Explore the vast range of titles available.

Dietary changes associated with industrialization increase the prevalence of chronic diseases, such as obesity, type II diabetes, and cardiovascular disease. This relationship is often attributed to an ‘evolutionary mismatch’ between human physiology and modern nutritional environments. Western diets enriched with foods that were scarce throughout human evolutionary history (e.g. simple sugars and saturated fats) promote inflammation and disease relative to diets more akin to ancestral human hunter-gatherer diets, such as a Mediterranean diet. Peripheral blood monocytes, precursors to macrophages and important mediators of innate immunity and inflammation, are sensitive to the environment and may represent a critical intermediate in the pathway linking diet to disease. We evaluated the effects of 15 months of whole diet manipulations mimicking Western or Mediterranean diet patterns on monocyte polarization in a well-established model of human health, the cynomolgus macaque ( Macaca fascicularis ). Monocyte transcriptional profiles differed markedly between diets, with 40% of transcripts showing differential expression (FDR < 0.05). Monocytes from Western diet consumers were polarized toward a more proinflammatory phenotype. The Western diet shifted the co-expression of 445 gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans, and dramatically altered behavior. For example, Western-fed individuals were more anxious and less socially integrated. These behavioral changes were also associated with some of the effects of diet on gene expression, suggesting an interaction between diet, central nervous system activity, and monocyte gene expression. This study provides new molecular insights into an evolutionary mismatch and uncovers new pathways through which Western diets alter monocyte polarization toward a proinflammatory phenotype.

Background Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating cerebrovascular condition with significant morbidity and mortality. While inflammation plays a critical role in post-hemorrhagic complications, the specific polarization dynamics of monocyte and T cell subpopulations in this context remain poorly understood. This study aims to investigate these immune cell shifts and their correlation with major complications such as angiographic cerebral vasospasm and delayed cerebral ischemia (DCI). Methods We conducted a prospective, controlled observational single-center cohort study in a neurovascular university center of maximum care in Germany. A total of 75 patients with aSAH and 20 healthy controls were included. Blood samples were collected on days 1, 4, 7, and 11 post-bleeding. Flow cytometry was used to analyze monocyte (M1, intermediate, M2) and T cell (Th1, Th2, Th17, Treg) polarization patterns. Primary outcomes included the incidence of angiographic cerebral vasospasm, clinical DCI and/or cerebral infarction due to DCI, and clinical outcome assessed at 6 months via the modified Rankin Scale (mRS). Results Compared to healthy controls, patients with aSAH exhibited a significant decrease in anti-inflammatory alternatively activated monocytes (6.3% vs. 3.0%; p  = 0.04) within 24 h post-bleeding, an increase in pro-inflammatory Th17 T cells (36.3% vs. 6.2%; p  < 0.001) and decrease in anti-inflammatory Th2 cells (45.5% vs. 75.2%; p  < 0.001). A loss of anti-inflammatory alternatively activated monocytes was observed prior to the onset of angiographic cerebral vasospasm (3.8% vs. 2.7%; p  = 0.031) and DCI (4.2% vs. 2.9%; p  = 0.006). No significant correlation was found between immune cell subpopulations and long-term clinical outcomes. Conclusions This study demonstrates a shift toward pro-inflammatory immune cell subpopulations following aSAH, with significant losses of alternatively activated monocytes preceding major complications such as vasospasm and DCI. These findings suggest that immune subpopulation profiling may hold potential as a diagnostic and therapeutic tool in the context of aSAH-related complications. Future studies should aim to clarify whether the observed peripheral immune changes reflect analogous intracerebral immune mechanisms and whether modulating these pathways can improve clinical outcomes.

Subclinical endotoxemia [low levels of bacterial endotoxin (LPS) in the blood stream] has been correlated with chronic inflammatory diseases, with less-understood mechanisms. We have previously shown that chronic exposure to super low doses of LPS polarizes monocytes/macrophages to a pro-inflammatory state characterized by up-regulation of pro-inflammatory regulators such as p62 and simultaneous down-regulation of anti-inflammatory/resolving regulators such as Nrf2. Building upon this observation, here we show that chronic exposure to super-low doses of LPS leads to accumulation of the Nrf2-inhibitory protein Keap1 in murine monocytes. This is accompanied by increases of p62 and MLKL, consistent with a disruption of autolysosome function in polarized monocytes challenged by super-low dose LPS. Monocytes subjected to persistent super-low dose LPS challenge also accumulate higher levels of IKKβ. As a consequence, SLD-LPS challenge leads to an inflammatory monocyte state represented by higher expression of the inflammatory marker Ly6C as well as lower expression of the anti-inflammatory marker CD200R. Further analysis revealed that Keap1 levels are significantly enriched in the Ly6C pro-inflammatory monocyte population. Finally, we show that the TLR4 signaling adaptor TRAM is essential for these effects. Together our study provides novel insight into signaling mechanisms behind low-grade inflammatory monocyte polarization unique to chronic super-low dose LPS exposure.

Three subsets of human monocytes in circulation have been identified and their characterization is still ill-defined. Although glucose and lipid intakes have been demonstrated to exert pro-inflammatory effects on mononuclear cells (MNCs) of healthy subjects, characterization of monocytes phenotypes following macronutrient (glucose, protein, and lipid) intake in humans remains to be determined. Thirty-six healthy, normal weight volunteers were recruited in the study. Subjects were randomly assigned into three groups, each group consisting of 12 participants. Each group drank equal calories (300 kcal) of either glucose or lipids or whey proteins. Each subject served as his own control by drinking 300 mL of water 1 week before or after the caloric intake. Baseline blood samples were drawn at 0, 1, 2, and 3-h intervals post caloric or water intakes. MNCs were isolated, and the expression levels of different cluster of differentiation (CD) markers (CD86, CD11c, CD169, CD206, CD163, CD36, CD68, CD11b, CD16, and CD14) and IL-6 were measured by RT-qPCR. Equicaloric intake of either glucose or lipids or whey proteins resulted in different monocyte phenotypes as demonstrated by changes in the expression levels of CD and polarization markers. Whey proteins intake resulted in significant mRNA upregulation in MNCs of CD68 and CD11b at 1, 2, and 3 h post intake while mRNA of IL-6 was significantly inhibited at 1 h. Lipids intake, on the other hand, resulted in mRNA upregulation of CD11b at 2 and 3 h and CD206 at 1, 2, and 3 h. There were no significant changes in the other CD markers measured (CD86, CD163, CD169, CD36, CD16, and CD14) following either whey proteins or lipids intakes. Glucose intake did not alter mRNA expression of any marker tested except CD206 at 3 h. Macronutrient intake alters the expression levels of polarization markers in MNCs of human subjects. A distinct population of different monocytes phenotypes may result in human circulation following the intake of different macronutrients. Further studies are required to characterize the immunomodulatory effects of macronutrients intake on monocytes phenotypes and their characteristics in humans.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2+, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

Macrophages are among the most abundant cells of the respiratory tract, being characterized by their ability to have different phenotypes, depending on signals from the microenvironment (classically activated M1, alternatively activated M2). Despite contradictory literature data describing role of various macrophage phenotypes, they appear to be coupled to the systems protecting the organism from infectious pathogens and preventing development of excessive tissue responses. Phenotypical changes of lung macrophages are found in various respiratory diseases including bronchial asthma, chronic obstructive pulmonary disease, pulmonary fibrosis and infectious conditions. In this review article, we focused on the biology, origin and characterization of different macrophage phenotypes, and presented current data highlighting their role in development of chronic lung diseases, i.e., bronchial asthma, chronic obstructive pulmonary disease and acute infectious diseases.

Background The continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined. Methods Here, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI. Results EphA4 expression is increased in the injured cortex as early as 2 h post-TBI and on CX3CR1 gfp -positive cells in the peri-lesion. Systemic inhibition or genetic deletion of EphA4 significantly reduced cortical lesion volume and shifted the inflammatory profile of peripheral-derived immune cells to pro-resolving in the damaged cortex. These findings were consistent with in vitro studies showing EphA4 inhibition or deletion altered the inflammatory state of LPS-stimulated monocyte/macrophages towards anti-inflammatory. Phosphoarray analysis revealed that EphA4 may regulate pro-inflammatory gene expression by suppressing the mTOR, Akt, and NF-κB pathways. Our human metadata analysis further demonstrates increased EPHA4 and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients. Conclusions Overall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.

Background/Aims: Macrophages, the most plastic cells in the haematopoietic system, are found in all tissues and show great functional heterogeneity. Sphingosine 1-phosphate (S1P)/ S1P receptors (S1PRs) system is widely involved in the process of inflammatory disease, whereas little evidence concerning its role in functional macrophage polarization is available. Thus, the present study was designed to evaluate the effects of S1P/S1PRs on functional polarization of macrophage in mouse bone marrow (BM)-derived monocyte/macrophages (BMMs). Methods: For the detection of M1 macrophage markers, such as CD86, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1/ chemokine (C-C motif) ligand (CCL) 2, nitric oxide synthase (NOS) 2, and macrophage inflammatory protein (MIP)-1β, RT-qPCR and cytometric bead array (CBA) were performed in cultured primary BMMs after the treatment with selective S1PR2/3 antagonists or specific S1PRs siRNA. Western blotting and immunofluorescence were used for the detection of phosphorylation of JNK1/2. Results: BMMs expressed S1PR1-3 and interestingly, S1PR2/3, but not S1PR1, mediates S1P-induced M1 macrophage polarization of BMMs as their siRNA or antagonists reduced M1 genes’ expression. We found that PTX (inhibitor of G(α)i/o), LY294002 (inhibitor of PI3K) or SP600125 (inhibitor of JNK1/2) prevented up-regulation of M1 genes expression mediated by S1P/S1PR2/3 signal, and S1P-induced JNK phosphorylation was inhibited by antagonists of S1PR2/3, PTX or LY294002. Conclusion: Collectively, our results demonstrate that S1P/S1PR2/3 plays a key role in regulating M1 type polarization of BMMs and acts by activating G(α)i/o/PI3K/JNK signaling pathway, with potential implications for new approaches to inflammatory liver disease therapy.

Macrophages are among the most abundant cells of the respiratory tract, being characterized by their ability to have different phenotypes, depending on signals from the microenvironment (classically activated M1, alternatively activated M2). Despite contradictory literature data describing role of various macrophage phenotypes, they appear to be coupled to the systems protecting the organism from infectious pathogens and preventing development of excessive tissue responses. Phenotypical changes of lung macrophages are found in various respiratory diseases including bronchial asthma, chronic obstructive pulmonary disease, pulmonary fibrosis and infectious conditions. In this review article, we focused on the biology, origin and characterization of different macrophage phenotypes, and presented current data highlighting their role in development of chronic lung diseases, i.e., bronchial asthma, chronic obstructive pulmonary disease and acute infectious diseases.