Puerarin prevents sepsis-associated encephalopathy by regulating the AKT1 pathway in microglia.

BACKGROUND: Previous studies have reported that puerarin possesses cardioprotective, vasodilatory, anti-inflammatory, anti-apoptotic, and hypoglycemic properties. However, the impact of puerarin on sepsis-associated encephalopathy (SAE) remains unexplored. In this study, we explored whether puerarin can modulate microglia-mediated neuroinflammation for the treatment of SAE and delved into the underlying mechanisms. METHODS: We established a murine model of SAE through intraperitoneal injection of lipopolysaccharide (LPS). The puerarin treatment group received pretreatment with puerarin. For in vitro experiments, BV2 cells were pre-incubated with puerarin for 2 h before LPS exposure. We employed network pharmacology, the Morris Water Maze (MWM) test, Novel Object Recognition (NOR) test, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), Western blotting, and quantitative real-time PCR (qRT-PCR) to elucidate the molecular mechanism of underlying puerarin's effects in SAE treatment. RESULTS: Our findings demonstrate that puerarin significantly reduced the production of inflammatory cytokines (TNF-α and IL-6) in the peripheral blood of LPS-treated mice. Moreover, puerarin treatment markedly ameliorated sepsis-associated cognitive impairment. Puerarin also exhibited inhibitory effects on the release of TNF-α and IL-6 from microglia, thereby preventing hippocampal neuronal cell death. Network pharmacology analysis identified AKT1 as a potential therapeutic target for puerarin in SAE treatment. Subsequently, we validated these results in both in vitro and in vitro experiments. Our study conclusively demonstrated that puerarin reduced LPS-induced phosphorylation of AKT1, with the AKT activator SC79 reversing puerarin's anti-inflammatory effects through the activation of the AKT1 signaling pathway. CONCLUSION: Puerarin exerts an anti-neuroinflammatory effect against SAE by modulating the AKT1 pathway in microglia.

Constrained DRL for Energy Efficiency Optimization in RSMA-Based Integrated Satellite Terrestrial Network.

To accommodate the requirements of extensive coverage and ubiquitous connectivity in 6G communications, satellite plays a more significant role in it. As users and devices explosively grow, new multiple access technologies are called for. Among the new candidates, rate splitting multiple access (RSMA) shows great potential. Since satellites are power-limited, we investigate the energy-efficient resource allocation in the integrated satellite terrestrial network (ISTN)-adopting RSMA scheme in this paper. However, this non-convex problem is challenging to solve using conventional model-based methods. Because this optimization task has a quality of service (QoS) requirement and continuous action/state space, we propose to use constrained soft actor-critic (SAC) to tackle it. This policy-gradient algorithm incorporates the Lagrangian relaxation technique to convert the original constrained problem into a penalized unconstrained one. The reward is maximized while the requirements are satisfied. Moreover, the learning process is time-consuming and unnecessary when little changes in the network. So, an on-off mechanism is introduced to avoid this situation. By calculating the difference between the current state and the last one, the system will decide to learn a new action or take the last one. The simulation results show that the proposed algorithm can outperform other benchmark algorithms in terms of energy efficiency while satisfying the QoS constraint. In addition, the time consumption is lowered because of the on-off design.

The Association Between Group Identity and Post-Traumatic Growth in the Post COVID-19 Era: The Mediating Effect of Social-Emotional Competence.

Purpose: To investigate the impact of human-society relationships on individual post-traumatic growth (PTG) in the post COVID-19 era, this study examined the association between group identity (GI) and PTG, and explored the mediating role of social-emotional competence (SEC). Patients and Methods: In this cross-sectional study, we surveyed 1203 high school students in an eastern region of China using the GI Scale, the SEC Scale, and the PTG Scale. We conducted correlation and mediation analyses using SPSS 23.0 and PROCESS software. Results: The results indicated that GI was a significant positive predictor of PTG (ß=0.219, p<0.001), and that the pathway between GI and PTG was partially mediated by SEC (Effect=0.074, 95% CI= [0.045,0.104]). Conclusion: GI can have both direct and indirect effects on PTG, with the latter mediated by SEC. These findings hold important theoretical and practical implications for promoting PTG and enhancing mental health in the post COVID-19 era.

Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia.

Sepsis is life-threatening organ dysfunction due to dysregulated systemic inflammatory and immune response to infection, often leading to cognitive impairments. Growing evidence shows that artemisinin, an antimalarial drug, possesses potent anti-inflammatory and immunoregulatory activities. In this study we investigated whether artemisinin exerted protective effect against neurocognitive deficits associated with sepsis and explored the underlying mechanisms. Mice were injected with LPS (750 µg · kg-1 · d-1, ip, for 7 days) to establish an animal model of sepsis. Artemisinin (30 mg · kg-1 · d-1, ip) was administered starting 4 days prior LPS injection and lasting to the end of LPS injection. We showed that artemisinin administration significantly improved LPS-induced cognitive impairments assessed in Morris water maze and Y maze tests, attenuated neuronal damage and microglial activation in the hippocampus. In BV2 microglial cells treated with LPS (100 ng/mL), pre-application of artemisinin (40 µΜ) significantly reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-6) and suppressed microglial migration. Furthermore, we revealed that artemisinin significantly suppressed the nuclear translocation of NF-κB and the expression of proinflammatory cytokines by activating the AMPKα1 pathway; knockdown of AMPKα1 markedly abolished the anti-inflammatory effects of artemisinin in BV2 microglial cells. In conclusion, atemisinin is a potential therapeutic agent for sepsis-associated neuroinflammation and cognitive impairment, and its effect is probably mediated by activation of the AMPKα1 signaling pathway in microglia.

The role of LR-TIMAP/PP1c complex in the occurrence and development of no-reflow.

BACKGROUND: The presence of no-reflow can increase the risk of major adverse cardiac events and is widely regarded as an important sign of serious prognosis. Previous studies show that laminin receptor (LR) is closely related to the morphology and function of microvessels. However, whether LR is involved in the occurrence and development of no-reflow is still unknown. METHODS: In vivo, positron emission tomography (PET) perfusion imaging was performed to detect the effects of intramyocardial gene (LR-AAV and LR-siRNA-AAV) delivery treatment on the degree of no-reflow. In vitro, LC-MS/MS analysis was conducted to identify the LR phosphorylation sites of human cardiac microvascular endothelial cells (HCMECs) treated with oxygen-glucose deprivation (OGD) for 4 h. Western blot analyses were used to evaluate the phosphorylation levels of LR at residues Tyr47 (phospho-Tyr47-LR/pY47-LR) and Thr125 (phospho-Thr125-LR/pT125-LR) and their effects on the phosphorylation of VE-cadherin residue Ser665 (phospho-Ser665-VE-cad). FINDINGS: LR over-expression, LRT125A (phosphonull) and LRY47A (phosphonull) treatments were found to reduce the level of phospho-Ser665-VE-cad, and subsequently maintain adherent junctions and endothelial barrier integrity in hypoxic environments. Mechanistically, TIMAP/PP1c can combine with LR on the cell membrane to form a novel LR-TIMAP/PP1c complex. The level of pY47-LR determined the stability of LR-TIMAP/PP1c complex. The binding of TIMAP/PP1c on LR activated the protein phosphatase activity of PP1c and regulated the level of pT125-LR. INTERPRETATION: This study demonstrates that low level of phospho-LR reduces no-reflow area through stabilizing the LR-TIMAP/PP1c complex and promoting the stability of adherens junctions, and may help identify new therapeutic targets for the treatment of no-reflow.

Preparation and Characterization of Protein-loaded PFC Nanoemulsions for the Treatment of Heart Diseases by Pulmonary Administration.

In the treatment of heart disease, strategies for the targeted delivery of protein therapeutics to the heart by inhalation are still immature. Perfluorocarbons (PFCs) are inert chemicals with good biocompatibility, and unique physico-chemical properties that have recently led to their applications in numerous fields. In this study, we combined the advantages of protein-phospholipid complexes and PFC emulsions and then synthesized protein-loaded PFC nanoemulsions (PNEs) to test whether, after inhalation, these nanoemulsions could deliver therapeutic proteins to the heart. After preparing protein-phospholipid complexes by lyophilization, we obtained PNEs by extrusion. The particle size and surface charge of PNEs were about 140 nm and -50 mV, respectively. In vitro results showed that the PNEs had a fine particle fraction of 35% and exhibited sustained protein release. Translocation studies were done using three types of pulmonary epithelial cells, and ~7% translocation was observed in the Calu-3 cell line. Further, they were easily absorbed by cells and had therapeutic effects in culture. In vivo results showed that the PNEs successfully delivered proteins to the myocardial tissue of rats and reduced ischemic myocardial injury caused by acute myocardial infarction (AMI). This study suggests that inhalation of PNEs is a new potential strategy to deliver proteins to cardiac tissues for treating heart diseases.

Novel angiogenesis strategy to ameliorate pulmonary hypertension.

OBJECTIVE: To select a suitable combination of classic angiogenic and vascular stabilization factors to improve the proliferation and maturity of neovascularization of lung tissue in a rat pulmonary arterial hypertension (PAH) model. METHODS: PAH rat model was established by intraperitoneal injection of monocrotaline. Proangiogenic factors hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), as well as vascular stabilization factors angiopoietin-1 (Ang-1), platelet-derived growth factor, and transforming growth factor-beta were transfected by pairs into the lung tissue of rats with PAH through lentivirus. Four weeks later, pulmonary artery angiography and hemodynamic parameters were determined to testify the remission of PAH. Immunofluorescence staining and Western blot were performed to investigate the structure and function of neovascularization. RESULTS: The pulmonary artery pressure and weight index of the right ventricle in HGF+Ang-1 and VEGF+Ang-1 groups were significantly decreased compared with vehicle group. The contrast medium filling time and right pulmonary artery root diameter were also significantly decreased. In addition, the maturity and perfusion of neovascularization in HGF+Ang-1 and VEGF+Ang-1 groups were promoted compared to vehicle group, and vascular leakage was reduced. Finally, the adherens junction integrity of vascular endothelial cells in HGF+Ang-1 and VEGF+Ang-1 combinations was upregulated compared with other combinations. CONCLUSIONS: HGF+Ang-1 transfection and VEGF+Ang-1 transfection alleviate PAH by promoting maturation and stability of new blood vessels, which may be potential candidates for PAH treatment.

Coronary Collateral Microcirculation Reserve Becomes Vestigial with Aging.

INTRODUCTION: Our previous study indicated that coronary collateral microcirculation reserve (CCMR), native collaterals, transports blood flow to an ischemic area to reduce ischemic tissue injury. This study aimed to observe the changes of CCMR in the hearts of different month-old rats. METHODS: We selected 2-, 8-, 16-, and 24-month-old rats as the research objects to monitor the changes of CCMR in rats with aging. After acute myocardial infarction, lectin-FITC was injected into the femoral vein vessels of rats to mark CCMR vessels in the ischemic area. RESULTS: Results of the lectin-FITC perfusion experiment indicated that the number and collagen IV coverage of CCMR vessels declined with aging. Moreover, data suggested a correlation between endothelial nitric oxide synthase and a decline in the number of CCMR vessels. CONCLUSION: Aging causes CCMR decline in rats.

Silencing of circFoxO3 Protects HT22 Cells from Glutamate-Induced Oxidative Injury via Regulating the Mitochondrial Apoptosis Pathway.

Recent studies demonstrated that FoxO3 circular RNA (circFoxO3) plays an important regulatory role in tumourigenesis and cardiomyopathy. However, the role of circFoxO3 in neurodegenerative diseases remains unknown. The aim of this study was to examine the possible role of circFoxO3 in neurodegenerative diseases and the underlying mechanisms. To model human neurodegenerative conditions, hippocampus-derived neurons were treated with glutamate. Using molecular and cellular biology approaches, we found that circFoxO3 expression was significantly higher in the glutamate treatment group than that in the control group. Furthermore, silencing of circFoxO3 protected HT22 cells from glutamate-induced oxidative injury through the inhibition of the mitochondrial apoptotic pathway. Collectively, our study demonstrates that endogenous circFoxO3 plays a key role in inducing apoptosis and neuronal cell death and may act as a novel therapeutic target for neurodegenerative diseases.

Pigment Epithelium-Derived Factor Increases Native Collateral Blood Flow to Improve Cardiac Function and Induce Ventricular Remodeling After Acute Myocardial Infarction.

Background We previously found that the structural defects of the coronary collateral microcirculation reserve (CCMR) prevent these preformed collateral vessels from continuously delivering the native collateral blood and supporting the ischemic myocardium in rats. Here, we tested whether these native collaterals can be remodeled by artificially increasing pigment epithelium-derived factor (PEDF) expression and demonstrated the mechanism for this stimulation. Methods and Results We performed intramyocardial gene delivery (PEDF-lentivirus, 2×107 TU) along the left anterior descending coronary artery to artificially increase the expression of PEDF in the tissue of the region for 2 weeks. By blocking the left anterior descending coronary artery, we examined the effects of PEDF on native collateral blood flow and CCMR. The results of positron emission tomography perfusion imaging showed that PEDF increased the native collateral blood flow and significantly inhibited its decline during acute myocardial infarction. In addition, the number of CCMR vessels decreased and the size increased. Similar results were obtained from in vitro experiments. We tested whether PEDF induces CCMR remodeling in a fluid shear stress-like manner by detecting proteins and signaling pathways that are closely related to fluid shear stress. The nitric oxide pathway and the Notch-1 pathway participated in the process of CCMR remodeling induced by PEDF. Conclusions PEDF treatment activates the nitric oxide pathway, and the Notch-1 pathway enabled CCMR remodeling. Increasing the native collateral blood flow can promote the ventricular remodeling process and improve prognosis after acute myocardial infarction.

PEDF increases GLUT4-mediated glucose uptake in rat ischemic myocardium via PI3K/AKT pathway in a PEDFR-dependent manner.

BACKGROUND: Targeted increase in glucose uptake of ischemic myocardium is a potential therapeutic strategy for myocardial ischemia. PEDF presents a profound moderating effect on glucose metabolism of cells, but its role is still controversial. Here, we try to demonstrate the direct effect of PEDF on glucose uptake in ischemic myocyte and to elucidate its underlying mechanism. METHODS AND RESULTS: Lentivirus vectors carrying PEDF gene were delivered into the myocardium to locally overexpress PEDF in a myocardial ischemia/reperfusion rat model. PET imaging showed that PEDF local overexpression increased [18F]-FDG uptake of ischemic myocardium. In vitro, PEDF directly increased the glucose uptake in hypoxic cardiomyocytes. The expression of glucose transporter 4 (GLUT4) on plasma membrane of hypoxic cardiomyocytes was significantly upregulated by PEDF, but its total amount was not changed. The increased glucose uptake and cardioprotective effects induced by PEDF were blocked by the GLUT4 inhibitor indinavir. PEDF-mediated GLUT4 translocation and glucose uptake increase in hypoxic cardiomyocytes were prevented by phosphatidyl-inositol-3 kinase (PI3K) inhibitor or AKT inhibitor. The PEDF-mediated glucose uptake was also diminished when PEDF receptor (PEDFR) was downregulated or potent phospholipase A2 enzymatic activity was inhibited. CONCLUSIONS: PEDF can increase glucose uptake in ischemic myocardium through a PEDFR-dependent mechanism, involving PI3K/AKT signaling and GLUT4 translocation.

Native Coronary Collateral Microcirculation Reserve in Rat Hearts.

Background We occasionally noticed that native collateral blood flow showed a recessive trend in the early stages of acute myocardial infarction in rats, which greatly interferes with the accurate assessment of native collateral circulation levels. Here, we sought to recognize the coronary collateral circulation system in depth, especially the microcirculation part, on this basis. Methods and Results In this study, we detected native collateral flow with positron emission tomography perfusion imaging in rats and found that the native flow is relatively abundant when it is initially recruited. However, this flow is extremely unstable in the early stage of acute myocardial infarction and quickly fails. We used tracers to mark the collateral in an ischemic area and a massive preformed collateral network was labeled. The ultrastructures of these collateral microvessels are flawed, which contributes to extensive leakage and consequent interstitial edema in the ischemic region. Conclusions An unrecognized short-lived native coronary collateral microcirculation reserve is widely distributed in rat hearts. Recession of collateral blood flow transported by coronary collateral microcirculation reserve contributes to instability of native collateral blood flow in the early stage of acute myocardial infarction. The immature structure determines that these microvessels are short-lived and provide conditions for the development of early interstitial edema in acute myocardial infarction.

A Charrelation Matrix-Based Blind Adaptive Detector for DS-CDMA Systems.

In this paper, a blind adaptive detector is proposed for blind separation of user signals and blind estimation of spreading sequences in DS-CDMA systems. The blind separation scheme exploits a charrelation matrix for simple computation and effective extraction of information from observation signal samples. The system model of DS-CDMA signals is modeled as a blind separation framework. The unknown user information and spreading sequence of DS-CDMA systems can be estimated only from the sampled observation signals. Theoretical analysis and simulation results show that the improved performance of the proposed algorithm in comparison with the existing conventional algorithms used in DS-CDMA systems. Especially, the proposed scheme is suitable for when the number of observation samples is less and the signal to noise ratio (SNR) is low.

Constraints on the early uplift history of the Tibetan Plateau.

The surface uplift history of the Tibetan Plateau and Himalaya is among the most interesting topics in geosciences because of its effect on regional and global climate during Cenozoic time, its influence on monsoon intensity, and its reflection of the dynamics of continental plateaus. Models of plateau growth vary in time, from pre-India-Asia collision (e.g., approximately 100 Ma ago) to gradual uplift after the India-Asia collision (e.g., approximately 55 Ma ago) and to more recent abrupt uplift (<7 Ma ago), and vary in space, from northward stepwise growth of topography to simultaneous surface uplift across the plateau. Here, we improve that understanding by presenting geologic and geophysical data from north-central Tibet, including magnetostratigraphy, sedimentology, paleocurrent measurements, and (40)Ar/(39)Ar and fission-track studies, to show that the central plateau was elevated by 40 Ma ago. Regions south and north of the central plateau gained elevation significantly later. During Eocene time, the northern boundary of the protoplateau was in the region of the Tanggula Shan. Elevation gain started in pre-Eocene time in the Lhasa and Qiangtang terranes and expanded throughout the Neogene toward its present southern and northern margins in the Himalaya and Qilian Shan.

Change and significance of T-cell subsets and TNF-α in patients with advanced malignant obstructive jaundice treated by percutaneous transhepatic biliary external and internal drainage.

The aim of this article was to study the influence of immunity function of advanced malignant obstructive jaundice (MOJ) treated by percutaneous transhepatic biliary external and internal drainage. Ninety-six cases of MOJ were divided into two groups according to the different ways of biliary drainage. Fifty-two external drainage tubes were placed in 41 cases of percutaneous transhepatic biliary external drainage group and 66 metal stents were placed in 55 cases of percutaneous transhepatic biliary internal drainage group. Liver function, serum TNF-α and cellular function were examined one day before operation and one week after operation and liver function was re-examined two weeks after operation, in order to observe the change and analyze the association among them and compare with the control group. All patients' conditions were improved after operation. In the percutaneous transhepatic biliary external and internal drainage groups, the total level of bilirubin decreased from (343.54±105.56) µmol/L and (321.19±110.50) µmol/L to (290.56±103.46) µmol/L and (283.72±104.95) µmol/L after operation respectively, which were significantly lower than pre-operation (P<0.05), but there was no significant difference between the two groups (P>0.05). Serum alanine aminotransferase (ALT) of all patients one week after operation was significantly lower than that before operation. TNF-α in percutaneous transhepatic biliary external and internal groups decreased from (108.58±19.95) pg/mL, (109.98±16.24) pg/mL of pre-operation to (104.32±19.59) pg/mL, (83.92±13.43) pg/mL of post-operation respectively, there was notable improvement (P<0.01) in internal drainage group after operation. Patients' serum CD4, CD3 and CD4/CD8 were notably increased, but CD8 was notably decreased (P<0.05). There was no difference in external drainage group (P>0.05). There was a significant difference between the two groups. Serum TNF-α and ALT had positive correlation. Percutaneous transhepatic biliary internal or external drainage was an effective and important method to treat MOJ. Patients' immune function was weak when they suffered MOJ, but body's cellular immune function can be notably improved after internal biliary drainage.

Differences in infarct evolution between lipopolysaccharide-induced tolerant and nontolerant conditions to focal cerebral ischemia.

OBJECT: Although brain tissue may be protected by previous preconditioning, the temporal evolution of infarcts in such preconditioned brain tissue during focal cerebral ischemia is largely unknown. Therefore, in this study the authors engaged in long-term observation with magnetic resonance (MR) imaging to clarify the difference in lesion evolution between tolerant and nontolerant conditions. METHODS: Bacterial lipopolysaccharide (LPS; 0.9 mg/kg) was administered intravenously to induce cross-ischemic tolerance. Focal cerebral ischemia was induced 72 hours later in spontaneously hypertensive rats. Serial brain MR images were obtained 6 hours, 24 hours, 4 days, 7 days, and 14 days after ischemia by using a 7.05-tesla unit. Lesion-reducing effects were evident 6 hours after ischemia in the LPS group. Preconditioning with LPS does not merely delay but prevents ischemic cell death by reducing lesion size. Lesion reduction was a sustained effect noted up to 14 days after ischemia. Reduction of local cerebral blood flow (ICBF) in the periinfarct area was significantly inhibited in the LPS group, which was correlated with endothelial nitric oxide synthase (eNOS) expression. CONCLUSIONS: Significant preservation of ICBF in the periinfarct area, which is relevant to sustained upregulation of eNOS, could be a candidate for the long-term inhibiting effect on infarct evolution in the LPS-induced tolerant state.