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Bullous pemphigoid (BP) is an organ-specific disease. Its pathogenesis has not been clearly studied yet; However, studies in recent years have shown that its pathogenesis is related to T helper cells. The pathogenesis of BP is mainly related to Th2 and Th17-related cytokines. IL-4, IL-5 and IL-13 cause eosinophil recruitment, promote antibody production, trigger pruritus and promote blister formation and other symptoms. IL-17 and IL-23 promote the production of matrix metalloproteinase-9 (MMP-9) by related cells, which causes dermo-epidermal junction (DEJ) separation to form bullae and blisters, and can persist in BP inflammation. The serum concentrations of IL-17 and IL-23 are related to the prognosis of BP. In this paper, we focus on the role of related cytokines in the pathogenesis of bullous pemphigoid and the relationship between the related cytokine populations secreted by three major T helper cells—helper T lymphocytes 1 (Th1), Th2, and Th17. A better understanding of the biological and immunological functions of cytokines associated with BP patients will provide opportunities for therapeutic targets in BP. [ABSTRACT FROM AUTHOR]

This paper shows how SARS-CoV-2 alters tight junctions (TJs) in human organs. The effect of SARS-CoV-2 on the ACE/Ang II/AT1R pathway and immune cells culminates in the release of numerous pro-inflammatory mediators, leading to the presence of certain symptoms in COVID-19, such as acute lung injury (ALI), pulmonary hypertension, and pulmonary fibrosis. Furthermore, the cytokines released alter different TJs components. The study shows how the irregular release of pro-inflammatory cytokines leads to claudin disruption in various tissues of the body, resulting in different symptoms, such as alveolar fibrosis, pulmonary edema, conjunctivitis, altered fertility in males, gastrointestinal symptoms, Covid toes, and others. SARS-CoV-2 also alters occludin expression in the endothelial and blood-testis barriers (BTB) resulting in edema and altered fertility. Viral disruption of JAM-A leads to activation of the RhoA GTPase, which leads to ALI. Taken together, these results define ACE/Ang II/AT1R pathway receptors and tight junctional components as potential therapeutic targets in COVID-19. [ABSTRACT FROM AUTHOR]

Objectives: To perform a review of the literature of published articles assessing the role of genetic factors in the etiology of temporomandibular disorders (TMDs).Methods: A PubMed search was carried out by looking for all controlled clinical trials related to the topic and limiting the search to English language and humans. The references from the studies included and those from review articles were also examined for further relevant papers.Results: A total of 1999 articles were first identified, 24 of which were considered relevant to the topic. Two other papers were found while searching the references. While TMD signs and symptoms' co-occurrence was not found in subjects within the same family, many gene polymorphisms were shown to be associated with a higher or lower risk of TMD. Such genes were mainly related to serotonin activity and metabolism, Tcellreceptor pathway, catecholamine activity and metabolism, estrogen activity, folate metabolism, glutathione activity, ANKH gene, major histocompatibility complex, extracellular matrix metabolism, genes studied in the orofacial pain prospective evaluation risk and assessment (OPPERA) study, and related to cytokines activity and metabolism.Discussion: This new understanding of the pathophysiology of TMD can lead to a different treatment approach by identifying the subjects at higher risk for this pathology, and possibly by creating new drugs targeted at interfering with the expression of the genes that enhance such risk. [ABSTRACT FROM AUTHOR]

People often simultaneously expose to acceptable/tolerable daily intake of food additives and pesticides in daily life. Exposure in adult rodents to acceptable/tolerable daily intake of food additives and pesticides chemical mixtures (AFACM) is reported to cause health damage. Our recently study reported that AFACM exposure of pregnant mice resulted in neuroinflammation and abnormal emotional behaviours in offspring. Here, we found that neutralising IFN-γ with neutralising antibodies completely blocked the influences induced by maternal AFACM exposure, including the increased IFN-γ level in serum, increased IFN-γ, interleukin-6 and tumour necrosis factor-a levels in prefrontal cortex(PFC) in offspring on postnatal day(PND)7, the abnormal emotional behaviours in offspring on PND56, and the decreased of ATPase phospholipid flippase 8A2(ATP8A2) in the PFC of offspring on PND7. In sum, maternal AFACM exposure induced the PFC neuroinflammation, abnormal emotional behaviours and decreased PFC ATP8A2 expression through increasing systemic IFN-γ in offspring. [ABSTRACT FROM AUTHOR]

Lantana camara Linn. (Verbenaceae) is used for improving memory in certain African societies. This study investigated the effect of prophylactic treatment with hydroethanolic leaf extract of Lantana camara (LCE) on short-term memory deficit and neuroinflammation induced with scopolamine in zebrafish and mice. Zebrafish (AB strain) and mice (ICR) were given donepezil (0.65 mg/kg, oral) and LCE (10, 30, 100 mg/kg, oral) for 7, and 10 days, respectively, before induction of cognitive impairment with scopolamine immersion (200 µM) and intraperitoneal injection (2 mg/kg), respectively. Spatial short-term memory was assessed in zebrafish using both Y- and T-mazes, whereas Y-maze was used in mice. Mice hippocampal and cortical tissues were analyzed for mRNA expression of proinflammatory genes (IL-1β, IL-6, TNF-α, COX-2) using qRT-PCR. In the zebrafish Y-maze, LCE (10 and 100 mg/kg) increased time spent in the novel arm by 55.89 ± 5.70%, and 68.21 ± 2.75%, respectively, but not at 30 mg/kg. In the zebrafish T-maze, there was an increase in time spent in the food-containing arm at 30 (44.23 ± 2.13) and 100 mg/kg (52.30 ± 1.94). In the mouse Y-maze, spontaneous alternation increased by 52.89 ± 4.98% at only 10 mg/kg. LCE (10, 30, 100 mg/kg) inhibited proinflammatory gene (IL-1β, IL-6, TNF-α, COX-2) mRNA expression, with the highest inhibitory effect on IL-6 in both the hippocampus (83.27 ± 2.49%; 100 mg/kg) and the cortex (98.74 ± 0.11%; 10 mg/kg). LCE ameliorated scopolamine-induced AD in both zebrafish and mice. [ABSTRACT FROM AUTHOR]

Whereas cytokine-induced tyrosine phosphorylation of STAT (signal transducer and activator of transcription) proteins by JAK kinases has been well studied, much less is known about STAT-specific serine kinases and their signal-dependent regulation. The paper by Joanna Bancerek and colleagues published recently in Immunity reports that upon interferon-γ (IFNγ) stimulation of cells the chromatin-associated cyclindependent kinase 8 (CDK8) phosphorylates the regulatory serine residue 727 in the transactivation domain of STAT1. The authors state that the CDK8 module of the Mediator complex is a key component in the STAT1 signal pathway, linking serine phosphorylation to genespecific transcriptional events [ABSTRACT FROM AUTHOR]

A new instrument, namely the 1 × 3 tandem differential mobility analyzer (1 × 3-TDMA), has been developed. Its primary measurement is the irreversibility of the hygroscopic growth factor of aerosol particles. The instrument uses the hysteresis of phase transitions to infer the solid or aqueous state of the particles. A first DMA passes particles of a selected electric mobility at relative humidity RH0. Exiting this DMA, the particles are split into three separate flows. The first flow is exposed to RH0 → (RH0+ δ) → RH0 in a deliquescence test before passing through a second DMA that is set to the same electric mobility as the first DMA. The second flow passes directly to a third DMA without change in RH, thereby serving as a reference arm. This DMA is also set to the same electric mobility as the first DMA. The transmission ratio of the 1 × 3-TDMA is defined as the particle concentration passing the deliquescence test divided by that passing through the reference arm. The transmission ratio is unity in the absence of deliquescence and zero when a phase transition occurs, at least for ideal instrument performance in application to a test aerosol of fully deliquesceable particles. For the third flow passing out of the first DMA, an efflorescence test is run by using the RH profile of RH0 → (RH0-δ) → RH0 before passing through a fourth DMA. A full data set for the 1 × 3-TDMA is obtained by scanning RH0, typically from 20 to 85%. In the present paper, the 1 × 3-TDMA instrument is described, and laboratory data are presented for the phase transitions of externally mixed aerosols of aqueous and solid sodium chloride particles, aqueous and solid ammonium sulfate particles, and their mixtures, as well as a mixture of aqueous and solid sea salt particles. The observed transmission ratio is compared to a model analysis. The intent behind the development of this instrument is to deploy it for field measurements and use observations of the irreversibility of the growth factors of atmospheric particles as markers of their physical state. [ABSTRACT FROM AUTHOR]

IL-15 is a pleiotropic cytokine that plays an important role in both the innate and adaptive immune system. IL-15 promotes the activation of neutrophils and macrophages, and is critical to DC function. In addition, IL-15 is essential to the development, homeostasis, function and survival of natural killer (NK) cells, NK T (NKT) cells and CD8 + T cells. Based on these properties, IL-15 has been proposed as a useful cytokine for immunotherapy. It is currently being investigated in settings of immune deficiency, for the in vitro expansion of T and NK cells, as well as an adjuvant for vaccines. In this paper, we will review the targeting of IL-15 for immunotherapy, with a particular emphasis on its effects on CD8 + T cells. [ABSTRACT FROM AUTHOR]

The suppressor of the cytokine signaling-1 (SOCS1) gene is a short sequence located on chromosome 16 that functions to induce an appropriate immune response and is an essential physiological regulator of interferon (IFN) signaling. In addition to comparing the global DNA and SOCS1 gene promoter methylation status between our patients with coronavirus disease 2019 (COVID-19) and healthy controls, this study demonstrates the effect of the SOCS1 rs33989964 polymorphism on patients with COVID-19. The study group included 139 patients diagnosed with COVID-19 in our hospital's clinics between June and December 2020, and the control group included 78 healthy individuals. After comparing the initial gene polymorphisms of the patients with the healthy control group, three separate clinical subgroups were formed. The gene polymorphism distribution and the methylation status of SOCS1 were examined in these clinical subgroups. Hypomethylation of the SOCS1 gene was observed in the COVID-19 patient group compared to the healthy control group (p = 0.001). Between the patients divided into two separate clinical subgroups, those with severe and mild infections, the Del/Del genotype of the SOCS1 gene was more common in patients with severe infection than in patients with mild infection (p = 0.018). Patients with the CA/CA and CA/Del genotypes were 0.201 times more likely to have a severe infection (95% CI: 0.057–0.716, p = 0.007). Having a non-Del/Del genotype was a protective factor against severe infection. The effect of the SOCS1 rs33989964 polymorphism and methylation status of the SOCS1 gene throughout the COVID-19 pandemic could be significant contributions to the literature. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is an enormous public health issue worldwide. Recent data suggest that chronic arsenic exposure is linked to the risk of developing type 1 and type 2 DM, albeit the underlying mechanisms are unclear. This review discusses the role of the immune system as a link to possibly explain some of the mechanisms of developing T1DM or T2DM associated with arsenic exposure in humans, animal models, and in vitro studies. The rationale for the hypothesis includes: (1) Arsenic is a well-recognized modulator of the immune system; (2) arsenic exposures are associated with increased risk of DM; and (3) dysregulation of the immune system is one of the hallmarks in the pathogenesis of both T1DM and T2DM. A better understanding of DM in association with immune dysregulation and arsenic exposures may help to understand how environmental exposures modulate the immune system and how these effects may impact the manifestation of disease. [ABSTRACT FROM AUTHOR]

This review concentrates on how artificial cells can contribute to helping patients with COVID-19. Artificial cells have led to mRNA vaccines with more improvements to come. Excessive cytokines in severe COVID-19 can damage organs leading to death. Artificial cell-based collodion macroporous activated charcoal adsorbent can effectively remove middle molecular weight range molecules in patients. A novel hemoperfusion device based on collodion membrane macroporous synthetic resin effectively removes cytokines and recovery in COVID-19 patients. This has been approved as an emergency treatment for COVID-19 in China, Europe, and Canada. A recent nanobiotherapeutic containing haemoglobin and up to six times the concentration of red blood cell enzymes: catalase, superoxide dismutase and carbonic anhydrase. In an animal study, this can effectively lower the damaging increase in free radicals and the removal of increased tissue pCO2. This can also help as blood substitute for the severe and critical problem of COVID-19 pandemic donor blood supply crisis. COVID-19 and its variants have resulted in major pandemics, severe sicknesses, and deaths around the world. COVID-19 and its variants has only started less than 3 years ago, and it is even more recently that we know more about its mechanisms, requirements, prevention, and treatment. This being the case, this is the first review on the present status and future perspectives of the use of the principle of artificial cells for COVID-19 related to vaccines, treatment, and critical donor blood supply shortage. [ABSTRACT FROM AUTHOR]

Introduction: Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation. Clinical trials in breast, prostate, and pancreatic cancer using BATs armed with chemically heteroconjugated BiAbs demonstrated safety, feasibility, induction of anti-tumour immune responses and potential increases in overall survival (OS). Objectives: The primary objective of this study was to develop a recombinant BiAb that confers enhanced anti-tumour activity of BATs against a broad range of solid tumours. Methods: A recombinant anti-epidermal growth factor receptor (EGFR) x anti-CD3 (OKT3) BiAb (rEGFRBi) was designed and expressed in CHO cells, used to arm ATC (rEGFR-BATs), and tested for specific cytotoxicity against breast, pancreatic and prostate cancers and glioblastoma. Results: rEGFR-BATs exhibit remarkably enhanced specific cytotoxicity and T1 cytokine secretion against a wide range of solid tumour cell lines vs. their respective chemically-heteroconjugated BATs. Conclusion: rEGFR-BATs may provide a "universal" T cell therapy for treating a wide range of solid tumours. A (Gly4Ser)6 linker between the variable light and heavy chains of an scFv fused to the N-terminus of a heavy chain antibody confers unexpected stability to the heavy chain fusion protein and supports the efficient expression of the bispecific antibody. Arming of activated T cells with the rEGFRBi greatly enhances the relative cytotoxicity and Th1 cytokine secretion of theT cells relative to a chemically heteroconjugated BiAbs. rEGFR-BATs are promising candidates for the treatment of a broad range of solid tumours. [ABSTRACT FROM AUTHOR]

This study investigated the biochemical and histological changes associated with administering a methanolic extract of Zingiber officinale (MEZO) in Wistar rats. Fifteen (15) female rats with weights ranging from 120 - 160 g were randomly divided into three (3) groups (A-C). Group A received no treatment and served as the control group. Groups B and C received 200 and 400 mg/kg of MEZO orally for 21 days, respectively. There were no significant changes in the SOD, GSH, and CAT levels in all the groups treated with MEZO compared to the control (p < 0.05). There was no difference in the expression of inflammatory cytokines in the duodenum of rats treated with MEZO compared to the control. Histopathological studies showed acute duodenitis with intense inflammatory cell infiltrations and an eroded villus. This study shows that MEZO causes no significant oxidative changes in the female rat duodenum. However, it could elicit transient and non-dose-dependent proinflammatory potentials in the female duodenum of Wistar rats at a low dose which could not be explained by the tissue antioxidants and expression of IL1α and IL4. There is a need for reevaluation of the safety of ginger extracts in the female rat duodenum. [ABSTRACT FROM AUTHOR]

Aim: To describe the successful treatment of bone marrow edema in the setting of hip osteoarthritis using ultrasound-guided injection of photoactivated leukocyte-rich platelet-rich plasma (LR-PRP). Setting: Outpatient clinic. Patient: 65-year old female with antalgic and listing gait. Case description: The patient presented with a 2-week history of left hip pain. Exam revealed restriction and pain at end range of motion. Imaging showed extensive bone marrow edema and hip effusion. The patient underwent four weekly photoactivated LR-PRP treatments. Results: The patient reported a significant reduction in pain with MRI showing an extensive resolution of bone marrow edema and complete pain relief at 2 and 6 months post-treatment, respectively. Conclusion: Photoactivated LR-PRP may be considered as a treatment option for patients with marrow edema in the setting of hip osteoarthritis. Aim: To describe the successful treatment of bone marrow swelling in the setting of hip osteoarthritis using ultrasound-guided injection of enhanced platelet-rich plasma (PRP). Setting: Outpatient clinic. Patient: 65-year old female with an abnormal gait. Case description: The patient presented with a 2-week history of left hip pain. Exam revealed restriction and pain at end range of motion. Imaging showed extensive bone marrow and hip swelling. The patient underwent four weekly enhanced PRP treatments. Results: The patient reported a significant reduction in pain with MRI showing an extensive resolution of bone marrow edema and complete pain relief at 2 and 6 months post-treatment, respectively. Conclusion: This specific enhanced PRP may be considered as a treatment option for patients with marrow edema in the setting of hip osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs), which present a therapeutic wound healing effect. Despite having been correlated with an immunomodulatory function, the administration of PRP has not yet been investigated in atherosclerosis models. Aim: Evaluate the effect of lyophilized PRP on atherosclerosis in mice models through serum analysis. Methods: Animals received a high-fat diet for disease induction and a weekly PRP retro-orbital application. Effectiveness was evaluated by measuring inflammatory markers in plasma following the treatment of mice with either PRP or saline solution. Results: PRP was well characterized for platelet and GF concentrations; the atherosclerotic profile was established. Cytokine concentrations were altered after PRP applications. Conclusion: PRP could modulate the inflammatory pattern in the early stages of atherosclerosis. Platelet-rich plasma (PRP) contains growth factors, which stimulate normal wound healing. This product seems to be a good modulator of white blood cells and has not been investigated in atherosclerosis. This study aimed to evaluate PRP in atherosclerosis using mice models. The PRP was produced from animals and preserved using the lyophilization technique; the product was then applied weekly in the vein. For atherosclerosis induction, genetically modified animals were fed a high-fat diet. The effectiveness was evaluated by measuring plasma inflammatory markers after treatment, and PRP seemed to alter cell-signaling molecules (cytokines). This study concluded that PRP was capable of modulating the inflammatory pattern during the early stages of atherosclerosis. [ABSTRACT FROM AUTHOR]

Immunostimulatory effects of monoclonal antibodies (mAb) through binding to Fcγ receptors (FcγR) on immune cells are a likely cause of cytokine release syndrome. However, it is difficult to detect the potential risk of FcγR-dependent cytokine release associated with mAb in the current standard cytokine release assays (CRA), including the air-drying solid-phase method using human peripheral blood mononuclear cells (PBMC). To increase the sensitivity to detect FcγR-dependent cytokine release due to mAb, a high-density preculture (HDC) method was incorporated into the air-drying solid-phase CRA. Here, PBMC were exposed to panitumumab, trastuzumab, rituximab, or alemtuzumab at 0.1, 0.3, 1, and 3 μg/well for 24 or 48 hr under both non-HDC and HDC conditions. T-cell agonists (anti-CD3 mAb, anti-CD28 super-agonist [SA] mAb) were used as reference mAb. Panitumumab, trastuzumab, rituximab, or alemtuzumab induced cytokine release under both non-HDC and HDC conditions, and cytokine release caused by alemtuzumab was more pronounced under HDC conditions. To investigate FcγR involvement in cytokine release associated with panitumumab, trastuzumab, rituximab, and alemtuzumab, CRA of these four mAb were conducted with anti-FcγRI, -FcγRII, or -FcγRIII F(ab')2 fragments. The results showed cytokine release caused by trastuzumab, rituximab, and alemtuzumab was significantly suppressed by anti-FcγRIII F(ab')2 pretreatment, and slightly reduced by anti-FcγRI or anti-FcγRII pretreatment, indicating these mAb induced FcγR (especially FcγRIII)-dependent cytokine release from PBMC. Cytokine release caused by panitumumab was slightly suppressed by anti-FcγRIII F(ab')2 pretreatment. Anti-CD3 mAb and anti-CD28 SA mAb also induced significant release of cytokines under HDC conditions compared with that under non-HDC conditions. In conclusion, CRA incorporating HDC into the air-drying solid-phase method using human PBMC could sensitively capture the FcγR-dependent cytokine release potential of mAb. [ABSTRACT FROM AUTHOR]

Schizophrenia is a complex disorder owing to diversity in clinical phenotypes, overlapping symptoms, and heterogeneous clinical presentation. Even after decades of research, the exact causative mechanisms of schizophrenia are not completely known. Recent evidence indicates the role of immune dysfunction in schizophrenia pathogenesis as observed from alteration in immune cells, increased activity of complement cascade, and development of autoantibodies against neurotransmitter receptors. Immunotherapy involving immunosuppressants and cytokine-targeting drugs, have shown promising results in several clinical studies and it demands further research in this area. Here, the authors review the immunopathogenesis of schizophrenia, limitations of conventional, and atypical antipsychotic drugs and the potential role and limitations of immunotherapeutic drugs in schizophrenia management. Schizophrenia is a complex disorder and poses a challenge to the currently available treatment approaches. Nearly 30% schizophrenia patients exhibit minimal response toward conventional and atypical antipsychotic drugs. Immune system dysfunction plays an important part of schizophrenia pathophysiology and existing monoclonal antibody (mAb) drugs targeting specific components of the immune system are being repositioned in schizophrenia. The authors call upon public and private funders to facilitate urgent and rigorous research efforts in exploring potential role of immunotherapy in schizophrenia. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33. [ABSTRACT FROM AUTHOR]

Copper has been shown to plays an important role in immune functions. The aim of the study was to determine the effect of inorganic and organic forms of copper on the concentrations of cytokines, acute phase proteins and prostanoids in the peripheral blood and liver of poultry. The concentration of copper in serum and tissues was also determined. A total of 900 1-day-old Ross 308 male chickens were used. The rearing period was 42 days. The material for analysis comprised samples of peripheral blood, liver, intestine and muscle of experimental chickens. The obtained results indicate that the supplementation of broilers feed with copper chelates promotes secretion of pro and anti-inflammatory cytokines. Increased synthesis of the immunoregulatory serum amyloid A (SAA) and alpha-1-acid glycoprotein (α-AGP) and prostanoids following the administration of copper-glycine chelates in the diet indicates the stimulatory effect of copper on cellular and humoral immune mechanisms. [ABSTRACT FROM AUTHOR]

Background: Obesity is a complex disease involving the accumulation of body fat that can inflict a substantial risk to health due to the potent role it plays in the development of a series of chronic diseases including cardiovascular diseases (CVD), nonalcoholic fatty liver diseases (NAFLD), kidney diseases, diabetes, and some cancers. Despite all efforts made, no therapy has succeeded in reversing the obesity pandemic and its associated diseases. Herein, the aim was to study the effect of adipose-derived mesenchymal stem cells on obesity-induced multi-organ injuries in a diet-induced obese mouse model. Male C57BL/6 mice were fed with regular chow diet or high fat diet (HFD) to induce obesity for 15 weeks after which the mice were administered two doses of adipose-derived mesenchymal stem cells (ASC-treated groups) or media as control (media-treated groups). Animals were sacrificed and adipose, hepatic, renal, and cardiac tissues were obtained for histopathological evaluation. Mice on HFD showed excessive pathological alterations such as epididymal adipose tissue expansion, hepatic fat accumulation, glomerular swelling, and cardiomyocyte hypertrophy. However, treatment with ASCs significantly reversed the significant histopathological abnormalities induced by obesity. In conclusion, this study demonstrated the therapeutic effects of adipose-derived mesenchymal stem cells on obesity-associated complications such as NAFLD, CVD, and kidney disorders in a diet-induced obese animal model, which were partly due to the attenuation of inflammatory cytokines such as TNF-α and IL-6. [ABSTRACT FROM AUTHOR]

Enhanced intestinal permeability is a pervasive issue in modern medicine, with implications demonstrably associated with significant health consequences such as sepsis, multiorgan failure, and death. Key issues involve the trigger mechanisms that could compromise intestinal integrity and increase local permeability allowing the passage of larger, potentially dangerous molecules. Heat stress, whether exertional or environmental, may modulate intestinal permeability and begs interesting questions in the context of global climate change, increasing population vulnerabilities, and public health. Emerging evidence indicates that intestinal leakage of digestive enzymes and associated cell dysfunctions––a process referred to as autodigestion––may play a critical role in systemic physiological damage within the body. This increased permeability is exacerbated in the presence of elevated core temperatures. We employed Latent Dirichlet Allocation (LDA) topic modeling methods to analyze the relationship between heat stress and the nascent theory of autodigestion in a systematic, quantifiable, and unbiased manner. From a corpus of 11,233 scientific articles across four relevant scientific journals (Gut, Shock, Temperature, Gastroenterology), it was found that over 1,000 documents expressed a relationship between intestine, enhanced permeability, core temperature, and heat stress. The association has grown stronger in recent years, as heat stress and potential autodigestion are investigated in tandem, yet still by a limited number of specific research studies. Such findings justify the design of future studies to critically test novel interventions against digestive enzymes permeating the intestinal tract, especially the small intestine. [ABSTRACT FROM AUTHOR]

The non-receptor protein tyrosine kinase 2β (Pyk2) phosphorylated tricellular tight junction (tTJ) molecules angulin-1/LSR and tricellulin (TRIC) and the inhibitor PF-431396 (PF43) suppress angulin-1/LSR and TRIC recruitment to tTJs. The disruption of the intestinal epithelial barrier by high mobility group box 1 (HMGB1) and the inflammatory cytokines TNFα and IFNγ contributes to downregulation of angulin-1/LSR and TRIC in 2.5D culture of Caco-2 cells as a novel model of inflammatory bowel disease (IBD). In the present study, to investigate the roles of Pyk2 phosphorylated angulin-1/LSR and TRIC in the intestinal epithelial barrier, 2D and 2.5D cultures of Caco-2 cells were treated with the Pyk2 inhibitor PF-43 with or without HMGB1, inflammatory cytokines TNFα and IFNγ. Treatment with PF-43 increased expression of angulin-1/LSR, phosphorylated AMPK and phosphorylated MAPK and decreased that of phosphorylated JNK, with upregulation of the epithelial barrier and cellular metabolism measured as basal oxygen consumption rate (OCR) and ATP production in 2D culture. Treatment with PF-43 prevented the downregulation of the epithelial barrier by HMGB1 and inflammatory cytokines in 2D culture. Treatment with PF-43 prevented the epithelial hyperpermeability induced by HMGB1 and inflammatory cytokines in 2.5D culture. In 2.5D culture, treatment with PF-43 inhibited the decreases of angulin-1/LSR, TRIC, pJNK, pAMPK and pMAPK induced by HMGB1 and the inflammatory cytokines. Treatment with PF-43 inhibited in part the induced phosphorylation of the serine of angulin-1/LSR and TRIC. Pyk2 inhibitor PF-43 may have potential for use in therapy for IBD via its actions with regard to phosphorylated tTJs and cellular metabolism. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) modulate the distribution of drugs and toxins across the blood-brain barrier (BBB). Animal studies reported that infection-induced disruption of these transporters in the developing BBB impairs fetal brain protection. However, the impact of infection mimics on P-gp/BCRP function in human brain endothelium is less well understood. We hypothesized that Toll-like receptor ligands mimicking bacterial and viral infection would modify the expression and function of P-gp and BCRP in human brain endothelial cells (BECs). Human cerebral microvascular endothelial cells (hCMEC/D3) were challenged with bacterial [Lipopolysaccharide (LPS)] and viral-mimics [polyinosinic:polycytidylic acid (PolyI:C) or single-stranded RNA (ssRNA)], or pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-ɣ. P-gp and BCRP function was assessed after 4 or 24 h, using Calcein-AM and Chlorin-6 assays, respectively. Western blot and qPCR quantified P-gp/ABCB1 and BCRP/ABCG2 expression following treatments. Infection mimics are potent modulators of drug transporters in human BECs in vitro. LPS and PolyI:C increased, while ssRNA exposure reduced P-gp activity. In contrast, LPS and PolyI:C decreased, while ssRNA increased BCRP activity (P <.05). There was little correlation between drug transporter function, gene expression and total protein level. Altered plasma membrane BCRP may suggest modified intracellular trafficking induced by infection in human BECs. Bacterial and viral infection mimics modify P-gp and BCRP transport function in human BECs, in vitro. This knowledge may contribute and have important implications for human brain protection and possible altered biodistribution of drugs and xenobiotics in the brain following exposure to TLR agonists. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is the most aggressive histological subtype of breast cancer and is characterized by poor outcomes and a lack of specific-targeted therapies. Transforming growth factor-β (TGF-β) acts as the key cytokine in the epithelial–mesenchymal transition (EMT) and the metastasis of TNBC. However, the regulatory mechanisms of the TGF-β signaling pathway remain largely unknown. In this study, we identified that the USP1/WDR48 complex could effectively enhance TGF-β-mediated EMT and migration of TNBC cells. Furthermore, lower phosphorylation of Smad2/3, Erk, Jnk, and p38 was noted on the suppression of the expression of endogenous USP1 or WDR48. Moreover, the USP1-WDR48 complex was found to downregulate the polyubiquitination of TAK1 and mediate its in vitro stability. Therefore, our findings have shed a light on the novel role of the USP1/WDR48 complex in promoting TGF-β-induced EMT and migration in TNBC via in vitro stabilization of TAK1. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) has been associated with a chronic inflammation state; the specific causative etiology to the MetS will need further investigation. The present study aims to explore the levels and roles of pro- and anti-inflammatory biomarkers and antioxidant enzymes in MetS development. Subjects were divided into five groups: healthy controls; patients with dyslipidemia; patients with dyslipidemia and obesity; patients with dyslipidemia, obesity, and hypertension; patients with dyslipidemia, obesity, hypertension, and hyperglycemia. Antioxidant enzyme activities were dramatically decreased in MetS patients, whereas inflammatory marker levels were elevated. The levels of interleukin (IL)-8, IL-23, IL-33, nuclear factor kappa B (NF-κΒ), resistin, and nitric oxide were positively correlated to triglyceride, low-density lipoprotein-cholesterol, fasting plasma glucose, and glycosylated hemoglobin levels. Therefore, the data indicate that antioxidant enzymes, IL-8, IL-23, IL-33, NF-κΒ, and resistin might be used as tools to ameliorate and treat metabolic diseases. [ABSTRACT FROM AUTHOR]

Scavenger receptors are part of a complex surveillance system expressed by host cells to efficiently orchestrate innate immune response against bacterial infections. Stabilin-1 (STAB-1) is a scavenger receptor involved in cell trafficking, inflammation, and cancer; however, its role in infection remains to be elucidated. Listeria monocytogenes (Lm) is a major intracellular human food-borne pathogen causing severe infections in susceptible hosts. Using a mouse model of infection, we demonstrate here that STAB-1 controls Lm-induced cytokine and chemokine production and immune cell accumulation in Lm-infected organs. We show that STAB-1 also regulates the recruitment of myeloid cells in response to Lm infection and contributes to clear circulating bacteria. In addition, whereas STAB-1 appears to promote bacterial uptake by macrophages, infection by pathogenic Listeria induces the down regulation of STAB-1 expression and its delocalization from the host cell membrane. We propose STAB-1 as a new SR involved in the control of Lm infection through the regulation of host defense mechanisms, a process that would be targeted by bacterial virulence factors to promote infection. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33. [ABSTRACT FROM AUTHOR]

Negative energy balance (NEB) occurs in dairy cows during the transition period, during which time the blood concentrations of nonesterified fatty acids (NEFA) and metabolic ketones such as β-hydroxybutyric acid (BHBA) are elevated. These increased levels may disrupt immune functions and are regarded as risk factors associated with postparturient inflammatory disorders. Therefore, the aim of this study was to investigate the effects of NEFAs and BHBA on inflammatory cytokine expression in bovine peripheral leukocytes in vitro. Peripheral blood mononuclear cells (PBMCs) and peripheral polymorphonuclear leukocytes (PMNLs) were collected from 16 Holstein cows and treated for 4 h with NEFA (0.1, 0.6, and 1.5 mM) or BHBA (5 and 10 mM), alone or combination with lipopolysaccharides (LPS, 1 µg/mL). The expression levels of the inflammatory cytokines TNF-α, IL-1β, IL-6, IL-8, and IL-10 were then determined. The results indicated that PBMCs and PMNLs responded to NEFA but tolerated BHBA. NEFA treatment dose-dependently induced the expression of TNF-α, IL-1β, IL-8, and IL-10 in PBMCs and that of IL-1β, IL-6, IL-8, and IL-10 in PMNLs. Combination treatment of LPS with NEFA further increased the levels of IL-10 expression in PBMCs and IL-1β and IL-6 expression in PMNLs. Taken together, these findings suggest that NEFA and BHBA enhance the expression of inflammatory cytokines in PBMCs and PMNLs and may disrupt the immune regulation of peripheral leukocytes, leading to an increased risk of inflammatory disorders. Preventing increases in blood NEFA concentration may thus help to reduce the risk of inflammatory disorders in dairy cows during the transition period. In cows with NEB, during the transition period, NEFA but not BHBA induced proinflammatory cytokine expression in PBMCs and PMNLs. NEFA enhanced LPS-induced proinflammatory cytokine expression in both PBMCs and PMNLs. [ABSTRACT FROM AUTHOR]

There are two clinical subtypes of chronic rhinosinusitis (CRS): chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). The aim of the study here was to determine the levels of invasive inflammatory markers in nasal mucosa samples taken from CRSwNP patients during the surgery and to identify markers that could serve as targets for potential clinical and therapeutic interventions. The study was carried out in 59 patients with proven CRSwNP and a control group consisting of 52 healthy individuals. Concentrations of the inflammatory markers of interest were determined using a LuminexR Assay multiplex kit. The data obtained indicated that levels of inflammatory cytokines interleukin (IL)-2, -4, -5, -7, -12, -17 and -22 were all significantly higher in the nasal polyps (NP) than those in the mucosa of control participants. No differences were seen between the study groups for IL -6, -10, -13, -21 and interferon (IFN)-γ. OR (Odds Ratio) analyses confirmed that elevations in mucosal levels of IL-2, -4, -5, -7, -12, -17, and -22 were likely immune markers of CRSwNP. In conclusion, the present study demonstrated that IL-2, -4, -12 and -22 may be important in the etiopathogenesis of CRSwNP; as markers, each show moderate sensitivity, but high specificity in the Lithuanian population. IL-17 had good sensitivity, but low specificity in the CRSwNP patients. [ABSTRACT FROM AUTHOR]

The prevalence of iron (Fe) deficiency and subclinical lead (Pb) toxicity is high in developing countries like India, and information on their potential additive effects on immune responses is scant. The current study assessed immune parameters in dual Pb-exposed\Fe-deficient weanling SD rats. Rats were fed a control (CD) or Fe-deficient (ID) diet for 4 weeks and then evaluated for hemoglobin (Hb) and serum Fe status. Then, half the rats in each group began to receive daily oral Pb exposure (25 mg/4 ml/kg BW; gavage) or vehicle for a further 4 weeks (while maintained on original respective diets). After the 4-weeks of dosing, rats were assessed for Hb and serum Fe, and for blood lead level (BLL) and δ-aminolevulinic acid dehydratase (ALAD) activity. At this point, half the rats in each group (now n = 8) were then vaccinated with tetanus toxoid (TT), and then two boosters at 2-week intervals. All the time, rats stayed on their original respective diets along with exposure to Pb on alternate days. At 2 weeks after the final booster, rats were euthanized and blood collected to assess total/specific IgG and IgM levels; mucosal (intestinal) IgA levels were also determined. Spleens were taken to assess CD4+ and CD8+ cell levels and for ex vivo measures of splenocyte proliferation/TH1 and TH2 cytokine formation. The results indicated significant lowering of Hb and serum Fe levels in ID rats and increased blood Pb and decreased ALAD activity in all Pb-exposed rats. Fe-deficiency alone induced significant increases in ALAD activity, but only in an absence of Pb. While there was no impact of any regimen on total or TT-specific IgG, significant decreases in mucosal IgA and TT-specific IgM were seen in ID-fed Pb-exposed rats. CD4+ cell levels were not impacted by treatment; CD8+ levels were increased in all ID/Pb-exposed rats. Ex-vivo splenocyte proliferation was significantly higher among vaccinated rats, as well as ID-fed Pb-exposed unvaccinated rats. Cytokine formation in all cases was highly variable. The results suggest that Fe deficiency compromised cell-mediated, mucosal, and/or humoral immune response-related endpoints and that Pb exposure during the deficiency further impacted these outcomes. [ABSTRACT FROM AUTHOR]

Objective: Previous investigations suggest the use of extract from the roots of Pelargonium sidoides (EPs 7630) for improvement of the symptoms of uncomplicated upper airway inflammations, due to its antimicrobial and immunomodulatory actions. The aim of this investigation was to evaluate the effects of EPs 7630 on chemokine production in nasal mucosa and clinical parameters of patients with acute postviral rhinosinusitis (APRS). Methods: Twenty-six (n=26) APRS patients and 25 (n?25) control subjects were included in this prospective study. We measured the concentrations of thirteen chemokines in nasal secretions of APRS patients and controls by flow cytometry. The patients with APRS were treated by EPs 7630 20mg oral tablets, three times daily for 10 days. We compared the chemokine levels in nasal secretions, nasal symptoms and endoscopic findings in patients, before and after therapy. Results: We found higher Total Symptom Score (TSS) and higher concentrations of MCP-1, MIP-1a, MIP-1b, MIP-3a, ENA-78 and IL-8 in nasal secretions of APRS patients than in controls. After therapy by EPs 7630, we found significant improvement in all symptoms and endoscopic findings of APRS. The concentrations of MCP-1, IP-10 and MIP-1b were significantly increased and levels of MIP-1a, ENA-78, GROa and IL-8 significantly decreased in nasal fluid samples after therapy. No adverse effects were reported during the treatment. Conclusion: Our results suggest the presence of modulatory effects of EPs 7630 on production of chemokines regulating the function of neutrophils and monocytes in the site of inflammation of the nasal mucosa in patients with APRS. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the potential ability of autologous conditioned serum (ACS) to decrease pain and improve joint functionality in patients affected by knee osteoarthritis (OA). Methods: Fifteen patients with clinical and radiological signs of OA of the knee were recruited for this study. Each patient received 4 injections of ACS (Orthokine; orthogen, Dusseldorf, Germany) at the site of OA once per week for 4weeks. Clinical and functional evaluation was performed using the VAS scale for pain, WOMAC scale and KSS functional and clinical scores before the first injection, at one week, at two weeks, at three weeks, at one month and at six months. Statistical analysis was done with the Wilcoxon Signed-Rank Test. Results: Our results show an improvement of all the evaluation scales at 6months follow-up. Particularly, VAS scales among all patients decreased by 35.8% (p=.00148), KSS functional scores improved by 38.2% (p=.00148), KSS clinical scores improved by 28.9% (p=.00236) and WOMAC scores were reduced by 19.8% (p=.00188). Few adverse effects were observed in our sample. The most common complaint was pain and swelling in the subsequent days after performing the intraarticular injection. Only one patient reported rigidity following the injection of the ACS. Conclusion: Our results, in conjunction with preexisting studies in the medical literature regarding ACS, demonstrate the viability of this therapy for the treatment of knee OA, showing positive influence on pain and joint function without significant adverse effects. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) can trigger a cytokine response storm (CRS) that is associated with high mortality but for which the underlying pathophysiology and diagnostics are not yet well characterized. This review provides an overview of the underlying immune profile of COVID-19-related CRS as well as laboratory markers for acute diagnosis and chronic follow-up of patients with SARS-CoV-2 and CRS. Innate and acquired immune profiles in COVID-19-CRS, RNA-detection methods for SARS-CoV-2 in the setting of CRS including factors that affect assay performance, serology for SARS-CoV-2 in the setting of CRS, and other biomarkers for COVID-19 will be discussed. Studies support the implication of CRS in the pathogenesis, clinical severity and outcome of COVID-19 through the production of multiple inflammatory cytokines and chemokines from activated innate and adaptive immune cells. Although these inflammatory molecules, including IL-6, IL-2 R, IL-10, IP-10 and MCP-1, often correlate with disease severity as possible biomarkers, the pathogenic contributions of individual molecules and the therapeutic benefits of targeting them are yet to be demonstrated. Detection of SARS-CoV-2 RNA is the gold standard method for diagnosis of COVID-19 in the context of CRS but assay performance varies and is susceptible to false-negative results even as patients clinically deteriorate due to decreased viral shedding in the setting of CRS. Biomarkers including CRP, ferritin, D-dimer and procalcitonin may provide early clues about progression to CRS and help identify thrombotic and infectious complications of COVID-19. [ABSTRACT FROM AUTHOR]

IL-12 and IL-23 are two cytokines that appear to play a key role in the pathogenesis of multiple sclerosis. Blocking these cytokines via a neutralizing antibody caused dramatic improvements in animal models of the disease, and Phase I trials found the antibody to be safe in humans. The paper under review is a Phase II clinical trial of ustekinumab, an anti-IL-12/23p40 antibody for treatment of multiple sclerosis. Investigators found no clinical or radiologic improvement in any treatment group compared with placebo controls. We consider the known mechanisms of action for IL-12/23 in multiple sclerosis and suggest that ustekinumab's lack of efficacy was partially due to the study's inclusion of patients with advanced disease. Studies of the antibody in a more limited subset of patients (those with very early disease) might show a treatment effect. [ABSTRACT FROM AUTHOR]

Chronic inflammatory skin disorders are frequently associated with impaired skin barrier function. Selective phosphodiesterase-4 (PDE4) inhibition constitutes an effective therapeutic strategy for the treatment of inflammatory skin diseases. We now report the pharmacological anti-inflammatory profile of DRM02, a novel pyrazolylbenzothiazole derivative with selective in vitro inhibitory activity toward PDE4 isoforms A, B and D. DRM02 treatment of cultured primary human and mouse epidermal keratinocytes interfered with pro-inflammatory cytokine production elicited by interleukin-1α and tumor necrosis factor-α. Similarly, DRM02 inhibited the production of pro-inflammatory cytokines by human peripheral blood mononuclear cells ex vivo and cultured THP-1 monocyte-like cells, with IC50 values of 0.6–14 µM. These anti-inflammatory properties of DRM02 were associated with dose-dependent repression of nuclear factor-κB (NF-κB) transcriptional activity. In skin inflammation in vivo mouse models, topically applied DRM02 inhibited the acute response to phorbol ester and induced Th2-type contact hypersensitivity reactivity. Further, DRM02 also decreased cutaneous clinical changes and expression of Th17 immune pathway cytokines in a mouse model of psoriasis evoked by repeated topical imiquimod application. Thus, the overall pharmacological profiling of the PDE4 inhibitor DRM02 has revealed its potential as a topical therapy for inflammatory skin disorders and restoration of skin homeostasis. [ABSTRACT FROM AUTHOR]

Circadian rhythm is essential for cellular regulation of physiological, metabolic, and immune functions. Perturbations of circadian rhythms have been correlated with increased susceptibility to cancer and poor prognosis in the cancer treatment. Our aim is to investigate the role of doxorubicin (DOX) treatment on clock genes expression and inflammation in intraperitoneal macrophages and the antitumoral response. Methods: Macrophages were extracted from intraperitoneal cavity of mice without or with Lewis lung carcinoma (LLC) and treated with DOX totaling four groups (CTL, LLC, LLC+DOX and DOX) and analyzes of clock genes in six time points (ZT02, ZT06, ZT10, ZT14, ZT18 AND ZT22). Intraperitoneal macrophages cell culture was stimulated with LPS and DOX and clock genes and inflammatory profile were analyzed. In tumor were analyzed macrophages markers. Results: The expression of F4/80 (ZT22) and CD11c (ZT06) tumor tissue was significantly differed between LLC and LCC+DOX groups. In the intraperitoneal macrophages, DOX increased Clock (ZT10), Rev-Erbα (ZT18 and ZT22) and Per2 expressions (ZT18); in the LLC+DOX group was increased Bmal1 (ZT10), Per2 (ZT18) and NF-kB (ZT22) expressions; IL-6 expression increased in the LCC group (ZT02). In intraperitoneal macrophages cell culture stimulated with DOX and LPS after 24 h decreased Clock and Per1. DOX causes depression after 6 and 24 h in TNF-α content and Per2 gene expression after 24 h IL-1β expression was reduced also. Conclusion: DOX treatment in vivo disrupted cytokine and clock genes expression in intraperitoneal macrophages suppressing immune response. Moreover, macrophages cultured with DOX had decreased expression of LPS-stimulated inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Leptospirosis causes a wide range of clinical outcomes, including organ failure and death. Early treatment significantly increases the chances of cure. Interleukin-8 (IL-8) is a chemoattractant cytokine for neutrophil and is associated with multiple organ failure. Research has indicated IL-8 to be raised in severe and fatal cases of leptospirosis, but its suitability as a prognostic biomarker has yet to be confirmed. This study aimed to evaluate the significance of IL-8 with the clinical outcomes of leptospirosis patients. Plasma IL-8 was measured in fifty-two samples from hospitalized patients and nineteen healthy controls. The comparisons were made between mild, severe-survived and fatal groups identified by clinical or laboratory findings. IL-8 was significantly higher in fatal (p = 0.01) compared to mild cases. IL-8 was also significantly higher in fatal (p = 0.02) when compared to survived cases of leptospirosis. IL-8 levels in the plasma of fatal leptospirosis cases were significantly elevated compared to survived cases and may serve as a potential prognostic biomarker in determining the possible outcome of leptospirosis patients. [ABSTRACT FROM AUTHOR]

The pathogenic bacteria delay wound healing due to their interaction in the wound area. This study is aimed to evaluate the efficiency of topical rosemary essential oil (REO) loaded into the nanostructured lipid carriers (NLCs) on in vitro antibacterial activity and in vivo infected wound healing process in the animal model. REO-NLCs morphology, size and in vitro antibacterial activity were done. Two circular full-thickness wound (each 6 mm) were made on the back of each mouse and each wound was infected with a solution containing 107 CFU Staphylococcus aureus and Pseudomonas aeruginosa. Animals were divided into four groups including control, Mupirocin® and two treated groups with a gel containing REO and REO-NLCs. For this purpose, tissue bacterial count, histological assessment, serum level of IL-3, IL-10, VEGF and SDF-1α were evaluated. REO-NLCs showed antibacterial activity against Staphylococcus epidermidis, Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Pseudomonas aeruginosa. Moreover, REO-NLCs could reduce the rate of tissue bacterial colonization and wound size, while they increased the vascularization, fibroblast infiltration, re-epithelialization, collagen production, IL-3, IL-10, VEGF and SDF-1α serum levels. Our finding revealed the REO-NLCs have antibacterial properties and accelerated infected wound healing, and so that confirming their potential clinical uses for the treatment of infected wounds. [ABSTRACT FROM AUTHOR]

Objective: In this in vitro study we have used an RNA quantification technique, nanoString, and a conventional protein analysis technique (Western Blot) to assess the genetic and protein expression of B16 murine melanoma cells following a modest magnetic nanoparticle hyperthermia (mNPH) dose equivalent to 30 minutes @ 43°C (CEM43 30) and/or a clinically relevant 8 Gy radiation dose. Methods: Melanoma cells with mNPs(2.5 μg Fe/106 cells) were pelleted and exposed to an alternating magnetic field (AMF) to generate the targeted thermal dose. Thermal dose was accurately monitored by a fiber optic probe and automatically maintained at CEM43 30. All cells were harvested 24 hours after treatment. Results: The mNPH dose demonstrated notable elevations in the thermotolerance/immunogenic HSP70 gene and a number of chemoattractant and toll-like receptor gene pathways. The 8 Gy dose also upregulated a number of important immune and cytotoxic genetic and protein pathways. However, the mNPH/radiation combination was the most effective stimulator of a wide variety of immune and cytotoxic genes including HSP70, cancer regulating chemokines CXCL10, CXCL11, the T-cell trafficking chemokine CXCR3, innate immune activators TLR3, TLR4, the MDM2 and mTOR negative regulator of p53, the pro-apoptotic protein PUMA, and the cell death receptor Fas. Importantly a number of the genetic changes were accurately validated by protein expression changes, i.e., HSP70, p-mTOR, p-MDM2. Conclusion: These results not only show that low dose mNPH and radiation independently increase the expression of important immune and cytotoxic genes but that the effect is greatly enhanced when they are used in combination. [ABSTRACT FROM AUTHOR]

The immunotoxicant bisphenol A (BPA) may produce toxic effects on organs and systems, in part, by altering the secretion of cytokines and chemokines. However, systematic studies of the effects of BPA, let alone of its analogs and in cases when there are interactions with other chemicals, on innate immunity and cytokine modulation are limited. The objectives of this study were to investigate the immunomodulatory effects of: (1) BPA and its analogs, BPS and BPAF; and (2) the interaction between BPA and genistein (GEN), a partial estrogen agonist or antagonist. BPA, BPS, and BPAF were incubated with PMA-differentiated-U937 cells (a widely used cell line for primary human macrophages) at concentrations of 0, 0.1, 1, 10, 100 µM for up to 96 h. BPA (0, 0.1, 1, 10 µM) and GEN (0, 1, 10 µM) were also applied at various combinations. Cell viability and 30 cytokines/chemokines were measured. The results showed that the cell viability-inhibiting effect of these three bisphenols was BPAF > BPA > BPS. At 0.1 µM, BPA and BPAF generally increased the secretion of cytokines/chemokines, while BPS had minimal effects. All three bisphenols generally suppressed the secretion of cytokines/chemokines at 1 µM, while increased their secretion at 10 µM. The most increased cytokines/chemokines were interferon (IFN)-γ, interleukin (IL)-1RA, IL-8 and MIP-1β, and the most decreased was IL-10. GEN increased cell viability at low BPA concentrations but had no effect when BPA levels were high. In general, GEN attenuated the BPA-induced secretion of cytokines/chemokines but enhanced it at low BPA concentrations. In conclusion, this study showed that BPA, BPS, and BPAF were immunotoxic to macrophages: BPS was the least toxic, while BPAF was the most toxic. Further, GEN reversed suppressive effects on macrophages that resulted from exposure to high concentrations of BPA and produced synergetic effects with BPA at low concentrations. [ABSTRACT FROM AUTHOR]

Polysaccharides are one of many bioactive compounds found in edible mushrooms. Edible mushrooms have become attractive as “health foods” and as source materials for immunomodulators. The aim of this project was to study the immunoregulatory effects of a purified polysaccharide derived from wild Russula griseocarnosa (PRG1-1) on macrophages. Our data showed that in RAW264.7 macrophage cells, PRG1-1 increased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, PRG1-1 increased the production of nitric oxide (NO) and cytokines, including interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α). Western blotting demonstrated that the regulation of NO and cytokines was mediated through the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways. Therefore, PRG1-1 has the capacity to activate macrophages via the NF-κB and MAPK pathways. These findings helped to elucidate the immune-modulatory properties of the polysaccharide from R. griseocarnosa. [ABSTRACT FROM AUTHOR]

Context: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception. Objective: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed. Materials and methods: Behavioural (von Frey's/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 μG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7. Results: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy. Conclusions: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders. [ABSTRACT FROM AUTHOR]

Introduction: Millions of people worldwide suffer from depression, but despite advances in pharmacological therapies, many patients do not experience symptomatic remission or treatment response, even after treatments with several medications. As such, there is an urgent need to identify biomarkers that can not only predict the treatment response but also allow a rational selection of optimal therapy for each patient. Areas covered: This review examines the recent findings, coming from different ‘omic sciences,’ in human blood-based biomarkers associated with antidepressant treatment response with particular attention on genetic/epigenetic and biochemical biomarkers. Specific emphasis will be placed on key molecules related to neuroplasticity and inflammation because of their involvement in the pathophysiology of depression and antidepressant response. Expert commentary: Biomarker identification is still an ongoing work. Indeed, to date, no biomarkers have sufficiently proven specificity, sensitivity, and reproducibility to be used in the clinical setting. However, ‘omic’ approaches hold great promise in identifying multiple features for predicting antidepressant response, making a personalized treatment strategy possible for each patient, and thereby assist with quick and efficacious responsiveness. It is thus necessary that future studies take an integrative approach that includes clinical assessment, environment influences, and molecular and biological biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Inflammation seems to play a role in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). In the last years several studies have shown increased levels of inflammatory and/or immune markers in patients with mood disorders. Accordingly, the immune system has become a target of interest for the development of biomarkers and therapeutics for mood disorders. Areas covered: Here, we review the evidence showing low-grade inflammation in mood disorders and the studies evaluating immune-based strategies for the treatment of these conditions. Expert commentary: Clinical trials with non-steroidal anti-inflammatory drugs, polyunsaturated acids, N-acetylcysteine, anti-cytokines, physical activity and probiotics have provided promising results in terms of antidepressant efficacy in patients with MDD and BD. Regarding stem cells, only studies with animal models have been performed so far with interesting pre-clinical results. Due to the preliminary nature of the results, most of the clinical studies need to be replicated and/or confirmed in larger clinical settings, embracing the highly heterogeneous pathophysiology of mood disorders. [ABSTRACT FROM PUBLISHER]

Transmissible gastroenteritis virus (TGEV) infection causes acute enteritis in swine of all ages, and especially in suckling piglets. Small intestinal inflammation is considered a central event in the pathogenesis of TGEV infections, and nuclear factor-kappa B (NF-κB) is a key transcription factor in the inflammatory response. However, it is unclear whether NF-κB is crucial for inducing inflammation during a TGEV infection. Our results show that NF-κB was activated in swine testicular (ST) cells and intestinal epithelial cell lines J2 (IPEC-J2) cells infected with TGEV, which is consistent with the up-regulation of pro-inflammatory cytokines. Treatment of TGEV-infected ST cells and IPEC-J2 cells with the NF-κB-specific inhibitor caused the down-regulation of pro-inflammatory cytokine expression, but did not significantly affect TGEV replication. Individual TGEV protein screening results demonstrated that Nsp2 exhibited a high potential for activating NF-κB and enhancing the expression of pro-inflammatory cytokines. Functional domain analyzes indicated that the first 120 amino acid residues of Nsp2 were essential for NF-κB activation. Taken together, these data suggested that NF-κB activation was a major contributor to TGEV infection-induced inflammation, and that Nsp2 was the key viral protein involved in the regulation of inflammation, with amino acids 1-120 playing a critical role in activating NF-κB. Abbreviations: TCID50: 50% tissue culture infectious dose; DMEM: Dulbecco's Modified Eagle Medium; eNOS: Endothelial nitric oxide synthase; FBS: fetal bovine serum; IFA: Indirect immunofluorescence; IκB: inhibitor of nuclear factor kappa-B; IL: interleukin; IPEC-J2: intestinal epithelial cell lines J2; IKK: IκB kinase; Luc: luciferase reporter gene; mAbs: monoclonal antibodies; MOI: multiple of infection; Nsp: nonstructural protein; NF-κB: nuclear factor-kappa ; ORFs: open reading frames; PBS: phosphate-buffered saline; p65 p-p65: phosphorylated; RT-PCR: reverse transcription PC; SeV: Sendai virus; ST: swine testicular; TGEV: Transmissible gastroenteritis virus; TNF-α: tumor necrosis factor α; UV-TGEV: Ultraviolet light-inactivated TGEV; ZnF: zinc finger [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa, an opportunistic pathogen involved in skin and lung diseases, possesses numerous virulence factors, including type 2 and 3 secretion systems (T2SS and T3SS) and its flagellum, whose functions remain poorly known during cutaneous infection. Using isogenic mutants deleted from genes encoding each or all of these three virulence factors, we investigated their role in induction of inflammatory response and in tissue invasiveness in human primary keratinocytes and reconstructed epidermis. Our results showed that flagellum, but not T2SS and T3SS, is involved in induction of a large panel of cytokine, chemokine, and antimicrobial peptide (AMP) mRNA in the infected keratinocytes. Chemokine secretion and AMP tissular production were also dependent on the presence of the bacterial flagellum. This pro-inflammatory effect was significantly reduced in keratinocytes infected in presence of anti-toll-like receptor 5 (TLR5) neutralizing antibody. Bacterial invasion of human epidermis and persistence in a mouse model of sub-cutaneous infection were dependent on the P. aeruginosa flagellum. We demonstrated that flagellum constitutes the main virulence factor of P. aeruginosa involved not only in early induction of the epidermis inflammatory response but also in bacterial invasion and cutaneous persistence. P. aeruginosa is mainly sensed by TLR5 during the early innate immune response of human primary keratinocytes. [ABSTRACT FROM AUTHOR]

Celastrol, a constituent from a traditional Chinese medicinal herb belonging to the familyCelastraceae, has been shown to impart anti-inflammatory properties, in part, by inhibiting NF-κB activity and related induction of pro-inflammatory cytokine formation/release. The present study investigated the effects of celastrol in an animal model of acute respiratory distress syndrome (ARDS) induced by intratracheal administration of lipopolysaccharides (LPSs). Celastrol pre-treatment groups received celastrol by intraperitoneal injection on seven consecutive days before LPS treatment. In rats evaluated 24 h after LPS administration, oxygenation indices and lung injury were measured, as were levels of inflammatory cells and cytokines in isolated bronchoalveolar lavage fluid (BALF). Lung tissue expression of proteins involved in NF-κB and ERK/MAPK pathways were measured by Western blot analyses. Celastrol pre-treatments appeared to attenuate LPS-induced lung injury and inflammatory responses in the rats, including decreases in inducible aggregation\infiltration of inflammatory cells and production/release of pro-inflammatory cytokines into the lung airways. Celastrol appeared to also inhibit NF-κB activation, but had no effect on ERK/MAPK pathways in the LPS-induced ARDS. The results here thus indicated that celastrol pre-treatment could impart protective effects against LPS-induced ARDS, and that these effects may be occurring through an inhibition of induction of NF-κB signaling pathways. [ABSTRACT FROM PUBLISHER]

Many Vietnamese citizens have been and continue to be inadvertently exposed to dioxins and dioxin-like compounds deposited in the country during the Vietnam War. Dioxins may be involved in the pathogenesis of inflammatory diseases in part via by affecting expression of aryl hydrocarbon receptor (Ahr) and inflammatory cytokines in animal models. As the role of the Ahr in dioxin-exposed people is not well defined, a study was conducted to examine gene expression levels ofAhr, inflammatory cytokines, and the incidence of diseases in dioxin-exposed citizens who had/still resided near a heavily dioxin-contaminated area in Vietnam. Whole blood from citizens at/around Da Nang airbase and control individuals living in unsprayed areas was collected. Serum levels of dioxins were analyzed by using a dioxins-responsive chemical-activated luciferase gene expression bioassay. Gene expression ofAhr,interleukin (IL)-1β,TNFα, IL-6, and IL-22in whole blood was examined by quantitative real-time PCR. The results showed levels of dioxins and expression ofAhr,IL-1β,TNFα,andIL-6were up-regulated whileIL-22expression was down-regulated in dioxin-exposed people. Various disease incidences in the study subjects was also examined. Interestingly, the incidence of rheumatoid arthritis (RA) in these individuals was increased compared to the estimated prevalence of this disease in the general Vietnamese population. Analyses also showed that expression levels ofAhrcorrelated to those ofIL-6andIL-22in the dioxin-exposed people. Taken together, dioxins might be involved in an up-regulated expression ofAhrthat might possibly relate to changes in level of inflammatory cytokines and, ultimately, in the incidence of select diseases in residents of Vietnam who had/continue to live near a dioxins-contaminated site. [ABSTRACT FROM PUBLISHER]