The potential mediating role of the gut microbiome and metabolites in the association between PFAS and kidney function in young adults: A proof-of-concept study

Article

作者: Conti, David V. ; Conti, David V ; Goodrich, Jesse A. ; Wang, Hongxu ; Goodrich, Jesse A ; Walker, Douglas I. ; Chatzi, Leda ; Gilliland, Frank D. ; Hampson, Hailey E. ; Costello, Elizabeth ; Nelson, Jonathan ; Aung, Max ; Bjornstad, Petter ; Walker, Douglas I ; Rock, Sarah ; Alderete, Tanya L. ; Alderete, Tanya L ; Pyle, Laura ; Gilliland, Frank D ; Jia, Qiran ; Chen, Zhanghua ; Li, Shiwen ; Hampson, Hailey E

BACKGROUNDChronic kidney disease (CKD) affects over 10 % of the global population and can lead to kidney failure and death. Exposure to per- and polyfluoroalkyl substances (PFAS) is associated with increased risk of CKD, yet studies examining the mechanisms linking PFAS and kidney function are lacking. In this exploratory study, we examined longitudinal associations of PFAS exposure with kidney function, and tested if associations were mediated by altered gut bacterial taxa or plasma metabolites using a multi-omics mediation analysis.METHODSSeventy-eight young adults from the Children's Health Study were included in this longitudinal cohort study. At baseline, seven plasma PFAS and untargeted plasma metabolomics were measured using liquid chromatography/mass-spectrometry. Baseline gut bacterial abundance was characterized using 16S rRNA sequencing and examined at the genus level. At follow-up, serum creatinine and cystatin-C concentrations were quantified to estimate glomerular filtration rate (eGFR). High-dimensional multi-omics analyses were conducted to assess the association between baseline PFAS exposure with follow-up eGFR, mediated by gut microbiome and circulating metabolite levels.RESULTSPFAS burden score, a variable developed to estimate exposure to chemical mixtures, was associated with kidney function. Each standard deviation increase in baseline PFAS burden score was associated with a 2.4 % lower eGFR at follow-up (95 % CI:[0.1 %,4.8 %]). Following high-dimensional mediation analyses with the microbiome and circulating metabolites, a joint component (characterized by reduced Lachnospiraceae and 17b-estradiol and increased succinate, retinoate and dodecanoic acid) and a metabolite component (characterized by increased hypotaurine and decreased D-pinitol and ureidopropionate) mediated 38 % and 50 % of the effect between PFAS burden score and eGFR, respectively.CONCLUSIONOur proof-of-concept analysis provides the first evidence that reduced short-chain fatty acid-producing bacteria and anti-inflammatory metabolites may link PFAS exposure with impaired kidney function. This study raises the possibility of future targeted interventions that can alter gut microbiome or circulating metabolite profiles to prevent PFAS induced kidney damage.

2024-11-01·Future Medicinal Chemistry

Novel Bis-1,2,3-triazole-thiazolidinone hybrid as anticancer agents that induce apoptosis and molecular modeling study

Article

作者: Ait Itto, Moulay Youssef ; Riadi, Yassine ; Morjani, Hamid ; Ejaz, Syeda Abida ; Oubella, Ali ; Aziz, Mubashir ; Robert, Anthony ; Riahi, Abdelkhalek ; Attaullah, Hafiz Muhammad ; Auhmani, Aziz ; Alossaimi, Manal A ; Bimoussa, Abdoullah

Aim: A series of (R)-Carvone-based 1,2,3-triazole-thiazolidinone 17a-h hybrids were synthesized and characterized by spectroscopic techniques NMR and HRMS. The chemical reactivity and the stability parameters were observed via DFT.Method/results: The objective was to evaluate the anticancer activity of the synthesized compounds against cancer cell lines. The mechanism of action by which the 17b and 17g exert their effect suggested that they may induce apoptosis through activation of caspase-3/7. This effect was observed against the most important NIMA-related kinases via Docking investigation. The designed compounds were identified as the best inhibitors of the NEK family via the inactivation of the caspase-3. The Docking results were supported by Dynamics where the binding energies justified the medicinal importance of the synthesized derivatives.

2020-07-01·Journal of Ethnopharmacology

Abeliophyllum distichum Nakai alleviates postmenopausal osteoporosis in ovariectomized rats and prevents RANKL-induced osteoclastogenesis in vitro

Article

作者: Kim, Eun-Young ; Jung, Hyuk-Sang ; Sohn, Youngjoo ; Kim, Jae-Hyun ; Kim, Minsun ; Park, Jae Ho

ETHNOPHARMACOLOGICAL RELEVANCEAbeliophyllum distichum Nakai (AD), called Miseon, is one of Korea's monotypic endemic species. As a folk remedy, the AD has been used to treat inflammatory disease, stomachaches, diarrhea, and gynecologic disease in Korea. Some researchers have reported that the AD has anti-cancer, anti-inflammatory, and anti-oxidant effects. But the protective effect of AD leaf for osteoporosis has not been reported yet.AIM OF THE STUDYThis study aimed to analyze the effects and mechanism of AD-ethyl acetate fraction (EA) extract on the osteoporosis, one of the gynecologic disease.MATERIALS AND METHODSThe RAW 264.7 cells were used as a model for RANKL-induced osteoclastogenesis. We measured the TRAcP activity, expressions of NFATc1, c-fos, and MAPK to investigate the effect of AD-EA. OVX-induced osteoporosis rat model was used as menopausal osteoporosis. After both ovaries were removed through a surgical procedure, and AD-EA or 17b-estradiol was orally administered for 8 weeks. BMD of femurs was measured as well as the bone morphometric parameter, such as BV/TV, trabecular thickness, number and surface using a micro CT.RESULTSAD-EA significantly inhibited TRAcP activity, actin ring formation, pit formation and the expressions of osteoclast-related genes in a dose-dependent manner through the inhibition of the MAPK and c-fos/NFATc1 pathway. In addition, low dose administration of AD-EA improved the deterioration of trabecular bone microarchitecture caused by OVX through the inhibition of bone resorption by TRAcP and CTK.CONCLUSIONSThese results suggest that AD-EA may contribute to the therapy of osteoporosis caused by menopause in women.

100 项与 BET-HDAC Dual Inhibitors 17b (Second Military Medical University) 相关的药物交易

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