Typical Inflammatory Response Research Articles

Parotid glands have a dysregulated immune response following radiation therapy.

Head and neck cancer treatment often consists of surgical resection of the tumor followed by ionizing radiation (IR), which can damage surrounding tissues and cause adverse side effects. The underlying mechanisms of radiation-induced salivary gland dysfunction are not fully understood, and treatment options are scarce and ineffective. The wound healing process is a necessary response to tissue injury, and broadly consists of inflammatory, proliferative, and redifferentiation phases with immune cells playing key roles in all three phases. In this study, select immune cells were phenotyped and quantified, and certain cytokine and chemokine concentrations were measured in mouse parotid glands after IR. Further, we used a model where glandular function is restored to assess the immune phenotype in a regenerative response. These data suggest that irradiated parotid tissue does not progress through a typical inflammatory response observed in wounds that heal. Specifically, total immune cells (CD45+) decrease at days 2 and 5 following IR, macrophages (F4/80+CD11b+) decrease at day 2 and 5 and increase at day 30, while neutrophils (Ly6G+CD11b+) significantly increase at day 30 following IR. Additionally, radiation treatment reduces CD3- cells at all time points, significantly increases CD3+/CD4+CD8+ double positive cells, and significantly reduces CD3+/CD4-CD8- double negative cells at day 30 after IR. Previous data indicate that post-IR treatment with IGF-1 restores salivary gland function at day 30, and IGF-1 injections attenuate the increase in macrophages, neutrophils, and CD4+CD8+ T cells observed at day 30 following IR. Taken together, these data indicate that parotid salivary tissue exhibits a dysregulated immune response following radiation treatment which may contribute to chronic loss of function phenotype in head and neck cancer survivors.

Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

The term "neuroinflammation" defines the typical inflammatory response of the brain closely related to the onset of many neurodegenerative diseases (NDs). Neuroinflammation is well known, but its mechanisms and pathways are not entirely comprehended. Some progresses have been achieved through many efforts and research. Consequently, new cellular and molecular mechanisms, diverse and conventional, are emerging. In listing some of those that will be the subject of our description and discussion, essential are the important roles of peripheral and infiltrated monocytes and clonotypic cells, alterations in the gut-brain axis, dysregulation of the apelinergic system, alterations in the endothelial glycocalyx of the endothelial component of neuronal vascular units, variations in expression of some genes and levels of the encoding molecules by the action of microRNAs (miRNAs), or other epigenetic factors and distinctive transcriptional factors, as well as the role of autophagy, ferroptosis, sex differences, and modifications in the circadian cycle. Such mechanisms can add significantly to understanding the complex etiological puzzle of neuroinflammation and ND. In addition, they could represent biomarkers and targets of ND, which is increasing in the elderly.

Potential role of S100A8/A9 and RNA-binding protein in microvascular complications of type2 diabetes mellitus

Background & objective: Persistent hyperglycemia is the driving force for the progression of diabetic vascular complications and inflammatory response. S100A8 and S100A9 are small calcium-binding proteins involved in various cellular processes, including inflammation and immune responses. Tristetraprolin (TTP), alternatively known as zinc finger protein 36, acts as an RNA-binding molecule that has an important role in regulating the expression of messenger RNAs containing AU-rich elements. We aimed to address the involvement of inflammatory mediators like S100A8/A9 proteins and, RNA-binding proteins, in microvascular complications of type 2 diabetes mellitus (T2DM).
 Methodology: The study was conducted from October 2022 to April 2023. We enrolled 200 subjects in this study involved in five equal groups: T2DM, diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic neuropathy (DNR) and 40 normal healthy subjects as control group. CBC analysis was performed directly using the hematology analyzer CBC (Sysmex, Japan) technique. Serum S100 A8/A9 were measured by ELISA, and TTP gene expression was measured by RT-qPCR.
 Results: The study's findings revealed a notable increase in neutrophil/lymphocytes ratio (NLR) and S100A8/A9 levels in patients groups compared to the healthy group (P < 0.05), while decreased TTP mRNA expression was observed in all patient groups compared to control (P < 0.05)
 Conclusion: An increase in S1008A/9A levels with down regulation of anti-inflammatory binding protein (TTP) in patients suffering from type 2 diabetes mellitus with diabetic nephropathy, diabetic retinopathy, or diabetic neuropathy, suggests to be the therapeutic targets to regulate inflammatory response in type 2 diabetes mellitus and its complications.
 Abbreviations: T2DM - Type 2 Diabetes Mellitus; DN - Diabetic Nephropathy; DR - Diabetic Retinopathy; DNR - Diabetic Neuropathy; NLR- Neutrophil/Lymphocyte Ratio; TTP - Tristetraprolin
 Key words: Diabetes Mellitus; Inflammation; S100A8/A9; Inflammation; RNA-binding protein; T2DM; Neutrophil/Lymphocyte Ratio
 Citation: Sarhan A, Almzaiel AJ, Majeed Alrufaie MM. Potential role of S100A8/A9 and RNA-binding protein in microvascular complications of type2 diabetes mellitus. Anaesth. pain intensive care 2023;27(6):673−680.
 DOI: 10.35975/apic.v27i6.2338
 Received: August 15, 2023; Reviewed: September 03, 2023; Accepted: September 15, 2023

Combination of Eucheuma Cottonii and Corticosteroids has a Superior Immunomodulatory Effect on Asthma

Asthma prevalence has been increasing globally which is commonly treated using corticosteroid as gold standard treatment. However, corticosteroids have adverse effects and cases of corticosteroid-resistant asthma are emerging. Eucheuma cottonii (EC) has been shown to potentially attenuate inflammatory response in type I hypersensitivity. This study aimed to investigate the effect of Eucheuma cottonii extract and methylprednisolone combination on IL-4, IL-10, and histamine levels in Ovalbumin-induced asthma BALB/c mice. Thirty female BALB/c mice were randomly assigned to 6 groups : (1) Sham; (2) Ovalbumin-induced asthma mice; (3) Ovalbumin-induced asthma mice treated with methylprednisolone (MP) 0.24 mg/day; (4) Ovalbumin-induced asthma mice treated with EC extract 300 mg/kgBW/day; (5) Ovalbumin-induced asthma mice treated with combination of both. Treatments were given respectively for 7 days. Plasma IL-4, IL-10, and histamine levels were measured using ELISA method. The combination group showed both the lowest IL-4 levels (89.30 ± 1.37 pg/ml) and the highest IL-10 levels (487.03 ± 20.57 pg/ml) compared to other asthma-like mouse groups (p = 0.001). No significant difference was observed in histamine levels among all treatments (p > 0.05). The administration of a combination of methylprednisolone and Eucheuma cottonii extract significantly affected plasma IL-4 and IL-10 levels compared to monotherapies. However, there was no significant difference in plasma histamine levels compared to monotherapies.

Site-Specifically Launched Microneedles for the Combined Treatment of Psoriasis-Diabetic Comorbidity.

Psoriasis and diabetes are both common comorbidities for each other, where inflammation and insulin resistance act in a vicious cycle, driving the progression of disease through the activation of the NF-κB signaling pathway. Therefore, disrupting the linkage between inflammation and insulin resistance by inhibiting the NF-κB pathway presents a promising therapeutic strategy for addressing psoriasis-diabetic comorbidity. Herein, an open-loop therapy was developed by integrating microneedle-mediated short- and long-range missiles to target psoriasis and diabetes, respectively. The short-range missile (curcumin nanoparticle) could be stationed in the psoriatic skin for topical and prolonged antipsoriasis therapy, while the long-range missile (metformin) is capable of penetrating transdermal barriers to induce a systemic hypoglycemic effect. More attractively, the short- and long-range missiles could join hands to inhibit the NF-κB signaling pathway and diminish inflammation, effectively disrupting the crosstalk between inflammation and insulin resistance. Pharmacodynamic studies showed that this microneedle-mediated combination, possessing dual anti-inflammatory and antihyperglycemic properties, proves to be highly efficacious in alleviating typical symptoms and inflammatory response in both nondiabetic and diabetic mice with imiquimod (IMQ)-induced psoriasis models. Hence, the microneedle-mediated open-loop therapy shows great potential in the management of psoriasis-diabetes comorbidity.

Blocking prokineticin receptors attenuates synovitis and joint destruction in collagen-induced arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated by an interdependent network of proinflammatory molecules such as chemokines. Prokineticin 2 (PK2) is a chemokine-like peptide that modulates nociceptive threshold and immuno-inflammatory processes via two G-protein-linked receptors, prokineticin receptor 1 and 2 (PKR1 and PKR2). In the present study, we investigated the effects of the prokineticin receptor antagonist PC1 on arthritic pain and the inflammatory response in type II collagen-induced arthritis (CIA) in mice. We demonstrated that PC1, administered subcutaneously from day 25 to day 35 after CIA, improved clinical signs of arthritis such as paw edema, pain, and impaired locomotor activity. In CIA mice, PC1 was also able to lower plasma malondialdehyde (MDA) levels, suggesting a role in reducing oxidative damage, as well as joint expression levels of PK2, PKRs, TNFα, IL-1β, CD4, CD8, and NF-kB. These results suggest that blocking PKRs may be a successful strategy to control arthritic pain and pathology development. KEY MESSAGES: PK2/PKRs expression levels strongly increase in the synovium of RA mice. PC1 treatment shows anti-arthritic activity and reduces arthritis-induced pain. PC1 treatment significantly lowers synovial PK2/PKRs levels. PC1 treatment lowers plasma MDA levels and synovial levels of TNFα and IL -1β PC1 treatment is a viable therapeutic option for RA.

Investigating the Biodegradation Mechanism of Poly(trimethylene carbonate): Macrophage-Mediated Erosion by Secreting Lipase.

Poly(trimethylene carbonate) (PTMC), as one of the representatives of biodegradable aliphatic polycarbonates, has been found to degrade in vivo via surface erosion. This unique degradation behavior and the resulting nonacidic products make it more competitive with aliphatic polyesters (e.g., polylactide) in clinical practice. However, this surface degradation mechanism is complicated and not fully understood to date despite the findings that several reactive oxygen species and enzymes can specifically degrade PTMC in vitro. Herein, the biodegradation mechanism of PTMC was investigated by using possible degradation factors, distinct cell lines, and the inhibitors of these factors. The results demonstrate that PTMC undergoes a specific macrophage-mediated erosion. Macrophages tend to fuse into giant cells and elicit a typical inflammatory response by releasing proinflammatory cytokines. In addition, macrophages are suggested to primarily secrete enzymes (lipase specifically) to erode the PTMC bulk extracellularly as inhibiting their activity effectively prevented this eroding process. The clarification of the biodegradation mechanism in this work suggests that the degradation of PTMC highly depends on the foreign body response. Thus, it reminds the researchers to consider the effect of the microenvironment on the degradation and drug release of PTMC-based implantation devices and localized drug delivery systems.

SAV Nsp2 regulates NF-κB signaling to induce inflammatory responses by targeting host DDX3

Salmon alphavirus (SAV) infection leads to severe pancreas disease (PD) with typical inflammatory responses in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). Nsp2, an important nonstructural protein of SAV, can activate NF-κB signaling pathway to reduce inflammatory responses. However, the molecular mechanism remains unclear. In this study, the ML (279-421aa) of Nsp2 was revealed to be the key domain for activating NF-κB. We focused on a host protein, DEAD-box RNA helicase 3 (DDX3), that may interact with Nsp2 to regulate NF-κB-induced inflammatory. The interaction between DDX3 and Nsp2 was confirmed in vitro. Overexpression of DDX3 inhibited the activation of NF-κB by Nsp2. SAV Nsp2 relieves the inhibitory effect of DDX3 on NF-κB, thereby initiating the innate immune response. This study revealed the molecular mechanism of Nsp2-induced inflammatory response by targeting DDX3 to activate NF-κB, providing a theoretical basis for revealing the underlying infection mechanism and pathogenesis of SAV.

Hyperglycemia remission after Roux-en-Y gastric bypass: Implicated to altered monocyte inflammatory response in type 2 diabetes rats

Hyperglycemia remission by metabolic surgery is implicated in the resolution of low-grade inflammation in type 2 diabetes mellitus (T2DM). However, whether this beneficial effect of metabolic surgery is related to improving monocyte inflammatory response remains undefined. This investigation is addressed to evaluate this relationship. For this purpose, T2DM rats were subjected to Roux-en-Y gastric bypass (RYGB) and/or monocyte depletion or splenic sympathetic denervation. Fasting blood glucose (FBG), plasma tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were measured, and monocyte inflammatory response was assessed in vitro. The data showed that RYGB significantly reduced lipopolysaccharide (LPS)-induced release of TNF-α and IL-1β from peripheral monocytes while alleviating hyperglycemia and reducing plasma TNF-α and IL-1β levels. Hyperglycemia resulting from monocyte depletion by injection of clodronate liposomes resolved one week earlier than vehicle control after RYGB. Splenic denervation abrogated the glucose-lowering effect and decreased LPS-stimulated TNF-α and IL-1β release from monocytes following RYGB. Overall, our results reveal that a marked reduction of monocyte inflammatory response after RYGB contributes to hyperglycemia remission in T2DM rats. The beneficial effect of RYGB is mediated through vagal-spleen axis anti-inflammatory activity.

Changes of macrophage and CD4+ T cell in inflammatory response in type 1 diabetic mice

Immune cells play an important role in the development of inflammation in type 1 diabetes mellitus, so we want to explore the changes of CD4+ T cells and macrophages in vivo, which can provide an experimental basis for immunotherapy based on CD4+ T cells and macrophages. The intraperitoneal injection of streptozocin was used to induce a type 1 diabetes mellitus mouse model; the blood glucose, body weight, and the expression of inflammatory factors in the kidney were measured. Immunohistochemistry was applied to determine and analyze the infiltration of CD4+ T cells and macrophages in the spleen, pancreas, and kidney. The subtypes of macrophages in the kidney and CD4+ T cells in the spleen were analyzed by flow cytometry. Our study suggests that CD4+ T cells and macrophages increase, while the inflammatory immune response system is activated in the development of T1DM. CD4+ T cells positively correlated with macrophages in the pancreas and kidney of T1DM. CD4+ T cells turn to pro-inflammatory subtypes in the spleen of T1DM, while macrophages turn to pro-inflammatory subtypes in the kidney of T1DM. Therefore, regulation of CD4+ T cells and macrophages may be a potential target for T1DM and kidney complications.

Salmonid alphavirus non-structural protein 2 is a key protein that activates the NF-κB signaling pathway to mediate inflammatory responses

Salmonid alphavirus (SAV) infection of Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) causes pancreas disease (PD) with typical inflammatory responses, such as necrosis of the exocrine pancreas, cardiomyopathy and skeletal myopathy. However, the pathogenic mechanism underlying SAV infection is still unclear. Inflammation may cause damage to the body, but it is a defense response against infection by pathogenic microorganisms, of which nuclear factor-kappa B (NF-κB) is the main regulator. This study revealed that SAV can activate NF-κB, of which the viral nonstructural protein Nsp2 is the major activating protein. SAV activates the NF-κB signaling pathway by simultaneously up-regulating TLR3, 7, 8 and then the expression of the signaling molecule myeloid differentiation factor 88 (Myd88) and tumor necrosis factor receptor-associated factor 6 (TRAF6). We found that Nsp2 can induce IκB degradation and p65 phosphorylation and transnucleation, and activate NF-κB downstream inflammatory cytokines. Nsp2 may simultaneously activate NF-κB through TLR3,7,8-dependent signaling pathways. Overexpression of Nsp2 can up-regulate mitochondrial antiviral signaling protein (MAVS) and then promote the expression of IFNa1 and antiviral protein Mx, which inhibits viral replication. This study shows that Nsp2 acts as a key activator protein for the NF-κB signaling pathway, which induces inflammation post-SAV infection. This study systematically analyzes the molecular mechanism of SAV activation of the NF-κB signaling pathway, and provides a theoretical basis for revealing the mechanism of innate immune response and inflammatory injury caused by SAV.

011 A new immunocompetent skin model recapitulates molecular features of psoriasis

Psoriasis is a chronic inflammatory skin disease involving interactions between keratinocytes and both the innate and adaptive immune systems. The IL-17/IL-23 axis is described to drive the release of inflammatory and immune factors in keratinocytes (cytokines, antimicrobial peptides, chimiokines), which sit at the heart of an inflammation amplification loop. To this date, there are very few immunocompetent models recapitulating as close as possible psoriatic skin. In this context, the aim of this work was to develop a 3D model of psoriatic lesional skin summarizing biological features of the pathology. As the dialogue between Th17 lymphocytes (LTh17) and keratinocytes plays a central role in psoriasis pathogenesis, a model taking into account these two biological actors was developed. A reconstructed epidermis (RE) was co-cultured with differentiated LTh17. RE morphology as well as proliferation/differentiation imbalance and inflammatory immune response were explored. As it is reported in psoriatic lesions, results showed that IL-17 family cytokines were increased. Histological analysis demonstrated that the psoriatic mimic epidermis exhibited morphological changes. Moreover, mechanisms of proliferation and differentiation appeared profoundly altered while a high keratinocyte inflammatory response characteristic of psoriasis was observed. In conclusion, we have succeeded in designing a 3D in vitro model reproducing molecular alterations of psoriatic skin. The co-culture of the RE with differentiated LTh17 led to a typical inflammatory response in keratinocytes, thus proving the successful communication of the two biological compartments. This physiological relevant model is suitable for the assessment of natural therapeutic molecules dedicated to psoriasis treatment.

Cartilage debris and osteoarthritis risk factors influence gene expression in the synovium in end stage osteoarthritis

BackgroundGene expression in healthy synovium remains poorly characterised. Thus, synovial functional activity changes associated with osteoarthritis (OA) are difficult to define. This study sought to identify differentially expressed genes (DEG) of end-stage OA and assess the influence of OA risk factors on these DEG. MethodsAnonymised patient clinical data and x-ray images were analysed. Osteoarthritic and non-osteoarthritic patients with soft tissue or traumatic knee injuries were matched for body mass index (BMI) and sex. Tissue samples were partitioned for immunocytochemistry (IHC) and microarray analysis. Multiple bioinformatics applications were utilised to determine changes in functional and canonical pathway activation. ResultsAge, disease-modifying injections and hypertension were confounding factors between patient groups. Inflammation was present in all tissues. Cartilage debris and inflammatory aggregates were noted in many osteoarthritic patient tissues. IHC and expression analyses revealed upregulation of synoviolin 1 (SYVN1) in osteoarthritic synovium. Significant differential expression was noted in 2084 genes. Osteoarthritic synovium displayed a significant upregulation of 95% of DEG coding for proteins, relative to non-osteoarthritic synovium tissues. Unfolded protein response (UPR)-related genes were upregulated in osteoarthritic synovium; gene expression of molecules within many canonical pathways including protein ubiquitination and UPR pathways was modified by BMI and sex. ConclusionsThe synovium of all three pathologies exhibited elements of an inflammatory response. Cartilage debris, age, BMI and sex influence DEG of osteoarthritic synovium. UPR pathway is the top deregulated canonical pathway identified in osteoarthritic synovium regardless of BMI and sex, while typical OA-associated inflammatory and matrix gene responses were minimal.

An Alternative "Trojan Horse" Hypothesis for COVID-19: Immune Deficiency of IL-10 and SARS-CoV-2 Biology.

The coronavirus disease 2019 (COVID-19) pandemic has been a challenge for emergency care units worldwide due to the large numbers of patients, the scarcity of information, the medical resources, and the uncertainty regarding the disease's etiology and pathogenesis. The transmission of the virus and a probable post-pandemic of SARS-CoV-2 will depend on how deep this disease, the duration of immunity and the degree of cross immunity between SARS-CoV-2 and other pathogens either bacteria or fungi can be understood. Most mortalities have been related to an atypical pneumonia consisted of a sudden worsening of general condition of the admitted positive COVID-19 patients. The severe thromboembolism, often characterized by violent pulmonary and systemic complications, have been described with a blend of inflammatory-infectious patterns that rapidly shifted into a typical systemic inflammatory response syndrome (SIRS) or into an acute respiratory distress syndrome (ARDS) that eventually concluded into a multi-organ failure (MOF) and death. The fatality rate reported in our Covid-19 structure, SG Moscati Hospital of Taranto province in Italy, was higher in elderly male people with preexisting chronic pulmonary disease (COPD), patients with cancer and preexisting cardio-vascular diseases (CVD). We assumed a different theoretical position to clarify the higher mortality seen among those patients that was not as obvious as it appeared, we thus offered different pathophysiological picture that could help to recent solutions in therapy and prevention.

Apela inhibits systemic and renal inflammatory reactions in mice with type I cardiorenal syndrome.

This study investigated the effect of apela on renal function and anti-inflammatory effect on whole body and kidney tissue in mice with type I cardiorenal syndrome (CRS). The murine type I CRS model was established and apela was subcutaneously infused for two weeks. Cardiac and renal functions were evaluated by echocardiography and blood biochemistry, respectively. The systemic and renal inflammatory responses were examined with molecular biological and histological methods. Human renal glomerular endothelial cells (RGECs) were used to evaluate the adhesion effect of monocytes in vitro. Compared to mice from the control group (CRS + vehicle), the plasma levels of N-terminal pro-brain natriuretic peptide, blood urea nitrogen and creatinine were significantly decreased, while the mean left ventricular ejection fraction was increased in apela-treated CRS mice at the 4th week. The expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the circulation and kidney was decreased in apela-treated mice compared with control mice, and apela improved cardio-renal pathology in mice with type I CRS. Additionally, Apela significantly suppressed the expression of MCP-1, TNF-α, intercellular adhesion molecule-1 and vascular intercellular adhesion molecule-1 in RGECs induced by angiotensin II (Ang II), and inhibited the promoting effect of Ang II on the adhesion of THP-1 cells to RGECs. Western blot results showed that the expression of phosphorylated nuclear factor kappa B (phospho-NFκB) in CRS mice was increased, but the expression of phospho-NFκB was down-regulated after apela treatment. Furthermore, apela significantly inhibited the Ang II-mediated increase in phospho-NFκB expression in RGECs in vitro, but the administration of an apelin peptide jejunum receptor (APJ) inhibitor blocked the inhibitory effect of apela. This study revealed that apela improves cardiorenal function and reduces systemic and renal inflammatory response in type I CRS mice and the apela/APJ system may alleviate renal inflammatory responses by inhibiting the NFκB signalling pathway.

Efficacy of SPG-ODN 1826 Nanovehicles in Inducing M1 Phenotype through TLR-9 Activation in Murine Alveolar J774A.1 Cells: Plausible Nano-Immunotherapy for Lung Carcinoma.

Alveolar macrophages are the first line of defense against intruding pathogens and play a critical role in cancer immunology. The Toll-like receptor (TLR) family mediates an important role in recognizing and mounting an immune response against intruding microbes. TLR-9 is a member of the intracellular TLR family, which recognizes unmethylated CG motifs from the prokaryotic genome. Upon its activation, TLR-9 triggers downstream of the MyD-88-dependent transcriptional activation of NF-κB, and subsequently results in abundant inflammatory cytokines expression that induces a profound inflammatory milieu. The present exploratory investigation aimed at elucidating the potency of schizophyllan for entrapping ODN 1826 (SPG-ODN 1826)-mediated stimulation of TLR-9 in provoking an inflammatory-type response in murine alveolar macrophages. Schizophyllan (SPG), a representative of the β-glucan family, was used in the present study as a nanovehicle for endosomal trafficking of CpG ODN 1826. TEM analysis of SPG-ODN 1826 nanovehicles revealed that the prepared nanovehicles are spherical and have an average size of about 100 nm. Interestingly, SPG-ODN 1826 nanovehicles were competent in delivering their therapeutic payload within endosomes of murine alveolar macrophage (J774A.1) cells. Exposure of these nanovehicles within LPS stimulated J774A.1, resulted in a significant provocation of reactive oxygen species (ROS) (p < 0.01) in comparison to CpG ODN 1826 alone. Moreover, the formulated nanovehicles succeeded in generating a profound Th1-based cytokine profile constituted by enhanced expression of IFN-γ (p < 0.001) and IL-1β (p < 0.001) inflammatory cytokines. These findings clearly indicated the immunostimulatory potential of SPG-ODN 1826 nanovehicles for inducing the Th1-type phenotype, which would certainly assist in skewing M2 phenotype into the much-desired M1 type during lung cancer.

A New Dermal Substitute Containing Polyvinyl Alcohol with Silver Nanoparticles and Collagen with Hyaluronic Acid: In Vitro and In Vivo Approaches.

The experimental use of poly (alcohol-vinyl) (PVA) as a skin curative is increasing widely. However, the use of this hydrogel is challenging due to its favorable properties for microbiota growth. The association with silver nanoparticles (AgNPs) as an antimicrobial agent turns the match for PVA as a dressing, as it focuses on creating a physical barrier to avoid wound dehydration. When associated with extracellular components, such as the collagen matrix, the device obtained can create the desired biological conditions to act as a skin substitute. This study aimed to analyze the anti-microbiological activity and the in vitro and in vivo responses of a bilaminar device of PVA containing AgNPs associated with a membrane of collagen–hyaluronic acid (col-HA). Additionally, mesenchymal stem cells were cultured in the device to evaluate in vitro responses and in vivo immunomodulatory and healing behavior. The device morphology revealed a porous pattern that favored water retention and in vitro cell adhesion. Controlled wounds in the dorsal back of rat skins revealed a striking skin remodeling with new epidermis fulfilling all previously injured areas after 14 and 28 days. No infections or significant inflammations were observed, despite increased angiogenesis, and no fibrosis-markers were identified as compared to controls. Although few antibacterial activities were obtained, the addition of AgNPs prevented fungal growth. All results demonstrated that the combination of the components used here as a dermal device, chosen according to previous miscellany studies of low/mid-cost biomaterials, can promote skin protection avoiding infections and dehydration, minimize the typical wound inflammatory responses, and favor the cellular healing responses, features that give rise to further clinical trials of the device here developed

Hyperforin Ameliorates Imiquimod-Induced Psoriasis-Like Murine Skin Inflammation by Modulating IL-17A-Producing γδ T Cells.

Hyperforin is a major active constituent of Hypericum perforatum L. extract, which is widely used for the treatment of depressive disorders. Recent studies have reported that hyperforin reduced inflammation in stroke and suppressed proliferation and differentiation in keratinocytes. Psoriasis is a chronic immune-mediated inflammatory skin disease in which the IL-23/IL-17 axis plays an important role. To investigate the underlying inflammatory mechanisms and response of hyperforin in psoriasis, we use imiquimod (IMQ)-induced mice model, in vitro cultured murine splenic γδ T cells, and HaCaT cells in this study. Data showed that hyperforin reduced epidermal thickness and decreased IMQ-induced pathological scores of cutaneous skin lesions in mice. Meanwhile we proved that hyperforin suppressed infiltration of CD3+ T cells and downregulated expression of Il1, Il6, Il23, Il17a, Il22, antimicrobial peptides (AMPs) in the skin lesion. Hyperforin significantly inhibited imiquimod-induced splenomegaly, reduced serum levels of TNF-α and IL-6, and IL-17A in splenocytes and draining lymph nodes. Our study also suggested that hyperforin lessened the infiltration of γδ T cell and CCR6+ γδ T cells in spleen and lymph nodes. Hyperforin also suppressed the typical psoriasis-like inflammatory responses and the infiltration of IL-17A+ cells in dermal γδ T cells of IMQ treated Tcrd −/− mice transferred with γδ T cells. In vitro studies, hyperforin reduced the expression and secretion of IL-17A in γδ T cells, and suppressed the activation of MAPK/STAT3 pathways in human keratinocyte HaCaT cells and γδ T cells. In conclusion, hyperforin alleviates IMQ-induced inflammation in psoriasis through suppressing the immune responses exerted by IL-17 A-producing γδ T cells and related cytokines by modulating MAPK/STAT3 pathways. Our study provided a novel therapeutic tragedy for psoriasis by which hyperforin attenuates psoriasis-related inflammatory responses.

Microglial mTOR is Neuronal Protective and Antiepileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy.

Excessive activation of mammalian target of rapamycin (mTOR) signaling is epileptogenic in genetic epilepsy. However, the exact role of microglial mTOR in acquired epilepsy remains to be clarified. In the present study, we found that mTOR is strongly activated in microglia following excitatory injury elicited by status epilepticus. To determine the role of microglial mTOR signaling in excitatory injury and epileptogenesis, we generated mice with restrictive deletion of mTOR in microglia. Both male and female mice were used in the present study. We found that mTOR-deficient microglia lost their typical proliferative and inflammatory responses to excitatory injury, whereas the proliferation of astrocytes was preserved. In addition, mTOR-deficient microglia did not effectively engulf injured/dying neurons. More importantly, microglial mTOR-deficient mice displayed increased neuronal loss and developed more severe spontaneous seizures. These findings suggest that microglial mTOR plays a protective role in mitigating neuronal loss and attenuating epileptogenesis in the excitatory injury model of epilepsy.SIGNIFICANCE STATEMENT The mammalian target of rapamycin (mTOR) pathway is strongly implicated in epilepsy. However, the effect of mTOR inhibitors in preclinical models of acquired epilepsy is inconsistent. The broad presence of mTOR signaling in various brain cells could prevent mTOR inhibitors from achieving a net therapeutic effect. This conundrum has spurred further investigation of the cell type-specific effects of mTOR signaling in the CNS. We found that activation of microglial mTOR is antiepileptogenic. Thus, microglial mTOR activation represents a novel antiepileptogenic route that appears to parallel the proepileptogenic route of neuronal mTOR activation. This may explain why the net effect of mTOR inhibitors is paradoxical in the acquired models of epilepsy. Our findings could better guide the use of mTOR inhibitors in preventing acquired epilepsy.

Could COVID-19 have an impact on male fertility?

The pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to several hypotheses of functional alteration of different organs. The direct influence of this virus on the male urogenital organs is still to be evaluated. However some hypotheses can already be made, especially in the andrological field, for the biological similarity of the SARS‐CoV and SARS‐CoV2. As well as SARS‐CoV, SARS CoV‐2 uses the ‘Angiotensin Converting Enzyme‐2’ (ACE2) as a receptor to enter human cells. It was found that ACE2, Angiotensin (1‐7) and its MAS receptors are present, over in the lung, also in the testicles, in particular in Leydig and Sertoli cells. A first hypothesis is that the virus could enter the testicle and lead to alterations in testicular functionality. A second hypothesis is that the binding of the virus to the ACE2 receptor, could cause an excess of ACE2 and give rise to a typical inflammatory response. The inflammatory cells could interfere with the function of Leydig and Sertoli cells. Both hypotheses should be evaluated and confirmed, in order to possibly monitor fertility in patients COVID‐19+.