Role of hormones in the regulation of RACK1 expression as a signaling checkpoint in immunosenescence

Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence

Mechanism-Based Screen Establishes Signalling Framework for DNA Damage-Associated G1 Checkpoint Response

DNA damage activates checkpoint controls which block progression of cells through the division cycle. Several different checkpoints exist that control transit at different positions in the cell cycle. A role for checkpoint activation in providing resistance of cells to genotoxic anticancer therapy, including chemotherapy and ionizing radiation, is widely recognized. Although the core molecular functions that execute different damage activated checkpoints are known, the signals that control checkpoint activation are far from understood. We used a kinome-spanning RNA interference screen to delineate signalling required for radiation-mediated retinoblastoma protein activation, the recognized executor of G1 checkpoint control. Our results corroborate the involvement of the p53 tumour suppressor (TP53) and its downstream targets p21CIP1/WAF1 but infer lack of involvement of canonical double strand break (DSB) recognition known for its role in activating TP53 in damaged cells. Instead our results predict signalling involving the known TP53 phosphorylating kinase PRPK/TP53RK and the JNK/p38MAPK activating kinase STK4/MST1, both hitherto unrecognised for their contribution to DNA damage G1 checkpoint signalling. Our results further predict a network topology whereby induction of p21CIP1/WAF1 is required but not sufficient to elicit checkpoint activation. Our experiments document a role of the kinases identified in radiation protection proposing their pharmacological inhibition as a potential strategy to increase radiation sensitivity in proliferating cancer cells

Immunomodulators Inspired by Nature: A Review on Curcumin and Echinacea

The immune system is an efficient integrated network of cellular elements and chemicals developed to preserve the integrity of the organism against external insults and its correct functioning and balance are essential to avoid the occurrence of a great variety of disorders. To date, evidence from literature highlights an increase in immunological diseases and a great attention has been focused on the development of molecules able to modulate the immune response. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of herbal medicines as integrative, complementary and preventive therapy. The active components in medical plants have always been an important source of clinical therapeutics and the study of their molecular pharmacology is an enormous challenge since they offer a great chemical diversity with often multi-pharmacological activity. In this review, we mainly analysed the immunomodulatory/antinflammatory activity of Echinacea spp. and Curcuma longa, focusing on some issues of the phytochemical research and on new possible strategies to obtain novel agents to supplement the present therapies

176. Viper envenomation with ocular neurotocic effects managed without antidote admiistration:a case report 39th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 21-24 May 2019, Naples, Italy

Along with the more common clinical features, European viper envenomations may rarely present with neurotoxic manifestations. Those include muscle weakness, drowsiness, paresthesia, dyspnea and ocular complaints among others. Ocular neurotoxicity as an indication for antidote administration is still debated In this case the management with supportive/symptomatic treatment was sufficient. CASE REPORT. In May 2018, a 19-­‐year old man was admitted to an external emergency unit 20 minutes after a viper bite on the proximal phalanges of the right hand. The Poison Control Centre (PCC) of Policlinico Umberto I Hospital – Sapienza University of Rome was contacted immediately. Local signs of envenomation with fang marks, and swelling of the hand were present. Initial lab work showed no abnormalities. In the following 2 hours edema extended to the middle forearm (Figure 1), and one episode of vomiting was registered. The patient was hydrated and analgesics administered. Four hours post-­‐bite, edema did not progress proximally, but weakness, vertigo and mild abdominal pain were reported. LeuKocytosis (17.0 × 109/L, 90% neutrophils) and increased creatinkinase (245 U/L) were present. The PCC provided two vials of Viper Venom Antitoxin (Biomed) with no indication to administer at this time, but to closely monitor patient for any systemic and neurological manifestations. Seven hours post-­ bite,the swelling was stable, abdominal pain and previous neurological symptomsm regressed, and left ptosis appeared. Laboratory exams showed persistence of leukocytosis (16.6 × 109/l), glucose 123 mg/dL and creatinkinase 216 U/L. The PCC recommended further monitoring. Eighteen hours post-­‐bite ptosis ameliorated, no systemic signs had developed. The patient was discharged 40 hours post-­‐bite with no ptosis, edema in regression and leucocytes towards normalization. This case report suggests the following observations: i) as previously reported, neurological manifestations due to neurotoxins in some viper species venom may be characterized by delayed onset (up to 24 hours, 4-­‐7 hours in this case), association with mild local effects and reversibility; ii) weakness and vertigo preceded the ocular signs, and resolved in about 3 hours; iii) symptomatic management and close monitoring might be the best approach in such cases, with antitoxin recommended as soon as rapid edema extension and/or severe systemic/neurological symptoms appear

Role of spliceosome proteins in the regulation of glucocorticoid receptor isoforms by cortisol and dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) can counteract the activity of cortisol by modulating the glucocorticoid receptor \u3b2 (GR\u3b2) expression and antagonizing the binding of GR\u3b1 to the glucocorticoid responsive element (GRE) in RACK1 (Receptor for Activated C Kinase 1) promoter. These observations are important in the context of immunosenescence and can be extended to recognize a complex hormonal balance in the control of GR isoform expression and consequently in the expression of GR responsive genes. To elucidate the mechanism of DHEA on GR alternative splicing, we investigated its possible involvement in the expression of proteins such as the Serine/arginine (SR)-Rich Splicing Factors (SRSF) regulating GR splicing, specifically SRSF9 and SRSF3 also known as SRp30c and SRp20 respectively. We demonstrated that DHEA can induce the up-regulation of GR mRNA which is preferentially directed toward the \u3b2 isoform. The effect is due to an increase in expression of the splicing factor SRSF9. On the other hand cortisol up-regulated SRSF3, the splicing factor promoting GR\u3b1 isoform. We demonstrated that DHEA and cortisol modulate SRSF9 and SRSF3 in a different way and our data suggest that the anti-glucocorticoid effect of DHEA, among other mechanisms, is also exerted by modulating the expression of proteins involved in the splicing of the GR pre-mRNA