Consequences of Exposure to Famine Exposure on the Later Life eGFR Decline Among Survivors of the Great Chinese Famine: A Retrospective Study.

OBJECTIVES: Chronic kidney disease (CKD) significantly contributes to the socio-economic burden both in China and worldwide. Previous research has shown that experiencing childhood famine is linked to various chronic conditions like diabetes, hypertension, and proteinuria. However, the long-term effects of early-life famine exposure on adult kidney function remain unclear. This study investigates whether exposure to the Chinese Great Famine (1959-1962) is associated with a decline in glomerular filtration rate (GFR) later in life. DESIGN AND METHODS: China Health and Retirement Longitudinal Study is a population-based observational study. We analyzed data from 8,828 participants in the 2011-2012 baseline survey, updated in 2014. Participants were categorized based on their birth year into fetal-exposed (1959-1962), childhood-exposed (1949-1958), adolescence/adult-exposed (1912-1948), and nonexposed (1963-1989) groups. The estimated GFR (eGFR) was calculated using the CKD-EPI-Cr-Cys equation (2021), with CKD defined as an eGFR below 60 mL/min/1.73 m2. RESULTS: Average eGFR values were 103.0, 96.8, 91.2, and 76.3 mL/min/1.73 m2 for the fetal-exposed, childhood-exposed, adolescence/adult-exposed, and nonexposed groups, respectively. The eGFR in the exposed groups was significantly lower compared to the nonexposed group. Specifically, famine exposure correlated with a lower eGFR (coefficient estimates [CE] -9.14, 95% confidence interval [CI] -9.46, -8.82), with the strongest association observed in the adolescence/adult-exposed group (CE -26.74, 95% CI -27.75, -25.74). Adjusting for variables such as demographics, physical and laboratory tests, complications, and personal habits like smoking and drinking did not qualitatively alter this association (CE -1.38, 95% CI -1.72, -1.04). Further stratification by sex, body mass index, alcohol consumption history, hypertension, diabetes, Center for Epidemiologic Studies Depression score, and education level showed that the association remained consistent. CONCLUSIONS: Exposure to famine during different life stages can have enduring effects on GFR decline in humans.

Cellular Fates of Manganese(II) Pentaazamacrocyclic Superoxide Dismutase (SOD) Mimetics: Fluorescently Labeled MnSOD Mimetics, X-ray Absorption Spectroscopy, and X-ray Fluorescence Microscopy Studies.

Manganese(II) pentaazamacrocyclic complexes (MnPAMs) can act as small-molecule mimics of manganese superoxide dismutase (MnSOD) with potential therapeutic application in conditions linked to oxidative stress. Previously, the in vitro mechanism of action has been determined, their activity has been demonstrated in cells, and some representatives of this class of MnSOD mimetics have entered clinical trials. However, MnPAM uptake, distribution, and metabolism in cells are largely unknown. Therefore, we have used X-ray fluorescence microscopy (XFM) and X-ray absorption spectroscopy (XAS) to study the cellular fate of a number of MnPAMs. We have also synthesized and characterized fluorescently labeled (pyrene and rhodamine) manganese(II) pyane [manganese(II) trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene] derivatives and investigated their utility for cellular imaging of MnPAMs. Their SOD activity was determined via a direct stopped-flow technique. XFM experiments show that treatment with amine-based manganese(II) pyane type pentaazamacrocycles leads to a 10-100-fold increase in the overall cellular manganese levels compared to the physiological levels of manganese in control cells. In treated cells in general, manganese was distributed throughout the cell body, with a couple of notable exceptions. The lipophilicity of the MnPAMs, examined by partitioning in octanol-buffer system, was a good predictor of the relative cellular manganese levels. Analysis of the XAS data of treated cells revealed that some fraction of amine-based MnPAMs taken up by the cells remained intact, with the rest transformed into SOD-active manganese(II) phosphate. Higher phosphate binding constants, determined from the effect of the phosphate concentration on in vitro SOD activity, were associated with more extensive metabolism of the amine-based MnPAMs to manganese(II) phosphate. In contrast, the imine-based manganese(II) pydiene complex that is prone to hydrolysis was entirely decomposed after uptake and free manganese(II) was oxidized to a manganese(III) oxide type species, in cytosolic compartments, possibly mitochondria. Complex stability constants (determined for some of the MnPAMs) are less indicative of the cellular fate of the complexes than the corresponding phosphate binding constants.

Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation.

Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pressure, neurotransmission and inflammation. The mechanisms behind these effects are still largely elusive and oxidative posttranslational modification of cysteine residues (protein persulfidation or S-sulfhydration) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled. Using an improved tag-switch assay for persulfide detection we show here that protein persulfide levels are controlled by the thioredoxin system. Recombinant thioredoxin showed an almost 10-fold higher reactivity towards cysteine persulfide than towards cystine and readily cleaved protein persulfides as well. This reaction resulted in H2S release suggesting that thioredoxin could be an important regulator of H2S levels from persulfide pools. Inhibition of the thioredoxin system caused an increase in intracellular persulfides, highlighting thioredoxin as a major protein depersulfidase that controls H2S signalling. Finally, using plasma from HIV-1 patients that have higher circulatory levels of thioredoxin, we could prove depersulfidase role in vivo.

Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells.

A novel approach to circumvent multidrug resistance is hybridization of natural products in dimers. We analyzed homodimers of two artesunic acid molecules and heterohybrids of artesunic acid and betulin in human CCRF-CEM and multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells. Multidrug-resistant cells were not cross-resistant to the novel compounds. Collateral sensitivity was observed for artesunic acid homodimer. Artesunic acid and artesunic acid homodimer induced G0/G1 cell cycle arrest, apoptosis, and formation of reactive oxygen species.