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Oncolytic viruses (OVs) have emerged as effective gene therapy and immunotherapy drugs. As an important gene delivery platform, the integration of exogenous genes into OVs has become a novel path for the advancement of OV therapy, while the herpes simplex virus type 1 (HSV-1) is the most commonly used. However, the current mode of administration of HSV-1 oncolytic virus is mainly based on the tumor in situ injection, which limits the application of such OV drugs to a certain extent. Intravenous administration offers a solution to the systemic distribution of OV drugs but is ambiguous in terms of efficacy and safety. The main reason is the synergistic role of innate and adaptive immunity of the immune system in the response against the HSV-1 oncolytic virus, which is rapidly cleared by the body's immune system before it reaches the tumor, a process that is accompanied by side effects. This article reviews different administration methods of HSV-1 oncolytic virus in the process of tumor treatment, especially the research progress in intravenous administration. It also discusses immune constraints and solutions of intravenous administration with the intent to provide new insights into HSV-1 delivery for OV therapy. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is the third most common cause of death worldwide. The incidence of VTE varies according to different countries, ranging from 1–2 per 1000 person-years in Western Countries, while it is lower in Eastern Countries (<1 per 1000 person-years). Many risk factors have been identified in patients developing VTE, but the relative contribution of each risk factor to thrombotic risk, as well as pathogenetic mechanisms, have not been fully described. Herewith, we provide a comprehensive review of the most common risk factors for VTE, including male sex, diabetes, obesity, smoking, Factor V Leiden, Prothrombin G20210A Gene Mutation, Plasminogen Activator Inhibitor-1, oral contraceptives and hormonal replacement, long-haul flight, residual venous thrombosis, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, trauma and fractures, pregnancy, immobilization, antiphospholipid syndrome, surgery and cancer. Regarding the latter, the incidence of VTE seems highest in pancreatic, liver and non-small cells lung cancer (>70 per 1000 person-years) and lowest in breast, melanoma and prostate cancer (<20 per 1000 person-years). In this comprehensive review, we summarized the prevalence of different risk factors for VTE and the potential molecular mechanisms/pathogenetic mediators leading to VTE. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell‐released, heterogenous nanoparticles that play important roles in (patho)physiological processes through intercellular communication. EVs are often depicted as having a single lipid bilayer, but many studies have demonstrated the existence of multilayered EVs. There has been minimal inquiry into differences between unilamellar and multilamellar EVs in terms of biogenesis mechanisms and functional effects. This commentary speculates on potential causes and roles of multilamellar EVs and serves as a call to action for the research community to unravel the complex layers of EVs. [ABSTRACT FROM AUTHOR]

Objective: The mechanisms underlying therapeutic hypothermia, which protects neurons following severe brain damage, are only partially understood. We previously demonstrated that hypothermia reduced, whereas hyperthermia augmented, the release of tumor necrosis factor (TNF)‐α and interleukin (IL)‐17. Cerebral ischemia causes the loss of the blood–brain barrier (BBB) integrity, thereby increasing cerebral vascular permeability, which directly contributes to vasogenic edema, hemorrhagic transformation, and increased mortality. Brain microvascular endothelial cells (BMVECs) are a major component of BBB and tight junction proteins (TJPs) in these cells maintain the BBB integrity. In this study we determined the mechanisms underlying this treatment by measuring the effects of TNF‐α and IL‐17 on BMVEC barrier function and TJP expression in BMVECs, and by evaluating the effects of hypothermia and hyperthermia on TJP expression. Methods: The barrier function of BMVECs was evaluated by measuring transepithelial electrical resistance (TEER). The expression of several TJPs, such as claudin‐5 and junctional adhesion molecule (JAM)‐B, was measured at the mRNA and protein levels using real‐time polymerase chain reaction and immunocytochemistry, respectively. Results: TNF‐α and IL‐17 decreased TEER values, and TNF‐α decreased claudin‐5 and JAM‐B mRNA and protein levels, whereas IL‐17 decreased JAM‐B mRNA and protein levels, and all of these effects were concentration‐dependent. Compared with normothermia, claudin‐5 and JAM‐B proteins were not affected by hypothermia, whereas JAM‐B protein was reduced by hyperthermia. Conclusion: The hypothermic suppression of TNF‐α and IL‐17 release may contribute to the maintenance of BBB function by ameliorating the decrease of TJP(s). In contrast, hyperthermia may decrease barrier function through a decrease in JAM‐B expression. However, the contribution of changes in the JAM‐B expression to the barrier function of BMVECs remains to be clarified. [ABSTRACT FROM AUTHOR]

Elevated expression of CD47 in some cancers is associated with poor survival related to its function as an innate immune checkpoint when expressed on tumor cells. In contrast, elevated CD47 expression in cutaneous melanomas is associated with improved survival. Previous studies implicated protective functions of CD47 expressed by immune cells in the melanoma tumor microenvironment. RNA sequencing analysis of responses induced by CD3 and CD28 engagement on wild type and CD47-deficient Jurkat T lymphoblast cells identified additional regulators of T cell function that were also CD47-dependent in mouse CD8 T cells. MYCN mRNA expression was upregulated in CD47-deficient cells but downregulated in CD47-deficient cells following activation. CD47 also regulated alternative splicing that produces two N-MYC isoforms. The CD47 ligand thrombospondin-1 inhibited expression of these MYCN mRNA isoforms, as well as induction of the oncogenic decoy MYCN opposite strand (MYCNOS) RNA during T cell activation. Analysis of mRNA expression data for melanomas in The Cancer Genome Atlas identified a significant coexpression of MYCN with CD47 and known regulators of CD8 T cell function. Thrombospondin-1 inhibited the induction of TIGIT, CD40LG, and MCL1 mRNAs following T cell activation in vitro. Increased mRNA expression of these T cell transcripts and MYCN in melanomas was associated with improved overall survival. [ABSTRACT FROM AUTHOR]

Apolipoprotein CIII (ApoCIII) represents a key regulator of plasma lipid metabolism and a recognized risk factor for atherosclerosis and cardiovascular diseases. Beyond the regulation of lipoprotein trafficking, ApoCIII is also involved in endothelial dysfunction and monocyte recruitment related to atherothrombosis. With tissue factor (TF) being the primary initiator of the blood coagulation cascade, we hypothesized that ApoCIII-treated monocytes could express it. Hence, human CD14+-monocytes and autologous neutrophils were incubated with ApoCIII and sera from human subjects containing previously measured ApoCIII amounts. By RT-qPCR and ELISA, CD14+-monocytes, but not neutrophils, were found to show increased mRNA expression and production of TNFα, IL-1β and IL-6 as well as TF mRNA once exposed to ultra-purified ApoCIII. By flow cytometry, CD14+-monocytes were found to rapidly express TF on their cell surface membrane when incubated with either ApoCIII or sera with known concentrations of ApoCIII. Finally, preincubation with specific ApoCIII-neutralizing antibodies significantly reduced the ability of most sera with known concentrations of ApoCIII to upregulate TF protein, other than partially inhibiting cytokine release, in CD14+-monocytes. In sum, herein we demonstrate that ApoCIII activates CD14+-monocytes to express TF. The data identify a potential mechanism which links circulating apolipoproteins with inflammation and atherothrombosis-related processes underlying cardiovascular risk. [ABSTRACT FROM AUTHOR]

Increased von Willebrand Factor (vWF) activity mediates platelet adhesion and might be a contributor to the development of thrombotic complications after surgery. Although in vitro studies have shown that hyperoxia induces endovascular damage, the effect of perioperative supplemental oxygen as a possible trigger for increased vWF activity has not been investigated yet. We tested our primary hypothesis that the perioperative administration of 80% oxygen concentration increases postoperative vWF activity as compared to 30% oxygen concentration in patients at risk of cardiovascular complications undergoing major noncardiac surgery. A total of 260 patients were randomly assigned to receive 80% versus 30% oxygen throughout surgery and for two hours postoperatively. We assessed vWF activity and Ristocetin cofactor activity in all patients shortly before the induction of anesthesia, within two hours after surgery and on the first and third postoperative day. Patient characteristics were similar in both groups. We found no significant difference in vWF activity in the overall perioperative time course between both randomization groups. We observed significantly increased vWF activity in the overall study population throughout the postoperative time course. Perioperative supplemental oxygen showed no significant effect on postoperative vWF and Ristocetin cofactor activity in cardiac risk patients undergoing major noncardiac surgery. In conclusion, we found no significant influence of supplemental oxygen in patients undergoing major non-cardiac surgery on postoperative vWF activity and Ristocetin cofactor activity. [ABSTRACT FROM AUTHOR]

The coronavirus 2019 (COVID-19) pandemic was caused by a positive sense single-stranded RNA (ssRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, other human coronaviruses (hCoVs) exist. Historical pandemics include smallpox and influenza, with efficacious therapeutics utilized to reduce overall disease burden through effectively targeting a competent host immune system response. The immune system is composed of primary/secondary lymphoid structures with initially eight types of immune cell types, and many other subtypes, traversing cell membranes utilizing cell signaling cascades that contribute towards clearance of pathogenic proteins. Other proteins discussed include cluster of differentiation (CD) markers, major histocompatibility complexes (MHC), pleiotropic interleukins (IL), and chemokines (CXC). The historical concepts of host immunity are the innate and adaptive immune systems. The adaptive immune system is represented by T cells, B cells, and antibodies. The innate immune system is represented by macrophages, neutrophils, dendritic cells, and the complement system. Other viruses can affect and regulate cell cycle progression for example, in cancers that include human papillomavirus (HPV: cervical carcinoma), Epstein–Barr virus (EBV: lymphoma), Hepatitis B and C (HB/HC: hepatocellular carcinoma) and human T cell Leukemia Virus-1 (T cell leukemia). Bacterial infections also increase the risk of developing cancer (e.g., Helicobacter pylori). Viral and bacterial factors can cause both morbidity and mortality alongside being transmitted within clinical and community settings through affecting a host immune response. Therefore, it is appropriate to contextualize advances in single cell sequencing in conjunction with other laboratory techniques allowing insights into immune cell characterization. These developments offer improved clarity and understanding that overlap with autoimmune conditions that could be affected by innate B cells (B1+ or marginal zone cells) or adaptive T cell responses to SARS-CoV-2 infection and other pathologies. Thus, this review starts with an introduction into host respiratory infection before examining invaluable cellular messenger proteins and then individual immune cell markers. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin–angiotensin system in depressive-like behaviours. Methods: 8–12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic deletion of MrgD (MrgD KO) or Mas receptors (Mas KO) were subjected to the Forced Swim Test (FST) and the Tail Suspension Test (TST). Brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay (ELISA). Blockade of Mas was performed by acute intracerebroventricular (icv) injection of its selective antagonist, A779. Results: No statistical difference in immobility time was observed between MrgD KO and WT male animals subjected to FST and TST. However, acute icv injection of A779 significantly increased the immobility time of MrgD KO male mice subjected to FST and TST, suggesting the involvement of Mas in preventing depressive-like behaviour. Indeed, Mas KO male animals showed increased immobility time in FST and TST, evidencing a depressive-like behaviour in these animals, in addition to a reduction in BDNF levels in the prefrontal cortex and hippocampus. No changes in BDNF levels were observed in MrgD KO male animals. Conclusion: Our data showed that Mas plays an important role in the neurobiology of depression probably by modulating BDNF expression. On the contrary, lack of MrgD did not alter depressive-like behaviour, which was supported by the lack of alterations in BDNF levels. [ABSTRACT FROM AUTHOR]

Background: The inflammatory response induced by intestinal ischaemia‒reperfusion injury (I/R) is closely associated with infectious complications and mortality in critically ill patients, and the timely and effective clearance of apoptotic cells is an important part of reducing the inflammatory response. Studies have shown that the efferocytosis by phagocytes plays an important role. Recently, studies using small intestine organoid models showed that macrophage efferocytosis could promote the repair capacity of the intestinal epithelium. However, no studies have reported efferocytosis in the repair of I/R in animal models. Results: We used an in vivo efferocytosis assay and discovered that macrophage efferocytosis played an indispensable role in repairing and maintaining intestinal barrier function after I/R. In addition, the specific molecular mechanism that induced macrophage efferocytosis was Cth-ERK1/2 dependent. We found that Cth drove macrophage efferocytosis in vivo and in vitro. Overexpression/silencing Cth promoted/inhibited the ERK1/2 pathway, respectively, which in turn affected efferocytosis and mediated intestinal barrier recovery. In addition, we found that the levels of Cth and macrophage efferocytosis were positively correlated with the recovery of intestinal function in clinical patients. Conclusion: Cth can activate the ERK1/2 signalling pathway, induce macrophage efferocytosis, and thus promote intestinal barrier repair. ANik3mFzVX11c2tZJFb62z Video Abstract [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions. [ABSTRACT FROM AUTHOR]

Background:- renal biopsy the gold standard for diagnosing lupus nephritis (LN) is an invasive technique, other laboratory markers lack sensitivity and specificity. Aim:- to evaluate serum fractalkine (CX3CL1) as a predictor for LN in children with systemic lupus erythematosus (SLE). Methods:- forty-four children "5 - 18 years old" newly diagnosed with SLE, 22 (50.0%) of them were complicated with lupus nephritis "diagnosed by renal biopsy", and 22 healthy age and sex matched children were included as a control group. Serum Fractalkine levels were determined using human CX3CL1 ELISA. Results:- healthy children had lower serum fractalkine levels (median: 950.56 pg/ml, range: 591.55-1583.29) than both patient groups p<0.001, while there were as no significant differences between patients with LN (median: 1389.35 pg/ml, range 711.22 -16547.51) and without LN (median: 1429.39 pg/ml, range 591.55 - 4700.21), p=0.46. Moreover, serum Fractalkine was not correlated with the stage of LN (r=0.29, P=0.21) Conclusion:- Serum fractalkine is a poor predictor of lupus nephritis in children with SLE, although more studies are still required. [ABSTRACT FROM AUTHOR]

Lacticaseibacillus paracasei strain PS23 (PS23) exhibits some probiotic properties. In this study, a genomic analysis of PS23 revealed no genes related to virulence or antibiotic resistance. Moreover, ornithine decarboxylase activity was not detected in vitro. In addition, PS23 was sensitive to the tested antibiotics. Genotoxicity tests for PS23 including the Ames test and chromosomal aberrations in vitro using Chinese hamster ovary cells and micronuclei in immature erythrocytes of ICR mice were all negative. Moreover, following a 28-day study involving repeated oral dose toxicity tests (40, 400, and 4000 mg/kg equal 1.28 × 1010, 1.28 × 1011, and 1.28 × 1012 CFU/kg body weight, respectively) using an ICR mouse model, no adverse effects were observed from any doses. In addition, supplementation with live or heat-killed PS23 ameliorates DSS-induced colonic inflammation in mice. Our findings suggest that PS23 is safe and has anti-inflammatory effects and may therefore have therapeutic implications. [ABSTRACT FROM AUTHOR]

Extravasation of T cells from the bloodstream into inflamed tissues requires interactions between T cells and vascular endothelial cells, a necessary step that allows T cells to exert their effector function during the immune response to pathogens and to sterile insults. This cellular cross talk involves adhesion molecules on both the vascular endothelium and the T cells themselves that function as receptor-ligand pairs to slow down circulating T cells. These will eventually extravasate into sites of inflammation when they receive the correct chemokine signals. Accumulation of T cells within the vascular wall can lead to vessel thickening and vascular disease, whereas T-cell extravasation into the myocardium often leads to cardiac chronic inflammation and adverse cardiac remodeling, hallmarks of heart failure. On the flip side, T-cell trafficking is required for pathogen clearance and to promote tissue repair after injury resulting from cardiac ischemia. Thus, a better understanding of the central players mediating these interactions may help develop novel therapeutics to modulate vascular and cardiac inflammation. Here, we review the most recent literature on pathways that regulate T-cell transendothelial migration, the last step leading to T-cell infiltration into tissues and organs in the context of vascular and cardiac inflammation. We discuss new potential avenues to therapeutically modulate these pathways to enhance or prevent immune cell infiltration in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms. [ABSTRACT FROM AUTHOR]

African swine fever (ASF) is a hemorrhagic viral disease of domestic pigs and wild suids (all Sus scrofa) caused by the ASF virus (ASFV). The disease is spreading worldwide without control, threatening pig production due to the absence of licensed vaccine or commercially available treatments. A thorough understanding of the immunopathogenic mechanisms behind ASFV infection is required to better fight the disease. Cytokines are small, non-structural proteins, which play a crucial role in many aspects of the immune responses to viruses, including ASFV. Infection with virulent ASFV isolates often results in exacerbated immune responses, with increased levels of serum pro-inflammatory interleukins (IL-1α, IL-1β, IL-6), TNF and chemokines (CCL2, CCL5, CXCL10). Increased levels of IL-1, IL-6 and TNF are often detected in several tissues during acute ASFV infections and associated with lymphoid depletion, hemorrhages and oedemas. IL-1Ra is frequently released during ASFV infection to block further IL-1 activity, with its implication in ASFV immunopathology having been suggested. Increased levels of IFN-α and of the anti-inflammatory IL-10 seem to be negatively correlated with animal survival, whereas some correlation between virus-specific IFN-γ-producing cells and protection has been suggested in different studies where different vaccine candidates were tested, although future works should elucidate whether IFN-γ release by specific cell types is related to protection or disease development. [ABSTRACT FROM AUTHOR]

Aging of the cardiovascular regulatory function manifests as an imbalance between the sympathetic and parasympathetic (vagal) components of the autonomic nervous system (ANS). The most characteristic change is sympathetic overdrive, which is manifested by an increase in the muscle sympathetic nerve activity (MSNA) burst frequency with age. Age-related changes that occur in vagal nerve activity is less clear. The resting tonic parasympathetic activity can be estimated noninvasively by measuring the increase in heart rate occurring in response to muscarinic cholinergic receptor blockade; animal study models have shown this to diminish with age. Humoral, cellular, and neural mechanisms work together to prevent non-resolving inflammation. This review focuses on the mechanisms underlying age-related alternations in the ANS and how an imbalance in the ANS, evaluated by MSNA and heart rate variability (HRV), potentially facilitates inflammation when the homeostatic mechanisms between reflex neural circuits and the immune system are compromised, particularly the dysfunction of the cholinergic anti-inflammatory reflex. Physiologically, the efferent arm of this reflex acts via the α 7 nicotinic acetylcholine receptors expressed in macrophages, monocytes, dendritic cells, T cells, and endothelial cells to curb the release of inflammatory cytokines, in which inhibition of NF‑κB nuclear translocation and activation of a JAK/STAT-mediated signaling cascade in macrophages and other immune cells are implicated. This reflex is likely to become less adequate with advanced age. Consequently, a pro-inflammatory state induced by reduced vagus output with age is associated with endothelial dysfunction and may significantly contribute to the development and propagation of atherosclerosis, heart failure, and hypertension. The aim of this review is to summarize the relationship between ANS dysfunction, inflammation, and endothelial dysfunction in the context of aging. Meanwhile, this review also attempts to describe the role of HRV measures as a predictor of the level of inflammation and endothelial dysfunction in the aged population and explore the possible therapeutical effects of vagus nerve stimulation. [ABSTRACT FROM AUTHOR]

Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury. [ABSTRACT FROM AUTHOR]

We recently reported a positive relationship between occlusal disharmony and cardiovascular disease via activation of β-adrenergic signaling in mice. Furthermore, inhibition of type 5 adenylyl cyclase (AC5), a major cardiac subtype in adults, protects the heart against oxidative stress. Here, we examined the role of AC5 in the development of occlusal-disharmony-induced cardiovascular disease in bite-opening (BO) mice, prepared by cementing a suitable appliance onto the mandibular incisor. We first examined the effects of BO treatment on cardiac function in mice treated or not treated for 2 weeks with vidarabine, which we previously identified as an inhibitor of cardiac AC. Cardiac function was significantly decreased in the BO group compared to the control group, but vidarabine ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and myocyte oxidative DNA damage were significantly increased in the BO group, but vidarabine blocked these changes. The BO-induced cardiac dysfunction was associated with increased phospholamban phosphorylation at threonine-17 and serine-16, as well as increased activation of the Ca2+-calmodulin-dependent protein kinase II/receptor-interacting protein 3 signaling pathway. These data suggest that AC5 inhibition with vidarabine might be a new therapeutic approach for the treatment of cardiovascular disease associated with occlusal disharmony. [ABSTRACT FROM AUTHOR]

Formyl peptide receptors, abbreviated as FPRs in humans, are G-protein coupled receptors (GPCRs) mainly found in mammalian leukocytes. However, they are also expressed in cell types crucial for homeostatic brain regulation, including microglia and blood–brain barrier endothelial cells. Thus, the roles of these immune-associated receptors are extensive, from governing cellular adhesion and directed migration through chemotaxis, to granule release and superoxide formation, to phagocytosis and efferocytosis. In this review, we will describe the similarities and differences between the two principal pro-inflammatory and anti-inflammatory FPRs, FPR1 and FPR2, and the evidence for their importance in the development of neuroinflammatory disease, alongside their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Visfatin, a multifunctional adipocytokine, is particularly important in the regulation of apoptosis and inflammation through an unidentified mechanism. Clarifying the control mechanisms of visfatin on inflammation and apoptosis in RAW264.7 cells and mice immunological organs was the goal of the current investigation. In order to create a pathophysiological model, the RAW264.7 cells were stimulated with 200 ng/mL visfatin and 20 μg/mL lipopolysaccharide (LPS), either separately or combined. The effects of exogenous visfatin on inflammation and apoptosis in RAW264.7 cells were investigated by flow cytometry assay, RNA-seq analysis and fluorescence quantitative PCR. According to the findings, exogenous visfatin exhibits dual effects on inflammation by modulating the expression of IL-1α, TNFRSF1B, and LIF as well as taking part in various signaling pathways, including the MAPK and Rap1 signaling pathways. By controlling the expression levels of Bcl2l1, Bcl2a1a, and Fas and primarily participating in the PI3K/AKT signaling pathway and Hippo signaling pathway, exogenous visfatin can inhibit apoptosis in RAW264.7 cells. The visfatin inhibitor FK866 was used to further confirm the effects of visfatin on inflammation and apoptosis in mice immune organs. Subsequently, mice spleen and thymus were collected. It is interesting to note that in LPS-treated mice, suppression of endogenous visfatin might worsen the immune system’s inflammatory response and even result in rapid mortality. Additionally, endogenous visfatin promotes the apoptosis in mice immune organs by regulating the expression levels of Bcl2l1, Fas, Caspase 3, Bcl2a1a, and Bax. Together, these results imply that visfatin is a multifaceted molecule that regulates inflammation and apoptosis in RAW264.7 cells and mice immunological organs by taking part in a variety of biological processes and regulating the amounts of associated cytokines expression. Our findings offer additional understandings of how visfatin affects apoptosis and inflammation. [ABSTRACT FROM AUTHOR]

Context: Interleukin-17 (IL-17) plays an important function in initiation, progression of any inflammatory condition. It is a pro-inflammatory cytokine and considered to be founding member. Periodontitis being an inflammatory condition of periodontium, IL-17 does have a potential role in periodontitis. The current research has shown positive correlation between the IL-17 and severity of periodontitis. Therefore, this research study aimed to evaluate the levels of IL-17 in aggressive periodontitis (AgP), chronic periodontitis (CP), and "healthy gingival sites." Materials and Methods: A total of 45 selected subjects (90 samples) were equally divided into three different groups. Group 1 (Healthy gingiva on clinical examination): Subjects with healthy gingiva and no evidence of periodontal attachment level (PAL), probing pocket depth (PPD) <3 mm papillary bleeding index (PBI) <1. Group 2 (AgP): Subjects having age <35 years with at least six permanent teeth apart from the incisors and first molars with PPD and PAL ≥5 mm. Group 3 (CP): It consist of subjects with clinical features of inflammation of gingiva with minimum six teeth in each jaw, with PPD ≥4 mm, PAL ≥4 mm. IL-17 levels were analyzed by using Gingival crevicular fluid (GCF). It was collected from the sulcus of first maxillary molar sites for quantitative analysis. Results: GCF IL-17 levels in AgP were found to be 1.12 ± 0.29, 1.96 ± 1.71 in CP and 0.64 ± 0.23 in healthy gingival sites. Clinical parameters such as (1) plaque index (Turesky et al., modification of Quigley-Hein), (2) PPD, (3) PBI were higher (significantly) in periodontitis group as compared to healthy gingiva. Positive correlation was found to be significant between levels of IL-17 with PAL and PPD in AgP however in cases of CP, positive correlation of IL-17 levels was found only with PAL but not PPD. Conclusion: Our study shows that the IL-17 levels were comparatively higher in GCF of AgP, CP in comparison to healthy gingiva, but the GCF IL-17 levels were higher in CP as compared to AgP. [ABSTRACT FROM AUTHOR]

Secukinumab is an anti-interleukin (IL)-17A IgG1-κ monoclonal antibody approved for psoriasis, psoriatic arthritis, and ankylosing spondylitis. Its efficacy is well documented, but the complete safety profile of secukinumab, especially on long-term use, needs to be studied. IL-17 inhibitors increase the risk of infections, especially respiratory tract infections and candidiasis, and inflammatory bowel disease; the causal relationships are well described. However, evidence regarding the other adverse events is scarce, and causal associations between the adverse events and the biologic remain unresolved. This review aims to present a narrative perspective on the safety of secukinumab and identify some key areas where the safety of secukinumab may potentially be useful in understanding the scope of secukinumab therapy and making informed clinical decisions. [ABSTRACT FROM AUTHOR]

Background: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid‐lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta‐analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. Methods: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. Results: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: −73.9%; 95%CI: −93.5%, −54.2; p <.001 I2 = 89.05%; p <.001); VLDL‐C level (MD: −71.0%; 95%CI: −76.6%, −65.4%; p <.001 I2 = 94.1%; p <.001); Apo‐B48 level (MD: −69.03%; 95%CI: −98.59.4%, −39.47%; p <.001, I2 = 93.51%; p <.001) and Apo‐CIII level (MD: −80.0%; 95%CI: −97.5%, −62.5; p <.001 I2 = 94.1%; p <.001) with an increase in HDL‐C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p <.001 I2 = 94.34%; p <.001) and in LDL‐C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p <.001 I2 = 96.18%; p <.001) without a significant elevation of Apo‐B100 level (MD: +4.58%, 95%CI: −5.64%, +14.79%; p =.380 I2 = 95.09%; p <.001) in 139 volanesorsen patients as compared to 100 placebo‐treated controls. Most of adverse events were mild and related to local injection site reactions. Conclusions: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL‐C, Apo‐B48 and non‐HDL‐C and increment of HDL‐C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile. [ABSTRACT FROM AUTHOR]

The use of probiotics is expected to be an intervention in neurodegenerative conditions that cause dementia owing to their ability to modulate neuroinflammatory responses via the microbiome-gut–brain axis. Therefore, we selected Lactiplantibacillus plantarum OLL2712 (OLL2712), the optimal anti-inflammatory lactic acid bacteria strain with high IL-10-inducing activity in immune cells, and aimed to verify its protective effects on memory function in older adults. A 12-week, randomized, double-blind, placebo-controlled trial was performed with older adults over the age of 65 years with declining memory. The participants consumed either powder containing heat-treated OLL2712 cells or placebo. Memory function was assessed using a computer-assisted cognitive test, Cognitrax. Daily dietary nutrient intake was assessed using the Brief-type Self-administered Diet History Questionnaire (BDHQ). The composition of the gut microbiota was analyzed by fecal DNA extraction and 16S rDNA sequencing. Data from 78 participants who completed the entire procedure were analyzed, and significant improvements in composite memory and visual memory scores were observed in the active group, after accounting for the effect of daily nutritional intake (p = 0.044 and p = 0.021, respectively). In addition, the active group had a lower abundance ratio of Lachnoclostridium, Monoglobus, and Oscillibacter genera, which have been reported to be involved in inflammation. The present study suggests that OLL2712 ingestion has protective effects against memory function decline in older adults. [ABSTRACT FROM AUTHOR]

Background: Human population exposed to influenza viruses exhibited wide variation in susceptibility. The ratio of neutrophils to lymphocytes (NLR) has been examined to be a marker of systemic inflammation. We sought to investigate the relationship between influenza susceptibility and the NLR taken before influenza virus infection. Methods: We investigated blood samples from five independent influenza challenge cohorts prior to influenza inoculation at the cellular level by using digital cytometry. We used multi-cohort gene expression analysis to compare the NLR between the symptomatic infected (SI) and asymptomatic uninfected (AU) subjects. We then used a network analysis approach to identify host factors associated with NLR and influenza susceptibility. Results: The baseline NLR was significantly higher in the SI group in both discovery and validation cohorts. The NLR achieved an AUC of 0.724 on the H3N2 data, and 0.736 on the H1N1 data in predicting influenza susceptibility. We identified four key modules that were not only significantly correlated with the baseline NLR, but also differentially expressed between the SI and AU groups. Genes within these four modules were enriched in pathways involved in B cell-mediated immune responses, cellular metabolism, cell cycle, and signal transduction, respectively. Conclusions: This study identified the NLR as a potential biomarker for predicting disease susceptibility to symptomatic influenza. An elevated NLR was detected in susceptible hosts, who may have defects in B cell-mediated immunity or impaired function in cellular metabolism, cell cycle or signal transduction. Our work can serve as a comparative model to provide insights into the COVID-19 susceptibility. [ABSTRACT FROM AUTHOR]

We discuss the fascinating pharmacology of formylpeptide receptor 2 (FPR2; often referred to as FPR2/ALX since it binds lipoxin A4 ). Initially identified as a low-affinity 'relative' of FPR1, FPR2 presents complex and diverse biology. For instance, it is activated by several classes of agonists (from peptides to proteins and lipid mediators) and displays diverse expression patterns on myeloid cells as well as epithelial cells and endothelial cells, to name a few. Over the last decade, the pharmacology of FPR2 has progressed from being considered a weak chemotactic receptor to a master-regulator of the resolution of inflammation, the second phase of the acute inflammatory response. We propose that exploitation of the biology of FPR2 offers innovative ways to rectify chronic inflammatory states and represents a viable avenue to develop novel therapies. Recent elucidation of FPR2 structure will facilitate development of the anti-inflammatory and pro-resolving drugs of next decade. [ABSTRACT FROM AUTHOR]

Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly. [ABSTRACT FROM AUTHOR]

With the arrival of the era of tumor immunotherapy, Immune Checkpoint Inhibitors have benefited countless tumor patients. However, the emergence of Immune-Related Adverse Events, especially Immune Checkpoint Inhibitor-Mediated Colitis (IMC), has become an important obstacle to immunotherapy. Therefore, it is very important to clarify themechanism and influencing factors of IMC. The effect of gut microbiota on IMC is gradually becoming a research hotspot. Gut microbiota from different phyla can affect IMC by regulating innate and acquired immunity of tumor patients in various ways. In this review, wemake a systematic and comprehensive introduction of the effect of gut microbiota on IMC. Through understanding the specific effects of gut microbiota on IMC, and then exploring the possibility of reducing IMC by regulating gut microbiota. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system (RAS), as a critical system for controlling body fluid and hemostasis, contains peptides and receptors, including angiotensin 1-7 (Ang 1-7) and Mas receptor (MasR). Ang 1-7 implements its function via MasR. Ang II is another peptide in RAS that performs its actions via two Ang II type 1 and 2 receptors (AT1R and AT2R). The functions of AT2R and MasR are very similar, and both have a vasodilation effect, while AT1R has a vasoconstriction role. MasR affects many mechanisms in the brain, heart, blood vessels, kidney, lung, endocrine, reproductive, skeletal muscle, and liver and probably acts like a paracrine hormone in these organs. The effect of Ang 1-7 in the kidney is complex according to the hydroelectrolyte status, the renal sympathetic nervous system, and the activity level of the RAS. The MasR expression and function seem more complex than Ang II receptors and have interacted with Ang II receptors and many other factors, including sex hormones. Also, pathological conditions including hypertension, diabetes, and ischemia-reperfusion could change MasR expression and function. In this review, we consider the role of sex differences in MasR expression and functions in the renal system under physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

CD47 regulates the trafficking of specific coding and noncoding RNAs into extracellular vesicles (EVs), and the RNA contents of CD47+ EVs differ from that of CD63+ EVs released by the same cells. Single particle interferometric reflectance imaging sensing combined with immunofluorescent imaging was used to analyse the colocalization of tetraspanins, integrins, and CD47 on EVs produced by wild type and CD47‐deficient Jurkat T lymphoblast and PC3 prostate carcinoma cell lines. On Jurkat cell‐derived EVs, β1 and α4 integrin subunits colocalized predominantly with CD47 and CD81 but not with CD63 and CD9, conserving the known lateral interactions between these proteins in the plasma membrane. Although PC3 cell‐derived EVs lacked detectable α4 integrin, specific association of CD81 with β1 and CD47 was preserved. Loss of CD47 expression in Jurkat cells significantly reduced β1 and α4 levels on EVs produced by these cells while elevating CD9+, CD63+, and CD81+ EVs. In contrast, loss of CD47 in PC3 cells decreased the abundance of CD63+ and CD81+ EVs. These data establish that CD47+ EVs are mostly distinct from EVs bearing the tetraspanins CD63 and CD9, but CD47 also indirectly regulates the abundance of EVs bearing these non‐interacting tetraspanins via mechanisms that remain to be determined. [ABSTRACT FROM AUTHOR]

Transmembrane 4 L six family member 5 (TM4SF5) is involved in chronic liver disease, although its role in glucose homeostasis remains unknown. TM4SF5 deficiency caused age‐dependent glucose (in)tolerance with no link to insulin sensitivity. Further, hepatic TM4SF5 binding to GLUT1 promoted glucose uptake and glycolysis. Excessive glucose repletion caused hepatocytes to secrete small extracellular vesicles (sEVs) loaded with TM4SF5 (hep‐sEVTm4sf5), suggesting a role for sEVTm4sf5 in glucose metabolism and homeostasis. Hep‐sEVTm4sf5 were smaller than sEVControl and recruit proteins for efficient organ tropism. Liver‐derived sEVs, via a liver‐closed vein circuit (LCVC) using hepatic TM4SF5‐overexpressing (Alb‐Tm4sf5 TG) mice (liv‐sEVTm4sf5), improved glucose tolerance in Tm4sf5−/− KO mice and targeted brown adipose tissues (BATs), possibly allowing the clearance of blood glucose as heat independent of UCP1. Taken together, hep‐sEVTm4sf5 might clear high extracellular glucose levels more efficiently by targeting BAT compared with hep‐sEVControl, suggesting an insulin‐like role for sEV™4SF5 in affecting age‐related metabolic status and thus body weight (BW). [ABSTRACT FROM AUTHOR]

Purpose: This study explored the interactive effects between polymorphonuclear neutrophils (PMNs) and vascular endothelial cells under intermittent hypoxia (IH) and investigated the mechanisms underlying these effects. Methods: Endothelial cells were co-cultured with PMNs isolated from rats exposed to normoxia or IH. The PMN apoptotic rate was determined using flow cytometry. Expression of apoptosis-related proteins in the endothelial cells were evaluated using Western blotting, and the levels of intercellular adhesion molecules in the co-culture supernatants were measured using enzyme-linked immunosorbent assay. Results: The PMN apoptotic rate in the IH-exposed rat group was significantly lower than that of the normoxia control group. There was a positive relationship between the PMN apoptotic rate and IH exposure time. In endothelial cells co-cultured with PMNs isolated from IH-exposed rats, a significant increase in the protein expression levels of Bax, Bcl-2, and caspase-3 and a significant decrease in the Bcl-2/Bax ratio were observed. Furthermore, the intercellular cell adhesion molecule-1(ICAM-1) and E-select element (E-S) levels were elevated significantly in the co-cultured supernatants of endothelial cells and PMNs from IH-exposed rats compared to that from controls. The above IH-induced alterations were partially restored by tempol pretreatment. Conclusions: The apoptotic rate was low in PMNs from IH-exposed rats, which consequently increased the apoptotic signals in endothelial cells in vitro. This may be associated with the increased levels of intercellular adhesion molecules. Further, tempol partially attenuates the PMN-mediated pro-apoptotic effects on endothelial cells under IH. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to identify the mechanistic role of γδ T cells in the pathogenesis of experimental psoriatic arthritis (PsA). Methods: In this study, we performed interleukin‐23 (IL‐23) gene transfer in wild‐type (WT) and T cell receptor δ–deficient (TCRδ−/−) mice and conducted tissue phenotyping in the joint, skin, and nails to characterize the inflammatory infiltrate. We further performed detailed flow cytometry, immunofluorescence staining, RNA sequencing, T cell repertoire analysis, and in vitro T cell polarization assays to identify regulatory mechanisms of γδ T cells. Results: We demonstrated that γδ T cells support systemic granulopoiesis, which is critical for murine PsA‐like pathology. Briefly, γδ T cell ablation inhibited the expression of neutrophil chemokines CXCL1 and CXCL2 and neutrophil CD11b+Ly6G+ accumulation in the aforementioned PsA‐related tissues. Although significantly reduced expression of granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and IL‐17A was detected systemically in TCRδ−/− mice, no GM‐CSF+/IL‐17A+ γδ T cells were detected locally in the inflamed skin or bone marrow in WT mice. Our data showed that nonresident γδ T cells regulate the expansion of an CD11b+Ly6G+ neutrophil population and their recruitment to joint and skin tissues, where they develop hallmark pathologic features of human PsA. Conclusion: Our findings do not support the notion that tissue‐resident γδ T cells initiate the disease but demonstrate a novel role of γδ T cells in neutrophil regulation that can be exploited therapeutically in PsA patients. [ABSTRACT FROM AUTHOR]

The synthetic hexapeptide WKYMVm, screened from a synthetic peptide library, has been identified as an agonist of FPRs with the strongest activating effect on FPR2. WKYMVm plays an anti-inflammatory role in most inflammatory diseases by increasing the chemotaxis of phagocytes and regulating the secretion of inflammatory factors. WKYMVm can inhibit or promote the progression of different types of tumors, which depends on the regulation of WKYMVm on various components such as immune cells, inflammatory factors, chemokines, and tumor epithelial cells. Another major function of WKYMVm is to promote angiogenesis, which is reflected in its therapeutic value in ischemic diseases, wound healing and bone repair. In addition to the above functions, this paper also reviews the effects of WKYMVm on fibrosis, insulin resistance, osteolytic diseases and neurodegenerative diseases. By summarizing related studies, this review can increase people's comprehensive understanding of WKYMVm, promote its broad and in-depth research, and help to exert its therapeutic value as soon as possible. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is characterized by impairment and apoptosis of endothelial cells, continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells, which is documented as the traditional cellular paradigm. However, the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis, transdifferentiation and novel cell death forms such as ferroptosis, pyroptosis, and extracellular trap were reported. Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets. On the other side, the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden. Stem cell- or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects. Given the complexity of pathological changes of AS, attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging. In this review, the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation. The future challenges and improvements were also discussed., (© 2024. The Author(s).)

Physiologically, cytokines play an extremely important role in maintaining cellular and subcellular homeostasis, as they interact almost with every cell in the organism. Therefore, cytokines play a significantly critical role in the field of pathogenic pharmacological therapy of different types of pathologies. Cytokine is a large family containing many subfamilies and can be evaluated into groups according to their action on epithelial cell proliferation; stimulatory include transforming growth factor-α (TGF-α), Interlukine-22 (IL-22), IL-13, IL-6, IL-1RA and IL-17 and inhibitory include IL-1α, interferon type I (IFN type I), and TGF-β. The balance between stimulatory and inhibitory cytokines is essential for maintaining normal epithelial cell turnover and tissue homeostasis. Dysregulation of cytokine production can contribute to various pathological conditions, including inflammatory disorders, tissue damage, and cancer. Several cytokines have shown the ability to affect programmed cell death (apoptosis) and the capability to suppress non-purpose cell proliferation. Clinically, understanding the role of cytokines' role in epithelial tissue is crucial for evaluating a novel therapeutic target that can be of use as a new tactic in the management of carcinomas and tissue healing capacity. The review provides a comprehensive and up-to-date synthesis of current knowledge regarding the multifaceted effects of cytokines on epithelial cell proliferation, with a particular emphasis on the intestinal epithelium. Also, the paper will highlight the diverse signaling pathways activated by cytokines and their downstream consequences on epithelial cell division. It will also explore the potential therapeutic implications of targeting cytokine- epithelial cell interactions in the context of various diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The aim of this study was to analyze the percentages of T helper 17 cells (Th17s) and T regulatory cells (Tregs) in autoimmune Hashimoto’s thyroiditis (HT), and the expression of the checkpoint molecules programmed death receptor 1/programmed death ligand 1 (PD-1/PD-L1) on these cells. Methods: This is a case-control study involving 53 initially diagnosed HT patients (HT group) and 21 normal controls (NC group). The peripheral blood mononuclear cells from the individuals of the two groups were isolated and restimulated ex vivo; the percentage of Th17s, Tregs, PD-1+ Th17s, PD-L1+ Th17s, PD-1+ Tregs, and PD-L1+ Tregs was assessed by flow cytometric analysis. Results: (1) The percentage of Th17s in the peripheral blood of the HT group was significantly higher than that of the NC group [(6.38 ± 1.32)% versus (3.12 ± 0.66)%; t = 14.110, P < 0.001], while the percentage of peripheral blood Tregs was significantly lower [(3.82 ± 1.48)% versus (5.61 ± 1.60)%; t = −4.599, P < 0.001]. (2) HT patients’ Th17s expressed PD-1 at a significantly lower frequency than their counterparts in the NC [(6.46 ± 2.77)% versus (18.51 ± 3.96)%; t = −14.842, P < 0.001], while no difference was observed for PD-L1 between the two groups. (3) In contrast, both PD-1 and PD-L1 were expressed at significantly higher frequency on HT patients’ Tregs than on NC [respectively: (17.01 ± 3.04)% versus (10.23 ± 2.77)%; t = 8.850, P < 0.001 for PD-1; (16.60 ± 9.58)% versus (11.36 ± 10.14)%; t = 2.089, P < 0.005, for PD-L1]. Conclusion: (1) The increased percentage of Th17s and decreased percentage of PD-1+ Th17s in the HT group suggest that a loss of control on Th17 activity through the checkpoint inhibitory axis PD-1/PD-L1 may participate in disease pathogenesis. (2) While the decreased percentage of Tregs in HT patients may explain a lack of regulatory functions able to prevent the autoimmune destruction of the thyroid, the significance of the increased frequency of Tregs expressing PD-1 and PD-L1, previously reported to boost Tregs differentiation, remains to be established. Elucidating this apparent contradiction may reveal important mechanisms underlying HT pathogenesis. [ABSTRACT FROM AUTHOR]

Body fat distribution is a well-established predictor of adverse medical outcomes, independent of overall adiposity. Studying body fat distribution sheds insights into the causes of obesity and provides valuable information about the development of various comorbidities. Compared to total adiposity, body fat distribution is more closely associated with risks of cardiovascular diseases. The present review specifically focuses on the sexual dimorphism in body fat distribution, the biological clues, as well as the genetic traits that are distinct from overall obesity. Understanding the sex determinations on body fat distribution and adiposity will aid in the improvement of the prevention and treatment of cardiovascular diseases (CVD). [ABSTRACT FROM AUTHOR]

Mycoplasmas as economically important and pantropic pathogens can cause similar clinical diseases in different hosts by eluding host defense and establishing their niches despite their limited metabolic capacities. Besides, enormous undiscovered virulence has a fundamental role in the pathogenesis of pathogenic mycoplasmas. On the other hand, they are host-specific pathogens with some highly pathogenic members that can colonize a vast number of habitats. Reshuffling mycoplasmas genetic information and evolving rapidly is a way to avoid their host's immune system. However, currently, only a few control measures exist against some mycoplasmosis which are far from satisfaction. This review aimed to provide an updated insight into the state of mycoplasmas as pathogens by summarizing and analyzing the comprehensive progress, current challenge, and future perspectives of mycoplasmas. It covers clinical implications of mycoplasmas in humans and domestic and wild animals, virulence-related factors, the process of gene transfer and its crucial prospects, the current application and future perspectives of nanotechnology for diagnosing and curing mycoplasmosis, Mycoplasma vaccination, and protective immunity. Several questions remain unanswered and are recommended to pay close attention to. The findings would be helpful to develop new strategies for basic and applied research on mycoplasmas and facilitate the control of mycoplasmosis for humans and various species of animals. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells. [ABSTRACT FROM AUTHOR]

The aim of this systematic review and meta-analysis was to investigate the effects of resistant starch (RS) on inflammation and oxidative stress related indicators. PubMed, Embase and The Cochrane library were systematically searched to find randomized controlled trials (RCTs) of RS intervention up to February 2020. We used from the effect size, as estimated by the standardized mean difference (SMD) with 95% confidence intervals (95%CI) to perform the random method meta-analysis, with P value ≦0.05 as statistically significant. The 16 included trials with 17 effect sizes included a total of 739 participants in this paper. The intervention duration was from 2 weeks to 3 months. The analysis indicated that RS decreases the levels of tumor necrosis factor-α (TNF‐α) (SMD = −0.711; 95%CI: −1.227, −0.194; P = 0.007) and interleukin 6 (IL‐6) (SMD = −0.609; 95%CI: −0.924, −0.294; P < 0.001), increases total antioxidant capacity (TAC) (SMD = 2.543, 95% CI: 0.069: 5.017, P = 0.044). No significant effects on C‐reactive protein (CRP) (SMD = −0.583; 95%CI: −1.270, 0.104; P = 0.096), superoxide dismutase (SOD) (SMD = 0.091; 95%CI: −0.156, 0.338; P = 0.471), and malondialdehyde (MDA) (SMD = −0.320; 95%CI: −0.907, 0.266; P = 0.285). Subgroup analysis shown that CRP level significant reduced in subjects from the east (SMD = −1.501; 95%CI: −2.662, −0.340; P = 0.011) or suffering from diseases (SMD: −1.057; 95%CI: −1.999, −0.115; P = 0.028). Supplemental data for this article is available online at [ABSTRACT FROM AUTHOR]

Background: Current biomarkers for the early detection of sepsis have low sensitivity and specificity. Serum microRNAs (miRNAs) have been proposed as novel noninvasive biomarkers for various diseases. The aim of the present study was to discover a novel diagnostic biomarker for sepsis in human subjects. Methods: miRNA expression profiling was performed using peripheral blood from three sepsis patients in the sepsis stage and improved condition stage using microarray screening. The differentially expressed miRNAs were primary validated by real-time quantitative polymerase chain reaction (RT-qPCR) in a further set of 20 sepsis patients in the sepsis stage and improved condition stage. Finally, we validated the differentially expressed miRNAs in 95 sepsis patients and 66 nonsepsis patients. The validated miRNAs and patients' clinical indictors were analysed in a multivariate logistic regression model. The diagnostic value of the changed miRNA in sepsis was determined and compared with CRP and WBC by analysing the receiver operating characteristic (ROC) curves. Results: According to the criteria, we detected 11 miRNAs regulated by the miRNA chip. RT-qPCR detection showed that the expression of hsa-let-7d-3p in sepsis patients was upregulated compared with that in nonsepsis patients. In a multiple logistic regression analysis, serum miRNA hsa-let-7d-3p was found to be an independent predictor of sepsis. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of serum hsa-let-7d-3p was 0.696 [95% confidence interval (0.615, 0.778)]. Conclusion: The miRNA hsa-let-7d-3p was identified as a novel biomarker for the early detection of sepsis. [ABSTRACT FROM AUTHOR]