Background: Several cellular functions for cytosolic carboxypeptidase 1 (CCP1) have been proposed. Results: Various experimental approaches support a role for CCP1 in the removal of Glu residues from both ␣-and ␤-tubulin. Conclusion: CCP1 functions in tubulin processing and is not involved in intracellular peptide degradation. Significance: Neurodegeneration in mice lacking CCP1 is a result of altered tubulin processing.

Conflict of interest: JT is a cofounder of Principia Biopharma, which has licensed the p90RSK inhibitor FMK-MEA.

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), and hepatitis B and C viruses. EBV, a member of the human gamma herpesvirus family, is a double-stranded DNA virus and the primary cause of infectious mononucleosis. Most EBV infections cause no long-term complications. However, it was reported that EBV infection is responsible for around 200,000 malignancies worldwide every year. Currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection. Recently, the gut microbiota has been investigated for its pivotal roles in pathogen protection and regulating metabolic, endocrine, and immune functions. Several studies have investigated the efficacy of antiviral agents, gut microbial metabolites, and natural products against EBV infection. In this review, we aim to summarise and analyse the reported molecular mechanistic and clinical studies on the activities of gut microbial metabolites and natural medicines against carcinogenic viruses, with a particular emphasis on EBV. Gut microbial metabolites such as short-chain fatty acids were reported to activate the EBV lytic cycle, while bacteriocins, produced by Enterococcus durans strains, have shown antiviral properties. Furthermore, several natural products and dietary bioactive compounds, such as curcumin, epigallocatechin gallate, resveratrol, moronic acid, and andrographolide, have shown antiviral activity against EBV. In this review, we proposed several exciting future directions for research on carcinogenic viruses.

Background: The incidence of cardiovascular disease (CVD) is higher in HIV + patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for CVD. However, the molecular mechanisms that link cART and CVD are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species (ROS)-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. Methods: Peripheral whole blood from cART-treated HIV + individuals and non-treated HIV − individuals was treated with H 2 O 2 (200 μM) for 4 minutes, and p90RSK activity in CD14 + monocytes was measured. Plaque formation in the carotids were also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK specific inhibitor (FMK-MEA) or dominant negative p90RSK (DN-p90RSK), and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild type and DN-p90RSK transgenic mice. Results: Monocytes from HIV + patients exhibited higher levels of p90RSK activity and were also more sensitive to ROS than monocytes from HIV − individuals. A multiple linear regression analysis involving cART, Reynolds CV risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the two significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H 2 O 2-induced over-activation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Lastly, the data obtained from our gain-or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. Conclusions: cART increased monocyte/macrophage sensitivity to ROS in HIV + individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and pro-inflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing CVD, especially in HIV + patients treated with cART.

Conflict of interest: JT is a cofounder of Principia Biopharma, which has licensed the p90RSK inhibitor FMK-MEA.