Chemical diversity, traditional uses, and bioactivities of Rosa roxburghii Tratt: A comprehensive review.

Rosa roxburghii Tratt (RRT), known as chestnut rose, has been a subject of growing interest because of its diverse chemical composition and wide range of traditional uses. This comprehensive review aimed to thoroughly examine RRT, including its traditional applications, chemical diversity, and various bioactivities. The chemical profile of this plant is characterized by the presence of essential nutrients such as vitamin C (ascorbic acid), flavonoids, triterpenes, organic acids, tannins, phenolic compounds, polysaccharides, carotenoids, triterpenoids, volatile compounds, amino acids, and essential oils. These constituents contribute to the medicinal and nutritional value. Additionally, we explore the multifaceted bioactivities of RRT, including its potential as an anticancer agent, antioxidant, antiaging agent, antiatherogenic agent, hypoglycemic agent, immunoregulatory modulator, radioprotective agent, antimutagenic agent, digestive system regulator, anti-inflammatory agent, cardioprotective agent, and antibacterial agent, and its intriguing role in modulating the gut microbiota. Furthermore, we discuss the geographical distribution and genetic diversity of this plant species and shed light on its ecological significance. This comprehensive review provides a holistic understanding of RRT, bridges traditional knowledge with contemporary scientific research, and highlights its potential applications in medicine, nutrition, and pharmacology.

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3ß pathway in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANT: Dendrobium is a traditional and precious Chinese medicinal herb. The Compendium of Materia Medica describes its effects as "benefiting intelligence and dispelling shock, lightning the body and extending life". Dendrobium nobile Lindl. is a precious variety of Dendrobium. Our previous data showed Dendrobium nobile Lindl. alkaloid (DNLA) has significant neuroprotective effects and can improve cognitive dysfunction. However, the specific effects and mechanisms of action of its main active component, DNLA, on cognitive dysfunction caused by Tau hyperphosphorylation, are still unclear. AIM OF THE RESEARCH: This study aimed to determine the effects of DNLA on phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3ß (GSK-3ß) pathway, thus to explore the mechanisms of DNLA to inhibit Tau hyperphosphorylation. MATERIALS AND METHODS: We used wortmannin (WM) and GF-109203X (GFX)-induced hyperphosphorylation of Tau in N2a cells and rats to detect the protective mechanism of DNLA in vivo and in vitro. In vitro, the effect of modeling method on Tau hyperphosphorylation was screened and verified by Western Blotting (WB), and the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA was detected by WB. In vivo, MWM was used to detect the effect of DNLA on model rats, and then Nissl staining was used to detect the loss of neurons. Finally, WB was used to detect the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3ß pathway by different concentrations of DNLA. RESULTS: DNLA could rescue the abnormal PI3K/Akt/GSK-3ß pathway and reverse the hyperphosphorylation of Tau induced by WM and GFX in N2a cells. Furthermore, DNLA improved the learning and memory of WM and GFX-induced model rats. Moreover, DNLA regulated PI3K/Akt/GSK-3ß pathway and reduced the p-Tau and neuronal damage in the hippocampus of model rats. CONCLUSION: DNLA may be a promising candidate for reducing hyperphosphorylation of Tau.

Proteomic analysis of anti-aging effects of Dendrobium nobile Lindl. alkaloids in aging-accelerated SAMP8 mice.

Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit cognitive defects and neuron loss with aging, and were used to study anti-aging effects of Dendrobium nobile alkaloids (DNLA). DNLA (20 and 40 mg/kg) were orally administered to SAMP8 mice from 6 to 10 months of age. At 10-month of age, behavioral tests via Y-maze and Open-field and neuron damage via Nissl staining were evaluated. Protein was extracted and subjected to phosphorylated proteomic analysis followed by bioinformatic analysis. The cognitive deficits and neuron loss in hippocampus and cortex of aged SAMP8 mice were improved by DNLA. Hippocampal proteomic analysis revealed 196 differentially expressed protein/genes in SAMP8 compared to age-matched senescence-accelerated resistant SAMR1 mice. Gene Oncology enriched the tubulin binding, microtubule binding, and other activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed endocytosis, mRNA surveillance, tight junction, protein processing in endoplasmic reticulum, aldosterone synthesis and secretion, and glucagon signaling pathway changes. Upregulated protein/genes in the hippocampus of SAMP8 mice, such as Lmtk3, Usp10, Dzip1, Csnk2b, and Rtn1, were attenuated by DNLA; whereas downregulated protein/genes, such as Kctd16, Psd3, Bsn, Atxn2l, and Kif1a, were rescued by DNLA. The aberrant protein/gene expressions of SAMP8 mice were correlated with transcriptome changes of Alzheimer's disease in the Gene Expression Omnibus (GEO) database, and the scores were attenuated by DNLA. Thus, DNLA improved cognitive dysfunction and ameliorated neuronal injury in aged SAMP8 mice, and attenuated aberrant protein/gene expressions.

Natural bioactive compounds in Alzheimer's disease: From the perspective of type 3 diabetes mellitus.

There is a close relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the link between the two is often referred to as type 3 diabetes mellitus (T3DM). Many natural bioactive compounds have shown the potential to treat AD and diabetes. We mainly review the polyphenols represented by resveratrol (RES) and proanthocyanidins (PCs) and alkaloids represented by berberine (BBR) and Dendrobium nobile Lindl. alkaloids (DNLA) from the perspective of T3DM to review the neuroprotective effects and molecular mechanisms of natural compounds in AD.

Two new alkaloids from Dendrobium nobile Lindl. exhibited neuroprotective activity, and dendrobine alleviated Aß1-42 -induced apoptosis by inhibiting CDK5 activation in PC12 cells.

Dendrobium nobile Lindl. is registered in the Chinese Pharmacopoeia as a traditional medicine. Phytochemical investigation of the ethanol extract of D. nobile Lindl. stems yielded three alkaloid compounds, including two new compounds dendroxine B (2) and denrine B (3) as well as one known compound dendrobine (1). Here, we identified the structure of these compounds using spectroscopic analyses and compared them with those described in previous studies. Compounds 1-3 were found to show protective effect against amyloid-ß 1-42 (Aß1-42 )-induced neurotoxicity in rat pheochromocytoma (PC12) cells, among which dendrobine exhibited the most significant neuroprotective effect. Hoechst 33342/propidium iodide staining indicated that dendrobine ameliorated Aß1-42 -induced apoptosis. Moreover, quantitative real-time polymerase chain reaction and western blot analysis analysis demonstrated that dendrobine suppressed the activation of cyclin-dependent kinase 5 (CDK5), upregulated Bcl-2 expression, and downregulated Bax, cyto-c, and caspase-3 expression. Molecular docking analysis and surface plasmon resonance assay suggested that dendrobine directly bound to CDK5 protein with a KD value of 2.05 × 10-4 M. In summary, alkaloids are the neuroprotective constituents of D. nobile Lindl., and dendrobine protected PC12 cells against Aß1-42 -induced apoptosis by inhibiting CDK5 activation.

Neferine Suppresses Experimental Colitis-Associated Colorectal Cancer by Inhibition of NF-[Formula: see text]B p65 and STAT3.

Colitis is an important risk factor for the development of colorectal cancer (CRC). The inhibitory effect and the underlying mechanism of neferine on colitis-associated colorectal cancer (CA-CRC) were investigated using an azoxymethane (AOM)/dextran sulfate sodium (DSS) triggered mice model. Compared with the CA-CRC model, oral treatment of neferine (2.5 and 5.0 mg/kg) significantly inhibited the DAI scores, decreased the tumor number, and reduced the tumor size. Neferine decreased inflammatory cell infiltration and epithelial hyperplasia in colon tissues. The levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-1beta (IL-1[Formula: see text], and interleukin 6 (IL-6) in colon tissues were decreased by neferine. Furthermore, neferine significantly decreased protein expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), p-p65, and p-STAT3 in both tumor and non-tumor tissues. In addition, neferine inhibited LPS and IL-6-induced phosphorylation of both NF-[Formula: see text]B p65 and STAT3. Molecular docking demonstrated the interactions of neferine with both NF-[Formula: see text]B p65 and STAT3. In conclusion, these results suggested that neferine inhibited CA-CRC carcinogenesis possibly by regulating NF-[Formula: see text]B and STAT3. Neferine might be a lead compound for the chemoprevention of CA-CRC.

Hypothalamic response with PKA/CREB signaling is associated with direct cerebroventricular administration of bombesin-induced scratching.

Bombesin (BN) is an itch-specific mediator that causes intense itch-scratching activity in mammals. Although most examinations of BN-induced itch processing have focused on the spinal cord, the involvement of central nervous system mechanisms remains unclear. Here, we investigated how relationships among hypothalamic regions regulate BN-mediated itch-scratch processes. We found that intracerebroventricular (i.c.v.) administration of BN (0.04-4 µg) elicited intense itch scratching in mice, whereas BN (0.4-400 µg) administered via intravenous tail injection failed to evoke a scratching response. Additionally, nalfurafine had no significant effects on BN-induced scratching behavior, indicating that central modulation of BN is distinct from histamine-mediated histaminergic itch and chloroquine-mediated non-histaminergic itch signaling pathways. We labeled BN with a fluorescent tag, 7-nitrobenz-2-oxa-1 (NBD), and traced its fluorescence in the hypothalamus for 30 min following i.c.v. NBD-BN administration. Accordingly, we confirmed that i.c.v. administration of BN enhanced c-Fos expression in the dorsal medial nucleus of the hypothalamus, where neuromedin B receptors and gastrin-releasing peptide receptors are highly expressed. Interestingly, in situ injection of BN into the hypothalamus immediately and robustly induced itch-scratching behavior. Moreover, gene transcripts and western blot assay revealed that BN receptor-dependent PKA/CREB signaling was upregulated in the hypothalamus after i.c.v. administration of BN. Consistently, pretreatment with a PKA inhibitor, Rp-cAMP, significantly reduced BN-induced scratching behavior. Our results indicate that the dorsal medial nucleus of the hypothalamus may be a key nucleus in mediating BN-mediated itch and hypothalamic PKA/CREB signaling is involved in regulating BN-mediated itch.

Trilobatin promotes angiogenesis after cerebral ischemia-reperfusion injury via SIRT7/VEGFA signaling pathway in rats.

Angiogenesis plays a pivotal role in the recovery of neurological function after ischemia stroke. Herein, we investigated the effect of trilobatin (TLB) on angiogenesis after cerebral ischemia-reperfusion injury (CIRI). The effect of TLB on angiogenesis after CIRI were investigated in mouse brain microvascular endothelium bEnd.3 cells and middle cerebral artery occlusion (MCAO)-induced CIRI rat model. The cell proliferation and angiogenesis were observed using immunofluorescence staining. The cell cycle, expressions of cell cycle-related proteins and SIRT 1-7 were determined by flow cytometry and western blot, respectively. The binding affinity of TLB with SIRT7 was predicted by molecular docking. The results showed that TLB concentration-dependently promoted bEnd.3 cell proportion in the S-phase. TLB significantly increased the protein expressions of SIRT6, SIRT7, and VEGFA, but not affected SIRT1-SIRT5 protein expressions. Moreover, TLB not only dramatically alleviated neurological impairment after CIRI, but also enhanced post-stroke neovascularization and newly formed functional vessels in cerebral ischemic penumbra. Furthermore, TLB up-regulated the protein expressions of CDK4, cyclin D1, VEGFA and its receptor VEGFR-2. Intriguingly, TLB not only directly bound to SIRT7, but also increased SIRT7 expression at day 28. Our findings reveal that TLB promotes cerebral microvascular endothelial cells proliferation, and facilitates angiogenesis after CIRI via mediating SIRT7/VEGFA signaling pathway in rats. Therefore, TLB might be a novel restorative agent to rescue ischemia stroke.

Trilobatin rescues cognitive impairment of Alzheimer's disease by targeting HMGB1 through mediating SIRT3/SOD2 signaling pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable. Previous study shows that trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect in experimental models of AD. In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro. APP/PS1 transgenic mice were administered TLB (4, 8 mg· kg-1 ·d-1, i.g.) for 3 months; rats were subjected to ICV injection of Aß25-35, followed by administration of TLB (2.5, 5, 10 mg· kg-1 ·d-1, i.g.) for 14 days. We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models, assessed in open field test, novel object recognition test, Y-maze test and Morris water maze test. Furthermore, TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1 (HMGB1), TLR4 and NF-κB. In Aß25-25-treated BV2 cells, TLB (12.5-50 µM) concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway. HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aß25-35 insults. Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a KD value of 8.541×10-4 M. Furthermore, we demonstrated that TLB inhibited Aß25-35-induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway, thereby restoring redox homeostasis and suppressing neuroinflammation. These results, for the first time, unravel a new property of TLB: rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway.

Protective Effects of Dendrobium nobile Lindl. Alkaloids on Alzheimer's Disease-like Symptoms Induced by High-methionine Diet.

BACKGROUND: High methionine-diet (HMD) causes Alzheimer's disease (AD)-like symptoms. Previous studies have shown that Dendrobium nobile Lindle. alkaloids (DNLA) have potential benefits for AD Object: The objective of this study has been to explore whether DNLA can improve AD-like symptoms induced by HMD. METHODS: Mice were fed with 2% HMD diet for 11 weeks; the DNLA20 control group (20 mg/kg), DNLA10 group (10 mg/kg), and DNLA20 group (20 mg/kg) were administered DNLA for 3 months. Morris water maze test was used to detect learning and memory ability. Neuron damage was evaluated by HE and Nissl staining. Levels of homocysteine (Hcy), beta-amyloid 1-42 (Aß1-42), S-adenosine methionine (SAM) and S-adenosine homocysteine (SAH) were detected by ELISA. Immunofluorescence and western blotting (WB) were used to determine the expression of proteins. CPG island methylation levels were accessed by Methylation-specific PCR (MSP) and MethylTarget methylation detection. RESULTS: Morris water maze test revealed that DNLA improved learning and memory dysfunction. HE, Nissl, and immunofluorescence staining showed that DNLA alleviated neuron damage and reduced the 5-methylcytosine (5-mC), Aß1-40) and Aß1-42) levels. DNLA also decreased the levels of Hcy and Aß1-42) in the serum, along with decreasing SAM/SAH level in the liver tissue. WB results showed that DNLA down-regulated the expression of amyloid-precursor protein (APP), presenilin-1 (PS1), beta-secretase-1 (BACE1), DNA methyltransferase1 (DNMT1), Aß1-40) and Aß1-42) proteins. DNLA also up-regulated the proteins expression of insulin-degrading enzyme (IDE), neprilysin (NEP), DNMT3a and DNMT3b. Meanwhile, DNLA increased CPG island methylation levels of APP and BACE1 genes. CONCLUSION: DNLA alleviated AD-like symptoms induced by HMD via the DNA methylation pathway.

Protective Effects and Mechanisms of Dendrobium nobile Lindl. Alkaloids on PC12 Cell Damage Induced by Aß 25-35.

BACKGROUND: Aß deposition abnormally in the mitochondria can damage the mitochondrial respiratory chain and activate the mitochondrial-mediated apoptosis pathway, resulting in AD-like symptoms. OBJECTIVE: To observe the protective effects of Dendrobium nobile Lindl. alkaloids (DNLA) on Aß 25-35-induced oxidative stress and apoptosis in PC12 cells explore its possible protective mechanisms. METHODS: PC12 cells were treated with DNLA with different concentrations (0.035 mg/L, 0.3 mg/L, and 3.5 mg/L) for 6 h, followed by administration with Aß 25-35 (10 µM) for 24 h. MTT assay and flow cytometer observe the effect of DNLA on Aß 25-35-induced cytotoxicity and apoptosis of PC12 cell. Based on the mitochondrial apoptosis pathway to study the antiapoptotic effect of DNLA on this model and its relationship with oxidative stress, flow cytometer detected the level of reactive oxygen species (ROS), and ELISA kits were used to detect superoxide dismutase activity (SOD) and glutathione (GSH) content in cells. The JC-1 fluorescent staining observed the effect of DNLA on the mitochondrial membrane potential (MMP) with inverted immunofluorescence microscopy. Western blot was used to detect the levels of mitochondrial apoptosis pathway-related protein and its major downstream proteins Bax, Bcl-2, cleaved-caspase-9, and cleaved-caspase-3. RESULTS: DNLA can significantly improve the viability and apoptosis rate of PC12 cell damage induced by Aß 25-35. It also can restore the reduced intracellular ROS content and MMP, while SOD activity and GSH content increase significantly. The expression of apoptosis-related protein Bax, cleaved-caspase-9, and cleaved-caspase-3 decreased when the Bcl-2 protein expression was significantly increased. CONCLUSION: These findings suggest that it can significantly inhibit the apoptosis of PC12 cell damage induced by Aß 25-35. The mechanism may reduce the level of cellular oxidative stress and thus inhibit the mitochondrial-mediated apoptosis pathway.

Signaling mechanisms underlying inhibition of neuroinflammation by resveratrol in neurodegenerative diseases.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), and Parkinson's disease (PD), are characterized by the progressive loss of the structure and function of neurons and most commonly occur in the elderly population. Microglia are resident macrophages of the central nervous system (CNS). The neuroinflammation caused by excessive microglial activation is closely related to the onset and progression of many NDs. Therefore, inhibiting excessive microglial activation is a potential drug target for controlling neuroinflammation. In recent years, natural products as modulators of microglial polarization have attracted considerable attention in the field of NDs therapy. Furthermore, resveratrol (RES) has been found to have a protective effect in NDs through the inhibition of microglial activation and the regulation of neuroinflammation. In this review, we mainly summarize the therapeutic potential of RES and its various molecular mechanisms in the treatment of NDs through the modulation of microglial activation.

Icariin protects against sodium azide-induced neurotoxicity by activating the PI3K/Akt/GSK-3ß signaling pathway.

BACKGROUND: Icariin (ICA) is one of the major active flavonoids extracted from the traditional Chinese herb Epimedium brevicornum Maxim and has been shown to have neuroprotective effects. This study was designed to investigate the effect of ICA on sodium azide (NaN3)-induced rat adrenal pheochromocytoma (PC12) cell damage and to further examine the underlying mechanisms. METHODS: To explore its possible mechanism, we used NaN3 (50 mM)-induced neuronal PC12 cell damage. Cell viability was evaluated by CCK-8 and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (MMP) was detected by JC-1. Glucose concentration was assessed by the glucose oxidase method. The role of ICA in the PI3K/Akt/GSK-3ß signaling pathway was explored by Western blotting. RESULTS: The results indicate that pretreatment with ICA reduced NaN3-induced cell damage and significantly reduced the leakage rate of LDH in PC12 cells. ICA pretreatment increased the MMP and a decrease in glucose concentration indicate increased glucose consumption. Furthermore, the protein levels of p-PI3K (p85), PI3K-110α, p-Ser473-Akt and p-Ser9-GSK-3ß were markedly decreased in PC12 cells after NaN3 treatment for 24 h, whereas these effects were reverted after pretreatment with ICA. Tau phosphorylation at the Ser396/404 and Thr217 sites was significantly decreased by pretreatment with ICA. CONCLUSIONS: These results suggest that ICA protects against NaN3-induced neurotoxicity in PC12 cells by activating the PI3K/Akt/GSK-3ß signaling pathway.

Neuroprotective Effects of Trilobatin, a Novel Naturally Occurring Sirt3 Agonist from Lithocarpus polystachyus Rehd., Mitigate Cerebral Ischemia/Reperfusion Injury: Involvement of TLR4/NF-κB and Nrf2/Keap-1 Signaling.

Aims: Neuroinflammation and oxidative stress are deemed the prime causes of brain injury after cerebral ischemia/reperfusion (I/R). Since the silent mating-type information regulation 2 homologue 3 (Sirt3) pathway plays an imperative role in protecting against neuroinflammation and oxidative stress, it has been verified as a target to treat ischemia stroke. Therefore, we attempted to seek novel Sirt3 agonist and explore its underlying mechanism for stroke treatment both in vivo and in vitro. Results: Trilobatin (TLB) not only dramatically suppressed neuroinflammation and oxidative stress injury after middle cerebral artery occlusion in rats, but also effectively mitigated oxygen and glucose deprivation/reoxygenation injury in primary cultured astrocytes. These beneficial effects, along with the reduced proinflammatory cytokines via suppressing Toll-like receptor 4 (TLR4) signaling pathway, lessened oxidative injury via activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, in keeping with the findings in vivo. Intriguingly, the TLB-mediated neuroprotection on cerebral I/R injury was modulated by reciprocity between TLR4-mediated neuroinflammatory responses and Nrf2 antioxidant responses as evidenced by molecular docking and silencing TLR4 and Nrf2, respectively. Most importantly, TLB not only directly bonded to Sirt3 but also increased Sirt3 expression and activity, indicating that Sirt3 might be a promising therapeutic target of TLB. Innovation: TLB is a naturally occurring Sirt3 agonist with potent neuroprotective effects via regulation of TLR4/nuclear factor-kappa B and Nrf2/Kelch-like ECH-associated protein 1 (Keap-1) signaling pathways both in vivo and in vitro. Conclusion: Our findings indicate that TLB protects against cerebral I/R-induced neuroinflammation and oxidative injury through the regulation of neuroinflammatory and oxidative responses via TLR4, Nrf2, and Sirt3, suggesting that TLB might be a promising Sirt3 agonist against ischemic stroke.

ROCK1 activation-mediated mitochondrial translocation of Drp1 and cofilin are required for arnidiol-induced mitochondrial fission and apoptosis.

BACKGROUND: Arnidiol is a pentacyclic triterpene diol that has multiple pharmacological activities. However, the apoptotic activities of arnidiol in human cancer cells have not yet been explored, nor has the mechanism by which arnidiol induces apoptosis been examined in depth. METHODS: MDA-MB-231 cells and xenografted mice were treated with arnidiol. Mitochondrial fission and apoptosis were determined by immunofluorescence, flow cytometry and related molecular biological techniques. The interaction and colocalization of cofilin and Drp1 was determined by immunoprecipitation and immunofluorescence assays. RESULTS: Arnidiol induces mitochondrial fission and apoptosis through mitochondrial translocation of Drp1 and cofilin. Importantly, the interaction of Drp1 and cofilin in mitochondria is involved in arnidiol-induced mitochondrial fission and apoptosis. Knockdown of either Drp1 or cofilin abrogated arnidiol-induced mitochondrial translocation, interaction of Drp1 and cofilin, mitochondrial fission and apoptosis. Only dephosphorylated Drp1 (Ser637) and cofilin (Ser3) were translocated to the mitochondria. Mutants of Drp1 S637A and cofilin S3A, which mimic the dephosphorylated forms, enhanced mitochondrial fission and apoptosis induced by arnidiol, whereas mutants of Drp1 S637D and cofilin S3E, which mimic the phosphorylated forms, suppressed mitochondrial fission and apoptosis induced by arnidiol. A mechanistic study revealed that ROCK1 activation plays an important role in the arnidiol-mediated Drp1 and cofilin dephosphorylation and mitochondrial translocation, mitochondrial fission, and apoptosis. CONCLUSIONS: Our data reveal a novel role of both Drp1 and cofilin in the regulation of mitochondrial fission and apoptosis and suggest that arnidiol could be developed as a potential agent for the treatment of human cancer.

Pharmacological effects of icariin.

Icariin (ICA) is a principal active component from traditional Chinese medicine Epimedium grandiflorum. To explain its traditional medical usages by modern science, a variety of pharmacological effects have been studied for ICA. In this review, we summarized the pharmacokinetics of ICA as well as its pharmacological mechanisms in neurodegenerative disease, cardiovascular disease, anti-osteoporosis, anti-inflammation, anti-oxidative stress, anti-depression and anti-tumors.

Icariside II inhibits lipopolysaccharide-induced inflammation and amyloid production in rat astrocytes by regulating IKK/IκB/NF-κB/BACE1 signaling pathway.

ß-amyloid (Aß) is one of the inducing factors of astrocytes activation and neuroinflammation, and it is also a crucial factor for the development of Alzheimer's disease (AD). Icariside II (ICS II) is an active component isolated from a traditional Chinese herb Epimedium, which has shown to attnuate lipopolysaccharide (LPS)-induced neuroinflammation through regulation of NF-κB signaling pathway. In this study we investigated the effects of ICS II on LPS-induced astrocytes activation and Aß accumulation. Primary rat astrocytes were pretreated with ICS II (5, 10, and 20 µM) or dexamethasone (DXMS, 1 µM) for 1 h, thereafter, treated with LPS for another 24 h. We found that ICS II pretreatment dose dependently mitigated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) in the astrocytes. Moreover, ICS II not only exerted the inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation, but also decreased the levels of Aß1-40, Aß1-42, amyloid precursor protein (APP) and beta secretase 1 (BACE1) in the astrocytes. Interestingly, molecular docking revealed that ICS II might directly bind to BACE1. It is concluded that ICS II has potential value as a new therapeutic agent to treat neuroinflammation-related diseases, such as AD.

CZYH Alleviates ß-Amyloid-Induced Cognitive Impairment and Inflammation Response via Modulation of JNK and NF-κB Pathway in Rats.

Cu-Zhi-Yi-Hao (CZYH), an empirical formula of traditional Chinese medicine (TCM), has been used for amnesia treatment in clinical practice. However, its underlying pharmacological mechanism has not been fully illuminated. The current study was designed to investigate the neuroprotective effect of CZYH on a ß-amyloid 25-35- (Aß 25-35-) induced learning and memory deficit rat model. CZYH (200, 400, or 800 mg/kg), donepezil (1.0 mg/kg), or distilled water was given to Aß 25-35-stimulated animals for 17 days consecutively. The Morris water maze test revealed that CZYH (400 or 800 mg/kg) administration improved the Aß 25-35-induced cognitive impairments in rats, and Nissl staining demonstrated that CZYH mitigated the Aß-caused neuron loss. In addition, CZYH treatment markedly inhibited the activation of microglia as evidenced by a decreased level of IBA-1 and increased YM-1/2 protein expression. The protein expression levels of TNF-α, IL-1ß, and COX-2 were also repressed by CZYH. Besides, CZYH treatment alleviated Aß-induced IκB-α degradation and NF-κB p65 phosphorylation, as well as reduced the JNK phosphorylation level. In conclusion, the present study suggests that CZYH could improve learning and memory abilities and relieve neuron loss in Aß 25-35-induced rats, at least partly through inhibition of the neuroinflammatory response via inhibiting the JNK-dependent NF-κB activation, indicating that CZYH might be a promising formula for the treatment of AD.

Resveratrol delays 6-hydroxydopamine-induced apoptosis by activating the PI3K/Akt signaling pathway.

This study aimed to determine whether resveratrol (Res) delays the progression of 6-hydroxydopamine (6-OHDA)-induced apoptosis via activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Sprague-Dawley (SD) rats were unilaterally injected with 6-OHDA (8 µg/4 µL) into the substantia nigra of the midbrain. Res (15 and 30 mg/kg) was given orally to the rats for a total of 36 days to examine its protective effects. We first tested whether Res can delay the progression of 6-OHDA-induced damage by measuring weight and performance on behavioral tests (rotarod, open field test and grid test) and further explored whether this effect is related to the activation of the PI3K/Akt signaling pathway using immunohistochemistry (IHC) and Western blotting (WB). Our results showed that the damage induced by 6-OHDA gradually worsened, while Res 30 mg/kg treatment significantly improved motor function and increased body weight. Compared with those in the model group, the number of dopaminergic neurons cells and the expression of PI3K-110α, p-Akt Ser473, and pro-caspase-3 in the Res 30 mg/kg group were significantly increased, and the Bax/Bcl-2 ratio and the level of activated caspase-3 was decreased. The results indicate that Res ameliorates 6-OHDA-induced apoptosis and motor dysfunction via activating the PI3K/Akt signaling pathway, delaying the progression of Parkinson's disease (PD) symptoms in this model.

Icariin protects rotenone-induced neurotoxicity through induction of SIRT3.

Sirtuin-3 (SIRT3) is a mitochondrial NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that icariin (ICA) is neuroprotective over various neurotoxicant induced oxidative stress. This study aimed to determine whether ICA exerts neuroprotective effects on rotenone (ROT)-induced neurotoxicity through activation of SIRT3. Rats treated with ROT exhibited a marked loss of dopamine (DA) neurons and a decline in motor function, along with a decrease in protein expressions of SIRT3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the substantia nigra (SN). Administration of ICA significantly alleviated the loss of DA neurons, improved behavioral function, and concomitantly enhanced SIRT3 and PGC-1α expressions. The neuroprotective effect of ICA on ROT-induced cytotoxicity was further confirmed in the PC12 cell model, which showed significant improvement in the survival of ROT-treated cells with ICA pretreatment. The cytoprotective effect of ICA was abolished in ROT-treated cells by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), along with a resultant decrease in PGC-1α expression. In addition, knockdown of PGC-1α by siRNA suppressed ICA-mediated protective effects but did not affect SIRT3 expression, indicating the role of regulation of PGC-1α by SIRT3 in the protective action of ICA. Furthermore, we showed that ICA improved mitochondrial respiration, oxidative status, enhanced antioxidant enzyme SOD activity and GSH/GSSG ratio in cells treated with ROT. However, these protective effects of ICA on ROT-treated cells was markedly abolished by SIRT3 inhibitor 3-TYP. Our findings demonstrate that ICA exerts a neuroprotective role through upregulation of SIRT3.