scholarly journals L-Carnitine Ameliorates the Muscle Wasting of Cancer Cachexia through the AKT/FOXO3a/MaFbx Axis

2021 ◽  
Author(s):  
Changpeng Wu ◽  
Mingxing Zhu ◽  
Zongliang Lu ◽  
Yaowen Zhang ◽  
Long Li ◽  
...  
Keyword(s):  
Cancer Cachexia ◽  
Muscle Protein ◽  
Interleukin 1 ◽  
Serum Levels ◽  
C2c12 Cells ◽  
Cross Sectional ◽  
Protein Ubiquitination ◽  
Tnf Α

Abstract Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. We found that L-carnitine increased the gastrocnemius muscle (GM) weight in the CT-26-bearing cachexia mouse model and the cross-sectional fiber area (CFA) of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of muscle RING-type E3 ubiquitin ligase 1 (MuRF1), muscle atrophy F-box protein (MaFbx) and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro, indicating that L-carnitine inhibits muscle protein ubiquitination in models of cachexia. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of interleukin-1 (IL-1) and interleukin-6 (IL-6), factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia. Taken together, these results revealed a novel mechanism of action by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.

scholarly journals L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Changpeng Wu ◽  
Mingxing Zhu ◽  
Zongliang Lu ◽  
Yaowen Zhang ◽  
Long Li ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cancer Cachexia ◽  
Cell Model ◽  
Horse Serum ◽  
Serum Levels ◽  
C2c12 Cells ◽  
In Vivo Model ◽  
Cross Sectional ◽  
Tnf Α

Abstract Background Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. Methods C2C12 cells were differentiated into myotubes by growing them in DMEM for 24 h (hrs) and then changing the media to DMEM supplemented with 2% horse serum. Differentiated myotubes were treated for 2 h with TNF-α to establish a muscle atrophy cell model. After treated with L-carnitine, protein expression of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K was determined by Western blotting. Then siRNA-Akt was used to determine that L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx. In vivo, the cancer cachexia model was established by subcutaneously transplanting CT26 cells into the left flanks of the BALB/c nude mice. After treated with L-carnitine, serum levels of IL-1, IL-6 and TNF-α, and the skeletal muscle content of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K were measured. Results L-carnitine increased the gastrocnemius muscle (GM) weight in the CT26-bearing cachexia mouse model and the cross-sectional fiber area of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of MuRF1, MaFbx and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K and p-p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of IL-1 and IL-6, factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia, in the in vivo model. Conclusion These results revealed a novel mechanism by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.

scholarly journals Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2529
Author(s):  
Haeyeop Kim ◽  
Woo Seok Yang ◽  
Khin Myo Htwe ◽  
Mi-Nam Lee ◽  
Young-Dong Kim ◽  
...  
Keyword(s):  
Ethanol Extract ◽  
Serum Levels ◽  
Hepatoprotective Activity ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Related Proteins ◽  
Pro Inflammatory Cytokines ◽  
Inflammatory Effect

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

scholarly journals Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

1992 ◽  
Vol 1 (5) ◽  
pp. 347-353 ◽  
Author(s):  
Andrew C. Issekutz ◽  
Nancy Lopes ◽  
Thomas B. Issekutz
Keyword(s):  
Monoclonal Antibody ◽  
Umbilical Vein ◽  
Interleukin 1 ◽  
E Coli ◽  
Tnf Α ◽  
Lps Activation ◽  
Necrosis Factor

The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF.

scholarly journals Dangshen Erling Decoction Ameliorates Myocardial Hypertrophy via Inhibiting Myocardial Inflammation

2022 ◽  
Vol 12 ◽  
Author(s):  
Yigang Zhong ◽  
Liuying Chen ◽  
Miaofu Li ◽  
Lian Chen ◽  
Yufeng Qian ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cardiac Tissue ◽  
Myocardial Hypertrophy ◽  
Cell Model ◽  
H9c2 Cell ◽  
Myocardial Inflammation ◽  
Cross Sectional ◽  
Tnf Α

Myocardial hypertrophy plays an essential role in the structural remodeling of the heart and the progression to heart failure (HF). There is an urgent need to understand the mechanisms underlying cardiac hypertrophy and to develop treatments for early intervention. Dangshen Erling decoction (DSELD) is a clinically used formula in Chinese medicine for treating coronary heart disease in patients with HF. However, the mechanism by which DSELD produces its cardioprotective effects remains largely unknown. This study explored the effects of DSELD on myocardial hypotrophy both in vitro and in vivo. In vitro studies indicated that DSELD significantly (p &lt; 0.05) reduced the cross-sectional area of the myocardium and reduced elevated lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 levels in the induced H9C2 cell model to study inflammation. In vivo experiments revealed that DSELD restores cardiac function and significantly reduces myocardial fibrosis in isoproterenol (ISO)-induced HF mouse model (p &lt; 0.05). In addition, DSELD downregulated the expression of several inflammatory cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), IL-1α, IL-1β, IL-3, IL-5, IL-7, IL-12, IL-13, and TNF-α in HF (p &lt; 0.05). Further analysis of the cardiac tissue demonstrated that DSELD produces its anti-inflammatory effects via the Toll-like receptor (TLR)4 signaling pathway. The expression of TLR4 downstream proteins such as matrix metalloproteinase-9 (MMP9) and myeloid differentiation factor-88 (MyD88) was among the regulated targets. In conclusion, these observations suggest that DSELD exerts antihypertrophic effects by alleviating the inflammatory injury via the TLR4 signaling pathway in HF and thus holds promising therapeutic potentials.

scholarly journals Fermented Antler Improves Endurance during Exercise Performance by Increasing Mitochondrial Biogenesis and Muscle Strength in Mice

2021 ◽  
Vol 11 (12) ◽  
pp. 5386
Author(s):  
Seongeun Jung ◽  
Sung-Hwan Kim ◽  
Woonhee Jeung ◽  
Jehyun Ra ◽  
Keon Heo ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Mitochondrial Biogenesis ◽  
Exercise Performance ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Central Research Institute ◽  
C2c12 Cells ◽  
Central Research

In this study, we investigated whether antler fermented with lactic acid bacteria (LAB) increases mitochondrial biogenesis and muscle strength in vitro and in vivo. LAB from a strain library were grown in antler extract agar at the Yakult Central Research Institute of Korea. Isolated LAB, named Lactobacillus curvatus HY7602, were used to ferment antlers. Analysis of the effects of fermented antler (FA) revealed that it enhanced the insulin-like growth factor 1 (IGF-I), signaling pathway and mitochondrial metabolic activity in mouse skeletal myotube (C2C12) cells. Next, we evaluated the effect of non-fermented antler (NFA) and FA on exercise performance in C57BL/6J mice. The results showed that HY7602-FA increased treadmill exercise capacity and forced swimming endurance. Furthermore, blood markers associated with muscle fatigue, endurance, and energy supply (e.g., alanine aminotransferase, lactate dehydrogenase, creatinine, creatine kinase, and lactate) in the FA-intake group were lower than in the NFA-intake group. In addition, the expression index of genes associated with muscle protein synthesis, and with mitochondrial energy production and supply, in muscle tissue was remarkably higher in the FA group than in the control and NFA groups. Taken together, these results suggested that HY7602-FA may be an effective functional food and health supplement.

scholarly journals Interleukin-5 modulates interleukin-8 secretion in eosinophilic inflammation

1998 ◽  
Vol 7 (1) ◽  
pp. 41-47 ◽  
Author(s):  
L. H. Faccioli ◽  
A. I. Medeiros ◽  
A. Malheiro ◽  
R. C. L. R. Pietro ◽  
A. Januário ◽  
...  
Keyword(s):  
Serum Levels ◽  
Lavage Fluid ◽  
Eosinophilic Inflammation ◽  
Blood Eosinophilia ◽  
Interleukin 5 ◽  
Parallel Increase ◽  
Tnf Α ◽  
First Time

Serum and BALF (bronchoalveolar lavage fluid) IL-8 levels and serum levels were investigated inTox ocara canisinfected guinea-pigs and the role of IL-5 as a modulator of cytokine secretion was studied. Serum levels increased early in infected animals, exceeding control levels 4 h after infection, peaked between days 6 and 18, and continued to exceed control levels after 48 days of infection. Serum and BALF IL-8 levels showed the same profile as blood eosinophilia, increasing 6 days post-infection and peaking between days 18 and 24. Treatment of infected animals with anti-IL-5 Ab suppressed eosinophilia with a parallel increase in blood IL-8 levels, whereas no change was found in levels. To support ourin vivoobservation we carried out experimentsin vitrousing guinea-pig LPS-stimulated adherent peritoneal cells which release large amounts of IL-8 into the supernatants. When rIL-5 was added to LPS-stimulated cells, 65% inhibition of IL-8 release into the supernatants was observed. Pre-incubation of cells with anti-IL-5 Ab prevented the inhibition of IL-8 release into the supernatants induced by rIL-5. Our results demonstrate for the first time that TNF- α and IL-8 are released concomitant with or after IL-5 in the eosinophilic inflammation induced byT. canis. Moreover, in addition to showing that IL-5 is fundamental for the induction of blood eosinophilia, the present results suggest that this cytokine may play a new biological role by acting as modulator of IL-8 secretion.

scholarly journals Lactobacillus plantarum B7 attenuates Salmonella typhimurium infection in mice: preclinical study in vitro and in vivo

2019 ◽  
Vol 12 (5) ◽  
pp. 211-218 ◽  
Author(s):  
Siwaporn Wongsen ◽  
Duangporn Werawatganon ◽  
Somying Tumwasorn
Keyword(s):  
Salmonella Typhimurium ◽  
Lactobacillus Plantarum ◽  
Serum Levels ◽  
Preclinical Study ◽  
Control Group ◽  
Protective Effects ◽  
Tnf Α ◽  
Factor Α

Abstract Background Salmonella typhimurium is a cause of gastroenteritis including diarrhea. Lactobacillus plantarum is a probiotic widely used to prevent and treat diarrhea. Objectives To determine the protective effects of L. plantarum B7 on diarrhea in mice induced by S. typhimurium. Methods Inhibition of S. typhimurium growth by L. plantarum B7 was determined using an agar spot method. Mice were divided into 3 groups (n = 8 each): a control group, an S group administered 3 × 109 CFU/mL S. typhimurium, and an S + LP group administered 1 × 109 CFU/mL L. plantarum B7 and 3 × 109 CFU/mL S. typhimurium daily for 3 days. Counts of S. typhimurium and percentage of fecal moisture content (%FMC) were determined from stool samples. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CXCL1 were determined. Results L. plantarum B7 produced a clear zone on S. typhimurium. There were significantly less S. typhimurium in the feces from mice in the S+LP group than in the S group. Serum levels of TNF-α, IL-6, and CXCL1 in mice from the S group were significantly higher than levels in the S+LP and control groups. Feces from mice in the S group were soft and loose, whereas in the S+LP group they were hard and rod shaped. The %FMC in the S+LP group was significantly less than in the S group. Conclusions L. plantarum B7 can inhibit growth of S. typhimurium, decrease levels of proinflammatory cytokines, and attenuate symptoms of diarrhea induced in mice by S. typhimurium.

scholarly journals Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0252135
Author(s):  
Hyun-Jun Kim ◽  
Ji-Hyung Lee ◽  
Seon-Wook Kim ◽  
Sang-Hoon Lee ◽  
Da-Woon Jung ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Cancer Metastasis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Atrophy ◽  
Differentiation Markers ◽  
Cross Sectional

Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.

scholarly journals A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

2019 ◽  
Vol 20 (24) ◽  
pp. 6302
Author(s):  
Jae Hyun Han ◽  
Ok-Hee Kim ◽  
Sang Chul Lee ◽  
Kee-Hwan Kim ◽  
Jung Hyun Park ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Serum Levels ◽  
Genetically Engineered ◽  
Control Group ◽  
Adipose Derived Stem Cells ◽  
Tnf Α ◽  
Factor Α

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.

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