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BMC Cancer Jun 2024The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been...
BACKGROUND AND AIMS
The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort.
METHODS
The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted.
RESULTS
Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 10/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 10/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 10/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98).
CONCLUSION
Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.
Topics: Humans; Fluorouracil; Colorectal Neoplasms; Male; Female; Middle Aged; Cardiotoxicity; Retrospective Studies; Aged; Inflammation; Antimetabolites, Antineoplastic; Monocytes; Adult
PubMed: 38951749
DOI: 10.1186/s12885-024-12568-0 -
Scientific Reports Jun 2024Bovine alveolar macrophages (AMs) defend the lungs against pathogens such as Mycobacterium bovis (M. bovis), the causative agent of bovine tuberculosis. However, little...
Bovine alveolar macrophages (AMs) defend the lungs against pathogens such as Mycobacterium bovis (M. bovis), the causative agent of bovine tuberculosis. However, little is known about the surface molecules expressed by bovine AMs and whether there is heterogeneity within the population. The purpose of this study was to characterise the bovine AM cell surface phenotype using flow cytometry. Bronchoalveolar lavage samples from four different calves were stained with a combination of antibodies against immune cell molecules prior to flow cytometric analysis. To assess the degree of expression, we considered the distribution and relative intensities of stained and unstained cells. We demonstrated that bovine AMs have high expression of CD172a, ADGRE1, CD206, and CD14, moderate expression of CD80, MHC II, CD1b, and CD40, low expression of CX3CR1 and CD86, and little or no expression of CD16 and CD26. Two distinct subsets of bovine AMs were identified based on CD163 expression. Subsequent analysis showed that the CD163 subset had greater expression of other typical macrophage molecules compared to the CD163 subset, suggesting that these cells may perform different roles during infection. The characterisation of the uninfected bovine AM phenotype will provide a foundation for the examination of M. bovis-infected AMs.
Topics: Animals; Cattle; Macrophages, Alveolar; Antigens, Differentiation, Myelomonocytic; Antigens, CD; Receptors, Cell Surface; Phenotype; Mycobacterium bovis; Flow Cytometry; Tuberculosis, Bovine; Immunophenotyping; Bronchoalveolar Lavage Fluid
PubMed: 38951667
DOI: 10.1038/s41598-024-65868-7 -
Nature Communications Jun 2024Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is...
Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2 mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.
Topics: Animals; Interferon-gamma; Interleukin-12; Male; Insulin Resistance; Obesity; Mice; Fatty Liver; Mice, Knockout; Macrophages; Signal Transduction; Liver; Mice, Inbred C57BL; Diet, High-Fat; Receptors, Interferon; Interferon gamma Receptor; Liver Cirrhosis
PubMed: 38951527
DOI: 10.1038/s41467-024-49633-y -
Nature Communications Jun 2024HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein...
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Topics: Humans; Macrophages; vpr Gene Products, Human Immunodeficiency Virus; HIV-1; Trans-Activators; Proto-Oncogene Proteins; Immunity, Innate; Ubiquitin-Protein Ligases; HIV Infections; HEK293 Cells; Virion; Protein Serine-Threonine Kinases
PubMed: 38951492
DOI: 10.1038/s41467-024-49635-w -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Apr 2024This article reviews the development history of chimeric antigen receptor macrophage (CAR-M) therapy, discusses its application in malignant hematologic diseases,... (Review)
Review
This article reviews the development history of chimeric antigen receptor macrophage (CAR-M) therapy, discusses its application in malignant hematologic diseases, introduces related clinical trials, analyzes the advantages and challenges faced by CAR-M therapy in clinical application, and looks forward to its future use in the treatment of malignant hematologic diseases.
Topics: Humans; Hematologic Neoplasms; Macrophages; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Hematologic Diseases
PubMed: 38951075
DOI: 10.3760/cma.j.cn121090-20231103-00248 -
Microbes and Infection Jun 2024Trypanosoma cruzi, the etiological agent of Chagas' disease, can infect both phagocytic and non-phagocytic cells. T. cruzi gp82 and gp90 are cell surface proteins...
Trypanosoma cruzi, the etiological agent of Chagas' disease, can infect both phagocytic and non-phagocytic cells. T. cruzi gp82 and gp90 are cell surface proteins belonging to Group II trans-sialidases known to be involved in host cell binding and invasion. Phosphatidylinositol kinases (PIK) are lipid kinases that phosphorylate phospholipids in their substrates or in themselves, regulating important cellular functions such as metabolism, cell cycle and survival. Vps34, a class III PIK, regulates autophagy, trimeric G-protein signaling, and the mTOR (mammalian Target of Rapamycin) nutrient-sensing pathway. The mammalian autophagy gene Beclin1 interacts to Vps34 forming Beclin 1-Vps34 complexes involved in autophagy and protein sorting. In T. cruzi epimastigotes, (a non-infective replicative form), TcVps34 has been related to morphological and functional changes associated to vesicular trafficking, osmoregulation and receptor-mediated endocytosis. We aimed to characterize the role of TcVps34 during invasion of HeLa cells by metacyclic (MT) forms. MTs overexpressing TcVps34 showed lower invasion rates compared to controls, whilst exhibiting a significant decrease in gp82 expression in the parasite surface. In addition, we showed that T. cruzi Beclin (TcBeclin1) colocalizes with TcVps34 in epimastigotes, thus suggesting the formation of complexes that may play conserved cellular roles already described for other eukaryotes.
PubMed: 38950642
DOI: 10.1016/j.micinf.2024.105385 -
The Journal of Clinical Investigation Jul 2024
Topics: Animals; Mice; Signal Transduction; Macrophages; Receptors, CCR2; NF-kappa B; Disease Models, Animal; Myocardium; Humans; Arrhythmogenic Right Ventricular Dysplasia; Mice, Knockout
PubMed: 38949031
DOI: 10.1172/JCI183441 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024Intracerebral hemorrhage (ICH), the second most common type of stroke, can cause long-lasting disability in the afflicted patients. The study was conducted to examine...
[Relationship Between the Migration of Endogenous Neural Stem Cells and the Pattern of Change in Immune Cell Phenotypes in the Microenvironment After Intracerebral Hemorrhage in Rats].
OBJECTIVE
Intracerebral hemorrhage (ICH), the second most common type of stroke, can cause long-lasting disability in the afflicted patients. The study was conducted to examine the patterns of change in endogenous neural stem cells (eNSCs) and in the regenerative microenvironment after ICH, to observe the relationship between the migration of eNSCs and the pattern of change in the polarization state of immune cells in the microenvironment, and provide a research basis for research on clinical nerve repair.
METHODS
The collagenase injection method was used for modeling. The ICH model was induced in adult female Sprague-Dawley (SD) rats by injecting type VII collagenase (2 U) into the brain tissue of rats. All the experimental rats weighed 280-300 g. In order to simulate the ICU at different time points, including the acute phase (within 1 week), subacute phase (1-3 weeks), and the chronic phase (over 3 weeks), brain tissues were harvested at 3 day post injection (3 DPI), 10 DPI, 20 DPI, and 30 DPI to evaluate the modeling effect. Immunofluorescence staining of the brain tissue sections was performed with DCX antibody to observe the pattern of change in the migration of eNSCs in the brain tissue at different time points. Immunofluorescence staining of brain tissue sections was performed with CD206 antibody and CD86 antibody for respective observation of the pattern of change in pro-inflammatory (M1-type) and anti-inflammatory (M2-type) immune cells in the regenerative microenvironment of the brain tissue after ICM.
RESULTS
Spontaneous ICH was successfully induced by injecting type Ⅶ collagenase into the brain tissue of SD rats. The volume of the hematoma formed started to gradually increase at 3 DPI and reached its maximum at 10 DPI. After that, the hematoma was gradually absorbed and was completely absorbed by 30 DPI. Analysis of the pattern of changes in eNSCs in the brain tissue showed that a small number of eNSCs were activated at 3 DPI, but very soon their number started to decrease. By 10 DPI, eNSCs gradually began to increase. A large number of eNSCs migrated to the hemorrhage site at 20 DPI. Then the number of eNSCs decreased significantly at 30 DPI (<0.01). Analysis of the immune microenvironment of the brain tissue showed that pro-inflammatory (M1 type) immune cells increased significantly at 10 and 20 DPI (<0.01) and decreased at 30 DPI. Anti-inflammatory (M2 type) immune cells began to increase gradually at 3 DPI, decreased significantly at 20 DPI (<0.05), and then showed an increase at 30 DPI.
CONCLUSION
After ICH in rats, eNSCs migrating toward the site of ICH first increase and then decrease. The immune microenvironment demonstrates a pattern of change in which inflammation is suppressed at first, then promoted, and finally suppressed again. Inflammation may have a stimulatory effect on the migration of eNSCs, but excessive inflammatory activation has an inhibitory effect on the differentiation and further activation of eNSCs. After ICH, the early stage of repair and protection (10 d) and the subacute phase (20 d) may provide the best opportunities for intervention.
Topics: Animals; Rats, Sprague-Dawley; Cerebral Hemorrhage; Rats; Female; Doublecortin Protein; Neural Stem Cells; Cell Movement; Disease Models, Animal; Phenotype; Brain; Macrophages
PubMed: 38948290
DOI: 10.12182/20240560402 -
Theranostics 2024Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs...
Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism. In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay. The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation and . Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.
Topics: Animals; Extracellular Vesicles; Mesenchymal Stem Cells; Osteoporosis; Apoptosis; Mice; Female; Osteogenesis; Cell Differentiation; Mesenchymal Stem Cell Transplantation; Cell Proliferation; Mice, Inbred C57BL; Disease Models, Animal; Ovariectomy; Proteomics; Signal Transduction
PubMed: 38948067
DOI: 10.7150/thno.96174 -
Theranostics 2024Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates...
Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of mA modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. mA modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-β1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing mA modification on and mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-β1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting mA modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.
Topics: Humans; Methyltransferases; Monocytes; Fibrosis; Male; Animals; NF-kappa B; Erythrocytes; Adenosine; Female; Methylation; Mice; Transforming Growth Factor beta1; Cell-Derived Microparticles; Leukocytes, Mononuclear; Angiotensin II; Receptors, Interleukin-8B; Ventricular Remodeling; Myocardium; Nanomedicine
PubMed: 38948064
DOI: 10.7150/thno.95664