Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established
. Here we report lifespan and healthspan extension in a mouse model ...with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1
) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1
knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho
have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals.
Cisplatin (CP)-induced nephrotoxicity is widely accepted as a model for acute kidney injury (AKI). Although cisplatin-induced chronic kidney disease (CKD) in rodent has been reported, the role of ...phosphate in the cisplatin-induced CKD progression is not described. In this study, we gave a single peritoneal injection of CP followed by high (2%) phosphate diet for 20 weeks. High dose CP (20 mg/Kg) led to high mortality; whereas a lower dose (10 mg/Kg) resulted in a full spectrum of AKI with tubular necrosis, azotemia, and 0% mortality 7 days after CP injection. After consuming a high phosphate diet, mice developed CKD characterized by low creatinine clearance, interstitial fibrosis, hyperphosphatemia, high plasma PTH and FGF23, low plasma 1,25(OH)2 Vitamin D3 and αKlotho, and classic uremic cardiovasculopathy. The CP model was robust in demonstrating the effect of aging, sexual dimorphism, and dietary phosphate on AKI and also AKI-to-CKD progression. Finally, we used the CP-high phosphate model to examine previously validated methods of genetically manipulated high αKlotho and therapy using exogenous soluble αKlotho protein supplementation. In this CP CKD model, αKlotho mitigated CKD progression, improved mineral homeostasis, and ameliorated cardiovascular disease. Taken together, CP and high phosphate nephrotoxicity is a reproducible and technically very simple model for the study of AKI, AKI-to-CKD progression, extrarenal complications of CKD, and for evaluation of therapeutic efficacy.
A high phosphate diet accelerates cisplatin–induced acute kidney injury (AKI) progression to chronic kidney disease (CKD). Aging, male gender, and Klotho deficiency exacerbate and Klotho administration mitigates CKD progression, mineral disorders, and cardiovasculopathy. This is a technically simple model to study AKI-to-CKD transition, complications of CKD, and potential therapies.
Individual susceptibility to allergic diseases is developmentally programmed by early-life exposures. Evidence from preclinical studies suggests that intrauterine growth restriction is protective ...against later inflammatory responses to allergens.
We sought to evaluate whether prenatal growth affects susceptibility to allergy in human subjects.
We systematically searched for relevant studies in 11 databases, including Web of Science, ProQuest, EMBASE, and PubMed. We included only studies that corrected for gestational age or were restricted to full-term infants to separate effects of fetal growth from those of prematurity.
The 42 eligible studies included prospective and retrospective cohort, cross-sectional, and case-control studies. Only 2 studies reported allergic asthma. A birth weight increase of 1 kg was associated with a 44% greater risk of food allergy in children (odds ratio OR, 1.44; 95% CI, 1.04-1.99; P = .001), a 17% greater risk of ever allergic dermatitis in children (OR, 1.17; 95% CI, 1.04-1.32; P = .008), and a 34% greater risk of ever or current allergic dermatitis in infants up to 2 years of age (OR, 1.34; 95% CI, 1.08-1.68; P = .009). Risks of allergic rhinitis were not associated with birth weight.
The results of these meta-analyses suggest that intrauterine growth restriction protects against allergic diseases in human subjects consistent with preclinical evidence but that effects might differ between allergic diseases. The strongest evidence is available for infancy and early childhood, and additional studies in older children and adults are needed to determine whether the effects of prenatal growth on each allergic disease persist or differ between those with severe and mild phenotypes.
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The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ...ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.
In this Letter, the graphs in Fig. 2a and c were inadvertently the same owing to a copy and paste error from the original graphs in Prism. The Source Data files containing the raw data were correct. ...Fig. 2c has been corrected online.
The administration of an efficacious vaccine is the most effective long-term measure to control the oculogenital infections caused by Chlamydia trachomatis in humans. Chlamydia genome sequencing has ...identified a number of potential vaccine candidates, and the current challenge is to develop an effective delivery vehicle for induction of a high level of mucosal T and complementary B cell responses. Vibrio cholerae ghosts (VCG) are nontoxic, effective delivery vehicles with potent adjuvant properties, and are capable of inducing both T cell and Ab responses in mucosal tissues. We investigated the hypothesis that rVCG could serve as effective delivery vehicles for single or multiple subunit chlamydial vaccines to induce a high level of protective immunity. rVCG-expressing chlamydial outer membrane proteins were produced by a two-step genetic process, involving cloning of Omp genes in V. cholerae, followed by gene E-mediated lysis of the cells. The immunogenicity and vaccine efficacy of rVCG-expressing single and multiple subunits were compared. Immunologic analysis indicated that i.m. immunization of mice with either vaccine construct induced a strong mucosal and systemic specific Th1 response against the whole chlamydial organism. However, there was an immunogenic advantage associated with the multiple subunit vaccine that induced a higher frequency of Th1 cells and a relatively greater ability to confer protective immunity, compared with the single subunit construct. These results support the operational theory that the ability of a vaccine to confer protective immunity against Chlamydia is a function of the level of Th1 response elicited.
Autophagy increases lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established
1
,
2
. Here, we report lifespan and healthspan extension in a mouse model ...with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a F121A (
Becn1
F121A/F121A
) mutation in beclin 1 that decreases its interaction with the negative regulator, Bcl-2. We demonstrate that beclin 1/Bcl-2 interaction is disrupted in multiple tissues in
Becn1
F121A/F121A
knock-in (KI) mice in association with higher levels of basal autophagic flux. Compared to wild-type (WT) littermates, the lifespan of both male and female KI mice is significantly increased. The healthspan of the KI mice also improves as aging-related phenotypes are diminished, including age-related renal and cardiac pathological changes and spontaneous tumorigenesis. Moreover, mice deficient in the anti-aging protein, Klotho
3
, have increased beclin 1/Bcl-2 interaction, decreased autophagy, premature lethality and infertility which are rescued by the beclin 1 F121A mutation. Taken together, our data demonstrate that disruption of the beclin 1/Bcl-2 complex is an effective mechanism to increase autophagy, prevent premature aging, improve healthspan and promote longevity in mammals.
The objective of this systematic review is to synthesize the best available evidence on the relationship between size at birth or fetal growth and postnatal allergy. Specifically, this review aims to ...assess evidence regarding relationships between absolute birth weight at term, birth weight corrected for gestational age, expressed as relative to population or customized growth data, or fetal growth measures and physician-diagnosed or parent- and self-reported postnatal clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis).The specific review question is: what is the association between the absolute birth weight at full-term or birth weight relative to population or customized data and corrected for gestational age or direct measures of fetal growth, and physician-diagnosed or parent- and self-reported clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis)?
Spatial normalization of neuroimaging data is a standard step when assessing group effects. As a result of divergent analysis procedures due to different normalization algorithms or templates, not ...all published coordinates refer to the same neuroanatomical region. Specifically, the literature is populated with results in the form of MNI or Talairach coordinates, and their disparity can impede the comparison of results across different studies. This becomes particularly problematic in coordinate-based meta-analyses, wherein coordinate disparity should be corrected to reduce error and facilitate literature reviews. In this study, a quantitative comparison was performed on two corrections, the Brett transform (i.e., “mni2tal”), and the Lancaster transform (i.e., “icbm2tal”). Functional magnetic resonance imaging (fMRI) data acquired during a standard paired associates task indicated that the disparity between MNI and Talairach coordinates was better reduced via the Lancaster transform, as compared to the Brett transform. In addition, an activation likelihood estimation (ALE) meta-analysis of the paired associates literature revealed that a higher degree of concordance was obtained when using the Lancaster transform in the form of fewer, smaller, and more intense clusters. Based on these results, we recommend that the Lancaster transform be adopted as the community standard for reducing disparity between results reported as MNI or Talairach coordinates, and suggest that future spatial normalization strategies be designed to minimize this variability in the literature.
ABSTRACT
Introduction: ACE‐031 is a fusion protein of activin receptor type IIB and IgG1‐Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development ...and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). Methods: ACE‐031 was administered subcutaneously every 2–4 weeks to DMD boys in a randomized, double‐blind, placebo‐controlled, ascending‐dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. Results: ACE‐031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6‐minute walk test (6MWT) distance in the ACE‐031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. Conclusion: ACE‐031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non–muscle‐related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458–464, 2017
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