Salidroside Protects Dopaminergic Neurons by Preserving Complex I Activity via DJ-1/Nrf2-Mediated Antioxidant Pathway.

The pathogenic mechanism of Parkinson's disease (PD) remains to be elucidated; however, mitochondrial dysfunction at the level of complex I and oxidative stress is suggestively involved in the development of PD. In our previous work, salidroside (Sal), an active component extracted from the medicinal plant Rhodiola rosea L., might protect dopaminergic (DA) neurons through modulating ROS-NO-related pathway. However, the mechanism of Sal-induced neuroprotective effects against PD remains poorly understood. Therefore, we further investigated whether Sal plays neuroprotective effects by activating complex I via DJ-1/Nrf2-mediated antioxidant pathway. The results showed that Sal remarkably attenuated MPP+/MPTP-induced decline in cell viability, accompanied by decreases in reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) contents and increases in the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as glutathione (GSH) levels. Furthermore, Sal greatly improved the behavioral performance and prevented the severe reduction of TH-positive neuron numbers in the substantia nigra (SN). Moreover, in comparison with the MPP+/MPTP group, Sal increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I. Furthermore, silencing of DJ-1/Nrf2 inhibited the increase of complex I activity and cell viability elicited by Sal. Together, these results support the neuroprotective effect of Sal against MPP+/MPTP-induced DA neurons damage.

Salidroside Promotes the Pathological α-Synuclein Clearance Through Ubiquitin-Proteasome System in SH-SY5Y Cells.

Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) in the surviving SNc neurons. LBs formation is caused by the accumulation of α-synuclein (α-syn) or phosphorylated α-syn at serine-129 (pSer129-α-syn), which is implicated in the pathological progression of PD. Salidroside (Sal), the main active ingredient of the root of Rhodiola rosea L., has been reported to have potent neuroprotective properties in our previous investigations. Here, we investigated the effects of Sal on 6-OHDA and overexpresssion of WT/A30P-α-syn-induced pathological α-syn increase and the mechanism behind it in SH-SY5Y cells. We found Sal displays neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. Sal decreased the pSer129-α-syn level mainly by maintaining the normal function of ubiquitin-proteasome system (UPS). Furthermore, Sal promoted the clearance of α-syn and protected the cell viability mainly through recovered the 20S proteasome activity in WT/A30P-α-syn-transfected cells. These data provide new mechanistic insights into the neuroprotective effects of Sal and Sal may be a promising therapy to slow neurodegeneration in PD. Highlights: Sal protects cells and decreases the pSer129-α-syn protein level in 6-OHDA-induced impairmental and dysfunctional SH-SY5Y cells. Sal promotes the clearance of α-syn and protects the cell viability mainly through recovering the 20S proteasome activity in WT/A30P-α-syn plasmids transfected cells. Maintaining the normal function of the UPS may be one of the important mechanisms of Sal in neuroprotective effects.

Antihypertensive drugs use and the risk of prostate cancer: a meta-analysis of 21 observational studies.

BACKGROUND: Due to the lack of strong evidence to identify the relationship between antihypertensive drugs use and the risk of prostate cancer, it was needed to do a systematic review to go into the subject. METHODS: We systematically searched PubMed, Web of Science and Embase to identify studies published, through May 2015. Two evaluators independently reviewed and selected articles involving the subject. We used the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies. All extracted results to evaluate the relationship between antihypertensive drugs usage and prostate cancer risk were pool-analysed using Stata 12.0 software. RESULTS: A total of 12 cohort and 9 case-control studies were ultimately included in our review. Most of the studies were evaluated to be of high quality. There was no significant relationship between angiotensin converting enzyme inhibitors (ACEI) usage and the risk of prostate cancer (RR 1.07, 95% CI 0.96-1.20), according to the total pool-analysed. Use of angiotensin receptor blocker (ARB) was not associated with the risk of prostate cancer (RR 1.09, 95% CI 0.97-1.21), while use of CCB may well increase prostate cancer risk based on the total pool-analysed (RR 1.08, 95% CI 1-1.16). Moreover, subgroup analysis suggested that use of CCB clearly increased prostate cancer risk (RR 1.10, 95% CI 1.04-1.16) in terms of case-control studies. There was also no significant relationship between use of diuretic (RR 1.09, 95% CI 0.95-1.25) or antiadrenergic agents (RR 1.22, 95% CI 0.76-1.96) and prostate cancer risk. CONCLUSIONS: There is no significant relationship between the use of antihypertensive drugs (ACEI, ARB, beta-blockers and diuretics) and prostate cancer risk, but CCB may well increase prostate cancer risk, according to existing observational studies.

Salidroside Protects against MPP+-Induced Neuronal Injury through DJ-1-Nrf2 Antioxidant Pathway.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have found that salidroside (Sal) exhibited neuroprotective effects against MPP+ toxicity. However, the molecular mechanism is not fully understood. In this study, we found that Sal significantly prevented MPP+-induced decrease of mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in SH-SY5Y cells. Moreover, silencing of Nrf2 significantly inhibited Sal-induced increase in mRNA and protein expression of GCLc, SOD1, and SOD2. But Nrf2 silence did not significantly impact Sal-exhibited effects on DJ-1 expression. Silencing of Nrf2 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. Sal significantly prevented MPP+-induced decrease of the mRNA and protein expression of DJ-1 in SH-SY5Y cells. Moreover, silencing of DJ-1 significantly inhibited Sal-induced increase in mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in MPP+-treated SH-SY5Y cells. These results indicated that DJ-1 was an upstream regulator of Nrf2 in the neuroprotective effects of Sal. Furthermore, silencing of DJ-1 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. In conclusion, Sal prevented MPP+-induced neurotoxicity through upregulation of DJ-1-Nrf2-antioxidant pathway. Our findings provide novel insights into the neuroprotective effects of Sal against PD.

Potential molecular mechanisms mediating the protective effects of tetrahydroxystilbene glucoside on MPP+-induced PC12 cell apoptosis.

Our previous work demonstrated that tetrahydroxystilbene glucoside (TSG) was able to effectively attenuate 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in PC12 cells partially via inhibiting reactive oxygen species (ROS) generation. However, the precise molecular mechanisms of TSG responsible for suppressing neuronal apoptosis have not been fully elucidated. To investigate the possible mechanism, we studied the neuroprotective effects of TSG on MPP+-induced PC12 cells apoptosis and explored the molecular mechanisms that mediated the effects of TSG. Our results showed that treatment with TSG prior to MPP+ exposure effectively attenuated the cell viability decrease in PC12 cells, reversed the cell apoptosis, and further restored the mitochondria membrane potential (MMP). In addition, TSG remarkably enhanced the anti-oxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and efficiently reduced the malondialdehyde (MDA) content in the PC12 cells. Meanwhile, TSG markedly upregulated the Bcl-2/Bax ratio, reversed release of Cytochrome c, and inhibited the activation of caspase-3 induced by MPP+. Furthermore, TSG significantly inhibited the activation of p38 mitogen-activated protein kinase (p38MAPK) signaling pathway, while extracellular signal-regulated protein kinases (ERK) phosphorylation was not affected. Together, these findings provide the basis for TSG clinical application as a new therapeutic strategy in the treatment of neurodegenerative diseases.

The influence of simulated microgravity on proliferation and apoptosis in U251 glioma cells.

Several studies have indicated that microgravity can influence cellular progression, proliferation, and apoptosis in tumor cell lines. In this study, we observed that simulated microgravity inhibited proliferation and induced apoptosis in U251 malignant glioma (U251MG) cells. Furthermore, expression of the apoptosis-associated proteins, p21 and insulin-like growth factor binding protein-2 (IGFBP-2), was upregulated and downregulated, respectively, following exposure to simulated microgravity. These findings indicate that simulated microgravity inhibits proliferation while inducing apoptosis of U251MG cells. The associated effects appear to be mediated by inhibition of IGFBP-2 expression and stimulation of p21 expression. This suggests that simulated microgravity might represent a promising method to discover new targets for glioma therapeutic strategy.

Neuroprotective Effects of Salidroside in the MPTP Mouse Model of Parkinson's Disease: Involvement of the PI3K/Akt/GSK3ß Pathway.

The degenerative loss through apoptosis of dopaminergic neurons in the substantia nigra pars compacta plays a primary role in the progression of Parkinson's disease (PD). Our in vitro experiments suggested that salidroside (Sal) could protect against 1-methyl-4-phenylpyridine-induced cell apoptosis in part by regulating the PI3K/Akt/GSK3ß pathway. The current study aims to increase our understanding of the protective mechanisms of Sal in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine- (MPTP-) induced PD mouse model. We found that pretreatment with Sal could protect against MPTP-induced increase of the time of turning downwards and climbing down to the floor. Sal also prevented MPTP-induced decrease of locomotion frequency and the increase of the immobile time. Sal provided a protection of in MPTP-induced loss of tyrosine hydroxylase-positive neurons in SNpc and the level of DA, DOPAC, and HVA in the striatum. Furthermore, Sal could increase the phosphorylation level of Akt and GSK3ß, upregulate the ratio of Bcl-2/Bax, and inhibit the activation of caspase-3, caspase-6, and caspase-9. These results show that Sal prevents the loss of dopaminergic neurons and the PI3K/Akt/GSK3ß pathway signaling pathway may have mediated the protection of Sal against MPTP, suggesting that Sal may be a potential candidate in neuroprotective treatment for PD.

Diosgenin stimulates rat TM4 cell proliferation through activating plasma membrane translocation and transcriptional activity of estrogen receptors.

Sertoli cells (SCs) function as "nurse cells," which play crucial roles in supporting spermatogenesis through establishing a unique and essential environment in the male reproductive tract. Given the important roles of SCs in male fertility, this study was designed to evaluate the effect of diosgenin, an aglycone of the steroidal saponin, on TM4 cell proliferation and to elucidate the possible mechanisms. We showed that diosgenin increased the proliferation of TM4 cell and primary SCs in a time- and concentration-dependent manner. Diosgenin increased cyclins D1 and E as well as CDK4/6 and CDK2 expression but inhibited P27 expression, with no significant alterations of cyclin B and cdc2 (cell division cycle 2), resulting in cell-cycle G1/S transition. Diosgenin significantly inhibited apoptosis, as reflected by decreased percentage of TUNEL-positive cells; decreased expression of Bax (Bcl-2-associated X protein), AIF (apoptosis-inducing factor), and cleaved caspases 3 and 9; and increased expression of Bcl-2 (B-cell lymphoma 2). Diosgenin induced an immediate and transient plasma membrane translocation of ESR1 and ESR2 from the nucleus, which was inhibited by the antiestrogen ICI 182 780 and PP2, an inhibitor of SRC. Moreover, ICI 182 780 and PP2 significantly inhibited diosgenin-induced cell-cycle transition and inhibition of apoptosis. Activation of extracellular regulated protein kinase (ERK)/Akt signaling was also involved in diosgenin-induced TM4 cell proliferation, which was SRC- and ESR-dependent. Furthermore, diosgenin induced late activation of nuclear ESR transcriptional activity, which in turn directly regulated cell cycle and apoptosis-related factors, such as cyclin D and Bcl-2. Taken together, the results show that diosgenin activated SRC-ESR translocation-ERK/Akt-ESR transcriptional activity, leading to cell-cycle transition and inhibition of apoptosis and thus final cell proliferation. These findings may better our understanding of the pharmacological actions of diosgenin and advance therapeutic approaches to male infertility.