Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Curcumin ameliorates pulmonary fibrosis progression by inhibiting the fibrotic process of lung fibroblasts.

The objective of this study was to analyze the effect of curcumin (Cur) on pulmonary fibrosis (PF), so as to provide new clinical evidence for future PF treatment. To achieve these goals, the researchers set up bought human lung fibroblasts MRC-5 as a control group without treatment, a model group for PF cell modeling, and an intervention group for Cur intervention after PF modeling. Cell proliferation capacity and cellular TGF-ß1, α-SMA, Collagen I, Collagen III, Bax, N-cadherin and E-cadherin protein expression were determined. The results show that markedly enhanced cell proliferation capacity and TGF-ß1, α-SMA, Collagen I and Collagen III protein levels were observed in the model group, while the cell activity and fibrosis degree in the intervention group were significantly decreased compared with the model group (P<0.05). In addition, the intervention group exhibited lower N-cadherin and Bax with higher E-cadherin than the model group (P<0.05). In addition, the team found that the inflammatory response and oxidative stress were also more significantly improved in the intervention group (P<0.05). These experimental results tell us that Cur can ameliorate the fibrotic process of PF by inhibiting the activity of MRC-5.

Biochar amendments and climate warming affected nitrification associated N2O and NO production in a vegetable field.

Soil nitrification driven by ammonia-oxidizing microorganisms is the most important source of nitrous oxide (N2O) and nitric oxide (NO). Biochar amendment has been proposed as the most promising measure for combating climate warming; both have the potential to regulate the soil nitrification process. However, the comprehensive impacts of different aged biochars and warming combinations on soil nitrification-related N2O and NO production are not well understood. Here, 1-octyne and acetylene were used to investigate the relative contributions of ammonia-oxidizing bacteria (AOB) and archaea (AOA) to potential nitrification-mediated N2O and NO production from the fertilized vegetable soil with different aged biochar amendments and soil temperatures in microcosm incubations. Results demonstrated that AOB dominated nitrification-related N2O and NO production across biochar additions and climate warming. Biochar amendment did not significantly influence the relative contribution of AOB and AOA to N2O and NO production. Field-aged biochar markedly reduced N2O and NO production via inhibiting AOB-amoA gene abundance and AOB-dependent N2O yield while fresh- and lab-aged biochar produced negligible effects on AOB-dependent N2O yield. Climate warming significantly increased N2O production and AOB-dependent N2O yield but less so on NO production. Notably, the relative contribution of AOB to N2O production was enhanced by climate warming, whereas AOB-derived NO showed the opposite tendency. Overall, the results revealed that field-aged biochar contributed to mitigating warming-induced increases in N2O and NO production via inhibiting AOB-amoA gene abundance and AOB-dependent N2O yield. Our findings provided guidance for mitigating nitrogen oxide emissions in intensively managed vegetable production under the context of biochar amendments and climate warming.

Remifentanil preconditioning promotes liver regeneration via upregulation of ß-arrestin 2/ERK/cyclin D1 pathway.

Remifentanil is a potent, short-acting opioid analgesic drug that can protect tissues from ischemia and reperfusion injury though anti-inflammatory effects. However, the utility of remifentanil in liver regeneration after hepatectomy is not known. Using a 70% hepatectomy mouse model (PHx), we found that preconditioning animals with 4 µg/kg remifentanil enhanced liver regeneration through supporting hepatocyte proliferation but not through anti-inflammatory effects. These effects were also phenocopied in vitro where 40 mM remifentanil promoted the proliferation of primary mouse hepatocyte cultures. We further identified that remifentanil treatment increased the expression of ß-arrestin 2 in vivo and in vitro. Demonstrating specificity, remifentanil preconditioning failed to promote liver regeneration in liver-specific ß-arrestin 2 knockout (CKO) mice subjected to PHx. While remifentanil increased the expression of activated (phosphorylated)-ERK and cyclin D1 in PHx livers, their levels were not significantly changed in remifentanil-treated CKO mice nor in WT mice pretreated with the ERK inhibitor U0126. Our findings suggest that remifentanil promotes liver regeneration via upregulation of a ß-arrestin 2/ERK/cyclin D1 axis, with implications for improving regeneration process after hepatectomy.

Anthocyanin extract from Lycium ruthenicum enhanced production of biomass and polysaccharides during submerged fermentation of Agaricus bitorquis (Quél.) Sacc. Chaidam.

Agaricus bitorquis (Quél.) Sacc. Chaidam (ABSC) is a wild edible fungus uniquely found in the Tibet Plateau. ABSC is rich in polysaccharides that are considered biologically active. This study aimed to determine the feasibility of enhancing exopolysaccharide (EPS) production by ABSC in shake flask culture by supplementing the fermentation medium with anthocyanin extract. Different concentrations of Lycium ruthenicum Murr. (LRM) anthocyanin crude extract were tested on ABSC fermentation. The activity of phosphoglucose isomerase (PGI), phosphoglucose mutase (PGM), and phosphomannose isomerase (PMI), enzymes presumably involved in EPS synthesis by ABSC, was determined. ABSC transcriptomic profile in response to the presence of anthocyanins during fermentation was also investigated. LRM anthocyanin crude extract (0.06 mg/mL) was most effective in increasing EPS content and mycelial biomass (by 208.10% and 105.30%, respectively, P < 0.01). The activity of PGI, PGM, and PMI was increased in a medium where LRM anthocyanin extract and its main components (proanthocyanidins and petunia anthocyanin) were added. RNA-Seq analysis showed that 349 genes of ABSC were differentially expressed during fermentation in the medium containing anthocyanin extract of LRM; 93 genes were up-regulated and 256 genes down-regulated. From gene ontology enrichment analysis, differentially expressed genes were mostly assigned to carbohydrate metabolism and signal transduction categories. Collectively, LRM anthocyanins extract positively affected EPS production and mycelial biomass during ABSC fermentation. Our study provides a novel strategy for improving EPS production and mycelial growth during ABSC liquid submerged fermentation.

Dioscorea deltoidea Leaf Extract (DDLE) Targets PI3K/AKT/mTOR Pathway and Inhibits Ovarian Cancer Cell Growth.

Ovarian cancer is the malignant tumour of the female reproductive organ with highest mortality rate among all the types of gynaecological tumours. This study investigated the effect of Dioscorea deltoidea leaf extract (DDLE) on OV-90 and CAOV4 ovarian cancer cells. The results demonstrated that DDLE suppresses OV-90 and CAOV3 cell viability significantly in dose dependent manner. The OV-90 and CAOV3 cell viability were reduced to 24 and 27% respectively with 20 mg/mL DDLE treatment. Five mg/mL DDLE treatment of OV-90 and CAOV4 cells raised percentage of cells in G2-phase to 55.9 and 51.2%, respectively. In 5 mg/mL DDLE -treated OV-90 and CAOV4 cells a prominent suppression in cyclin-D1 and cyclin B1 proteins was observed in 48 h. The DDLE treatment promoted OV-90 and CAOV3 cell apoptosis to 34.65 and 29.89%, respectively. The Fas, FasL, cleaved caspase-3, and Bax levels were up-regulated markedly in the cells after DDLE treatment. Moreover, DDLE treatment suppressed p-mTOR, p-AKT and p-PI3K expression in OV-90 and CAOV3 cells. Thus, DDLE suppressed ovary cancer cell viability and elevated cell apoptosis. Inhibitory effect of DDLE on ovarian cancer cells is associated with targeting PI3K/AKT/mTOR pathway.

EpCAM inhibits differentiation of human liver progenitor cells into hepatocytes in vitro by activating Notch1 signaling.

In both normal turnover of the hepatic tissue and acute hepatic injury, the liver predominantly activates terminally differentiated hepatocytes to proliferate and repair. However, in chronic and severe chronic injury, this capacity fails, and liver progenitor cells (LPCs) can give rise to hepatocytes to restore both hepatic architecture and liver metabolic function. Although the promotion of LPC-to-hepatocyte differentiation to acquire a considerable number of functional hepatocytes could serve as a potentially new therapeutic option for patients with end-stage liver disease, its development first requires the identification of the molecular mechanisms driving this process. Here, we found that the epithelial cell adhesion molecule (EpCAM), a progenitor cell marker, regulates the differentiation of LPCs into hepatocytes through Notch1 signaling pathway. Western blotting (WB) revealed a consistent expression pattern of EpCAM and Notch1 during LPC-to-hepatocyte differentiation in vitro. Additionally, overexpression of EpCAM blocked LPC-to-hepatocyte differentiation, which was in consistent with the repressive role of Notch signaling during hepatic differentiation. WB and immunofluorescence data also showed that the upregulation of EpCAM expression increased the generation of Notch intracellular domain (N1ICD), indicating the promotion of Notch1 activity. Our results established the EpCAM-Notch1 signaling axis as an inhibitory mechanism preventing LPC-to-hepatocyte differentiation in vitro.

Protective role of histone deacetylase 4 from ultraviolet radiation-induced DNA lesions.

Ultraviolet B (UVB) exposure is a core factor that leads to skin disease or carcinogenesis through the insufficient repair of DNA lesions. UVB-induced DNA lesions are mainly removed by the nucleotide excision repair (NER) mechanism. The expression of histone deacetylase 4 (HDAC4) is altered in the skin upon UVB exposure, indicating its possible implication in UVB-induced DNA lesions repair. Here, we investigated the role of HDAC4 in the NER removal of the main classes of UVB-induced DNA lesions consisting of cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). We found that UVB irradiation increased HDAC4 expression at both the mRNA and protein levels. HDAC4 interacted with NER factor XPC, which played an important role in effectively removing the UVB-induced DNA lesions. This study provides an understanding of the HDAC4 function in DNA repair, which will allow the development of efficient strategies to protect the skin from UVR-induced diseases.

[Phenolic constituents from Wikstroemia chamaedaphne].

The phenolic constituents of Wikstroemia chamaedaphne were investigated by various column chromatographic methods including silica gel,Sephadex LH-20,ODS and preparative HPLC,and their chemical structures were identified by physico-chemical properties and spectral analyses. Thirteen phenolic compounds were isolated and elucidated,including five flavonoids: luteolin 7-O-ß-D-glucopyranoside(1),luteolin 4'-O-ß-D-glucopyranoside(2),kaempferol 3-O-ß-D-glucopyranoside(3),chrysoeriol 4'-O-ß-D-glucopyranoside(4),chrysoeriol(5); and eight lignans:(-)-secoisolariciresinol(6),acanthosessilin A(7),(-)-nortrachelogenin(8),(+)-isolariciresinol(9),sesamin(10),syringaresinol(11),(+)-epipinoresinol(12),and [3,3',4,4'-tetrahydro-6,6'-dimethoxy-3,3'-bi-2 H-benzopyran]-4,4'-diol(13). Compounds 1, 3, 5-8, 10, 11 and 13 were obtained from the plants of W. chamaedaphne for the first time,and compounds 1,5,7,10 and 13 were obtained from the Wikstroemia genus for the first time.

S100A4 protects mice from high-fat diet-induced obesity and inflammation.

As a member from S100 calcium-binding protein family, S100A4 is ubiquitous and elevated in tumor progression and metastasis, but its role in regulating obesity has not been well characterized. In this study, we showed that S100A4 was mainly expressed by stromal cells in adipose tissue and the S100A4 level in adipose tissue was decreased after high-fat diet (HFD). S100A4 deficient mice exhibited aggravated symptoms of obesity and suppressed insulin signaling after 12 weeks of HFD. Aggravated obesity in S100A4 deficient mice were found to be positively correlated with higher inflammatory status of the liver. Then, we found that extracellular S100A4 or overexpressed S100A4 inhibited adipogenesis and decreased mRNA levels of inflammation gene in 3T3-L1 adipocytes in vitro; whereas small interfering RNA (siRNA)-mediated suppression of S100A4 displayed the opposite results. Additionally, the protective effect induced by S100A4 during HFD-induced obesity was tightly related with activation of Akt signaling in adipose tissues, as well as livers and muscles. Taken together, we demonstrate that S100A4 is an inhibitory factor for obesity and attenuates the inflammatory reaction, while activating the Akt signaling, which suggest that S100A4 is a potential candidate for the treatment of diet-induced obesity and its complications.