Sinapic Acid

Androgenetic alopecia (AGA), commonly known as male pattern hair loss, with limited effective treatments. Sinapic acid (S) and glabridin (G) are two ingredients in Zhimo herbal extract (ZMHE), identified with UPLC-Q/TOF-MS. We comparatively investigated the effects and mechanisms of S and G, individually and synergistically (S&G), on dihydrotestosterone (DHT)-induced AGA model mice and in dermal papilla cells (DPCs). In our work, S&G showed superior effect on DHT induced oxidative stress in DPCs and on hair growth in AGA mice, compared to application of these two compounds individually. Additionally, S&G significantly reversed the DHT induced abnormal high level of ferrous ions and 4-HNE, overexpressed ACSL4 and FTH1, and morphological variation of mitochondria in mice and in DPCs, as well as lipid peroxidation in DPCs assays. These results suggested that S&G has beneficial effect on DHT induced ferroptosis. To uncover the mechanism, we found that S&G could significantly improve the content of β-Catenin in DHT treated DPCs by inhibiting the phosphorylation induced ubiquitin-dependent degradation. The result of molecular docking and cellular thermal shift assay tests indicated that S&G enhanced the stability of β-Catenin by binding at Ser191 and Glu163/Gln165/Thr201. And the translocated β-Catenin/Tcf-4 triggered expression of GPX4 in DHT treated DPCs and murine skins, which ameliorated the DHT induced peroxidation and reversed the harmful effect of DHT on hair growth. This study suggested that S&G could be applied for AGA treatment, which could attenuate DHT induced ferroptosis by improving the ubiquitin-dependent degradation of β-Catenin.

The current study aimed to evaluate the neuroprotective potential of sinapic acid (SA) administration in alleviating Parkinson's disease (PD) features, focusing on its effects in amelioration of endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) signaling, oxidative stress, and alpha-synucleinopathy in chronic ROT-induced PD rats. PD was induced using 11 ROT injections (1.5 mg/kg/48h; s.c.). One day following the fifth ROT dose, rats started treatment with SA (10 mg/kg), SA (20 mg/kg), SA (40 mg/kg), or L-dopa/carbidopa (100/10 mg/kg) daily via oral gavage for 21 consecutive days, followed by assessment of neurobehavioral parameters and subsequent histopathological and neurochemical analyses. Treatment with a high dose of SA amended ROT-induced locomotor deficits with significantly improved open-field ambulation, grooming, and rearing behavior, as well as increased cylinder wall forelimb placements, and prolonged rotarod fall-off latency. Additionally, SA treatment protected nigral dopaminergic neurons from ROT-induced neurodegeneration and dose-dependently preserved nigral tyrosine hydroxylase (TH) immunoexpression. Furthermore, SA treated rats showed markedly improved striatal dopamine (DA) content and diminished striatal alpha synuclein (α-Syn) overexpression. Additionally, SA treatment provided antioxidant properties as evidenced by improved striatal GSH/SOD/Catalase and suppressed MDA levels. Notably, SA administration resulted in significant, dose-dependent attenuation of ER stress sensors PERK, eIF2α, CHOP/GADD135, IRE1α, and ATF6 signaling. These findings provide novel in vivo insights into SA's beneficial neuroprotective properties in amelioration of ROT-induced ER stress via modulation of all three UPR branches, particularly the PERK/eIF2α/CHOP signaling axis, and establishes SA as a promising neurotherapeutic candidate for possible management of PD.