GAD1 alleviates injury-induced optic neurodegeneration by inhibiting retinal ganglion cell apoptosis.

The degeneration of the optic nerve narrows the visual field, eventually causing overall vision loss. This study aimed to identify global protein changes in the retina of optic nerve crushing (ONC) mice and to identify key regulators and pathways involved in injury-induced cell death during the progression of optic neurodegeneration. Label-free quantitative proteomics combined with bioinformatic analysis was performed on retinal protein extracts from ONC and sham-operated mice. Among the 1433 proteins detected, 121 proteins were differentially expressed in the retina of ONC mice. Further bioinformatic analysis showed that various metabolic pathways, including glutamate metabolism and γ-aminobutyric acid (GABA) synthesis, were significantly dysregulated in the injured mouse retinas. Glutamate decarboxylase 1 (GAD1) is the enzyme that converts glutamate into GABA, which was significantly up-regulated during ONC injury. Exogenous GAD1 treatment increased retinal ganglion cell (RGC) survival in the ONC-injured retina. In addition, changes in GAD1 expression were also observed in several other ophthalmic diseases. Vascular endothelial growth factor B (VEGF-B) has previously been reported to protect RGCs from apoptosis and positively regulated the expression of GAD1 in the retina. Notably, combination treatment with GAD1 and VEGF-B also provided strong protection against injury-induced RGC apoptosis. These results suggest that GAD1 expression may serve as an intrinsic protective mechanism that is commonly activated during retinal injury. Targeting GAD1 may serve as a potential strategy to treat optic neurodegenerative diseases.

Restoration Contributes to Maintain Ecosystem Services and Bio-Cultural Linkages Between Wetlands and Local Communities: a Case from a Botanical Diversity Hotspot in Japan.

The Circum-Ise Bay region in central Japan is characterized by a high concentration of species-rich seepage wetlands that provide various ecosystem services to local communities. However, the non-native conifers Cryptomeria japonica and Chamaecyparis obtusa have been widely introduced to the wetlands and compete with native plants. Here, we report the results of a 4-year restoration experiment that involved removing the conifers from a seepage wetland and observing the effects on plant composition, diversity, and ecosystem services to local communities. The experiment was conducted at a seepage wetland in Nakatsugawa city, Japan. The wetland includes many threatened and endemic plants but is also dominated by the conifers. We established three experimental plots within the wetland and removed the conifers from two of them. The stem density of overstory (i.e., canopy-tree) and understory (i.e., sub-canopy to shrub) layers in the conifer-removal plots decreased by 50% while simultaneously increasing the proportion of threatened woody plants by 14.3-50.0%. Despite these changes, plant species diversity in the groundcover layer remained high, and threatened and culturally important species became more concentrated on removal plots than on the control. We did not observe any negative regime shift, such as the establishment of introduced species. The restoration appeared to promote the occurrence of plants associated with bio-cultural linkages between the seepage wetland and local communities and that supply multiple ecosystem services. Supplementary Information: The online version contains supplementary material available at 10.1007/s13157-022-01639-2.

Role of vascular endothelial growth factor B in nonalcoholic fatty liver disease and its potential value.

Nonalcoholic fatty liver disease (NAFLD) refers to fatty liver disease caused by liver injury factors other than alcohol. The disease is characterized by diffuse fat infiltration, including simple steatosis (no inflammatory fat deposition), nonalcoholic fatty hepatitis, liver fibrosis, and so on, which may cause liver cirrhosis, liver failure, and even liver cancer in the later stage of disease progression. At present, the pathogenesis of NAFLD is still being studied. The "two-hit" theory, represented by lipid metabolism disorder and inflammatory reactions, is gradually enriched by the "multiple-hit" theory, which includes multiple factors, such as insulin resistance and adipocyte dysfunction. In recent years, vascular endothelial growth factor B (VEGFB) has been reported to have the potential to regulate lipid metabolism and is expected to become a novel target for ameliorating metabolic diseases, such as obesity and type 2 diabetes. This review summarizes the regulatory role of VEGFB in the onset and development of NAFLD and illustrates its underlying molecular mechanism. In conclusion, the signaling pathway mediated by VEGFB in the liver may provide an innovative approach to the diagnosis and treatment of NAFLD.

Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion.

BACKGROUND: Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes. AIM: To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT. METHODS: We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics. RESULTS: In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway. CONCLUSION: VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.

Circular RNA 4099 aggravates hydrogen peroxide-induced injury by down-regulating microRNA-706 in L02 cells.

AIMS: Hepatitis is a kind of liver dysfunction and usually refers to a variety of pathogenic factors. Circular RNA (circRNA) participates in diverse diseases. This study aimed to explore the roles and regulatory mechanisms of the circRNA-4099 in L02 cell line. MAIN METHODS: Cells were induced with H2O2 dilutions and transfected with circRNA-4099 overproduction vectoer and the specific siRNA (si-circRNA-4099), as well as microRNA-706 (miR-706) mimic or the corresponding controls. Cell viability was detected with the CCK-8. The apoptotic rate was determined by the annexin v-FITC/PI with flow cytometer. The expression of circRNA-4099 or miR-706 was quantified depending on qRT-PCR. The reactive oxygen species (ROS) level was examined through ROS assay. The relative proteins were individually determined via western blot. The relationship between the circRNA-4099 and miR-706 was detected through bioinformatics analysis and luciferase reporter assay. KEY FINDINGS: H2O2 induced inhibition of viability and promotion of apoptosis, ROS production and cell fibrosis as well as keap1/Nrf2 and p38MAPK cascades on L02 cell line. circRNA-4099 was stimulated by H2O2. Plentiful circRNA-4099 augmented H2O2-resulted damage by inhibiting miR-706. miR-706 mimic partly abolished the influence of circRNA-4099 on L02 cells. Meanwhile, circRNA-4099 silence exerted opposite effect on these elements above. SIGNIFICANCE: circRNA-4099 aggravated H2O2-induced injury by inhibiting miR-706 through triggering keap1/Nrf2 and p38MAPK in the L02 cells.

The safety and efficacy of dexmedetomidine-remifentanil in children undergoing flexible bronchoscopy: A retrospective dose-finding trial.

Flexible bronchoscopy is more and more used for diagnosis and management of various pulmonary diseases in pediatrics. As poor coordination of children, the procedure is usually performed under general anesthesia with spontaneous or controlled ventilation to increase children and bronchoscopists' safety and comfort. Previous studies have reported that dexmedetomidine (DEX) could be safely and effectively used for flexible bronchoscopy in both adulate and children. However, there is no trial to evaluate the dose-finding of safety and efficacy of dexmedetomidine-remifentanil (DEX-RF) in children undergoing flexible bronchoscopy.The objective of this study is to evaluate the dose-finding of safety and efficacy of DEX-RF in children undergoing flexible bronchoscopy.One hundred thirty-five children undergoing flexible bronchoscopy with DEX-RF were divided into 3 groups: Group DR1 (n = 47, DEX infusion at 0.5 µg·kg for 10 minutes, then adjusted to 0.5-0.7 µg kg h; RF infusion at 0.5 µg kg for 2 minutes, then adjusted to 0.05-0.2 µg kg min), Group DR2 (n = 43, DEX infusion at 1 µg kg for 10 minutes, then adjusted to 0.5-0.7 µg kg h; RF infusion at 1 µg kg for 2 minutes, then adjusted to 0.05-0.2 µg kg min), Group DR3 (n = 45, DEX infusion at 1.5 µg kg for 10 minutes, then adjusted to 0.5-0.7 µg kg h; RF infusion at 1 µg kg for 2 minutes, then adjusted to 0.05-0.2 µg kg min). Ramsay sedation scale of the 3 groups was maintained 3. Anesthesia onset time, total number of intraoperative children movements, hemodynamics (heart rate, arterial pressure, pulse oxygen saturation (SpO2), respiratory rate), total cumulative dose of dexmedetomidine and remifentanil, the amount of midazolam and lidocaine, time to first dose of rescue midazolam and lidocaine, postoperative recovery time, adverse events, bronchoscopist satisfaction score were recorded.Anesthesia onset time was significantly shorter in DR3 group (14.23 ±â€Š5.45 vs 14.45 ±â€Š5.12 vs 11.13 ±â€Š4.51 minutes, respectively, of DR1, DR2, DR3, P = 0.003). Additionally, the perioperative hemodynamic profile was more stable in group DR3 than that in the other 2 groups. Total number of children movements during flexible bronchoscopy was higher in DR1 group than the other 2 groups (46.81% 22/47 vs 34.88% 15/43 vs 17.78% 8/45, respectively, of DR1, DR2, DR3, P = 0.012). Total doses of rescue midazolam and lidocaine were significantly higher in DR1 and DR2 groups than that of DR3 group (P = 0.000). The time to first dose of rescue midazolam and lidocaine was significantly longer in DR3 group than DR1 and DR2 groups (P = 0.000). Total cumulative dose of dexmedetomidine was more in DR2 and DR3 groups (P = 0.000), while the amount of remifentanil was more in DR1 and DR2 groups (P = 0.000). The time to recovery for discharge from the PACU was significantly shorter in DR1 group compared with the other 2 groups (P = 0.000). Results from bronchoscopist satisfaction score showed significantly higher in DR2 and DR3 groups than that of DR1 group (P = 0.025). There were significant differences among the 3 groups in terms of the overall incidence of hypertension, tachycardia, hypoxemia, and cough (P < 0.05).Though it required longer recovery time, high dose of DEX-RF, which provided better stable hemodynamic profiles and bronchoscopist satisfaction score, less amount of rescue scheme, and children movements, could be safely and efficacy used in children undergoing flexible bronchoscopy.

Restorative effects of hydroxysafflor yellow A on hepatic function in an experimental regression model of hepatic fibrosis induced by carbon tetrachloride.

Hepatic fibrosis is a reversible pathological process, in which fibrotic tissue is excessively deposited in the liver during the repair process that follows hepatic injury. Early prevention or treatment of hepatic fibrosis has great significance on the treatment of chronic hepatic diseases. Hydroxysafflor yellow A (HSYA) is a water-soluble monomer extracted from safflower, which serves numerous pharmacological roles. However, it remains to be elucidated how HSYA regulates hepatic fibrogenesis. The aim of the present study was to reveal the possible mechanisms underlying the effects of HSYA on the prevention and treatment of hepatic fibrosis. A rat model of hepatic fibrosis was established in the present study, and the rats were administered various doses of HSYA. The effects of HSYA on pathological alterations of the liver tissue in rats with hepatic fibrosis were observed using hematoxylin-eosin staining and Masson staining. In order to explore the anti­hepatic fibrosis effects and underlying mechanisms of HSYA, serum levels, and hepatic function and hepatic fibrosis indices were evaluated. The results demonstrated that HSYA can improve the general condition of rats with hepatic fibrosis and relieve cellular swelling of the liver, fatty degeneration, necrosis, inflammatory cell infiltration and fibroplastic proliferation. Subsequent to administration of HSYA, globulin was increased during hepatic fibrosis caused by tetrachloromethane. However, total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase and levels of hyaluronic acid, laminin, procollagen â…¢ N­terminal peptide, collagen type â…£ and hydroxyproline were significantly reduced. The results additionally demonstrated that HSYA could enhance superoxide dismutase activity and reduce malondialdehyde levels, inhibiting lipid peroxidation caused by free radicals.