SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Anti-inflammatory

168

Angioedema is the end result of deep dermal, subcutaneous and/or mucosal swelling, and is potentially a life-threatening condition in cases where the pharynx or larynx is involved. Drug-induced angioedema has been reported to occur in response to a wide range of drugs and vaccines. Drug-induced angioedema, like other cutaneous drug reactions, has been reported to be most frequently elicited by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs, although reliable data from epidemiologic studies are scarce. Recent reports suggested an increasing role of angiotensin-converting enzyme inhibitors (ACEIs) in the causation of life-threatening angioedema. ACEI-related angioedema is never accompanied by urticaria and occurs via a kinin-dependent mechanism. ACEI-related angioedema not only can start years after beginning the treatment, but it can then recur irregularly while under that treatment. Furthermore, allergy tests are unreliable for the diagnosis of ACEI-related angioedema, and so the relationship between angioedema and ACEIs is often missed and consequently quite underestimated. Accordingly, better understanding of the kinin-dependent mechanism, which is particular to angioedema, is necessary for the appropriate management of drug-induced angioedema.

Concepts: Pharmacology, Drug, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Drug addiction, Penicillin, Angioedema, ACE inhibitor

167

Cycloxygenase-2 (COX-2) is an attractive target for molecular imaging because it is an inducible enzyme that is expressed in response to inflammatory and proliferative stimuli. Recently, we reported that conjugation of indomethacin with carboxy-X-rhodamine dyes results in the formation of effective, targeted, optical imaging agents able to detect COX-2 in inflammatory tissues and pre-malignant and malignant tumors (Uddin et al. Cancer Res. 2010, 70, 3618-3627). The present paper summarizes the details of the structure-activity relationship (SAR) studies performed for lead optimization of these dyes. A wide range of fluorescent conjugates were designed and synthesized, and each of them was tested for their ability to selectively inhibit COX-2 as the purified protein and in human cancer cells. The SAR study revealed that indomethacin conjugates are the best COX-2-targeted agents compared to the other carboxylic acid-containing non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors (COXIBs). An n-butyldiamide linker is optimal for tethering bulky fluorescent functionalities onto the NSAID or COXIB cores. The activity of conjugates also depends on the size, shape, and electronic properties of the organic fluorophores. These reagents are taken up by COX-2-expressing cells in culture, and the uptake is blocked by pretreatment with a COX inhibitor. In in vivo settings, these reagents become highly enriched in COX-2-expressing tumors compared to surrounding normal tissue, and they accumulate selectively in COX-2-expressing tumors as compared with COX-2-negative tumors implanted in the same mice. Thus, COX-2-targeted fluorescent inhibitors are useful for preclinical and clinical detection of lesions containing elevated levels of COX-2.

Concepts: Cancer, Cyclooxygenase, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Paracetamol, Ibuprofen, Diclofenac, Celecoxib

167

Endothelial activation characterized by the expression of multiple chemokines and adhesive molecules is a critical initial step of vascular inflammation which results in recruitment of leukocytes into sub-endothelial layer of vascular wall and triggers vascular inflammatory diseases such as atherosclerosis. Although inhibiting the endothelial inflammation has already been well recognized as a therapeutic strategy in vascular inflammatory diseases, the therapeutic targets are still elusive. In the present study we found that Zc3h12c, a recently discovered CCCH-zinc finger containing protein, significantly inhibited endothelial cell inflammatory response in vitro. Overexpression of Zc3h12c significantly attenuated tumor necrosis factor a (TNFa) induced expression of chemokines and adhesive molecules, and thus reduced monocyte adherence to human umbilical vein endothelial cells (HUVECs). Conversely, siRNA-mediated knocking down of Zc3h12c increased TNFα-induced expression of chemokines and adhesive molecules in HUVECs. Furthermore, forced expression of Zc3h12c decreased TNFα-induced IKKa/b and IkBa phosphorylation and p65 nuclear translocation, suggesting that Zc3h12c exerted the anti-inflammatory function probably by suppressing nuclear factor-kB (NF-kB) pathway. Thus, Zc3h12c is an endogenous inhibitor of TNFα-induced inflammatory signaling in HUVECs and might be a therapeutic target in vascular inflammatory diseases.

Concepts: Immune system, Inflammation, Atherosclerosis, Blood vessel, Endothelium, Anti-inflammatory, C-reactive protein, Tumor necrosis factor-alpha

131

To date, most studies on the anti-inflammatory effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in humans have used a mixture of the 2 fatty acids in various forms and proportions.

Concepts: Fatty acid, Fatty acids, Omega-3 fatty acid, Anti-inflammatory, Carboxylic acid, Eicosapentaenoic acid, Docosahexaenoic acid, Prostaglandin

127

It is currently widely accepted among clinicians that chronic tendinopathy is caused by a degenerative process devoid of inflammation. Current treatment strategies are focused on physical treatments, peritendinous or intratendinous injections of blood or blood products and interruption of painful stimuli. Results have been at best, moderately good and at worst a failure. The evidence for non-infammatory degenerative processes alone as the cause of tendinopathy is surprisingly weak. There is convincing evidence that the inflammatory response is a key component of chronic tendinopathy. Newer anti-inflammatory modalities may provide alternative potential opportunities in treating chronic tendinopathies and should be explored further.

Concepts: Immune system, Inflammation, Causality, Asthma, Extracellular matrix, Blood vessel, Rheumatoid arthritis, Anti-inflammatory

111

The prevalence of inflammatory diseases is increasing in modern urban societies. Inflammation increases risk of stress-related pathology; consequently, immunoregulatory or antiinflammatory approaches may protect against negative stress-related outcomes. We show that stress disrupts the homeostatic relationship between the microbiota and the host, resulting in exaggerated inflammation. Repeated immunization with a heat-killed preparation of Mycobacterium vaccae, an immunoregulatory environmental microorganism, reduced subordinate, flight, and avoiding behavioral responses to a dominant aggressor in a murine model of chronic psychosocial stress when tested 1-2 wk following the final immunization. Furthermore, immunization with M. vaccae prevented stress-induced spontaneous colitis and, in stressed mice, induced anxiolytic or fear-reducing effects as measured on the elevated plus-maze, despite stress-induced gut microbiota changes characteristic of gut infection and colitis. Immunization with M. vaccae also prevented stress-induced aggravation of colitis in a model of inflammatory bowel disease. Depletion of regulatory T cells negated protective effects of immunization with M. vaccae on stress-induced colitis and anxiety-like or fear behaviors. These data provide a framework for developing microbiome- and immunoregulation-based strategies for prevention of stress-related pathologies.

Concepts: Immune system, Inflammation, Bacteria, Pathology, Infection, Ulcerative colitis, Inflammatory bowel disease, Anti-inflammatory

95

Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases.

Concepts: Immune system, Inflammation, Medicine, Interleukin 1, Infection, Rheumatoid arthritis, Anti-inflammatory, Tumor necrosis factor-alpha

67

Upper respiratory tract inflammatory diseases such as asthma and chronic obstructive pulmonary diseases (COPD) affect more than one-half billion people globally and are characterized by chronic inflammation that is often exacerbated by respiratory pathogens such as nontypeable Haemophilus influenzae (NTHi). The increasing numbers of antibiotic-resistant bacterial strains and the limited success of currently available pharmaceuticals used to manage the symptoms of these diseases present an urgent need for the development of novel anti-inflammatory therapeutic agents. Resveratrol has long been thought as an interesting therapeutic agent for various diseases including inflammatory diseases. However, the molecular mechanisms underlying its anti-inflammatory properties remain largely unknown. Here we show for the first time that resveratrol decreases expression of pro-inflammatory mediators in airway epithelial cells and in the lung of mice by enhancing NTHi-induced MyD88 short, a negative regulator of inflammation, via inhibition of ERK1/2 activation. Furthermore, resveratrol inhibits NTHi-induced ERK1/2 phosphorylation by increasing MKP-1 expression via a cAMP-PKA-dependent signaling pathway. Finally, we show that resveratrol has anti-inflammatory effects post NTHi infection, thereby demonstrating its therapeutic potential. Together these data reveal a novel mechanism by which resveratrol alleviates NTHi-induced inflammation in airway disease by up-regulating the negative regulator of inflammation MyD88s.

Concepts: Immune system, Inflammation, Bacteria, Asthma, Pneumonia, Chronic obstructive pulmonary disease, Respiratory system, Anti-inflammatory

56

Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain.

Concepts: Immune system, Inflammation, Monocyte, Central nervous system, Neuron, Stem cell, Neurogenesis, Anti-inflammatory

49

Primary dysmenorrhea is common among women of reproductive age. Non-steroidal anti-inflammatory drugs and oral contraceptives are effective treatments, although the failure rate is around 20-25%. Therefore additional evidence-based treatments are needed. In recent years, the use of smartphone applications (apps) has increased rapidly and may support individuals in self-management strategies.

Concepts: Combined oral contraceptive pill, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Paracetamol, Menstrual cycle, Acupuncture, Menstruation, Dysmenorrhea