Rose essential oil diminishes dopaminergic neuron degenerations and reduces α-synuclein aggregation in Caenorhabditis elegans models of Parkinson's disease.

Parkinson's disease (P.D.) is the second most progressive neurodegenerative disorder in the elderly. Degeneration of dopaminergic (DA) neurons and α-synuclein (α-Syn) accumulated toxicity is the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop the disease progression in P.D. patients. Screening novel and effective drugs in P.D. animal models is time- and cost-consuming. Rose Essential Oil (REO) extracted from Rosa Rugosa species (R. Setate × R. Rugosa). REO contains Citronellol, Geraniol, and Octadiene that possess anti-Aß, anti-oxidative, and anti-depression-like properties, but no reports have defined the REO effect on P.D. yet. The present study examines the REO neuroprotective potential in transgenic Caenorhabditis elegans P.D. models. We observed that REO reduced α-Syn aggregations and diminished DA neuron degenerations induced by 6-OHDA, reduced food-sensing behavioural disabilities, and prolonged the lifespan of the nematode. Moreover, REO augmented the chymotrypsin-like proteasome and SOD-3 activities. Further, we observed the anti-oxidative role of REO by reducing internal cells ROS. Together, these findings supported REO as an anti-PD drug and may exert its effects by lowering oxidative stress via the anti-oxidative pathway.

Autophagy activation by Terminalia chebula Retz. reduce Aß generation by shifting APP processing toward non-amyloidogenic pathway in APPswe transgenic SH-SY5Y cells.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid ß plaques (Aß) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor protein (APP) metabolism pathway to non-amyloidogenic ways and inducing autophagy play key roles in AD pathology. In published reports, there is no research on the APP metabolic process of Terminalia chebula Retz. (T. Chebula). PURPOSE: The study aims to assess the effects of T. Chebula in AD transgenic SH-SY5Y cells to determine its underlying mechanisms on reducing Aß level by regulating APP metabolic process. METHODS: The effects of T. Chebula water extract (TWE) on APPswe transgenic SH-SY5Y cells were analyzed by cell viability. ELISA used to quantify extracellular Aß1-40 and Aß1-42 generations. Western blot and RT-PCR assays were chosen to detect the expression of proteins and genes. The acridine orange (AO) stain was used to label autophagic-vesicles. RESULTS: Treatment with TWE significantly suppressed the Aß1-40 and Aß1-42 generations of APPswe transgenic cells. TWE inhibited amyloidogenic pathway by reducing BACE1 expression, and promote non-amyloidogenic pathway by inducing ADAM10 level of APP metabolism. Additionally, TWE induced autophagy in APPswe transgenic cells involved in APP metabolism to shift the balance to non-amyloidogenic pathway. CONCLUSION: In summary, our finding first time expounded that TWE can inhibit the generation of Aß1-40 and Aß1-42 in APPswe transgenic SH-SY5Y cells, which were regulated APP metabolism tends to non-amyloid metabolism pathway and mediated by autophagy. The results presented a novel finding for AD treatment of traditional natural medicines.

Protective effect of Terminalia chebula Retz. extract against Aß aggregation and Aß-induced toxicity in Caenorhabditis elegans.

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia chebula Retz. (T.chebula) is an important medicinal plant in Tibetan medicine and Ayurveda. T.chebula is known as the "King of Tibetan Medicine", due to its widespread clinical pharmacological activity such as anti-inflammatory, antioxidative, antidiabetic as well as anticancer in lots of in vivo and in vitro models. In this study, we use transgenic and/or RNAi Caenorhabditis elegans (C.elegans) model to simulation the AD pathological features induced by Aß, to detect the effect of TWE on improving Aß-induced toxicity and the corresponding molecular mechanism. AIM OF STUDY: The study aimed to tested the activities and its possible mechanism of T.chebula to against Aß1-42 induced toxicity and Aß1-42 aggregation. MATERIALS AND METHODS: Using transgenic C.elegans strain CL2006 and CL4176 as models respond to paralytic induced by Aß toxicity. The transcription factors DAF-16 and SKN-1 were analyzed used a fluorescence microscope in transgenic strains (DAF-16:GFP, SKN-1:GFP). The function of DAF-16 and SKN-1 was further investigated using loss-of-function strains by feeding RNA interference (RNAi) bacteria. To evaluate the aggregation level of Aß in the transgenic C.elegans, Thioflavin S (ThS) staining and WB visualized the levels of Aß monomers and oligomers. RESULTS: TWE treatment can significantly improve the paralysis of transgenic C.elegans caused by Aß aggregation (up to 14%). The Aß aggregates in transgenic C.elegans are significantly inhibited under TWE exposure (up to 70%). TWE increases the nuclear localization of the key transcription factor DAF-16 and HSF-1, which in turn leads to the expression of downstream Hsp-16.2 protein and exerts its inhibitory effect on Aß aggregation. Meanwhile, paralysis improved has not observed in SKN-1 mutation and/or RNAi C.elegans. CONCLUSION: Our results indicate that TWE can protect C.elegans against the Aß1-42-induced toxicity, inhibition Aß1-42 aggregation and delaying Aß-induced paralysis. The neuroprotective effect of TWE involves the activation of DAF-16/HSF-1/Hsp-16.2 pathway.

A novel realgar-indigo naturalis formula more effectively induces apoptosis in NB4 cells.

Realgar as a kind of arsenic agent is currently used to treat APL in China. The effectiveness and low toxicity of realgar have been verified, lower than arsenic trioxide. Although the therapeutic efficacy of realgar is blocked severely by its poor insolubility in water. In our lab, we addressed this problem by obtaining realgar bioleaching solution (RBS) from microbiological leaching technique. To develop a tradition Chinese medicinal formula (TCMF) for clinical application realgar is usually used with other herbs. However, treated realgar with RBS has not been evaluated in TCMF contain realgar. In the present study we used NB4 to investigate the effects of novel Realgar-Indigo naturalis formula (FRBS) on cell proliferation and apoptosis. We used MTT assay to measure anti proliferative activity of FRBS. We further study the effects of FRBS on cell growth and apoptosis according flow cytometry, DNA fragmentation assay and Fluorescence microscopy and Western blot. The results revealed that FRBS significantly inhibited growth in a dose-dependent manner, and induced apoptosis in NB4 cells. NB4 cell inhibitory response to FRBS at 2µg ml-1 of arsenic concentration was twofold higher, dissimilar to RIF, and induced apoptosis more effectively. Further, a higher expression of caspase-3, caspase-9 and cytochrome C from increased from FRBS. RBS can substitute the traditional realgar powder in RIF in order to provide a novel and promising Realgar-Indigo naturalis formula to treat acute promyelocytic leukemia.

Realgar transforming solution suppresses angiogenesis and tumor growth by inhibiting VEGF receptor 2 signaling in vein endothelial cells.

Realgar (As4S4), as an arsenic sulfide mineral drug, has a good therapeutic reputation for anticancer in Traditional Chinese Medicine, and has recently been reported to inhibit angiogenesis in tumor growth. However, considering the poor solubility and low bioavailability of realgar, large dose of realgar and long period of treatment are necessary for achieving the effective blood medicine concentration. In present study, we resolved the crucial problem of poor solubility of realgar by using intrinsic biotransformation in microorganism, and investigated underlying mechanisms of realgar transforming solution (RTS) for antiangiogenesis. Our results demonstrated that RTS had a strong activity to inhibit HUVECs proliferation, migration, invasion, and tube formation. Moreover, RTS inhibited VEGF/bFGF-induced phosphorylation of VEGFR2 and the downstream protein kinases including ERK, FAK, and Src. In vivo zebrafish and chicken chorioallantoic membrane model experiments showed that RTS remarkably blocked angiogenesis. Finally, compared with the control, administration of 2.50 mg/kg RTS reached more than 50% inhibition against H22 tumor allografts in KM mice, but caused few toxic effects in the host. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay. In summary, our findings suggest that RTS inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.

Realgar transforming solution displays anticancer potential against human hepatocellular carcinoma HepG2 cells by inducing ROS.

Realgar (As4S4), as a mineral drug containing arsenic compound, has been employed in clinical therapy of cancer for its good therapeutic reputation in Chinese traditional medicine. However, large dose of realgar and long period of treatment are necessary for achieving the effective blood medicine concentration due to its low bioavailability resulted from poor solubility. In this study, we obtained realgar transforming solution (RTS) using intrinsic biotransformation in microorganism, and investigated underlying mechanisms of RTS for HepG2 cells. Our results demonstrated that an effective biotransformation of realgar method by A. ferrooxidans was established, in which realgar was biologically converted into an aqueous solution, and RTS had a strong activity inducing apoptosis and interrupting G2/M progression in HepG2 cells via upregulation of cellular ROS. Importantly, RTS inhibited the cellular antioxidant defense system leading to abundant ROS accumulation, and activated cell cycle arrest and mitochondrial pathway of apoptosis mediated by activating p53 due to cellular uncontrolled ROS. Collectively, our findings suggest that RTS is a potential candidate for therapy of human hepatocellular carcinoma.