Abstract Histoplasma capsulatum (Hc) is a dimorphic fungus that is affected by environmental temperature. Hc is distributed worldwide. When inhaled, the microconidia and spores reach the lung and are converted to the pathogenic yeast phase within the phagosomes of macrophages. The Hc replicates intracellularly until these phagocytes are activated by cytokines, typically from activated T cells. Excluding iron, the effect of trace metals on Hc interaction with innate immune cells has been inadequately studied. The cells’ metabolic processes are altered, and the cytokine macro/microenvironment change in the pathogen’s face. Zn2+ metalloproteins constitute about 10% of the mammalian proteome, and many transcription factors and enzymes use this metal. Metalloproteins are linked to many energy-producing pathways, including carbohydrate metabolism, amino acid metabolism, and the redox chain. Our experiments showed that ablation of Metallothioneins 1 and 2 (MT1/2) decreases the immune system’s ability to clear Hc from the lungs. The numbers of T cells are not affected by the MT1/2 ablation; rather, the cells’ activity is decreased. MT1/2 ablated dendritic cells (DC) are not defective. MT1/2 ablated CD4 T cells show an alternative metabolic profile. MT1/2 ablated CD4 T cells show a decrease in their genome acetylation.

The current work aimed to synthesize selenium and zinc nanoparticles using the aqueous extract of Ephedra aphylla as a valuable medicinal plant. The prepared nanoparticles were characterized by TEM, zeta potential, and changes in the phytochemical constituents. Hence, the phenolic, flavonoid, and tannin contents were reduced in the case of the prepared samples of nanoparticles than the original values in the aqueous extract. The prepared extract of Ephedra aphylla and its selenium and zinc nanoparticles showed high potency as antioxidant agents as a result of the DPPH• assay. The samples were assessed as anticancer agents against six tumor cells and a normal lung fibroblast (WI-38) cell line. The selenium nanoparticles of Ephedra aphylla extract revealed very strong cytotoxicity against HePG-2 cells (inhibitory concentration (IC50) = 7.56 ± 0.6 µg/mL), HCT-116 cells (IC50 = 10.02 ± 0.9 µg/mL), and HeLa cells (IC50 = 9.23 ± 0.8 µg/mL). The samples were evaluated as antimicrobial agents against bacterial and fungal strains. Thus, selenium nanoparticles showed potent activities against Gram-negative strains (Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli), Gram-positive strains (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus, and Staphylococcus epidermidis), and the fungal strain Candida albicans. In conclusion, the preparation of nanoparticles of either selenium or zinc is crucial for improved biological characteristics.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus causing respiratory disease commonly known as COVID-19. This novel coronavirus transmits from human to human and has caused profound morbidity and mortality worldwide leading to the ongoing pandemic. Moreover, disease severity differs considerably from individual to individual. Investigating the virology of COVID-19 and immunological pathways underlying its clinical manifestations will enable the identification and design of effective vaccines and potential therapies. In this review, we explore COVID-19 virology, the contribution of the immune system (innate and adaptive) during infection and control of the virus. Finally, we highlight vaccine development and implications of immune system modulation for potential therapeutic interventions to design better therapeutic strategies to guide future cure.

Regulatory B cells (Bregs) are unique subpopulations of B cells with immune-regulating or immune-suppressing properties and play a role in peripheral tolerance. Due to the current limitations of human Breg studies among periodontal diseases, in the present study, we tried to analyze the change in circulating Bregs, pro-inflammatory, and anti-inflammatory cytokines in patients with periodontitis. Peripheral blood from 55 patients with stage 2 periodontitis and 20 healthy controls was analyzed using flow cytometry to evaluate the frequency of CD19+CD24+CD38+ Breg cells. ELISA was used to assess the serum levels of the pro-inflammatory cytokines, including interleukins (IL)-1β, IL-6, TNF-α, and anti-inflammatory cytokines including IL-10, IL-35, and TGF-β. Increased proportions of Breg cells were observed in patients with stage 2 periodontitis compared to controls. Serum levels of cytokines were significantly higher in patients with periodontitis compared to controls. A significant positive correlation was observed between the frequencies of Breg cells and IL35 levels, IL10 levels, and TGF-β. In conclusion, our results suggest that the increase in peripheral Breg cells and serum cytokine levels among periodontitis patients seems to be closely associated with disease progression, a possible link between periodontitis, and systemic inflammatory process.

Background: Sodium valproate (VPA) is an antiepileptic drug (AED) licensed for epilepsy and used during pregnancy in various indications. Alpha-lipoic acid (ALA) is a natural compound inducing endogenous antioxidant production. Our study aimed to investigate the effect of prenatal administration of VPA on the pancreas of rat offspring and assess the potential protective role of ALA co-administration during pregnancy. Methods: Twenty-eight pregnant female albino rats were divided into four groups: group I (negative control), group II (positive control, ALA treated), group III (VPA-treated), and group IV (VPA-ALA-treated). The pancreases of the rat offspring were removed at the fourth week postpartum and prepared for histological, immune-histochemical, morphometric, molecular, and oxidative stress marker studies. Results: In group III, there were pyknotic nuclei, vacuolated cytoplasm with ballooning of acinar, α, and β cells of the pancreas. Ultrastructural degeneration of cytoplasmic organelles was detected. Additionally, there was a significant increase in oxidative stress, a decrease in insulin-positive cell percentage, and an increase in glucagon positive cells in comparison to control groups. Moreover, VPA increased the gene expression of an apoptotic marker, caspase-3, with a decrease in anti-apoptotic Bcl2 and nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional factor. Conversely, ALA improved oxidative stress and apoptosis in group VI, and a consequent improvement of the histological and ultrastructure picture was detected. Conclusion: ALA co-administration with VPA significantly improved the oxidative stress condition, histological and morphometric picture of the pancreas, and restored normal expression of related genes, including Nrf2, caspase-3, and Bcl-2. Administration of α-lipoic acid has a protective effect against VPA-induced pancreatic oxidative damage via its cytoprotective antioxidant effect.

Background and aim: CD10 is expressed in urothelial carcinoma cells and cancer associated fibroblasts (CAF). In the current study, CD10 immunohistochemical staining (IHC) and CD10 mRNA expression in urothelial carcinoma of bladder (UCB) were assessed, and its relationship with tumor progression and prognosis was investigated. Patients and Methods: In this study, 106 formalin fixed paraffin-embedded (FFPE) tissue of UCB, obtained through radical cystectomy specimen, and 10 matched normal tissue samples were included.CD10 expression was evaluated by immunohistochemistry and real time PCR techniques. Results: CD10 expression in tumor cells and associated stromal fibroblasts was significantly associated with high tumor grade and advanced stage. Significant correlation was found between CD10 tumor expression and lymphovascular invasion (LVI) (P<0.001) as well as perineural invasion (PNI). CD10 expression in stromal fibroblasts was significantly associated with squamous differentiation of tumor cells, lymph node metastasis (LNM), and tumor necrosis. Positive CD10 expression in both tumor cells and associated stromal fibroblasts was associated with shorter OS . CD10 mRNA was overexpressed in tumors in comparison with the matched normal tissues. CD10 mRNA was significantly higher in invasive tumor, advanced stage tumor, and high grade tumor. There was significant correlation between CD10 mRNA tumor expression and LVI, PNI, and tumor recurrence. Conclusion: Increased expression of CD10 in the tumor and CAF was strongly correlated with tumor progression, invasion, metastasis, shorter OS, and RFS in urothelial carcinoma patients. CD10 mRNA showed significantly higher expression in tumor tissue than in matched normal tissue. CD10 mRNA was associated with depth of invasion, TNM stage, tumor grade, vascular tumor invasion, and tumor recurrence.

Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function. MT3 was requisite for metabolic reprograming in IL-4-stimulated macrophages or M(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1α activation, and thwarted the emergence of a proinflammatory M1 program in macrophages. MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon γ (IFNγ) responsiveness and a dampened M(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M(IL-4) macrophages.

Hepatocellular carcinoma (HCC) is the commonest primary liver neoplasm that usually develop in the background of cirrhosis. Hepatitis C virus is endemic in Egypt and is the major cause of cirrhosis. Studying the characteristics of patients with HCC may help in clarifying the schedule for screening of high-risk patients for an early detection of HCC. The 492 patients attending the hepatology and HCC clinics in Specialized Medical Hospital, Mansoura University for follow up of liver cirrhois and HCC were subjected to full history, physical examination, laboratory profile, and imaging studies needed for the diagnosis. Data were collected and analyzed. According to the radiological results, patients were divided into three groups (fibrosis, cirrhosis, and HCC) and compared. The study included 336 males and 156 females. Patients with HCC were mainly males with a mean age of 58 years. A statistically significant difference between HCC group and the other groups with respect to hemoglobin level, white blood cells count, platelet count, aspartate aminotransferase, alanine aminotransferase, albumen level, serum bilirubin, international normalized ratio, and α-fetoprotein (AFP) was found. The sensitivity and specificity of AFP in differentiating HCC cases are 81.1 and 71.9%, respectively. Logistic regression for prediction of HCC showed that males with age greater than 58 years, hypoalbuminaemia, and AFP greater than 11.2 ng/dl have a 76.3% positive predicted value. Cirrhotic patients with age greater than 58 years, males, hypoalbuminaemia, and AFP greater than 11.2 ng/dl are at a higher risk to develop HCC more than other patients and should be monitored at close quarters with better contrast-enhanced technique either contrast-enhanced ultrasound or computed tomography scan.

Objective: Identification of new molecular markers to enhance early diagnosis, prognosis and/or treatment of hepatocellular carcinoma (HCC) is a need. TOM34 (34 kDa-translocase of the outer mitochondrial membrane) protein expression deregulation has demonstrated to be involved in the growth of many cancers. Here, we aimed at evaluating serum TOM34 and some heat shock proteins (HSPA4, HSPA1B, and HSP90AA1) expressions in hepatitis C virus (HCV)-related cirrhosis and HCV-induced HCC relative to controls and correlating these expressions to the clinicopathological data. Methods: Serum specimens were collected from 90 patients with HCV associated complications (30 cirrhotic, 30 early HCC and 30 late HCC) and 60 controls. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed for relative quantification of the four target genes using the Livak method. In silico network analysis was also executed to explore the contribution of the genes in liver cancer. Results: The serum TOM34 and HSP90AA1 transcripts were significantly upregulated in HCC patients compared to cirrhotic ones with more up-regulation in late HCC patients. Receiver operating characteristic analysis showed the optimum cutoff value of 0.625 corresponding to 71.7% sensitivity and 56.7% specificity, and an area under the curve (AUC) of 0.705 to discriminate HCC from cirrhotic groups (P = .002). In multivariate analysis, ordination plot showed obvious demarcation between the study groups caused by the higher levels of TOM34 among other variables. Conclusions: TOM34 and its partner HSP90AA1 might be used as a potential biomarker for monitoring HCV-induced HCC progression in the Egyptian population. Future large-scale validation studies are warranted.

F „Eine krankhafte und sehr komplexe Immunreaktion der Haut“ – so beschreiben Ärzte und Wissenschaftler die Psoriasis. Zu ihren charakteristischen Merkmalen gehört eine beschleunigte Zellteilung in den oberen Hautschichten mit einer Vermehrung von Hautzellen und einer Entzündung der darunterliegenden Haut. In dem komplexen Geschehen spielen neben Keratinozyten auch verschiedene Zellen des Immunsystems – unter anderem T-Lymphozyten, Makrophagen, Mastzellen und andere mehr – eine Rolle.

Nature Communications 7 Article number: 11724 doi: 10.1038/ncomms11724(2016); Published: 25 May 2016; Updated: 2 August 2016. The affiliation details for Amiya K. Patra are incomplete in this Article. The correct affiliations are given below: Institute of Translational and Stratified Medicine, Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK.

In peripheral lymphocytes, the transcription factors (TFs) NF‐κB, NFAT, and AP‐1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF‐κB factors share several properties, such as a similar mode of induction and architecture in their DNA‐binding domain, and there is a subgroup of κB‐like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP‐1 factors that interact and collaborate in binding to DNA, NFAT, and NF‐κB seem neither to interact nor to collaborate. We show here that NF‐κB1/p50 and c‐Rel, the most prominent NF‐κB proteins in BCR‐induced splenic B cells, control the induction of NFATc1/αA, a prominent short NFATc1 isoform. In part, this is mediated through two composite κB/NFAT‐binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/αA by BCR signals. In concert with coreceptor signals that induce NF‐κB factors, BCR signaling induces a persistent generation of NFATc1/αA. These data suggest a tight connection between NFATc1 and NF‐κB induction in B lymphocytes contributing to the effector function of peripheral B cells.