Regulating STING in health and disease.

The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases

Frequent attenders in general medical practice in Italy: a preliminary report on clinical variables related to low functioning

Claudia Carmassi,1 Valerio Dell’Oste,1 Diana Ceresoli,1 Stefano Moscardini,2 Enrico Bianchi,3 Roberto Landi,4 Gabriele Massimetti,1 Cristiana Nisita,1 Liliana Dell’Osso1 1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 2General Medicine Outpatient Clinic, ASL 5 Tuscany, Pisa, Italy; 3General Medicine Outpatient Clinic, ASL 6 Tuscany, Livorno, Italy; 4General Medicine Outpatient Clinic, ASL 2 Tuscany, Lucca, Italy Background: Frequent attenders (FAs), defined as patients reporting a disproportionate number of visits to general practitioners (GPs), may represent up to one-third of GP patients responsible for a high burden of care not always justified by the severity of the medical condition. The aim of this study was to explore sociodemographic and clinical characteristics of FAs of GP in Italy with particular attention to functional impairment. Methods: A total sample of 75 FAs (defined as individuals who had consulted GPs 15 times or more during 2015) of GPs of three primary care centers (Pisa, Livorno, and Lucca) in Italy were enrolled and assessed by sociodemographic scale, Structured Clinical Interview for DSM-5 (SCID-5), global functioning (Global Assessment of Functioning [GAF]), illness behavior and perceived health (Illness Behavior Inventory), and somatic comorbidity (Cumulative Illness Rating Scale). Results: Most of the sample were females, middle aged, married, or cohabiting, with low levels of education. One-third of FAs was low functioning (LF; GAF score <70), with no differences in the sociodemographic variables. Approximately 70.3% of the patients reported a current SCID diagnosis, in particular, major depressive disorder, somatic symptom disorders, and panic disorder, all being more frequent in LF patients. Half of the patients were taking a psychopharmacological therapy, mostly benzodiazepines (BDZs). Conclusion: Most FAs were female with current medical disorders, and LF. All claimed to be worried about their own health and perceived themselves as more impaired also regarding the health perception and social role. LF patients were, or had been more likely to be under psychopharmacological treatment. FAs seem to constitute a special population that should be carefully evaluated for mental disorders and appropriate treatment. Keywords: primary care, global functioning, medically unexplained symptoms, mental disorders, DSM-

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I-related chain (MIC) A/B and UL16-binding proteins (ULBP)1-6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell-mediated lysis of infected cells. Inhibition of viral DNA replication with phosphonoformic acid did not prevent ligand upregulation, thus indicating that early phases of HCMV infection are involved in ligand increase. Indeed, the major immediate early (IE) proteins IE1 and IE2 stimulated the expression of MICA and PVR, but not ULBP3. IE2 directly activated MICA promoter via its binding to an IE2-responsive element that we identified within the promoter and that is conserved among different alleles of MICA. Both IE proteins were instead required for PVR upregulation via a mechanism independent of IE DNA binding activity. Finally, inhibiting IE protein expression during HCMV infection confirmed their involvement in ligand increase. We also investigated the contribution of the DNA damage response, a pathway activated by HCMV and implicated in ligand regulation. However, silencing of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related protein, and DNA-dependent protein kinase did not influence ligand expression. Overall, these data reveal that MICA and PVR are directly regulated by HCMV IE proteins, and this may be crucial for the onset of an early host antiviral response

Red-Light Photocatalytic Activation Of Pt(IV) Anticancer Prodrugs Using Methylene Blue

Catalysis-based approaches offer versatile strategies for activating anticancer prodrugs, potentially allowing precise control over drug release and localization within tumor tissues, while reducing systemic toxicity. In this study, we explore the role of the phenothiazine dye methylene blue (MB+) as a photocatalyst in conjunction with biologically relevant electron donors to facilitate the red-light conversion of two Pt(IV) complexes, denoted as cis,cis,trans-[PtCl2(NH3)2(O2CCH2CH2COOH)2] (1) and trans-[Pt(O2CCH2CH2COOH)21R,2R-(DACH)(ox)] (2), into cisplatin and oxaliplatin, respectively. Combining spectroscopic techniques (NMR, UV-Vis, flash photolysis) with computational methods, we reveal that the doubly reduced MB+ (leucomethylene blue, LMB) triggers the reductive elimination of axial ligands in the two Pt(IV) precursors, generating the corresponding Pt(II) anticancer drugs. In vitro experiments conducted on the human cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV-16 genome, and on non-tumoral cells (HaCat) demonstrate that co-administration with Pt(IV) prodrugs improves MB+\u27s antiproliferative efficacy in cancer cells, particularly under red light exposure. This enhancement arises from the catalytic production of Pt(II) species within the cellular environment

IFI16 Impacts Metabolic Reprogramming during Human Cytomegalovirus Infection

Cellular lipid metabolism plays a pivotal role in human cytomegalovirus (HCMV) infection, as increased lipogenesis in HCMV-infected cells favors the envelopment of newly synthesized viral particles. As all cells are equipped with restriction factors (RFs) able to exert a protective effect against invading pathogens, we asked whether a similar defense mechanism would also be in place to preserve the metabolic compartment from HCMV infection. Here, we show that gamma interferon (IFN-g)-inducible protein 16 (IFI16), an RF able to block HCMV DNA synthesis, can also counteract HCMV-mediated metabolic reprogramming in infected primary human foreskin fibroblasts (HFFs), thereby limiting virion infectivity. Specifically, we find that IFI16 downregulates the transcriptional activation of the glucose transporter 4 (GLUT4) through cooperation with the carbohydrate-response element-binding protein (ChREBP), thereby reducing HCMV-induced transcription of lipogenic enzymes. The resulting decrease in glucose uptake and consumption leads to diminished lipid synthesis, which ultimately curbs the de novo formation of enveloped viral particles in infected HFFs. Consistently, untargeted lipidomic analysis shows enhanced cholesteryl ester levels in IFI16 KO versus wild-type (WT) HFFs. Overall, our data unveil a new role of IFI16 in the regulation of glucose and lipid metabolism upon HCMV replication and uncover new potential targets for the development of novel antiviral therapies. IMPORTANCE Human cytomegalovirus (HCMV) gathers all the substrates and enzymes necessary for the assembly of new virions from its host cell. For instance, HCMV is known to induce cellular metabolism of infected cells to favor virion assembly. Cells are, however, equipped with a first-line defense represented by restriction factors (RFs), which after sensing viral DNA can trigger innate and adaptive responses, thereby blocking HCMV replication. One such RF is IFN-g-inducible protein 16 (IFI16), which we have shown to downregulate viral replication in human fibroblasts. Thus, we asked whether IFI16 would also play a role in preserving cellular metabolism upon HCMV infection. Our findings highlight an unprecedented role of IFI16 in opposing the metabolic changes elicited by HCMV, thus revealing new promising targets for antiviral therapy. © 2022 Griffante et al.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]