Circulatory Levels Research Articles

Aging Is Associated with a Circulating Endothelial Cell-Derived Microvesicle Phenotype that Increases Cerebral Oxidative Stress

Aging is associated with increased risk and prevalence of ischemic stroke. Vascular oxidative stress impairs cell function and is considered to be an important mechanism underlying the age-related increase in cerebrovascular accidents (CVA). However, the direct, and indirect, effects of aging on endothelial cell oxidative stress are complex and not completely understood. Increase in reactive oxygen species coupled with reduced anti-oxidative capacity creates a prooxidative endothelial phenotype resulting in impaired cell dysfunction, accelerated unprogrammed cell death and, in turn, CVAs. Several recent seminal studies have demonstrated that circulating endothelial cell- derived microvesicles (EMVs) are etiologically involved in the development and progression of endothelial dysfunction and CVA. We have previously demonstrated that aging is associated with increased circulating levels of EMVs. The aim of this study was to determine, in vitro, the effect of circulating EMVs isolated from young and older adults on brain endothelial cell oxidative stress. We hypothesized that EMVs from older adults would induce a prooxidative endothelial phenotype. As part of an ongoing study, 16, non-obese, normotensive, sedentary adults were studied: 8 young (5M/3F; age: 25±1 yr) and 8 older (4M/4F; 69±2 yr). EMV identification (CD144+) and isolation from peripheral blood was performed by flow cytometry. Human cerebral microvascular endothelial cells (hCMECs) were cultured and separately treated with EMVs from each subject for 24 hours. Intracellular reactive oxygen species (ROS) production was determined using CellROX Deep Red Reagent. Circulating EMVs were ~75% higher (P=0.002) in older (140±13 EMV/μL) vs young (82±8 EMV/μL) adults. Cellular ROS was significantly higher (~40%) in hCMECs treated with EMVs from older (141±14%) compared with young (101±5%) adults. In addition, intracellular expression of key anti-oxidant proteins were significantly lower in cells treated with EMVs from older adults. Cell expression of both superoxide dismutase 1 (SOD-1: 20.6±2.3 vs 36.3±3.1 AU) and catalase (17.1±1.9 vs 27.5±3.0 AU) were ~35% lower in hCMECs treated with EMVs from older adults. Moreover, intracellular ROS was inversely and significantly correlated with SOD-1 (r=-0.54; P=0.03) and catalase (r=-0.62; P=0.01) expression reflective of the cellular oxidative milieu. In conclusion, circulating EMVs may contribute to the increased risk of ischemic stroke with aging by increasing brain endothelial cell oxidative stress and reducing oxidative defense mechanisms. EMVs may represent a viable therapeutic target for mitigating the risk of CVA with aging. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Role of neuraminidase in promoting the shedding of endothelial mechanosensing structures in type 2 diabetes

Endothelial dysfunction represents a causal factor in the pathogenesis of cardiovascular disease associated with type 2 diabetes (T2D). Previous work shows that endothelial mechanosensing structures are degraded in T2D, resulting in impaired shear stress mechanotransduction and decreased endothelial-derived nitic oxide (NO) bioavailability. Recent evidence suggests that glypican-1, a well-known mechanosensor, is a substrate of the proinflammatory enzyme a disintegrin and metalloproteinase-17 (ADAM17). A key step in ADAM17 activation is externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane, which can be mediated by the phospholipid scramblase anoctamin-6 (ANO6). However, whether ANO6-mediated activation of ADAM17 leads to glypican-1 shedding in endothelial cells remains unknown. Also unknown are the mechanisms by which this pathway becomes overactive in T2D. We recently reported that T2D is associated with increased circulating levels of neuraminidase, a soluble enzyme that cleaves sialic acid residues. We also showed that intraluminal exposure of isolated arteries to neuraminidase impairs shear stress mechanotransduction. Herein, we tested the hypothesis that neuraminidase-induced impaired shear stress mechanotransduction is mediated by ANO6-induced ADAM17 activation and consequent shedding of glypican-1. All reported differences are significant at P<0.05. In support of our hypothesis, we show that neuraminidase and ADAM17 activities are increased, while nitrite (NO surrogate) is decreased, in plasma of men and women with T2D who also display evidence of impaired shear stress mechanotransduction ( i.e., diminished flow-mediated dilation). In cultured endothelial cells, we show that neuraminidase exposure decreases sialic acid content and increases intracellular Ca2+ mobilization, adhesion of lactadherin (a peptide that binds externalized PS), ADAM17 activity, and shedding of glypican-1. Also in cultured endothelial cells, overexpression of ADAM17 increases shedding of glypican-1 and impairs shear stress-induced activation of endothelial NO synthase. Congruently, intraluminal exposure of human omental arteries to active ADAM17 recombinant protein impairs flow-mediated dilation. Furthermore, silencing of ANO6 reduces ADAM17 activity, leading to increased presence of glypican-1 on the endothelial cell surface. Taken together, we provide evidence that neuraminidase, an enzyme increased in the circulation of individuals with T2D, promotes ANO6-dependent externalization of PS in endothelial cells, which in turn leads to ADAM17 activation and consequent shedding of glypican-1. Thus, this work supports the idea that the neuraminidase-ANO6-ADAM17 axis should be considered as a potential target for restoring endothelial mechanosensation and improving NO bioavailability in T2D. R01HL151384 (to LAML and JP), R01HL153264 (to LAML and JP), R01HL137769 (to JP), and R21DK116081 (to CM-A). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Elevation of circulating DNAs of disease-associated cytokines in serum cell-free DNA from patients with alopecia areata.

Alopecia areata (AA) is an autoimmune disease characterized by damage to hair follicles and hair loss. Cell-free DNA (cfDNA) has recently received attention as a biomarker of various disorders including inflammatory skin diseases. In this study, we aimed to investigate the clinical significance of cfDNA and the circulating DNAs of disease-associated cytokines in AA patients. Serum samples were obtained from 63 patients with AA and 32 healthy controls (HC). Using droplet digital polymerase chain reaction, circulating C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL11, C-X-C motif chemokine receptor 3, interferon (IFN)-γ, interleukin (IL) -7, IL-15, and Janus kinase (JAK) 2 were detectable in both HC and AA patients. Among the detectable DNAs, copies of circulating CXCL9, CXCL11, IL-15, IFN-γ, and JAK2 were significantly higher in AA patients than in HC. These results suggest that increased circulating DNA levels may reflect damage to hair follicles in AA patients.

Evaluation of Serum Amyloid A and some Biochemical markers in Iraqi patients with systemic lupus erythematosus

An autoimmune condition called systemic lupus erythematosus (SLE) is caused by long-term inflammation. Amyloid A (AA) amyloidosis results in nephropathy and other internal symptoms, including death. The current study set out to look at the relationship between serum amyloid A (SAA) levels in circulation and SLE patients. Methods: Sixty SLE patients and 30 healthy with age range (19-55) yearswere involved in this study. A SLE patient wasidentified in the teaching hospital in Baghdad. In this study, laboratory indicators such as blood lipid, kidney function, test results, and total cholesterol (TC), triglyceride (TG), SAA, and ALB were assessed using an automated biochemical analyzer. Results: Patients with active SLE had serum amyloid A (SAA) values 5.83 mg/L [IQR: 2.08–10.87], 4.92 mg/L [IQR: 1.57–11.43], and 1.33 mg/L [IQR: 0.13–3.12], respectively, substantially upper than personswith inactive SLE or healthy control subjects (P < 0.001). ESR values in healthy control subjects, patients with inactive SLE, and patients with active SLE. In conclusion, the current study's findings offered more proof of SAA's potential involvement in SLE and suggested that it might be valuable biomarkers that could reveal more details about the disease's activity.

Dual circulation strategy, regional healthcare development, and medical collaborative innovation efficiency: evidence from Chinese cities.

This study analyzes panel data of Chinese cities from 2003 to 2018 as a sample in the context of the dual circulation strategy in China to ascertain the impact of urban healthcare development on medical collaborative innovation efficiency by using the GS2SLS method. Furthermore, it empirically examines the influence mechanism of regional healthcare development on medical collaborative innovation efficiency by using a threshold regression model. Additionally, we identified the heterogeneity of this impact in different cities. The results show the following: (1) There is a significant positive spatial correlation between regional healthcare development and medical collaborative innovation efficiency; (2) Under the dual circulation strategy, the regional investment level in international circulation has the most significant role in the overall strategy, and domestic circulation has been significantly improved after the launch of the innovation-driven strategy; (3) The results of the threshold test show that while domestic and international circulation promote the efficiency of collaborative innovation by 0.83, the promotion effect is more obvious under a higher regional healthcare development level. The research in this paper can provide specific guidance for the development of China's healthcare industry under the background of dual-cycle strategy, and can also provide valuable reference for developing countries in the world.

Antiarrhythmic and Anti-Inflammatory Effects of Sacubitril/Valsartan on Post-Myocardial Infarction Scar.

Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine. After MI, 22 pigs were randomized to receive β-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis. Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.009 and P=0.026, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.034) and the number of deceleration zones (P=0.016). After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

Novel PLGA-encapsulated-nanopiperine promotes synergistic interaction of p53/PARP-1/Hsp90 axis to combat ALX-induced-hyperglycemia

The present study predicts the molecular targets and druglike properties of the phyto-compound piperine (PIP) by in silico studies including molecular docking simulation, druglikeness prediction and ADME analysis for prospective therapeutic benefits against diabetic complications. PIP was encapsulated in biodegradable polymer poly-lactide-co-glycolide (PLGA) to form nanopiperine (NPIP) and their physico-chemical properties were characterized by AFM and DLS. ∼ 30 nm sized NPIP showed 86.68% encapsulation efficiency and − 6 mV zeta potential, demonstrated great interactive stability and binding with CT-DNA displaying upsurge in molar ellipticity during CD spectroscopy. NPIP lowered glucose levels in peripheral circulation by > 65 mg/dL compared to disease model and improved glucose influx in alloxan-induced in vivo and in vitro diabetes models concerted with 3-folds decrease in ROS production, ROS-induced DNA damage and 27.24% decrease in nuclear condensation. The 25% increase in % cell viability and inhibition in chromosome aberration justified the initiation of p53 and PARP DNA repairing protein expression and maintenance of Hsp90. Thus, the experimental study corroborated well with in silico predictions of modulating the p53/PARP-1/Hsp90 axis, with predicted dock score value of − 8.72, − 8.57, − 8.76 kcal/mol respectively, validated docking-based preventive approaches for unravelling the intricacies of molecular signalling and nano-drug efficacy as therapeutics for diabetics.

Interleukin-4 inhibits the hypothalamic appetite control by modulating the insulin-AKT and JAK-STAT signaling in leptin mutant mice.

Our previous research identified interleukin-4 (IL-4) as a key regulator of glucose/lipid metabolism, circulatory leptin levels, and insulin action, suggesting its potential as a therapeutic target for obesity and related complications. This study aimed to further elucidate the role of IL-4 in regulating hypothalamic appetite-controlling neuropeptides using leptin dysfunctional Leptin145E/145E mice as the experimental model. IL-4 significantly reduces body weight, food intake, and serum glucose levels. Our data demonstrated that IL-4 exhibits multiple functions in regulating hypothalamic appetite control, including downregulating orexigenic agouti-related peptide and neuropeptide Y levels, promoting expression of anorexigenic proopiomelanocortin, alleviating microenvironmental hypothalamic inflammation, enhancing leptin and insulin pathway, and attenuating insulin resistance. Furthermore, IL-4 promotes uncoupling protein 1 expression of white adipose tissue (WAT), suggesting its role in triggering WAT-beige switch. In summary, this study uncovers novel function of IL-4 in mediating food-intake behaviors and metabolic efficiency by regulating hypothalamic appetite-control and WAT browning activities. These findings support the therapeutic potential of targeting hypothalamic inflammation and reducing adiposity through IL-4 intervention for tackling the pandemic increasing prevalence of obesity and associated metabolic disorders.

Acute effects of moderate-intensity constant training on circulatory fibroblast growth factor 21, resis-tin, and adiponectin of physically inactive young adults

Introduction: physical inactivity affects metabolic health, and it has been described that physical exercise is able to counter these disturbances. Fibroblast growth factor (FGF) 21, resistin, and adiponectin are known cytokines that are sensitive to physical inactivity and exercise, however, their acute behaviour after one session of exercise in physically inactive young adults is unclear. Therefore, this study aimed to investigate the effects of a session of moderate-intensity continuous training (MICT) on the circulatory levels of FGF21, resistin, and adiponectin of physically inactive young adults. Material and methods: quasi-experimental study, where 20 physically inactive young adults, with body mass indexes between 18 and 30 kg/m2 were included. All performed one MICT session, with an intensity of 60% of their heart rate reserve on a treadmill for 30 minutes. Anthropometric measurements were evaluated (weight, height, waist and hip circumferences, lean and fat mass) prior to exercise, and venous blood samples were taken before and after exercise, where glycemia, insulin, lipid profiles, transaminases, FGF21, resistin, and adiponectin were assessed. Results: one MICT session decreased the circulatory levels of insulin (median 23.5 vs 10.9 µUI/ml; p<0.05) and FGF21 (median 527 vs 409 pg/ml; p<0.05). On the other hand, resistin and adiponectin levels did not change after exercise (both p>0.05). Conclusion: one MICT session decreased FGF21 plasma levels, whereas it did not modify resistin and adiponectin circulatory levels. The specific mechanisms behind this different behavior are needed to be elucidated in future studies. Keywords: exercise, sedentary behavior, metabolic syndrome, endurance training, cytokines

Unravelling genetic architecture of circulatory amino acid levels, and their effect on risk of complex disorders.

Variations in serum amino acid levels are linked to a multitude of complex disorders. We report the largest genome-wide association study (GWAS) on nine serum amino acids in theUK Biobank participants (117944, European descent). We identified 34 genomic loci for circulatory levels of alanine, 48 loci for glutamine, 44 loci for glycine, 16 loci for histidine, 11 loci for isoleucine, 19 loci for leucine, 9 loci for phenylalanine, 32 loci for tyrosine and 20 loci for valine. Our gene-based analysis mapped 46-293 genes associated with serum amino acids, including MIP,GLS2, SLCgene family, GCKR, LMO1, CPS1and COBLL1.The gene-property analysis across 30 tissues highlighted enriched expression of the identified genes in liver tissues for all studied amino acids, except for isoleucine and valine, in muscle tissues for serum alanine and glycine, in adrenal gland tissues for serum isoleucine and leucine, and in pancreatic tissues for serum phenylalanine. Mendelian randomization (MR) phenome-wide association studyanalysis and subsequent two-sample MR analysis provided evidence that every standard deviation increase in valine is associated with 35% higher risk of type 2 diabetes and elevated levels of serum alanine and branched-chain amino acidswith higher levels of total cholesterol, triglyceride andlow-density lipoprotein, and lower levels ofhigh-density lipoprotein. In contrast to reports by observational studies, MR analysis did not support a causal association between studied amino acids and coronary artery disease, Alzheimer's disease, breast canceror prostate cancer. In conclusion, we explored the genetic architecture of serum amino acids and provided evidence supporting a causal role of amino acids in cardiometabolic health.

Development and experimental validation of 3D QSAR models for the screening of thyroid peroxidase inhibitors using integrated methods of computational chemistry

The intricate network of glands and organs that makes up the endocrine system. Hormones are used to regulate and synchronize the nervous and physiological systems. The agents which perturbate an endocrine system are called endocrine disruptors and they can eventually affect cellular proliferation and differentiation in target tissues. A subclass of endocrine disruptors known as thyroid disruptors (TDs) or thyroid disrupting chemicals (TDCs) influence the hypothalamo-pituitary-thyroid axis or directly interfere with thyroid function by binding to thyroid hormone receptors. Thyroid hormone levels in circulation are now included in more test guidelines (OECD TG 441, 407, 408, 414, 421/422, 443/416). Although these might be adequate to recognize thyroid adversity, they are unable to explain the underlying mechanism of action. Thyroid peroxidase (TPO) and sodium iodide symporter (NIS), two proteins essential in the biosynthesis of thyroid hormones, are well-accepted molecular targets for inhibition. The screening of a large number of molecules using high throughput screening (HTS) requires a minimum quantity of sample, cost, and time consuming. Whereas 3-dimensional quantitative structure-activity relationship (3D-QSAR) analysis can screen the TDCs before synthesizing a compound. In the present study, the human TPO (hTPO) and NIS (hNIS) structures were modelled using homology modeling and the quality of the structures was validated satisfactorily using MD simulation for 100ns. Further, 190 human TPO inhibitors with IC50 were curated from Comptox and docked with the modelled structure of TPO using D238, H239 and D240 centric grid. The binding conformation of a molecule with low binding energy was used as a reference and the rest other molecules were aligned after generating the possible conformers. The activity-stratified partition was performed for aligned molecules and training set (139), test set (51) were defined. The machine learning models such as k Nearest Neighbor (kNN) and Random Forest (RF) models were built and validated using external experimental dataset containing 10 molecules. Among the 10 molecules, all 10 molecules were identified as TPO inhibitors and demonstrated 100 % accuracy qualitatively. To confirm the selective TPO inhibition all 10 molecules were docked with the modelled structure of hNIS and the results have demonstrated the selective TPO inhibition.

Assessment of TNF-α (-857 C/T) gene polymorphism in oral lichen planus disease: A case-control study.

Oral lichen planus (OLP) is an inflammatory mucocutaneous disorder with an immune-mediated pathogenesis. The tumor necrosis factor-α (TNF-α) level in the serum of OLP patients is significantly higher than in the control group. TNF-α-857 C/T polymorphism can be related to the increased TNF-α level in blood circulation. This study investigated the relationship between TNF-α (-857 C/T) polymorphism and OLP patients in an Iranian population. Saliva samples were taken from 200 people, including 100 patients with OLP and 100 healthy people who did not have significant differences in age and sex. Then, DNA was extracted from them and the TNF-α (-857 C/T) genotype was identified using the polymerase chain reaction with confronting two-pair primers method. Statistical Package for the Social Sciences version 16 software analyzed the results. The frequency of C/C, C/T, and T/T genotypes of the TNF-α-857 C/T polymorphism in the patient group were 78%, 18%, and 4%, respectively, and in the control group were 72%, 23%, and 5%, respectively. The differences between the two groups regarding allele (χ 2 = 0.97, p = 0.32) and genotype (χ 2 = 0.96, p = 0.62) frequency among the studied population were insignificant. This study showed that the difference in the frequency ofsingle nucleotide polymorphism TNF-α-857 C/T polymorphism in the patient and control group had no significant relationship with the increased OLP incidence. Also, no significant association was observed between allele and genotype frequency of TNF-α (-857 C/T) with OLP subtypes.

Circulatory endostatin level and risk of cardiovascular events in patients with end-stage renal disease on hemodialysis.

Endostatin is released during extracellular matrix remodeling and is involved in the development of vascular pathology and cardiovascular (CV) disease. However, the role of circulating endostatin as a biomarker of vascular calcification and CV events in patients undergoing hemodialysis (HD) remains unclear. A total of 372 patients undergoing HD were prospectively recruited. Plasma endostatin levels were measured at baseline, and their associations with circulating mineral bone disease (MBD) biomarkers and abdominal aortic vascular calcification scores were analyzed. The primary endpoint was defined as a composite of CV and cardiac events. Plasma levels of patients in endostatin tertile 3 were significantly associated with low-density lipoprotein cholesterol levels and predialysis systolic blood pressure in multivariate analysis. However, endostatin levels did not correlate with circulating MBD biomarkers or vascular calcification scores. Patients in endostatin tertile 3 had a significantly higher cumulative event rate for the composite of CV events (p = 0.006). Endostatin tertile 3 was also associated with an increased cumulative rate of cardiac events (p = 0.04). In multivariate Cox regression analyses, endostatin tertile 3 was associated with a 4.37-fold risk for composite CV events and a 3.88-fold risk for cardiac events after adjusting for multiple variables. Higher circulating endostatin levels were independently associated with atherosclerotic risk factors but did not correlate with MBD markers or vascular calcification. Higher circulating endostatin levels were associated with a greater risk of composite CV events in patients undergoing HD, and endostatin is a biomarker that helps to determine the high risk of CV events.

Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer’s disease

Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood–brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN−/−5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer’s disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aβ in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aβ-induced IL-1β and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.Graphical

Integrated transcriptomic and metabolomic analysis provides insights into the responses to Vibrio infection in Plectropomus leopardus

Frequent outbreaks of infectious disease in fish aquaculture have led to significant economic losses. The leopard coral grouper (Plectropomus leopardus) is an economically important fish species, but suffering from the vibriosis caused by Vibrio harveyi. Here, we used time-course transcriptomic and metabolomic analysis of the intestine and liver to investigate how the leopard coral grouper responds to the infection of the pathogen V. harveyi. We found that the differentially expressed genes (DEGs) were enriched in lipid synthesis and metabolism, DNA, RNA, and protein synthesis, and peroxisome metabolism pathways. The differential metabolites (DMs) included glycerophospholipids (GPLs), eicosanoids, bile acids (BAs), and amino acids. Further integrated analyses showed that Vibrio infection triggered the arachidonic acid (AA) metabolic process, leading to significant increases in the levels of prostaglandin J2 (PGJ2) and prostaglandin A2 (PGA2), and that this was potentially regulated by the higher expression of key genes in the AA metabolic pathway such as plaat2 and ptgs1. Moreover, the upregulation of the key genes cyp7a1, cyp27a1, and baat enhanced the BA synthesis, resulting in a significant elevation of glycocholic acid (GCA) levels in the enterohepatic circulation. Concurrently, the microbially conjugated BAs in intestine were altered, suggesting a crucial role of various BAs in defending the Vibrio infection. These findings provide novel insights into the molecular responses to Vibrio infection in the leopard coral grouper, serving as a foundation for unraveling the molecular mechanisms underlying the immune responses to Vibrio infection in fish.

Abnormal surges and the effects of the Seto Inland Sea circulation in Hiroshima Bay, Japan

The Seto Inland Sea (SIS) is the largest semienclosed coastal sea in Japan and has three connections with the outer seas. When a typhoon approached the SIS in September 2011, spatial variations of sea level elevation were observed across the SIS. Additionally, an unusual sea level rise (abnormal surge) occurred in Hiroshima Bay approximately 8 days after the typhoon passed, with the Itsukushima Shrine in the bay flooded by the surge. To understand the mechanism of the abnormal surge in the bay and the relationship between sea level variations and circulation in the SIS, we investigated the 2011 event by applying a high-resolution numerical ocean circulation model using SCHISM with bias correction for sea surface heights (SSHs) at the open boundary. The overall easterly throughflow due to the west-high east-low SSH pattern in the SIS and temporary SSH disturbances due to typhoons were well reproduced in the model results. Among the three connections, the Bungo Channel mainly determined the overall net flux into the SIS and contributed significantly to sea level variations within the SIS. Additionally, the Kii Channel played more crucial roles in shaping the circulation and local sea level variations. The Kanmon Strait exhibited minor impacts. The abnormal tide in Hiroshima Bay was mainly attributed to seawater flux input from the outer seas, in conjunction with the subtidal internal seiche with the bay. The results will help us to further understand the physical processes of the ocean and establish evidence-based safety plans for reducing natural hazard damage.

Antioxidant and antihyperlipidemic effects of hawthorn extract (Crataegus oxyacantha) in broiler chickens.

One of the main problems in the poultry industry is excess body fat, and the anti-fat effect of Cratagus extract has been confirmed in several studies. The present study was carried out to investigate the effects of hawthorn extract (Crataegus oxyacantha) on growth performance, haematological variables and hepatic gene expression in broiler chickens reared at high altitude (2100m). A total of 225-day-old chicks (Ross 308) were randomly distributed into three treatments. Experimental treatments were prepared by adding 0.0, 0.2 and 0.4mL of hawthorn extract per litre of consumption of water. The results showed that weight gain and feed conversion ratio were significantly improved and abdominal fat decreased by consumption of two levels of Crateagus extract when compared to the control (p<0.05). Consumption of hawthorn extract decreased circulatory levels of malondialdehyde, triacylglycerol, total cholesterol and low-density lipoproteins cholesterol but increased ferric reducing antioxidant power and high-density lipoproteins cholesterol (p<0.05). Hawthorn extract caused an up-regulation of catalase, superoxide dismutase1, glutathione peroxidase1 and peroxisome proliferator-activated receptor alpha but reduced the expression of key lipogenic enzymes (p<0.05). Overall, consumption of 0.4mL hawthorn extract per litre of drinking water, improved growth performance, suppressed lipogenesis and enhanced antioxidant response.

Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery

Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).Graphical

Circulatory resistin levels in inflammatory bowel disease: a systematic review and meta-analysis

BackgroundInflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing-remitting systemic disease of the gastrointestinal tract with rising incidence. Studies have shown that adipocytes play a crucial role in patients with IBD by actively participating in systemic immune responses. The present study was designed to investigate the correlation between the circulatory levels of resistin, as an adipokine, and active and remission phases of IBD in comparison with healthy controls.MethodsRelevant articles were retrieved from PubMed, Embase, the Web of Science, and Scopus from inception until June 2023. Estimation of the standardized mean difference (SMD) and 95% confidence interval (CI) for comparison of plasma/serum resistin levels between IBD patients, patients in remission, and healthy controls were conducted through random-effect meta-analysis.ResultsA total of 19 studies were included, assessing 1836 cases. Meta-analysis indicated that generally, serum/plasma resistin levels were higher in IBD patients in comparison with healthy controls (SMD 1.33, 95% CI 0.58 to 2.08, p-value < 0.01). This was true for each of the UC and CD separate analyses, as well. Moreover, it was shown that higher serum/plasma resistin levels were detected in the active phase of IBD than in the remission phase (SMD 1.04, 95% CI 0.65 to 1.42, p-value = 0.01). Finally, higher serum/plasma resistin levels were found in the remission phase compared to healthy controls (SMD 0.60, 95% CI 0.15 to 1.06, p-value < 0.01).ConclusionThe results of this systematic review and meta-analysis support the conclusion that circulating resistin levels are increased in IBD (both UC and CD). Also, higher resistin levels were recorded in the remission phase of IBD in comparison with healthy controls. This indicates that further studies may provide valuable insights into the role of resistin in the pathogenesis of IBD.

Impaired immune responses in the airways are associated with poor outcome in critically ill COVID-19 patients.

Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.