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Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol (CBD) possesses various pharmacological activities, including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for the treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system (eCBs), the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome proliferator-activated receptor (PPAR) receptor.

Severe burns predispose to shock and necessitate escharectomy and skin grafting. Previous studies show that mesenchymal stem cells are effective for burn wound healing and immune regulation. In this study, we combined escharectomy and skin grafting after burn injury with stem cell application, so as to examine the immune regulation of stem cells and the effect on the transplanted skin graft. SD rats were randomly divided into normal group, sham group, normal + hUCMSCs group, and normal + SB203580 group. Normal saline, hUCMSCs, and SB203580 were injected into the tail vein of each group, and serum inflammatory factors were detected by ELISA. The expression of p38 MAPK/NF-κB pathway proteins in rat liver was detected by western blot. Skin activity was detected by Trypan blue staining and western blot. Skin graft inflammatory infiltration was detected by histological analysis. We found that hUCMSCs could regulate the phosphorylation levels of P38MAPK and NF-B P65 proteins in the liver to reduce the inflammatory response. These effects could continue to reduce the production of inflammatory factors HMGB-1, IL-6, and TNF-α, and increase the anti-inflammatory factor IL-10. The infiltration of inflammatory cells in skin graft was significantly reduced in the normal + hUCMSCs group, and the macrophages in the hUCMSCs group polarized to the anti-inflammatory M2 direction in 3 days. However, the changes of skin graft activity and necroptosis markers protein RIP3 were not observed. The present study demonstrates the immunomodulatory effects of hUCMSCs on the systemic and skin graft microenvironment after excision.

Diabetes and cognitive dysfunction are highly prevalent disorders, while the underlying mechanism is still elusive. The effects of Gastrodin on central nervous system have been emphasized recently. In this study, we aim to explore the potential mechanism leading to cognitive dysfunction in diabetes and the therapeutic effect of Gastrodin. Diabetes was induced by a single injection of streptozotocin. RNA sequencing technique was used to identify the potential factors involved. Western blot and immunofluorescence were applied to detect the protein expression. Our results have shown that spatial learning was impaired and hippocampal pyramidal neurons were damaged in diabetic rats, which could be ameliorated by Gastrodin intervention. Transcriptional analysis identified differential expression genes, which were confirmed by qPCR and western blot. Furthermore, p21 activated kinase 2 (PAK2) was selected and its inhibitor could promote the survival of primary hippocampal neurons. It suggested that PAK2 pathway may be involved in cognitive dysfunction in diabetes and a therapeutic target for Gastrodin intervention.

Refereed/Peer-reviewed Oxidative stress plays a crucial role in the pathophysiology of diastolic dysfunction associated with diabetic cardiomyopathy. Novel oral edaravone (OED) alleviates oxidative stress by scavenging free radicals and may be suitable for the treatment of chronic diseases such as diabetic cardiomyopathy. Oral administration of OED to type 2 diabetic rats (induced by high-sugar/high-fat diet and intraperitoneal injection of streptozotocin) for 4 w decreased malondialdehyde and increased superoxide dismutase. Moreover, it significantly improved ratios of early to late diastolic peak velocity, myocardium hypertrophy accompanied by decreased cross-sectional areas of cardiomyocytes, the proportion of apoptotic cells, collagen volume fractions, and deposition of collagen I/III. In H9c2 cells, OED reduced reactive oxygen species, cell surface area, and numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells induced by glucolipotoxicity. OED remarkably upregulated expression of the nuclear factor E2-related factor (Nrf2) signaling pathway both in vivo and in vitro. In addition, OED promoted Nrf2 nuclear translocation and upregulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase and heme oxygenase. Silencing of Nrf2 abolished the protective effect of OED in H9c2 cells. Our findings demonstrate that OED has the therapeutic potential to ameliorate diastolic dysfunction associated with diabetic cardiomyopathy. Its effect was mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocyte hypertrophy, apoptosis, and fibrosis by activating the Nrf2 signaling pathway.

Background Diastolic dysfunction is the most common change of diabetic cardiomyopathy (DCM), but there is no effective clinical treatment at present. Oxidative stress plays a crucial role in the pathophysiological process of diabetic diastolic dysfunction including hypertrophy, apoptosis and fibrosis. The novel Oral-edaravone (OED) alleviates oxidative stress by scavenging free radical and may be suitable for the treatment of chronic diseases such as DCM. Methods DCM was induced by high sugar and high fat diet with intraperitoneal injection of streptozotocin (STZ) in rats. OED (3mg/kg/day) was administration for 4 weeks. Cardiac structure and function were measured using transthoracic echocardiography. H9C2 cardiomyocytes with Nrf2 transfection or not were incubated in glucolipotoxicity and treated with OED for 48 hours to further explore the mechanism. Results In type 2 diabetic rats,oral administration of OED for 4 weeks decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD). OED significantly improved E/A ratio and myocardium hypertrophy accompanied by decreased cross-sectional area of cardiomyocytes, proportion of apoptotic cells, collagen volume fractions and depositions of collagen I/III. In H9C2 cells, OED reduced reactive oxygen species (ROS), cell surface area and TUNEL-positive cells induced by glucolipotoxicity. OED remarkably up-regulated the expression of the Nrf2 signaling pathway both in vivo and in vitro, further promoted Nrf2 nuclear translocation and up-regulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase (NQO1) and heme oxygenase (HO-1). Moreover, Nrf2 gene silencing abolished the protective effect of OED in H9c2 cells. Conclusion Our findings demonstrated that OED treatment has the therapeutic potential to ameliorate diastolic dysfunction of DCM. The effect is mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocytes hypertrophy, apoptosis and fibrosis via activating the Nrf2 signaling pathway.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Evidence suggests that people can benefit from consumption of diets rich in plant phenolics because they can attenuate AD symptoms. The phenolic glucoside gastrodin is the main bioactive compound of Rhizoma Gastrodiae and is widely used for treating various neurological disorders. In this study, we assess whether long term oral administration of gastrodin can improve cognitive impairment and AD-like pathology. Our results showed that chronic gastrodin administration inhibits aggregation and disaggregate oligomeric and fibrillar species of A beta 42, prevents A beta 42 induced neurotoxicity in cell SH-SY5Y, decreases the levels of A beta plaques and hyperphosphorylated tau, alleviates activation of glial cells and proinflammatory cytokines, attenuates oxidative stress in the APP/PS1 transgenic mice. The mechanisms underlying can be attributed to the inhibition levels of enzymes of A beta and prevention GSK3 beta activity. Our results suggest that gastrodin might be a potential agent for the treatment of AD. Refereed/Peer-reviewed

Amyloid plaque is one of the hallmarks of Alzheimer's disease (AD). The key component beta-amyloid (Aβ) is generated via proteolytic processing of amyloid precursor protein (APP). Sortilin (encoded by the gene Sort1) is a vacuolar protein sorting 10 protein domain-containing receptor, which is up-regulated in the brain of AD, colocalizes with amyloid plaques and interacts with APP. However, its role in amyloidogenesis remains unclear. In this study, we first found that the protein level of sortilin was up-regulated in the neocortex of aged (7 and 9 months old) but not young (2 and 5 months old) AD mice (APP/PS1). 9 months old APP/PS1 transgenic mice with Sort1 gene knockout showed increased amyloid pathology in the brain; and this phenotype was rescued by intrahippocampal injection of AAV-hSORT1. Moreover, the 9 months old APP/PS1 mice without Sort1 also displayed a decreased number of neurons and increased astrocyte activation in the hippocampus. In addition, the present study showed that the intracellular domain of sortilin was involved in the regulation of the non-specific degradation of APP. Together, our findings indicate that sortilin is a beneficial protein for the reduction of amyloid pathology in APP/PS1 mice by promoting APP degradation. Refereed/Peer-reviewed

Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) within extracellular spaces of the brain. Aggregation of Aβ has been shown to trigger oxidative stress, inflammation, and neurotoxicity resulting in cognitive dysfunction. In this study, we use models of cerebral Aβ amyloidosis to investigate anti-amyloidogenic effects of scutellarin in vitro and in vivo. Our results show that scutellarin, through binding to Aβ42, efficiently inhibits oligomerization as well as fibril formation and reduces Aβ oligomer-induced neuronal toxicity in cell line SH-SY5Y. After nine months of treatment in APP/PS1 double-transgenic mice, scutellarin significantly improves behavior, reduces soluble and insoluble Aβ levels in the brain and plasma, decreases Aβ plaque associated gliosis and levels of proinflammatory cytokines TNF-α and IL-6, attenuates neuroinflammation, displays anti-amyloidogenic effects, and highlights the beneficial effects of intervention on development or progression of AD-like neuropathology. Refereed/Peer-reviewed

Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis. Refereed/Peer-reviewed

Chronic stress has been known as a main cause for human mood disorders. The understanding of the pathogenesis of the mood disorders are primarily based on the usage of animal models.Low reproducibility and complicacy of production are commonly known shortcomings in the current models with chronic stress. Here, we tested a simple stress paradigm, daily exposure of 6-min tail-suspension (TS), in modelling chronic stress-induced mood disorders in mice. We found that after 2-3-weeks of TS stress mice displayed a significant decrease in exploratory behavior, increases in anxiety-like and depression-like behaviors as well as significant decreases of NeuN and GFAP levels in the hippocampus. We also found that longer exposure of mice to TS stress (up to 4 weeks) resulted in significant adaptation of these responses and reversal of most of the behavioural and biochemical changes. This study suggests that chronicTS stress for 2-3 weeks could be used as a model of mood disorders usc Refereed/Peer-reviewed

The extracellular accumulation of amyloid beta protein (Aβ), reactive gliosis and cerebral amyloid angiopathy (CAA) play critical roles in the pathogenesis of Alzheimer’s disease (AD). Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported to exhibit strong neuroprotection against cytotoxic insults induced by oxidative stress and amyloid beta, but it remains unclear whether ginkgetin has therapeutic effect on Alzheimer’s disease (AD) in vivo. In the present study, we investigated 9 months treatment effects of ginkgetin diet in APP/PS1 mice. Our results show that ginkgetin can significantly reduce plasma Aβ levels 59% and Aβ plaque 51% in the brain of APP/PS1 transgenic mice (P

Accumulated evidence suggests that polyphenolic antioxidants present in herbs play important roles in prevention of AD; the molecular mechanisms behind neuroprotective actions rely on the phenols through different effects on the amyloid-aggregation pathway. Fagopyrum dibotrys is a traditional herbal medicine which contains high quantity phenols. In present study, we investigate the beneficial pharmacological actions of Fagopyrum dibotrys extract in the APP/PS1 transgenic mouse mode; meanwhile, effects of the FDE on the fibrillation and cytotoxicity of Aβ peptide were evaluated in vitro. After 9-month treatment, FDE exhibited multifunctional properties on Aβ-related pathologies, which cleaned Aβ deposits in the brain and decreased Aβ burden in the plasma, inhibited microhaemorrhage, and reduced reactive microglia in APP/PS1 transgenic mice and also promoted Aβ fibrils disaggregation and inhibited neurotoxicity induced by Aβ in SH-SY5Y cells. These results highlighted that FDE is an AD type pathology modulator with therapeutic potential against AD.

Accumulated evidence suggests that polyphenolic antioxidants present in herbs play important roles in prevention of AD; the molecular mechanisms behind neuroprotective actions rely on the phenols through different effects on the amyloid-aggregation pathway. Fagopyrum dibotrys is a traditional herbal medicine which contains high quantity phenols. In present study, we investigate the beneficial pharmacological actions of Fagopyrum dibotrys extract in the APP/PS1 transgenic mouse mode; meanwhile, effects of the FDE on the fibrillation and cytotoxicity of Aβ peptide were evaluated in vitro. After 9-month treatment, FDE exhibited multifunctional properties on Aβ-related pathologies, which cleaned Aβ deposits in the brain and decreased Aβ burden in the plasma, inhibited microhaemorrhage, and reduced reactive microglia in APP/PS1 transgenic mice and also promoted Aβ fibrils disaggregation and inhibited neurotoxicity induced by Aβ in SH-SY5Y cells. These results highlighted that FDE is an AD type pathology modulator with therapeutic potential against AD.

Isodon xerophilus has been used as a herbal cold tea for the prevention and treatment of sore throat and inflammation in southernwestern China. A phytochemical study on the ethyl acetate (EtOAc) soluble fraction of I. xerophilus leaves led to the isolation of two new ent-kauranoids, xerophinoids A (1) and B (2), together with 14 known diterpenoids. The structures of xerophinoids A (1) and B (2) were illustrated using spectroscopic methods including 1D and 2D NMR analyses. To study their biological activities, the effects of xerophinoids A (1) and B (2) on nitrite production, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were examined. In addition, xerophinoids A (1) and B (2) also exhibited potent cytotoxicity against several human tumor cell lines (IC50 < 11 microM), but they had no toxicity on human T-lymphocyte (C8166).

Five new oleanane-type triterpene saponins, named foenumosides A ( 1), B ( 2), C ( 3), D ( 4) and E ( 5), were isolated from the aerial parts of Lysimachia foenum-graecum Hance. Their structures were identified on the basis of 1D and 2D NMR techniques, including H-H COSY, HMQC, HMBC, HMQC-TOCSY, ROESY experiments as well as chemical methods. We have evaluated the cytotoxity of 1 - 5 against rat and human polymorphonuclear leukocytes and the effect of 5 on the arachidonic acid metabolizing enzyme. All compounds showed a high degree of toxicity except for compound 5, while 5 notably reduced the production of leukotriene B (4) (LTB (4)) from rat peritoneal leukocytes with an IC (50) value of 74 microM without inhibiting human elastase. Compound 5 also reduced the production of 12-HHTrE and 12-HETE by 14 % and 50 % as a measurement for cyclooxygenase-1 and 12-lipoxygenase inhibition at 100 microM.

Xerophilusin A (1), xerophilusin B (2), longikaurin B (3), and xerophilusin F (4) from Isodon xerophylus inhibit LPS-induced NO production in RAW 264.7 macrophages, with IC(50) values of 0.60, 0.23, 0.44, and 0.67 muM, respectively, and they all inhibited mRNA production in these same cells. They decreased the luciferase activity in RAW 264.7 cells transiently transfected with the NF-kappaB-dependent luciferase reporter, with IC(50) values of 1.8, 0.7, 1.2, and 1.6 muM, respectively. Compounds 1-3 reduced NF-kappaB activation, with compound 4 showing no effect, but p65 translocation from the cytoplasm to the nucleus and the LPS-induced degradation of IkappaB were inhibited by all four test compounds. These findings indicate that ent-kauranes are potential anti-inflammatory agents, with a specific mechanism in which both the inhibition of NF-kappaB translocation and the consequent decrease of pro-inflammatory mediators are implicated.

Refereed/Peer-reviewed Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by the pathological hallmarks of β-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Hyperoside, a flavone glycoside isolated from Rhododendron brachycarpum G. Don (Ericaceae), has neuroprotective effects against Aβ both in vitro and in vivo. However, whether hyperoside could delay AD pathogenesis remains unclear. In the present study, we observed if chronic treatment with hyperoside can reverse pathological progressions of AD in the APP/PS1 transgenic mouse model. Meanwhile, we attempted to elucidate the molecular mechanisms involved in regulating its effects. After 9 months of treatment, we found that hyperoside can improve spatial learning and memory in APP/PS1 transgenic mice, reduce amyloid plaque deposition and tau phosphorylation, decrease the number of activated microglia and astrocytes, and attenuate neuroinflammation and oxidative stress in the brain of APP/PS1 mice. These beneficial effects may be mediated in part by influencing reduction of BACE1 and GSK3β levels. Hyperoside confers neuroprotection against the pathology of AD in APP/PS1 mouse model and is emerging as a promising therapeutic candidate drug for AD.