We propose that hyper‐inflammation (HYPi) is a ‘‘runaway’’ consequence of acute inflammation (ACUi) that arises more easily (and also abates less easily) in those who host a pre‐existing chronic inflammation (CHRi), because (i) most factors involved in generating an ACUi to limit viral proliferation are already present when there is an underlying CHRi, and also because (ii) anti‐inflammatory (AI) mechanisms for the abatement of ACUi (following containment of viral proliferation) are suppressed and desensitized where there is an (...) underlying CHRi, with this causing the ACUi to spiral into a HYPi. Stress, pollution, diet, and gut microbiomes (alterable in weeks through dietary changes) have an intimate and bidirectional cause‐effect relationship with CHRi. We propose that avoidance of CHRi‐promoting foods and adoption of CHRi‐suppressing foods could reduce susceptibility to HYPi, in Covid‐19 and in other viral diseases, such as influenza, which are characterized by episodic and unpredictable HYPi. (shrink)

A striking and unexplained feature of granulomatous inflammation is its anatomical association with the lymphatic system. Accumulating evidence suggests that lymphatic tracks and granulomas may alter the function of each other. The formation of new lymphatics, or lymphangiogenesis, is an adaptive response to tumor formation, infection, and wound healing. Granulomas also may induce lymphangiogenesis which, through a variety of mechanisms, could contribute to disease outcomes in tuberculosis and sarcoidosis. On the other hand, alterations in lymph node function and lymphatic (...) draining may be primary events which attenuate the risk and severity of granulomatous inflammation. This review begins with an introduction of granulomatous inflammation and the lymphatic system. A role of the lymphatic system in tuberculosis and sarcoidosis is then hypothesized. With a focus on lymphangiogenesis in these diseases, and on the potential for this process to promote dissemination, parallels are established with the well‐established role of lymphangiogenesis in tumor biology. (shrink)

Galectin-3 and LTB4 are pro-inflammatory molecules recently shown to directly cause insulin resistance in mouse and human cells. They are highly expressed in the obese state, and can be targeted both genetically and pharmacologically to improve insulin sensitivity in vivo. This expands on previous research showing that targeting inflammatory cytokines can be insulin sensitizing in animal models. However, translating these potential therapies into the human setting remains challenging. Here we review this latest research, and discuss how balancing their pleiotropic functions, (...) the action of the microbiome, and the ability to identify relevant patient populations are vital considerations for successful anti-inflammatory insulin sensitizing therapy. Recent advances have indicated that a diverse range of inflammatory molecules, including leukotriene B4 and Galectin-3 can cause insulin resistance. Key challenges for translating these new targets into therapies include their pleiotropic effects and likely patient heterogeneity, such as is caused by the intestinal microbiome. (shrink)

Inflammatory responses are essential for the clearance of pathogens and the repair of injured tissues; however, if these responses are not properly controlled chronic inflammation can occur. Chronic inflammation is now recognized as a contributing factor to many age‐associated diseases including metabolic disorders, arthritis, neurodegeneration, and cardiovascular disease. Due to the connection between chronic inflammation and these diseases, it is essential to understand underlying mechanisms behind this process. In this review, factors that contribute to chronic inflammation (...) are discussed. Further, we emphasize the emerging roles of microRNAs (miRNAs) and other noncoding RNAs (ncRNA) in regulating chronic inflammatory states, making them important future diagnostic markers and therapeutic targets. Copyright Line: © 2015 The Authors BioEssays Published by Wiley‐VCH Verlag GmbH & Co. KGaA. (shrink)

Discovery of a second, inducible prostaglandin synthase provides explanations for many previously puzzling observations, but also raises new questions about prostanoid synthesis. A cis‐acting sequence closely related to the cyclic AMP response element has been shown to play a role in both basal and induced prostaglandin synthase 2 gene expression. Aspirin and other currently available non‐steroidal anti‐inflammatory drugs that inhibit prostaglandin synthase activity do not effectively discriminate between the inducible prostaglandin synthase 2 and constitutive prostaglandin synthase 1 enzymes. Identification of (...) a second prostaglandin synthase, induced by inflammatory stimuli, initiated a search for isoform‐specific inhibitors. Use of prostaglandin synthase 2 specific inhibitors and antisense oligonucleotides has led to the suggestion that specific ligands activate alternative pathways of prostanoid production, using one of the prostaglandin synthase isoforms preferentially. The coupling mechanisms by which these pathways are activated in response to alternative stimuli should provide additional routes of intervention in prostanoid production. (shrink)

The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the (...) result of a chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. (shrink)

During the transition to calving, dairy ruminants undergo physiological changes affecting several metabolic functions, including feeding behavior, nutrient flux and redistribution, hormonal patterns, and immune responses. Failure in those adaptations often induces a physiological imbalance condition, predisposing animals to developing several metabolic and infectious disorders at the onset of lactation.The immune system exerts a pivotal role in allowing a proper adaptation of dairy ruminants to the transition period, as immune dysfunctions and chronic inflammatory conditions contribute to increasing the development of (...) physiological imbalance condition. Several managerial practices could be adopted to improve dairy ruminants’ adaptation to the transition period through improving the immune system function and mainly mitigating the inflammatory conditions. This chapter is aimed at (1) exploring physiological adaptations affecting metabolic functions of dairy ruminants while approaching calving, (2) understanding metabolic processes that are more likely affected by a physiological imbalance condition, (3) highlighting the role of the immune system in affecting a successful adaptation to the transition period, and (4) listing possible intervention aimed at improving such adaptation, mainly through modulating inflammation. (shrink)

Frailty is a complex geriatric syndrome with multifactorial associated mechanisms that need to be examined more deeply to help reverse the adverse health-related outcomes. Specific inflammatory and physical health markers have been associated with the onset of frailty, but the associations between these factors and psycho-social health outcomes seem less studied. This systematic review aimed to identify, in the same study design, the potential associations between frailty and markers of inflammation, and physical or psycho-social health. A literature search was (...) performed from inception until March 2021 using Medline, Psycinfo, and EMBASE. Three raters evaluated the articles and selected 22 studies, using inclusion and exclusion criteria. Regarding biomarkers, 95% of the included studies showed significant links between inflammation [especially the higher levels of C-reactive protein and interleukin-6 ], and frailty status. Approximately 86% of the included studies showed strong links between physical health decline, and frailty status. At most, 13 studies among the 22 included ones evaluated psycho-social variables and mixed results were observed regarding the relationships with frailty. Results are discussed in terms of questioning the medical perception of global health, centering mostly on the physical dimension. Therefore, the development of future research studies involving a more exhaustive view of frailty and global health is strongly encouraged. (shrink)

In the past decade, the availability of genetically modified animals has enabled the discovery of interesting roles for phosphatidylinositol 3‐kinase‐γ (PI3Kγ) and ‐δ (PI3Kδ) in different cell types orchestrating innate and adaptive immune responses. Therefore, these PI3K isoforms appear to be attractive drug targets for the treatment of diseases caused by unrestrained immune reactions. Currently, pharmacological targeting of PI3Kγ and/or PI3Kδ represents one of the most promising challenges for companies interested in the development of novel safe treatments for inflammatory diseases. (...) In this review we provide a general outline of PI3Kγ‐ and PI3Kδ‐specific functions in distinct subsets of inflammatory cells. We also discuss the therapeutic impact of novel compounds targeting PI3Kγ, PI3Kδ or both, in mouse models of autoimmune disorders (systemic lupus erythematosus (SLE) and rheumatoid arthritis), respiratory diseases (allergic asthma and chronic obstructive pulmonary disease) and cardiovascular dysfunctions (atherosclerosis and myocardial infarction). (shrink)

The de‐repression of transposable elements (TEs) in mammalian genomes is thought to contribute to genome instability, inflammation, and ageing, yet is viewed as a cell‐autonomous event. In contrast to mammalian cells, prokaryotes constantly exchange genetic material through TEs, crossing both cell and species barriers, contributing to rapid microbial evolution and diversity in complex communities such as the mammalian gut. Here, it is proposed that TEs released from prokaryotes in the microbiome or from pathogenic infections regularly cross the kingdom barrier (...) to the somatic cells of their eukaryotic hosts. It is proposed this horizontal transfer of TEs from microbe to host is a stochastic, ongoing catalyst of genome destabilization, resulting in structural and epigenetic variations, and activation of well‐evolved host defense mechanisms contributing to inflammation, senescence, and biological ageing. It is proposed that innate immunity pathways defend against the horizontal acquisition of microbial TEs, and that activation of this pathway during horizontal transposon transfer promotes chronic inflammation during ageing. Finally, it is suggested that horizontal acquisition of prokaryotic TEs into mammalian genomes has been masked and subsequently under‐reported due to flaws in current sequencing pipelines, and new strategies to uncover these events are proposed. (shrink)

Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre‐clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress‐induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation of oxygen and nutrients. (...) The resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors. (shrink)

Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion‐dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue homeostasis? (...) Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others. (shrink)

The Malnutrition-Inflammation Score was initially proposed to evaluate malnutrition-inflammation complex syndrome in end-stage renal disease patients. Although MICS should be routinely evaluated to reduce the hospitalization and mortality rate of ESRD patients, the inconvenience of the MIS might limit its use. Cerebral complications in ESRD, possibly induced by MICS, were previously assessed by using spectral electroencephalography via the delta/theta ratio and microstate analysis. Correspondingly, EEG could be used to directly assess MICS in ESRD patients, but the relationships among (...) MICS and these EEG features remain inconclusive. Thus, we aimed to investigate the delta/theta ratio and microstates in ESRD patients with high and low risks of MICS. We also attempted to identify the correlation among the MIS, delta/theta ratio, and microstate parameters, which might clarify their relationships. To achieve these objectives, a total of forty-six ESRD subjects were willingly recruited. We collected their blood samples, MIS, and EEGs after receiving written informed consent. Sixteen women and seven men were allocated to low risk group. Additionally, high risk group contains 15 women and 8 men. Here, we discovered that delta/theta ratio and most microstate parameters were significantly different between subject groups. We also found that the delta/theta ratio was not correlated with MIS but was strongly with the average microstate duration ; hence, we suggested that the average microstate duration might serve as an alternative encephalopathy biomarker. Coincidentally, we noticed positive correlations for most parameters of microstates A and B and stronger negative correlations for all microstate C parameters. These findings unveiled a novel EEG biomarker, the MIC index, that could efficiently distinguish ESRD patients at high and low risk of MICS when utilized as a feature in a binary logistic regression model. We expected that the average microstate duration and MIC index might potentially contribute to monitor ESRD patients in the future. (shrink)

Neutrophil extracellular traps (NETs)—web‐like DNA structures extruded by neutrophils in response to various stimuli, including pathogens, sterile inflammation, and mechanical stress—play a dual role in immunity and disease. While NETs serve to trap and neutralize pathogens during host defense, excessive or dysregulated NET formation, known as NETosis, can amplify inflammation and contribute to thrombotic complications such as atherosclerosis and valve disease. Increasing evidence supports that NETosis is a regulated, signaling‐driven process, and that mechanical forces—including shear stress, tensile force, (...) and matrix stiffness—can act as noncanonical danger signals capable of inducing NETosis. Mechanosensitive ion channels such as Piezo1, have emerged as key transducers of these biophysical cues, enabling cells to convert changes in shear stress levels into intracellular calcium flux, cytoskeletal remodeling, and ultimately NET release. Furthermore, exposure to pathologically high levels of shear stress may improve the sensitivity of neutrophils to secondary stimuli, lowering their activation threshold and amplifying inflammatory and thrombotic cascades. This mechanosensitive framework highlights shear‐induced NETosis as a critical pathway by which neutrophils contribute to inflammation and thrombosis in mechanically stressed vascular environments. (shrink)

No cure yet exists for devastating Alzheimer's disease (AD), despite many years and humongous efforts to find efficacious pharmacological treatments. So far, neither designing drugs to disaggregate amyloid plaques nor tackling solely inflammation turned out to be decisive. Mesenchymal stem cells (MSCs) and, in particular, extracellular vesicles (EVs) originating from them could be proposed as an alternative, strategic approach to attack the pathology. Indeed, MSC‐EVs—owing to their ability to deliver lipids/proteins/enzymes/microRNAs endowed with anti‐inflammatory, amyloid‐β degrading, and neurotrophic activities—may be (...) exploited as therapeutic tools to restore synaptic function, prevent neuronal death, and slow down memory impairment in AD. Herein the results presented in the most recently published studies on this topic are critically evaluated, providing a strong rationale for possible employment of MSC‐EVs in AD. (shrink)

Regulators of G protein signaling (RGS) proteins provide timely termination of G protein‐coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti‐inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS proteins. (...) We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide. (shrink)

SummaryHistorians have explored the continuities between science and the arts in the Industrial Revolution, with much recent historiography emphasizing the hybrid nature of the activities of men of science around 1800. Chemistry in particular displayed this sort of hybridity between the philosophical and practical because the materials under investigation were important across the research spectrum. Inflammable gases were an example of such hybrid objects: pneumatic chemists through the eighteenth century investigated them, and in the process created knowledge, processes and instruments (...) essential for the creation of a new gaslight industry from 1800. Once this industry began to expand and mature, the interests and experiments of the gas industry stimulated new research work which in turn had relevance for theoretical debates.This paper explores how the emergence of the gas industry from 1800 provided an impetus for new work in theoretical chemistry. Boulton & Watt, important pioneers of the gas industry, explored the compositions of inflammable gases for practical purposes: the composition of these gases had an important effect on the luminosity of gaslights, and hence the economics of the new technology compared to older forms of lighting. As they explored these questions in their engineering work, they stimulated their friend William Henry to explore the nature of these gases further, and he carried out a series of experiments to determine their composition more exactly than Boulton & Watt had done. Henry published a series of paper between 1805 and 1820 where he made arguments about the compositions of inflammable airs, and further related these to contemporary debates about the laws of multiple and definite proportions, as well as John Dalton's atomism. Henry's research was also a hybrid of the theoretical and practical in that he tried to develop results useful for the fledgling gas industry. Specifically, he suggested the best kind of coal to use, and showed how gas quality varied with distillation time and temperature. (shrink)

Biomarkers are widely used not only as prognostic or diagnostic indicators, or as surrogate markers of disease in clinical trials, but also to formulate theories of pathogenesis. We identify two problems in the use of biomarkers in mechanistic studies. The first problem arises in the case of multifactorial diseases, where different combinations of multiple causes result in patient heterogeneity. The second problem arises when a pathogenic mediator is difficult to measure. This is the case of the oxidative stress (OS) theory (...) of disease, where the causal components are reactive oxygen species (ROS) that have very short half-lives. In this case, it is usual to measure the traces left by the reaction of ROS with biological molecules, rather than the ROS themselves. Borrowing from the philosophical theories of signs, we look at the different facets of biomarkers and discuss their different value and meaning in multifactorial diseases and system medicine to inform their use in patient stratification in personalized medicine. (shrink)

ZusammenfassungNach zwölf Jahren intensiver Forschung etablierte der Ophthalmologe Theodor Leber (1840–1917) am Ende des 19. Jahrhunderts in der Entzündungsforschung die Chemotaxis der Leukozyten. Obwohl sich seine Theorie damals reibungslos in die immunologische Forschung einschrieb, wird sein Name jedoch bis heute nur in der englischsprachigen Fachliteratur mit der Chemotaxis verknüpft. In seinem Experimentalsystem hatte Leber zwar schon Anfang der 1880er Jahre eine Theorie der chemischen Attraktion der Leukozyten beim Entzündungsprozess entwickeln können. Aber seine unkonventionelle Methodik—die Einführung von chemisch indifferentem Fremdmaterial zur (...) Auslösung einer Entzündung am Kaninchenauge—widersprach schon vom Ansatz her dem zu diesem Zeitpunkt dominant bakteriologischen Denkstil der Entzündungsforschung. In diesem Forschungsfeld hielt Leber an einer Forschungspraxis fest, die aus einer engen Verzahnung von experimenteller und theoretischer Arbeit bestand. Erst als eine Öffnung des bakteriologischen Denkstils eingetreten war, gelang es Leber seine auf losen Protokollseiten festgehaltenen Versuchsbeobachtungen in überzeugende Belege seiner Entzündungstheorie zu transformieren. Die mikrohistorische Rekonstruktion von Lebers experimenteller und schriftlicher Arbeit anhand seiner Laborprotokolle erschließt die Forschungspraxis eines Wissenschaftlers, der in der damals etablierten mikrobiologischen Entzündungsforschung kaum Anerkennung fand. Durch Verbindung der mikrohistorischen Rekonstruktion mit einer makrohistorischen Analyse lassen sich außerdem Beharrungsfaktoren im Prozess der Wissensentstehung offenlegen. Leber entwickelte eine spezifische Papiertechnik, durch die er seine experimentellen Erkenntnisse zwar mobilisierte und stabilisierte, aber nicht mit dem Fortschreiten der Wissenschaft mithalten konnte. (shrink)

Background: Meditation is gaining recognition as a tool to impact health and well-being. Samyama is an 8-day intensive residential meditation experience conducted by Isha Foundation requiring several months of extensive preparation and vegan diet. The health effects of Samyama have not been previously studied. The objective was to assess physical and emotional well-being before and after Samyama participation by evaluating psychological surveys and objective health biomarkers.Methods: This was an observational study of 632 adults before and after the Isha Samyama retreat. (...) All participants were invited to complete surveys. Controls included household significant others. Surveys were completed at baseline, just before Samyama, immediately after Samyama, and 3 months later to assess anxiety, depression, mindfulness, joy, vitality, and resilience through validated psychometric scales. Voluntary blood sampling for biomarker analysis was done to assess hemoglobin, HbA1c, lipid profile, and C-reactive protein. Primary outcomes were changes in psychometric scores, body weight, and blood biomarkers.Results: Depression and anxiety scores decreased from T1 to T3, with the effect most pronounced in participants with baseline depression or anxiety. Scores at T4 remained below baseline for those with pre-existing depression or anxiety. Vitality, resilience, joy, and mindfulness increased from T1 to T3. Body weight decreased by 3% from T1 to T3. Triglycerides were lower from T2 to T3. Participants had lower HbA1c and HDL at T2, and lower CRP at all timepoints compared with controls.Conclusions: Participation in the Isha Samyama program led to multiple benefits. The 2-month preparation reduced anxiety, and participants maintained lower anxiety levels at 3 months post-retreat. Physical health improved over the course of the program as evidenced by weight loss and improved HbA1C and lipid profile. Practices associated with the Samyama preparation phase and the retreat may serve as an effective way to improve physical and mental health. Future studies may examine their use as an alternative therapy in patients with depression and/or anxiety.Clinical Trial Registration:www.ClinicalTrials.gov, Identifier: 1801728792. Registered retrospectively on 4/17/2020. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and (...) number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Inflammation is said to be a healthy component of the body's immune system's reaction. Inflammation is characterised by four key symptoms: pain, redness, heat or warmth and swelling. As secondary metabolites, plants may produce a wide range of phytochemical compounds, which possess anti-inflammatory characteristics. Herbal remedies are important therapies for a wide range of ailments all over the world. There are around 7,500 species of medicinal plants, including representatives from over 17,000 flowering plant species. Even though synthetic chemistry (...) has developed its expectations, the use of natural ingredients in the manufacture of drugs used in contemporary medicine is unparalleled. By interfering with the biology of inflammation, anti-inflammatory medications may assist to minimising tissue damage and increase patient comfort. Because of the bulky figure of species reachable for study, the effective development of novel naturally taking place anti-inflammatory drugs is mostly dependent on a multidisciplinary approach to discovering new chemicals. Despite the statistic that many review papers have been produced in this field, the conventional of them simply examined the issue from an area perspective. Several non-steroidal anti-inflammatory drugs have been shown to reduce inflammation and pain by decreasing the isoform of the cyclooxygenase enzyme's digestion of arachidonic acid, hence lowering prostaglandin production. Non-steroidal anti-inflammatory drugs have a host of harmful effects. There are, however, medicinal herbs with anti-inflammatory pharmacological properties that have few or no negative effects. (shrink)

Stretching exercises to increase the range of motion (ROM) of joints have been used by sports coaches and medical professionals for improving performance and rehabilitation. The ability of connective and muscular tissues to change their architecture in response to stretching is important for their proper function, repair and performance. Given the dearth of relevant data in the literature, this review examined two key elements of stretching: stretch intensity and stretch position; and their significance to ROM, delayed onset muscle soreness (DOMS), (...) and inflammation in different populations. A search of three databases, Pub-Med, Google Scholar, and Cochrane Reviews, identified 152 articles, which were subsequently categorized into four groups; athletes (n = 24), clinical (n = 29), elderly (n = 12), and general population (n = 87). The use of different populations facilitated a wider examination of the stretching components and their effects. All 152 articles incorporated information regarding duration, frequency and stretch position, whereas only 79 referred to the intensity of stretching and 22 of these 79 studies were deemed high quality. It appears that the intensity of stretching is relatively under-researched, and the importance of body position and its influence on stretch intensity, is largely unknown. In conclusion, this review has highlighted areas for future research, including stretch intensity and position and their effect on musculo-tendinous tissue, in relation to the sensation of pain, delayed onset muscle soreness, inflammation, as well as muscle health and performance. (shrink)

Preterm birth (PTB), delivery before 37 weeks of gestation, is the leading cause of neonatal mortality globally, accounting for nearly half of all neonatal deaths. While numerous established risk factors for PTB have been identified, ongoing research continues to elucidate additional contributing factors. Epidemiological studies increasingly demonstrate that elevated ambient temperature is an environmental risk factor for PTB, with odds increasing 16% during heat waves and 5% per 1°C temperature rise. This is particularly concerning given escalating global warming trends. While (...) maternal heat susceptibility during pregnancy may be linked to compromised thermoregulation from gestational adaptations, the exact pathophysiological mechanisms leading to heat‐associated PTB remain unclear, hindering therapeutic development. This review proposes multitudes potential pathophysiologic mechanisms leading to PTB that can be induced by heat. They include but are not limited to metabolic derangement, mitochondria dysfunction, inflammation, endothelial dysfunction, oxidative stress, and change in cell fate. These mechanisms are derived from integrated knowledge of pregnancy physiology, parturition processes, and temperature effects on physiological pathways. We also outline future experimental approaches to test these hypotheses. (shrink)

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptors hypersensitivity may result from the systemic state of inflammation characteristic of obesity as (...) well as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally-released neuropeptides sustain immunocytes’ function. Here, we posit that along with mechanical stressed stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping the harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity. (shrink)

This paper argues that the DSM diagnostic category 'major depression' is so permissive that it fails to distinguish the phenomenology of depression from a general 'feeling of being ill' that is associated with a range of somatic illnesses. We start by emphasizing that altered bodily experience is a conspicuous and commonplace symptom of depression. We add that the experience of somatic illness is not exclusively bodily; it can involve more pervasive experiential changes that are not dissimilar to those associated with (...) depression. Then we consider some recent work on inflammation and depression, which suggests that the experience of depression and the 'feeling of being ill' are, in some cases at least, much the same . However, we add that the phenomenology of depression is heterogeneous and that many cases involve additional or different symptoms. We conclude that 'major depression' is a placeholder for a range of different experiences, which are almost certainly aetiologically diverse too. (shrink)

The mastery of fire transformed human evolution through advantages spanning diet, behavior, physiology, and ecology. While these benefits are well established, here we highlight a previously overlooked cost — and selective pressure — unique to humans: high‐temperature burn injury. Unlike other species, humans and their hominin ancestors have faced increased lifetime risk of burns, which we argue has driven genetic adaptation. Drawing on comparative genomic evidence across primates, we suggest that genes associated with burn injury response — relating to wound (...) healing and inflammation — show signs of accelerated evolution in humans. We propose that recurrent exposure to burns acted as a selective force in our lineage, helping to explain both beneficial adaptations and paradoxical maladaptive responses to severe injury. By framing burns as an evolutionary pressure, the Burn Selection Hypothesis invites a re‐evaluation of how fire shaped human biology and offers new perspectives for understanding both the evolutionary past and modern burn care. (shrink)

BET proteins such as Brd3 and Brd4 are chromatin‐associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti‐inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules (...) that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually. (shrink)

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under‐investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune‐modulatory properties, including the creation of an immunoinhibitory, immune‐privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of (...) yeast and bacterial species, along with increasing proinflammatory sebum by‐products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune‐microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs. (shrink)

Recent research has pointed to the importance of the prenatal environment in the etiology of autism spectrum disorder (ASD) but the biological mechanisms which mitigate these environmental factors are not clear. Mitochondrial metabolism abnormalities, inflammation and oxidative stress as common physiological disturbances associated with ASD. Network analysis of the scientific literature identified several leading prenatal environmental factors associated with ASD, particularly air pollution, pesticides, the microbiome and epigenetics. These leading prenatal environmental factors were found to be most associated with (...) inflammation, followed by oxidative stress and mitochondrial dysfunction. Other prenatal factors associated with ASD not identified by the network analysis were also found to be significantly associated with these common physiological disturbances. A better understanding of the biological mechanism which mediate the effect of prenatal environmental factors can lead to insights of how ASD develops and the development of targeted therapeutics to prevent ASD from occuring. (shrink)

The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine‐rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits (...) the growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN. (shrink)

Caffeine, a known CNS stimulant is given as an adjunct component in most abused drugs which could be fatal with repeated administration in many circumstances. This paper presents a study to investigate the effect of repeated administration of caffeine at high dose on rat liver, and discusses ethical and policy issues of caffeine use. Long Evans rats were treated with pure caffeine solution in distilled water through intragastric route once daily for consecutive 56 days. Three groups of rats recognized as (...) low dose, high dose and control group received 6mg caffeine / kg BW, 12mg caffeine / kg BW and distilled water, respectively. Rat plasma was examined for liver transaminases and alkaline phosphatases concentrations which were significantly increased in plasma as compared to the control. Both rat plasma and liver homogenate were subjected to estimate malondialdehyde, advanced oxidation protein product, nitric oxide, antioxidant enzyme catalase, glutathione and superoxide dismutase activity. MDA, AOPP, NO levels increased and SOD activity decreased significantly in both plasma and liver as compared to those of control where as CAT and GSH activity remain unchanged. Rat liver tissues were studied histochemically with Hematoxylin and Eosin, and Picro Sirius Red staining. Significantly increased infiltration of inflammatory cells and progressive deposition of collagen fibre were visible in liver tissue of caffeine treated both dose groups as compared to the control. Long term administration of caffeine at higher dose, significantly contributes to liver inflammation and consequent fibrogenesis. This raises significant ethical and policy issues. (shrink)

Widespread expression of the transcription factor, nuclear factor (erythroid‐derived 2)‐like 2 (NRF2), which maintains redox homeostasis, has recently been identified in the hair follicle (HF). Small molecule activators of NRF2 may therefore be useful in the management of HF pathologies associated with redox imbalance, ranging from HF greying and HF ageing via androgenetic alopecia and alopecia areata to chemotherapy‐induced hair loss. Indeed, NRF2 activation has been shown to prevent peroxide‐induced hair growth inhibition. Multiple parameters can increase the levels of reactive (...) oxygen species in the HF, for example melanogenesis, depilation‐induced trauma, neurogenic and autoimmune inflammation, toxic drugs, environmental stressors such as UV irradiation, genetic defects and aging‐associated mitochondrial dysfunction. In this review, the potential mechanisms whereby NRF2 activation could prove beneficial in treatment of redox‐associated HF disorders are therefore discussed. (shrink)

Inflammatory mediators have an established role in inducing insulin resistance and promoting hyperglycemia. In turn, hyperglycemia has been argued to drive immune cell dysfunction as a result of mitochondrial dysfunction. Here, the authors review the evidence challenging this view. First, it is pointed out that inflammatory mediators are known to induce altered mitochondrial function. In this regard, critical care patients suffer both an elevated inflammatory tone as well as hyperglycemia, rendering it difficult to distinguish between the effects of inflammation (...) and hyperglycemia. Second, emerging evidence indicates that a decrease in mitochondrial respiration and an increase in reactive oxygen species (ROS) production are not necessarily manifestations of pathology, but adaptations taking shape as the mitochondria is abdicating its adenosine triphosphate (ATP)‐producing function (which is taken over by glycolysis) and instead becomes “retooled” for an immunological role. Collectively, these observations challenge the commonly held belief that acute hyperglycemia induces mitochondrial damage leading to immune cell dysfunction. (shrink)

Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune‐obesogenic memory that hinders long‐term weight loss management. Lipid‐associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT. Our previous study found that LAM abundance increases with weight loss via (...) intermittent fasting (IF) in obese mice, which is driven by adipocyte p53 signalling. However, the specific signals causing LAM accumulation in AT under IF remain unknown. In this piece, we hypothesise on a range of adipocyte‐secreted signals that can harbor immune‐attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including cell death signalling, matrikines, and other damage‐associated molecular patterns (DAMPs), as well as adipo(‐cyto)kines, lipid mediators, metabolites, extracellular vesicles, and epigenetic rewiring. Finally, we consider how advances in mechanisms of AT LAM recruitment gleaned from preclinical models might be translatable to long‐term weight management in humans. Thus, we provide vantage points to study signals driving monocyte recruitment, polarisation towards LAMs, and LAM retention, to harness the therapeutic potential of modulating AT LAM levels by impacting the immune‐obesogenic memory in metabolic disease. (shrink)

Criticisms of the “container” model of pregnancy picturing female and embryo as separate entities multiply in various philosophical and scientific contexts during the last decades. In this paper, we examine how this model underlies received views of pregnancy in evolutionary biology, in the characterization of the transition from oviparity to viviparity in mammals and in the selectionist explanations of pregnancy as an evolutionary strategy. In contrast, recent evo-devo studies on eutherian reproduction, including the role of inflammation and new maternal (...) cell types, gather evidence in favor of considering pregnancy as an evolved relational novelty. Our thesis is that from this perspective we can identify the emergence of a newhistoricalindividual in evolution. In evo-devo, historical units are conceptualized as evolved entities which fulfill two main criteria, their continuous persistence and their non-exchangeability. As pregnancy can be individuated in this way, we contend that pregnant females are historical individuals. We argue that historical individuality differs from, and coexists with, other views of biological individuality as applied to pregnancy (the physiological, the evolutionary and the ecological one), but brings forward an important new insight which might help dissolve misguided conceptions. (shrink)

In a recent paper, Reuter, Seinhold and Sytsma put forward an implicature account to explain the intuitive failure of the pain-in-mouth argument. They argue that utterances such as ‘There is tissue damage / a pain / an inflammation in my mouth’ carry the conversational implicature that there is something wrong with the speaker’s mouth. Appealing to new empirical data, this paper argues against the implicature account and for the entailment account, according to which pain reports using locative locutions, such (...) as ‘There is a pain in my mouth’, are intuitively understood as entailing corresponding predicative locutions, such as ‘My mouth hurts.’ On this latter account, the pain-in-mouth argument seems invalid because the conclusion is naturally understood as entailing something which cannot be inferred from the premisses. Implications for the philosophical debate about pain are also drawn. (shrink)

Alterations in the gut microbiome have increasingly been implicated in driving obesity and its associated diseases, but underlying mechanisms remain poorly defined. Herein, in addition to reviewing the field, we hypothesize that a highly significant causative factor of such inflammatory disease‐associated microbiome alterations is a more aggressive microbiota that encroaches upon its host, with components having high potential to activate host pro‐inflammatory gene expression in a manner that drives metabolic disease. We further hypothesize that a range of societal changes, including (...) use of antibiotics and increasing consumption of food additives, have provoked such microbiota aggression and, consequently, may be contributing factors to the increased incidence of obesity and its associated diseases. (shrink)

In bioethics vaccine refusal is often discussed as an instance of free riding on the herd immunity of an infectious disease. However, the social science of vaccine refusal suggests that the reasoning behind refusal to vaccinate more often stems from previous negative experiences in healthcare practice as well as deeply felt distrust of healthcare institutions. Moreover, vaccine refusal often acts like an exit mechanism. Whilst free riding is often met with sanctions, exit, according to Albert Hirschman’s theory of exit and (...) voice is most efficiently met by addressing concerns and increasing the quality and number of feedback channels. If the legitimate grievances responsible for vaccine refusal are not heard or addressed by healthcare policy, further polarization of attitudes to vaccines is likely to ensue. Thus, there is a need in the bioethics of vaccine refusal to understand the diverse ethical questions of this inflammable issue in addition to those of individual responsibility to vaccinate. (shrink)

There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open: why are psychiatric disorders and immune responses intertwined? To address this would require (...) a step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question: translation, unification, and simulation. To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the immune response and psychiatric illness both be explained in terms of self-organising systems responding to threatening stimuli in their external environment, whether those stimuli happen to be pathogens, predators, or people? Does false inference at an immunological level alter the message passing at a psychological level (or vice versa) through a principled exchange between the two systems? (shrink)