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British Journal of Pharmacology Feb 2016The continued focus of attention on the diversity of mechanisms underpinning inflammation has improved our understanding of the potential to target specific pathways in...
The continued focus of attention on the diversity of mechanisms underpinning inflammation has improved our understanding of the potential to target specific pathways in the inflammatory network to achieve meaningful therapeutic gains. In this themed issue of the British Journal of Pharmacology our scope was deliberately broad, ranging across both acute and chronic disease in various organs. Pro- and anti-inflammatory mechanisms receive attention as does the phenotype of macrophages. Whilst the manifestations of neuro-inflammation are less obvious than those in peripheral tissues, central innate and adaptive immunity in brain and the M1/M2 phenotypes of microglia are topics of special interest. The contributions to the inflammatory milieu of cytokines, chemokines and associated signalling cascades are considered. Overall, the coverage herein advances the basic science underpinning our understanding of inflammation and emphasizes its importance in different pathologies.
Topics: Animals; Anti-Inflammatory Agents; Brain; Cytokines; Humans; Inflammation; Models, Biological
PubMed: 26847725
DOI: 10.1111/bph.13389 -
Neurotherapeutics : the Journal of the... Oct 2016The immune response to acute cerebral ischemia is a major factor in stroke pathobiology and outcome. While the immune response starts locally in occluded and... (Review)
Review
The immune response to acute cerebral ischemia is a major factor in stroke pathobiology and outcome. While the immune response starts locally in occluded and hypoperfused vessels and the ischemic brain parenchyma, inflammatory mediators generated in situ propagate through the organism as a whole. This "spillover" leads to a systemic inflammatory response first, followed by immunosuppression aimed at dampening the potentially harmful proinflammatory milieu. In this overview we will outline the inflammatory cascade from its starting point in the vasculature of the ischemic brain to the systemic immune response elicited by brain ischemia. Potential immunomodulatory therapeutic approaches, including preconditioning and immune cell therapy will also be discussed.
Topics: Animals; Brain; Humans; Inflammation; Stroke
PubMed: 27730544
DOI: 10.1007/s13311-016-0483-x -
Frontiers in Cellular and Infection... 2021Mixed vaginitis is the simultaneous presence of at least two types of vaginitis, contributing to an abnormal vaginal milieu and leading to vaginal symptoms and signs.... (Review)
Review
Mixed vaginitis is the simultaneous presence of at least two types of vaginitis, contributing to an abnormal vaginal milieu and leading to vaginal symptoms and signs. However, associations between symptoms and the type of mixed vaginitis have not been clearly elucidated, and research on mixed vaginitis is still in the preliminary stage. Therefore, the pathogenic mechanism of mixed vaginitis remains understudied. Mixed vaginitis generally involves the formation of mixed biofilms. The study of polymicrobial interactions and mixed biofilms will provide a new idea for the understanding of mixed vaginitis. Moreover, this review summarizes some effective management and laboratory diagnosis of mixed vaginitis to avoid inappropriate therapy, recurrence, and reinfection. It is of high clinical importance to obtain relevant clinical data to improve clinical knowledge about mixed vaginitis.
Topics: Candidiasis, Vulvovaginal; Female; Humans; Vulvovaginitis
PubMed: 34796129
DOI: 10.3389/fcimb.2021.759795 -
Nephrology, Dialysis, Transplantation :... Oct 2018Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as... (Review)
Review
Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as chronic kidney disease, inflammation becomes maladaptive, uncontrolled and persistent. Systemic persistent inflammation has, for almost 20 years, been recognized as a major contributor to the uraemic phenotype (such as cardiovascular disease, protein energy wasting, depression, osteoporosis and frailty), and a predictor of cardiovascular and total mortality. Since inflammation is mechanistically related to several ageing processes (inflammageing), it may be a major driver of a progeric phenotype in the uraemic milieu. Inflammation is likely the consequence of a multifactorial aetiology and interacts with a number of factors that emerge when uraemic toxins accumulate. Beside interventions aiming to decrease the production of inflammatory molecules in the uraemic milieu, novel strategies to increase the removal of large middle molecules, such as expanded haemodialysis, may be an opportunity to decrease the inflammatory allostatic load associated with retention of middle molecular weight uraemic toxins.
Topics: Chronic Disease; Humans; Inflammation; Kidney Failure, Chronic; Renal Dialysis; Risk Factors
PubMed: 30281126
DOI: 10.1093/ndt/gfy175 -
Frontiers in Physiology 2020The grand challenge to physiology, as was first described in an essay published in the inaugural issue of Frontiers in Physiology in 2010, remains to integrate function... (Review)
Review
The grand challenge to physiology, as was first described in an essay published in the inaugural issue of Frontiers in Physiology in 2010, remains to integrate function from molecules to intact organisms. In order to make sense of the vast volume of information derived from, and increasingly dependent upon, reductionist approaches, a greater emphasis must be placed on the traditional integrated and more holistic approaches developed by the scientists who gave birth to physiology as an intellectual discipline. Our understanding of physiological regulation has evolved over time from the Greek idea of body humors, through Claude Bernard's "milieu intérieur," to Walter Cannon's formulation of the concept of "homeostasis" and the application of control theory (feedback and feedforward regulation) to explain how a constant internal environment is achieved. Homeostasis has become the central unifying concept of physiology and is defined as a self-regulating process by which an organism can maintain internal stability while adjusting to changing external conditions. Homeostasis is not static and unvarying; it is a dynamic process that can change internal conditions as required to survive external challenges. It is also important to note that homeostatic regulation is not merely the product of a single negative feedback cycle but reflects the complex interaction of multiple feedback systems that can be modified by higher control centers. This hierarchical control and feedback redundancy results in a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. The health and vitality of the organism can be said to be the end result of homeostatic regulation. An understanding of normal physiology is not possible without an appreciation of this concept. Conversely, it follows that disruption of homeostatic mechanisms is what leads to disease, and effective therapy must be directed toward re-establishing these homeostatic conditions. Therefore, it is the purpose of this essay to describe the evolution of our understanding of homeostasis and the role of physiological regulation and dysregulation in health and disease.
PubMed: 32210840
DOI: 10.3389/fphys.2020.00200 -
The Journal of Clinical Investigation Sep 2023Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care.... (Review)
Review
Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care. Within this space is the cardiac macrophage, a key modulator of cardiac function in health and disease. After a myocardial infarction, myeloid macrophages both protect and harm the heart. To varying degrees, such outcomes are a function of myeloid ontogeny and heterogeneity, as well as functional cellular plasticity. Diversity is further shaped by the extracellular milieu, which fluctuates considerably after coronary occlusion. Ischemic limitation of nutrients constrains the metabolic potential of immune cells, and accumulating evidence supports a paradigm whereby macrophage metabolism is coupled to divergent inflammatory consequences, although experimental evidence for this in the heart is just emerging. Herein we examine the heterogeneous cardiac macrophage response following ischemic injury, with a focus on integrating putative contributions of immunometabolism and implications for therapeutically relevant cardiac injury versus cardiac repair.
Topics: Humans; Myocardial Infarction; Heart; Heart Injuries; Cell Plasticity; Macrophages
PubMed: 37712418
DOI: 10.1172/JCI171953 -
Signal Transduction and Targeted Therapy Jun 2022Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of...
Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.
Topics: Amino Acids, Branched-Chain; Graft vs Host Disease; Heart; Humans; Mesenchymal Stem Cells; Myocardial Infarction
PubMed: 35654769
DOI: 10.1038/s41392-022-00971-7 -
Frontiers in Oncology 2022Tumours develop within complex tissue environments consisting of aberrant oncogenic cancer cells, diverse innate and adaptive immune cells, along with structural stromal... (Review)
Review
Tumours develop within complex tissue environments consisting of aberrant oncogenic cancer cells, diverse innate and adaptive immune cells, along with structural stromal cells, extracellular matrix and vascular networks, and many other cellular and non-cellular soluble constituents. Understanding the heterogeneity and the complex interplay between these cells remains a key barrier in treating tumours and cancers. The immune status of the pre-tumour and tumour milieu can dictate if the tumour microenvironment (TME) supports either a pro-malignancy or an anti-malignancy phenotype. Identification of the factors and cell types that regulate the dysfunction of the TME is crucial in order to understand and modulate the immune status of tumours. Among these cell types, tumour-associated fibroblasts are emerging as a major component of the TME that is often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of tumour-associated fibroblasts in regulating tumour immunity and cancer therapy could provide new insight into targeting the TME in various human cancers. In this review, we summarize recent studies investigating the role of immune and key stromal cells in regulating the immune status of the TME and discuss the therapeutic potential of targeting stromal cells, especially tumour-associated fibroblasts, within the TME as an adjuvant therapy to sensitize immunosuppressive tumours and prevent cancer progression, chemo-resistance and metastasis.
PubMed: 35814453
DOI: 10.3389/fonc.2022.908156 -
Human Vaccines & Immunotherapeutics 2014Obesity is one of the largest and fastest growing public health problems in the world. Last century social changes have set an obesogenic milieu that calls for micro and... (Review)
Review
Obesity is one of the largest and fastest growing public health problems in the world. Last century social changes have set an obesogenic milieu that calls for micro and macro environment interventions for disease prevention, while treatment is mandatory for individuals already obese. The cornerstone of overweight and obesity treatment is diet and physical exercise. However, many patients find lifestyle modifications difficult to comply and prone to failure in the long-term; therefore many patients consider anti-obesity drugs an important adjuvant if not a better alternative to behavioral approach or obesity surgery. Since the pharmacological options for obesity treatment remain quite limited, this is an exciting research area, with new treatment targets and strategies on the horizon. This review discusses the development of innovative therapeutic agents, focusing in energy homeostasis regulation and the use of molecular vaccines, targeting hormones such as somatostatin, GIP and ghrelin, to reduce body weight.
Topics: Drug Discovery; Humans; Obesity; Vaccines
PubMed: 24365968
DOI: 10.4161/hv.27537 -
Seminars in Cancer Biology Nov 2022Cancer cells reside amongst a complex milieu of stromal cells and structural features known as the tumor microenvironment. Often cancer cells divert and co-opt functions... (Review)
Review
Cancer cells reside amongst a complex milieu of stromal cells and structural features known as the tumor microenvironment. Often cancer cells divert and co-opt functions of stromal cells of the microenvironment to support tumor progression and treatment resistance. During therapy targeting cancer cells, the stromal cells of the microenvironment receive therapy to the same extent as cancer cells. Stromal cells therefore activate a variety of responses to the damage induced by these therapies, and some of those responses may support tumor progression and resistance. We review here the response of stromal cells to cancer therapy with a focus on radiotherapy in glioblastoma. We highlight the response of endothelial cells and the vasculature, macrophages and microglia, and astrocytes, as well as describing resulting changes in the extracellular matrix. We emphasize the complex interplay of these cellular factors in their dynamic responses. Finally, we discuss their resulting support of cancer cells in tumor progression and therapy resistance. Understanding the stromal cell response to therapy provides insight into complementary therapeutic targets to enhance tumor response to existing treatment options.
Topics: Humans; Tumor Microenvironment; Endothelial Cells; Stromal Cells; Glioblastoma; Extracellular Matrix
PubMed: 35143991
DOI: 10.1016/j.semcancer.2022.02.011