sirolimus and 4-phenylbutylamine

Overexposure to manganese (Mn) has been known to induce alpha-synuclein (α-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced α-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in α-Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4-PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased α-Syn oligomers. However, 3-MA pretreatment inhibited autophagy resulting in increase of α-Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3-MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross-talking between autophagy and ER stress might play an important role in the α-Syn oligomerization and neurotoxicity by Mn.

Topics: Adenine; alpha-Synuclein; Animals; Apoptosis; Autophagy; Brain; Butylamines; Chlorides; Endoplasmic Reticulum Stress; Environmental Pollutants; Manganese; Manganese Compounds; Mice, Inbred C57BL; Neurons; Phenylbutyrates; Polymerization; Signal Transduction; Sirolimus

Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1 activation in OA initiation, and identify the underlying mechanisms.. Expression of mTORC1 in articular cartilage of OA patients and OA mice was assessed by immunostaining. Cartilage-specific tuberous sclerosis complex 1 (Tsc1, mTORC1 upstream inhibitor) knockout (TSC1CKO) and inducible Tsc1 KO (TSC1CKO. mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR.

Topics: Adult; Aged; Animals; Butylamines; Cartilage, Articular; Cell Proliferation; Chondrocytes; Down-Regulation; Female; Humans; Hypertrophy; Immunosuppressive Agents; Knee Joint; Male; Mechanistic Target of Rapamycin Complex 1; Menisci, Tibial; Mice; Mice, Knockout; Middle Aged; Osteoarthritis; Osteoarthritis, Knee; Receptor, Fibroblast Growth Factor, Type 3; Receptor, Parathyroid Hormone, Type 1; Reverse Transcriptase Polymerase Chain Reaction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Young Adult