scholarly journals Macrophages protect against loss of adipose tissue during cancer cachexia

2018 ◽  
Author(s):  
Merve Erdem ◽  
Diana Möckel ◽  
Sandra Jumpertz ◽  
Cathleen John ◽  
Athanassios Fragoulis ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
Immune Cells ◽  
Visceral Fat ◽  
Clinical Studies ◽  
Cancer Cachexia ◽  
Myeloid Cell ◽  
Fat Loss ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractCancer cachexia represents a central obstacle in medical oncology as it is associated with poor therapy response and reduced overall survival. Systemic inflammation is considered to be a key driver of cancer cachexia, however, clinical studies with anti-inflammatory drugs failed to show a robust cachexia-inhibiting effect. To address this contradiction, we investigated the functional importance of innate immune cells for hepatocellular carcinoma (HCC)-associated cachexia. To this end, we used a transgenic HCC mouse model intercrossed with mice harboring a defect in myeloid cell-mediated inflammation. We identified robust cachexia in the HCC mouse model as evidenced by a marked loss of visceral fat and lean mass. Computed tomography-based analyses demonstrated that a subgroup of human HCC patients displays reduced visceral fat mass, complementing the murine data. While the myeloid cell-mediated inflammation defect resulted in reduced expression of pro-inflammatory cytokines in the serum of HCC-bearing mice, this unexpectedly did not translate into diminished, but rather enhanced cachexia-associated fat loss. Defective myeloid cell-mediated inflammation was associated with decreased macrophage abundance in visceral adipose tissue, suggesting a role for local macrophages in the regulation of cancer-induced fat loss. Taken together, myeloid cell-mediated inflammation displays a rather unexpected beneficial function in a murine HCC model. These results demonstrate that immune cells are capable of protecting the host against cancer-induced tissue wasting, adding a further layer of complexity to the pathogenesis of cachexia and providing a potential explanation for the contradictory results of clinical studies with anti-inflammatory drugs.

scholarly journals Potential Biomarkers of Fat Loss as a Feature of Cancer Cachexia

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Maryam Ebadi ◽  
Vera C. Mazurak
Keyword(s):  
Adipose Tissue ◽  
Plasma Levels ◽  
Cancer Cachexia ◽  
Prognostic Biomarker ◽  
Prognostic Biomarkers ◽  
Plasma Biomarker ◽  
Fat Loss ◽  
Early Detection And Prevention ◽  
Potential Biomarkers

Fat loss is associated with shorter survival and reduced quality of life in cancer patients. Effective intervention for fat loss in cachexia requires identification of the condition using prognostic biomarkers for early detection and prevention of further depletion. No biomarkers of fat mass alterations have been defined for application to the neoplastic state. Several inflammatory cytokines have been implicated in mediating fat loss associated with cachexia; however, plasma levels may not relate to adipose atrophy. Zinc-α2-glycoprotein may be a local catabolic mediator within adipose tissue rather than serving as a plasma biomarker of fat loss. Plasma glycerol and leptin associate with adipose tissue atrophy and mass, respectively; however, no study has evaluated their potential as a prognostic biomarker of cachexia-associated fat loss. This review confirms the need for further studies to identify valid prognostic biomarkers to identify loss of fat based on changes in plasma levels of biomarkers.

Abstract 374: Interleukin-19: A Novel Pro-Angiogenic and Anti-Inflammatory Adipokine

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Christine Vrakas ◽  
Sheri E Keleman ◽  
Rosario Scalia ◽  
Michael V Autieri
Keyword(s):  
Adipose Tissue ◽  
Visceral Fat ◽  
Subcutaneous Fat ◽  
Chow Diet ◽  
Vascular Cells ◽  
Regulatory Factor ◽  
Normal Chow ◽  
Gene Regulatory ◽  
Anti Inflammatory ◽  
Normal Chow Diet

Uncontrolled inflammation leads to many of the chronic diseases associated with obesity. Due to a lack of oxygen in the tissue, expanding adipose tissue becomes hypoxic and pro-inflammatory. Adipocytes release pro-angiogenic factors in an effort to restore blood flow to the tissue. Presently, little is known about the potential for endogenously expressed anti-inflammatory cytokines to attenuate inflammation and also provide pro-angiogenic effects. IL-19 is uniquely anti-inflammatory, pro-angiogenic and is both expressed by and targets various cells types. IL-19 expression in adipocytes and stromal vascular cells is increased in visceral compared to subcutaneous fat, and is also increased in visceral fat on high fat diet (HFD) compared to normal chow diet. There is no known mechanism to explain the role of IL-19 in adipose tissue expansion, and we hypothesized that IL-19 may have pro-angiogenic and anti-inflammatory properties in expanding adipose tissue. We have identified a gene regulatory factor, Interleukin Enhancer-Binding Factor 3 (ILF3) that is induced in adipocytes and stromal vascular cells by HFD and IL-19 treatment. We found that both IL-19 and VEGF induce ILF3 expression in cultured human endothelial cells (hECs). Proliferation is significantly reduced when ILF3 is knocked down using siRNA in hECs. Furthermore, when ILF3 is knocked down and hECs are stimulated with VEGF several angiogenic cytokines are also decreased. Through immunohistochemistry we found that ILF3 translocates from the nucleus to the cytoplasm in visceral fat of C57BL/6 mice fed a HFD, and remains in the nucleus when fed a normal chow diet. In summary IL-19 may be a unique HFD responsive adipokine functioning to reduce inflammation and increase angiogenesis in expanding adipose tissue. The angiogenic function of IL-19 may work through induction of the gene regulatory factor, ILF3.

scholarly journals Inflammation in the Pathophysiology and Therapy of Cardiometabolic Disease

2019 ◽  
Vol 40 (4) ◽  
pp. 1080-1091 ◽  
Author(s):  
Marc Y Donath ◽  
Daniel T Meier ◽  
Marianne Böni-Schnetzler
Keyword(s):  
Metabolic Syndrome ◽  
Clinical Studies ◽  
Cell Function ◽  
Therapeutic Interventions ◽  
Metabolic Inflammation ◽  
Inflammatory Conditions ◽  
Β Cell Function ◽  
Associated Conditions ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Abstract The role of chronic inflammation in the pathogenesis of type 2 diabetes mellitus and associated complications is now well established. Therapeutic interventions counteracting metabolic inflammation improve insulin secretion and action and glucose control and may prevent long-term complications. Thus, a number of anti-inflammatory drugs approved for the treatment of other inflammatory conditions are evaluated in patients with metabolic syndrome. Most advanced are clinical studies with IL-1 antagonists showing improved β-cell function and glycemia and prevention of cardiovascular diseases and heart failure. However, alternative anti-inflammatory treatments, alone or in combinations, may turn out to be more effective, depending on genetic predispositions, duration, and manifestation of the disease. Thus, there is a great need for comprehensive and well-designed clinical studies to implement anti-inflammatory drugs in the treatment of patients with metabolic syndrome and its associated conditions.

scholarly journals SUN-LB101 NRF2 Represses Obesity-Associated Adipose Tissue Inflammation in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yoko Yagishita ◽  
Akira Uruno ◽  
Thomas W Kensler ◽  
Masayuki Yamamoto
Keyword(s):  
Adipose Tissue ◽  
Myeloid Cell ◽  
Potential Effect ◽  
Luciferase Reporter ◽  
Standard Diet ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Pathway Activation ◽  
Nrf2 Signaling Pathway ◽  
Anti Inflammatory

Abstract Obesity is associated with type 2 diabetes, cardiovascular disease and increased incidence of cancer. Chronic inflammation, mainly emanating from adipose tissue, has been proposed to be one of the links between obesity and these pathologies. Thus, identification of new targets against obesity and especially obesity-induced inflammation is needed urgently. Transcription factor Nrf2 (NF-E2-related-factor-2) plays a central role in cytoprotective responses to oxidative and electrophilic stresses and also exerts anti-inflammatory effects in rodent models of inflammation. However, whether activation of Nrf2 signaling pathway influences obesity-associated inflammation in adipose tissue is not well established. To this end, we generated mice with systemic activation of the Nrf2 pathway (Keap1flox/–), as well as mouse models with tissue-specific Nrf2 pathway activation: adipocyte-specific (Fabp4Cre::Keap1flox/ flox) and myeloid cell-specific (LymCre::Keap1flox/ flox). These mice were exposed to a high-fat diet (HFD) 60% kcal fat regimen for 6-weeks or crossed into the db/db background. Keap1flox/– mice showed a dramatic decrease of the numbers of F4/80-positive macrophages in white adipose tissue (WAT). Interestingly, both Fabp4Cre::Keap1flox/ flox and LymCre::Keap1flox/ flox mice showed suppression of F4/80-positive macrophages in WAT as well, suggesting enhanced Nrf2 signaling in either adipocytes or myeloid cells might contribute to anti-inflammatory effects in WAT under the stress of HFD. Transcript levels of inflammatory markers, especially macrophage F4/80 and Cd68 and the chemokine Ccl2 were decreased in the WAT from Keap1flox/– mice on the standard diet and also in the WAT of Keap1flox/– mice in the db/db background. Pharmacological activation of the Nrf2 pathway by treatment with CDDO-Im also suppressed Ccl2 expression in WAT of HFD fed mice and db/db mice. As CCL2 is a key mediator of macrophage accumulation in adipose tissue, we further studied the potential effect of Nrf2 on the transcriptional regulation of Ccl2 using 3T3-L1 preadipocyte and RAW264.7 macrophage cell lines. Treatment of both lines with the small molecule inducer of Nrf2, diethyl maleate significantly suppressed LPS-induced expression of Ccl2. Analysis using luciferase reporter assay revealed that a Nrf2 binding site in the Ccl2 5’ flanking region from -235 to +85 contributed to gene silencing of Ccl2 by activation of Nrf2. Our findings suggest that the druggable Nrf2 pathway may be an effective target to combat obesity-associated inflammation in adipose tissue and its’ concomitant metabolic disorders. Supported by AMED BINDS JP19am0101001 (MY), 19H05649 (MY), 16KK0195 (AU), NIH R35 CA197222 (TWK), JSPS OT 290125 (YY).

Aspirin Blocks Orthodontic Relapse via Inhibition of CD4+ T Lymphocytes

2017 ◽  
Vol 96 (5) ◽  
pp. 586-594 ◽  
Author(s):  
Y. Liu ◽  
T. Zhang ◽  
C. Zhang ◽  
S.S. Jin ◽  
R.L. Yang ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Relapse Rate ◽  
Immune Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th1 Cells ◽  
Tnf Α ◽  
Inflammatory Drugs ◽  
Ifn Γ ◽  
Anti Inflammatory

Immunologic response plays an important role in orthodontic tooth movement (OTM) and relapse. Nonsteroidal anti-inflammatory drugs, such as aspirin, affect immune cells and clinical orthodontic treatment. However, the mechanisms by which nonsteroidal anti-inflammatory drugs regulate immune cells to affect orthodontic relapse are unclear. In this study, male Sprague-Dawley rats were grouped as relapse and relapse + aspirin for 10 d after 14 d of OTM. Silicone impressions of the rats’ maxillary dentitions were obtained to record the distance of OTM at the indicated time point. CD4+ T lymphocytes in spleen were examined by flow cytometry. Serum levels of type 1 T-helper (Th1) cell–associated cytokines tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) were determined through enzyme-linked immunosorbent assay. The effects of aspirin on CD4+ T and Th1 cells were also analyzed in vitro. Aspirin treatment significantly reduced the relapse rate. More interestingly, injection of CD25 neutralizing antibody basiliximab or TNF-α inhibitor etanercept can significantly reduce the relapse rate as well. Correspondingly, aspirin treatment significantly accelerated the decrease of orthodontic force–induced secretion of TNF-α and IFN-γ in serum and the expression of TNF-α and IFN-γ in periodontal ligament during relapse. Furthermore, aspirin treatment in vitro significantly repressed the differentiation of CD4+ T and Th1 cells. Overall, results indicated that aspirin treatment can block orthodontic relapse by regulating Th1 cells.

Non-steroidal anti-inflammatory drugs for the treatment of cancer cachexia: A systematic review

2012 ◽  
Vol 27 (4) ◽  
pp. 295-303 ◽  
Author(s):  
J Reid ◽  
CM Hughes ◽  
LJ Murray ◽  
C Parsons ◽  
MM Cantwell
Keyword(s):  
Systematic Review ◽  
Cancer Cachexia ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Sexually dimorphic responses to fat loss after caloric restriction or surgical lipectomy

2007 ◽  
Vol 293 (1) ◽  
pp. E316-E326 ◽  
Author(s):  
Haifei Shi ◽  
April D. Strader ◽  
Stephen C. Woods ◽  
Randy J. Seeley
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Visceral Fat ◽  
Subcutaneous Fat ◽  
Distribution Patterns ◽  
Male And Female ◽  
Fat Loss ◽  
Female Mice

White adipose tissue is the principal site for lipid accumulation. Males and females maintain distinctive white adipose tissue distribution patterns. Specifically, males tend to accumulate relatively more visceral fat, whereas females accumulate relatively more subcutaneous fat. The phenomenon of maintaining typical sex-specific fat distributions suggests sex-specific mechanisms that regulate energy balance and adiposity. We used two distinct approaches to reduce fat mass, caloric restriction (CR), and surgical fat removal (termed lipectomy) and assessed parameters involved in the regulation of energy balance. We found that male and female mice responded differentially to CR- and to lipectomy-induced fat loss. Females decreased energy expenditure during CR or after lipectomy. In contrast, males responded by eating more food during food return after CR or after lipectomy. Female CR mice conserved subcutaneous fat, whereas male CR mice lost adiposity equally in the subcutaneous and visceral depots. In addition, female mice had a reduced capability to restore visceral fat after fat loss. After CR, plasma leptin levels decreased in male but not in female mice. The failure to increase food intake after returning to ad libitum intake in females could be due to the relatively stable levels of leptin. In summary, we have found sexual dimorphisms in the response to fat loss that point to important underlying differences in the strategies by which male and female mice regulate body weight.

scholarly journals Justification of the use of non-steroidal anti-inflammatory drugs injectable forms

2020 ◽  
Vol 4 (8) ◽  
pp. 518-524
Author(s):  
A.E. Karateev ◽  
Keyword(s):  
Clinical Studies ◽  
Adverse Reactions ◽  
Ease Of Use ◽  
Open Label ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Fast Acting ◽  
Active Substances ◽  
Russian Medical ◽  
Injectable Form

Treatment of acute intense pain requires the use of strong fast-acting analgesics, such as parenteral forms of non-steroidal anti-inflammatory drugs (NSAIDs). Intravenous and intramuscular (i.m.) NSAIDs administration increases the bioavailability of active substances, allows for analgesic therapy in the presence of restrictions for oral administration, and is predominant in the rate of analgesic action onset versus the latter. When choosing NSAIDs for i.m. administration, the risk of topical post-injection and systemic adverse reactions should be considered. Original meloxicam for i.m. injection is characterized by a favorable risk-benefit ratio and ease of use. In clinical studies, there was no significant increase in creatinine phosphokinase levels, reflecting damage to muscle fibers, after a series of injections of meloxicam i.m. versus other NSAIDs, such as diclofenac and piroxicam. During the search in PubMed, Medline, Google, there was no description of serious topical complications after i.m. administration of meloxicam. In recent years, several large open-label studies have been conducted in Russia demonstrating the efficacy and safety of meloxicam injectable form in acute/subacute non-specific back pain and injuries. The review provides a brief description of the main clinical studies concerning the original meloxicam for i.m. injection.KEYWORDS: NSAIDs, meloxicam, intramuscularly, efficacy, safety.FOR CITATION: Karateev A.E. Justification of the use of non-steroidal anti-inflammatory drugs injectable forms. Russian Medical Inquiry. 2020;4(8):518–524. DOI: 10.32364/2587-6821-2020-4-8-518-524.

Abstract 590: Loss of Myeloid Cell Prostaglandin E Receptor 4 Does Not Alter Diabetes-Accelerated Atherosclerosis in a Murine Model of Type 1 Diabetes

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Sara N Vallerie ◽  
Farah Kramer ◽  
Jenny E Kanter ◽  
Shelley Barnhart ◽  
Richard M Breyer ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Mouse Model ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Prostaglandin E ◽  
Lesion Area ◽  
Accelerated Atherosclerosis ◽  
Anti Inflammatory

Diabetes is associated with an increased risk of cardiovascular disease, largely due to increased atherosclerosis. Our studies have suggested myeloid cell prostaglandin E 2 (PGE 2 ) production as a possible mediator of diabetes-accelerated atherosclerosis in a virally-induced mouse model of type 1 diabetes. Prostaglandin E Receptor 4 (EP4; Ptger4 ) is a major PGE 2 receptor in myeloid cells. We hypothesized that generation of a mouse model of myeloid cell-targeted EP4-deficiency would allow us to test the role of myeloid EP4 in diabetes-accelerated atherosclerosis. Thus, we generated a Ptger4 flox/flox LysM-Cre tg/tg mouse model. Peritoneal macrophages isolated from these myeloid cell EP4-deficient (EP4 M-/- ) mice expressed <90% Ptger4 mRNA compared to LysM-Cre tg/tg controls (n=10; p<0.0001). To analyze the role of myeloid cell EP4 in diabetes-accelerated atherosclerosis, we transplanted bone marrow from EP4 M-/- mice and littermate controls into lethally irradiated Ldlr -/- RIP-LCMV mice (the model of type 1 diabetes) and, after 7 weeks of recovery, induced diabetes by viral infection and fed the mice a low-fat semi-purified diet for an additional 12 weeks. Diabetic EP4 M-/- mice had similar blood glucose (568 ± 15 vs. 569 ± 15 mg/dl), blood cholesterol (531 ± 29 vs. 510 ± 37 mg/dl), and plasma triglycerides (249 ± 49 vs. 247 ± 44 mg/dl) as diabetic controls (n=15 all groups; mean ± SEM). At the endpoint, aortas were harvested for lesion area quantification. Diabetic EP4 M-/- and diabetic wild type mice had similar lesion area (1.9% ± 0.2 vs. 1.7% ± 0.2), which were both increased (p < 0.01; n=9-15) as compared to their non-diabetic controls. Additionally, we analyzed the role of EP4 in inflammatory activation of myeloid cells ex vivo. EP4-deficiency had no significant effect on basal or lipopolysaccharide (LPS)-induced inflammatory gene expression in the absence of PGE 2 . Pretreatment of the cells with PGE 2 (10 nM) followed by LPS stimulation resulted in a significant reduction of Tnfa and Il6 mRNA compared to LPS alone, and this anti-inflammatory effect of PGE 2 was completely blocked in EP4-deficient cells. These results suggest that myeloid cell EP4 mediates anti-inflammatory actions of PGE 2 but that it is not involved in diabetes-accelerated atherosclerosis.

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