Search Results (139)

Sepsis is a serious public health problem. sTREM-1 is a marker of inflammatory and infectious processes that has the potential to become a useful tool for predicting the evolution of sepsis. A prediction model for sepsis was constructed by combining sTREM-1, CRP, and a leukogram via a Bayesian network. A translational study carried out with 32 children with congenital heart disease who had undergone surgical correction at a public referral hospital in Northeast Brazil. In the postoperative period, the mean value of sTREM-1 was greater among patients diagnosed with sepsis than among those not diagnosed with sepsis (394.58 pg/mL versus 239.93 pg/mL, p < 0.001). Analysis of the ROC curve for sTREM-1 and sepsis revealed that the area under the curve was 0.761, with a 95% CI (0.587–0.935) and p = 0.013. With the Bayesian model, we found that a 100% probability of sepsis was related to postoperative blood concentrations of CRP above 71 mg/dL, a leukogram above 14,000 cells/μL, and sTREM-1 concentrations above the cutoff point (283.53 pg/mL). The proposed model using the Bayesian network approach with the combination of CRP, leukocyte count, and postoperative sTREM-1 showed promise for the diagnosis of sepsis. Full article

Neuroinflammation is a key feature of Alzheimer’s disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm². Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD. Full article

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

Ursodeoxycholic acid (UDCA) is widely used to treat cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), yet its molecular mechanisms remain unclear. This study investigated the impact of long-term UDCA therapy on circulating levels of the microRNAs miR-34a and miR-506, which are implicated in PBC pathogenesis, and explored associated changes in inflammatory markers and signaling pathways. Serum samples from patients with PBC and PSC were collected before and after UDCA treatment and analyzed for miRNA expression as well as levels of TREM-2 and sCD163. In vitro studies using human cholangiocytes and lipopolysaccharide (LPS) stimulation assessed changes in the expression of miR-34a, TREM-2, and ADAM17. The results showed that the baseline levels of miR-34a and miR-506 were significantly elevated in PBC patients compared to controls and were significantly reduced after UDCA therapy in PBC but not in PSC. UDCA also decreased serum levels of TREM-2 and sCD163. In vitro, it suppressed the LPS-induced expression of miR-34a and ADAM17 while enhancing TREM-2 expression. Single-cell RNA sequencing of liver tissue and immunofluorescence staining confirmed TREM-2 expression in cholangiocytes. These findings suggest that UDCA modulates key inflammatory pathways and miRNAs in PBC, providing mechanistic insights into its therapeutic effect Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and represents a major public health challenge. With increasing life expectancy, the incidence of AD has also increased, highlighting the need for early diagnosis and improved monitoring. Traditionally, diagnosis has relied on clinical symptoms and neuroimaging; however, the introduction of biomarkers has revolutionized disease assessment. Traditional biomarkers, including the Aβ42/Aβ40 ratio, phosphorylated tau (p-Tau181, p-Tau217, and p-Tau231), total tau (t-tau), and neurofilament light chain (NfL), are fundamental for staging AD progression. Updated guidelines introduced the ATX(N) model, which extends biomarker classification to include additional promising biomarkers, such as SNAP-25, YKL-40, GAP-43, VILIP-1, progranulin (PGRN), TREM2, IGF-1, hFABP, MCP-1, TDP-43, and BDNF. Recent advancements have allowed for the detection of these biomarkers not only in CSF but also in plasma and neuron-derived exosomes, offering less invasive and more accessible diagnostic options. This review explores established and emerging biomarkers and emphasizes their roles in early diagnosis, patient stratification, and precision medicine. Full article

TREM2 (triggering receptor expressed on myeloid cells 2) is a membrane-bound receptor primarily expressed on microglia in the central nervous system (CNS). TREM2 plays a crucial role in regulating immune responses, phagocytosis, lipid metabolism, and inflammation. Mutations in the TREM2 gene have been linked to various neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and Nasu–Hakola disease (NHD). These mutations are suggested to impair microglial activation and reduce the ability to clear amyloid aggregates, leading to exacerbated neuroinflammatory responses and accelerating disease progression. This review provides an overview of TREM2 structure, functions, and known pathogenic variants—including Arg47His, Arg62His, His157Tyr, Tyr38Cys, and Thr66Met. Furthermore, the molecular and cellular consequences of TREM2 mutations are introduced, such as impaired ligand binding, altered protein folding and trafficking, enhanced TREM2 shedding, and dysregulated inflammatory signaling. We also highlight recent advances in therapeutic strategies aimed at modulating TREM2 signaling. These include monoclonal antibodies (e.g., AL002, CGX101), small molecule agonists, and gene/cell-based therapies that seek to restore microglial homeostasis, enhance phagocytosis, and reduce neuroinflammation. While these approaches show promise in in vivo/in vitro studies, their clinical translation may be challenged by disease heterogeneity and mutation-specific responses. Additionally, determining the appropriate timing and precise dosing will be essential. Full article

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer’s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn₇MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer’s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer’s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer’s disease, providing a new strategy for innovative drug development. Full article

Apolipoprotein E (APOE) alleles play distinct roles in the pathogenesis of Alzheimer’s disease (AD), with APOEε4 being the strongest genetic risk factor for late-onset AD, while APOEε2 appears protective. Despite extensive research, the precise mechanisms by which APOE alleles contribute to AD pathology remain incompletely understood. Recent advances in multi-omics technologies and single-cell analyses have revealed that APOE alleles shape microglial phenotypes, thereby affecting amyloid clearance, inflammatory responses, tau pathology, and lipid metabolism. In this review, we provide a detailed overview of how APOE alleles differentially regulate microglial activation, inflammatory signaling, phagocytic activity, and lipid metabolism in the context of AD, with a particular focus on the APOEε4-mediated disruption of microglial homeostasis via pathways such as TREM2 signaling, NF-κB/NLRP3 activation, ACSL1 upregulation, and HIF-1α induction. These insights not only advance our understanding of APOE allele-specific contributions to AD pathology, but also highlight novel therapeutic strategies targeting the APOE–microglia axis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) accumulation and neuroinflammation. A previous multicenter, phase 2, double-blind, placebo-controlled trial randomized 179 participants into placebo or resveratrol over 52 weeks. Sub-analysis of CSF biomarkers of neuronal damage, inflammation, and microglial activity was performed in a subset of patients treated with a placebo (n = 21) versus resveratrol (n = 30). Markers of neuronal damage, including neuron-specific enolase and hyperphosphorylated neurofilaments, were reduced. Microglial activation was measured via a triggering receptor expressed on myeloid cells (TREM)-2 at baseline and after resveratrol treatment. Resveratrol significantly reduced CSF TREM2 levels and decreased inflammation and tissue damage, including matrix metalloprotease (MMP)-9. Cathepsin D, a lysosomal marker of autophagy, was reduced in the resveratrol group compared with placebo, while angiogenin, a marker of vascular angiogenesis, was increased. These data suggest that resveratrol may exert anti-inflammatory and neuroprotective effects in AD by reducing CSF TREM2 and other markers of neuronal damage. Further research is needed to assess the significance of these biomarker changes on clinical outcomes in patients with neurodegenerative diseases. Full article

Women entrepreneurs in small to medium enterprises (SMEs) in emerging countries play an essential role in the economy of developing countries such as Indonesia. Drawing on the resource-based view and entrepreneurship effectuation theory, this study examines how women’s entrepreneurial effectuation (WEE) modeled as a higher-order construct (HOC) comprising its four dimensions (LOCs)—namely, flexibility, experimentation, affordable loss, and pre-commitment—can influence employee performance (EMPRF) mediated by structural (STREM) and psychological empowerment (PSYEM). Using a disjointed two-stage PLS-SEM approach with data from 218 female SME employees, our results confirm that flexibility is the most salient effectuation dimension. WEE strongly predicts both STREM and PSYEM but shows no direct impact on EMPRF, highlighting that effectuation must be activated via empowerment mechanisms. PSYEM emerges as the strongest mediator of WEE on EMPRF, with STREM also contributing significantly and being amplified by gender equality practices; market orientation, by contrast, fails to moderate any paths. Theoretically, these findings enrich resource-based view (RBV) theory by integrating entrepreneurial effectuation dimensions and empowerment as human resource capabilities that generate inimitable performance gains. Practically, they suggest that women-led SMEs should integrate effectuation heuristics with targeted empowerment programs to realize the full potential of their human capital. Full article

The formation of amyloid beta (Aβ) plaques is a central process in the development of Alzheimer’s disease (AD). Although its causative role or the effectiveness of therapeutic targeting is still debated, the key involvement of Aβ in the pathogenesis of neuroinflammation and neurodegeneration in AD is broadly accepted. In this review, we emphasize the role of lipid rafts, both in APP cleavage producing Aβ in neurons and in mediating Aβ inflammatory signaling in microglia. We introduce the term inflammarafts to characterize the Aβ-driven formation of enlarged, cholesterol-rich lipid rafts in activated microglia, which support protein–protein and lipid–protein interactions of inflammatory receptors. Examples reviewed include toll-like receptors (TLR2, TLR4), scavenger receptors (CD36, RAGE), and TREM2. The downstream pathways lead to the production of cytokines and reactive oxygen species, intensifying neuroinflammation and resulting in neuronal injury and cognitive decline. We further summarize emerging therapeutic strategies and emphasize the utility of apolipoprotein A-I binding protein (AIBP) in selective targeting of inflammarafts and attenuation of microglia-driven inflammation. Unlike the targeting of a single inflammatory receptor or a secretase, selective disruption of inflammarafts and preservation of physiological lipid rafts offer a novel approach to targeting multiple components and processes that contribute to neuroinflammation in AD. Full article

COVID-19 has caused millions of deaths around the world. The respiratory system is the main target of this disease, but it has also been reported to attack the central nervous system, creating a neuroinflammatory environment with the release of proinflammatory cytokines. There are several studies suggesting a possible relationship between Alzheimer’s disease and COVID-19. Therefore, in this study, machine learning microarray analysis was performed to identify key genes in COVID-19 that may be associated with Alzheimer’s disease. The dataset is identified as GSE177477, containing 47 samples. A bioconductor oligo package in the RStudio (version 4.3.3) environment was used to process and normalize the data. Subsequently, one-way ANOVA was used to obtain differentially expressed genes. We used decision tree generation to classify 47 samples. The study identified 1856 differentially expressed genes. Three decision trees were generated where three genes (DNAJC16, TREM1, and UCP2) were identified that differentiated patients. The best decision tree obtained an accuracy of 72.34%, with a sensitivity of 72.34% and a specificity of 86.17%. The genes identified with the decision trees may be involved in processes like those of Alzheimer’s disease, such as in the inflammation process, amyloid pathologies, and related to type 2 diabetes mellitus. Full article

The Slovenian autochthonous breed, Krškopolje pig, is known for high fatness and better adaptability to different environmental conditions and feed resources. However, the metabolic processes underlying these adaptations, especially in response to different diets, have not yet been studied. A deeper understanding of these mechanisms could provide valuable insights into the breed’s adaptability to different environmental conditions. Therefore, the main objective of this study was to evaluate the effect of a low-protein (LP) diet on adipose tissue in Krškopolje pigs reared in either organic outdoor (n = 2 × 12) or conventional indoor (n = 2 × 14) systems. In the outdoor system, the LP diet had no effect on adipocyte size compared to the control (high-protein) diet, while it increased lipogenic enzyme activities and monounsaturated fatty acid content, and decreased polyunsaturated fatty acid content (p < 0.05). RNA sequencing revealed the upregulation of 28 genes and the downregulation of 37 genes. The upregulated genes were mainly involved in lipid metabolism (ACLY, FASN, ACACA, MOGAT2), oxidative stress, and mitochondrial function. In the indoor system, pigs on the LP diet had smaller adipocytes (p < 0.05), whereas no differences were detected in the lipogenic enzyme activities or fatty acid composition (p > 0.10). RNA sequencing revealed 30 upregulated and 28 downregulated genes. In the indoor system, heat shock proteins (HSP70.2, HSPA6) were upregulated in pigs on the LP diet, while genes involved in the innate immune system (MSR1, TREM2, CSF3R) were downregulated. To conclude, the present study showed that LP diet affected adipose tissue metabolism and gene expression in Krškopolje pigs, with different transcriptomic responses observed in outdoor and indoor rearing conditions. Full article

Antibiotic de-escalation (ADE) is important to help optimize antibiotic use and balance the positive and negative effects of antimicrobial therapy. ADE should be performed promptly, and infections should be treated with the shortest course of antimicrobials as clinically feasible to avoid unnecessary use of broad-spectrum antimicrobials. Several tools have been developed to increase efficient ADE, including rapid diagnostic tests (ex. multiplex PCR), MRSA nasal PCR/culture, and biomarkers. Multiplex PCR and MRSA nasal PCR/culture have been associated with reductions in inappropriate antibiotic use. Procalcitonin, a biomarker, has been associated with shorter antimicrobial durations in some studies; however, widespread use may be limited by lack of specificity for bacterial infections, cost, and lack of set cut-off points. Additional biomarkers such as IL-6, HMGB1, presepsin, sTREM-1, CD64, PSP, proadrenomedullin, and pentraxin-3 are currently being studied. As technology improves, additional tools may be leveraged to better optimize ADE even better, such as antimicrobial spectrum scoring tools and artificial intelligence (AI). Spectrum scores, which quantify antibiotic activity using specific numeric values, could be incorporated into electronic health records to identify patients on unnecessarily broad antibiotics. AI modeling has the potential to predict personal antibiograms or provide the probability that an empiric regimen may cover a particular infection, among other potential applications. This review will discuss the literature associated with ADE in the ICU, selected tools to help guide ADE, and perspectives on how to implement ADE into clinical practice. Full article

Background/Objectives: The activation of microglia and the activity of innate immunity have recently been recognized as part of Parkinson’s Disease (PD) pathophysiology. Triggering receptor expressed on myeloid cells 2 (TREM2) is a gene with neuroprotective roles. Its variations are associated with microglial-associated neurodegeneration. The objective of the present review is to investigate the current evidence on the role of TREM2 in PD pathophysiology. Methods: A comprehensive search was performed using PubMed, Medline, and Web of Science, looking for English papers investigating the role of TREM2 in PD, or more in general, the genetic profile of microglia. Results: Thirty-one papers were considered relevant. Preclinical studies with PD models showed some contradictory results, even if a loss of function of TREM2 is generally associated with a microglial activation in α-synuclein-induced inflammatory processes. The role for TREM2 genetic variations in PD patients should be taken with even more caution. The increase in the soluble extracellular segment of TREM2 (sTREM2) in cerebrospinal fluid of PD patients seems to be associated with increased risk of cognitive decline. Conclusions: There is increasing evidence that TREM2 may have an important role in PD pathophysiology as demonstrated by preclinical and clinical studies. Further investigations are needed to confirm this role and may lead the way for future targeted therapies for different neurodegenerative disorders. Full article