| Background:With the accelerated pace of life in modern society and rising work pressures,fatigue is becoming more and more serious.Compared with drug treatment,natural products have lower side effects and have received worldwide attention.The occurrence of cachexia seriously reduces the quality of life and survival of cancer patients.Currently,there are no drugs approved by FDA to treat cancer cachexia.Cordyceps has anti-fatigue,anti-tumor and anti-oxidation functions.SBCC is a new substitute for Cordyceps gunnii(Berk.)Berk,the valuable traditional Chinese medicine.It is unclear whether it has anti-fatigue and anti-cancer cachexia activities and how it works.So,further exploration is needed.Alanlactone is a natural decane sesquiterpene lactone extracted from plants such as scented wood.It has been proven to be a stat3 inhibitor with anti-tumor,anti-inflammatory and other effects.The stat3 and NF-κB signaling pathways promote the progression of cancer cachexia.At present,the effect of AL on cancer cachexia and its molecular mechanism remain unclear.Goal: Our studies focused on the anti-fatigue activity of SBCC and the mitigation effect of SBCC and AL on cancer cachexia.Also,their possible pharmacological mechanisms are explored.Methods:(1)The anti-fatigue activity of SBCC is evaluated by mouse swimming test,running test and forelimb grip test.The safety of SBCC is assessed by food intake,body weight and organ index of mice.(2)The C26 model is used to evaluate the efficacy of SBCC and AL in relieving cancer cachexia.(3)Mouse myofiber area and fat cell size are analysed by tissue H&E staining.(4)Cell viability is measured by CCK-8and MTT method.(5)The diameter of C2C12 myotubes is counted by immunofluorescence staining or cell H&E staining.(6)The level of inflammatory cytokines on serum in mice are detected by ELISA kit.(7)The glycerol and triglyceride detection kits are used to detect the glycerol and triglyceride content respectively,and the oil red O staining is used to observe the size of lipid droplet.(8)Western Blot is used to detect signal pathway protein levels in cells.Results:(1)SBCC has significant anti-fatigue activity in mice,and enhances muscle strength and exercise tolerance possibly by activating AKT-m TOR and AMPK/PGC-1αpathways in muscle tissue.(2)SBCC partially ameliorates the cancer cachexia symptoms in C26 tumor-bearing mice,which can alleviate fat degradation and excessive energy consumption possibly by inhibiting AMPK and P38 MAPK pathways.Although SBCC has no effect on muscle weight loss in cachexia mice,it may activate AKT-m TOR and PGC-1ɑ pathways in muscle tissue to increase the myofiber area and maintain energy metabolism balance in muscle cells.(3)AL relieves C2C12 myotube atrophy induced by C26 medium,IL-6 and TNF-αpossibly by targeting p-stat3 and p-P65.(4)AL attenuates 3T3-L1 adipocyte lipolysis induced by C26 medium possibly by inhibiting signaling pathways such as AMPK.(5)In vivo,AL has a certain effect on relieving cancer cachexia,and has a strong effect on muscle tissue by the same pharmacological mechanism in vitro and a weak effect on adipose tissue.Conclusion: SBCC exerts strong anti-fatigue activity possibly by activating AKT-m TOR and AMPK/PGC-1α pathways,and alleviates the degradation of adipose tissue in cancer cachexia mice possibly by inhibiting P38 MAPK and AMPK pathways.AL exhabits the efficacy in relieving cancer cachexia possibly by targeting stat3 and NF-κB signaling pathways.As a new type of Acremonium acremonium mycelium powder,SBCC is the first time for research on anti-fatigue and cancer cachexia treatment,and it is of great value to promote it as a clinical adjuvant therapy.AL has never been reported before for the study on cancer cachexia,and is proved to be a potent anti-cachexia drug with great potential in this study. |
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