Compensatory Response Research Articles

Assessment of Serum Cortisol Levels in Hypothyroidism Patients: A Cross-Sectional Study.

Hypothyroidism, characterized by insufficient thyroid hormone production, affects a significant global population, particularly women and the elderly. Recent research has emphasized the interaction between hypothyroidism and the hypothalamic-pituitary-adrenal (HPA) axis, highlighting cortisol's crucial role in the disease's physiological manifestations. This study aims to evaluate serum cortisol levels in hypothyroid patients, examining the intricate relationship between these two endocrine systems. By exploring the potential impact of altered cortisol levels on hypothyroidism's clinical presentation and progression, the study seeks to contribute valuable insights to enhance diagnostic approaches and develop more effective treatment strategies. A cross-sectional observational study was conducted at the Indira Gandhi Institute of Medical Sciences, assessing 65 hypothyroid cases and 65 age-matched euthyroid controls. Demographic data, medical history, and blood samples were collected, and serum cortisol, thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels were measured. The study adhered to ethical considerations and received institutional approval. The study included 65 hypothyroid cases (56 females, 9 males) and 65 euthyroid controls. Serum cortisol showed a significant correlation with TSH and T4 levels. Linear regression revealed a negative correlation between serum T4 and T3 levels and serum cortisol in hypothyroidism. A positive correlation was observed between TSH and cortisol. These findings align with previous studies, suggesting potential regulatory mechanisms and compensatory responses in hypothyroid patients. The study's results emphasize the complex interaction between cortisol and thyroid function, suggesting a direct relationship between serum cortisol and TSH levels in hypothyroidism. Patients with severe hypothyroidism exhibited elevated cortisol concentrations, indicating a potential compensatory mechanism initiated by the HPA axis. Integrating serum cortisol assessment with conventional thyroid function tests could offer comprehensive insights into hypothyroidism severity and progression, providing a more holistic approach to patient care. This study contributes to understanding the complex relationship between serum cortisol levels and hypothyroidism, emphasizing the need for further research to uncover underlying mechanisms and therapeutic implications. A comprehensive understanding holds the potential for more tailored and effective treatment strategies for individuals with hypothyroidism.

Continuous-time modeling of the multivariate relationships between physical activity levels and stationary time in preschool-aged children: an investigation of the ActivityStat hypothesis

BackgroundThe ActivityStat hypothesis proposes that an increase or decrease in physical activity (PA) greater than a certain set point activates behavioural and/or energy compensatory responses to maintain a stable level of total energy expenditure. Few studies have tested this hypothesis in children and even fewer have focused on young children. Therefore, the purpose of this study was to investigate the ActivityStat hypothesis by examining the presence and timeframe of the relationships among PA levels and stationary time (ST) in preschool-aged children.MethodsA secondary analysis was performed on repeated measurement data (i.e., day-to-day activity) involving 98 preschool-aged children (age: 4.5 ± 0.7 years) in Edmonton, Canada. Participants were asked to wear an ActiGraph wGT3X-BT on the waist for 7 consecutive days to assess PA levels (i.e., light PA [LPA], and moderate-to-vigorous PA[MVPA]) and ST. Bayesian continuous-time structural equation modeling (CT-SEM) was used to examine the relationship between behaviours over time and the timeframe during which these relationships occur.ResultsEach behaviour (i.e., LPA, MVPA, and ST) positively and meaningfully predicted itself at a later time. These relationships persisted up to 0.5 days later, at which point past behaviour no longer meaningfully predicted future behaviour. In contrast, no relationships were observed between the three behaviours.ConclusionsThis is the first study to investigate the ActivityStat hypothesis using Bayesian CT-SEM in preschool-aged children. When simultaneously taking into account all dynamic relationships suggested by the ActivityStat, the findings fail to support the hypothesis.

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis

AbstractUp to 30% of patients with autoimmune hemolytic anemia (AIHA) show inadequate bone marrow (BM) compensatory response with inappropriately low levels of reticulocytes and endogenous erythropoietin. Ineffective BM compensation is associated with more severe anemia, transfusion need, and hospital admission, and treatment with recombinant erythropoietin (rEPO) may be beneficial. Here, we prospectively analyzed the efficacy and safety of rEPO in a single-center cohort of 47 patients with AIHA with inadequate reticulocytosis and endogenous erythropoietin at baseline. Epoetin alpha 40 000 international units per week were administered subcutaneously until hemoglobin (Hb) >11 g/dL and then tapered off. Overall response was 55% at 15 days, 74% at 1 month, 74% at 3 months, 80% at 6 months, and 91% at 12 months. Consistently, Hb values significantly increased from baseline to each subsequent time point (P<.001) with a median increase of +1.4, +2.4, +3.4, +3.8, and +4.4 g/dL, respectively. Transfusion needs reduced from 30% to <10% at 15 days and thereafter (P < .001). Concomitant medications included prednisone or methylprednisolone (N = 40, stable since >2 weeks from enrollment), mycophenolate mofetil (N = 1, ongoing since >3 months from enrollment), and rituximab (N = 7 patients with cold agglutinin disease from day 8). No association between concomitant medications and response to rEPO was found. Treatment was generally safe without rEPO-related severe adverse events. The comparison with an AIHA population not treated with rEPO showed a significant benefit of rEPO at 15 days and 1 month on response and Hb increase. These data support the use of rEPO as an add on to standard immunosuppression in AIHA with inadequate BM compensation. This trial was registered at www.clinicaltrials.gov as #NCT05931718.

Optineurin regulates osteoblast function in an age-dependent fashion in a mouse model of Paget's disease of bone.

Paget's disease of bone (PDB) is a degenerative disorder affecting the skull and bones. Hyperactive osteoclasts (OCs) initiate bone degradation in the early stage, followed by increased bone formation by osteoblasts (OBs) in trabecular bones during the advanced stage. This OB-OC uncoupling results in bone deformations and irregular trabecular bone patterns. Current mouse models poorly replicate the advanced-stage characteristics of PDB. Optineurin (Gene: OPTN in humans, Optn in mice, protein: OPTN) has been implicated in PDB by genetic analyses. We identified PDB-like cortical lesions associated with OC hyperactivation in an Optn knockout (Optn-/-) mouse model. However, the effects of OPTN dysfunction on OBs and trabecular bone in advanced PDB remain unclear. In this study, we used the Optn-/- mouse model to investigate trabecular bone abnormalities and OB activity in PDB. Micro-computed tomography analysis revealed severe pagetic alterations in craniofacial bones and femurs of aged Optn-/- mice, resembling clinical manifestations of PDB. Altered OB activity was observed in aged Optn-/- mice, implicating compensatory OB response in trabecular bone anomalies. To elucidate the role of OC-OB interactions in PDB, we conducted in vitro experiments using OC conditioned media (CM) to examine the effects on OB osteogenic potential. We found OC CM restored compromised osteogenic induction of Optn-/- bone marrow stromal cells (BMSCs) from young mice, suggesting OCs maintain OB activity through secreted factors. Strikingly, OC CM from aged Optn-/- mice significantly enhanced osteogenic capability of Optn-/- BMSCs, providing evidence for increased OB activity in advanced stages of PDB. We further identified TGF-β/BMP signaling pathway in mediating the effects of OC CM on OBs. Our findings provide insights into Optn's role in trabecular bone abnormalities and OB activity in PDB. This enhances understanding of PDB pathogenesis and may contribute to potential therapeutic strategies for PDB and related skeletal disorders.

Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease

AbstractBackgroundOsteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD.MethodThe Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694.ResultAβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p &lt; 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p &lt; 0.001), SYT1 (p = 0.001), SNAP25 (p &lt; 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374).ConclusionOur results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.

Signatures of resolution reprogramming in amyloid‐challenged microglia

AbstractBackgroundSpecialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on innate immune cells like monocytes and microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the signatures ofMethodThe Ts65Dn mouse develops amyloid hyperexpression, neuroinflammation and neurodegeneration. We administered the SPM, Resolvin E1 (RvE1), for 1 month to control and Ts65Dn mice and measured memory using a series of tasks. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We then challenged Human innate immune cell culture models (monocytes and microglia) with amyloid‐beta and tau oligomer activation and/or administered RvE1 to promote resolution. We will employ RNASeq to learn how RvE1 resolution reprogramming affects transcriptional outcomes in these cell culture models.ResultRvE1 significantly reduced microglial activation and cytokine expression in the Ts65Dn mice, suggesting broad effects on central and peripheral innate immunity. We discovered that chronic RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family and in the PPAR‐gamma receptor and to specific signaling events. We are quantifying transcriptional outcomes to better define the nuclear program that underlies resolution.ConclusionWe have demonstrated that RvE1 modulates inflammation in a mouse model. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms.

Efficacy and trade-offs of an innovative hyperthermia device to control Varroa destructor in honeybee colonies

For decades, the honeybee, Apis mellifera, has suffered from severe colony losses due to the ectoparasitic mite Varroa destructor. Various strategies based on chemicals fail to adequately control varroa mite populations, and often comprise side-effects on the host, parasite resistance and residues in hive products. Reduced temperature tolerance of V. destructor compared to its host has long been recognised and accordingly, the potential of hyperthermia to disrupt mite reproduction within honeybee brood cells or even kill adult parasites. Yet, earlier studies on hyperthermia remain largely anecdotal, and readily implementable solutions have so far been lacking. This study investigates autonomously controlled interval heating from within brood combs throughout the season compared to control colonies maintained according to good apicultural practice. We documented treatment-dependent colony growth dynamics and honey production at three apiaries, complemented by regular monitoring of varroa mite levels and comprehensive digital assessments of brood development over time. Our one-year field trial suggests the evaluated hyperthermia device efficiently suppresses mite populations below critical thresholds until autumn. Whilst a general winter reference-curing revealed similar mite infestations of colonies previously treated with hyperthermia versus formic acid (control), only the latter imposed substantial overwintering burdens indirectly through frequent late-season queen supersedure. However, relative to targeted pupae, increased mortality particularly of heat-treated non-target brood stages (eggs and larvae) appeared to trigger compensatory colony-level responses, translating into temporarily decreased numbers of adult workers coupled with increased pollen foraging and overall lower honey harvests. Valuable insights into previously unrecognised side-effects of hyperthermia and mitigation thereof may ultimately permit successful routine applications of this chemical-free approach to combat the major threat to honeybees worldwide.

Neurobiology of emotions in animal relationships: Facial expressions and their biological functions in mammals

This article aims to analyze the biological and communicative function of facial expressions and their relation to emotions in mammals. Facial expressions and their causes constitute an important yet largely unexplored field of scientific research. While the clinical usefulness of these expressions for recognizing pain in many species has been demonstrated, there is evidence that animals can also emit facial movements with other connotations. Reports show that facial expressions have a biological function by predicting and promoting social interaction in species that form complex social groups, but their meaning depends on the social context. For animals, the unconscious identification of facial expressions also implies an emotional value by modifying the compensatory physiological response, as occurs in species that have close relationships with humans. This corpus of evidence suggests that facial expressions have a kind of communicative function and may transmit emotions and, therefore, participate in affiliative or adverse relations as animals develop. Hence, exploring whether this nonverbal behavior may perform such a dual function is necessary.

Why Intracranial Compliance Is Not Utilized as a Common Practical Tool in Clinical Practice.

Intracranial compliance (ICC) holds significant potential in neuromonitoring, serving as a diagnostic tool and contributing to the evaluation of treatment outcomes. Despite its comprehensive concept, which allows consideration of changes in both volume and intracranial pressure (ICP), ICC monitoring has not yet established itself as a standard component of medical care, unlike ICP monitoring. This review highlighted that the first challenge is the assessment of ICC values, because of the invasive nature of direct measurement, the time-consuming aspect of non-invasive calculation through computer simulations, and the inability to quantify ICC values in estimation methods. Addressing these challenges is crucial, and the development of a rapid, non-invasive computer simulation method could alleviate obstacles in quantifying ICC. Additionally, this review indicated the second challenge in the clinical application of ICC, which involves the dynamic and time-dependent nature of ICC. This was considered by introducing the concept of time elapsed (TE) in measuring the changes in volume or ICP in the ICC equation (volume change/ICP change). The choice of TE, whether short or long, directly influences the ICC values that must be considered in the clinical application of the ICC. Compensatory responses of the brain exhibit non-monotonic and variable changes in long TE assessments for certain disorders, contrasting with the mono-exponential pattern observed in short TE assessments. Furthermore, the recovery behavior of the brain undergoes changes during the treatment process of various brain disorders when exposed to short and long TE conditions. The review also highlighted differences in ICC values across brain disorders with various strain rates and loading durations on the brain, further emphasizing the dynamic nature of ICC for clinical application. The insight provided in this review may prove valuable to professionals in neurocritical care, neurology, and neurosurgery for standardizing ICC monitoring in practical application related to the diagnosis and evaluation of treatment outcomes in brain disorders.

Acute and prolonged competing effects of activation history on human motor unit firing rates during contractile impairment and recovery

AbstractThe purpose of this study was to investigate the effect of inducing post‐activation potentiation (PAP) during prolonged low‐frequency force depression (PLFFD) on motor unit (MU) firing rates. In 10 participants, grouped firing rates of 3027 MUs from the tibialis anterior were recorded with tungsten microelectrodes. Baseline MU firing rates at 25% isometric maximal voluntary contraction (MVC) were ∼14 Hz. A 1 min dorsiflexion MVC reduced torque and maximal MU firing rates (36 Hz) by 49% and 52%, respectively. Following task completion, firing rates at 25% of baseline MVC torque and torque in response to electrically evoked (single twitch, 10 Hz and 50 Hz) stimulation were assessed before and after a 5 s MVC (to induce PAP) every 10 min for 60 min. From 10 to 60 min after task completion, the torque ratios (twitch:50 Hz and 10:50 Hz) were depressed (∼30%) relative to baseline (P &lt; 0.001), indicating PLFFD; and firing rates were higher by ∼15% relative to baseline (P &lt; 0.001). This occurred despite recovery of MVC rates (∼99%) and torque (∼95%) by 10 min (P &gt; 0.3). Inducing PAP during PLFFD increased both low to high torque ratios (twitch and 10:50 Hz) by ∼200% and ∼135%, respectively (P &lt; 0.001) and firing rates were ∼18% lower relative to PLFFD rates (P &lt; 0.001), despite a speeding of evoked contractile properties (P = 0.001). Thus, firing rates appear strongly matched to alterations in torque, rather than contractile speed when modified by contractile history, and lower rates during PAP may be a mechanism to mitigate effects of PLFFD. The effect of activation history on contractile function demonstrates acute compensatory responses of motoneuron output. imageKey points Prolonged low frequency force depression (PLFFD) following a sustained 1 min isometric maximal voluntary contraction causes an increase in submaximal mean motor unit (MU) firing rates. Inducing post‐activation potentiation (PAP) during PLFFD, however, causes a reduction in mean submaximal MU firing rates to a level below those at baseline. The mean firing rate reduction during PAP occurs despite a speeding of evoked contractile properties and thus firing rates are more strongly matched to alterations in torque, rather than contractile speed when modified by various contractile histories. The reductions in firing rates during PAP may mitigate the effects of PLFFD during voluntary contractions. These results demonstrate that firing rates are highly responsive to opposing influences on the contractile state and can make rapid compensatory rate adjustments dependent on the active state of the muscle.

Compensatory Processes in Striatal Neurons Expressing the Tyrosine Hydroxylase Gene in Transgenic Mice in a Model of Parkinson's Disease.

The mammalian striatum is known to contain non-dopaminergic neurons that express dopamine (DA)-synthesizing enzymes and produce DA, responsible for the regulation of motor function. This study assessed the expression of DA-synthesizing enzymes in striatal neurons and their role in DA synthesis in transgenic mice expressing the green fluorescent protein (GFP) gene under the tyrosine hydroxylase (TH) gene promoter in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). We showed that, in Parkinsonian animals, the number of neurons expressing the TH gene increased by 1.9 times compared with the control (0.9% NaCl), which indicates a compensatory response to the DAergic denervation of the striatum. This assumption is supported by a 2.5-fold increase in the expression of genes for TH and transcription factor Nurr1 and a 1.45-fold increase in the expression of the large amino acid transporter 1 gene. It is noteworthy that, in Parkinsonian mice, in contrast to the controls, DA-synthesizing enzymes were found not only in nerve fibers but also in neuronal cell bodies. Indeed, TH or TH and aromatic L-amino acid decarboxylase (AADC) were detected in GFP-positive neurons, and AADC was detected in GFP-negative neurons. These neurons were shown to synthesize DA, and this synthesis is compensatorily increased in Parkinsonian mice. The above data open the prospect of improving the treatment of PD by maintaining DA homeostasis in the striatum.

IkBz is an inhibitor of the serine/threonine kinase and liquid-liquid phase separation that causes transition from adaptive cardiac hypertrophy to heart failure during pressure overload

Abstract Background and Purpose Inflammation contributes to both adaptive cardiac hypertrophy and heart failure. However, how inflammation causes transition from compensatory response to heart failure remains largely unknown. IkBz is a transcriptional modulator that changes gene expression pattern in the NF-kB system. IkBz does not have a DNA-binding domain and is suggested to exert its function through protein-protein interaction. IkBz is upregulated in the murine failing heart. This study was performed to elucidate the roles of IkBz and their mechanisms in the pathogenesis of heart failure. Methods Eight- to 12-week old wild-type (WT) and IκB hetero knockout (HKO) mice were used for animal experiments. Pressure overload was induced by transverse aortic constriction (TAC). Cardiac phenotype was assessed by echocardiographic and histological analyses. Bone marrow transplantation experiment was performed by injecting bone marrow cells isolated from donor femurs and tibias into 8-week-old mice. Neonatal rat ventricular myocytes (NRVMs) were used for in vitro experiments. Transcriptome was assessed in NRVMs treated with IkBz or control siRNA. Immunoprecipitation coupled with mass spectrometry (IP-MS) was performed by using NRVMs overexpressing FLAG-tag-labelled IkBz. Gene and protein expression levels were assessed by quantitative RT-PCR and Western blot. Results Pressure overload induced adaptive cardiac hypertrophy until 14 days after TAC and heart failure at 28 days after TAC in WT mice. TAC induced adaptive cardiac hypertrophy in HKO mice similarly to WT mice, whereas at 28 days after TAC HKO hearts showed preserved systolic function with attenuated left ventricular dilatation compared with WT hearts. Bone marrow transplantation experiment revealed that IkBz expressed in bone marrow-derived cells has little effect on cardiac phenotype after TAC. Transcriptome analysis showed that IkBz knockdown leads to upregulation of genes related to muscle contraction and extracellular matrix organization, which was confirmed by quantitative RT-PCR in heart samples of WT and HKO mice. IP-MS and IP/western blot demonstrated that IkBz binds to the epigenetic modulator and the serine/threonine kinase. IkBz inhibited liquid-liquid phase separation induced by the epigenetic modulator. In WT failing hearts, the serine/threonine kinase protein level was suppressed compared with sham-operated WT hearts, while the protein level of the serine/threonine kinase was higher in HKO hearts at 28 days after TAC compared with WT hearts. Pharmacological inhibition of the serine/threonine kinase in WT mice impaired cardiac compensatory response at 14 days after TAC. Conclusion Our results suggest that IkBz causes transition from adaptive cardiac hypertrophy to heart failure through inhibition of the serine/threonine kinase activity and liquid-liquid phase separation. IkBz might be a novel therapeutic target for heart failure.

Abstract 18753: Dynamic Phenotypic Transition of Smooth Muscle Cells During Human Ascending Thoracic Aortic Disease Progression: From Compensation in Aortic Aneurysm to Decompensation in Aortic Dissection

Introduction: Although ascending thoracic aortic aneurysm (ATAA) and ascending thoracic aortic dissection (ATAD) share common pathologic features of aortic degeneration, the specific elements that lead to rapid disease progression in ATAD remain poorly understood. We examined the molecular and cellular dynamics in smooth muscle cells (SMCs) of aortic tissues from ATAA and ATAD patients and further examined mechanisms in a mouse model. Methods: Single-cell RNA sequencing (scRNA-seq) analyses were performed in ascending aortic tissues from individuals without aortic disease (n=8), patients with ATAA without dissection (n=9), and patients with acute ATAD (n=9). Further, scRNA-seq and scATAC-seq were performed in ascending aortic tissues from mice infused with angiotensin II (AngII) or control mice; scRNA-seq analyses were performed on SMC-specific Tgfbr2 -/- mice. Results: Six SMC subtypes were identified in human aortic tissues. Cluster proportion and trajectory analyses indicated a profound SMC transition from contractile in control to extracellular matrix (ECM)-contractile phenotype in ATAA, however, was reduced in ATAD tissues. Instead, ATAD showed significant SMC transition to inflammatory phenotype. Consistently, many genes in ECM organization and muscle contraction, collectively termed compensatory response, were upregulated in ATAA but downregulated in ATAD tissues compared with controls, whereas inflammatory response and cell death pathway genes were significantly upregulated in ATAD compared with control and ATAA tissues. Cell-cell interaction, regulatory network, and motif analysis suggested that TGF-beta-MEF2C signaling contributed to the induction of the ECM-contractile SMC phenotype. MEF2C + SMCs exhibited the capacity of transition towards ECM-producing SMCs in both mouse and human aorta. SMC-specific Tgfbr2 -/- mice showed compromised SMC transition to ECM-producing phenotype. Conclusions: Our study reveals SMC phenotypic transitions to ECM-producing SMCs in ATAA and to inflammatory and pro-death SMCs in ATAD, which represent a compensatory response in ATAA and a decompensatory status in ATAD. TGF-beta-MEF2C, a novel regulatory axis, promoted the compensatory response in SMCs of the ascending aorta.

Abstract 16825: Brahma Related Gene-1 (BRG1) Protein Mediates Helpful Compensatory Response to Retard Development of Heart Failure

Background: Chromatin remodeling can modulate transcription by changing gene accessibility. Brahma Related Gene-1 (Brg1) protein, which is an adenosine triphosphate catalytic subunit that supports chromatin remodeling, has been implicated in development of hypertrophic cardiomyopathy. However, contribution of Brg1 to the development of heart failure (HF) has not been clearly elucidated. Hypothesis: We hypothesize that Brg1 mediates compensatory response to cardiac stress; therefore, loss of Brg1 function will accelerate development of HF. Methods: The myosin light chain-2 Cre/loxP system was used to produce cardiac myocyte specific deletion of Brg1(-/-) mouse model with floxed littermates as control. Results: At baseline, Brg1(-/-) hearts showed mildly reduced left ventricular ejection fraction (LVEF). Aging to 12 months caused LV dilation and further reduction of LVEF in Brg1(-/-). We used trans-aortic constriction (TAC) for pressure overload challenge and chose similarly severe TAC induced pressure gradient as indicated by similarly fast peak flow velocities across the constriction. At 2-weeks post-TAC, Brg1(-/-) hearts exhibited severely reduced LVEF, severely dilated LV, and decreased ability to thicken LV wall during systole. In contrast, control hearts did not dilate and maintained its LVEF with increased LV wall thickness. Thus, Brg1 deletion greatly diminished the heart’s ability to compensate for aging and pressure challenge, thereby accelerating development of heart failure with reduced ejection fraction (HFrEF). Separately, RNA sequence analyses of 12-months aged hearts showed Brg1 deletion caused upregulation of 810 genes including HF associated long noncoding RNA XIST and down regulation of 50 genes, while 3-months old hearts were not significantly different. Conclusion: Brg1 mediates compensatory responses that are helpful to the heart to prevent development of HF; therefore, it is a potential treatment mechanism for HF.

Lufenuron treatment temporarily represses gene expression and affects the SUMO pathway in liver of Atlantic salmon.

Lufenuron is a benzoylurea insecticide currently in use to combat sea lice infestation in salmon aquaculture in Chile. With pending approval in Norway, the aim of this work was to study the uptake and toxicity of lufenuron in liver tissue of Atlantic salmon. Juvenile salmon weighing 40 g were given a standard 7-day oral dose, and bioaccumulation and transcriptional responses in the liver were examined 1 day after the end-of-treatment (day 8) and after 1 week of elimination (day 14). Bioaccumulation levels of lufenuron were 29 ± 3 mg/kg at day 8 and 14 ± 1 mg/kg at day 14, indicating relatively rapid clearance. However, residues of lufenuron were still present in the liver after 513 days of depuration. The exposure gave a transient inhibition of transcription in the liver at day 8 (2437 significant DEGs, p-adj < .05), followed by a weaker compensatory response at day 14 (169 significant DEGs). Pathways associated with RNA metabolism such as the sumoylation pathway were most strongly affected at day 8, while the apelin pathway was most profoundly affected at day 14. In conclusion, this study shows that lufenuron easily bioaccumulates and that a standard 7-day oral dose induces a transient inhibition of transcription in liver of salmon.

PSXIV-22 Impact of Maternal Plane of Nutrition in Combination with Strategic One-Carbon Metabolites Supplementation During Early Pregnancy on Vascularity and Cell Proliferation in the Fetal Small Intestine

Abstract Objective of our study were to investigate the impact of maternal nutrition during early pregnancy on the vascularity and proliferation of fetal intestine and whether supplementing one-carbon metabolites (OCM) could mitigate any changes arising from altered maternal nutrition. We used a 2 x 2 factorial arrangement of treatments with two levels of heifer gain: control (CON; 0.45 kg/d) and restricted (RES; -0.23 kg/d), with and without (+/- OCM) supplementation. Crossbred Angus beef heifers were estrous synchronized and bred via artificial insemination with single-sire female-sexed semen. Heifers were divided into four nutritional treatments (n = 8 ± 1 per treatment) at breeding. Targeted heifer gain (achieved by changing in intake of a common diet) and OCM treatments were administered from d 0 to 63 of gestation and then all heifers were fed a common diet targeting 0.45 kg/d gain. Treatments containing OCM were given rumen-protected methionine (10 g/d) and choline (60 g/d) in a fine-ground corn carrier administered daily, with weekly injections of folate (320 mg) and vitamin B12 (20 mg). The non-supplemented treatment (-OCM) received the corn carrier and saline injections. On day 161 of gestation heifers were harvested and samples were collected from fetal jejunum for analysis. Vascularity was assessed via measurement of capillary density using anti-CD31 and anti-CD34 fluorescent staining. Cell proliferation within intestinal tissues was assessed by KI-67 fluorescent staining. Images were analyzed using ImagePro-Premiere software. Maternal gain × OCM interactions were not present (P &amp;gt; 0.11). Fetuses from restricted dams had greater (P = 0.05) capillary area density in the villi compared with CON (5.48 vs. 4.72 ± 0.38%), while OCM had no effect. Crypt and total cell proliferation were greater (P &amp;lt; 0.05) in CON. Providing OCM reduced (P = 0.01) total intestinal cell proliferation. The observed increase in capillary density in the villi of fetuses from restricted dams may be a compensatory response to reduced maternal nutrient availability, aimed at preparing the offspring for increasing post-natal nutrient delivery. Conversely, the decreased proliferation in crypt cells appears to be a logical response to restricted nutrition and may indicate a slowing of the rate of cell division, which could have long-term consequences for intestinal development. Our results also demonstrate that maternal OCM can reduce total intestinal cell proliferation in the fetal intestine, regardless of maternal nutrition. One-carbon metabolites have crucial roles in DNA methylation and other cellular processes for proper cellular function and development. Observed decreases resulting from the provision of OCM may indicate enhanced energetic efficiency, reduced epithelial cell turnover, and/or reduce apoptotic events in the villa. Further studies are needed to determine the long-term effects of maternal OCM on fetal intestinal development and function. USDA is an equal opportunity provider and employer.

Correlation between Serum Levels of Vaspin, BMI, and Waist Circumference on Obese and Non-Obese Subjects

Obesity is the accumulation of excessive fat resulting from an imbalance in energy intake compared to energy used for a long period. Vaspin is secreted in adipose tissue and may exhibit compensatory responses related to obesity, insulin resistance, and type 2 diabetes mellitus. This study aimed to determine vaspin levels in obese and non-obese subjects. An observational research design with a cross-sectional approach was used in this study. A total of 80 research subjects were included in this study. The research was conducted at the Clinical Pathology Laboratory at the Department of Clinical Pathology, Hasanuddin University Hospital in January 2022. Kolmogorov-Smirnov test was used to determine the normality of the data. Chi-Square, unpaired T-test, Mann-Whitney test, and Spearman test were used as statistical tests. This study showed a significant difference in anthropometric parameters between the obese and non-obese groups (p &lt; 0.001). There was a significant difference in the mean levels of vaspin between the obese and non-obese groups (707.68±774.47 ng/mL vs. 510.60±460.08 ng/mL, p=0.004). There was a positive correlation between vaspin levels and waist circumference (r = 0.245, p=0.004) and between vaspin levels and BMI (r = 0.322, p=0.028). The serum levels of vaspin tended to be higher in obese subjects compared to non-obese subjects. The positive correlation between vaspin levels and BMI and waist circumference indicated that a higher BMI and/or waist circumference led to a higher vaspin level.

Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells

The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.

The heart patient at high altitude: not just thin air

The exposure to high altitude, with its inherent hypobaric hypoxia, elicits transient compensatory physiological responses of the cardiovascular and respiratory system which, however, do not preclude a safe sojourn at least up to 3500 m to the vast majority of well compensated patients with heart disease on stable drug therapy. Existing scientific statements of the European and American Societies of Cardiovascular and High-Mountain Medicine have released specific and helpful recommendations, though mostly based on expert consensus rather than solid evidence. The risk of cardiac events has been recorded only during sports activities, does not seem to depend on altitude and is similar to what is observed during intense exercise at sea level. Besides altitude itself, other aspects of the mountain environment should be considered, such as lower temperature, wind and dehydration which all require careful planning and equipment typical of the alpine sports. The distance of most mountain areas from medical centers able to provide effective care in time-dependent emergencies, and the lack in most cases of dedicated protocols, should also be considered as an important, most likely the most important limiting factor in high-risk patients.

From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity Populations: Decreased Bone Turnover Bioactivity.

A bone turnover marker reflects bone bioactivity. The effects of metabolically healthy compared with metabolically unhealthy obesity phenotypes on bone metabolism are not well understood. The aim of the study was to evaluate differences of bone transformation indexes in these two obesity phenotypes. A total of 419 obese subjects were recruited, 64 with metabolically healthy obesity (MHO) and 351 with metabolically unhealthy obesity (MuHO). BTMs and clinical parameters were measured. Bone metabolism indexes, including tartrate resistant acid phosphatase (TRACP, p < 0.05), β carboxyl terminal peptide of collagen (β-CTX, p < 0.01), and bone alkaline phosphatase (BAP, p < 0.01), were higher in subjects with MHO than MuHO, but parathyroid hormone (PTH) was lower (p < 0.05). The between-group difference in serum calcium was not significant. Low bone turnover activity was associated with significant hyperglycemia, insulin resistance, and body fat index (p < 0.05). Multivariate logistic regression found that TRACP, β-CTX, and BAP were independently associated with the presence of MHO. Receiver operating characteristic curve analysis found that the maximum area under the curve value for the definition of MHO was (0.8221) and was obtained when sex, age, body mass index (BMI), TRACP, β-CTX and BAP were included simultaneously, resulting in a sensitivity of 81.25% and specificity: 72.3%. The MHO group had significantly increased circulating TRACP and β-CTX compared with the MuHO group and BAP levels were within the physiological range. Obesity with the metabolically healthy phenotype had slightly increased bone turnover activity that may be an early compensatory response of skeletal metabolism to the increased BMI.