Restoration of CD3+CD56+ NKT-like cell function by TIGIT blockade in inactive carrier and immune tolerant patients of chronic hepatitis B virus infection.

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.

Spatial transcriptomics reveals heterogeneity of macrophages in the tumor microenvironment of granulomatous slack skin.

Granulomatous slack skin (GSS) is an extremely rare subtype of cutaneous T-cell lymphoma accompanied by an abundant number of macrophages and is clinically characterized by the development of pendulous skin folds. However, the characteristics of these macrophages in GSS remain unclear. Here, we conducted a spatial transcriptomic study on one frozen GSS sample and drew transcriptomic maps of GSS for the first time. Gene expression analysis revealed the enrichment of three clusters with macrophage transcripts, each exhibiting distinct characteristics suggesting that their primary composition consists of different subpopulations of macrophages. The CD163+ /CD206+ cluster showed a tumor-associated macrophage (TAM) M2-like phenotype and highly expressed ZFP36, CCL2, TNFAIP6, and KLF2, which are known to be involved in T-cell interaction and tumor progression. The APOC1+ /APOE+ cluster presented a non-M1 or -M2 phenotype and may be related to lipid metabolism. The CD11c+ /LYZ+ cluster exhibited an M1-like phenotype. Notably, these cells strongly expressed MMP9, MMP12, CHI3L1, CHIT1, COL1A1, TIMP1, and SPP1, which are responsible for extracellular matrix (ECM) degradation and tissue remodeling. This may partially explain the symptoms of cutaneous relaxation in GSS. Further immunohistochemistry on four GSS cases demonstrated that CD11c predominantly marked granulomas and multinucleated giant cells, whereas CD163 was mainly expressed on scattered macrophages, appearing as a mutually exclusive pattern. The expression pattern of MMP9 overlapped with that of CD11c, implying that CD11c+ macrophages may be a source of MMP9. Our data shed light on the characteristics of macrophages in the GSS microenvironment and provide a theoretical basis for the application of MMP9 inhibitors to prevent cutaneous relaxation of GSS. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Downregulation of MAL2 inhibits breast cancer progression through regulating ß-catenin/c-Myc axis.

PURPOSE: Myelin and lymphocyte protein 2 (MAL2) is mainly involved in endocytosis under physiological conditions and mediates the transport of materials across the membranes of cell and organelle. It has been reported that MAL2 is significantly upregulated in diverse cancers. This study aimed to investigate the role of MAL2 in breast cancer (BC). METHODS: Bioinformatics analysis and Immunohistochemical assay were applied to detect the correlation between MAL2 expression in breast cancer tissues and the prognosis of breast cancer patients. Functional experiments were carried out to investigate the role of MAL2 in vitro and in vivo. The molecular mechanisms involved in MAL2-induced ß-catenin and c-Myc expression and ß-catenin/c-Myc-mediated enhancement of BC progression were confirmed by western blot, ß-catenin inhibitor and agonist, Co-IP and immunofluorescence colocalization assays. RESULTS: Results from the cancer genome atlas (TCGA) and clinical samples confirmed a significant upregulation of MAL2 in BC tissues than in adjacent non-tumor tissues. High expression of MAL2 was associated with worse prognosis. Functional experiments demonstrated that MAL2 knockdown reduced the migration and invasion associating with EMT, increased the apoptosis of BC cells in vitro and reduced the metastatic capacity in vivo. Mechanistically, MAL2 interacts with ß-catenin in BC cells. MAL2 silencing reduced the expression of ß-catenin and c-Myc, while the ß-catenin agonist SKL2001 partially rescued the downregulation of c-Myc and inhibition of migration and invasion caused by MAL2 knockdown in BC cells. CONCLUSION: These observations provided evidence that MAL2 acted as a potential tumor promoter by regulating EMT and ß-catenin/c-Myc axis, suggesting potential implications for anti-metastatic therapy for BC.

A drug molecular classification model based on graph structure generation.

Molecular property prediction based on artificial intelligence technology has significant prospects in speeding up drug discovery and reducing drug discovery costs. Among them, molecular property prediction based on graph neural networks (GNNs) has received extensive attention in recent years. However, the existing graph neural networks still face the following challenges in node representation learning. First, the number of nodes increases exponentially with the expansion of the perception field, which limits the exploration ability of the model in the depth direction. Secondly, the large number of nodes in the perception field brings noise, which is not conducive to the model's representation learning of the key structures. Therefore, a graph neural network model based on structure generation is proposed in this paper. The model adopts the depth-first strategy to generate the key structures of the graph, to solve the problem of insufficient exploration ability of the graph neural network in the depth direction. A tendentious node selection method is designed to gradually select nodes and edges to generate the key structures of the graph, to solve the noise problem caused by the excessive number of nodes. In addition, the model skillfully realizes forward propagation and iterative optimization of structure generation by using an attention mechanism and random bias. Experimental results on public data sets show that the proposed model achieves better classification results than the existing best models.

Minocycline and Pyrrolidine Dithiocarbamate Attenuate Hypertension via Suppressing Activation of Microglia in the Hypothalamic Paraventricular Nucleus.

Proinflammatory cytokines, reactive oxygen species and imbalance of neurotransmitters are involved in the pathophysiology of angiotensin II-induced hypertension. The hypothalamic paraventricular nucleus (PVN) plays a vital role in hypertension. Evidences show that microglia are activated and release proinflammatory cytokines in angiocardiopathy. We hypothesized that angiotensin II induces PVN microglial activation, and the activated PVN microglia release proinflammatory cytokines and cause oxidative stress through nuclear factor-kappa B (NF-κB) pathway, which contributes to sympathetic overactivity and hypertension. Male Sprague-Dawley rats (weight 275-300 g) were infused with angiotensin II to induce hypertension. Then, rats were treated with bilateral PVN infusion of microglial activation inhibitor minocycline, NF-κB activation inhibitor pyrrolidine dithiocarbamate or vehicle for 4 weeks. When compared to control groups, angiotensin II-induced hypertensive rats had higher mean arterial pressure, PVN proinflammatory cytokines, and imbalance of neurotransmitters, accompanied with PVN activated microglia. These rats also had more PVN gp91phox (source of reactive oxygen species production), and NF-κB p65. Bilateral PVN infusion of minocycline or pyrrolidine dithiocarbamate partly or completely ameliorated these changes. This study indicates that angiotensin II-induced hypertensive rats have more activated microglia in PVN, and activated PVN microglia release proinflammatory cytokines and result in oxidative stress, which contributes to sympathoexcitation and hypertensive response. Suppression of activated PVN microglia by minocycline or pyrrolidine dithiocarbamate attenuates inflammation and oxidative stress, and improves angiotensin II-induced hypertension, which indicates that activated microglia promote hypertension through activated NF-κB. The findings may offer hypertension new strategies.

Design and evaluation of blended teaching in the smart classroom combined with virtual simulation training in basic nursing courses.

OBJECTIVE: This study explored the application effect of smart classrooms combined with virtual simulation training in basic nursing courses for nursing undergraduates. METHODS: In this quasi-experimental study, a total of 135 undergraduate nursing students in the 2021 matriculating cohort were selected as the research subjects. The experimental group of Class 1 had 71 students, and a blended teaching design utilizing a smart classroom and virtual simulation training was adopted. The control group of Class 2 had 64 students, and traditional lecture-based teaching design was adopted. After the course, the independent learning ability scale, test scores and teaching effectiveness questionnaire were used to evaluate the teaching effect. All tests had a maximum score of 100. RESULTS: Nursing undergraduates in the experimental group had scores of 86.32 ± 8.25 for virtual simulation training and 84.82 ± 9.04 for peer-assisted learning. The scores of the theoretical examination, experimental examination, and subjective questions in the experimental group were significantly higher than those in the control group (P < 0.05). The approval rate of nursing undergraduates in the experimental group was significantly higher than that of the control group for four items (Ps < 0.05). Among the 71 students, most students (91.55%) claimed that the use of instructional designs increased the fun of the classroom. In addition to the dimension of information literacy, the total score of independent learning ability and the other three dimensions of the experimental group were significantly higher than those of the control group (P < 0.05). CONCLUSION: The teaching design combining smart classrooms and virtual simulation training can be applied to realize online blended teaching and classroom informatization, improving the academic performance and independent learning ability of nursing undergraduates, and thus achieving good teaching effects.

Aeromonas veronii infection remarkably increases expression of lysozymes in grass carp (Ctenopharyngodon idellus) and injection of lysozyme expression cassette along with QCDC adjuvant significantly upregulates immune factors and decreases cumulative mortality.

Aeromonas veronii AvX005 is a pathogenic bacterium with high toxicity to grass carp (Ctenopharyngodon idellus). The expression levels of g-type (goose-type lysozyme, Lys-g) and c-type lysozyme (chicken-type lysozyme, Lys-c) in the spleen of grass carp infected with AvX005 were significantly increased by approximately 4.5 times and 27 times, respectively. The recombinant proteins rLys-g and rLys-c produced in a recombinant expression system of Escherichia coli showed significant antibacterial activity against the pathogenic bacteria AvX005. A challenge test was conducted after rLys-g and rLys-c were expressed in grass carp L8824 liver cells, and compared with the survival rate of the control cells (46.3%), the survival rate of the experimental cells (77.6% for rLys-g and 68.6% for rLys-c) was significantly increased. Grass carp were infected with AvX005 on the second day after delivering pcDNA3.1-lys-g and pcDNA-lys-c with the Quil A/cholesterol/DDA/Carbopol (QCDC) adjuvant, and both pcDNA3.1-lys-g and pcDNA-lys-c provided 70% relative protection for grass carp. The activity of lysozyme and alkaline phosphatase in the serum of grass carp was significantly increased after injection of DNA. The expression of the immune factors IgM, C3 and IL8 in the kidney was upregulated to varying degrees for pcDNA3.1-lys-g and immune factors C3 and IgM was upregulated for pcDNA-lys-c. The results indicated that pcDNA3.1-lys-g and pcDNA-lys-c may be used as immunostimulants to protect grass carp from the pathogenic bacterium AvX005.

Beneficial effects of metformin supplementation in hypothalamic paraventricular nucleus and arcuate nucleus of type 2 diabetic rats.

Background Oxidative stress and inflammation play important roles in the development of diabetes. Metformin (MET) is considered as the first-line therapy for patients with type 2 diabetes (T2D). Hypothalamic paraventricular nucleus (PVN) and hypothalamic arcuate nucleus (ARC) are vital in obesity and diabetes. However, there have been few studies on the effects of MET on inflammatory reaction and oxidative stress in the PVN and ARC of T2D diabetic rats. Methods Male Sprague-Dawley (SD) rats were fed with high-fat diet (HFD), and intraperitoneally injected with low-dose streptozotocin (STZ, 30 mg/kg) at 6th week to induce T2D diabetes. After injection of STZ, they were fed with HFD continually. Starting from the 8th week of HFD feeding, T2D rats received intragastrical administration of MET (150 mg/kg/day) in addition to the HFD for another 8 weeks. At the end of the 15th week, the rats were anaesthetized to record the sympathetic nerve activity and collect blood and tissue samples. Results In comparison with control rats, T2D diabetic rats had higher levels of pro-inflammatory cytokines (PICs) and excessive oxidative stress in the PVN and ARC, accompanied with more activated astrocytes. The renal sympathetic nerve activity (RSNA) and the plasma norepinephrine (NE) increased in T2D diabetic rats. The expression of tyrosine hydroxylase (TH) increased and the expression of 67-kDa isoform of glutamate decarboxylase (GAD67) decreased in T2D diabetic rats. Supplementation of MET decreased blood glucose, suppressed RSNA, decreased PICs (TNF-α, IL-1ß and IL-6) in PVN and ARC, attenuated oxidative stress and activation of astrocytes in ARC and PVN of T2D diabetic rats, as well as restored the balance of neurotransmitter synthetase. The number of Fra-LI (chronic neuronal excitation marker) positive neurons in the ARC and PVN of T2D diabetic rats increased. Chronic supplementation of MET also decreased the number of Fra-LI positive neurons in the ARC and PVN of T2D diabetic rats. Conclusion These findings suggest that the PVN and ARC participate in the beneficial effects of MET in T2D diabetic rats, which is possibly mediated via down-regulating of inflammatory molecules, attenuating oxidative stress and restoring the balance of neurotransmitter synthetase by MET in the PVN and ARC.

One-Step Synthesis of 3D Pore-Structured Adsorbent by Cross-Linked PEI and Graphene Oxide Sheets and Its Application in CO2 Adsorption.

In this study, a one-step method of polyethylenimine (PEI) cross-linking graphene oxide (GO) was used to prepare a 3D pore-structured adsorbent with abundant amine groups for chemisorption of CO2. The cross-linking of PEI with GO sheets and the vacuum freeze-drying step are the keys to the formation of the 3D pore structure. The results of characterization analysis revealed that the as-prepared adsorbent had a 3D porous structure rich in amine groups. Besides, the adsorption/desorption test showed that the prepared adsorbent has excellent and stable adsorption performance, and the maximum CO2 adsorption capacity is 2.18 mmol/g at 343 K and 10 vol % CO2. Moreover, the adsorption kinetics analysis indicated that the adsorption process was dominated by homogeneous adsorption, and the adsorbent had a strong affinity with CO2. Finally, the correlation analysis shows that the kinetic constants obtained by the Avrami model simulation can be effectively used for the actual CO2 adsorption process design.

Two Polyoxometalate-Encapsulated Two-Fold Interpenetrating dia Metal-Organic Frameworks for the Detection, Discrimination, and Degradation of Phenolic Pollutants.

Phenols are widely used for commercial production, while they pose a hazard to the environment and human health. Thus, investigation of convenient and efficient methods for the detection, discrimination, and degradation of phenols becomes particularly important. Herein, two new polyoxometalate (POM)-based compounds, [Co2(btap)4(H2O)4][SiW12O40] (Co-POM) and [Ni2(btap)4(H2O)4][SiW12O40] (Ni-POM) (btap = 3,5-bis(triazol-1-yl)pyridine), are prepared via a hydrothermal synthesis method. The compounds show a fascinating structural feature of a POM-encapsulated twofold interpenetrating dia metal-organic framework. More importantly, besides the novel structures, the compound Co-POM realizes three functions, namely, the simultaneous detection, discrimination, and degradation of phenols. Specifically, Co-POM shows an excellent colorimetric detection performance toward phenol with a detection limit (LOD) ca. 1.32 µM, which is lower than most reported colorimetric detectors for phenol. Also, a new colorimetric sensor system based on Co-POM can discriminate phenol, 4-chlorophenol, and o-cresol with ease. Further, Co-POM exhibits a photocatalytic degradation property for 4-chlorophenol under irradiation of visible light with the highest degradation rate at 62% after irradiation for 5 h. Therefore, this work provides the first example of a POMs-based multifunctional material for achieving the detection, discrimination, and degradation of phenolic pollutants.

Modulating Two Pairs of Chiral DyIII Enantiomers by Distinct ß-Diketone Ligands to Show Giant Differences in Single-Ion Magnet Performance and Nonlinear Optical Response.

Using Dy(dbm)3(H2O) and Dy(btfa)3(H2O)2 to react with enantiopure N-donors, (-)/(+)-4,5-pinenepyridyl-2-pyrazine (LR/LS), respectively, two pairs of chiral DyIII enantiomers, Dy(dbm)3LR/Dy(dbm)3LS (R-1-Dy/S-1-Dy) and Dy(btfa)3LR/Dy(btfa)3LS (R-2-Dy/S-2-Dy) were obtained, wherein one of the benzene rings of dbm- (dibenzoylmethanate) in R-1-Dy/S-1-Dy is displaced by the -CF3 group of btfa- (4,4,4-trifluoro-1-phenyl-1,3-butanedionate) in R-2-Dy/S-2-Dy. Interestingly, this substitution results not only in giant differences in their single-ion magnetic (SIM) performances but also in their completely different nonlinear optical (NLO) responses. R-1-Dy presents a large effective energy barrier (Ueff = 265.47 K) under zero applied field, being more than 4 × R-2-Dy (61.40 K). The discrepancy on their magnetic performances has been further elucidated by ab initio calculations. Meanwhile, R-1-Dy/S-1-Dy display the strongest third-harmonic generation responses (35/33 × α-SiO2) among the known lanthanide NLO-active coordination compounds (CCs). On the contrary, R-2-Dy/S-2-Dy exhibit moderate second-harmonic generation responses (0.65/0.70 × KDP). These results not only give the first example of the CCs with both SMM/SIM behavior and a THG response but also provide an efficient strategy for achieving the function regulation and switch in multifunctional CCs.

Isolation of a new Streptomyces virginiae W18 against fish pathogens and its effect on disease resistance mechanism of Carassius auratus.

The Streptomyces virginiae strain W18 was screened from soil, which exhibited broad-spectrum antibacterial activity against fish pathogens. Safety assays showed that strain W18 had no toxicity to fish. Additionally, strain W18 promoted the growth performance of Carassius auratus after feeding in feed mixed with bacteria for one month. Moreover, the activities of AKP, ACP, and SOD in the serum of C. auratus were significantly increased, while the activity of LZM did not greatly change. To detect the expression levels of the genes related to immune factors in the livers, kidneys, and spleens of C. auratus, qRT-PCR was performed. The expression levels of KEAP1, IL-8, TNF-α, IL-ß, and C3 were upregulated in all three organs compared to the control, but LZM expression was downregulated in the kidney. The challenge experiment illustrated that the probability of infection with Aeromonas veronii was reduced by 60% and 40% when C. auratus was fed with two different doses of strain W18 in advance. The whole genome of strain W18 was sequenced, and the gene clusters of secondary metabolites in strain W18 were analyzed by AntiSMASH. The results showed that strain W18 contained a total of 26 gene clusters, and functional annotation analysis was conducted by using the non-coding databases COG and KEGG. All of the above results indicated that the use of strain W18 as a feed additive could enhance the resistance of C. auratus toward pathogenic bacteria and disease. In conclusion, an antagonistic strain (W18) against fish pathogenic bacteria was obtained in this study, which is of great significance for finding new treatment methods for bacterial diseases in the aquaculture industry.

Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat.

Gut dysbiosis and dysregulation of gut-brain communication have been identified in hypertensive patients and animal models. Previous studies have shown that probiotic or prebiotic treatments exert positive effects on the pathophysiology of hypertension. This study aimed to examine the hypothesis that the microbiota-gut-brain axis is involved in the antihypertensive effects of curcumin, a potential prebiotic obtained from Curcuma longa. Male 8- to 10-week-old spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were divided into four groups: WKY rats and SHRs treated with vehicle and SHRs treated with curcumin in dosage of 100 or 300 mg/kg/day for 12 weeks. Our results show that the elevated blood pressure of SHRs was markedly decreased in both curcumin-treated groups. Curcumin treatment also altered the gut microbial composition and improved intestinal pathology and integrity. These factors were associated with reduced neuroinflammation and oxidative stress in the hypothalamus paraventricular nucleus (PVN). Moreover, curcumin treatment increased butyrate levels in the plasma, which may be the result of increased butyrate-producing gut microorganisms. In addition, curcumin treatment also activated G protein-coupled receptor 43 (GPR 43) in the PVN. These results indicate that curcumin reshapes the composition of the gut microbiota and ameliorates the dysregulation of the gut-brain communication to induce antihypertensive effects.

Chronic Infusion of Astaxanthin Into Hypothalamic Paraventricular Nucleus Modulates Cytokines and Attenuates the Renin-Angiotensin System in Spontaneously Hypertensive Rats.

ABSTRACT: Oxidative stress, the renin-angiotensin system (RAS), and inflammation are some of the mechanisms involved in the pathogenesis of hypertension. The aim of this study is to examine the protective effect of the chronic administration of astaxanthin, which is extracted from the shell of crabs and shrimps, into hypothalamic paraventricular nucleus (PVN) in spontaneously hypertensive rats. Animals were randomly assigned to 2 groups and treated with bilateral PVN infusion of astaxanthin or vehicle (artificial cerebrospinal fluid) through osmotic minipumps (Alzet Osmotic Pumps, Model 2004, 0.25 µL/h) for 4 weeks. Spontaneously hypertensive rats had higher mean arterial pressure and plasma level of norepinephrine and proinflammatory cytokine; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1ß, IL-6, ACE, and AT1-R; and lower PVN levels of IL-10 and Cu/Zn SOD, Mn SOD, ACE2, and Mas receptors than Wistar-Kyoto rats. Our data showed that chronic administration of astaxanthin into PVN attenuated the overexpression of reactive oxygen species, NOX2, NOX4, inflammatory cytokines, and components of RAS within the PVN and suppressed hypertension. The present results revealed that astaxanthin played a role in the brain. Our findings demonstrated that astaxanthin had protective effect on hypertension by improving the balance between inflammatory cytokines and components of RAS.

Protective effect of tanshinone IIA on H2O2-induced oxidative stress injury in rat cardiomyocytes by activating Nrf2 pathway.

To investigate the protective effect of tanshinone IIA on H2O2-induced oxidative stress injury in rat cardiomyocytes, and further to study its potential mechanisms. H9C2 cells were used to establish H2O2 injury model. The cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. ELISA was used to detect the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Moreover, the levels of malondialdehyde (MDA) and catalase (CAT) were tested by TBA and visible light methods, respectively. The Nrf2 pathway-related proteins were detected by Western blot. To validate the protective effect of tanshinone IIA on rat cardiomyocytes is worked by regulating the Nrf2 pathway, we further silenced Nrf2 and the above experiments were repeated. Tanshinone IIA could promote the proliferation, and reduce the apoptosis and ROS of rat cardiomyocytes induced by H2O2. Tanshinone IIA also could increase the activity of SOD, CAT, and GSH-Px, and decreased the activity of MDA and LDH. The protein expression of Nrf2, HO-1, and NQO1 was significantly up-regulated in tanshinone IIA groups, while the protein expression of Keap1 was significantly down-regulated. A further study has shown that silenced Nrf2 has completely opposite results. All those results suggested that tanshinone IIA could protect H2O2-induced oxidative stress injury in rat cardiomyocytes by activating Nrf2 pathway.

Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR.

The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 µL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects.

Irisin lowers blood pressure by activating the Nrf2 signaling pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

Exercise training is one of the major non-pharmacological treatments for hypertension. However, the central mechanism by which exercise training attenuates the hypertensive responses remains unclear. Irisin is a muscle-secreted cytokine derived from fibronectin type III domain containing 5 (FNDC5) that will be released into the circulation during exercise. We hypothesized that irisin may play a role in the blood pressure regulation by exercise. To examine the hypothesis, our study investigated the effect of irisin on hypertension and its central mechanism. The study was performed in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats. We found that intravenous injection of irisin effectively reduced blood pressure, plasma norepinephrine, paraventricular nucleus (PVN) levels of neuronal activation, oxidative stress and inflammation in SHRs. Moreover, irisin activated nuclear factor E2-related factor-2 (Nrf2) and restored the imbalance of neurotransmitters in the PVN. Our study also found PVN knockdown of Nrf2 abolished the protective effects of irisin on hypertension. These findings demonstrate irisin can improve hypertension via Nrf2-mediated antioxidant in the PVN.

Inhibition of Hypothalamic Inhibitor κB Kinase ß/Nuclear Transcription Factor κB Pathway Attenuates Metabolism and Cardiac Dysfunction in Type 2 Diabetic Rats.

BACKGROUND: Inflammation and oxidative stress play important roles in energy imbalance and its complications. Recent research indicates that hypothalamic inflammation may contribute to the pathogenesis of metabolic syndrome and cardiac dysfunction, but the mechanisms remain unclear. We hypothesized that suppression of the proinflammatory IKKß/NF-κB pathway in the hypothalamus can improve energy balance and cardiac function in type 2 diabetic (T2D) rats. METHODS: Normal and T2D rats received bilateral hypothalamic arcuate nucleus (ARC) infusions of the IKKß inhibitor SC-514 or vehicle via osmotic minipump. Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were used to investigate the outcomes of inhibition of the hypothalamic IKKß. Echocardiography and glucometer were used for measuring cardiac function and blood glucose, respectively. Blood samples were collected for the evaluation of circulating proinflammatory cytokines. Heart was harvested for cardiac morphology evaluations. The ARC was harvested and analyzed for IKKß, NF-κB, proinflammatory cytokines, reactive oxygen species (ROS), and NAD(P)H (gp91phox, p47phox) oxidase activity levels and neuropeptides. RESULTS: Compared with normal rats, T2D rats were characterized by hyperglycemia, hyperinsulinemia, glucose intolerance, cardiac dysfunction, as well as higher ARC levels of IKKß, NF-κB, proinflammatory cytokines, ROS, gp91phox, and p47phox. ARC infusion of the IKKß inhibitor SC-514 attenuated all these changes in T2D rats, but not in normal rats. CONCLUSIONS: Our results indicate that the hypothalamic IKKß/NF-κB pathway plays a key role in modulating energy imbalance and cardiac dysfunction, suggesting its potential therapeutic role during type 2 diabetes mellitus.

Nondestructive estimation of leaf area for 15 species of vines with different leaf shapes.

PREMISE: The nondestructive measurement of leaf area is important for expediting data acquisition in the field. The Montgomery equation (ME) assumes that leaf area (A) is a proportional function of the product of leaf length (L) and width (W), i.e., A = cLW, where c is called the Montgomery parameter. The ME has been successfully applied to calculate the surface area of many broad-leaved species with simple leaf shapes. However, whether this equation is valid for more complex leaf shapes has not been verified. METHODS: Leaf A, L, and W were measured directly for each of 5601 leaves of 15 vine species, and ME and three other models were used to fit the data. All four models were compared based on their root mean square errors (RMSEs) to determine whether ME provided the best fit. RESULTS: The ME was a reliable method for estimating the A of all 15 species. In addition, the numerical values of 13 of the 15 values of c fell within a previously predicted numerical range (i.e., between 1/2 and π/4). The data show that the numerical values of c are largely affected by the value of W/L, the concavity of the leaf base, and the number of lobes on the lamina. CONCLUSIONS: The Montgomery parameter can reflect the influence of leaf shape on leaf-area calculations and can serve as an important tool for nondestructive measurements of leaf area for many broad-leaved species and for the investigation of leaf morphology.

Molecular characterization of a novel fusarivirus infecting the plant-pathogenic fungus Botryosphaeria dothidea.

A novel virus, Botryosphaeria dothidea fusarivirus 1 (BdFV1), was isolated from a fungal strain, SDAU11-86 of Botryosphaeria dothidea, and its complete genome sequence was determined. BdFV1 has a single-stranded positive-sense (+ssRNA) genome with 6,179 nucleotides, excluding the poly(A) tail. The genome of BdFV1 contains two putative open reading frames (ORFs). The first ORF encodes a large polyprotein of 1,544 amino acids (aa) with conserved RNA-dependent RNA polymerase and viral helicase domains. The second ORF encodes a putative 481-aa protein with unknown function. Sequence comparisons and phylogenetic analysis suggested that BdFV1 is a novel mycovirus belonging to the newly proposed family "Fusariviridae". This is the first report of a +ssRNA mycovirus in B. dothidea.