Activation of the transcription factor NRF2 mediates the anti-inflammatory properties of a subset of over-the-counter and prescription NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes and are ubiquitously used for their anti-inflammatory properties. However, COX inhibition alone fails to explain numerous clinical outcomes of NSAID usage. Screening commonly used NSAIDs in primary human and murine myeloid cells demonstrated that NSAIDs could be differentiated by their ability to induce growth/differentiation factor 15 (GDF15), independent of COX specificity. Using genetic and pharmacologic approaches, NSAID-mediated GDF15 induction was dependent on the activation of nuclear factor erythroid 2-related factor 2 (NRF2) in myeloid cells. Sensing by Cysteine 151 of the NRF2 chaperone, Kelch-like ECH-associated protein 1 (KEAP1) was required for NSAID activation of NRF2 and subsequent anti-inflammatory effects both in vitro and in vivo. Myeloid-specific deletion of NRF2 abolished NSAID-mediated tissue protection in murine models of gout and endotoxemia. This highlights a noncanonical NRF2-dependent mechanism of action for the anti-inflammatory activity of a subset of commonly used NSAIDs.

Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Peptide-based allosteric inhibitor targets TNFR1 conformationally active region and disables receptor-ligand signaling complex.

Tumor necrosis factor (TNF) receptor 1 (TNFR1) plays a pivotal role in mediating TNF induced downstream signaling and regulating inflammatory response. Recent studies have suggested that TNFR1 activation involves conformational rearrangements of preligand assembled receptor dimers and targeting receptor conformational dynamics is a viable strategy to modulate TNFR1 signaling. Here, we used a combination of biophysical, biochemical, and cellular assays, as well as molecular dynamics simulation to show that an anti-inflammatory peptide (FKCRRWQWRMKK), which we termed FKC, inhibits TNFR1 activation allosterically by altering the conformational states of the receptor dimer without blocking receptor-ligand interaction or disrupting receptor dimerization. We also demonstrated the efficacy of FKC by showing that the peptide inhibits TNFR1 signaling in HEK293 cells and attenuates inflammation in mice with intraperitoneal TNF injection. Mechanistically, we found that FKC binds to TNFR1 cysteine-rich domains (CRD2/3) and perturbs the conformational dynamics required for receptor activation. Importantly, FKC increases the frequency in the opening of both CRD2/3 and CRD4 in the receptor dimer, as well as induces a conformational opening in the cytosolic regions of the receptor. This results in an inhibitory conformational state that impedes the recruitment of downstream signaling molecules. Together, these data provide evidence on the feasibility of targeting TNFR1 conformationally active region and open new avenues for receptor-specific inhibition of TNFR1 signaling.

The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids.

The pulmonary surfactant system of the lung is a lipid and protein complex, which regulates the biophysical properties of the alveoli to prevent lung collapse and the innate immune system in the lung. Pulmonary surfactant is a lipoprotein complex consisting of 90% phospholipids and 10% protein, by weight. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), exist at very high concentrations in the extracellular alveolar compartments. We have reported that one of the most dominant molecular species of PG, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and PI inhibit inflammatory responses induced by multiple toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6) by interacting with subsets of multiprotein receptor components. These lipids also exert potent antiviral effects against RSV and influenza A, in vitro, by inhibiting virus binding to host cells. POPG and PI inhibit these viral infections in vivo, in multiple animal models. Especially noteworthy, these lipids markedly attenuate SARS-CoV-2 infection including its variants. These lipids are natural compounds that already exist in the lung and, thus, are less likely to cause adverse immune responses by hosts. Collectively, these data demonstrate that POPG and PI have strong potential as novel therapeutics for applications as anti-inflammatory compounds and preventatives, as treatments for broad ranges of RNA respiratory viruses.

Harnessing prostaglandin E2 signaling to ameliorate autoimmunity.

The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E2 (PGE2) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE2 was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE2 plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack.

Non-coding RNA-based regulation of inflammation.

Inflammation is a multifactorial process and various biological mechanisms and pathways participate in its development. The presence of inflammation is involved in pathogenesis of different diseases such as diabetes mellitus, cardiovascular diseases and even, cancer. Non-coding RNAs (ncRNAs) comprise large part of transcribed genome and their critical function in physiological and pathological conditions has been confirmed. The present review focuses on miRNAs, lncRNAs and circRNAs as ncRNAs and their potential functions in inflammation regulation and resolution. Pro-inflammatory and anti-inflammatory factors are regulated by miRNAs via binding to 3'-UTR or indirectly via affecting other pathways such as SIRT1 and NF-κB. LncRNAs display a similar function and they can also affect miRNAs via sponging in regulating levels of cytokines. CircRNAs mainly affect miRNAs and reduce their expression in regulating cytokine levels. Notably, exosomal ncRNAs have shown capacity in inflammation resolution. In addition to pre-clinical studies, clinical trials have examined role of ncRNAs in inflammation-mediated disease pathogenesis and cytokine regulation. The therapeutic targeting of ncRNAs using drugs and nucleic acids have been analyzed to reduce inflammation in disease therapy. Therefore, ncRNAs can serve as diagnostic, prognostic and therapeutic targets in inflammation-related diseases in pre-clinical and clinical backgrounds.

Sepsis-Induced Immunosuppression.

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy.

Putative regulation of macrophage-mediated inflammation by catestatin.

Catestatin (CST) is a bioactive cleavage product of the neuroendocrine prohormone chromogranin A (CgA). Recent findings show that CST can exert anti-inflammatory and antiadrenergic effects by suppressing the inflammatory actions of mammalian macrophages. However, recent findings also suggest that macrophages themselves are major CST producers. Here, we hypothesize that macrophages produce CST in an inflammation-dependent manner and thereby might self-regulate inflammation in an autocrine fashion. CST is associated with pathological conditions hallmarked by chronic inflammation, including autoimmune, cardiovascular, and metabolic disorders. Since intraperitoneal injection of CST in mouse models of diabetes and inflammatory bowel disease has been reported to be beneficial for mitigating disease, we posit that CST should be further investigated as a candidate target for treating certain inflammatory diseases.

The potential role of HIV-1 latency in promoting neuroinflammation and HIV-1-associated neurocognitive disorder.

Despite potent suppression of HIV-1 viral replication in the central nervous system (CNS) by antiretroviral therapy (ART), between 15% and 60% of HIV-1-infected patients receiving ART exhibit neuroinflammation and symptoms of HIV-1-associated neurocognitive disorder (HAND) - a significant unmet challenge. We propose that the emergence of HIV-1 from latency in microglia underlies both neuroinflammation in the CNS and the progression of HAND. Recent molecular studies of cellular silencing mechanisms of HIV-1 in microglia show that HIV-1 latency can be reversed both by proinflammatory cytokines and by signals from damaged neurons, potentially creating intermittent cycles of HIV-1 reactivation and silencing in the brain. We posit that anti-inflammatory agents that also block HIV-1 reactivation, such as nuclear receptor agonists, might provide new putative therapeutic avenues for the treatment of HAND.

Mechanical stretch preconditioned adipose-derived stem cells elicit polarization of anti-inflammatory M2-like macrophages and improve chronic wound healing.

Transplantation of adipose-derived stem cells (ASCs) is a promising option in the field of chronic wounds treatment. However, the effectiveness of ASCs therapies has been hampered by highly inflammatory environment in chronic wound areas. These problems could be partially circumvented using efficient approaches that boost the survival and anti-inflammatory capacity of transplanted ASCs. Here, by application of mechanical stretch (MS), we show that ASCs exhibits increased survival and immunoregulatory properties in vitro. MS triggers the secretion of macrophage colony stimulating factor (M-CSF) from ASCs, a chemokine that is linked to anti-inflammatory M2-like macrophages polarization. When the MS-ASCs were transplanted to chronic wounds, the wound area yields significantly faster closure rate and lower inflammatory mediators, largely due to macrophages polarization driven by transplanted MS-ASCs. Thus, our work shows that mechanical stretch can be harnessed to enhance ASCs transplantation efficiency in chronic wounds treatment.

Expert consensus report on lipid mediators: Role in resolution of inflammation and muscle preservation.

This meeting report presents a consensus on the biological aspects of lipid emulsions in parenteral nutrition, emphasizing the unanimous support for the integration of lipid emulsions, particularly those containing fish oil, owing to their many potential benefits beyond caloric provision. Lipid emulsions have evolved from simple energy sources to complex formulations designed to improve safety profiles and offer therapeutic benefits. The consensus highlights the critical role of omega-3 polyunsaturated fatty acids (PUFAs), notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil and other marine oils, for their anti-inflammatory properties, muscle mass preservation, and as precursors to the specialized pro-resolving mediators (SPMs). SPMs play a significant role in immune modulation, tissue repair, and the active resolution of inflammation without impairing host defense mechanisms. The panel's agreement underscores the importance of incorporating fish oil within clinical practices to facilitate recovery in conditions like surgery, critical illness, or immobility, while cautioning against therapies that might disrupt natural inflammation resolution processes. This consensus not only reaffirms the role of specific lipid components in enhancing patient outcomes, but also suggests a shift towards nutrition-based therapeutic strategies in clinical settings, advocating for the proactive evidence-based use of lipid emulsions enriched with omega-3 PUFAs. Furthermore, we should seek to apply our knowledge concerning DHA, EPA, and their SPM derivatives, to produce more informative randomized controlled trial protocols, thus allowing more authoritative clinical recommendations.

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

BACKGROUND: Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. METHODS: Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. RESULTS: We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. CONCLUSIONS: Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability-Brief Report.

BACKGROUND: Trem2 (triggering receptor on myeloid cells 2), a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a Trem2 agonist antibody (AL002a) to atherogenic mice would enhance macrophage survival and decrease necrotic core formation to improve plaque stability. METHODS: To model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr [low-density lipoprotein receptor]-/-) were fed a high-fat diet for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on a high-fat diet. RESULTS: AL002a-treated mice had increased lesion size in both the aortic root and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single-cell RNA sequencing of whole aorta suspensions from isotype- and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2 agonism with AL002a promoted foamy macrophage oxidized low-density lipoprotein uptake, survival, and cholesterol efflux. CONCLUSIONS: Trem2 agonism expands atherosclerotic plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance cholesterol efflux and collagen deposition.

Targeting ectromelia virus and TNF/NF-κB or STAT3 signaling for effective treatment of viral pneumonia.

Viral causes of pneumonia pose constant threats to global public health, but there are no specific treatments currently available for the condition. Antivirals are ineffective when administered late after the onset of symptoms. Pneumonia is caused by an exaggerated inflammatory cytokine response to infection, but tissue necrosis and damage caused by virus also contribute to lung pathology. We hypothesized that viral pneumonia can be treated effectively if both virus and inflammation are simultaneously targeted. Combined treatment with the antiviral drug cidofovir and etanercept, which targets tumor necrosis factor (TNF), down-regulated nuclear factor kappa B-signaling and effectively reduced morbidity and mortality during respiratory ectromelia virus (ECTV) infection in mice even when treatment was initiated after onset of clinical signs. Treatment with cidofovir alone reduced viral load, but animals died from severe lung pathology. Treatment with etanercept had no effect on viral load but diminished levels of inflammatory cytokines and chemokines including TNF, IL-6, IL-1ß, IL-12p40, TGF-ß, and CCL5 and dampened activation of the STAT3 cytokine-signaling pathway, which transduces signals from multiple cytokines implicated in lung pathology. Consequently, combined treatment with a STAT3 inhibitor and cidofovir was effective in improving clinical disease and lung pathology in ECTV-infected mice. Thus, the simultaneous targeting of virus and a specific inflammatory cytokine or cytokine-signaling pathway is effective in the treatment of pneumonia. This approach might be applicable to pneumonia caused by emerging and re-emerging viruses, like seasonal and pandemic influenza A virus strains and severe acute respiratory syndrome coronavirus 2.

Inflammation in acute myocardial infarction: the good, the bad and the ugly.

Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare 'The Good' (repair and defence) while treating 'The Bad' (smouldering RIR) and capturing 'The Ugly' (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials.

Nonsteroidal anti-inflammatory drug "allergy" labeling is associated with increased postpartum opioid utilization.

BACKGROUND: Current guidelines recommend a stepwise approach to postpartum pain management, beginning with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids added only if needed. Report of a prior NSAID-induced adverse drug reaction (ADR) may preclude use of first-line analgesics, despite evidence that many patients with this allergy label may safely tolerate NSAIDs. OBJECTIVE: We assessed the association between reported NSAID ADRs and postpartum opioid utilization. METHODS: We performed a retrospective cohort study of birthing people who delivered within an integrated health system (January 1, 2017, to December 31, 2020). Study outcomes were postpartum inpatient opioid administrations and opioid prescriptions at discharge. Statistical analysis was performed on a propensity score-matched sample, which was generated with the goal of matching to the covariate distributions from individuals with NSAID ADRs. RESULTS: Of 38,927 eligible participants, there were 883 (2.3%) with an NSAID ADR. Among individuals with reported NSAID ADRs, 49.5% received inpatient opioids in the postpartum period, compared to 34.5% of those with no NSAID ADRs (difference = 15.0%, 95% confidence interval 11.4-18.6%). For patients who received postpartum inpatient opioids, those with NSAID ADRs received a higher total cumulative dose between delivery and hospital discharge (median 30.0 vs 22.5 morphine milligram equivalents [MME] for vaginal deliveries; median 104.4 vs 75.0 MME for cesarean deliveries). The overall proportion of patients receiving an opioid prescription at the time of hospital discharge was higher for patients with NSAID ADRs compared to patients with no NSAID ADRs (39.3% vs 27.2%; difference = 12.1%, 95% confidence interval 8.6-15.6%). CONCLUSION: Patients with reported NSAID ADRs had higher postpartum inpatient opioid utilization and more frequently received opioid prescriptions at hospital discharge compared to those without NSAID ADRs, regardless of mode of delivery.

Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines.

Ticks are hematophagous arachnids that parasitize mammals and other hosts, feeding on their blood. Ticks secrete numerous salivary factors that enhance host blood flow or suppress the host inflammatory response. The recruitment of leukocytes, a hallmark of inflammation, is regulated by chemokines, which activate chemokine receptors on the leukocytes. Ticks target this process by secreting glycoproteins called Evasins, which bind to chemokines and prevent leukocyte recruitment. This review describes the recent discovery of numerous Evasins produced by ticks, their classification into two structural and functional classes, and the efficacy of Evasins in animal models of inflammatory diseases. The review also proposes a standard nomenclature system for Evasins and discusses the potential of repurposing or engineering Evasins as therapeutic anti-inflammatory agents.

Lumateperone Normalizes Pathological Levels of Acute Inflammation through Important Pathways Known to Be Involved in Mood Regulation.

Lumateperone is indicated for the treatment of schizophrenia in adults and for depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate (Calabrese et al., 2021). It is currently under evaluation for the treatment of major depressive disorder (www.ClinicalTrials.gov). Lumateperone acts by selectively modulating serotonin, dopamine, and glutamate neurotransmission in the brain. However, other mechanisms could be involved in the actions of lumateperone, and because of the connection between the immune system and psychiatric health, we hypothesized that lumateperone might improve symptoms of depression, at least in part, by normalizing pathologic inflammation. Here, we show that in male and female C57BL/6 mice subjected to an acute immune challenge, lumateperone reduced aberrantly elevated levels of key proinflammatory cytokines (e.g., IL-1ß, IL-6, and TNF-α) in both brain and serum; lumateperone also reduced proinflammatory cytokines in male mice under acute behavioral stress. Further, we demonstrate that lumateperone altered key genes/pathways involved in maintaining tissue integrity and supporting blood-brain barrier function, such as claudin-5 and intercellular adhesion molecule 1. In addition, in acutely stressed male Sprague Dawley rats, lumateperone conferred anxiolytic- and antianhedonic-like properties while enhancing activity in the mammalian target of rapamycin complex 1 pathway in the PFC. Together, our preclinical findings indicate that lumateperone, in addition to its ability to modulate multiple neurotransmitter systems, could also act by reducing the impact of acute inflammatory challenges.SIGNIFICANCE STATEMENT Lumateperone is indicated in adults to treat schizophrenia and depressive episodes associated with bipolar I or II disorder, as monotherapy and adjunctive therapy with lithium or valproate. Because aberrant immune system activity is associated with increased depressive symptoms, the relationship between lumateperone and immune function was studied. Here, lumateperone reduced the levels of proinflammatory cytokines that were increased following an immune challenge or stress in mice. Additionally, lumateperone altered genes and pathways that maintain blood-brain barrier integrity, restored an index of blood-brain barrier function, reduced anxiety-like behavior in rodents, and enhanced mammalian target of rapamycin complex 1 pathway signaling in the PFC. These results highlight the anti-inflammatory actions of lumateperone and describe how lumateperone may reduce immune pathophysiology, which is associated with depressive symptoms.

Anti-inflammatory and immunoregulatory effects of colistin sulphate on human PBMCs.

In previous studies, CST has been identified as having an immunostimulatory effect on Caenorhabditis elegans and macrophage of rats. Here, we further investigated its immunomodulatory effects on human peripheral blood mononuclear cells (PBMCs). LPS-stimulated PBMCs inflammatory model was established. Flow cytometry was applied to measure phagocytosis of PBMCs. Cytokine mRNA and protein expression levels of LPS-stimulated PBMCs with or without CST were measured by qRT-PCR and ELISA. The transcriptomic profile of CST-treated PBMCs was investigated by RNA-sequencing. Gene Ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) were applied to find potential signalling pathways. PBMCs showed a significant increase in phagocytic activity at 6 h after being incubated with CST at the concentration of 10 µg/mL. In the presence of LPS, CST maintained and promoted the expression of TNF-α and chemokine CCL24. The content of pro-inflammatory cytokines, such as IL-1ß, IL-6 and IFN-γ, which were released from LPS-stimulated PBMCs, was reduced by CST at 6 h. Anti-inflammatory cytokines, such as IL-4, IL-13 and TGF-ß1, were significantly increased by CST at 24 h. A total of 277 differentially expressed immune-related genes (DEIRGs) were detected and cytokine-cytokine receptor interaction was highly enriched. CST presented obvious anti-inflammatory and immunoregulatory effects in LPS-induced PBMCs inflammatory model not only by improving the ability of PBMCs to clear pathogens but also by decreasing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. And the mechanism may be related to cytokine-cytokine receptor interaction.

New paradigms in the study of the cholinergic system and metabolic diseases: Acetyl-and-butyrylcholinesterase.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that belong to the neuromuscular cholinergic system, their main function is to hydrolyze the neurotransmitter acetylcholine (ACh), through their hydrolysis these enzymes regulate the neuronal and neuromuscular cholinergic system. They have recently attracted considerable attention due to the discovery of new enzymatic and nonenzymatic functions. These discoveries have aroused the interest of numerous scientists, consolidating the relevance of this group of enzymes. Recent investigations have revealed a positive correlation between several risk factors for metabolic syndrome (MetS) and the expression of cholinesterases (ChE's), which underscore the impact of high ChE's activity on the pro-inflammatory state associated with MetS. In addition, the excessive hydrolysis of ACh and other choline esters (succinylcholine, propionylcholine, butyrylcholine, etc.) by both ChE's results in the overproduction of fatty acid precursor metabolites, which facilitate the synthesis of very low-density lipoproteins and triacylglycerols. Participation in these processes may represent the link between ChE's and metabolic disorders. However, further scientific research is required to fully elucidate the involvement of ChE's in metabolic diseases. This review aims to collect recent research studies that contribute to understanding the association between the cholinergic system and metabolic diseases.