Lipidomics reveals the lipid metabolism disorders in Fructus Psoraleae-induced hepatotoxicity in rats with kidney-yin deficiency syndrome.

Fructus Psoraleae (FP), one of the important traditional Chinese medicines, is widely used in clinic and has been reported to be hepatotoxic. However, there is no report on the mechanism of FP-induced hepatotoxicity based on the theory of You Gu Wu Yun. In this study, plasma samples of rats with different kidney deficiency syndromes were investigated using a lipidomics approach based on UPLC/Q-TOF-MS technique. Firstly, multivariate statistical analysis, VIP value test, statistical test and other methods were used to find the lipid metabolites in the two syndrome model groups that were different from the normal group. The screening of differential lipid metabolites revealed that there were 12 biomarkers between the blank group and the kidney-yang deficiency model group as well as 16 differential metabolites between the kidney-yin deficiency model group, and finally a total of 17 relevant endogenous metabolites were identified, which could be used as differential lipid metabolites to distinguish between kidney-yin deficiency and kidney-yang deficiency evidence. Secondly, the relative content changes of metabolites in rats after administration of FP decoction were further compared to find the substances associated with toxicity after administration, and the diagnostic ability of the identified biomarkers was evaluated using a receiver operating characteristic curve (ROC). Results a total of 14 potential differential lipid metabolites, including LysoPC(20:0/0:0) and LysoPC(16:0/0:0), which may be related to hepatotoxicity in rats with kidney-yin deficiency syndrome were further screened, namely, the potential active lipid metabolites related to hepatotoxicity in rats induced by FP. Finally, cluster analysis, MetPA analysis and KEGG database were used to analyze metabolic pathways. It was discovered that the metabolism of glycerophospholipid and sphingolipid may be strongly related to the mechanism of hepatotoxicity brought on by FP. Overall, we described the lipidomics changes in rats treated with FP decoction and screened out 14 lipid metabolites related to hepatotoxicity in rats with kidney-yin deficiency, which served as a foundation for the theory of "syndrome differentiation and treatment" in traditional Chinese medicine and a guide for further investigation into the subsequent mechanism.

Food Processing, According to the Nova Classification System, and Dietary Intake of US Infants and Toddlers.

BACKGROUND: High intake of ultra-processed foods (UPFs) is associated with increased risk of chronic disease; thus, it is important to understand how UPFs influence diet quality early in life. OBJECTIVES: We describe complementary foods and beverages (CFBs) according to the Nova Classification System of Food Processing for infants and toddlers in the United States and estimate how Nova groups and subgroups contribute to energy and select nutrients and food groups. METHODS: We used day 1 24-h recall from infants and toddlers aged 6-23 mo from the cross-sectional, nationally representative 2013-18 National Health and Nutrition Examination Survey (n = 1140). We estimated contributions of Nova groups and subgroups to energy and select nutrients and food groups consumed as CFBs (excluding human milk and formula) using the population ratio with weighted survey commands in SAS. RESULTS: For infants and toddlers in the United States, 42 ± 0.9% (mean ± standard error of the mean) of energy intake from CFBs came from unprocessed/minimally processed foods (U/MPFs) and 45 ± 0.8% from UPFs. U/MPFs contributed most to nutrient intakes (except iron, zinc, and sodium); ≥20% of all selected nutrients was from UPFs. UPFs contributed most to iron (75 ± 1.0%) and zinc (48 ± 1.3%); breakfast cereals were the top source. Most fruit, vegetables, and dairy were from U/MPFs. More than 80% of total grains, whole grains, refined grains, and added sugars were UPFs. CONCLUSIONS: U/MPFs support healthy dietary intake of infants and toddlers in the United States, whereas UPFs contribute meaningfully to nutrients and food groups to be encouraged (iron, zinc, and whole grains), as well as some that should be limited (added sugars and sodium). More research is needed to better understand the utility and sensitivities of using Nova for providing dietary guidance for infants and toddlers in the United States.

Dietary supplement use among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Adult survivors of childhood cancer have poor adherence to nutrition guidelines and inadequate intake of dietary vitamins D and E, potassium, fiber, magnesium, and calcium. The contribution of vitamin and mineral supplement use to total nutrient intake in this population is unclear. METHODS: We examined the prevalence and dose of nutrient intake among 2570 adult survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study, and the association of dietary supplement use with treatment exposures, symptom burden, and quality of life. RESULTS: Nearly 40% of the adult survivors of cancer survivors reported regular use of dietary supplements. Although cancer survivors who used dietary supplements were less likely to have inadequate intake of several nutrients, they were also more likely to have excessive intake (total nutrient intake ≥ tolerable upper intake levels) of folate (15.4% vs. 1.3%), vitamin A (12.2% vs. 0.2%), iron (27.8% vs. 1.2%), zinc (18.6% vs. 1%), and calcium (5.1% vs. 0.9%) compared with survivors who did not use dietary supplements (all p < 0.05). Treatment exposures, symptom burden, and physical functioning were not associated with supplement use, whereas emotional well-being and vitality were positively associated with supplement use among childhood cancer survivors. CONCLUSIONS: Supplement use is associated with both inadequate and excessive intake of specific nutrients, but positively impacts aspects of quality of life among childhood cancer survivors.

Amelioration of Lung Fibrosis by Total Flavonoids of Astragalus via Inflammatory Modulation and Epithelium Regeneration.

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.

Integrating Nutrition into Outpatient Oncology Care-A Pilot Trial of the NutriCare Program.

Nutrition is an essential part of oncology care; however, nutrition advice and guidance are not always provided. This six-week pilot pretest-posttest intervention was designed to test the feasibility and effectiveness of integrating a nutrition education program (NutriCare) into outpatient oncology care. Twenty breast cancer survivors were recruited through Tufts Medical Centre. Nutrition impact symptoms and demographics were collected at baseline, dietary quality and quality of life measures were collected pre and post-intervention and an evaluation form was completed post-intervention. Forty-four percent of eligible participants were recruited, and 90% of those completed the study. The NutriCare program was well received with participants reporting that goals were feasible (94.4%), the program had a positive impact on their diet (77.8%), and over 80% would recommend the program. There was an interest in continuing with the program (89%) and in receiving additional guidance from the healthcare team (83%). There was a significant improvement (p = 0.04) in physical function over the six weeks; however, no additional significant differences in quality of life or dietary quality were seen. In conclusion, cancer survivors were positive about the NutriCare program and its integration into practice.

Perceptions of Oncology Providers and Cancer Survivors on the Role of Nutrition in Cancer Care and Their Views on the "NutriCare" Program.

Cancer patients and survivors can experience treatment related side effects that impact nutrition status, as well as unwanted weight loss, weight gain and poor dietary quality. Therefore, they are a group that would benefit from nutrition intervention. A qualitative study was conducted online (six focus groups and two interviews) with 12 oncology providers and 12 survivors in the United States. Participants were asked about the role of nutrition in survivors' health, appropriate components of nutrition care for cancer patients, and strategies to integrate nutrition into oncology care. Feedback on a proposed program, "NutriCare", was also sought. Focus groups were recorded, transcribed verbatim, and analyzed for themes. Four main themes emerged: (1) nutrition is an important component of oncology care and source of empowerment for cancer patients; (2) in the NutriCare program, the prescription pad component was viewed as a critical aspect, and there was also a preference for dealing with patients and survivors separately; (3) for implementation, the most appropriate time for providers to talk to patients about nutrition is during the development of the treatment plan. Reinforcement of key nutrition messages by providers was also highlighted; (4) major barriers included lack of time and motivation by providers. Survivors were interested in and providers supportive of integrating nutrition into oncology care.

Dietary Supplement Use among Adult Cancer Survivors in the United States.

BACKGROUND: Many cancer patients initiate dietary supplement use after cancer diagnosis. How dietary supplement use contributes to the total nutrient intake among cancer survivors as compared with individuals without cancer needs to be determined. OBJECTIVES: We aimed to evaluate nutrient intakes from dietary supplements among cancer survivors in relation to their total nutrient intake and compare those with individuals without cancer. METHODS: We evaluated the prevalence, dose, and reason for using dietary supplements among 2772 adult cancer survivors and 31,310 individuals without cancer who participated in the NHANES 2003-2016. RESULTS: Cancer survivors reported a higher prevalence of any (70.4% vs. 51.2%) and multivitamin/mineral (48.9% vs. 36.6%) supplement use and supplement use of 11 individual vitamins and 8 minerals than individuals without cancer. Overall, cancer survivors had significantly higher amounts of nutrient intake from supplements but lower nutrient intakes from foods for the majority of the nutrients. Compared with individuals without cancer, cancer survivors had a higher percentage of individuals with inadequate intake (total nutrient intake 

[Analysis of lipophilic components of Salvia miltiorrhiza roots and S. yunnanensis roots by UPLC and LC-MS/MS].

Fingerprints of lipophilic components in the roots of Salvia miltiorrhiza and S.yunnanensis were analyzed by UPLC-DADand UPLC coupled with mass spectroscopy to evaluate the differences and similarities of the lipophilic components in the two kinds of herbs.The UPLC analysis of 18 batches of S.miltiorrhiza and 16 batches of S.yunnanensis was performed on a 25℃Thermo Accucore C_(18)column(2.1 mm×100 mm,2.6µm)by Shimadzu LC-20AD;mobile phase was 0.026%phosphoric acid(A)-acetonitrile(B)with gradient elution;flow rate was 0.4 m L·min~(-1);detection wavelength was set at 270 nm;injection volume was 2µL.The molecular structures of the lipophilic components were analyzed on a 25℃Thermo Accucore C_(18)column(2.1 mm×100 mm,2.6µm)by Thermo U3000 UPLC Q Exactive Orbitrap LC-MS/MS with a mobile phaseconsisting of 0.1%formic acid water(A)and 0.1%formic acidacetonitrile(B).The mass spectrometry was acquired in positive modes using ESI.There are 10 common peaks in the lipophilic components of S.miltiorrhiza.The similarity between the 16 batches of S.miltiorrhiza and their own reference spectra was greater than 0.942,and the average similarity was 0.973.There are 12 common peaks in the lipophilic components of S.yunnanensis.The similarity between the 18 batches of S.yunnanensis and their own reference spectra was greater than 0.937,and the average similarity was 0.976.The similarity between the reference chromatograms of S.miltiorrhiza and S.yunnanensis was only 0.900.There are three lipophilic components in S.yunnanensis,which are not found in S.miltiorrhiza,and one of which isα-lapachone.There is a lipophilic component in S.miltiorrhiza not found in S.yunnanensis,which may be miltirone.The two herbs contain 8 common lipophilic components including dihydrotanshinoneⅠ,cryptotanshinone,tanshinoneⅠ,tanshinoneⅡ_A,nortanshinone in which the content of tanshinoneⅡ_A,dihydrotanshinoneⅠand cryptotanshinone of S.yunnanensisis significantly lower than that of S.miltiorrhiza(P<0.01),and the contents of tanshinoneⅠand nortanshinone are significantly lower than that of S.miltiorrhiza too(P<0.05).There are significant differences in the types and contents of lipophilic components between the roots of S.miltiorrhiza and S.yunnanensis,and the similarity between the fingerprints of interspecies is much lower than that between the same species.Therefore,the roots of S.miltiorrhiza and S.yunnanensis are two kinds of herbs which are quite different in chemical compounds and compositions.

Association Among Dietary Supplement Use, Nutrient Intake, and Mortality Among U.S. Adults: A Cohort Study.

Background: The health benefits and risks of dietary supplement use are controversial. Objective: To evaluate the association among dietary supplement use, levels of nutrient intake from foods and supplements, and mortality among U.S. adults. Design: Prospective cohort study. Setting: NHANES (National Health and Nutrition Examination Survey) data from 1999 to 2010, linked to National Death Index mortality data. Participants: 30 899 U.S. adults aged 20 years or older who answered questions on dietary supplement use. Measurements: Dietary supplement use in the previous 30 days and nutrient intake from foods and supplements. Outcomes included mortality from all causes, cardiovascular disease (CVD), and cancer. Results: During a median follow-up of 6.1 years, 3613 deaths occurred, including 945 CVD deaths and 805 cancer deaths. Ever-use of dietary supplements was not associated with mortality outcomes. Adequate intake (at or above the Estimated Average Requirement or the Adequate Intake level) of vitamin A, vitamin K, magnesium, zinc, and copper was associated with reduced all-cause or CVD mortality, but the associations were restricted to nutrient intake from foods. Excess intake of calcium was associated with increased risk for cancer death (above vs. at or below the Tolerable Upper Intake Level: multivariable-adjusted rate ratio, 1.62 [95% CI, 1.07 to 2.45]; multivariable-adjusted rate difference, 1.7 [CI, -0.1 to 3.5] deaths per 1000 person-years), and the association seemed to be related to calcium intake from supplements (≥1000 mg/d vs. no use: multivariable-adjusted rate ratio, 1.53 [CI, 1.04 to 2.25]; multivariable-adjusted rate difference, 1.5 [CI, -0.1 to 3.1] deaths per 1000 person-years) rather than foods. Limitations: Results from observational data may be affected by residual confounding. Reporting of dietary supplement use is subject to recall bias. Conclusion: Use of dietary supplements is not associated with mortality benefits among U.S. adults. Primary Funding Source: National Institutes of Health.

Stimulation of nuclear receptor REV-ERBs suppresses production of pronociceptive molecules in cultured spinal astrocytes and ameliorates mechanical hypersensitivity of inflammatory and neuropathic pain of mice.

The orphan nuclear receptors REV-ERBα and REV-ERBß (REV-ERBs) are crucial in the regulation of inflammatory-related gene transcription in astroglioma cells, but their role in nociceptive transduction has yet to be elaborated. Spinal dorsal horn astrocytes contribute to the maintenance of chronic pain. Treatment of cultured spinal astrocytes with specific REV-ERBs agonists SR9009 or GSK4112 significantly prevented lipopolysaccharide (LPS)-induced mRNA upregulation of pronociceptive molecules interleukin-1ß (IL-1ß) mRNA, interleukin-6 (IL-6) mRNA and matrix metalloprotease-9 (MMP-9) mRNA, but not CCL2 mRNA expression. Treatment with SR9009 also blocked tumor necrosis factor-induced IL-1ß mRNA, IL-6 mRNA and MMP-9 mRNA. In addition, treatment with SR9009 significantly blocked LPS-induced upregulation of IL-1ß protein, IL-6 protein and MMP-9 activity. The inhibitory effects of SR9009 on LPS-induced expression of pronociceptive molecules were blocked by knockdown of REV-ERBs expression with short interference RNA, confirming that SR9009 exerts its effect through REV-ERBs. Intrathecal LPS treatment in male mice induces hind paw mechanical hypersensitivity, and upregulation of IL-1ß mRNA, IL-6 mRNA and glial fibrillary acidic protein (GFAP) expression in spinal dorsal horn. Intrathecal pretreatment of SR9009 prevented the onset of LPS-induced mechanical hypersensitivity, cytokine expression and GFAP expression. Intrathecal injection of SR9009 also ameliorated mechanical hypersensitivity during the maintenance phase of complete Freund's adjuvant-induced inflammatory pain and partial sciatic nerve ligation-, paclitaxel-, and streptozotocin-induced neuropathy in mice. The current findings suggest that spinal astrocytic REV-ERBs could be critical in the regulation of nociceptive transduction through downregulation of pronociceptive molecule expression. Thus, spinal REV-ERBs could be an effective therapeutic target in the treatment of chronic pain.

[Effect of Transcutaneous Electrical Acupoint Stimulation on Post-surgical Gastrointestinal Function, Autonomic Nerve Activities and Plasma Brain-gut Peptide Levels in Patients Undergoing Gastrointestinal Surgery].

OBJECTIVE: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on ileus-postope-rative gastrointestinal functions and plasma ghrelin, motilin, and gastrin contents, and heart rate variability (HRV) in patients undergoing gastrointestinal surgery, so as to explore the interaction of vagus-brain-gut peptide. METHODS: A total of 58 patients undergoing elective gastrointestinal surgery were randomly assigned to TEAS (n=29) and sham-TEAS group (n=29, patients had no subjective sensation to 1 mA TEAS, thus, being considered to be sham-TEAS). TEAS (2 Hz/100 Hz, 6-8 mA for LI 4-PC 6, 12-18 mA for ST 36-SP 6) was applied to bilateral Hegu (LI 4)-Neiguan (PC 6) from 30 min pre-operation to the end of the operation and to bilateral LI 4-PC 6 and Zusanli (ST 36)-Sanyinjiao (SP 6) for 30 minutes twice daily in 3 consecutive post-operative days. ECGs of 12 leads were recorded to analyze different parameters of HRV from 2 days before and 4 days after surgery. Plasma ghrelin, motilin and gastrin contents were assayed by radioimmunoassay, and the patients' first bowel sound, first independent walk, first flatus, first solid food-intake and first defecation were recorded to evaluate the recovery state of gastrointestinal motility. RESULTS: Postoperative gastrointestinal motility:compared with the sham-TEAS group, the first bowel sound and the first defecation after surgery appeared apparently earlier in the TEAS group (P<0.05), but no significant differences were found between the two groups at the time of the first independent walk, first flatus and the first solid food-intake in patients undergoing gastrointestinal surgery. Plasma brain-gut peptides:the plasma ghrelin and motilin contents 4 days post-surgery were significant increased in the TEAS group than in the sham-TEAS group (P<0.05). No significant difference was found between the two groups in plasma gastrin contents (P>0.05). HRV domains:in comparison with pre-surgery, the levels of low frequency (LF) and high frequency (HF) of frequency domain (FD) and root mean square of successive differences (rMSSD) of the time domain (TD) of HRV 4 days after surgery were significantly decreased in the sham-TEAS group (P<0.05), but no significant changes were found in both FD and TD domains of the TEAS group 4 days after surgery (P>0.05). Compared with the sham-TEAS group, the HF and rMSSD levels were significantly increased in the TEAS group 4 days after the surgery (P<0.05). No significant differences were found between the two groups in the levels of very low frequency, LF and LF/HF levels of FD, and standard deviation of NN (beat-to-beat) intervals, the standard deviation of the average NN intervals and the proportion of NN 50 (the number of pairs of successive NNs that differ by more than 50 ms) divided by total number of NNs of TD. CONCLUSIONS: TEAS can promote gastrointestinal activities (i.e., reducing the time spending of first bowel sound and the first defecation) in gastrointestinal surgery patients, which may be related to its effects in up-regulating ghrelin and motilin contents and parasympathetic activity.

The relationship of major American dietary patterns to age-related macular degeneration.

PURPOSE: We hypothesized that major American dietary patterns are associated with risk for age-related macular degeneration (AMD). DESIGN: Cross-sectional study. METHODS: We classified 8103 eyes in 4088 eligible participants in the baseline Age-Related Eye Disease Study (AREDS). They were classified into control (n = 2739), early AMD (n = 4599), and advanced AMD (n = 765) by the AREDS AMD Classification System. Food consumption data were collected by using a 90-item food frequency questionnaire. RESULTS: Two major dietary patterns were identified by factor (principal component) analysis based on 37 food groups and named Oriental and Western patterns. The Oriental pattern was characterized by higher intake of vegetables, legumes, fruit, whole grains, tomatoes, and seafood. The Western pattern was characterized by higher intake of red meat, processed meat, high-fat dairy products, French fries, refined grains, and eggs. We ranked our participants according to how closely their diets line up with the 2 patterns by calculating the 2 factor scores for each participant. For early AMD, multivariate-adjusted odds ratio (OR) from generalized estimating equation logistic analysis comparing the highest to lowest quintile of the Oriental pattern score was ORE5O = 0.74 (95% confidence interval (CI): 0.59-0.91; Ptrend =0.01), and the OR comparing the highest to lowest quintile of the Western pattern score was ORE5W = 1.56 (1.18-2.06; Ptrend = 0.01). For advanced AMD, the ORA5O was 0.38 (0.27-0.54; Ptrend < 0.0001), and the ORA5W was 3.70 (2.31-5.92; Ptrend < 0.0001). CONCLUSIONS: Our data indicate that overall diet is significantly associated with the odds of AMD and that dietary management as an AMD prevention strategy warrants further study.

Antitumor effects of two extracts from Oxytropis falcata on hepatocellular carcinoma in vitro and in vivo.

AIMS: To investigate the antitumor effects of extracts from Oxytropis falcata on human hepatocellular carcinoma SMMC-7721 cells in vitro and in transplanted murine H22 tumors in vivo. METHODS: Cell proliferation, cell cycle distribution and apoptosis in SMMC-7721 cells were determined and tumor growth inhibition in H22 tumors was investigated. Cell cycle distribution was analyzed by flow cytometry with propidium iodide (PI) and Annexin V-FITC/ PI double staining. RESULTS: MTT assay revealed that essential oil and flavonoids of O. falcata (named EOOF and FOF) inhibited proliferation of SMMC-7721 cells in a dose-dependent manner. The IC50 value of EOOF and FOF were 0.115 and 0.097 mg·mL(-1), respectively. Cell cycle was arrested at G(1) phase, and induction of apoptosis occurred in SMMC-7721 cells when subjected to FOF. Growth inhibition in H22 solid tumors transplanted mice was significantly pronounced after being treated with FOF, and the inhibition ratio were 56.1% and 70.8% at the concentration of 30 and 60 mg·kg(-1). CONCLUSION: The results suggest that FOF promotes apoptosis in SMMC-7721 cells and inhibits H22 tumor growth, resulting in a potential antitumor effect on hepatic cancer.

Folate polyglutamylation is involved in chromatin silencing by maintaining global DNA methylation and histone H3K9 dimethylation in Arabidopsis.

DNA methylation and repressive histone Histone3 Lysine9 (H3K9) dimethylation correlate with chromatin silencing in plants and mammals. To identify factors required for DNA methylation and H3K9 dimethylation, we screened for suppressors of the repressor of silencing1 (ros1) mutation, which causes silencing of the expression of the RD29A (RESPONSE TO DESSICATION 29A) promoter-driven luciferase transgene (RD29A-LUC) and the 35S promoter-driven NPTII (NEOMYCIN PHOSPHOTRANSFERASE II) transgene (35S-NPTII). We identified the folylpolyglutamate synthetase FPGS1 and the known factor DECREASED DNA METHYLATION1 (DDM1). The fpgs1 and ddm1 mutations release the silencing of both RD29A-LUC and 35S-NPTII. Genome-wide analysis indicated that the fpgs1 mutation reduces DNA methylation and releases chromatin silencing at a genome-wide scale. The effect of fpgs1 on chromatin silencing is correlated with reduced levels of DNA methylation and H3K9 dimethylation. Supplementation of fpgs1 mutants with 5-formyltetrahydrofolate, a stable form of folate, rescues the defects in DNA methylation, histone H3K9 dimethylation, and chromatin silencing. The competitive inhibitor of methyltransferases, S-adenosylhomocysteine, is markedly upregulated in fpgs1, by which fpgs1 reduces S-adenosylmethionine accessibility to methyltransferases and accordingly affects DNA and histone methylation. These results suggest that FPGS1-mediated folate polyglutamylation is required for DNA methylation and H3K9 dimethylation through its function in one-carbon metabolism. Our study makes an important contribution to understanding the complex interplay among metabolism, development, and epigenetic regulation.

Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice.

BACKGROUND/AIMS: Fluorofenidone [1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD], a novel pyridone agent, showed potent antifibrotic properties. The aim of the present study was to investigate the effects of AKF-PD on diabetic nephropathy and kidney fibrosis, and to obtain an insight into its mechanisms of action. METHODS: We administered AKF-PD to diabetic db/db mice for 12 weeks. Moreover, we performed in vitro cultures using murine mesangial cells exposed to high ambient glucose concentrations. RESULTS: AKF-PD reduced renal hypertrophy, mesangial matrix expansion and albuminuria in the db/db mice. The upregulated expression of α1(I)- and α1(IV)-collagen and fibronectin mRNAs, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and tissue inhibitors of metalloproteinase 1 (TIMP-1) mRNAs and proteins was inhibited by AKF-PD treatment in the renal cortex of db/db mice. The maximal effective dose of AKF-PD was about 500 mg/kg body weight. AKF-PD inhibited the upregulated expression of α1(I)- and α1(IV)-collagens, TGF-ß1, TIMP-1 and α-SMA induced by high glucose concentrations in cultured mesangial cells. CONCLUSIONS: Our data indicate that AKF-PD diminishes the abnormal accumulation of mesangial matrix through the inhibition of upregulated expression of TGF-ß target genes in kidneys of db/db mice, resulting in attenuation of renal fibrosis and amelioration of renal dysfunction despite persistent hyperglycemia. Therefore, AKF-PD, a potent antifibrotic agent, holds great promise in the treatment of diabetic nephropathy.

Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy.

Fluorofenidone (FD) is a novel pyridone agent with significant antifibrotic effects in vitro. The purpose of this study is to investigate the effects of FD on renal interstitial fibrosis in rats with obstructive nephropathy caused by unilateral ureteral obstruction (UUO). With pirfenidone (PD, 500 mg/kg/day) and enalapril (10 mg/kg/day) as the positive treatment controls, the rats in different experimental groups were administered with FD (500 mg/kg/day) from day 4 to day 14 after UUO. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and type III collagen, transforming growth factor-ß(1) (TGF-ß(1)), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), α-smooth muscle actin (α-SMA), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed. FD treatment significantly attenuated the prominently increased scores of tubulointerstitial injury, interstitial collagen deposition, and protein expression of type I and type III collagen in ureter-obstructed kidneys, respectively. As compared with untreated rats, FD also significantly reduced the expression of α-SMA, TGF-ß(1), CTGF, PDGF, and inhibitor of TIMP-1 in the obstructed kidneys. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy through its regulation on fibrogenic growth factors, tubular cell transdifferentiation, and extracellular matrix.