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The diverse physicochemical properties of polymers make them perfect candidates for developing biosensor elements when combined with porous substrates. For example, microfluidic channels, valves, reservoirs and biorecognition elements have been proposed that rely on filling the cavities of porous cellulose with different polymers. Yet, highly concentrated polymers are often too viscous to dispense them with precision using conventional printing methods. This increases the manufacturing variability, which degrades the performance of the biosensors. Here this issue is solved with a new method for infusing porous materials (filter paper) with concentrated polymers (PSS) that circumvents the dropwise addition of highly viscous reagents. The resulting films contain homogenously distributed polymers, which reduces the intra- and inter-batch variabilities of biosensors based on dispensing nanoparticles from the reservoirs. The proposed method was utilized to develop immunosensors for detecting the cytokines IL-6 and IL-5 in aerosols, which were trapped by the polypropylene layer of a surgical face mask (limit of detection 10−2 pg·mL−1). Using this approach, we were able to detect elevated levels of airways cytokines when exacerbated COPD patients and eosinophilic asthma patients wore the face mask for 30 min. The results shown here pave the way for upscaling the manufacturing of paper-based nanoparticle biosensors, which is a crucial step towards their future commercialization. [Display omitted] • Nanoparticle reservoirs are fabricated by infusing filter paper with polystyrene sulfonate • The proposed method reduces the intra- and inter-batch fabrication variability • Biosensors against IL-6 and IL-5 in aerosols are developed • Non-invasive detection of airways cytokines in patient samples is demonstrated [ABSTRACT FROM AUTHOR]

Abstract: Total hip-joint arthroplasty is performed in increasing numbers where it translates to about 0.16–0.2% of population per year in industrial countries. In most cases, an implant is a metallic component articulating with a metal, ceramic or poly-ethylene liner as seen in the case of hip, knee and spine. The metal implants release ions in vivo. Therefore, there is a need to study metallic implants and ions released as a result. Toxic concentrations of ions can lead to many adverse physiological effects, including cytotoxicity, genotoxicity, carcinogenicity, and metal sensitivity. There is a need to map ion concentrations establishing boundaries between normal and toxic levels; which however, does not exist. Reference levels of ion concentrations in body fluids and tissues determined by many studies are compiled, reviewed, and presented in this paper. The concentrations of ions released from different alloys, including cobalt, chromium, nickel, molybdenum titanium, aluminum, and vanadium, are presented in this paper. This paper reviews the literature pertaining to clinical data on metal ion concentrations in patients with metal joint prostheses, and laboratory data on the physiological effects of the metals. [Copyright &y& Elsevier]

We examined the utility of dried blood on filter paper for the source of cytokine messenger RNA (mRNA). Total RNA was isolated from the dried blood of mice infected with Plasmodium yoelii, and cDNA was amplified by reverse transcription-polymerase chain reaction (RT-PCR). As a reference, we extracted total RNA from peripheral blood collected at the same time as the preparation for dried blood. There was no difference in cytokine mRNA expression between the two sources; the dried blood on filter paper and the peripheral blood. Th1 cells, Th2 cells, and monocytes/macrophages derived cytokine mRNAs in the dried blood from infected mice were detected, and the increase of some of the cytokines mRNAs after infection was also observed. These results suggested that the dried blood on filter paper is satisfactory RNA source for immunological examination in field-based studies. [Copyright &y& Elsevier]

BACKGROUND CONTEXT Acute sciatica secondary to lumbar disc herniation (AS/LDH) is thought to be caused by mechanical compression of the spinal nerve root and/or chemical inflammatory mechanisms involving pro-inflammatory cytokines (IC) such as interleukin (IL)-1α, IL-8and tumor necrosis factor (TNF)-α). Although chiropractic high velocity low amplitude (HVLA) spinal manipulative therapy (CSMT) is commonly used to treat AS/LDH patients, randomized controlled studies demonstrating efficacy have not been carried out to date. In addition, preliminary studies have reported decreases in serum ICs following CSMT. PURPOSE To evaluate the feasibility of conducting a randomized controlled trial (RCT) of the clinical and biological effects of chiropractic spinal manipulative therapy (CSMT) on in vivo IC expression and clinical outcomes in patients with acute sciatica and lumbosacral disc herniation (AS/LDH). STUDY DESIGN/SETTING Randomized controlled clinical trial. Enzyme linked immunosorbent assay (ELISA) of serum and disc tissue inflammatory cytokine content. PATIENT SAMPLE Inclusion: AS/LDH ofless than 6 months' duration with a McCulloch criteria score of 5/5. Exclusion: red flag condition, cauda equina syndrome, progressive neurological deficit. OUTCOME MEASURES VAS and Roland Morris Disability scores and serum IC levels at baseline, 6, 12 and 24 weeks. Physical examination findings of nerve root tension signs, motor and sensory spinal nerve root deficit and Schober's test of lumbar flexion recorded at all data collection points. IC levels measured by ELISA in disc tissue, nerve root and disc lavagate collected in patients undergoing surgery. METHODS Patients with AS/LDH of less than 16 weeks duration were randomized to 6 weeks of CSMT or the approximately 6 weeks surgical wait list. Standardized neurological and lumbar spine examinations, VAS and Roland Morris Disability scores, and serum IC levels were assessed at baseline, 6, 12 and 24 weeks. ICs were also measured in disc tissue, nerve root and disc lavagate collected during surgery. Research ethics approval was obtained. RESULTS A total of 40 of 44 (91%) invited patients participated and were randomized. A total of 13 patients avoided surgery. Post-CSMT improvement was associated with longer duration of sciatica, absence of cross-over sign and motor deficit, reduced lumbar flexion increment and lower IC levels at baseline. CONCLUSIONS It appears feasibleto conduct a RCT with patients randomized to CSMT or a waitlist control group. There may be a sub-group of AS/LDH patients who will significantly benefit from HVLA CSMT. A large scale clinical trial is now required to test this preliminary finding. [ABSTRACT FROM AUTHOR]

Stevens-Johnson's Syndrome (SJS) and Toxic Epidermal Necrolysis are rare, life-threatening dermatologic conditions with acute onset and not clearly established treatment protocol. A plethora of observational studies are present with lack of up-to-date consensus based on evaluation of objective endpoints, among others mortality. Thorough analysis of available databases (Pubmed, EMBASE, Cinahl, Web of Science, Clinical Trials) was conducted according to PRISMA guidelines. Authors initially identified 700 papers, with 82 of them potentially eligible according to adopted criteria. A total of 42 studies were included into pooled synthesis. For continuous outcomes we analyzed the pooled means for endpoint scores using observed cases data. Categorical outcomes were analyzed by calculating the pooled event rates. We conducted subgroup and exploratory maximum likelihood random effects meta-regression analyses regarding SCORTEN of all outcomes. Using random-effects model, the overall pooled Mortality Rate was 0.191 (95%CI, 0.132-0.269). The lowest mortality rate was found to be linked with Etanercept and highest in Total Plasma Exchange (TPE) and Intravenous Immunoglobulin (IVIG). Overall reepithelization was 13.278 days (95%CI, 8.773-17.784),The highest was found in cyclosporine treatment; 14.739 whilst the lowest for steroids. Length of hospital stay in overall analysis was 19.99 days (95%CI, 16.53-23.44),the highest was linked with TPE/TPE+IvIg treatment, the lowest with steroids. Risk of bias of assessed studies was estimated to be high (for observational studies mean STROBE score 12.44). High quality TEN and SJS studies are lacking. Almost all papers report observational data without randomization and double-blind control. Therefore, the pooled analysis cannot be presented with initial bias. In our meta-analysis the most successful regimen was Etanercept treatment. It was linked with the lowest mortality. The most negative treatment outcome was observed in studies reporting TPE and IVIG. Randomized trials of high quality are needed in SJS and TEN. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation. [ABSTRACT FROM AUTHOR]

SUMO (small ubiquitin like modifier) conjugated proteins have emerged as an important post translational modifier of cellular function. SUMOylation modulates several cellular processes involved in transcriptional regulation of genes, protein-protein interactions and DNA damage and repair. Since abnormalities in SUMOylation has been observed in neoplastic and neurodegenerative disorders, the SUMO pathway has become an attractive site for targeting of new therapies to regulate SUMOylation and reduce disease burden. Conjugation of SUMO to their respective substrates is orchestrated by an enzymatic cascade involving three main enzymes, E1, activation enzyme, E2, conjugating enzyme and E3, a protein ligase. Each of these enzymes are therefore potential "druggable" sites for future therapeutics. SUMOylation is a well-known mechanism by which the innate immune response is regulated in response to viral infections and in the adaptive immune response to tumor immunity. We have shown that small molecules which inhibit the SUMO activation pathway are also capable of inhibiting autoimmune response. TAK981 which forms adducts with SUMO and anacardic acid which inhibits the E1 enzyme of the SUMO pathway were effective in preventing the development of experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis. Anacardic acid and TAK981 inhibited activation of TH17 cells and reduced clinical and pathological injury in IL-17 mediated myelin oligodendrocyte glycoprotein (MOG) induced EAE. Ginkgolic acid, another known inhibitor of SUMO pathway, was also shown to be effective in reducing the severity of inflammatory arthropathies which is also IL-17 mediated. In addition, the increase in the transcription of myelin genes with TAK981 and anacardic acid improved remyelination in experimental models of demyelination. In the present review paper, we examine the mechanism of action of inhibitors of the SUMO pathway on regulating the immune response and the possibility of the use of these agents as therapeutics for MS. • Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. • Inhibition of SUMOylation is accomplished by inhibiting the enzymes of the SUMO pathway. • Inhibition of SUMOylation is accompanied by increase in innate immunity and increased production of beta Interferon. • Inhibition of SUMOylation increases the expression of myelin genes and inhibits TH17 expression. • The effects of SUMO inhibitors on a immune response and promoting myelination offers a novel treatment approach for multiple sclerosis [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) is a neurodevelopmental disturbance, diagnosed in early childhood. It is associated with varying degrees of dysfunctional communication and social skills, repetitive and stereotypic behaviors. Regardless of the constant increase in the number of diagnosed patients, there are still no established treatment schemes in global practice. Many children with ASD have allergic symptoms, often in the absence of mast cell (MC) positive tests. Activation of MCs may release molecules related to inflammation and neurotoxicity, which contribute to the pathogenesis of ASD. The aim of the present paper is to enrich the current knowledge regarding the relationship between MCs and ASD by providing PPI network analysis-based data that reveal key molecules and immune pathways associated with MCs in the pathogenesis of autism. Network and enrichment analyzes were performed using receptor information and secreted molecules from activated MCs identified in ASD patients. Our analyses revealed cytokines and key marker molecules for MCs degranulation, molecular pathways of key mediators released during cell degranulation, as well as various receptors. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, is important for elucidating the pathogenesis of ASD and developing effective future treatments for autistic patients by discovering new therapeutic target molecules. • PPI networks of key molecules and immune pathways related to MCs in ASD. • Involvement of receptors for MCs degranulation markers, TPSAB1 and cytokines in ASD. • Novel therapeutic strategies for ASD based on MCs and their molecular interactions. [ABSTRACT FROM AUTHOR]

• This paper is a large scale clinical studies between cytokines and prognosis of Kawasaki disease in China. • The prominent feature of this paper is the large amount of data. • The number of mediators detected in this study is large. Kawasaki disease (KD) is a type of pediatric vasculitis. Ten to twenty percent of children with KD do not respond to initial intravenous immunoglobulin (IVIG) treatment which called refractory Kawasaki disease. If untreated, approximately 15–25% of KD patients have complications. Therefore, it is important to predict whether KD is resistant to IVIG at an early stage. The aim of this study was to determine whether cytokines are predictors of refractory KD in children. We retrospectively reviewed the medical records of 265 children diagnosed with KD who received IVIG within 10 days of fever onset at Beijing Children's Hospital. Refractory Kawasaki disease was defined as persistent or recrudescent fever beyond 36 h after IVIG. Before IVIG and 3 days after temperature normalization following IVIG treatment, the concentrations of cytokines in the serum including interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-6 (IL-6), interleukin-4 (IL-4), interleukin-2 (IL-2) and other conventional inflammatory mediators including white blood cells counts (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and albumin were detected. The patients were divided into 2 groups: IVIG-sensitive group and refractory group. Of the 265 patients, 47 (17.7%) were refractory. After treatment with IVIG, the serum levels of IFN-γ, TNF-α, IL-10 and IL-6 in both groups were significantly lower than those before treatment (P < 0.05). Before treatment, the serum levels of IFN-γ, TNF-α, IL-10 and IL-6 in refractory group were significantly higher than those in IVIG-sensitive group (P < 0.05). There were no significant differences in IL-4 or IL-2 levels between the 2 groups. The results of logistic regression analysis showed that IFN-γ, IL-6, fever duration and serum albumin were independent risk factors for refractory KD. The area under the receiver operating characteristic curve (ROC curve) for IFN-γ was 0.781, and the cut-off value for refractory was 7.37 pg/ml, while the area under the ROC curve for IL-6 was 0.837, and the cut-off value for refractory was 70.13 pg/ml. IFN-γ and IL-6 were independent risk factors for refractory Kawasaki disease in children. KD patients with serum levels of IFN-γ above 7.37 pg/ml and IL-6 above 70.13 pg/ml before treatment were prone to refractory. [ABSTRACT FROM AUTHOR]

Blood-retinal barrier (BRB) disruption is a common accompaniment of intermediate, posterior and panuveitis causing leakage into the retina and macular oedema resulting in vision loss. It is much less common in anterior uveitis or in patients with intraocular lymphoma who may have marked signs of intraocular inflammation. New drugs used for chemotherapy (cytarabine, immune checkpoint inhibitors, BRAF inhibitors, EGFR inhibitors, bispecific anti-EGFR inhibitors, MET receptor inhibitors and Bruton tyrosine kinase inhibitors) can also cause different types of uveitis and BRB disruption. As malignant disease itself can cause uveitis, particularly from breast, lung and gastrointestinal tract cancers, it can be clinically difficult to sort out the cause of BRB disruption. Immunosuppression due to malignant disease and/or chemotherapy can lead to infection which can also cause BRB disruption and intraocular infection. In this paper we address the pathophysiology of BRB disruption related to intraocular inflammation and malignancy, methods for estimating the extent and effect of the disruption and examine why some types of intraocular inflammation and malignancy cause BRB disruption and others do not. Understanding this may help sort and manage these patients, as well as devise future therapeutic approaches. • Blood-retinal barrier disruption is affected by changes in cytokine profiles, related to types of uveitis and malignancies. • Understanding cytokine targets related to blood-retinal barrier disruption presents opportunities for therapeutic targets. • Understanding the cellular pathways of blood-retinal barrier disruption opens more options for direct retinal drug delivery. • Blood-retinal barrier disruption can be quantified in patients using fluorescein angiography to localize areas of disruption. [ABSTRACT FROM AUTHOR]

Most researchers working in the field of immunopsychiatry would agree with the statement that "severe psychiatric disorders are associated with inflammation and more broadly with changes in immune variables". However, as many other fields in biology and medicine, immunopsychiatry suffers from a replication crisis characterized by lack of reproducibility. In this paper, we will comment on four types of immune variables which have been studied in psychiatric disorders: Acute Phase Proteins (AAPs), cytokines, lipid mediators of inflammation and immune cell parameters, and discuss the rationale for looking at them in blood. We will briefly describe the analytical methods that are currently used to measure the levels of these biomarkers and comment on overlooked analytical and statistical methodological issues that may explain some of the conflicting data reported in the literature. Lastly, we will briefly summarize what cross-sectional, longitudinal and mendelian randomization studies have brought to our understanding of schizophrenia (SZ). [ABSTRACT FROM AUTHOR]

Objective To quantify and characterize the role of biomarkers in peri-implant crevicular fluid (PICF) at each stage of healing during osseointegration. Design This systematic review was performed in accordance with PRISMA guidelines using several databases: MedLine (PubMed), Embase, ISI Web of Science, Scopus, and Cochrane Library. Medical subject headings and their indexers were used with no other limitations until December 2017. The dataset was extended with relevant papers from the reference lists of selected papers and from the gray literature. Data was summarized for study objectives, patient demographics, methods used to analyze PICF, biomarker concentrations, results and main findings. Methodologic quality of each included study was assessed using the checklist created by Downs and Black. Results Electronic search resulted in 1698 articles. After excluding the duplicates, reading titles, abstracts and reference list reviews 30 prospective studies with longitudinal follow-up were selected. In total, 52 different biomarkers were identified. The most studied cytokines were interleukin (IL)-1, IL-1β, tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). The earliest PICF specimens were collected immediately after implantation, and the latest at 16 weeks prior to occlusal loading. 36 biomarkers were quantified during week 1, 49 between day 10 and week 6, and 49 between weeks 8 and 12. Only 5 articles received good quality ratings. Conclusion The mechanism by which inflammatory and bone biomarkers are released during osseointegration has not yet been identified. However, some hypotheses based on immune-modulated reactions are being explored to investigate early and asymptomatic implant failures. Given the available clinical studies, it was not possible to further explore the performance of all biomarkers already analyzed and to extrapolate their results to propose a consultable data system based on release volume or concentration because of clinical study and data heterogeneity. [ABSTRACT FROM AUTHOR]

As one of the important traditional Chinese medicines, Alpinia oxyphylla could warm and tonify the kidney and spleen. It has been used as anti-salivation, anti-diarrhea in various diseases. In recent years, many studies have reported the significant effect of Alpinia oxyphylla on improving cognitive ability, anti oxidative stress and protecting neurons. In this paper, we studied whether AE and its main active components could improve M1 and M2 polarization, inhibit neuroinflammation through triggering receptor expressed on myeloid cells 2 (TREM2), and exert anti-inflammatory effects. In this paper, the concentrations of inflammatory cytokines such as NO, TNF-α, IL-10 were assessed using detection kits respectively. Arg-1 and Iba-1, as polarized markers of M1 and M2, were detected by Immunofluorescence staining. CD86 and CD206 were tested by flow cytometry as surface markers of M1 and M2. Furthermore, RT-PCR was performed to determinate TNF-α, IL-10, Arg-1, and Iba-1. Western blot was used to test the activation of PI3K/AKT/GSK3β and BDNF/TrkB/TLR4 signaling pathways. TREM2 siRNA treatment further verified the action target of Chrysin, the main active ingredient of Alpinia oxyphylla. Molecular docking study was performed to investigate the binding mode between Chrysin and the human TREM2. We found that AE could promote the phenotypic transformation of microglia from M1 to M2, and similar effects of Chrysin were observed. Furthermore, downregulation of TREM2 blocked the anti-neuroinflammation of Chrysin, and inhibited the shift of M1 phenotype to M2 phenotype. Additionally, TREM2-siRNA suppressed the effects of Chrysin on PI3K/AKT/GSK3β and BDNF/TrkB/TLR4 signaling pathways. Our findings indicated that AE could improve the polarization response of microglia. TREM2 plays a vital role in the microglial repolarization effects of Chrysin through PI3K/AKT/GSK3β and BDNF/TrkB/TLR4 signaling pathways regulated by neuroinflammation. [Display omitted] • Alpinae Oxyphyllae Fructus could regulate the phenotypic transformation of LPS-induced BV2 cells. • Chrysin is the key component of Alpinae Oxyphyllae Fructus to exert anti-inflammatory activity. • TREM2 plays a vital role in promoting M2 phenotype polarization. [ABSTRACT FROM AUTHOR]

It is still an open question as to whether or not aseptic injuries affect the generation of fever due to exogenous pyrogens including bacterial products. Therefore, in the present paper we have investigated the course of endotoxin fever in rats induced with lipopolysaccharide (LPS; given intraperitoneally in a dose of 50 μg/kg) 48 h after subcutaneous administration of turpentine oil (TRP; 0.1 mL per rat) that causes aseptic necrosis of tissues. We found that febrile response was significantly augmented in the animals pre-treated with turpentine compared to control rats (pre-treated with saline), and that observed excessive elevation of body temperature (Tb) was accompanied by enhanced release of fever mediators: interleukin-6 (IL-6) and prostaglandin E 2 (PGE 2) into plasma. Moreover, we found that sensitization to pyrogenic effects of lipopolysaccharide was associated with the increase in plasma level of high mobility group box 1 protein (HMGB1), one of the best-known damage-associated molecular patterns (DAMP), which was recently discovered as inflammatory mediator. Since the injection of anti-HMGB1 antibodies weakened observed hyperpyrexia in the animals pre-treated with turpentine, we conclude that HMGB1 is a plasma-derived factor released in the course of aseptic injury that enhances pyrogenic effects of LPS. • Aseptic necrosis of tissues sensitizes to pyrogenic effects of LPS. • TRP pre-injection increases plasma IL-6, PGE2 and HMGB1 levels after LPS administration. • anti-HMGB1 antibodies weakens hyperpyrexia to LPS in turpentine pre-treated rats. [ABSTRACT FROM AUTHOR]

Study on the constituents of bioactive culture broth extract (CBE) of Pseudomonas sp. (ABS-36) explored the secretion of an array of cyclic dipeptides (CDPs) and twenty of them had been isolated and reported in the present paper. Six major CDPs [(cyclo(Leu-Pro) (1), cyclo(Val-Pro) (2), cyclo(Leu-hydroxy-Pro) (9), cyclo(Pro-Tyr) (10), cyclo(Pro-Ala) (11) and cyclo(Gly-Pro) (12)] exhibited pan cytokine inhibition effect by inhibiting key pro-inflammatory cytokines IL-1β, TNF-α and IL-6 tested under various cell based assays. With this background, the effect of these six CDPs in treating renal inflammation was screened using crystal-induced nephropathy model in mice at 50 mg/kg body weight through oral administration. cis -Cyclo(Val-Pro) (2) exhibited 57% inhibition of plasma IL-1β protein expression and 35.2% inhibition of elevated blood urea nitrogen. Further, cis -cyclo(Val-Pro) (2) attenuated renal injury as demonstrated by significant reduction of mRNA expressions of IL-1β (P < 0.01) and kidney injury marker-1 (P < 0.001). Furthermore, evaluation of tubular-necrosis, -dilation and -cast in the histological sections exhibited moderate protection of renal tissues by cis -cyclo(Val-Pro) (2). All the tested CDPs reduced the nitrite production and were interestingly non-cytotoxic. • Culture broth extract (CBE) of Pseudomonas sp. (ABS-36) was found to inhibit pro-inflammatory cytokines. • Twenty cyclic dipeptides (CDPs) were isolated from CBE. Seventeen of them are reported for the first time from this source. • In-vitro studies explored pan cytokine inhibition effect (IL-1β, TNF-α and IL-6) of six proline-based CDPs • They were tested by crystal-induced nephropathy mice model to access renal anti-inflammation effect. • Cyclo(Val-Pro) attenuated renal injury by controlling the plasma IL-1β and BUN levels. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care. • Stress and TBI occur together and have overlapping biological mechanisms. • Stress with adequate recovery prior to TBI may be neuroprotective. • Stress immediately before TBI may exacerbate the injury. • TBI with post-injury stress may exacerbate the injury. • Research on the relationship between stress and TBI remains limited. [ABSTRACT FROM AUTHOR]

The cytokine storm includes a clinically heterogeneous set of life-threatening conditions that are manifested by extremely elevated serum cytokine levels and related symptoms (e.g., septic shock) and is devilishly mediated by Toll-like receptor (TLR) agonists in most situations. A tyrosine kinase inhibitor (TKIs), sunitinib, was screened in our group previously and showed antagonistic activity for cytokine release in a TLR7 stimulation model. In this paper, we further studied its mechanisms on interesting phenomena. In vitro , nearly all of the eleven TKIs decreased the TNF-α levels induced by the TLR7 agonist, especially sunitinib. Furthermore, sunitinib displayed potent inhibition of the cytokine levels triggered by several types of TLR ligands, including TLR3, TLR4, TLR7/8 and TLR9, in mouse spleen lymphocytes, mouse BMDCs and human PBMCs. The in vivo results showed that sunitinib efficiently depressed the LPS-induced cytokine storm, i.e., rapid and intense production of TNF-α and IL-6. Sunitinib further increased the survival time and decreased damage to mice. As for the immunosuppressive mechanisms of sunitinib, at least the PDGFR-activated ERK and p38 pathways were critical, although we could not rule out the possibility of other pathways being involved. In conclusion, our study demonstrated the inhibitory actions of TKIs on the cytokine storm induced by TLR ligands, primarily through PDGFR pathways, which could be potentially used to reduce cytokine storms in septic shock. Image 1 [ABSTRACT FROM AUTHOR]

The interplay of chronic stress, neuroinflammation and altered immune reactivity has been shown to be important for the pathophysiology of brain disorders such as schizophrenia, depressive disorders and post-traumatic stress disorder. This immuno-inflammatory theory has been extensively studied in the past three decades leading to the formation of the integrative discipline of psychoneuroimmunology. Targeting of the central nervous system by conventional pharmacotherapeutic methods is mainly through modulation of neuroendocrine systems such as the dopaminergic, GABA-ergic, adrenergic and serotoninergic systems. In recent years an increasing number of both experimental and clinical studies have shown that antidepressants can affect the immune system by reducing the production of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, due to the serious adverse effects accompanying the chronic administration of psychoactive drugs there is a continuous need to produce novel therapeutics that are both potent and safe. The present review aims to summarize the current knowledge in the field of psychoneuroimmunology and to delineate the main interactions between stress, inflammation, immunity and the brain. Additionally, this paper explores the use of plant-derived molecules that display a strong anti-stress effect and simultaneously modulate the immune response as an alternative or adjuvant to classical antidepressant drugs. • Immuno-inflammatory reactions play a role in stress-induced depression. • Antidepressants promote immunomodulation trough affecting cytokines production. • Natural plant-derived compounds appear promising in regulation of neuroinflammation. • Hybrid combinations with plant molecules could improve response to antidepressants. [ABSTRACT FROM AUTHOR]

Highlights • Traumatic dental injury often occurs in children and can result in root resorption. • External root resorption sometimes leads to tooth loss. • Gingival sulcus fluid analysis reveals ongoing process of root resorption. • Interleukin 1α may be considered as a biomarker of external root resorption. Abstract Objective External inflammatory root resorption (EIRR) is a common complication of traumatic dental injury (TDI) that can be detected radiologically. During EIRR, various proteins are released into gingival sulcus fluid (GCF). The aim of the study was to monitor the levels of selected proteins in GCF in children (8–16 years of age) in order to assess their utility in the early diagnosis of EIRR. Design Twenty five children who experienced TDI to permanent incisors with ended root development were enrolled. GCF was collected from injured and control teeth with paper strips within seven days after TDI and on three visits during six-month follow-up. Concentrations of IL-1α, IL-1β, IL-6, IL-8, TNFα, RANKL and MMP-9 in GCF were measured using enzyme-linked immunosorbent assays. EIRR was confirmed by radiological imaging techniques. Results Of all analyzed proteins, only the levels of IL-1α, Il-1β and TNFα in GCF from the injured teeth with resorption were higher than in GCF from control teeth on the visit during which the EIRR was diagnosed. In univariate logistic regression model, the concentration of IL-1α in GCF was found as the strongest risk factor for the occurrence of EIRR. Conclusions The composition of GCF may be indicative of EIRR after TDI. The monitoring of selected biomarkers in GCF may help to detect EIRR at its early stage and might be useful in reducing radiological exposure in children after TDI. IL-1α can be considered as a potential marker of the EIRR in children after TDI to the permanent teeth. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Preserving survival and function of beta cells is the logical management of diabetes. • Flavonoids are natural phenolic compounds, which are found in vegetables and fruits. • Flavonoids stimulate survival pathways and inhibit apoptotic signals in beta cells. • Flavonoids preserve the triggering and amplifying pathways of insulin secretion. Abstract Although the currently available antidiabetic medications are effective in managing hyperglycemia, vascular complications are common in diabetic patients. Cohort studies have shown preserved beta cell function has a protective role against the development of diabetic complications. Accordingly, beta cell mass and function are important pharmacological targets in the field of diabetes. Growing number of evidence supports the efficacy of flavonoids (e.g., quercetin, kaempferol, luteolin, and epicatechin) for prevention and attenuation of diabetes consequences. The focus of this paper is to give an overview regarding the effects of flavonoids on pancreatic beta cells. Experiments on insulin-releasing cell lines, isolated pancreatic islets, and diabetic animal models have shown that flavonoids strengthen the survival processes and insulin secretory capacity of beta cells. The proposed mechanisms by which flavonoids preserve beta cells survival (against cytokines, glucotoxicity, and lipotoxicity) include inhibition of NF-κB signaling, activation of PI3K/Akt pathway, inhibition of nitric oxide generation, and decrease of reactive oxygen species levels. Improving mitochondrial bioenergetic function and stimulating pathways of insulin secretion (e.g., PLC/PKC and/or cAMP/PKA signaling) are mechanisms by which flavonoids improve the secretory capacity of beta cells. These beneficial effects of flavonoids are of great importance because may protect beta cells of diabetic patients before dramatic dysfunction and degeneration. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Polyalthia is one of the largest and notable genera in Annonaceae family. Polyalthia species have been widely used in folklore medicine for the treatment of rheumatic fever, gastrointestinal ulcer and generalized body pain. Numerous in vitro and in vivo studies on Polyalthia Species have also corroborated the significant anti-inflammatory potential of its extracts and secondary metabolites. Aim of the study This review is an attempt to assess the anti-inflammatory activity of Polyalthia species by giving critical appraisal and establishing evidences of their traditional uses. Moreover this review will highlight the lead compounds for future drug development that can serve as a potential anti-inflammatory drug with comparative efficacy and minimum side effects. Materials and methods An extensive literature review, focusing the anti-inflammatory potential of Polyalthia species was conducted using the following databases:PubMed, ScienceDirect, SpringerLink, Ovid, Scopus and ProQuest, as well as the locally available books, journals and relevant documents. The reference lists of retrieved papers were also searched for additional studies. Results The Polyalthia species have shown significant anti-inflammatory activity through various mechanism of action. The most significant anti-inflammatory mechanism includes the inhibition of nuclear factor kappa B (NF-κB), prostaglandins (PGs), pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS). The data suggests that hydroxycleroda-3,13-dien-15,16-olide and 16-oxocleroda-3,13-dien-15-oic acid, quercetin, rutin, spinasterol, α-spinasterol, goniothalamin and (−)−5-hydroxygoniothalamin are the most potent anti-inflammatory compounds from Polyalthia species with comparable IC 50 with positive controls. Conclusions Numerous pharmacological studies have supported the use of Polyalthia species against pain, rheumatic fever, haemorrhages and inflammation in traditional medicine. Flavonoids, diterpenoids, sterols and styrylpyrones from genus Polyalthia are the most significant class of compounds with potent anti-inflammatory activity. Secondary metabolites from these classes should be brought into further research to fill the gaps of knowledge in pharmacokinetics, pharmacodynamics, bioavailability, and toxicity in order to convert the pre-clinical results into clinical data for further investigation. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract To date, numerable reviews are found in the literature prominent to the effect of caffeine on the immune system, with the latest review published in 2006. Database screening reveals around three thousand articles that have been published during the last decade. Interestingly, less than hundred articles involved humans and rodents as tested models, out of which 20% is of interest to this paper excluding studies done on the nervous and cardiac systems, and in pregnant and cancer cases. In this review, information pertaining to the experimental setup of various studies, namely, the tested model, the study type (in vivo or in vitro), and caffeine dose is covered to discern the behaviour of major cellular and molecular immune components in light of caffeine exposure. Although it is hard to extrapolate results done in rodents to humans and to relay conclusions from in vitro to in vivo studies, most of the collected data favor the suppressive effects of caffeine on the proliferation of stimulated lymphocytes. Macrophages and natural killer cells also exhibited a reduced activity in the presence of high caffeine doses compared to increased activity at low doses. Immunosuppression is also supported by reduced levels of major anti-inflammatory cytokines, IL-2, IL-6, TNF-α. Moreover, certain innate and adaptive immune receptors, such as TLR1, TLR2, TLR4, and MHC class I-related chain B (MICB) molecules, exhibited decreased expression levels. Thus, we support the use of caffeine to alleviate various inflammatory conditions and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract Mesenchymal stem cells (MSCs) are a population of multipotent cells with the ability of expansion and plastic-adherence in vitro. MSCs can differentiate into chondrocytes, osteocytes and adipocytes; they lack co-stimulatory molecules and have small amount of MHC-I that makes no immunogenicity. These characteristics are empowering MSCs' huge in vivo applications. In addition, MSCs possess the ability of regulating the immune responses in many diseases. Many studies have shown that MSCs have immunosuppressive as well as immunoenhancing properties such as inhibition of T-lymphocytes proliferation and cytokines production which lead to the balance of Th1 and Th2. Some other immunomodulatory features of MSCs are increasing suppressive capacity of T reg , reducing activity of B-lymphocytes and immunoglobulins secretion, inhibition of dendritic cells maturation and antigen presenting capacity, and inhibition of NK-cells activity. MSCs also exert inhibitory effects on neutrophil apoptosis and reduce reactive oxygen species production. The purpose of this paper is to focus on the MSCsʹ effects on immune cells, especially neutrophils. [ABSTRACT FROM AUTHOR]

Endometriosis refers to the growth of ectopic endometrial tissue outside the uterine cavity. About 10–15% of female in reproductive age suffer from endometriosis. Several etiologies – such as oxidative stress, inflammatory factors and cytokines, genetic etiology, and hormone role – have been reported for endometriosis. Indeed, oxidative stress leads to abnormalities by the production of ROS and RNS. The mechanism of endometriosis genesis is a complicated process that concerns the alterations in cellular immunity. Also, endometriosis is a hormonal response that illustrates stimulation in steroid hormone production. Genetic polymolymorphisms and epigenetic factors are also important in endometriosis initiation and progression. This review paper presents the role of oxidative stress, reactive oxygen species (ROS), and antioxidants and inflammatory, genetic, and epigenetic factors involved in the initiation and progression of the endometriosis. [ABSTRACT FROM AUTHOR]

Highlights • Dendritic cells with overexpression of SOCS1 are constructed with lentivirus encoding SOCS1. • SOCS1 could block maturation process of Dendritic cells through inhibition of JAK/STAT pathway signaling. • Dendritic cells with increased expression of SOCS1 could ameliorate LPS/D-GalN induced acute liver failure. Abstract Acute liver failure is a devastating clinical syndrome with extremely terrible inflammation reaction, which is still lack of effective treatment in clinic. Suppressor of Cytokine Signaling 1 protein is inducible intracellular negative regulator of Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathway that plays essential role in inhibiting excessive intracellular signaling cascade and preventing autoimmune reaction. In this paper, we want to explore whether dendritic cells (DCs) with overexpression of SOCS1 have a therapeutic effect on experimental acute liver failure. Bone marrow derived dendritic cells were transfected with lentivirus encoding SOCS1 and negative control lentivirus, thereafter collected for costimulatory molecules analysis, allogeneic Mixed Lymphocyte Reaction and Western blot test of JAK/STAT pathway. C57BL/6 mice were randomly separated into normal control and treatment groups which respectively received tail vein injection of modified DCs, negative control DCs and normal saline 12 h earlier than acute liver failure induction. Our results indicated that DCs with overexpression of SOCS1 exhibited like regulatory DCs (DCregs) with low level of costimulatory molecules and poor allostimulatory ability in vitro, which was supposed to correlate with block of JAK2/STAT1 signaling. In vivo tests, we found that infusion of modified DCs increased survival rate of acute liver failure mice and alleviate liver injury via inhibition of TLR4/HMGB1 pathway. We concluded that DCs transduced with SOCS1 gene exhibit as DCregs through negative regulation of JAK2/STAT1 pathway and ameliorated lipopolysaccharide/ d -galactosamine induced acute liver failure via inhibition of TLR4 pathway. [ABSTRACT FROM AUTHOR]

Abstract Numerous reports on the interactions between the immune and endocrine systems, especially growth hormone axis, can be found in the literature. Growth hormone acts mainly indirectly through insulin-like growth factor-1, which stimulates the growth and development processes, metabolism of lipids, proteins, and carbohydrates, and it also has a modulating effect on the cells of the immune system. Several studies have been conducted on the influence of growth hormone therapy on the immunological parameters in children and adults with and without growth hormone deficiency. However, there have been no definite results and some of them have been even contradictory. Some studies have suggested that administration of growth hormone increases the production of tumor necrosis factor and certain pro- and anti-inflammatory cytokines; whereas other studies have demonstrated the lack of correlation between growth hormone and interleukins. The aim of this paper was to evaluate the available literature on the interaction between growth hormone and TNF-α, pro-inflammatory (IL-1β, IL-2, IL-6) and anti-inflammatory (IL-4, IL-10) interleukins. [ABSTRACT FROM AUTHOR]

Background Recently, much attention has been devoted to the possible alterations of the immune system in obsessive-compulsive disorder (OCD). Therefore, the aim of this paper was to review the current literature on the relationships between OCD and immune system. Methods A PubMed and Google Scholar search was performed with specific keywords. Results In the childhood, much emphasis has been given to the relationship between group A Streptococcus (GAS) infection and the development of a group of clinical syndromes characterized by neuropsychiatric symptoms known as “pediatric autoimmune neuropsychiatric disorders associated with streptococcus” (PANDAS). However, more recently, PANDAS has been reconsidered and evolved towards pediatric acute-onset neuropsychiatric syndrome (PANS) and/or Childhood Acute Neuropsychiatric Syndrome (CANS) all characterized by the presence of typical of OCD symptoms and tics. In adult OCD patients, different immunological parameters have been described to differ from those of healthy control subjects, although a few numbers of studies were carred out and most of them performed in small samples. Conclusions Although the exact relationships between OCD and immune processes are still unclear, available literature supports their role in the pathophysiology of OCD, while providing a fascinating hint for possible immunotherapeutic treatments in OCD. [ABSTRACT FROM AUTHOR]

3D cell-printing technique has been under spotlight as an appealing biofabrication platform due to its ability to precisely pattern living cells in pre-defined spatial locations. In skin tissue engineering, a major remaining challenge is to seek for a suitable source of bioink capable of supporting and stimulating printed cells for tissue development. However, current bioinks for skin printing rely on homogeneous biomaterials, which has several shortcomings such as insufficient mechanical properties and recapitulation of microenvironment. In this study, we investigated the capability of skin-derived extracellular matrix (S-dECM) bioink for 3D cell printing-based skin tissue engineering. S-dECM was for the first time formulated as a printable material and retained the major ECM compositions of skin as well as favorable growth factors and cytokines. This bioink was used to print a full thickness 3D human skin model. The matured 3D cell-printed skin tissue using S-dECM bioink was stabilized with minimal shrinkage, whereas the collagen-based skin tissue was significantly contracted during in vitro tissue culture. This physical stabilization and the tissue-specific microenvironment from our bioink improved epidermal organization, dermal ECM secretion, and barrier function. We further used this bioink to print 3D pre-vascularized skin patch able to promote in vivo wound healing. In vivo results revealed that endothelial progenitor cells (EPCs)-laden 3D-printed skin patch together with adipose-derived stem cells (ASCs) accelerates wound closure, re-epithelization, and neovascularization as well as blood flow. We envision that the results of this paper can provide an insightful step towards the next generation source for bioink manufacturing. [ABSTRACT FROM AUTHOR]

In this paper, we investigate the effect of glabridin (Glab) on psoriasis. We observed that Glab significantly suppressed the levels of nitric oxide (NO), NF-κB subunit p65, interleukin (IL)-6, and IL-1β in lipopolysaccharide (LPS)-stimulated HaCaT cells. In addition, Glab treatment reduced the expression of IL-17A, IL-22, and IL-23 in TNF- α- stimulated-HaCaT cells. These findings prompted us to test whether Glab could be used to treat psoriasis in vivo. The effects of Glab on PASI scores, histopathological changes, oxidative/anti-oxidative indexes and pro-inflammatory cytokines in IMQ-induced mice were investigated. The results indicated that Glab could reduce the PASI scores and ameliorate the deteriorating histopathology. Interestingly, RT-PCR revealed that Glab significantly decreased the mRNA expression of p65, IL-6, IL-1β, IL-17A, IL-22, and IL-23. These results were confirmed by Western blot analysis and immunohistochemistry staining. In conclusion, our present study revealed that Glab had beneficial effects on psoriasis, and the underlying mechanism may be associated with the downregulation of pro-inflammatory cytokines and the improvement of antioxidant status. Hence, Glab is a promising candidate molecule for development of effective psoriasis therapies. [ABSTRACT FROM AUTHOR]

Spores and fungal fragments found in indoor and outdoor environments originate from opportunistic fungi and they can contribute to inflammatory responses, causing a broad range of symptoms. Papers were selected and reviewed with an emphasis on the molecular mechanisms involved in the effect of fungi on immune cells, especially mast cells (MCs). Fungi can bind to antibodies and complement them, allowing them to be recognized by cells of the innate immune system, including macrophages, dendritic cells, and MCs, which are then stimulated via Toll-like receptor signaling. Fungi can cause diseases mediated by MCs and aggravate allergic inflammation. Immunosuppressed subjects can be particularly susceptible to developing diseases caused by opportunistic fungi. Mold also liberates mycotoxins that could be on volatile spores and stimulate MCs to secrete pro-inflammatory cytokines/chemokines, but this mechanism is not known. Fungi can activate the immune system directly or through mycotoxins, leading to stimulation of immune cells and chronic neuroinflammatory symptoms. Some of these processes may be inhibited by the new anti-inflammatory cytokine interleukin 37. [ABSTRACT FROM AUTHOR]

Skeletal muscle tissue retains a remarkable regenerative capacity due to the activation of resident stem cells that in pathological conditions or after tissue damage proliferate and commit themselves into myoblasts. These immature myogenic cells undergo differentiation to generate new myofibers or repair the injured ones, giving a strong contribution to muscle regeneration. Cytokines and growth factors, potently released after tissue injury by leukocytes and macrophages, are not only responsible of the induction of the initial inflammatory response, but can also affect skeletal muscle regeneration. Growth factors exploit sphingosine kinase (SK), the enzyme that catalyzes the production of sphingosine 1-phosphate (S1P), to exert their biological effects in skeletal muscle. In this paper we show for the first time that bradykinin (BK), the leading member of kinin/kallikrein system, is able to induce myogenic differentiation in C2C12 myoblasts. Moreover, evidence is provided that SK1, the specific S1P-transporter spinster homolog 2 (Spns2) and S1P 2 receptor are involved in the action exerted by BK, since pharmacological inhibition/antagonism or specific down-regulation significantly alter BK-induced myogenic differentiation. Moreover, the molecular mechanism initiated by BK involves a rapid translocation of SK1 to plasma membrane, analyzed by time-lapse immunofluorescence analysis. The present study highlights the role of SK1/Spns2/S1P receptor 2 signaling axis in BK-induced myogenic differentiation, thus confirming the crucial involvement of this pathway in skeletal muscle cell biology. [ABSTRACT FROM AUTHOR]

While wound therapy remains a clinical challenge in current medical practice, much effort has focused on developing biological therapeutic approaches. This paper presents a comprehensive review of delivery systems for current biologicals for the treatment of chronic wounds and severe burns. The biologicals discussed here include proteins such as growth factors and gene modifying molecules, which may be delivered to wounds free, encapsulated, or released from living systems (cells, skin grafts or skin equivalents) or biomaterials. Advances in biomaterial science and technologies have enabled the synthesis of delivery systems such as scaffolds, hydrogels and nanoparticles, designed to not only allow spatially and temporally controlled release of biologicals, but to also emulate the natural extracellular matrix microenvironment. These technologies represent an attractive field for regenerative wound therapy, by offering more personalised and effective treatments. [ABSTRACT FROM AUTHOR]

Background Rheumatoid arthritis is characterized by the production of eicosanoids, cytokines, adhesion molecules, infiltration of T and B lymphocytes in the synovium and oxygen reduction accompanied by the cartilage degradation. Eicosanoids are responsible for the progressive destruction of cartilage and bone, however neither steroids, nor the non steroidal anti-inflammatory drugs (NSAIDs), cannot slow down cartilage and bone destruction providing only symptomatic improvement. The current rheumatoid arthritis treatment options include mainly the use of disease-modifying anti-rheumatic drugs, the corticosteroids, the NSAIDs and biological agents. Methods PubMed, Cochrane, and Embase electronic database were used as the main sources for extracting several articles, reviews, original papers in English for further review and analysis on the implication of arachidonic acid metabolites with rheumatoid arthritis and different strategies of targeting arachidonic acid metabolites, different enzymes or receptors for improving the treatment of rheumatoid arthritis patients. Results We first focused on the role of individual prostaglandins and leukotrienes, in the inflammatory process of arthritis, concluding with an outline of the current clinical situation of rheumatoid arthritis and novel treatment strategies targeting the arachidonic acid pathway. Conclusions Extended research is necessary for the development of these novel compounds targeting the eicosanoid pathway, by increasing the levels of anti-inflammatory eicosanoids (PGD 2 ,15dPGJ 2 ), by inhibiting the production of pro-inflammatory eicosanoids (PGE 2 , LTB 4 , PGI 2 ) involved in rheumatoid arthritis or also by developing dual compounds displaying both the COX-2 inhibitor/TP antagonist activity within a single compound. [ABSTRACT FROM AUTHOR]

Sepsis, a systemic inflammation as a response to a bacterial infection, is a huge unmet medical need. Data accumulated over the last decade suggest that the nutritional status of patients as well as composition of their gut microbiome, are strongly linked with the risk to develop sepsis, the severity of the disease and prognosis. In particular, the essential micronutrient zinc is essential in the resistance against sepsis and has shown to be protective in animal models as well as in human patients. The potential mechanisms by which zinc protects in sepsis are discussed in this review paper: we will focus on the inflammatory response, chemotaxis, phagocytosis, immune response, oxidative stress and modulation of the microbiome. A full understanding of the mechanism of action of zinc may open new preventive and therapeutic interventions in sepsis. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to examine the relationship between bracket design and ratio of five proinflammatory cytokine, in gingival crevicular fluid (GCF), and bacterial adhesion without tooth movement influence. Design The sample was comprised of 20 participants, aged 11 to 15 years old (mean age: 13.3 years ± 1.03). A conventional Gemini™ metallic bracket and two self-ligating brackets, In-Ovation ® R and SmartClip™, were bonded to the maxillary incisors and canines. GCF was collected using a standard filter paper strip before and 60 days after bonding. The cytokine levels (IL-12, IL-1α, IL-1β, IL-6 and TNF-α) were performed by the LUMINEX assay. The levels of the red and orange bacterial complexes were analyzed by the Checkerboard DNA-DNA hybridization. The data of cytokine and bacterial complexes were carried out using the non-parametric tests at 5% of significance level. Results Increased cytokine levels were observed. However, only the SmartClip™ group showed a significantly increased level of TNF-α (p = 0.046). The SmartClip™ brackets group presented higher levels of red complex bacteria. Conclusions The bracket design affected cytokine levels and bacterial adhesion since it was observed that the proinflammatory cytokines released in GCF to the SmartClip™ group showed an increase in the TNF-α levels associated with higher bacterial levels, which possibly represents greater inflammatory potential. Thereby, the bracket design should be considered in patients with risk of periodontal disease and root resorption. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2- b ]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC 50  = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2- b ]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions. [ABSTRACT FROM AUTHOR]

Rats are used as animal models for many human diseases. Cytokines can serve as biomarkers indicative of these diseases or disease states. Techniques for measuring cytokine expression levels often do not provide the sensitivity needed to measure these biomarkers in biological fluids because the concentrations of many cytokines are below the detection limits of conventional methods. In this paper, we present ultra-sensitive digital immunoassays using Single Molecule Arrays (Simoa) for seven rat cytokines: TNF-α, IL-10, IL-17F, GM-CSF, IFN-γ, IL-4, and IL-1α. These ultra-sensitive immunoassays have limits of detection (LODs) in the femtomolar range and provide the ability to measure rat cytokines in serum below the LODs of conventional immunoassays. We also measured these cytokines in healthy rat serum to obtain baseline levels. The ability to measure cytokines present at low concentrations in rat serum will facilitate future studies of disease using rats as animal models. [ABSTRACT FROM AUTHOR]

Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly ( d, l -lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain. [ABSTRACT FROM AUTHOR]

The skin is an important site for local or systemic application of drugs. However, most of the drugs have poor permeability through the skin’s outermost layer, stratum corneum. The aim of this study was to develop a method to enable transdermal delivery of morin (3, 5, 7, 2, 4-pentahydroxyflavone), which is a poorly water-soluble drug with anti-inflammatory properties obtained from natural products. Morin phospholipid complex (MPC) was prepared and then loaded in Carbopol 940 hydrogel (MPC-gel), which can significantly increase the transdermal flux of morin based on the in vitro skin penetration data presented in this paper. To further enhance permeation, different compositions of penetration enhancers were dispersed in the gel and screened. After applied onto the mouse skin, MPC-gel showed apparent reduction of ear swelling in 2, 4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD). Further determination of cytokines levels, histopathological analysis and T lymphocytes proliferation indicates that the MPC-gel is potent enough to reduce the inflammatory response mediated by the DNFB in ACD mice model. Collectively, we anticipate that such an approach may provide a new treatment for topical ACD. [ABSTRACT FROM AUTHOR]

Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1β and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity. [ABSTRACT FROM AUTHOR]

Abstract: Objective: This systematic review aimed to summarize published papers on the effect of physical activity (PA)/exercise on key atherosclerotic factors in patients with risk factors for or established cardiovascular disease (CVD). Methods: Studies involving PA and cytokines, chemokines, adhesion molecules, CRP and angiogenic factors were searched for in Medline and Cochrane library. Original human studies of more than 2 weeks of PA intervention were included. Study quality was assessed according to the GRADE system of evidence. Results: Twenty-eight papers fulfilled the inclusion criteria. PA decreases the cytokines, tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interferon-y IFN-y (high, moderate and low evidence, respectively). The effect of PA on chemokines; stromal derived factor-1 (SDF-1), interleukin-8 (IL-8) (insufficient evidence) and monocyte chemoattractant protein-1 (MCP-1) (low evidence) was inconclusive. Aerobic exercise decreased the adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) (moderate and high evidence, respectively), while effects of PA on E- and P-selectin were inconclusive. PA decreases C-reactive protein (CRP) (high evidence). The angiogenic actors, endothelial progenitor cells (EPCs) are increased (high evidence) and VEGF is decreased (moderate evidence) by PA. The effect of PA on these factors seems to depend on the type and duration of exercise intervention and patient factors, such as presence of ischemia. Conclusion: As presented in this review, there is a high level of evidence that physical activity positively affects key players in atherosclerosis development. These effects could partly explain the scientifically proven anti-atherogenic effects of PA, and do have important clinical implications. [Copyright &y& Elsevier]

Abstract: The diagnosis of Sweet''s syndrome rests on a combination of clinical symptoms and characteristic physical and pathologic features. Patients typically have fever and tender erythematous skin lesions (papules, nodules, or plaques). Neutrophilia, high levels of serum inflammatory markers, and diffuse mature neutrophil infiltration localized to the upper dermis are the most important findings. Sweet''s syndrome was first described by Robert Sweet in 1964, whose sentinel paper described 8 women with fever, leukocytosis, and erythematous plaques infiltrated by neutrophils. Subsequently, extracutaneous sites were included in the diagnosis. This review of publications between 1964 and April 2012 found 1683 reports of Sweet''s syndrome of which only 8 were published between 1964 and 1969, after which the number of the papers grew by decades to 59, 228, 459 and 692. With more articles, there are more reports of malignancy-associated Sweet''s syndrome. This may reflect the awareness by physicians of the disease and of the drugs which may cause it. There is considerable overlap in the constitutional findings of Sweet''s syndrome and malignant disorders. It is crucial that the possibility of Sweet''s syndrome be included in a hematologist or oncologist''s differential diagnosis of fever and skin lesions. [Copyright &y& Elsevier]

The immune response is complex, multifactorial, individualized and often unpredictable. There are multiple interconnected systems that allow a balance between physiological autoreactive processes and pathological autoimmunity with consequent organ-specific or systemic autoimmune disease. Based on the concept of the autoimmunity mosaic, up to 50% of autoimmune disorders do not have a clear etiological factor. In order to achieve a clear understanding of the different systems that influence the development of autoimmune diseases, the clinical auto–immunologist needs a dynamic and comprehensive vision of all interconnected pathways that maintain a precise balance in the organism. This has been and will remain a challenge. Understanding the different pathophysiological processes of these diseases will be the basis for predicting different clinical spectra and has the potential to offer innovative therapeutic approaches. This paper offers a practical overview of the bidirectional communication between the immune and endocrine system and the influence this has on the development of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Objectives The inflammatory effects of organic sub-10 nm particles generated and emitted from a diesel engine fueled with a biodiesel and a commercial diesel oil are analyzed in this paper. Diesel combustion is the major sources of ultrafine particles (UFP) in the environment, particularly in urbanized areas. In the last years, there is an increasing use of biomass-derived fuels because they are a renewable source of energy that may mitigate climate change through the reduction of net CO 2 with respect to conventional fossil fuels. Although there is a general agreement on biofuels ability to reduce conventional pollutants, new and potentially harmful pollutants can be formed during biofuel combustion. In particular, the emission of sub-10 nm particles is strongly increased with respect to that of larger soot particles. Methods Organic sub-10 nm particles are separated from larger sizes particulate matter by collection in water suspension for toxicological and inflammatory tests. After exposure to sub-10 nm particles, the effects on proliferation, apoptosis and secretion of cytokines, chemokines and growth factors networks production is analyzed in immortalized non-tumorigenic human dermal keratinocyte cell line (HaCaT) and human alveolar epithelial-like cells (A549). Results and conclusion Nanoparticles exert different cytotoxic effects in the two cell lines, suggesting that the dermal way of exposure is more sensitive than the inhalant way. These differences are most evident in the secretion of pro-inflammatory, angiogenic and proliferative cytokines and chemokines whose expression is more finely modulated in HaCaT cells compared to A-549 cells. Considering the size of these particles, it is important to promote the culture of prevention also for the dermal way in particularly exposed workers. [ABSTRACT FROM AUTHOR]

This paper shows that clay minerals, sepiolite and palygorskite collected from Torrejón El Rubio and Vallecas, Spain, respectively, altered the expression of four, namely, pro-inflammatory cytokines: interleukins IL-1 and IL-6, tumor necrosis factor (TNF-α), and interferon gamma (IFN-γ) as determined using a 12- O -tetradecanoylphorbol-13-acetate model for inflammation. Quantitative RT-PCR analyses after 4 and 24 h inflammatory stimuli showed that sepiolite or palygorskite brought about a reduction in mRNA expression. Sepiolite provoked the highest mRNA expression inhibition for all cytokines, except for TNF-α, and primarily after 4 h. Conversely, the anti-inflammatory effect for cytokine TNF-α was found to be true in the presence of palygorskite. Most notably, the significant reduction in mRNA expression of IL-1 registered just shortly after exposure pointed to that the anti-inflammatory effect may be important for modulation of the late inflammatory response. These clay minerals caused modifications in the mRNA expression of IL-1 and its receptor in endothelial cells and downstreaming inflammatory cascades resulting in the recruitment of neutrophils. In addition, polymorphonuclear peroxidase activity was severely reduced just after short exposure to either sepiolite or palygorskite. Evidence provided herein agree well with the idea that these clay minerals impaired neutrophils infiltration to inflamed skin, notwithstanding ear edema and deficient cell localization to skin coupled with such impairment may affect the later stages of inflammation. [ABSTRACT FROM AUTHOR]

Objective Close relationships are associated with pregnancy outcomes, but little is known about the mechanisms involved. This paper examines whether quality of women’s close relationships, specifically with romantic partner (RP) and closest friend or family member (CF), is associated with inflammatory biomarkers during the third trimester of pregnancy. Methods 90 pregnant women were assessed during the second and third trimester. At both visits they completed self-reports describing the positive and negative aspects of their RP and CF relationships. Peripheral blood was collected during these visits, and used to measure systemic levels of cytokines, including IFNγ, IL10, IL6, IL8 and IL13. An index of inflammatory regulation, as reflected by the ratio of IL6:IL10, was also computed. Results Positive (e.g. support, intimacy) and negative (e.g. conflict) aspects of the RP relationship interacted to predict third trimester cytokine values. Specifically, RP relationships relatively low in both positive and negative aspects were associated with lower third trimester anti-inflammatory (IL10, IL13) and anti-viral (IFNγ) cytokines, and a higher IL6:IL10 ratio, controlling for second trimester levels. These associations were independent of demographics, gestational age, weeks between assessment, parity, pre-pregnancy body mass index, maternal stress, distress, depressed mood and RP cohabitation. CF relationship aspects were not associated with inflammatory markers. Conclusions RP relationships relatively low in both positive, e.g. support and intimacy, and negative, e.g. conflict, aspects were associated with a less anti- and more pro-inflammatory cytokine profile during the third trimester. These findings have implications for understanding the associations amongst close relationships, inflammation, and potentially pregnancy outcomes. [ABSTRACT FROM AUTHOR]

FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. This paper compares peripheral blood mononuclear cell (PBMC) incubation with FXF and osthole, by studying FXF, osthole and histamine cytokine secretion in PBMC in vitro cultures. Mabtech kits determined the interleukins IL-1β, IL-4, IL-10, IL-13 and TNF-α. The influence of the above active substances on cytokine secretion in PBMC's and serum was assessed: cytokines were IL-1β, IL-4, IL-10, IL-13 and TNF-α; and cytokine levels secreted by untreated PBMCs in pure culture medium formed the absolute control (ctrl). We determined that osthole affects PBMC cytokine secretion to almost precisely the same extent as FXF (IL-1β, IL-4, IL-10 and TNF). In addition osthole had greater IL-13 blocking ability than FXF. Moreover, we observed significantly decreased IL-4 level in histamine/osthole theatment compared to histamine alone. Meanwhile, FXF not significantly decrease the level of IL-4 increased by histamine. This data indicates osthole's strong role in allergic inflamation. All results confirm our hypothesis that osthole is a natural histamine antagonist and therefore can be beneficially used in antihistamine treatment of conditions such as allergies. [ABSTRACT FROM AUTHOR]

The effect of exposure to polycyclic aromatic hydrocarbons (PAHs) to induce micronuclei (MN) measured using the lymphocytes cytokinesis-block micronucleus (CBMN) assay were evaluated in 34 studies according to the exposure: 20 studies in coke oven workers, 7 studies in different occupational exposures as alluminium industry workers, rubber factory workers, road construction workers, airport workers and diesel exposed workers, 6 studies on environmentaly exposed groups as police, volunteers and children. Reviewed papers indicate that the CBMN assay is a sensitive biomarker of PAHs exposure in polluted air. Reviewed studies confirmed previous conclusions, that the frequency of MN measured using the lymphocyte CBMN is not significantly affected by smoking, females are more sensitive to PAHs than males, the frequency of MN is increased with age. [ABSTRACT FROM AUTHOR]

Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects. Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM. The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway. The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection. The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research. [Display omitted] [ABSTRACT FROM AUTHOR]