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Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response to eliminate an infection. After the host immune response is activated, a complex, dynamic, and time-dependent process is triggered. This process promotes the production of inflammatory mediators, including acute-phase proteins, complement system proteins, cytokines, chemokines, and antimicrobial peptides, which are required to initiate an inflammatory environment for eliminating the invading pathogen. The physiological response of this sepsis-induced systemic inflammation can affect blood–brain barrier (BBB) function; subsequently, endothelial cells produce inflammatory mediators, including cytokines, chemokines, and matrix metalloproteinases (MMPs) that degrade tight junction (TJ) proteins and decrease BBB function. The resulting BBB permeability allows peripheral immune cells from the bloodstream to enter the brain, which then release a range of inflammatory mediators and activate glial cells. The activated microglia and astrocytes release reactive oxygen species (ROS), cytokines, chemokines, and neurochemicals, initiate mitochondrial dysfunction and neuronal damage, and exacerbate the inflammatory milieu in the brain. These changes trigger sepsis-associated encephalopathy (SAE), which has the potential to increase cognitive deterioration and susceptibility to cognitive decline later in life.

Sepsis is a life-threatening organ dysfunction, which demands notable attention for its treatment, especially in view of the involvement of immunodepressed patients, as the case of patients with diabetes mellitus (DM), who constitute a population susceptible to develop infections. Thus, considering this endocrine pathology as an implicatory role on the immune system, the aim of this study was to show the relationship between this disease and sepsis on neuroinflammatory and neurochemical parameters. Levels of IL-6, IL-10, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and mitochondrial respiratory chain complexes were evaluated in the hippocampus and prefrontal cortex 24 h after sepsis by cecal ligation and perforation (CLP) in Wistar rats induced to type 1 diabetes by alloxan (150 mg/kg). It was verified that diabetes implied immune function after 24 h of sepsis, since it contributed to the increase of the inflammatory process with higher production of IL-6 and decreased levels of IL-10 only in the hippocampus. In the same brain area, a several decrease in NGF level and activity of complexes I and II of the mitochondrial respiratory chain were observed. Thus, diabetes exacerbates neuroinflammation and results in mitochondrial impairment and downregulation of NGF level in the hippocampus after sepsis.

Mitochondria, the ‘powerhouse’ of eukaryotic cells, play a key role in cellular homeostasis. However, defective mitochondria increase mitochondrial ROS (mtROS) production and cell-free mitochondrial DNA (mtDNA) release, leading to increased inflammation. Mitophagy is a vital pathway, which selectively removes defective mitochondria through the process of autophagy. Thus, an impairment in the mitophagy pathway might trigger the gradual accumulation of defective mitochondria. Accumulating evidence suggest that inflammation and mitochondrial dysfunction are linked to the pathogenesis of depression. In this article, we have reviewed the role of impaired mitophagy as a contributing factor in depression pathophysiology. Further, we have discussed the potential therapeutic interventions aimed at modulating mitophagy in depression.

Sepsis survivors have persistent neurological changes, including cognitive and behavioral dysfunction, which are associated with increased production of neurodegenerative biomarkers and morphological changes in areas with mnemonic functions. 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach in sepsis, given their anti-inflammatory and antioxidant properties. Here we investigated the possible neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the hippocampus, prefrontal cortex, and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats (280 ± 30 g) were submitted to sepsis by cecal ligation and puncture (CLP, n = 28) or left as non-manipulated (control, n = 24). The animals were treated with simvastatin (20 mg/kg) or vehicle four days before and ten days after surgery. The treatment recovered expression of Smad-3 in hippocampus (F(3, 28) = 6.22; P F(3, 28) = 16.06; P F(3, 28) = 10.54; P F(3, 28) = 62.79; P F(3, 28) = 15.35; P (3, 12) = 7.533; P (3, 12) = 5.818; P

Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Surviving patients have cognitive and memory damage that started during sepsis. These neurologic damages have been associated with increased BBB permeability and microglial activation. However, a few discrete studies have seen over the years pointing to the potential role of astrocytes in the pathophysiology of neurological damage after sepsis. The purpose of this article is to review information on the potential role of astrocytes during sepsis, as well as to provoke further studies in this area. These published articles show astrocytic activation after sepsis; they also evidence the release of inflammatory mediators by these cells. In this sense, the role of astrocytes should be better elucidated during sepsis progression.

One hundred and thirty years after lymphoid and myeloid cells were discovered, in 2008, the researchers presented to the scientific community the population of innate lymphoid cells (ILCs) identified in humans and mice. Human ILC subsets were first identified in secondary lymphoid tissues and subsequently reported in the intestine, lung, liver, skin, and meninges. ILCs (ILC1, ILC2, ILC3, and ILCreg) subgroups present plastic properties concerning cytokines, chemokines, and other mediators present in the microenvironment. ILC1s were characterized by their ability to produce interferon (IFN)-γ. ILC2s have a function in innate and adaptive type 2 inflammation by producing effector cytokines such as interleukin (IL)-5 and IL-13. Meningeal ILC2s were activated in an IL-33-dependent mechanism releasing type-2 cytokines and demonstrating that ILC2s proliferate in reaction to IL-33 activation. ILC3s have been discovered as a significant contribution to the homeostasis of the gut barrier and as a source of IL-22. IL-22 presents a pleiotropic activity reinforcing the gut barrier immunity by stimulating anti-microbial peptide synthesis and promoting microbial regulation. Additionally, ILCs can have a pathogenic or protective effect on many disorders, and further research is needed to determine what elements influence the nature of their actions in diverse situations. The narrative review summarizes the role of the ILCs in mental health.

In the past three decades, research on the gut microbiome and its metabolites, such as trimethylamines (TMA), trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), bile acids, tryptophan and indole derivatives, has attracted the attention of many scientists and industrialists. Among these metabolites, TMAO is produced from dietary choline, phosphatidylcholine, carnitine,andbetaine. TMAO and other gut metabolites, such as TMA and SCFAs, reach the brain by crossing the blood-brain barrier (BBB) and are involved in brain development, neurogenesis, and behavior. Gut-microbiota composition is influenced by diet, lifestyle, antibiotics, and age. Several studies have confirmed that altered TMAO levels contribute to metabolic, vascular, psychiatric, and neurodegenerative disorders. This review focuses on how altered TMAO levels impact oxidative stress, microglial activation, and the apoptosis of neurons, and may lead to neuroinflammation, which can subsequently result in the development of psychiatric, cognitive, and behavioral disorders.

Major depressive disorder (MDD) is the most prevalent mood disorder globally. Most antidepressants available for the treatment of MDD increase the concentration of monoamines in the synaptic cleft. However, such drugs have a high latency time to obtain benefits. Thus, new antidepressants with fast action and robust efficacy are very important. This study evaluated the effects of escitalopram, ketamine, and probiotic Bifidobacterium infantis in rats submitted to the maternal deprivation (MD). MD rats received saline, escitalopram, ketamine, or probiotic for 10, 30, or 50 days, depending on the postnatal day (PND):21, 41, and 61. Following behavior, this study examined the integrity of the blood-brain barrier (BBB) and oxidative stress markers. MD induced depressive-like behavior in females with PND21 and males with PND61. All treatments reversed depressive-like behavior in females and escitalopram and ketamine in males. MD induced an increase in the permeability of the BBB, an imbalance between oxidative stress and antioxidant defenses. Treatments regulated the oxidative damage and the integrity of the BBB induced by MD. The treatment with escitalopram, ketamine, or probiotics may prevent behavioral and neurochemical changes associated with MDD, depending on the developmental period and gender.

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood-brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.

Background Sepsis is a disordered host immune reaction to pathogen invasion that leads to organ dysfunction, high mortality, and long-term consequences. More than 50% of sepsis survivors often suffer from severe and long-term cognitive deficits. We previously demonstrated in vivo microglial activation and neuroinflammation associated with cognitive deficits in an experimental model of sepsis. Recent studies have demonstrated the role of innate lymphoid cells (ILCs) in aging and neurodegeneration-induced cognitive loss. ILCs are enriched at barrier surfaces and regulate inflammation and tissue homeostasis in a disease condition. Here we aimed to explore the role of ILCs subtypes on experimental sepsis-induced cognitive deficits. Methods Male, 50-day-old C57BL/6 mice were subjected to cecal ligation and perforation (CLP) surgery to induce sepsis or sham surgery as a control group. At 10 days after sepsis, assessment of cognition was performed using novel object recognition (NOR) task. The ILCs subtypes ILC1, ILC2, and ILC3 were evaluated in the spleen, meninges, and choroid plexus (CP) using multicolor flow cytometry. Results Sepsis groups demonstrated cognitive decline as measured by decreased recognition index as compared to the control group. In the periphery, the spleen from the sepsis group demonstrated increased ILC1 and ILC3 levels as compared to control groups. In brain barriers, we observed increased accumulation of ILC2 subtype in CP in the sepsis group. However, there was no difference in the meningeal accumulation of ILCs between control and sepsis groups. Conclusion Targeting group 2 innate lymphoid cells may provide a new strategy to combat sepsis-associated long-term cognitive deficits. Supported by Alzheimer's Association grant to TB - AARGDNTF-19-619645. NIH/NIA grant to TB - 1RF1AG072491-01.