How do guideline recommended energy targets compare with measured energy expenditure in critically ill adults with obesity: A systematic literature review.

BACKGROUND: Critically ill patients with obesity have unique and complex nutritional needs, with clinical practice guidelines conflicting regarding recommended energy targets. The aim of this systematic review was to 1) describe measured resting energy expenditure (mREE) reported in the literature and; 2) compare mREE to predicted energy targets using the European (ESPEN) and American (ASPEN) guideline recommendations when indirect calorimetry is not available in critically ill patients with obesity. METHODS: The protocol was registered apriori and literature was searched until 17th March, 2022. Original studies were included if they reported mREE using indirect calorimetry in critically ill patients with obesity (BMI≥30 kg/m2). Group-level mREE data was reported as per the primary publication using mean ± standard deviation or median [interquartile range]. Where individual patient data was available, Bland-Altman analysis was used to assess mean bias (95% limits of agreement) between guideline recommendations and mREE targets (i.e. ASPEN for BMI 30-50, 11-14 kcal/kg actual weight compared to 70% mREE and ESPEN 20-25 kcal/kg adjusted weight compared to 100% mREE). Accuracy was assessed by the percentage (%) of estimates within ±10% of mREE targets. RESULTS: After searching 8019 articles, 24 studies were included. mREE ranged from 1607 ± 385 to 2919 [2318-3362]kcal and 12-32kcal/actual body weight. For the ASPEN recommendations of 11-14 kcal/kg, a mean bias of -18% (-50% to +13%) and 4% (-36% to +44%) was observed, respectively (n = 104). For the ESPEN recommendations 20-25 kcal/kg, a bias of -22% (-51% to +7%) and -4% (-43% to +34%), was observed, respectively (n = 114). The guideline recommendations were able to accurately predict mREE targets on 30%-39% occasions (11-14 kcal/kg actual) and 15%-45% occasions (20-25 kcal/kg adjusted), for ASPEN and ESPEN recommendations, respectively. CONCLUSIONS: Measured energy expenditure in critically ill patients with obesity is variable. Energy targets generated using predictive equations recommended in both the ASPEN and ESPEN clinical guidelines have poor agreement with mREE and are frequently not able to accurately predict within ±10% of mREE, most commonly underestimating energy needs.

Validation of Oura ring energy expenditure and steps in laboratory and free-living.

BACKGROUND: Commercial activity trackers are increasingly used in research and compared with research-based accelerometers are often less intrusive, cheaper, with improved storage and battery capacity, although typically less validated. The present study aimed to determine the validity of Oura Ring step-count and energy expenditure (EE) in both laboratory and free-living. METHODS: Oura Ring EE was compared against indirect calorimetry in the laboratory, followed by a 14-day free-living study with 32 participants wearing an Oura Ring and reference monitors (three accelerometers positioned at hip, thigh, and wrist, and pedometer) to evaluate Oura EE variables and step count. RESULTS: Strong correlations were shown for Oura versus indirect calorimetry in the laboratory (r = 0.93), and versus reference monitors for all variables in free-living (r ≥ 0.76). Significant (p < 0.05) mean differences for Oura versus reference methods were found for laboratory measured sitting (- 0.12 ± 0.28 MET), standing (- 0.27 ± 0.33 MET), fast walk (- 0.82 ± 1.92 MET) and very fast run (- 3.49 ± 3.94 MET), and for free-living step-count (2124 ± 4256 steps) and EE variables (MET: - 0.34-0.26; TEE: 362-494 kcal; AEE: - 487-259 kcal). In the laboratory, Oura tended to underestimate EE with increasing discrepancy as intensity increased. The combined activities and slow running in the laboratory, and all MET placements, TEE hip and wrist, and step count in free-living had acceptable measurement errors (< 10% MAPE), whereas the remaining free-living variables showed close to (≤13.2%) acceptable limits. CONCLUSION: This is the first study investigating the validity of Oura Ring EE against gold standard methods. Oura successfully identified major changes between activities and/or intensities but was less responsive to detailed deviations within activities. In free-living, Oura step-count and EE variables tightly correlated with reference monitors, though with systemic over- or underestimations indicating somewhat low intra-individual validity of the ring versus the reference monitors. However, the correlations between the devices were high, suggesting that the Oura can detect differences at group-level for active and total energy expenditure, as well as step count.

Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (-), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.

HIF-1α-Dependent Metabolic Reprogramming, Oxidative Stress, and Bioenergetic Dysfunction in SARS-CoV-2-Infected Hamsters.

The mechanistic interplay between SARS-CoV-2 infection, inflammation, and oxygen homeostasis is not well defined. Here, we show that the hypoxia-inducible factor (HIF-1α) transcriptional pathway is activated, perhaps due to a lack of oxygen or an accumulation of mitochondrial reactive oxygen species (ROS) in the lungs of adult Syrian hamsters infected with SARS-CoV-2. Prominent nuclear localization of HIF-1α and increased expression of HIF-1α target proteins, including glucose transporter 1 (Glut1), lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase-1 (PDK1), were observed in areas of lung consolidation filled with infiltrating monocytes/macrophages. Upregulation of these HIF-1α target proteins was accompanied by a rise in glycolysis as measured by extracellular acidification rate (ECAR) in lung homogenates. A concomitant reduction in mitochondrial respiration was also observed as indicated by a partial loss of oxygen consumption rates (OCR) in isolated mitochondrial fractions of SARS-CoV-2-infected hamster lungs. Proteomic analysis further revealed specific deficits in the mitochondrial ATP synthase (Atp5a1) within complex V and in the ATP/ADP translocase (Slc25a4). The activation of HIF-1α in inflammatory macrophages may also drive proinflammatory cytokine production and complement activation and oxidative stress in infected lungs. Together, these findings support a role for HIF-1α as a central mediator of the metabolic reprogramming, inflammation, and bioenergetic dysfunction associated with SARS-CoV-2 infection.

A theory-based model of cumulative activity.

Energy expenditure can be used to examine the health of individuals and the impact of environmental factors on physical activity. One of the more common ways to quantify energy expenditure is to process accelerometer data into some unit of measurement for this expenditure, such as Actigraph activity counts, and bin those measures into physical activity levels. However, accepted thresholds can vary between demographics, and some units of energy measurements do not currently have agreed upon thresholds. We present an approach which computes unique thresholds for each individual, using piecewise exponential functions to model the characteristics of their overall physical activity patterns corresponding to well established sedentary, light, moderate and vigorous activity levels from the literature. Models are fit using existing piecewise fitting techniques and software. Most participants' activity intensity profile is exceptionally well modeled as piecewise exponential decay. Using this model, we find emergent groupings of participant behavior and categorize individuals into non-vigorous, consistent, moderately active, or extremely active activity intensity profiles. In the supplemental materials, we demonstrate that the parameters of the model correlate with demographics of age, household size, and level of education, inform behavior change under COVID lockdown, and are reasonably robust to signal frequency.

Physical Activity, Energy Expenditure, Screen Time and Social Support in Spanish Adolescents-Towards an Explanatory Model about Health Risk Factors.

Youth obesity has been a pandemic for decades. One of its causes is a low level of physical activity. It is necessary to know the specific situation of adolescents and the factors that influence it in order to be able to act accordingly. The first aim of the current study is to create an explanatory model to establish the relationships between light physical activity time, light physical activity energy expenditure, screen time and social support. The second aim is to propose a theoretical model specifying the relationships between moderate-vigorous physical activity time, moderate-vigorous physical activity energy expenditure, screen time and social support. The study design was non-experimental (ex post facto), descriptive-correlational and cross-sectional. A total of 694 adolescents from the region of Soria (12-17 years) participated in the study. The instruments administered were the Four by One-Day Physical Activity Questionnaire, Parent Support Scale and Peer Support Scale. Two structural equation models were developed to analyse the relationships between the variables that comprised the explanatory models. The results show that social support had a negative influence on screen time in the proposed model in relation to light physical activity (r = -0.210; p ≤ 0.001) and in the proposed one regarding moderate-vigorous physical activity (r = -0.173; p ≤ 0.05). Social support was negatively related to light physical activity time (r = -0.167; p ≤ 0.05). Family support had a greater influence than did peer support. In conclusion, the models for light and moderate-vigorous physical activity are useful to describe the relationships between time, energy expenditure, screen time and social support.

TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection.

Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Balancing the scales: Preliminary investigation of total energy expenditure and daily metabolizable energy intake in Matschie's tree kangaroo (Dendrolagus matschiei).

Matschie's tree kangaroo (Dendrolagus matschiei) is an endangered arboreal marsupial native to Papua New Guinea. Detailed field studies of its behavior and ecology are scarce due largely to its occupation of remote cloud forests and cryptic nature. Although this species has been in human care since the 1950s, much of its biology is still unknown. The current ex situ population is not sustainable due to health and reproductive problems, believed to stem largely from issues with diet and obesity. To better assess potential discrepancies between energy requirements and energy intake, we sought to 1) quantify total energy expenditure (TEE) of two zoo-housed Matschie's tree kangaroos (body mass = 9.0-9.7 kg) on a diet composed largely of leafy browse; 2) quantify food and macronutrient intake, apparent dry matter macronutrient digestibility, and metabolizable energy (ME) intake over a 14-month period; and 3) test for seasonal changes in ME intake due to seasonal differences in the varieties of leafy browse offered. Using the doubly labeled water method, we determined TEE for the female (288 kcal day -1) and male (411 kcal day -1). Resulting mean TEE was well below the expected value for marsupials and macropods (i.e., ~60% of the expected value based on body mass). The mean calculated ME intakes for the female and male were 307 kcal day-1 and 454 kcal day-1, respectively. There were significant seasonal differences in ME intakes, driven by reduced intake in the autumn. These results demonstrate that Matschie's tree kangaroos can be maintained at healthy body weights and conditions on fiber-rich and browse-heavy diets. Our findings contribute important insights into tree kangaroo energetics and physiology and can be applied to help reformulate the diet of Matschie's tree kangaroos at captive facilities to improve population health and sustainability.

Ambient and Wearable Sensor Technologies for Energy Expenditure Quantification of Ageing Adults.

COVID-19 has affected daily life in unprecedented ways, with dramatic changes in mental health, sleep time and level of physical activity. These changes have been especially relevant in the elderly population, with important health-related consequences. In this work, two different sensor technologies were used to quantify the energy expenditure of ageing adults. To this end, a technological platform based on Raspberry Pi 4, as an elaboration unit, was designed and implemented. It integrates an ambient sensor node, a wearable sensor node and a coordinator node that uses the information provided by the two sensor technologies in a combined manner. Ambient and wearable sensors are used for the real-time recognition of four human postures (standing, sitting, bending and lying down), walking activity and for energy expenditure quantification. An important first aim of this work was to realize a platform with a high level of user acceptability. In fact, through the use of two unobtrusive sensors and a low-cost processing unit, the solution is easily accessible and usable in the domestic environment; moreover, it is versatile since it can be used by end-users who accept being monitored by a specific sensor. Another added value of the platform is the ability to abstract from sensing technologies, as the use of human posture and walking activity for energy expenditure quantification enables the integration of a wide set of devices, provided that they can reproduce the same set of features. The obtained results showed the ability of the proposed platform to automatically quantify energy expenditure, both with each sensing technology and with the combined version. Specifically, for posture and walking activity classification, an average accuracy of 93.8% and 93.3% was obtained, respectively, with the wearable and ambient sensor, whereas an improvement of approximately 4% was reached using data fusion. Consequently, the estimated energy expenditure quantification always had a relative error of less than 3.2% for each end-user involved in the experimentation stage, classifying the high level information (postures and walking activities) with the combined version of the platform, justifying the proposed overall architecture from a hardware and software point of view.

Energy expenditure in COVID-19 mechanically ventilated patients: A comparison of three methods of energy estimation.

BACKGROUND: Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure. Energy expenditure (EE) estimated by ventilator-derived carbon dioxide consumption (EEVCO2 ) has also been proposed. In the absence of IC, predictive weight-based equations have been recommended to estimate daily energy requirements. This study aims to compare simple predictive weight-based equations with those estimated by EEVCO2 and IC in mechanically ventilated patients of COVID-19. METHODS: Retrospective study of a cohort of critically ill adult patients with COVID-19 requiring mechanical ventilation and artificial nutrition to compare energy estimations by three methods through the calculation of bias and precision agreement, reliability, and accuracy rates. RESULTS: In 58 mechanically ventilated patients, a total of 117 paired measurements were obtained. The mean estimated energy derived from weight-based calculations was 2576 ± 469 kcal/24 h, as compared with 1507 ± 499 kcal/24 h when EE was estimated by IC, resulting in a significant bias of 1069 kcal/day (95% CI [-2158 to 18.7 kcal]; P < 0.001). Similarly, estimated mean EEVCO2 was 1388 ± 467 kcal/24 h when compared with estimation of EE from IC. A significant bias of only 118 kcal/day (95% CI [-187 to 422 kcal]; P < 0.001), compared by the Bland-Altman plot, was noted. CONCLUSION: The energy estimated with EEVCO2 correlated better with IC values than energy derived from weight-based calculations. Our data suggest that the use of simple predictive equations may potentially lead to overfeeding in mechanically ventilated patients with COVID-19.

Post-acute sequelae of COVID-19: A metabolic perspective.

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.

Energy requirements for critically ill patients with COVID-19.

Early reports suggested that predictive equations significantly underestimate the energy requirements of critically ill patients with coronavirus disease 2019 (COVID-19) based on the results of indirect calorimetry (IC) measurements. IC is the gold standard for measuring energy expenditure in critically ill patients. However, IC is not available in many institutions. If predictive equations significantly underestimate energy requirements in severe COVID-19, this increases the risk of underfeeding and malnutrition, which is associated with poorer clinical outcomes. As such, the purpose of this narrative review is to summarize and synthesize evidence comparing measured resting energy expenditure via IC with predicted resting energy expenditure determined via commonly used predictive equations in adult critically ill patients with COVID-19. Five articles met the inclusion criteria for this review. Their results suggest that many critically ill patients with COVID-19 are in a hypermetabolic state, which is underestimated by commonly used predictive equations in the intensive care unit (ICU) setting. In nonobese patients, energy expenditure appears to progressively increase over the course of ICU admission, peaking at week 3. The metabolic response pattern in patients with obesity is unclear because of conflicting findings. Based on limited evidence published thus far, the most accurate predictive equations appear to be the Penn State equations; however, they still had poor individual accuracy overall, which increases the risk of underfeeding or overfeeding and, as such, renders the equations an unsuitable alternative to IC.

Metabolic Impacts of Confinement during the COVID-19 Pandemic Due to Modified Diet and Physical Activity Habits.

While the detrimental effects of a chronic positive energy balance due to a sedentary lifestyle have been well established, the impacts of a short period of abruptly reduced physical activity and overeating arising from strict confinement due to the COVID-19 pandemic will soon start to emerge. To reasonably anticipate major consequences according to the available evidence, we hereby review the literature for studies that have explored the health impacts of several weeks of a reduction in physical activity and daily step-count combined with modified eating habits. These studies identify as main metabolic consequences increases in insulin resistance, total body fat, abdominal fat and inflammatory cytokines. All these factors have been strongly associated with the development of metabolic syndrome, which in turn increases the risk of multiple chronic diseases. A plausible mechanism involved in these impacts could be a positive energy balance promoted by maintaining usual dietary intake while reducing energy expenditure. This means that just as calorie intake restriction could help mitigate the deleterious impacts of a bout of physical inactivity, overeating under conditions of home confinement is very likely to exacerbate these consequences. Moreover, hypertension, diabetes, and cardiovascular disease have been identified as potential risk factors for more severely ill patients with COVID-19. Thus, adequate control of metabolic disorders could be important to reduce the risk of severe COVID-19.

Face Validity of Observed Meal Patterns Reported with 7-Day Diet Diaries in a Large Population-Based Cohort Using Diurnal Variation in Concentration Biomarkers of Dietary Intake.

In a cross-sectional analysis of a population-based cohort (United Kingdom, N = 21,318, 1993-1998), we studied how associations between meal patterns and non-fasting triglyceride and glucose concentrations were influenced by the hour of day at which the blood sample was collected to ascertain face validity of reported meal patterns, as well as the influence of reporting bias (assessed using formula of energy expenditure) on this association. Meal size (i.e., reported energy content), mealtime and meal frequency were reported using pre-structured 7-day diet diaries. In ANCOVA, sex-specific means of biomarker concentrations were calculated by hour of blood sample collection for quartiles of reported energy intake at breakfast, lunch and dinner (meal size). Significant interactions were observed between breakfast size, sampling time and triglyceride concentrations and between lunch size, sampling time and triglyceride, as well as glucose concentrations. Those skipping breakfast had the lowest triglyceride concentrations in the morning and those skipping lunch had the lowest triglyceride and glucose concentrations in the afternoon, especially among acceptable energy reporters. Eating and drinking occasion frequency was weakly associated with glucose concentrations in women and positively associated with triglyceride concentrations in both sexes; stronger associations were observed for larger vs. smaller meals and among acceptable energy reporters. Associations between meal patterns and concentration biomarkers can be observed when accounting for diurnal variation and underreporting. These findings support the use of 7-day diet diaries for studying associations between meal patterns and health.

SARS-CoV-2 infections in children: Understanding diverse outcomes.

SARS-CoV-2 infections mostly lead to mild or even asymptomatic infections in children, but the reasons for this are not fully understood. More efficient local tissue responses, better thymic function, and cross-reactive immunity have all been proposed to explain this. In rare cases of children and young people, but very rarely in adults, post-infectious hyperinflammatory syndromes can develop and be serious. Here, I will discuss our current understanding of SARS-CoV-2 infections in children and hypothesize that a life history and energy allocation perspective might offer an additional explanation to mild infections, viral dynamics, and the higher incidence of rare multisystem inflammatory syndromes in children and young people.

The Potential to Fight Obesity with Adipogenesis Modulating Compounds.

Obesity is an increasingly severe public health problem, which brings huge social and economic burdens. Increased body adiposity in obesity is not only tightly associated with type 2 diabetes, but also significantly increases the risks of other chronic diseases including cardiovascular diseases, fatty liver diseases and cancers. Adipogenesis describes the process of the differentiation and maturation of adipocytes, which accumulate in distributed adipose tissue at various sites in the body. The major functions of white adipocytes are to store energy as fat during periods when energy intake exceeds expenditure and to mobilize this stored fuel when energy expenditure exceeds intake. Brown/beige adipocytes contribute to non-shivering thermogenesis upon cold exposure and adrenergic stimulation, and thereby promote energy consumption. The imbalance of energy intake and expenditure causes obesity. Recent interest in epigenetics and signaling pathways has utilized small molecule tools aimed at modifying obesity-specific gene expression. In this review, we discuss compounds with adipogenesis-related signaling pathways and epigenetic modulating properties that have been identified as potential therapeutic agents which cast some light on the future treatment of obesity.

Diverse Roles of TRPV4 in Macrophages: A Need for Unbiased Profiling.

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective mechanosensitive ion channel expressed by various macrophage populations. Recent reports have characterized the role of TRPV4 in shaping the activity and phenotype of macrophages to influence the innate immune response to pathogen exposure and inflammation. TRPV4 has been studied extensively in the context of inflammation and inflammatory pain. Although TRPV4 activity has been generally described as pro-inflammatory, emerging evidence suggests a more complex role where this channel may also contribute to anti-inflammatory activities. However, detailed understanding of how TRPV4 may influence the initiation, maintenance, and resolution of inflammatory disease remains limited. This review highlights recent insights into the cellular processes through which TRPV4 contributes to pathological conditions and immune processes, with a focus on macrophage biology. The potential use of high-throughput and omics methods as an unbiased approach for studying the functional outcomes of TRPV4 activation is also discussed.

Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives.

Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.