Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury.

MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.

Salusin-ß Mediates High Glucose-Induced Inflammation and Apoptosis in Retinal Capillary Endothelial Cells via a ROS-Dependent Pathway in Diabetic Retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is characterized by retinal vascular endothelial cell death and vascular inflammation, which are microvascular complications of diabetes mellitus (DM). Salusin-ß, a newly identified peptide, is closely associated with hypertension, atherosclerosis and diabetic cardiomyopathy. However, the exact role of salusin-ß in high glucose (HG)-induced retinal capillary endothelial cell (REC) inflammation and apoptosis remains unclear. PATIENTS AND METHODS: A total of 60 patients with type 2 diabetes and 20 healthy controls were included in this study. Based on fundus fluorescein angiography findings, the diabetic patients were divided into three subgroups: diabetes without retinopathy (DWR), non-proliferative DR (NPDR) and proliferative DR (PDR). Serum salusin-ß levels were measured by enzyme-linked immunosorbent assay. Human RECs (HRECs) were cultured in normal glucose (NG) and HG medium with or without salusin-ß. Salusin-ß expression was analysed by Western blotting and immunofluorescence staining. Expression of the pro-inflammatory cytokines MCP-1, IL-1ß, TNF-α, and VCAM-1 was analysed by Western blotting. Reactive oxygen species (ROS) production was measured with 2',7'-dichlorofluorescein diacetate (DCFH-DA). Cell apoptosis rates were determined by flow cytometry. The levels of p38, JNK, p-p38, and p-JNK and the apoptosis-related proteins cleaved caspase-3, Bax, and cl2 were analysed by Western blotting. RESULTS: Serum salusin-ß levels were higher in diabetic patients than in healthy controls (p = 0.0027), especially in patients with NPDR and PDR (both p<0.01). HG upregulated salusin-ß expression in HRECs in a time-dependent manner. Salusin-ß exacerbated inflammation and apoptosis, upregulated intracellular ROS production in HG-induced HRECs, and activated ROS-dependent JNK and p38 MAPK signalling, while knockdown of salusin-ß suppressed these effects. CONCLUSION: Our findings indicate that salusin-ß can promote inflammation and apoptosis via ROS-dependent JNK and p38 MAPK signalling in HG-induced HRECs and could be a therapeutic target for DR.

Chemical components of the volatile oil from leaves of Cananga odorata and its anti-oxidant activity.

Cananga odorata (Lamk.) Hook. f. et Thoms., belonging to Annonaceae, is an evergreen tree. The oils extracted from its flower are a famous perfume and used in daily chemical and food industry. Although this plant has been widely cultivated in tropical regions of the world, the yield of oils from its flower is very limited. In order to develop the other parts of this plant, the chemical constituents of the volatile oils from the leaves of C. odorata was analyzed by gas chromatography/flame ionization detector (GC-FID) and GC/mass spectrometry (GC-MS). And the volatiles showed nitric oxide (NO) inhibitory activity with an IC50 value of 37.61µg/mL and anti-oxidant activity with an IC50 value of 3.84mg/mL, respectively.

Shikonofuran E plays an anti-inflammatory role by down-regulating MAPK and NF-κB signaling pathways in lipopolysaccharide-stimulated RAW264.7 macrophages.

The anti-inflammatory effects of shikonofuran E from Onosma paniculatum on RAW 264.7 murine macrophage cells induced by lipopolysaccharide (LPS) were first time examined. A series of non-cytotoxic concentrations of shikonofuran E (< 10 µM) treatments were found to reduce the accumulation of pro-inflammatory cytokine, including tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and inhibit the expression of nitric oxide synthase (iNOS) and cyclooxidase-2 (COX-2) in the LPS-stimulated macrophages as compared to the LPS-only treated cells. Nitric oxide (NO) production was also significantly suppressed in a dose-dependent manner (P < 0.05) with an IC50, the phosphorylation level of JNK of 3.5 µg/mL. In the anti-inflammatory pathway studies, ERK, p38 and IκBα were also decreased by shikonofuran E at 10 µM, in spite of the total levels of the MAPK isoforms and IκBα did not differ significantly. Our results indicate that shikonofuran E could exert an anti-inflammatory effect on LPS-induced RAW264.7 cells by down-regulating MAPK and NF-κB signaling pathways and regulating a series of cytokine production in lipopolysaccharide-stimulated RAW264.7 macrophages.

Neougonin A Inhibits Lipopolysaccharide-Induced Inflammatory Responses via Downregulation of the NF-kB Signaling Pathway in RAW 264.7 Macrophages.

Neougonin A is a prenylated flavonoid isolated from the whole plants of Helminthostachys zeylanica (Ophioglossaceae), which was usually used as traditional Chinese herbal medicine for the treatment of fever and inflammation. In this study, the pharmacological effects and underlying molecular mechanisms of neougonin A on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. We observed that neougonin A reduced the production of inflammatory mediators (TNFα, PGE2, NO, IL-1ß, and IL-6; P < 0.001) and inflammation-related proteins (iNOS and COX-2) induced by LPS in murine macrophage RAW 264.7 cells. Furthermore, Western blot and immunofluorescence analysis indicated that neougonin A could inhibit the phosphorylation of IkBα and block the translocation of NF-kB/p65 into the nucleus even at 1.25 µM (P < 0.05), but have no effect on JNK, ERK1/2, and p38MAPK phosphorylation. It was suggested that the anti-inflammatory actions of neougonin A might be due to the downregulation of TNFα, IL-1ß, IL-6, NO, and PGE2 via the suppression of NF-kB signal transduction pathway.

New 3,4-seco-Grayanane Diterpenoids from the Flowers of Pieris japonica.

Three new 3,4-seco-grayanane diterpenoids, neopierisoids D-F (2-4), and a new natural one, neopierisoid C (1), were isolated from the flowers of Pieris japonica. Their structures were elucidated on the basis of extensive spectroscopic analysis, including one and two dimensional (1- and 2D)-NMR, as well as high resolution-electron ionization (HR-EI)-MS.

Anti-inflammatory Prenylated Flavonoids from Helminthostachys zeylanica.

Two new [neougonins A (1) and B (2)] and nine known prenylated flavonoids were isolated from the whole plants of Helminthostachys zeylanica. The structures of the new isolates were elucidated by extensive NMR techniques, including one and two dimensional (1D)- and (2D)-NMR experiments, as well as comparison with spectroscopic data of known analogous compounds. Moreover, compound 1 inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells with an IC50 value of 3.32 µM.

[Effects of glycosides components and combinations of Buyang Huanwu decoction on vascular smooth muscle cells proliferation and related signaling pathway].

This paper was aimed to explore the effects of glycosides, the effective component of Buyang Huanwu decoction, and its main active components such as astragaloside Ⅳ, amygdalin, peoniflorin and their combinations on vascular smooth muscle cells (VSMC) proliferation, clarify the major active materials of anti-VSMC proliferation and investigate the mechanisms via the signal transduction pathway. Plasma containing drug was prepared via oral administration in rats. VSMCs of rats aorta were cultured, and then VSMC proliferation was stimulated by using platelet derived growth factor (PDGF).The plasma containing drug was added to detect the activity of cell proliferation, cell cycle and related protein expressions of signaling pathway such as extracellular signal-regulated kinase (ERK), phos-phatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and Janus kinase/signal transducer and activator of transcription (JAK/STAT). After being stimulated by PDGF, the proliferation activity of VSMC was strengthened (P<0.01), G0/G1 phase cells were decreased (P<0.01), S/M phase cells were increased (P<0.01), and PcNA, cyclin D1 protein expressions related to cell cycle were up-regulated (P<0.01). Glycosides, astragaloside Ⅳ, amygdalin, peoniflorin and their combinations could inhibit the cell proliferation (P<0.05 or P<0.01) in a dose-effect relationship and time-effect relationship. They could increase G0/G1 phase cells (P<0.01), decrease S/M phase cells (P<0.01), and down-regulate the protein expressions of PCNA, cyclin D1 (P<0.01); and the effects of the combinations were greater than those of single active component (P<0.05). After VSMC proliferation was induced by PDGF, p-ERK1/2 expression was increased (P<0.01), PI3K expression was down-regulated while p-PI3K expression was up-regulated (all P<0.01), and STAT3expression was reduced while p-STAT3 expression was increased (all P<0.01). Glycosides, astragaloside Ⅳ, amygdalin, peoniflorin and the combinations of these active components could reduce p-ERK1/2 expression (P<0.05), increase PI3K expression (P<0.01), decreasep-PI3K expression (P<0.05 or P<0.01), increase STAT3 expression (P<0.01), and decrease p-STAT3 expression (P<0.05 or P<0.01). These results suggested that PDGF could induce the cell cycle conversion of VSMC, leading to VSMC proliferation. The mechanism was related to the activation of ERK, PI3K/Akt and JAK/STAT signaling pathways. Glycosides and its main active components such as astragaloside Ⅳ, amygdalin, peoniflorin and their combinations can inhibit the cell cycle conversion of VSMC, with the effect against VSMC proliferation, and the mechanisms may be associated with the inhibition of PI3K/Akt, mitogen-activated protein kinase (MAPK) and JAK/STAT signaling pathways. astragaloside Ⅳ, amygdalin and peoniflorin were the major active materials of anti-VSMC proliferation, and their combination showed enhanced effect.

Safety-information-driven human mobility patterns with metapopulation epidemic dynamics.

With the help of mass media, people receive information concerning the status of an infectious disease to guide their mobility. Herein, we develop a theoretical framework to investigate the safety-information-driven human mobility with metapopulation epidemic dynamics. Individuals respond to the safety information of a city by taking safe moves (passing cities with a more number of healthy individuals) or unsafe moves (passing cities with a less number of healthy individuals). Our findings show that the critical threshold depends on mobility in such a way that personal execution of safe moves unexpectedly promotes the global spread of a disease, while unsafe moves counterintuitively cause a locally, relatively small outbreak size. Our analysis underlines the role of safety consideration in the spatial spread of an infectious disease with clear implications for the model of mobility driven by individuals' benefit.

Impacts of clustering on interacting epidemics.

Since community structures in real networks play a major role for the epidemic spread, we therefore explore two interacting diseases spreading in networks with community structures. As a network model with community structures, we propose a random clique network model composed of different orders of cliques. We further assume that each disease spreads only through one type of cliques; this assumption corresponds to the issue that two diseases spread inside communities and outside them. Considering the relationship between the susceptible-infected-recovered (SIR) model and the bond percolation theory, we apply this theory to clique random networks under the assumption that the occupation probability is clique-type dependent, which is consistent with the observation that infection rates inside a community and outside it are different, and obtain a number of statistical properties for this model. Two interacting diseases that compete the same hosts are also investigated, which leads to a natural generalization of analyzing an arbitrary number of infectious diseases. For two-disease dynamics, the clustering effect is hypersensitive to the cohesiveness and concentration of cliques; this illustrates the impacts of clustering and the composition of subgraphs in networks on epidemic behavior. The analysis of coexistence/bistability regions provides significant insight into the relationship between the network structure and the potential epidemic prevalence.

The σ law of evolutionary dynamics in community-structured population.

Evolutionary game dynamics in finite populations provide a new framework to understand the selection of traits with frequency-dependent fitness. Recently, a simple but fundamental law of evolutionary dynamics, which we call σ law, describes how to determine the selection between two competing strategies: in most evolutionary processes with two strategies, A and B, strategy A is favored over B in weak selection if and only if σR+S>T+σP. This relationship holds for a wide variety of structured populations with mutation rate and weak selection under certain assumptions. In this paper, we propose a model of games based on a community-structured population and revisit this law under the Moran process. By calculating the average payoffs of A and B individuals with the method of effective sojourn time, we find that σ features not only the structured population characteristics, but also the reaction rate between individuals. That is to say, an interaction between two individuals are not uniform, and we can take σ as a reaction rate between any two individuals with the same strategy. We verify this viewpoint by the modified replicator equation with non-uniform interaction rates in a simplified version of the prisoner's dilemma game (PDG).

Rendezvous effects in the diffusion process on bipartite metapopulation networks.

Epidemic outbreaks have been shown to be closely related to the rendezvous-induced transmission of infection, which is caused by casual contact with infected individuals in public gatherings. To investigate rendezvous effects in the spread of infectious diseases, we propose an epidemic model on metapopulation networks bipartite-divided into two sets of location and rendezvous nodes. At a given transition rate γ(kk')(p), each individual transfers from location k to rendezvous p (where rendezvous-induced disease incidence occurs) and thereafter moves to location k'. We find that the eigenstructure of a transition-rate-dependent matrix determines the epidemic threshold condition. Both analytical and numerical results show that rendezvous-induced transmission accelerates the progress of infectious diseases, implying the significance of outbreak control measures including prevention of public gatherings or decentralization of a large-scale rendezvous into downsized ones.

Evolution of cooperation on adaptively weighted networks.

Recent studies have explored interactions between evolutionary game dynamics and population structure. Yet most studies so far mainly paid attention to unweighted and static networks. Here we explore evolutionary games played on dynamically weighted networks. Players update their strategies according to the payoffs they obtain. Players also update weights of their adjacent links depending on payoffs they gain through those links; profitable links are reinforced whereas unprofitable ones are weakened. The system is characterized by two time scales, the one for strategy update, ß(S), and the other for weight adjustment, ß(W). We find that, under a mean-field approximation, the asymptotic behavior of the system is described by the replicator equation with an effective payoff matrix, which is a combination of the original game matrix A and its transpose, A(T). Both analytical and numerical results show that such an adaptive weight adjustment mechanism dramatically promotes evolution of cooperation.

Largest Laplacian eigenvalue predicts the emergence of costly punishment in the evolutionary ultimatum game on networks.

In recent years, there has been a growing interest in studying the role of costly punishment in promoting altruistic behaviors among selfish individuals. Rejections in ultimatum bargaining as a metaphor exemplify costly punishment, where the division of a sum of resources proposed by one side may be rejected by the other side, and both sides get nothing. Under a setting of the network of contacts among players, we find that the largest Laplacian eigenvalue of the network determines the critical division of players' proposals, below which pure punishers who never accept any offers will emerge as a phase transition in the system. The critical division of offers that predicts the emergence of costly punishment is termed as the selfishness tolerance of a network within evolutionary ultimatum game, and extensive numerical simulations on the data of the science collaboration network, and computer-generated small-world/scale-free networks support the analytical findings.

Mixed evolutionary strategies imply coexisting opinions on networks.

An evolutionary battle-of-the-sexes game is proposed to model the opinion formation on networks. The individuals of a network are partitioned into different classes according to their unaltered opinion preferences, and their factual opinions are considered as the evolutionary strategies, which are updated with the birth-death or death-birth rules to imitate the process of opinion formation. The individuals finally reach a consensus in the dominate opinion or fall into (quasi)stationary fractions of coexisting mixed opinions, presenting a phase transition at the critical modularity of the multiclass individuals' partitions on networks. The stability analysis on the coexistence of mixed strategies among multiclass individuals is given, and the analytical predictions agree well with the numerical simulations, indicating that the individuals of a community (or modular) structured network are prone to form coexisting opinions, and the coexistence of mixed evolutionary strategies implies the modularity of networks.

Consensus in a heterogeneous influence network.

We consider a dynamical network model in which a number of agents all move on the plane with the same constant absolute velocity. At each time step, each agent's direction is updated as the average of its direction plus the directions of other agents who can influence it. The influencing capability of each agent is represented by its influencing radius, which is randomly chosen according to a power-law distribution with a scaling exponent between 2 and infinity. As the value of the scaling exponent decreases, the radius distribution becomes more heterogeneous and the network becomes much easier to achieve direction consensus among agents due to the leading roles played by a few hub agents. Furthermore, almost all agents will finally move in the same desired direction in a strong heterogeneous influence network, if and only if a small fraction of hub agents can be controlled to move in the desired direction. These results also reflect the "robust yet fragile" feature of a heterogeneous influence network.