SummaryEmerging evidence suggests a significant role for inflammation and oxidative stress as main contributors to the neuroprogression that is observed in major depressive disorder (MDD), where patients show increased inflammatory and oxidative stress biomarkers. The process of neuroprogression includes stage-related neurodegeneration, cell death, reduced neurogenesis, reduced neuronal plasticity and increased autoimmune responses. Oxidative stress is a consequence of the biological imbalance between reactive oxygen species (ROS) and antioxidants, leading to the alteration of biomolecules and the loss of control of the intracellular redox-related signalling pathways. ROS serve as crucial secondary messengers in signal transduction and significantly affect inflammatory pathways by activating nuclear factor-jB and mitogen-activated protein kinase family stress kinases. When present in excess, ROS inflict damage, affecting cellular constituents with the formation of pro-inflammatory molecules, such as malondialdehyde, 4-hydroxynonenal, neoepitopes and damageassociated molecular patterns promoting immune response, and ultimately leading to cell death. The failure of cells to adapt to the changes in redox homeostasis and the subsequent cell death, together with the damage caused by inflammatory mediators, have been considered as major causes of neuroprogression and hence MDD. Both an activated immune-inflammatory system and increased oxidative stress act synergistically, complicating our understanding of the pathogenesis of depression. The cascade of antioxidative and inflammatory events is orchestrated by several transcription factors, with nuclear factor (erythroid-derived 2)-like 2 and nuclear factor-jB having particular relevance to MDD. This review focuses on potential molecular mechanisms through which impaired redox homeostasis and neuroinflammation can affect the neuronal environment and contribute to depression.

Increased pro-inflammatory cytokines and an overactive hypothalamic-pituitary-adrenal (HPA) axis have both been implicated in the pathogenesis of depression. However, these explanations appear contradictory because glucocorticoids are well recognised for their antiinflammatory effects. Two hypotheses exist to resolve this paradox: the mediating presence of glucocorticoid receptor resistance, or the possibility that glucocorticoids can be proinflammatory in some circumstances. We sought to investigate these hypotheses in a cell model with significant relevance to depression: human hippocampal progenitor cells. We demonstrated that dexamethasone in vitro given for 24 hours and followed by a 24-hour rest interval before an immune challenge produces pro-inflammatory effects in these neural cells, that is, potentiates the IL-6 protein secretion induced by stimulation with IL-1β (10ng/mL for 24 hours) by +49% (P<0.05) at a concentration of 100nM and by +70% (P<0.01) for 1µM.These effects are time-and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression.

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Background Sexual well-being is fundamental to physical and emotional health, and the ability to achieve it depends on access to comprehensive sexuality information and high-quality sexual health care from evidence-informed, nonjudgmental providers. Adequate and timely delivery of these components to individuals who are at high risk for sexually transmitted infections (STIs), including HIV, and unintended pregnancies promotes sexual health and mitigates consequences arising from risky sexual behavior. Brief interventions that allow health care providers to improve the information available to clients and motivate and help them to develop risk-reduction skills are seen as efficient ways to improve knowledge, change client behavior, and reduce provider stigma regarding sexual health. Objective The aim of the study is to evaluate five aspects of feasibility (acceptability, willingness, safety, satisfaction, and process) of a brief sexuality-related communication (BSC) intervention based on motivational interviewing and behavior change techniques in primary health care settings in low- and middle-income countries (LMICs). Methods This protocol outlines a multisite, multiphase study of feasibility of a BSC intervention in primary health care settings in LMICs that will be examined across four phases of the study. Phases I through III involve the collection of formative, qualitative data to examine provider and client perceptions of the feasibility of the intervention, adaptation of the intervention guide, and training providers on how to implement the final version of the BSC intervention. During phase IV, the feasibility of the intervention will be tested in a nonrandomized pre-post test trial where providers and clients will be followed for 6 months and participate in multiphase data collection. Results Phase I is currently underway in Moldova, and phases I and II were completed in Peru in late 2019. Results are expected for the feasibility study in 2021. Conclusions This feasibility study will determine whether the implementation of brief intervention programs aimed at improving sexual health outcomes is possible in the constraints of LMIC health systems and will add to our understanding of factors shaping clinical practice among primary care providers. International Registered Report Identifier (IRRID) DERR1-10.2196/15569