No abstract

No abstract

SummaryReactive oxygen species are implicated in age‐associated neurodegeneration, although direct in vivo evidence is lacking. We recently showed that mice with a mutation in the Inner Mitochondrial Membrane Peptidase 2‐like (Immp2l) gene had elevated levels of mitochondrial superoxide, impaired fertility and age‐associated phenotypes, including kyphosis and ataxia. Here we show that ataxia and cerebellar hypoplasia occur in old mutant mice (> 16 months). Cerebellar granule neurons (CGNs) are significantly underrepresented; Purkinje cells and cells in the molecular layer are not affected. Treating mutant mice with the mitochondria‐targeted antioxidant SkQ1 from 6 weeks to 21 months protected cerebellar granule neurons. Apoptotic granule neurons were observed in mutant mice but not in age‐matched normal control mice or SkQ1‐treated mice. Old mutant mice showed increased serum protein carbonyl content, cerebellar 4‐hydroxynonenal (HNE), and nitrotyrosine modification compared to old normal control mice. SOD2 expression was increased in Purkinje cells but decreased in granule neurons of old mutant mice. Mitochondrial marker protein VDAC1 also was decreased in CGNs of old mutant mice, suggesting decreased mitochondrial number. SkQ1 treatment decreased HNE and nitrotyrosine modification, and restored SOD2 and VDAC1 expression in CGNs of old mutant mice. Neuronal expression of nitric oxide synthase was increased in cerebella of young mutant mice but decreased in old mutant mice. Our work provides evidence for a causal role of oxidative stress in neurodegeneration of Immp2l mutant mice. The Immp2l mutant mouse model could be valuable in elucidating the role of oxidative stress in age‐associated neurodegeneration.

Currently, the human MEX3C gene is known to encode an RNA-binding protein of 659 amino acid residues. Here we show that the MEX3C gene has alternative splicing forms giving rise to multiple MEX3C variants, and some cells express MEX3C transcripts coding for short MEX3C isoforms but not transcripts for MEX3C(659AA) MEX3C(659AA) functions as an adaptor protein for Exportin 1 (XPO1)-mediated nuclear export since it increases the cytoplasmic distribution of poly(A)(+) RNA and since addition of the nuclear export signal (NES) sequence to a short MEX3C isoform MEX3C(464AA) confers similar cytoplasmic poly(A)(+) RNA accumulation activity as MEX3C(659AA) FOS mRNA is a potential MEX3C target mRNA. One mechanism by which MEX3C(659AA) could regulate FOS mRNA is by promoting its nuclear export. Overexpressing MEX3C(659AA) significantly increased FOS mRNA expression, whereas mutating the NES of MEX3C(659AA) and treating cells with leptomycin B to inhibit XPO1-mediated nuclear export attenuated FOS upregulation. FOS mRNA is unstable in somatic cells but less so in oocytes; how it is stabilized in the oocytes is unknown. Transcripts for the mouse counterpart of human MEX3C(659AA) (MEX3C(652AA)) are specifically expressed in developing oocytes in the ovary, although total Mex3c transcripts are expressed in both granulosa cells and oocytes. The specific expression of this long MEX3C isoform in oocytes and its ability to enhance FOS mRNA nuclear export and stability all suggest that MEX3C(659AA) is an RNA-binding protein that preserves maternal FOS mRNA in oocytes.

Increasing global temperature and sea-level rise have led to concern about expansions in the distribution and prevalence of complex-lifecycle parasites (CLPs). Indeed, numerous environmental variables can influence the infectivity and reproductive output of many pathogens. Digenean trematodes are CLPs with intermediate invertebrate and definitive vertebrate hosts. Global warming and sea level rise may affect these hosts to varying degrees, and the effect of increasing temperature on parasite prevalence has proven to be nonlinear and difficult to predict. Projecting the response of parasites to anthropogenic climate change is vital for human health, and a longer term perspective (10 4 y) offered by the subfossil record is necessary to complement the experimental and historical approaches of shorter temporal duration (10 −1 to 10 3 y). We demonstrate, using a high-resolution 9,600-y record of trematode parasite traces in bivalve hosts from the Holocene Pearl River Delta, that prevalence was significantly higher during the earliest stages of sea level rise, significantly lower during the maximum transgression, and statistically indistinguishable in the other stages of sea-level rise and delta progradation. This stratigraphic paleobiological pattern represents the only long-term high-resolution record of pathogen response to global change, is consistent with fossil and recent data from other marine basins, and is instructive regarding the future of disease. We predict an increase in trematode prevalence concurrent with anthropogenic warming and marine transgression, with negative implications for estuarine macrobenthos, marine fisheries, and human health.parasites | disease | global warming | paleoecology | mollusks P redictions for the increase of global temperature and concomitant sea-level rise in the coming decades and centuries have led to concerns about the range expansion or shift of parasites and pathogens to higher latitudes, resulting in an increase in prevalence and severity of diseases. Indeed, environmental factors such as temperature, humidity, and precipitation can strongly influence the infectivity and reproductive output of many pathogens (1, 2); however, the life cycles of parasites can be quite complex, and accurately predicting how their prevalence will be influenced by these factors can be difficult. For example, digenean trematodes are complex-lifecycle parasites (CLPs) with multiple intermediate invertebrate hosts and a definitive vertebrate host. Environmental change may affect each of these hosts to varying degrees, such that a modest increase in temperature could result in an increase of parasite reproductive output and infectivity. However, a more severe increase in temperature could be beyond the thermal tolerance of one of the hosts, thus ultimately resulting in a decrease in prevalence (3)(4)(5). Still other studies have produced quantitative models and compared spatial and temporal (seasonal-to historical-scale) aspects of climatic and other environmental variables with outbreak data i...

In this study, we investigated the therapeutic effects and mechanism of atractylodin (ATL) on dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. We found that atractylodin could significantly reverse the effects of DSS-induced ulcerative colitis, such as weight loss, disease activity index score; shorten the colon length, and reverse the pathological changes in the colon of mice. Atractylodin could inhibit the activation of colonic macrophages by inhibiting the MAPK pathway and alleviate intestinal inflammation in the mouse model of ulcerative colitis. Moreover, it could protect the intestinal barrier by inhibiting the decrease of the tight junction proteins, ZO-1, occludin, and MUC2. Additionally, atractylodin could decrease the abundance of harmful bacteria and increase that of beneficial bacteria in the intestinal tract of mice, effectively improving the intestinal microecology. In an LPS-induced macrophage model, atractylodin could inhibit the MAPK pathway and expression of the inflammatory factors of macrophages. Atractylodin could also inhibit the production of lactate, which is the end product of glycolysis; inhibit the activity of GAPDH, which is an important rate-limiting enzyme in glycolysis; inhibit the malonylation of GAPDH, and, thus, inhibit the translation of TNF-α. Therefore, ours is the first study to highlight the potential of atractylodin in the treatment of ulcerative colitis and reveal its possible mechanism.

No abstract

Atractylodes lancea (Thunb.) DC. is a herb widely used traditionally for the treatment of gastrointestinal diseases such as gastric ulcer, spleen deficiency, and diarrhea. In China, people fry raw A. lancea (SCZ) together with wheat bran to make bran-fried A. lancea (FCZ). Ancient Chinese texts have documented that FCZ can enhance the function of regulating the intestines and stomach. Nevertheless, the effect and mechanism of SCZ and FCZ on ulcerative colitis (UC) are still unclear. The aim of this study was to compare the therapeutic effects of SCZ and FCZ and their mechanisms on dextran sulfate sodium (DSS)-induced UC in mice. The chemical constituents of SCZ and FCZ were analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with six reference compounds. The effects of SCZ and FCZ were investigated based on their effects on weight loss, disease activity index (DAI) score, colon length shortening, goblet cell loss, and pathological changes using the colons from a mouse model of DSS-induced UC. The effects of SCZ and FCZ on levels of the inflammatory cytokines (tumor necrosis factor-[Formula: see text], interleukin-6, interleukin-1[Formula: see text], mucoprotein (MUC2), tight protein (ZO-1, occludin), and the activation of macrophages were determined using immunohistochemistry (IHC) and immunofluorescence (IF). 16s RNA sequencing technology was used to detect the composition of the intestinal flora in each group. Nontargeted metabonomics was used to detect the serum metabolite levels of mice in each group. Pearson analysis was used to determine the correlation between the intestinal flora, metabolites, and pathological indices. Reverse transcription-polymerase chain reaction was used to detect the genes of different metabolite-related enzymes. A pseudogerm free (PGF) mouse model was used to verify whether the effect of SCZ and FCZ in UC depends on the regulation of intestinal flora. SCZ and FCZ could inhibit weight loss and decrease the DAI score, colon length shortening, goblet cell loss, and the extent of pathological changes in the colons of mice with DSS-induced colitis. Moreover, SCZ and FCZ inhibited the decrease in MUC2, ZO-1, occludin, production of pro-inflammatory factors, and activation of pro-inflammatory macrophages in colonic tissue. The effect of FCZ was better than that of SCZ. SCZ and FCZ not only inhibited the abundance of harmful bacteria and increased the abundance of beneficial bacteria, but also regulated the metabolism of disease-related metabolites such as amino acid and cholesterol metabolism. Both preparations inhibited the gene expression (Slc6A7, PRODH, Sdsl, HMGCR, SREBP-2) of different metabolite-related enzymes. In the PGF mouse model, the above effects were not observed. Rhizoma Atractylodes was effective in alleviating DSS-induced UC in mice, and FCZ was found to be superior to SCZ. The mechanism of action of FCZ and SCZ is mainly related to the regulation of intestinal flora and their associated metabolites.