Intense noise exposure causes hearing loss by inducing degeneration of spiral ganglia neurites that innervate cochlear hair cells. Nicotinamide adenine dinucleotide (NAD+) exhibits axon-protective ...effects in cultured neurons; however, its ability to block degeneration in vivo has been difficult to establish due to its poor cell permeability and serum instability. Here, we describe a strategy to increase cochlear NAD+ levels in mice by administering nicotinamide riboside (NR), a recently described NAD+ precursor. We find that administration of NR, even after noise exposure, prevents noise-induced hearing loss (NIHL) and spiral ganglia neurite degeneration. These effects are mediated by the NAD+-dependent mitochondrial sirtuin, SIRT3, since SIRT3-overexpressing mice are resistant to NIHL and SIRT3 deletion abrogates the protective effects of NR and expression of NAD+ biosynthetic enzymes. These findings reveal that administration of NR activates a NAD+-SIRT3 pathway that reduces neurite degeneration caused by noise exposure.
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•The NAD+ precursor NR prevents noise-induced hearing loss•NR can be administered after acoustic trauma to prevent hearing loss•Prevention of noise-induced hearing loss by NAD+ and NR is dependent upon SIRT3•NAD+ and NR prevent noise-induced neurite retraction in the cochlea
Intense noise exposure causes hearing loss due to degeneration of cochlear neurites. Brown et al. show that the NAD+ precursor NR prevents noise-induced hearing loss and neurite degeneration in the cochlea, even after noise exposure. These effects are mediated by the NAD+-dependent mitochondrial sirtuin, SIRT3.
Vitamin D is an essential nutrient for bone health and may influence the risks of respiratory illness, adverse pregnancy outcomes, and chronic diseases of adulthood. Because many countries have a ...relatively low supply of foods rich in vitamin D and inadequate exposure to natural ultraviolet B (UVB) radiation from sunlight, an important proportion of the global population is at risk of vitamin D deficiency. There is general agreement that the minimum serum/plasma 25‐hydroxyvitamin D concentration (25(OH)D) that protects against vitamin D deficiency–related bone disease is approximately 30 nmol/L; therefore, this threshold is suitable to define vitamin D deficiency in population surveys. However, efforts to assess the vitamin D status of populations in low‐ and middle‐income countries have been hampered by limited availability of population‐representative 25(OH)D data, particularly among population subgroups most vulnerable to the skeletal and potential extraskeletal consequences of low vitamin D status, namely exclusively breastfed infants, children, adolescents, pregnant and lactating women, and the elderly. In the absence of 25(OH)D data, identification of communities that would benefit from public health interventions to improve vitamin D status may require proxy indicators of the population risk of vitamin D deficiency, such as the prevalence of rickets or metrics of usual UVB exposure. If a high prevalence of vitamin D deficiency is identified (>20% prevalence of 25(OH)D < 30 nmol/L) or the risk for vitamin D deficiency is determined to be high based on proxy indicators (e.g., prevalence of rickets >1%), food fortification and/or targeted vitamin D supplementation policies can be implemented to reduce the burden of vitamin D deficiency–related conditions in vulnerable populations.
Here we report the outcome of a working group convened in January and March 2017 by the Sackler Institute for Nutrition Science at the New York Academy of Sciences and the Bill & Melinda Gates Foundation to assess the global prevalence and disease burden of vitamin D deficiency, and population‐based strategies to improve vitamin D status, particularly in low‐ and middle‐income countries. The working group aimed to examine definitions of vitamin D deficiency based on biomarkers and correlations with disease or health outcomes.
Carbonic anhydrase IX (CAIX) and XII (CAXII) are transmembrane proteins that are associated with cancer progression. We have previously described the catalytic properties of CAIX in MDA-MB-231 breast ...cancer cells, a line of cells that were derived from a patient with triple negative breast cancer. We chose this line because CAIX expression in breast cancer is a marker of hypoxia and a prognosticator for reduced survival. However, CAXII expression is associated with better survival statistics than those patients with low CAXII expression. Yet CAIX and CAXII have similar catalytic activities. Here we compare the potential roles of CAIX and CAXII in the context of TNBC and estrogen receptor (ER)-positive breast cancer. In tumor graft models, we show that CAIX and CAXII exhibit distinct expression patterns and non-overlapping. We find the same pattern across a panel of TNBC and luminal breast cancer cell lines. This affords an opportunity to compare directly CAIX and CAXII function. Our data suggest that CAIX expression is associated with growth potentiation in the tumor graft model and in a TNBC line using knockdown strategies and blocking activity with an impermeant sulfonamide inhibitor, N-3500. CAXII was not associated with growth potentiation. The catalytic activities of both CAIX and CAXII were sensitive to inhibition by N-3500 and activated at low pH. However, pH titration of activity in membrane ghosts revealed significant differences in the catalytic efficiency and pKa values. These features provide evidence that CAIX is a more efficient enzyme than CAXII at low pH and that CAIX shifts the equilibrium between CO2 and bicarbonate in favor of CO2 production by consuming protons. This suggests that in the acidic microenvironment of tumors, CAIX plays a role in stabilizing pH at a value that favors cancer cell survival.
Carbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the ...tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Ki values for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation.
Owing to numerous pro-survival target genes, aberrant activation of the NF-
κ
B transcription factor is associated with a drug-resistant phenotype and aggressive breast tumor behavior. ...Transglutaminase 2 (TG2), a ubiquitously expressed protein cross-linking enzyme, activates NF-
κ
B through a non-conventional mechanism that disables the I
κ
Bα inhibitor. Our group has recently documented that the TG2 gene (termed
TGM2
) is a direct transcriptional target of NF-
κ
B. These developments uncover a novel self-reinforcing molecular feedback loop where TG2 activates NF-
κ
B and, in turn, NF-
κ
B directly upregulates the transcription of
TGM2
. This manuscript reviews the literature that supports the existence of the TG2/NF-
κ
B signaling loop, the nature of the signal transduction that activates this loop, and the phenotypic consequences stemming from the aberrant activation of this novel signaling mechanism in breast cancer.
Children with severe-to-profound unilateral hearing loss, including cases of single-sided deafness (SSD), lack access to binaural cues that support spatial hearing, such as recognizing speech in ...complex multisource environments and sound source localization. Listening in a monaural condition negatively impacts communication, learning, and quality of life for children with SSD. Cochlear implant (CI) use may restore binaural hearing abilities and improve outcomes as compared to alternative treatments or no treatment. This study investigated performance over 24 months of CI use in young children with SSD as compared to the better hearing ear alone and to children with bilateral normal hearing (NH).
Eighteen children with SSD who received a CI between the ages of 3.5 and 6.5 years as part of a prospective clinical trial completed assessments of word recognition in quiet, masked sentence recognition, and sound source localization at regular intervals out to 24-month postactivation. Eighteen peers with bilateral NH, matched by age at the group level, completed the same test battery. Performance at 24-month postactivation for the SSD group was compared to the performance of the NH group.
Children with SSD have significantly poorer speech recognition in quiet, masked sentence recognition, and localization both with and without the use of the CI than their peers with NH. The SSD group experienced significant benefits with the CI+NH versus the NH ear alone on measures of isolated word recognition, masked sentence recognition, and localization. These benefits were realized within the first 3 months of use and were maintained through the 24-month postactivation interval.
Young children with SSD who use a CI experience significant isolated word recognition and bilateral spatial hearing benefits, although their performance remains poorer than their peers with NH.
Aims
To investigate the hypothesis that weight loss with the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean ...tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, that also enhances GLP‐1 activity ‐ to determine the independent effects of each treatment.
Methods
A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (−390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase‐4 inhibitor sitagliptin (100 mg/d) as a weight‐neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x‐ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal‐Wallis test or Pearson's chi‐squared test.
Results
Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA‐IR).
Conclusions
Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.
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