Dendrobium officinale phenolic extract maintains proteostasis by regulating autophagy in a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 µg/mL) alleviated Aß and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy-lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.

Sec-O-Glucosylhamaudol Inhibits RANKL-Induced Osteoclastogenesis by Repressing 5-LO and AKT/GSK3ß Signaling.

Sec-O-glucosylhamaudol (SOG), an active flavonoid compound derived from the root of Saposhnikovia divaricata (Turcz. ex Ledeb.) Schischk., exhibits analgesic, anti-inflammatory, and high 5-lipoxygenase (5-LO) inhibitory effects. However, its effect on osteoclastogenesis was unclear. We demonstrated that SOG markedly attenuated RANKL-induced osteoclast formation, F-actin ring formation, and mineral resorption by reducing the induction of key transcription factors NFATc1, c-Fos, and their target genes such as TRAP, CTSK, and DC-STAMP during osteoclastogenesis. Western blotting showed that SOG significantly inhibited the phosphorylation of AKT and GSK3ß at the middle-late stage of osteoclastogenesis without altering calcineurin catalytic subunit protein phosphatase-2ß-Aα expression. Moreover, GSK3ß inhibitor SB415286 partially reversed SOG-induced inhibition of osteoclastogenesis, suggesting that SOG inhibits RANKL-induced osteoclastogenesis by activating GSK3ß, at least in part. 5-LO gene silencing by small interfering RNA in mouse bone marrow macrophages markedly reduced RANKL-induced osteoclastogenesis by inhibiting NFATc1. However, it did not affect the phosphorylation of AKT or GSK3ß, indicating that SOG exerts its inhibitory effects on osteoclastogenesis by suppressing both the independent 5-LO pathway and AKT-mediated GSK3ß inactivation. In support of this, SOG significantly improved bone destruction in a lipopolysaccharide-induced mouse model of bone loss. Taken together, these results suggest a potential therapeutic effect for SOG on osteoclast-related bone lysis disease.

Polygonum multiflorum Thunb extract extended the lifespan and healthspan of Caenorhabditis elegans via DAF-16/SIR-2.1/SKN-1.

Polygonum multiflorum Thunb (PMT), as a traditional Chinese herbal medicine, has been widely used in the prevention and treatment of aging-related diseases, including Alzheimer's disease, Parkinson's disease, hyperlipidemia, atherosclerosis and inflammation. However, the effect of PMT on the lifespan and its molecular mechanisms are still unclear. Here we found that 60% ethanol refined fraction (PMT-E) of Polygonum multiflorum Thunb at 50 µg mL-1, which contained two main bioactive compounds, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) and emodin-8-O-ß-D-glucoside (EG), could significantly increase the mean lifespan by 19.82%, delay the age-related decline of phenotypes, enhance stress resistance and reduce ROS accumulation in Caenorhabditis elegans. Moreover, we also found that the mitochondrial membrane potential (ΔΨ) and ATP content of worms treated with 50 µg mL-1 PMT-E were obviously improved. Further mechanistic studies revealed that DAF-16, SIR-2.1 and SKN-1 transcription factors were required for PMT-E-mediated lifespan extension. Finally, we found that PMT-E could significantly inhibit the toxicity induced by ß-amyloid (Aß) in Aß transgenic worms. Altogether, these findings laid the foundation for the use of Polygonum multiflorum Thunb to treat aging and age-related diseases.

Essential Oil of Acorus tatarinowii Schott Ameliorates Aß-Induced Toxicity in Caenorhabditis elegans through an Autophagy Pathway.

BACKGROUND: Acorus tatarinowii Schott [Shi Chang Pu in Chinese (SCP)] is a traditional Chinese medicine frequently used in the clinical treatment of dementia, amnesia, epilepsy, and other mental disorders. Previous studies have shown the potential efficacy of SCP against Alzheimer's disease (AD). Nevertheless, the active constituents and the modes of action of SCP in AD treatment have not been fully elucidated. PURPOSE: The aim of this study was to investigate the protective effects of SCP on abnormal proteins and clarify its molecular mechanisms in the treatment of AD by using a Caenorhabditis elegans (C. elegans) model. METHODS: This study experimentally assessed the effect of SCP-Oil in CL4176 strains expressing human Aß in muscle cells and CL2355 strains expressing human Aß in pan-neurons. Western blotting, qRT-PCR, and fluorescence detection were performed to determine the oxidative stress and signaling pathways affected by SCP-Oil in nematodes. RESULTS: SCP-Oil could significantly reduce the deposition of misfolded Aß and polyQ proteins and improved serotonin sensitivity and olfactory learning skill in worms. The analysis of pharmacological action mechanism of SCP-Oil showed that its maintaining protein homeostasis is dependent on the autophagy pathway regulated partly by hsf-1 and sir-2.1 genes. CONCLUSION: Our results provide new insights to develop treatment strategy for AD by targeting autophagy, and SCP-Oil could be an alternative drug for anti-AD.

Echinacoside, a phenylethanoid glycoside from Cistanche deserticola, extends lifespan of Caenorhabditis elegans and protects from Aß-induced toxicity.

Cistanche deserticola has been found to exert protection against aging and age-related diseases, but mechanisms underlying its longevity effects remain largely unclear. Here, the multicellular model organism Caenorhabditis elegans was employed to identify lifespan extending and protective effects against ß-amyloid (Aß) induced toxicity by echinacoside (ECH), a phenylethanoid glycoside isolated from C. deserticola. Our results showed that ECH extends the mean lifespan of worms and increases their survival under oxidative stress. Levels of intracellular reactive oxygen species and fat accumulation were also significantly suppressed by ECH. Moreover, ECH-mediated lifespan extension was found to be dependent on mev-1, eat-2, daf-2, and daf-16, but not sir-2.1 or hsf-1 genes. Furthermore, ECH triggered DAF-16 nuclear localization and upregulated two of its downstream targets, sod-3 and hsp-16.2. In addition, ECH significantly improved the survival of CL4176 worms in response to proteotoxic stress induced by Aß protein aggregation. Collectively, these findings suggested that reactive oxygen species scavenging, dietary restriction, and insulin/insulin-like growth factor signaling pathways could be partly involved in ECH-mediated lifespan extension. Thus, ECH may target multiple longevity mechanisms to extend lifespan and have a potency to prevent Alzheimer's disease progression.

Lignans from the roots of Acorus tatarinowii Schott ameliorate ß amyloid-induced toxicity in transgenic Caenorhabditis elegans.

A novel tetralignan, tatarinan T (1) with the rare C8-C7' linkage pattern, along with a known monolignan (2) were isolated from the roots of Acorus tatarinowii Schott. Their chemical structures were elucidated on the basis of NMR and X-ray diffraction analysis. We evaluated the protective effects of two rare lignans against ß-amyloid toxicity by using CL4176 transgenic C. elegans model for the first time, and found that they significantly delayed paralysis of worms at the concentration of 100 µM. Compound 2 exhibited the more potential protective effect against ß-amyloid toxicity, its value of PT50 extended up to 62.3% at 100 µM compared with control, especially, it still has 30.8% extension at 10 µM.