Exosomes are nano-membrane vesicles that various cell types secrete during physiological and pathophysiological conditions. By shuttling bioactive molecules such as nucleic acids, proteins, and lipids to target cells, exosomes serve as key regulators for multiple cellular processes, including cancer metastasis. Recently, microvesicles have emerged as a challenge in the treatment of prostate cancer (PCa), encountered either when the number of vesicles increases or when the vesicles move into circulation, potentially with an ability to induce drug resistance, angiogenesis, and metastasis. Notably, the exosomal cargo can induce the desmoplastic response of PCa-associated cells in a tumor microenvironment (TME) to promote PCa metastasis. However, the crosstalk between PCa-derived exosomes and the TME remains only partially understood. In this review, we provide new insights into the metabolic and molecular signatures of PCa-associated exosomes in reprogramming the TME, and the subsequent promotion of aggressive phenotypes of PCa cells. Elucidating the molecular mechanisms of TME reprogramming by exosomes draws more practical and universal conclusions for the development of new therapeutic interventions when considering TME in the treatment of PCa patients.

HEV is the most causative agent of acute viral hepatitis globally. HEV causes acute, chronic, and extrahepatic manifestations. Chronic HEV infection develops in immunocompromised patients such as organ transplant patients, HIV-infected patients, and leukemic patients. The source of chronic HEV infection is not known. Also, the source of extrahepatic manifestations associated with HEV infection is still unclear. Hepatotropic viruses such as HCV and HBV replicate in peripheral blood mononuclear cells (PBMCs) and these cells become a source of chronic reactivation of the infections in allograft organ transplant patients. Herein, we reported that PBMCs and bone marrow-derived macrophages (BMDMs), isolated from healthy donors (n = 3), are susceptible to HEV in vitro. Human monocytes (HMOs), human macrophages (HMACs), and human BMDMs were challenged with HEV-1 and HEV-3 viruses. HEV RNA was measured by qPCR, the marker of the intermediate replicative form (ds-RNA) was assessed by immunofluorescence, and HEV capsid protein was assessed by flow cytometry and ELISA. HEV infection was successfully established in primary HMOs, HMACs, and human BMDMs, but not in the corresponding cells of murine origin. Intermediate replicative form (ds RNA) was detected in HMOs and HMACs challenged with HEV. The HEV load was increased over time, and the HEV capsid protein was detected intracellularly in the HEV-infected cells and accumulated extracellularly over time, confirming that HEV completes the life cycle inside these cells. The HEV particles produced from the infected BMDMs were infectious to naive HMOs in vitro. The HEV viral load was comparable in HEV-1- and HEV-3-infected cells, but HEV-1 induced more inflammatory responses. In conclusion, HMOs, HMACs, and human BMDMs are permissive to HEV infection and these cells could be the source of chronic and recurrent infection, especially in immunocompromised patients. Replication of HEV in human BMDMs could be related to hematological disorders associated with extrahepatic manifestations.

| LIPIDS AND THE B R AINUnderstanding how the over 80 billion neurons in the human brain communicate with each other to generate a self-aware mind remains one of the great challenges of modern neurobiology. Despite decades of ever more sophisticated study and progress, the molecular mechanisms underpinning the exquisitely regulated neuronal communication at the heart of cognition, learning and memory remain incompletely understood. The discovery that neurotransmission is quantal (Del Castillo and Katz, 1954) led to the development of the vesicle hypothesis in which neurotransmitters are released following fusion of synaptic vesicles with the pre-synaptic membrane in a process known as neuroexocytosis. Decades of subsequent research validated this fundamental finding, and demonstrated the involvement of sophisticated protein machinery (e.g. SNAREs, N-ethylmaleimide-sensitive factor attachment receptors) in all aspects of vesicle trafficking. Most recently, the analysis of brain lipids and lipid metabolites has started to shift this somewhat 'proteocentric' view of neurotransmission to a more holistic view involving tightly regulated protein-protein, protein-lipid (Wenk and De Camilli, 2004) and lipid-lipid interactions, all of which are essential for neuronal communication.Indeed, the healthy human brain is composed of approximately 60% lipid by dry weight, higher than in any other tissue. Seminal chromatography experiments (O'Brien and Sampson, 1965) AbstractDespite the human brain being made of nearly 60% fat, the vast majority of studies on the mechanisms of neuronal communication which underpin cognition, memory and learning, primarily focus on proteins and/or (epi)genetic mechanisms. Phospholipids are the main component of all cellular membranes and function as substrates for numerous phospholipid-modifying enzymes, including phospholipases, which release free fatty acids (FFAs) and other lipid metabolites that can alter the intrinsic properties of the membranes, recruit and activate critical proteins, and act as lipid signalling molecules. Here, we will review brain specific phospholipases, their roles in membrane remodelling, neuronal function, learning and memory, as well as their disease implications. In particular, we will highlight key roles of unsaturated FFAs, particularly arachidonic acid, in neurotransmitter release, neuroinflammation and memory.In light of recent findings, we will also discuss the emerging role of phospholipase A 1 and the creation of saturated FFAs in the brain. K E Y W O R D S exocytosis, free fatty acids, learning, memory, phospholipases, phospholipids, synaptic plasticity | 301 JOENSUU Et al.

Breast cancer is the most common neoplastic disorder diagnosed in women.The main goal of this study was to explore the effect of melatonin against breast cancer metastasis and compared this with the actions of taxol (a well-known chemotherapeutic drug), and the impact of their combination against breast cancer metastasis. Melatonin showed no cytotoxic effect while taxol showed antiproliferative and cytotoxic effects on MCF-7 and MDA-MB-231 cells.Furthermore, melatonin inhibited the generation of reactive oxygen species. Melatonin and taxol clearly decreased cell migration and invasion at low doses, especially those matching the normal physiological concentration at night.Melatonin and taxol markedly reduced DJ-1 and ID-1 and increased KLF17 messenger RNA and protein expression levels. The present results also showed that melatonin and taxol induced GSK3-β nuclear and Snail cytosolic localization. These changes were accompanied by a concurrent rise in E-cadherin expression. The above data show that normal levels of melatonin may help in preventing breast cancer metastasis through inhibiting DJ-1/ KLF17/ID-1 signaling pathway. The combination of melatonin and taxol is a potent candidate against breast cancer metastasis, better than using melatonin or taxol as a single drug. K E Y W O R D S breast cancer invasion, DJ-1, KLF17, melatonin, taxol J Cell Biochem. 2019;120:3945-3957.wileyonlinelibrary.com/journal/jcb

A series of compounds 5-amino-2-ethylmercapto-4-phenyl-6-subistitutedthieno[2,3-d]pyrimidines (8a-d), 4-chloro-7-ethylmercapto-9-phenylpyrimido[5 0 ,4 0 :4,5]thieno[3,2-d]triazine (9), and 2-ethylmercapto-8-oxo-4-phenyl-7-(4-chlorophenyl)pyrimido [4 0 ,5 0 :4,5]thieno[2,3-d]pyrimidine (10) were synthesized and their structures were confirmed by 1 H NMR, 13 C NMR, and MS. All compounds were evaluated for their IC 50 values against three cancer cell lines (MCF-7, HUH-7 and BHK) and WISH cells. The IC 50 of compound (8d) was calculated for each cell line. Interestingly, the IC 50 for the normal human amnion WISH cell line was much higher (723 μg/mL) than those found for the tumor cell lines BHK (17 μg/mL), HUH-7 (5.8 μg/mL), and MCF-7 (8.3 μg/mL). The proliferation inhibition of normal (WISH) and tumor (BHK, HUH-7, and MCF-7) cells by compound (8d) was investigated using MTT assay, and the IC 50 was calculated after 48 h of treatment for each cell line.