprolactone）-block-poly（ethylene glycol）（PCL-b-PEO） with functional amino group（NH2） at the end of PEO block was synthesized. Then the copolymer was conjugated with folic acid（FA） and fluorescein isothiocyannate（FITC） via the PEO-NH2 terminus, and then assembled into micelles with the target moiety and fluorescence labeling. In addition, drug loaded micelles were also fabricated with anticancer drug doxorubicin（DOX） encapsulated in the hydrophobic core. The micelles were characterized in terms of size, drug loaded efficiency and critical micellization concentration（CMC） by means of DLS, UV and fluorescence spectra. In vitro cellular uptake and cytotoxicity studies showed that FA modified PCL-b-PEO-FA micelles have a greater targeting efficiency to human bladder cancer cell（T-24 cell） compared to PCL-b-PEO-NH2 micelles due to the conjugation of FA on the surface, while no targeting effect to normal tissue originated human embryonic kidney 293（HEK-293） cells was observed, enabling the micelles a promising drug carrier for intravesical instilled chemotherapy of bladder cancer.

关键词： Targeted drug delivery Superficial bladder cancer Intravesical instilled chemotherapy folic acid Micelles

folic acid protects against fluoride-induced oxidative stress and testicular damage in rats

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Asian pacific Journal of Reproduction 2021年第6期10卷 274-283页

作者： Ray Dibyendu Chatterjee Tiasa Monalisha Das Panda Pradip Mukherjee Sandip Department of Physiology Serampore CollegeSeramporeHooghly-712201West BengalIndia Department of Statistics Serampore CollegeSeramporeHooghly-712201West BengalIndia

Objective:To investigate the effects of folic acid on testicular oxidative damage in sodium fluoride-induced male Wistar rats.Methods:A total of 24 male Wistar rats were divided into 4 groups:the control,sodium fluoride(fed with 100 mg/L sodium fluoride through drinking water orally for 21 days),folic acid(36μg/kg body weight/day,orally),and sodium fluoride plus folic acid(received similar dose orally)groups.At the end of 21 days,epididymal sperm parameters,biochemical analysis of testicular tissue,and serum hormonal levels were performed along with histopathological studies.Results:Sodium fluoride intoxication resulted in marked reduction in gonado somatic index,serum luteinizing hormone,and testosterone level along with 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase activities.In addition,reduction in sperm density,as well as loss of sperm motility and sperm viability,were also observed.Besides,increased levels of testicular malondialdehyde,nitrite,interleukin-6 and tumor necrosis factor-α as well as decreased levels of superoxide dismutase and catalase activities and reduced glutathione content were found to be associated with this toxicity.folic acid co-treatment,on the other hand,could prevent all the sodium fluoride-induced testicular pathophysiology and oxidative stress related parameters.Histological examinations of testicular sections from the experimental rats supported these results.Conclusions:Combining all,this study suggests that being an antioxidant,folic acid plays a beneficial role against fluoride-induced adverse effects on the male reproductive system.

关键词： Sodium fluoride folic acid Testicular damage Sperm Oxidative stress Antioxidants

Effects of varying dietary folic acid during weaning stress of piglets

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Animal Nutrition 2021年第1期7卷 101-110页

作者： Lei Wang Xian Tan Huiru Wang Qiye Wang Pengfei Huang Yali Li Jianzhong Li Jing Huang Huansheng Yang Yulong Yin Laboratory of Animal Nutrition and Human Health Hunan International Joint Laboratory of Animal Intestinal Ecology and HealthCollege of Life ScienceHunan Normal UniversityChangsha410081China Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry ProductionKey Laboratory of Agro-ecological Processes in Subtropical RegionScientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-CentralMinistry of AgricultureInstitute of Subtropical AgricultureChinese Academy of SciencesChangsha410125China Department of Neuroscience Hengyang School of MedicineUniversity of South ChinaHengyang421000China

The present study was conducted to evaluate the effect of dietary folic acid on the growth performance,intestinal morphology,and intestinal epithelial cells renewal in post-weaning piglets.Twenty-eight piglets(weaned at day 21,initial body weight of 6.73±0.62 kg)were randomly allotted to 4 treat-ments with 7 pens per diet and 1 piglet per pen.The piglets were fed the same antibiotic-free and zinc oxide-free basal diets supplemented with folic acid at 0,3,9,and 18 mg/kg for 14 days.The results showed that dietary supplementation with folic acid increased villus height(VH)(P=0.003;linear,P=0.001),VH-to-crypt depth(VH:CD)ratio(P=0.002;linear,P=0.001),villus surface area(VSA)(P=0.026;linear,P=0.010).The analyzed parameters ADG,serum urea nitrogen(BUN)content,VH,VSA,and serum folate(SF)concentration responded linearly to the dietary folic acid concentration when the dietary folic acid concentration was below 4.42,5.26,4.79,3.47,and 3.53 mg/kg respectively(R2=0.995,0.995,0.999,0.999,0.872,P=0.09,0.07,0.09,0.09,0.36,respectively),as assessed by a two-linear broken-line regression.Above these breakpoints,the response of ADG,VH,VSA,and SF plateaued in response to changes in dietary folic acid concentration.Moreover,dietary supplementation with folic acid significantly increased the lactase(P=0.001;linear,P=0.001)and sucrase activities(P=0.021;linear,P=0.010)in the jejunal mucosa of weaned piglets.The mRNA expression of solute carrier family 6 member 19(SLC6a19),solute carrier family 1 member 1(SLC7a1),tumor necrosis factor-α(TNF-α),the number of Ki67 positive cells,and cell shedding rate had a significant linear contrast(P=0.023,0.021,0.038,0.049,and 0.008,respectively)in dietary folic acid groups.In conclusion,our results indicate that folic acid supplementation can improve the growth performance and intestinal morphology of weaned piglets by maintaining the balance of epithelial cell renewal.

关键词： folic acid Growth performance Antibiotic-free Intestinal morphology Post-weaning piglet