AB-free kava enhances resilience against the adverse health effects of tobacco smoke in mice.

Tobacco smoke remains a serious global issue, resulting in serious health complications, contributing to the onsets of numerous preventive diseases, and imposing significant financial burdens. Despite regulatory policies and cessation measures aimed at curbing its usage, novel interventions are urgently needed for effective damage reduction. Our preclinical and pilot clinical studies showed that AB-free kava has the potential to reduce tobacco smoke-induced lung cancer risk, mitigate tobacco dependence, and reduce tobacco use. To understand the scope of its benefits in damage reduction and potential limitations, this study evaluated the effects of AB-free kava on a panel of health indicators in mice exposed to 2 - 4 weeks of daily tobacco smoke exposure. Our comprehensive assessments included global transcriptional profiling of the lung and liver tissues, analysis of lung inflammation, evaluation of lung function, exploration of tobacco nicotine withdrawal, and characterization of the causal PKA signaling pathway. As expected, Tobacco smoke exposure perturbed a wide range of biological processes and compromised multiple functions in mice. Remarkably, AB-free kava demonstrated the ability to globally mitigate tobacco smoke-induced deficits at the molecular and functional levels with promising safety profiles, offering a unique promise to mitigate tobacco smoke-related health damages. Further pre-clinical evaluation and clinical translation are warranted to fully harness the potential of AB-free kava in combating tobacco smoke-related harms.

One-Week Kava Dietary Supplementation Increases Both Urinary N- and O-Glucuronides of NNAL, a Lung Carcinogen Major Metabolite, among Smokers.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (commonly known as NNK) is one of the most prevalent and potent pulmonary carcinogens in tobacco products that increases the human lung cancer risk. Kava has the potential to reduce NNK and tobacco smoke-induced lung cancer risk by enhancing urinary excretion of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major metabolite of NNK) and thus reducing NNK-induced DNA damage. In this study, we quantified N-glucuronidated NNAL (NNAL-N-gluc), O-glucuronidated NNAL (NNAL-O-gluc), and free NNAL in the urine samples collected before and after 1-week kava dietary supplementation. The results showed that kava increased both NNAL-N-glucuronidation and O-glucuronidation. Since NNAL-N-glucuronidation is dominantly catalyzed by UGT2B10, its representative single-nucleotide polymorphisms (SNPs) were analyzed among the clinical trial participants. Individuals with any of the four analyzed SNPs appear to have a reduced basal capacity in NNAL-N-glucuronidation. Among these individuals, kava also resulted in a smaller extent of increases in NNAL-N-glucuronidation, suggesting that participants with those UGT2B10 SNPs may not benefit as much from kava with respect to enhancing NNAL-N-glucuronidation. In summary, our results provide further evidence that kava enhances NNAL urinary detoxification via an increase in both N-glucuronidation and O-glucuronidation. UGT2B10 genetic status has not only the potential to predict the basal capacity of the participants in NNAL-N-glucuronidation but also potentially the extent of kava benefits.

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training.

OBJECTIVE: In this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice. METHODS: Combining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise. RESULTS: Muscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of 'exercise-training' responsive genes shared for each tissue between genotypes. CONCLUSIONS: Our investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

New role for cardiomyocyte Bmal1 in the regulation of sex-specific heart transcriptomes.

It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the the core clock genes are expressed in common in both sexes but the circadian transcriptome of the mouse heart is very sex-specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts and the temporal pattern of REGs was distinctly different between sexes. We next used a cardiomyocyte-specific knock out of the core clock gene, Bmal1, to investigate its role in sex-specific gene expression in the heart. All sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all the differentially expressed genes between male and female hearts. We conclude that cardiomyocyte-specific Bmal1, and potentially the core clock mechanism, is vital in conferring sex-specific gene expression in the adult mouse heart.

Longitudinal Profiling of Fasting Plasma Metabolome in Response to Weight-Loss Interventions in Patients with Morbid Obesity.

It is well recognized that patients with severe obesity exhibit remarkable heterogeneity in response to different types of weight-loss interventions. Those who undergo Roux-en-Y gastric bypass (RYGB) usually exhibit more favorable glycemic outcomes than those who receive adjustable gastric banding (BAND) or intensive medical intervention (IMI). The molecular mechanisms behind these observations, however, remain largely unknown. To identify the plasma metabolites associated with differential glycemic outcomes induced by weight-loss intervention, we studied 75 patients with severe obesity (25 each in RYGB, BAND, or IMI). Using untargeted metabolomics, we repeatedly measured 364 metabolites in plasma samples at baseline and 1-year after intervention. Linear regression was used to examine whether baseline metabolites or changes in metabolites are associated with differential glycemic outcomes in response to different types of weight-loss intervention, adjusting for sex, baseline age, and BMI as well as weight loss. Network analyses were performed to identify differential metabolic pathways involved in the observed associations. After correction for multiple testing (q < 0.05), 33 (RYGB vs. IMI) and 28 (RYGB vs. BAND) baseline metabolites were associated with changes in fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c). Longitudinal changes in 38 (RYGB vs. IMI) and 38 metabolites (RYGB vs. BAND) were significantly associated with changes in FPG or HbA1c. The identified metabolites are enriched in pathways involved in the biosynthesis of aminoacyl-tRNA and branched-chain amino acids. Weight-loss intervention evokes extensive changes in plasma metabolites, and the altered metabolome may underlie the differential glycemic outcomes in response to different types of weight-loss intervention, independent of weight loss itself.

Examining Reactivity and Recovery Patterns of Pain-Evoked Cortisol and Alpha-Amylase Trajectories: Relations Between Psychological Markers of Risk and Resilience.

Chronic low back pain (cLBP) is one of the leading causes of disability globally and represents an enormous burden to aging adults. While numerous factors contribute to cLBP, dysregulation in the hypothalamic-pituitary-adrenal axis and autonomic nervous system functioning have been implicated in its pathogenesis. It is well documented that negative psychological states can modulate biological stress responsivity in chronic pain; however, little is known regarding the influence of positive psychological factors in this relationship. The aim of this study was to examine the association between psychological risk and resilience factors with patterns of physiological stress reactivity and recovery in 60 older adults with cLBP. Participants completed measures of hope, optimism, pain catastrophizing, and perceived stress, and underwent psychophysical pain testing assessing responses to painful pressure, heat, and cold stimuli. Salivary samples were obtained prior to pain induction and at 7 time points spanning 90 minutes after pain testing terminated. To examine reactivity and recovery profiles in hypothalamic-pituitary-adrenal axis and autonomic nervous system function, samples were assayed for cortisol and alpha-amylase, respectively. Results revealed higher levels of hope and optimism were associated with increased cortisol reactivity (p's < .003) and more rapid recovery (p's = .001). Further, pain catastrophizing and perceived stress were associated with cortisol reactivity, with lower levels of these factors predicting larger increases in cortisol from baseline to peak levels (p's < .04). No significant differences in reactivity or recovery patterns emerged for alpha-amylase. Overall, findings highlight the role of psychological risk and resilience factors in modulating physiological stress reactivity. PERSPECTIVE: This article investigated whether psychosocial risk and resilience factors were associated with stress reactivity and recovery in response to laboratory-based pain testing in older adults with chronic low back pain. Results indicate that high resilience factors may be protective by modulating adrenocortical reactivity and recovery profiles.

Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using 31P MRS in older adults.

Aging is a major risk for cognitive decline and transition to dementia. One well-known age-related change involves decreased brain efficiency and energy production, mediated in part by changes in mitochondrial function. Damaged or dysfunctional mitochondria have been implicated in the pathogenesis of age-related neurodegenerative conditions like Alzheimer's disease (AD). The aim of the current study was to investigate mitochondrial function over frontal and temporal regions in a sample of 70 cognitively normal older adults with subjective memory complaints and a first-degree family history of AD. We hypothesized cerebral mitochondrial function and energy metabolism would be greater in temporal as compared to frontal regions based on the high energy consumption in the temporal lobes (i.e., hippocampus). To test this hypothesis, we used phosphorous (31P) magnetic resonance spectroscopy (MRS) which is a non-invasive and powerful method for investigating in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. We used a single voxel method (left temporal and bilateral prefrontal) to achieve optimal sensitivity. Results of separate repeated measures analyses of variance showed 31P MRS ratios of static energy, energy reserve, energy consumption, energy demand, and phospholipid membrane metabolism were greater in the left temporal than bilateral prefrontal voxels. Our findings that all 31P MRS ratios were greater in temporal than bifrontal regions support our hypothesis. Future studies are needed to determine whether findings are related to cognition in older adults.

Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by misfolding and accumulation of mutant alpha-1 antitrypsin (ZAAT) in the endoplasmic reticulum of hepatocytes. Hepatic ZAAT aggregates acquire a toxic gain-of-function that impacts the endoplasmic reticulum which is theorized to cause liver disease in individuals with AATD who present asymptomatic until late-stage cirrhosis. Currently, there is no treatment for AATD-mediated liver disease except liver transplantation. In our study of mitochondrial RNA, we identified that Sirtuin3 (SIRT3) plays a role in the hepatic phenotype of AATD. METHODS: Utilizing RNA and protein analysis in an in vitro AATD model, we investigated the role of SIRT3 in the pathophysiology of AATD-mediated liver disease while also characterizing our novel, transgenic AATD mouse model. RESULTS: We show lower expression of SIRT3 in ZAAT-expressing hepatocytes. In contrast, the overexpression of SIRT3 increases hepatic ZAAT degradation. ZAAT degradation mediated by SIRT3 appeared independent of proteasomal degradation and regular autophagy pathways. We observed that ZAAT-expressing hepatocytes have aberrant accumulation of lipid droplets, with ZAAT polymers localizing on the lipid droplet surface in a direct interaction with Perilipin2, which coats intracellular lipid droplets. SIRT3 overexpression also induced the degradation of lipid droplets in ZAAT-expressing hepatocytes. We observed that SIRT3 overexpression induces lipophagy by enhancing the interaction of Perilipin2 with HSC70. ZAAT polymers then degrade as a consequence of the mobilization of lipids through this process. CONCLUSIONS: In this context, SIRT3 activation may eliminate the hepatic toxic gain-of-function associated with the polymerization of ZAAT, providing a rationale for a potential novel therapeutic approach to the treatment of AATD-mediated liver disease.

Socioeconomic Status, Knee Pain, and Epigenetic Aging in Community-Dwelling Middle-to-Older Age Adults.

Chronic musculoskeletal pain is often associated with lower socioeconomic status (SES). SES correlates with psychological and environmental conditions that could contribute to the disproportionate burden of chronic stress. Chronic stress can induce changes in global DNA methylation and gene expression, which increases risk of chronic pain. We aimed to explore the association of epigenetic aging and SES in middle-to-older age individuals with varying degrees of knee pain. Participants completed self-reported pain, a blood draw, and answered demographic questions pertaining to SES. We used an epigenetic clock previously associated with knee pain (DNAmGrimAge) and the subsequent difference of predicted epigenetic age (DNAmGrimAge-Diff). Overall, the mean DNAmGrimAge was 60.3 (±7.6), and the average DNAmGrimAge-diff was 2.4 years (±5.6 years). Those experiencing high-impact pain earned less income and had lower education levels compared to both low-impact and no pain groups. Differences in DNAmGrimAge-diff across pain groups were found, whereby individuals with high-impact pain had accelerated epigenetic aging (∼5 years) compared to low-impact pain and no pain control groups (both ∼1 year). Our main finding was that epigenetic aging mediated the associations of income and education with pain impact, as such the relationship between SES and pain outcomes may occur through potential interactions with the epigenome reflective of accelerated cellular aging. PERSPECTIVE: Socioeconomic status (SES) has previously been implicated in the pain experience. The present manuscript aims to present a potential social-biological link between SES and pain via accelerated epigenetic aging.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).

Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy and mTOR/upstream pathways were determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400m walking speed, and leg power), and thigh muscle volume were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy and pexophagy (PPARGC1A, PPARA, EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion and fission related genes (NIPSNAP2, DNM1L, OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1) and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8 th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO 2peak ), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calcium-dependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (Chrna1, Chrnd, Chrne), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO 2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervation-responsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility and Aging (SOMMA).

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility and Aging. Expression levels of twenty-one protein coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including: maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation.

HDAC3 and HDAC8 have critical biological functions and represent highly sought-after therapeutic targets. Because histone deacetylases (HDACs) have a very conserved catalytic domain, developing isozyme-selective inhibitors remains challenging. HDAC3/8 also have deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Proteolysis-targeting chimeras (PROTACs) can selectively degrade a target enzyme, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3/8 without triggering pan-HDAC inhibitory effects. Unbiased quantitative proteomic experiments confirmed its high selectivity. HDAC3/8 degradation by YX968 does not induce histone hyperacetylation and broad transcriptomic perturbation. Thus, histone hyperacetylation may be a major factor for altering transcription. YX968 promotes apoptosis and kills cancer cells with a high potency in vitro. YX968 thus represents a new probe for dissecting the complex biological functions of HDAC3/8.

Application of Allostatic Load Theory in Cancer Management and Treatment Outcomes.

Efforts have been made to improve health outcomes management by identifying the factors associated with survival in patients with cancer. However, different social, nutritional, and management modalities and personal and clinical characteristics may lead to various mortalities and morbidities among patients with cancer. Although stress is known to influence health and well-being in humans, there is still a gap in the studies on how stress plays a significant role in clinical outcomes in patients with cancer. Allostatic load, accumulated physiologic damage because of stressors, differs on the basis of individual perception of stress, coping skills, and other factors. This theory depicts how stress affects and predicts long-term outcomes such as morbidity and mortality. The main goal of this study is to provide potential benefits of using this theory in the cancer field to identify stressors and develop personalized interventions. This study will describe allostatic load theory and explain the relationships between potential stressors and the outcomes through the various levels of dysregulations in cancer. In addition, this study will provide theory implementation in pancreatic cancer.

Brain-predicted age difference estimated using DeepBrainNet is significantly associated with pain and function-a multi-institutional and multiscanner study.

ABSTRACT: Brain age predicted differences (brain-PAD: predicted brain age minus chronological age) have been reported to be significantly larger for individuals with chronic pain compared with those without. However, a debate remains after one article showed no significant differences. Using Gaussian Process Regression, an article provides evidence that these negative results might owe to the use of mixed samples by reporting a differential effect of chronic pain on brain-PAD across pain types. However, some remaining methodological issues regarding training sample size and sex-specific effects should be tackled before settling this controversy. Here, we explored differences in brain-PAD between musculoskeletal pain types and controls using a novel convolutional neural network for predicting brain-PADs, ie, DeepBrainNet. Based on a very large, multi-institutional, and heterogeneous training sample and requiring less magnetic resonance imaging preprocessing than other methods for brain age prediction, DeepBrainNet offers robust and reproducible brain-PADs, possibly highly sensitive to neuropathology. Controlling for scanner-related variability, we used a large sample (n = 660) with different scanners, ages (19-83 years), and musculoskeletal pain types (chronic low back [CBP] and osteoarthritis [OA] pain). Irrespective of sex, brain-PAD of OA pain participants was ∼3 to 4.7 years higher than that of CBP and controls, whereas brain-PAD did not significantly differ among controls and CBP. Moreover, brain-PAD was significantly related to multiple variables underlying the multidimensional pain experience. This comprehensive work adds evidence of pain type-specific effects of chronic pain on brain age. This could help in the clarification of the debate around possible relationships between brain aging mechanisms and pain.

Epigenetic age acceleration mediates the relationship between neighborhood deprivation and pain severity in adults with or at risk for knee osteoarthritis pain.

An estimated 250 million people worldwide suffer from knee osteoarthritis (KOA), with older adults having greater risk. Like other age-related diseases, residents of high-deprivation neighborhoods experience worse KOA pain outcomes compared to their more affluent neighbors. The purpose of this study was to examine the relationship between neighborhood deprivation and pain severity in KOA and the influence of epigenetic age acceleration (EpAA) on that relationship. The sample of 128 participants was mostly female (60.9%), approximately half non-Hispanic Black (49.2%), and had a mean age of 58 years. Spearman bivariate correlations revealed that pain severity positively correlated with EpAA (ρ = 0.47, p ≤ 0.001) and neighborhood deprivation (ρ = 0.25, p = 0.004). We found a positive significant relationship between neighborhood deprivation and EpAA (ρ = 0.47, p ≤ 0.001). Results indicate a mediating relationship between neighborhood deprivation (predictor), EpAA (mediator), and pain severity (outcome variable). There was a significant indirect effect of neighborhood deprivation on pain severity through EpAA, as the mediator accounted for a moderate portion of the total effect, PM = 0.44. Epigenetic age acceleration may act as a mechanism through which neighborhood deprivation leads to worse KOA pain outcomes and may play a role in the well-documented relationship between the neighborhood of residence and age-related diseases.

DNA methylation is differentially associated with glycemic outcomes by different types of weight-loss interventions: an epigenome-wide association study.

BACKGROUND: Alterations in DNA methylation (DNAm) have been reported to be a mechanism by which bariatric surgeries resulted in considerable metabolic improvements. Previous studies have mostly focused on change in DNAm following weight-loss interventions, yet whether DNAm prior to intervention can explain the variability in glycemic outcomes has not been investigated. Here, we aim to examine whether baseline DNAm is differentially associated with glycemic outcomes induced by different types of weight-loss interventions. METHODS: Participants were 75 adults with severe obesity who underwent non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) or Roux-en-Y gastric bypass (RYGB) (n = 25 each). Changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) were measured at 1-year after intervention. DNAm was quantified by Illumina 450 K arrays in baseline peripheral blood DNA. Epigenome-wide association studies were performed to identify CpG probes that modify the effects of different weight-loss interventions on glycemic outcomes, i.e., changes in FPG and HbA1c, by including an interaction term between types of intervention and DNAm. Models were adjusted for weight loss and baseline clinical factors. RESULTS: Baseline DNAm levels at 3216 and 117 CpGs were differentially associated with changes in FPG and HbA1c, respectively, when comparing RYGB versus IMI. Of these, 79 CpGs were significant for both FPG and HbA1c. The identified genes are enriched in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Additionally, DNAm at 6 CpGs was differentially associated with changes in HbA1c when comparing RYGB versus BAND. CONCLUSIONS: Baseline DNAm is differentially associated with glycemic outcomes in response to different types of weight-loss interventions, independent of weight loss and other clinical factors. Such findings provided initial evidence that baseline DNAm levels may serve as potential biomarkers predictive of differential glycemic outcomes in response to different types of weight-loss interventions.