Shenqi Fuzheng injection alleviates chemotherapy-induced cachexia by restoring glucocorticoid signaling in hypothalamus

Chemotherapy-induced cachexia(CIC)is a debilitating condition characterized by weight loss,muscle atrophy,and anorexia[1].While peripheral mechanisms of cachexia have been extensively studied,the involvement of the central nervous system(CNS)in CIC is often overlooked.Chemotherapeutic drugs cause stress responses and inflammation,which may impact the hypothalamus and disrupt systemic energy and neuroendocrine functions.Understanding hypothalamic roles in regulating these processes can provide insights into CIC's mechanisms and aid in developing novel therapies.

Corynoxine B targets at HMGB1/2 to enhance autophagy forα-synuclein clearance in fly and rodent models of Parkinson's disease

Parkinson's disease(PD)is the most common neurodegenerative movement disease.It is featured by abnormal alphα-synuclein(α-syn)aggregation in dopaminergic neurons in the substantia nigra.Macroautophagy(autophagy)is an evolutionarily conserved cellular process for degradation of cellular contents,including protein aggregates,to maintain cellular homeostasis.Corynoxine B(Cory B),a natural alkaloid isolated from Uncaria rhynchophylla(Miq.)Jacks.,has been reported to promote the clearance ofα-syn in cell models by inducing autophagy.However,the molecular mechanism by which Cory B induces autophagy is not known,and theα-syn-lowering activity of Cory B has not been verified in animal models.Here,we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2.Depletion of HMGB1/2 impaired Cory B-induced autophagy.We showed for the first time that,similar to HMGB1,HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinaseⅢactivity both under basal and stimulated conditions.By applying cellular thermal shift assay,surface plasmon resonance,and molecular docking,we confirmed that Cory B directly binds to HMGB1/2 near the C106 site.Furthermore,in vivo studies with a wild-typeα-syn transgenic drosophila model of PD and an A53Tα-syn transgenic mouse model of PD,Cory B enhanced autophagy,promotedα-syn clearance and improved behavioral abnormalities.Taken together,the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinaseⅢactivity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.