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Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson’s disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (α-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of α-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of α-syn is involved in high-dose METH-induced α-syn aggregation. We measured the levels of α-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of α-syn SUMOylation on α-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of α-syn by transfecting a lentivirus containing the sequence of WT α-syn or K96/102R α-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT α-syn or K96/102R α-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of α-syn, although the expression of α-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in α-syn SUMOylation by UBC9 overexpression relieves METH-induced α-syn overexpression and aggregation, whereas the decrease in α-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of α-syn also aggravate α-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of α-syn plays a fundamental part in α-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

Due to the large lateral area of the trailer and variable road conditions, the handling stability of a heavy tractor semi-trailer under crosswind is very important for road safety. In this present work, numerical simulation is performed to study the crosswind effects on handling stability of a tractor semi-trailer. The aerodynamic characteristics of the tractor semi-trailer under different crosswind were computed by computational fluid dynamics (CFD). Then, mathematical models to reveal the relationship between the aerodynamic forces and crosswind were constructed to serve as inputs of the multi-body dynamics to analyze the handling stability under crosswind. The performance of crosswind stability is evaluated by the response of lateral acceleration, yaw rate and the lateral displacement. The lateral acceleration and yaw rate were decreased by a maximum of 14.6% and 16.5% compared to the truck without the deflector, which showed that the crosswind aerodynamics and stability were obviously improved.

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Introduction Chaperone‐mediated autophagy (CMA) is an autophagy–lysosome pathway (ALP) that is different from the other two lysosomal pathways, namely, macroautophagy and microautophagy, and can selectively degrade cytosolic proteins in lysosomes without vesicle formation. CMA activity declines in neurodegenerative diseases such as Parkinson's disease, and similar neurotoxicity can occur after methamphetamine (METH) treatment. The relationship between CMA and METH‐induced neurotoxicity is not clear. Methods We detected changes in the chaperone protein Hsc70 and the lysosomal surface receptor Lamp‐2a after METH treatment and then regulated these two proteins by small interfering RNA and DNA plasmid transfection to investigate how CMA influences METH‐induced neurotoxicity. Results We found that CMA activity is decreased after METH exposure in neurons and downregulated Lamp‐2a can aggravate the neurotoxicity induced by α‐Syn after METH exposure and that Hsc70 overexpression can relieve the abnormal levels of alpha‐synuclein and its aggregate forms and the increase in cell apoptosis induced by METH. Conclusions The results provide in vivo evidence for CMA plays a pivotal role in METH‐induced neurotoxicity, and upregulation of Hsc70 expression significantly protects neuronal cells against METH‐induced toxicity. This research may pave the way for potential therapeutic approaches targeting CMA for METH abuse and neurodegenerative disorders.

Often associated with sexual dysfunction (SD), chronic stress is the main contributing risk factor for the pathogenesis of depression. Radix bupleuri had been widely used in traditional Chinese medicine formulation for the regulation of emotion and sexual activity. As the main active component of Radix bupleuri, saikosaponin D (SSD) has a demonstrated antidepressant effect in preclinical studies. Herein, we sought to investigate the effect of SSD to restore sexual functions in chronically stressed mice and elucidate the potential brain mechanisms that might underly these effects. SSD was gavage administered for three weeks during the induction of chronic mild stress (CMS), and its effects on emotional and sexual behaviors in CMS mice were observed. The medial posterodorsal amygdala (MePD) was speculated to be involved in the manifestation of sexual dysfunctions in CMS mice. Our results revealed that SSD not only alleviated CMS-induced depressive-like behaviors but also rescued CMS-induced low sexual motivation and poor sexual performance. CMS destroyed astrocytes and activated microglia in the MePD. SSD treatment reversed the changes in glial pathology and inhibited neuroinflammatory and oxidative stress in the MePD of CMS mice. The neuronal morphological and functional deficits in the MePD were also alleviated by SSD administration. Our results provide insights into the central mechanisms involving the brain associated with sexual dysfunction. These findings deepen our understanding of SSD in light of the psychopharmacology of stress and sexual disorders, providing a theoretical basis for its potential clinical application.

The phosphorylation and aggregation of alpha-synuclein (α-Syn) play a key role in methamphetamine (METH)-induced dopaminergic neurotoxicity. The exact mechanism underlying the interaction between METH-induced neurotoxicity and α-Syn was poorly clarified. We aimed to figure out the role of serine 129 phosphorylation (pS129) of α-Syn on its aggregation and neurotoxicity in vitro and in vivo. In this study, we examined pS129 α-Syn expression in vitro and in vivo at the protein phosphorylation and genetic levels and evaluated its effect on METH-induced neurotoxicity. Here, we found that pS129 α-Syn was significantly increased after METH treatment; moreover, the neuronal α-Syn aggregation and apoptosis caused by METH exposure were significantly attenuated after inhibiting α-Syn phosphorylation. We demonstrate that pS129 α-Syn contributes to the aggregation of α-Syn, and that phosphorylated and aggregated forms of α-Syn play an important role in METH-induced neurotoxicity in dopaminergic neurons and SH-SY5Y cells, supporting a potential insight into the treatment of METH-induced neurotoxicity.