Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia.
Carnosol and its analogues attenuate muscle atrophy and fat lipolysis induced by cancer cachexia.
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鼠尾草酚及其类似物可减轻癌症恶病质引起的肌肉萎缩和脂肪分解
DOI：
10.1002/jcsm.12710
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Lu S;Li Y;Shen Q;Zhang W;Gu X;Ma M;Li Y;Zhang L;Liu X;Zhang X
癌症恶病质是一种多因素的衰弱综合征，直接占癌症死亡的20%以上，而没有有效的治疗方法来治疗癌症恶病质。鼠尾草酚（CS）是存在于唇形科物种中的生物活性二萜化合物，它已被证明具有抗氧化、抗炎和抗癌特性。但其对癌症恶病质的影响及其可能的机制仍是一个谜。使用C2 C12肌管萎缩和3 T3-L1成熟脂肪细胞脂解的体外细胞模型来检查CS及其合成类似物的活性。采用C26荷瘤BALB/c小鼠作为动物模型，检查其对癌症恶病质的体内治疗作用。采用蛋白质印迹法检测体内、体外实验中相关信号蛋白的表达水平，探讨其可能的作用机制。鼠尾草酚及其类似物[二甲基鼠尾草酚（DCS）和二甲基鼠尾草酚-D 6（DCSD）]在体外减轻C2 C12肌管的肌管萎缩和3 T3-L1脂肪细胞的脂解。有趣的是，CS及其类似物对肿瘤坏死因子-α（TNF-α）诱导的C2 C12成肌细胞肌萎缩的抑制作用（CS，P <0.001; DCS，P < 0.001; DCSD，P < 0.001）强于对IL-6诱导的肌萎缩的抑制作用（CS，P < 0.05; DCS，P = 0.08; DCSD，P < 0.05）。在C26荷瘤小鼠模型中，给予CS或其类似物DCSD可显著防止体重减轻，而不影响肿瘤大小。实验结束时，CS组和DCSD组小鼠体重分别比C26模型组增加11.09%（P < 0.01）和11.38%（P < 0.01）。CS和DCSD也能使C26模型小鼠附睾脂肪组织重量减轻，分别增加176.6%（P < 0.01）和48.2%（P < 0.05）。CS和DCSD治疗部分保留了腓肠肌肌纤维横截面积。CS治疗降低了C26荷瘤小鼠中TNF-α的血清水平（-95.02%，P < 0.01），但没有降低IL-6的血清水平。抑制NF-κB和激活Akt信号通路参与CS及其类似物在体内外对肌肉萎缩的改善作用。CS及其类似物还通过抑制体外和体内NF-κB和AMPK信号通路减轻脂肪组织损失。CS及其类似物主要通过抑制TNF-α/NF-κB通路，减少肌肉和脂肪组织的损失，发挥抗软骨病作用。CS及其类似物有望成为治疗癌症恶病质的候选药物。
Cancer cachexia is a multifactorial debilitating syndrome that directly accounts for more than 20% of cancer deaths while there is no effective therapeutic approach for treatment of cancer cachexia. Carnosol (CS) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti‐inflammatory, and anticancer properties. But its effects on cancer cachexia and the possible mechanism remain a mystery. The in vitro cell models of C2C12 myotube atrophy and 3T3‐L1 mature adipocyte lipolysis were used to check the activities of CS and its synthesized analogues. C26 tumour‐bearing BALB/c mice were applied as the animal model to examine their therapeutic effects on cancer cachexia in vivo. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. Carnosol and its analogues [dimethyl‐carnosol (DCS) and dimethyl‐carnosol‐D6 (DCSD)] alleviated myotube atrophy of C2C12 myotubes and lipolysis of 3T3‐L1 adipocytes in vitro. Interestingly, CS and its analogues exhibited stronger inhibitive effects on muscle atrophy induced by tumour necrosis factor‐α (TNF‐α) (CS, P < 0.001; DCS, P < 0.001; DCSD, P < 0.001) in C2C12 myoblasts than on muscle atrophy induced by IL‐6 (CS, P < 0.05; DCS, P = 0.08; DCSD, P < 0.05). In a C26 tumour‐bearing mice model, administration of CS or its analogue DCSD significantly prevented body weight loss without affecting tumour size. At the end of the experiment, the body weight of mice treated with CS and DCSD was significantly increased by 11.09% (P < 0.01) and 11.38% (P < 0.01) compared with that of the C26 model group. CS and DCSD also improved the weight loss of epididymal adipose tissue in C26 model mice by 176.6% (P < 0.01) and 48.2% (P < 0.05) increase, respectively. CS and DCSD treatment partly preserved gastrocnemius myofibres cross‐sectional area. CS treatment decreased the serum level of TNF‐α (−95.02%, P < 0.01) but not IL‐6 in C26 tumour‐bearing mice. Inhibition on NF‐κB and activation of Akt signalling pathway were involved in the ameliorating effects of CS and its analogues on muscle wasting both in vitro and in vivo. CS and its analogues also alleviated adipose tissue loss by inhibiting NF‐κB and AMPK signalling pathways both in vitro and in vivo. CS and its analogues exhibited anticachexia effects mainly by inhibiting TNF‐α/NF‐κB pathway and decreasing muscle and adipose tissue loss. CS and its analogues might be promising drug candidates for the treatment of cancer cachexia.
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影响因子：
8.2
作者：
Chen, Chien-chung;Chen, Hui-ling;Wung, Being-sun
通讯作者：
Wung, Being-sun
鼠尾草酚调节实验性自身免疫性脑脊髓炎中 Th17 细胞分化和小胶质细胞开关
影响因子：
7.3
作者：
Li X;Zhao L;Han JJ;Zhang F;Liu S;Zhu L;Wang ZZ;Zhang GX;Zhang Y
通讯作者：
Zhang Y
DOI：
10.1002/jcsm.12354
发表时间：
2018-10
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Brown JL;Lee DE;Rosa-Caldwell ME;Brown LA;Perry RA;Haynie WS;Huseman K;Sataranatarajan K;Van Remmen H;Washington TA;Wiggs MP;Greene NP
通讯作者：
Greene NP
影响因子：
9.7
作者：
Johnson, Jeremy J.
通讯作者：
Johnson, Jeremy J.
影响因子：
5.3
作者：
Kim, Sun-Joong;Tang, Tianyi;Sul, Hei Sook
通讯作者：
Sul, Hei Sook