Pharmacological effects of salidroside on central nervous system diseases.

Salidroside (SAL) is a phenylpropanoid glycoside monomer extracted from Rhodiola at high altitudes. It has been proven to have protective effects on myocardial injury, liver cancer, renal fibrosis, and other organ diseases, as well as play neuroprotective roles in central nervous system (CNS) diseases. Specifically, SAL can inhibit a series of pathological reactions in CNS diseases and improve neurological dysfunction. This review elucidated the pharmacological effects of SAL on inflammation, oxidative stress, apoptosis, autophagy, and neuronal regeneration. Furthermore, how SAL affects various signaling pathways to regulate pathological processes in CNS diseases is also assessed. However, the relationship between various pathways and the mechanisms in different pathological stages remains unclear. Additionally, the appropriate dosage and side effects of SAL on the clinical outcomes of CNS diseases have not been fully determined due to the limited number of clinical studies on SAL. Therefore, the regulatory mechanisms and clinical applications of SAL still need to be further demonstrated. This review tracked and summarized studies from the past eight years reported in databases, including PubMed, ScienceDirect, and Google Scholar, filtered using the keywords "salidroside" and/or paired with "diseases" and "CNS diseases".

Antioxidant and Immunomodulatory Activities of Essential Oil Isolated from Anti-Upper Respiratory Tract Infection Formulation and Their Chemical Analysis.

This study evaluates the in vitro antioxidant and immunomodulation activities of essential oils isolated from an anti-upper respiratory tract infection (URTI) formulation with a view to their therapeutic potential. The chemical components of the essential oil were analysed by gas chromatography-mass spectrometry (GC-MS). The antioxidative activity of the oils was investigated with regard to their ability to scavenge DPPH●, ABTS●+, and hydroxyl free radical (•OH). Their immunostimulatory activities were determined using murine macrophage cells. The main components of the oil with pharmacological and biological activities include 1,8-eucalyptol (42.9%), patchouli alcohol (19.9%), trans-erinolide (9.2%), and guaiacol (5%). The oils displayed high DPPH, ABTS, and hydroxyl radical scavenging activities and anti-inflammatory activities by reducing tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. The results indicate that essential oils have the potential to be used in products for anti-URTI treatment.

Effects of Sirtuin 1 on microglia in spinal cord injury: involvement of Wnt/ß-catenin signaling pathway.

Because posttraumatic inflammation contributes to the progression of neuron degeneration, attenuating inflammation is important for reducing neural degeneration. Sirtuin 1 (SIRT1) has been shown to play a critical role in the chronic diseases, such as neurodegenerative diseases and aging. However, the role that SIRT1 plays in regulating neuroinflammation in spinal cord injuries (SCIs) remains unclear. In this study, we investigate the effect of SIRT1 on the SCI model and on lipopolysaccharide (LPS)-treated primary microglia using a pharmacological intervention (SRT1720, an agonist of SIRT1). Results showed that SIRT1 levels gradually decreased in spinal cord until the fourth week after SCI, while the level of 8-hydroxy-2'-deoxyguanosine increased. SIRT1 was negatively correlated with the expression of ß-catenin following SCI. The administration of SRT1720 significantly improved number of neurons and the Basso, Beattie, and Bresnahan score after SCI. The number of ionizing calcium-binding adaptor molecule 1 (Iba1)-positive microglia, levels of ß-catenin and NF-kB p65, and proinflammatory cytokines [tumor necrosis factor alpha and interleukin (IL) 12] decreased significantly after SRT1720 treatment, while IL-10 increased after SCI. Furthermore, both SIRT1 and SRT1720 significantly inhibited ß-catenin gene and protein expression; ß-catenin transcriptional activity also decreased in a dose-dependent manner following SIRT1 treatment of LPS-treated microglia. These findings suggest that SIRT1 may have a neuroprotective effect by suppressing microglial activation via downregulation of the Wnt/ß-catenin signal following SCI.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes inflammation in mouse testes: The critical role of Klotho in Sertoli cells.

Increasing evidence shows that 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) enhances inflammation, and inflammation has a significant negative impact on fertility. Therefore, the aim of this study was to investigate the effects of TCDD on testis inflammation. Pregnant mice and primary Sertoli cells were treated with TCDD, and male offspring and Sertoli cells were treated with lipopolysaccharides(LPS). We then measured testis apoptotic cells, proinflammatory cytokines, and observed the Klotho/PDLIM2/p65 pathway. In vivo results revealed that TCDD further enhanced LPS-increased testis apoptotic cells and concentrations of testicular proinflammatory cytokines (IL1ß, IL18, and IL12) (p < 0.05). An in vitro investigation showed the levels of proinflammatory cytokines were increased in TCDD + LPS-treated cells compared with LPS-treated cells (p < 0.05). Compared with the LPS-treated cells, expression of Klotho and PDLIM2 was significantly decreased in TCDD + LPS-treated cells (p < 0.05), while expression of p65 and NLRP3 were significantly increased in the cotreatment cells (p < 0.05). However, the addition of Klotho to the TCDD + LPS-cotreated cells significantly increased PDLIM2 and decreased p65 activation and NLRP3 (p < 0.05). Meanwhile, mRNA levels and the secretion of proinflammatory cytokines were both suppressed by exogenous Klotho (p < 0.05). Administration of Klotho decreased TCDD + LPS-induced cytokines and apoptosis in mice (p < 0.05). Taken together, TCDD may increase testicular inflammation by affecting the secretion of proinflammatory cytokines in Sertoli cells via the Klotho/PDLIM2/p65 pathway, which influences the testicular microenvironment and induces germ cell apoptosis.

The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model.

Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs' transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I and ß-catenin were enhanced in the MNT group, while XAV939 (a ß-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF and ß-catenin could contribute to MDSCs' effects.

Klotho ameliorates cyclosporine A-induced nephropathy via PDLIM2/NF-kB p65 signaling pathway.

Klotho, an antiaging protein, can extend the lifespan and modulate cellular responses to inflammation and oxidative stress which can ameliorate chronic kidney diseases (CKD). To investigate the molecular mechanism of Klotho on inflammation in cyclosporine A (CsA) induced nephropathy, the mice were transfected with adenovirus mediated Klotho gene and treated with cyclosporine A (CsA; 30 mg/kg/day) for 4 weeks. Also, primary human renal proximal tubule epithelial cells (RPTECs) were treated with soluble Klotho protein and LPS. The results showed that Ad-klotho significantly reduced serum creatinine (Scr) and blood urea nitrogen (BUN) caused by CsA, and significantly increased creatinine clearance. Tubule interstitial fibrosis score (TIF), renal 8-OHdG excretion, macrophage infiltration and MCP-1 were decreased after Ad-klotho gene transfer. In addition, the overexpression of Klotho led to increase in the expression of PDLIM2, decreased in the amount of NF-kB p65, and inhibited the production of inflammatory cytokines (TNFα, IL-6, IL-12) and iNOS. Accordingly, in vitro results showed, Klotho enhanced PDLIM2 expression and reduced NF-kB p65 expression, while PDLIM2 siRNA could block the inhibitory effects of Klotho on expression of NF-kB p65. Secretion of inflammatory cytokines was also inhibited by Klotho treatment, and PDLIM2 siRNA hindered regulatory effects of Klotho on the cytokines. Real-time PCR and Luciferase assay showed that Klotho markedly increased expression of PDLIM2 mRNA and PDLIM2 reporter activity in a dose-dependent manner. These findings suggest that Klotho can modulate inflammation via PDLIM2/NF-kB p65 pathway in CsA-induced nephropathy.

VEGF inhibits the inflammation in spinal cord injury through activation of autophagy.

Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis and re-vascularization of spinal cord injury (SCI). VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neuron. However, the neuroprotective mechanism of VEGF is still unclear. The aim of this study was to investigate the effect of VEGF on spinal cord injury and its mechanisms. Young male Wistar rats were subjected to SCI and then VEGF165 were injected directly into the lesion epicenter 24 h post injury. We detected Basso, Beattie and Bresnahan (BBB) scores and numbers of motor neuron via Nissl staining. The expressions of autophagy related protein Beclin1 and LC3B were determined by Western blot and RT-PCR. We also detected the contents of inflammation factors interleukin-1ß (IL-1ß), tumor necrosis factor alpha (TNF-α) and interleukin-10(IL-10) in LPS (Lipopolysaccharide) treated spinal neuron-glia co-culture by ELISA. We found that VEGF165 administration increased the BBB score and reduced the loss of motor neuron of rats induced by SCI. VEGF decreased the protein expressions of IL-1ß, TNF-α and IL-10 and up-regulated the expressions of Beclin1 and LC3B of rats. In the in vitro study, VEGF165 decreased the levels of IL-1ß, IL-10 and TNF-a in the medium of LPS treated spinal neuron-glia co-culture, which was partially blocked by 3-MA, the inhibitor of autophagy. In addition, VEGF165 up-regulate the expressions of Beclin1 and LC3B in co-culture cells. The results suggested that VEGF165 attenuated the spinal cord injury by inhibiting the inflammation and increasing the autophagy function.

Protective effects of aerobic swimming training on high-fat diet induced nonalcoholic fatty liver disease: regulation of lipid metabolism via PANDER-AKT pathway.

This study aimed to investigate the mechanism by which aerobic swimming training prevents high-fat-diet-induced nonalcoholic fatty liver disease (NAFLD). Forty-two male C57BL/6 mice were randomized into normal-diet sedentary (ND; n = 8), ND exercised (n = 8), high-fat diet sedentary (HFD; n = 13), and HFD exercised groups (n = 13). After 2 weeks of training adaptation, the mice were subjected to an aerobic swimming protocol (60 min/day) 5 days/week for 10 weeks. The HFD group exhibited significantly higher mRNA levels of fatty acid transport-, lipogenesis-, and ß-oxidation-associated gene expressions than the ND group. PANDER and FOXO1 expressions increased, whereas AKT expression decreased in the HFD group. The aerobic swimming program with the HFD reversed the effects of the HFD on the expressions of thrombospondin-1 receptor, liver fatty acid-binding protein, long-chain fatty-acid elongase-6, Fas cell surface death receptor, and stearoyl-coenzyme A desaturase-1, as well as PANDER, FOXO1, and AKT. In the HFD exercised group, PPARα and AOX expressions were much higher. Our findings suggest that aerobic swimming training can prevent NAFLD via the regulation of fatty acid transport-, lipogenesis-, and ß-oxidation-associated genes. In addition, the benefits from aerobic swimming training were achieved partly through the PANDER-AKT-FOXO1 pathway.

Wnt signaling regulates hepatic metabolism.

The contribution of the Wnt pathway has been extensively characterized in embryogenesis, differentiation, and stem cell biology but not in mammalian metabolism. Here, using in vivo gain- and loss-of-function models, we demonstrate an important role for Wnt signaling in hepatic metabolism. In particular, ß-catenin, the downstream mediator of canonical Wnt signaling, altered serum glucose concentrations and regulated hepatic glucose production. ß-Catenin also modulated hepatic insulin signaling. Furthermore, ß-catenin interacted with the transcription factor FoxO1 in livers from mice under starved conditions. The interaction of FoxO1 with ß-catenin regulated the transcriptional activation of the genes encoding glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), the two rate-limiting enzymes in hepatic gluconeogenesis. Moreover, starvation induced the hepatic expression of mRNAs encoding different Wnt isoforms. In addition, nutrient deprivation appeared to favor the association of ß-catenin with FoxO family members, rather than with members of the T cell factor of transcriptional activators. Notably, in a model of diet-induced obesity, hepatic deletion of ß-catenin improved overall metabolic homeostasis. These observations implicate Wnt signaling in the modulation of hepatic metabolism and raise the possibility that Wnt signaling may play a similar role in the metabolic regulation of other tissues.

Expression and regulation of osteoprotegerin in adipose tissue.

PURPOSE: Osteoprotegerin (OPG), a potent inhibitor of osteoclastic bone resorption, has a variety of biological functions that include anti-inflammatory effects. Adipocytes and osteoblasts share a common origin, and the formation of new blood vessels often precedes adipogenesis in developing adipose tissue microvasculature. We examined whether OPG is secreted from adipocytes, therefore contributing to the prevention of neovascularization and protecting the vessels from intimal inflammation and medial calcification. MATERIALS AND METHODS: The mRNA expression of OPG and receptor activator of NF-kappaB ligand (RANKL) was measured in differentiated 3T3L1 adipocytes and adipose tissues. RESULTS: OPG mRNA expression increased with the differentiation of 3T3L1 adipocytes, while RANKL expression was not significantly altered. OPG mRNA was expressed at higher levels in white adipose tissue than in brown adipose tissue and was most abundant in the epididymal portion. In differentiated 3T3L1 adipocytes, Rosiglitazone and insulin reduced the OPG/RANKL expression ratio in a dose- and time- dependent manner. In contrast, tumor necrosis factor-alpha (TNF-alpha) increased the expression of both OPG and RANKL in a time-dependent manner. The OPG/RANKL ratio was at a maximum two hours after TNF-alpha treatment and then returned to control levels. Furthermore, OPG was abundantly secreted into the media after transfection of OPG cDNA with Phi C31 integrase into 3T3L1 cells. CONCLUSION: Our results indicate that OPG mRNA is expressed and regulated in the adipose tissue. Considering the role of OPG in obesity-associated inflammatory changes in adipose tissue and vessels, we speculate that OPG may have both a protective function against inflammation and anti-angiogenic effects on adipose tissue.