Breviscapine exerts neuroprotective effects through multiple mechanisms in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases and is characterized by progressive cognitive impairment and multiple neurological changes. To date, there are no effective drugs to delay or cure AD. Breviscapine (Bre) is an active ingredient of flavonoids extracted from breviscapus. Previous research suggests that Bre is an effective medicine for the prevention and treatment of AD. In the present study, we sought to explore the molecular mechanisms responsible for short-term beneficial effects of Breviscapine on Aß burden, neuronal and synaptic, cognitive function in APP/PS1 transgenic mice at 6 months age. Our results showed that 3 months of intraperitoneal treatment with Bre rescued learning deficits, relieved memory retention, improved the ability to explore the outside world, markedly decreased Aß burden, attenuated function of neocortical and hippocampal neuron, and increased the synaptic proteins levels in the brain of APP/PS1 mice by decreasing BACE1, promoting Aß-degrading enzyme IDE expression, suppressing RAGE expression, and regulating p38/p53/NT4 pathway. This finding provides more evidence of neuroprotective effects and action mechanisms of Bre antagonist AD, suggesting that Bre may have potential as anti-AD agent.

Total Saponins from Paris forrestii Reverse Multidrug Resistance of MCF-7/ADM Cells by Suppression of P-gp via ERK Signaling Pathway.

Our previous study demonstrated that the total saponins from Paris forristii (PCT3) had obvious inhibitory effect on the proliferation of adriamycin-resistant human breast adenocarcinoma cells (MCF-7/ADM), and this effect was significantly stronger than that in parental cells (MCF-7). This study was designed to test the reversal effect of PCT3 on MCF-7/ADM cells and to understand its mechanism of action. Results demonstrated that low cytotoxic concentrations of PCT3 (0.3, 1 and 3 µg/mL) reversed resistance of MCF-7/ADM cells to ADM, cisplatin (DDP) and 5-fluorouracil (5-FU), with reversal fold of 16.4, 19.5 and 31.7 for ADM, 1.6, 1.4 and 1.4 for DDP, 1.7, 1.8 and 5.6 for 5-FU, respectively. Moreover, PCT3 significantly increased the accumulation of ADM and Rhodamine 123 (Rh123) in MCF-7/ADM cells, suggesting that PCT3 may act by affecting the function of drug efflux pump P-glycoprotein (P-gp), which is encoded by MDR1 gene. Both MDR1 gene and P-gp protein expression was downregulated by PCT3 treatment. Further results demonstrated that p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway was remarkably activated in MCF-7/ADM cells, inhibition of p38 or ERK attenuated P-gp expression. While, only the phosphorylation level of ERK was downregulated by PCT3, indicating that PCT3 sensitized P-gp overexpressed MCF-7/ADM cells to ADM via inhibition of ERK signaling pathway.

Long non-coding RNA (LncRNA) RMST in triple-negative breast cancer (TNBC): Expression analysis and biological roles research.

Microarray showed that lncRNA RMST was differentially expressed in cervical cancer. Further experiments were conducted to detect the expression and biological function of RMST in triple-negative breast cancer (TNBC). Microarray was used to screen the differentially expressed lncRNAs in TNBC. QRT-PCR was applied to uncover the expression of RMST in TNBC tissues. The cell viability of RMST-transfected TNBC cells were probed by CKK-8 assay and colony formation assay. TUNEL assay was conducted to test the cell apoptosis and FCM assay was exerted to detect the cell cycle. The invasion and migration ability of transfected cells were examined by transwell assay. RMST played its biological function through regulating the mRNA or protein expression in cytoplasm. CCK-8 and colony formation assay unveiled that RMST could slow down the proliferation of TNBC cells to influence the tumor progression. TUNEL results revealed that RMST could enhance cell apoptosis in TNBC. The cell cycle detected by FCM assay indicated that RMST might induce the block of G0/G1 phase thus inhibiting TNBC cell proliferation. RMST overexpression could also restrain the invasion and migration abilities of TNBC cells. RMST played a role of tumor suppressor in TNBC through inhibiting cell proliferation, invasion and migration, enhancing cell apoptosis, and regulating cell cycle.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-ß (Aß) 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 Aß aggregation and attenuating Aß-induced oxidation in vitro. When given before or after the onset of Aß deposition via i.p. injection, Edaravone substantially reduces Aß 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.

Scutellarin Mitigates Aß-Induced Neurotoxicity and Improves Behavior Impairments in AD Mice.

Alzheimer's disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aß) within extracellular spaces of the brain. Aggregation of Aß has been shown to trigger oxidative stress, inflammation, and neurotoxicity resulting in cognitive dysfunction. In this study, we use models of cerebral Aß amyloidosis to investigate anti-amyloidogenic effects of scutellarin in vitro and in vivo. Our results show that scutellarin, through binding to Aß42, efficiently inhibits oligomerization as well as fibril formation and reduces Aß 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 Aß levels in the brain and plasma, decreases Aß 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.

Effects of astaxanthin on depressive and sleep symptoms: A narrative mini-review.

Major depressive disorder (MDD) is a prevalent psychiatric condition that results in persistent feelings of sadness and loss of interest, imposing a significant economic burden on health systems and society. Impaired sleep is both a symptom and a risk factor for depression. Natural astaxanthin (AST), a carotenoid primarily derived from algae and aquatic animals, possesses multiple pharmacological properties such as anti-inflammatory, anti-apoptotic, and antioxidant stress effects. Prior research suggests that AST may have antidepressant properties. This mini-review highlights the potential mechanisms by which AST can prevent depression, providing novel insights into drug research for depression treatment. Specifically, this mechanism suggests that astaxanthin may improve sleep and thus potentially aid in the treatment of depression.

Gastrodin ameliorates cognitive dysfunction in diabetes by inhibiting PAK2 phosphorylation.

Diabetes is associated with higher prevalence of cognitive dysfunction, while the underlying mechanism is still elusive. In this study, we aim to explore the potential mechanism of diabetes-induced cognitive dysfunction and assess the therapeutic effects of Gastrodin on cognitive dysfunction. Diabetes was induced by a single injection of streptozotocin. The Morris Water Maze Test was employed to assess the functions of spatial learning and memory. Transcriptome 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 in diabetic rats, coupled with damaged hippocampal pyramidal neurons. Gastrodin intervention ameliorated the spatial learning impairments and neuronal damages. Transcriptomics analysis identified differential expression genes critical for diabetes-induced hippocampal damage and Gastrodin treatment, which were further confirmed by qPCR and western blot. Moreover, p21 activated kinase 2 (PAK2) was found to be important for diabetes-induced hippocampal injury 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 could be a therapeutic target for Gastrodin intervention.

Roles of Cannabidiol in the Treatment and Prevention of Alzheimer's Disease by Multi-target Actions.

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.

Novel oral edaravone attenuates diastolic dysfunction of diabetic cardiomyopathy by activating the Nrf2 signaling pathway.

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.

Ginsenoside Rb1 exerts antidepressant-like effects via suppression inflammation and activation of AKT pathway.

Depression-like behaviors caused by chronic stress are related to inflammation and microglia activation. Antidepressant therapy may contribute to inhibiting inflammation responses and microglia activation. Ginsenoside Rb1 (GRb1) is known to display antidepressant-like effect on chronic unpredictable mild stress-induced depressive rats. However, the antidepressant-like effects of GRb1 on chronic restraint stress (CRS) mice and the potential anti-inflammatory mechanisms are unclear. Here, we focused on the molecular mechanisms related to inhibition of inflammation response and the protection on microglia. Our results showed that GRb1 had an antidepressant effects via relieving the depression-like behaviors in CRS model. Furthermore, GRb1 increased the protein expressions of brain-derived neurotrophic factor and phospho- protein kinase B/ protein kinase B (p-AKT/AKT), and decreased the protein expressions of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α) and ionized calcium binding adapter molecule 1 in hippocampus, reduced the levels IL-1ß and TNF-α in serum. Finally, GRb1 lowered the protein expressions of IL-1ß and TNF-α in BV-2 microglia induced by lipopolysaccharides. Taken together, the results indicate that GRb1 prevents CRS-induced depression-like behaviors in mice, which may be related to anti-inflammatory effects in hippocampus, serum and microglia and activation of AKT pathway.

Improving Alzheimer's disease by altering gut microbiota in tree shrews with ginsenoside Rg1.

Ginsenoside Rg1 (GRg1) has neuroprotective effects on Alzheimer's disease (AD). The occurrence and progression of AD are closely related to gut microbiota. Few studies have learned the direct relationship between GRg1 and gut microbiota. In this study, we found an original way to research this relationship by using GRg1 in the AD model of tree shrews. Morris water maze and immunohistochemistry were performed to test the cognition repairing function of GRg1 by tree shrews and 16S ribosomal RNA sequencing was used to explore the composition and abundance of gut microbiota. After GRg1 treatment, the result of Morris water maze showed an improvement in cognitive function, and immunohistochemistry revealed a decrease in tau protein. Moreover, 16SrRNA sequencing results showed the abundances of Proteobacteria and Verrucomicrobia were significantly different, and Lactobacillaceae was significantly increased in the GRg1 treatment group. It also showed that the gut microbiome with middle and high doses of GRg1 was close to the normal group. In conclusion, this study suggests that GRg1 at middle and high doses may change the abundance of gut microbiota to improve AD, and thatProteobacteria and Verrucomicrobia are key microbiota. This is the first report that has ever studied the relationship between GRg1 and gut microbiota in tree shrews.

Inhibition of NF-kappaB activation and iNOS induction by ent-kaurane diterpenoids in LPS-stimulated RAW264.7 murine macrophages.

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.

Sanyang Xuedai enhances the radiosensitivity of human non-small cell lung cancer cells via increasing iNOS/NO production.

OBJECTIVE: In this research, we aimed at finding out how San Yang Xue Dai (SYKT) promotes the radiosensitivity of non-small cell lung cancer (NSCLC) cell line NCI-H460. METHODS: Survival rate of NSCLC cells (A549, NCI-H460, NCI-H1650 and NCI-H1975) after the SYKT treatment or irradiation (IR) was calculated by the MTT assay. The radiosensitization of SYKT (0.5 g/mL and 1.0 g/mL) on cell line NCI-H460 and the radioresistant cell line NCI-H460R was studied by MTT assay and clone formation assay. The protein expression levels of iNOS, Cyclin B1 and CDC2 were determined by western blot, and the expression of NO was measured by Griess method. Finally, cell cycle and apoptotic rate of NSCLC cell line NCI-H460 were accessed by flow cytometry assay. BrdU staining was also applied to detect the cell proliferation after IR with or without SYKT treatment. RESULTS: The IC10 value of SYKT for NCI-H460 cells was 1.03 g/mL. After 1.0 g/mL SYKT treatment, the radiosensitivity of NCI-H460R cells was enhanced. The level of iNOS in the cells was found decreased after IR. We also found that SYKT could enhance iNOS and NO expressions while inhibit cyclin B1 and CDC2 expressions in radiation resistant cells. Combining ß-irradiation with SYKT caused cell cycle arrest in G2/M phase and increased cell apoptosis. CONCLUSION: SYKT resensitized radioresistant NCI-H460R cells via increasing cell apoptosis and cell cycle arrest. This was due to an elevated NO level caused by accumulating iNOS and effects of SYKT on radiosensitization of NSCLC should be further investigated in clinical application.

Sortilin inhibits amyloid pathology by regulating non-specific degradation of APP.

Amyloid plaque is one of the hallmarks of Alzheimer's disease (AD). The key component beta-amyloid (Aß) 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 9months old) but not young (2 and 5months old) AD mice (APP/PS1). 9months 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 9months 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.

Isolation of two bioactive ent-kauranoids from the leaves of Isodon xerophilus.

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).

Neuroprotective Effect of Fagopyrum dibotrys Extract against Alzheimer's Disease.

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 Aß peptide were evaluated in vitro. After 9-month treatment, FDE exhibited multifunctional properties on Aß-related pathologies, which cleaned Aß deposits in the brain and decreased Aß burden in the plasma, inhibited microhaemorrhage, and reduced reactive microglia in APP/PS1 transgenic mice and also promoted Aß fibrils disaggregation and inhibited neurotoxicity induced by Aß in SH-SY5Y cells. These results highlighted that FDE is an AD type pathology modulator with therapeutic potential against AD.

Evaluating the efficacy of post-surgery adjuvant therapies used for ductal carcinoma in situ patients: a network meta-analysis.

OBJECTIVE: Post-surgery adjuvant therapies are very important for patients suffering from ductal carcinoma in situ (DCIS). In this study we conducted a network meta-analysis (NMA) to evaluate the efficacy of different post-surgery adjuvant therapies including tamoxifen, anastrozole and radiation therapy (RT) and their combinations (RT+ tamoxifen and RT+ anastrozole). METHODS: We searched several databases, including Embase, MEDLINE / PUBMED, Cochrane Library, and Science Citation Index, for relevant studies. We then extracted the data from eligible studies in order to perform our NMA. We measured the comparative efficacy of each treatment option based on the calculated odds ratios (ORs) and the corresponding 95% credibility interval (95%CrI) for each treatment option. We calculated the surfaces under the cumulative ranking curves (SUCRA) in order to rank the therapies according to their different outcomes. RESULTS: In this study, local recurrence (LC) was chosen as the primary outcome. Metastasis, contralateral-breast cancer (CBC), ipsilateral-breast cancer (IBC) and death were secondary outcomes. Patients treated with RT and RT + tamoxifen exhibited a lower risk of LC compared with control group (OR=0.54, 95%CrI: 0.40-0.73; OR=0.41, 95%CrI: 0.19-0.90). Patients treated by RT and RT + tamoxifen also exhibited a significantly lower risk of IBC compared with control group (OR=0.55, 95%CrI: 0.37-0.82; OR=0.42, 95%CrI: 0.18-0.99). Results from the SUCRA indicated that RT + anastrozole and RT + tamoxifen were potentially the best adjuvant treatments for patients with DCIS. CONCLUSIONS: In conclusion, the RT + anastrozole and RT + tamoxifen are recommended for their performance and effectiveness.

Effects of (-)Epicatechin on the Pathology of APP/PS1 Transgenic Mice.

BACKGROUND: Alzheimer's disease (AD) is a multifactorial disorder characterized by the progressive deterioration of neuronal networks. The clearance of Aß from the brain and anti-inflammation are potential important strategies to prevent and treat disease. In a previous study, we demonstrated the grape seed extract (GSE) could reduce brain Aß burden and microglia activation, but which polyphenol plays a major role in these events is not known. Here, we tested pharmacological effects of (-)epicatechin, one principle polyphenol compound in GSE, on transgenic AD mice. METHODS: APP/PS1 transgenic mice were fed with (-)epicatechin diet (40 mg/kg/day) and curcumin diet (47 mg/kg/day) at 3 months of age for 9 months, the function of liver, Aß levels in the brain and serum, AD-type neuropathology, plasma levels of inflammatory cytokines were measured. RESULTS: Toward the end of the experiment, we found long-term feeding of (-)epicatechin diet was well tolerated without fatality, changes in food consumption, body weight, or liver function. (-)Epicatechin significantly reduced total Aß in brain and serum by 39 and 40%, respectively, compared with control diet. Microgliosis and astrocytosis in the brain of Alzheimer's mice were also reduced by 38 and 35%, respectively. The (-)epicatechin diet did not alter learning and memory behaviors in AD mice. CONCLUSION: This study has provided evidence on the beneficial role of (-)epicatechin in ameliorating amyloid-induced AD-like pathology in AD mice, but the impact of (-)epicatechin on tau pathology is not clear, also the mechanism needs further research.

Five new triterpene glycosides from Lysimachia foenum-graecum and evaluation of their effect on the arachidonic acid metabolizing enzyme.

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.