Physiology of Immune System: Regulation of Stem Cell Survival

The immune system is a complex defense mechanism, able to protect the body against pathogens. It consists of a network of cells, tissues, and organs that work together to protect the body. Leukocytes are key operatives of the immune system. Cells destined to become immune cells, like all blood cells, arise in your body's bone marrow from stem cells (HSC). A large body of evidence show the transcription factors play critical roles in the homeostasis of T cells, B cells, neutrophils and other non-lymphoid leneages. This review discusses the role of the Smek (Suppressor of mek null) gene, that acts in the stress response pathway of animals by binding to and enhancing the transcription of FoxO transcription factors. Furthermore, the review deals with tachykinins, involved in neurotransmission and immune/hematopoietic modulation. Both molecules, objects of recent patents, may have real therapeutic potential

BAG3 protects Bovine Papillomavirus type 1-transformed equine fibroblasts against pro-death signals

In human cancer cells, BAG3 protein is known to sustain cell survival. Here, for the first time, we demonstrated the expression of BAG3 protein in equine sarcoids in vivo as well as in an in vitro model of sarcoid-derived equine fibroblasts. Evidence of a possible involvement of BAG3 in equine sarcoid carcinogenesis was obtained by immunohistochemistry analysis of tumour samples. We found that the most of tumour samples stained positive for BAG3, even though to a different grade, while normal dermal fibroblasts from a healthy horse displayed very weak staining pattern for BAG3 expression. By siRNA technology, we demonstrated the role of BAG3 in counteracting basal as well as chemical-triggered pro-death signals. BAG3 down-modulation in EqSO4b, a sarcoid-derived fully transformed cell line harbouring bovine papilloma virus (BPV)-1 genome, promotes cell death and cell cycle arrest in G0/G1. In addition, we found that BAG3 silencing sensitized cells to phenethylisothiocyanate (PEITC), a promising cancer chemopreventive/chemotherapeitic agent present in edible cruciferous vegetables. Notably, such a pro-survival role of BAG3 was less relevant in E.Derm cells, taken as normal counterpart, thus suggesting a mutual cooperation between BAG3 and viral oncoproteins to sustain cell survival

BAG3 Protein: Role in Some Neoplastic Cell Types and Identification as a Candidate Target for Therapy

Neoplasia pathogenesis and resistance to therapy are largely determined by acquired resistance to apoptosis. Among apoptosis- regulating molecules, a role is emerging for BAG3, a member of the BAG co-chaperone protein family. Through its bag, WW and prolix-rich domains, BAG3 protein can interact with a variety of molecular partners, including Hsc70/Hsp70, phospholipase C- gamma and others. It has been recently shown that, in human primary lymphoid and myeloblastic leukemias, thyroid carcinoma and other human tumours, BAG3 expression sustains cell survival and impairs cell response to therapy. Here we summarize findings that assign to BAG3 an anti-apoptotic role in some neoplastic cell types, in addition to other biological activities, and identify the protein as a candidate target of therapy

BAG3 Protein Is Involved in Endothelial Cell Response to Phenethyl Isothiocyanate

Phenethyl isothiocyanate (PEITC), a cruciferous vegetable-derived compound, is a versatile cancer chemopreventive agent that displays the ability to inhibit tumor growth during initiation, promotion, and progression phases in several animal models of carcinogenesis. In this report, we dissect the cellular events induced by noncytotoxic concentrations of PEITC in human umbilical vein endothelial cells (HUVECs). In the early phase, PEITC treatment elicited cells’ morphological changes that comprise reduction in cell volume and modification of actin organization concomitantly with a rapid activation of the PI3K/Akt pathway. Downstream to PI3K, PEITC also induces the activity of Rac1 and activation of c-Jun N-terminal kinase (JNK), well-known regulators of actin cytoskeleton dynamics. Interestingly, PEITC modifications of the actin cytoskeleton were abrogated by pretreatment with JNK inhibitor, SP600125. JNK signaling led also to the activation of the c-Jun transcription factor, which is involved in the upregulation of several genes; among them is the BAG3 protein. This protein, a member of the BAG family of heat shock protein (Hsp) 70 cochaperones, is able to sustain survival in different tumor cell lines and neoangiogenesis by directly regulating the endothelial cell cycle. Furthermore, BAG3 is involved in maintaining actin folding. Our findings indicate that BAG3 protein expression is induced in endothelial cells upon exposure to a noncytotoxic concentration of PEITC and its expression is requested for the recovery of normal cell size and morphology after the stressful stimuli. This assigns an additional role for BAG3 protein in the endothelial cells after a stress event

BAG3 Protein Is Over-Expressed in Endometrioid Endometrial Adenocarcinomas

Endometrioid endometrial cancer is the most common gynaecological tumor in developed countries, and its incidence is increasing. The definition of subtypes, based on clinical and endocrine features or on histopathological characteristics, correlate to some extent with patient's prognosis, but there is substantial heterogeneity within tumor types. The search for molecules and mechanisms implied in determining the progression and the response to therapy for this cancer is still ongoing. BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumor types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby, modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. BAG3 expression in human endometrial cancer tissues was not investigated so far. Here, we show that BAG3 protein levels are elevated in tumoral and hyperplastic cells in respect to normal glands. Furthermore, BAG3 subcellular localization appears to be changed in tumoral compared to normal cells. Our results indicate a possible role for BAG3 protein in the maintenance of cell survival in endometrioid endometrial cancer and suggest that this field of studies is worthy of further investigations. J. Cell. Physiol. 232: 309–311, 2017. © 2016 Wiley Periodicals, Inc

miR-29b and miR-198 overexpression in CD8+ T cells of renal cell carcinoma patients down-modulates JAK3 and MCL-1 leading to immune dysfunction

Background: Mammalian microRNAs (miR) regulate the expression of genes relevant for the development of adaptive and innate immunity against cancer. Since T cell dysfunction has previously been reported in patients with renal cell carcinoma (RCC; clear cell type), we aimed to analyze these immune cells for genetic and protein differences when compared to normal donor T cells freshly after isolation and 35 days after in vitro stimulation (IVS) with HLA-matched RCC tumor cells. Methods: We investigated gene expression profiles of tumor-reactive CD8(+) T cells obtained from RCC patient and compared with their HLA-matched healthy sibling donors using a microarray approach. In addition, miRNAs analysis was performed in a validation cohort of peripheral blood CD8(+) T cells from 25 RCC patients compared to 15 healthy volunteers. Results: We observed that CD8(+) T cells from RCC patients expressed reduced levels of anti-apoptotic and proliferation-associated gene products when compared with normal donor T cells both pre- and post-IVS. In particular, JAK3 and MCL-1 were down-regulated in patient CD8(+) T cells versus their normal counterparts, likely due to defective suppressor activity of miR-29b and miR-198 in RCC CD8(+) T cells. Indeed, specific inhibition of miR-29b or miR-198 in peripheral blood mononuclear cells (PBMCs) isolated from RCC patients, resulted in the up-regulation of JAK3 and MCL-1 proteins and significant improvement of cell survival in vitro. Conclusions: Our results suggest that miR-29b and miR-198 dysregulation in RCC patient CD8(+) T cells is associated with dysfunctional immunity and foreshadow the development of miR-targeted therapeutics to correct such T cell defects in vivo

Epidemiological and Clinical Features of SARS-CoV-2 Variants Circulating between April-December 2021 in Italy

SARS-CoV-2 is constantly evolving, leading to new variants. We analysed data from 4400 SARS-CoV-2-positive samples in order to pursue epidemiological variant surveillance and to evaluate their impact on public health in Italy in the period of April–December 2021. The main circulating strain (76.2%) was the Delta variant, followed by the Alpha (13.3%), the Omicron (5.3%), and the Gamma variants (2.9%). The B.1.1 lineages, Eta, Beta, Iota, Mu, and Kappa variants, represented around 1% of cases. There were 48.2% of subjects who had not been vaccinated, and they had a lower median age compared to the vaccinated subjects (47 vs. 61 years). An increasing number of infections in the vaccinated subjects were observed over time, with the highest proportion in November (85.2%). The variants correlated with clinical status; the largest proportion of symptomatic patients (59.6%) was observed with the Delta variant, while subjects harbouring the Gamma variant showed the highest proportion of asymptomatic infection (21.6%), albeit also deaths (5.4%). The Omicron variant was only found in the vaccinated subjects, of which 47% had been hospitalised. The diffusivity and pathogenicity associated with the different SARS-CoV-2 variants are likely to have relevant public health implications, both at the national and international levels. Our study provides data on the rapid changes in the epidemiological landscape of the SARS-CoV-2 variants in Italy

Epidemiological and Clinical Features of SARS-CoV-2 Variants Circulating between April–December 2021 in Italy

SARS-CoV-2 is constantly evolving, leading to new variants. We analysed data from 4400 SARS-CoV-2-positive samples in order to pursue epidemiological variant surveillance and to evaluate their impact on public health in Italy in the period of April–December 2021. The main circulating strain (76.2%) was the Delta variant, followed by the Alpha (13.3%), the Omicron (5.3%), and the Gamma variants (2.9%). The B.1.1 lineages, Eta, Beta, Iota, Mu, and Kappa variants, represented around 1% of cases. There were 48.2% of subjects who had not been vaccinated, and they had a lower median age compared to the vaccinated subjects (47 vs. 61 years). An increasing number of infections in the vaccinated subjects were observed over time, with the highest proportion in November (85.2%). The variants correlated with clinical status; the largest proportion of symptomatic patients (59.6%) was observed with the Delta variant, while subjects harbouring the Gamma variant showed the highest proportion of asymptomatic infection (21.6%), albeit also deaths (5.4%). The Omicron variant was only found in the vaccinated subjects, of which 47% had been hospitalised. The diffusivity and pathogenicity associated with the different SARS-CoV-2 variants are likely to have relevant public health implications, both at the national and international levels. Our study provides data on the rapid changes in the epidemiological landscape of the SARS-CoV-2 variants in Italy