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European Journal of Pharmaceutics and... Jun 2024Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly...
Liposomes represent one of the most extensively studied nano-carriers due to their potential in targeted drug delivery. However, the complex in vivo fate, particularly under pathological conditions, presents challenges for clinical translation of liposomal therapeutics. Liver serves as the most important organ for liposome accumulation and metabolism. Unfortunately, the fate of liposomes under pathological liver conditions has been significantly overlooked. This study aimed to investigate the in vivo pharmacokinetic profile and biodistribution profile of liposomes under drug-induced liver injury (DILI) conditions. Two classic DILI animal models, i.e. acetaminophen-induced acute liver injury (AILI) and triptolide-induced subacute liver injury (TILI), were established to observe the effect of pathological liver conditions on the in vivo performance of liposomes. The study revealed significant changes in the in vivo fate of liposomes following DILI, including prolonged blood circulation and enhanced hepatic accumulation of liposomes. Changes in the composition of plasma proteins and mononuclear phagocyte system (MPS)-related cell subpopulations collectively led to the altered in vivo fate of liposomes under liver injury conditions. Despite liver injury, macrophages remained the primary cells responsible for liposomes uptake in liver, with the recruited monocyte-derived macrophages exhibiting enhanced ability to phagocytose liposomes under pathological conditions. These findings indicated that high capture of liposomes by the recruited hepatic macrophages not only offered potential solutions for targeted delivery, but also warned the clinical application of patients under pathological liver conditions.
PubMed: 38945407
DOI: 10.1016/j.ejpb.2024.114389 -
Poultry Science May 2024The proliferation and death of granulosa cells (GCs) in poultry play a decisive role in follicular fate and egg production. The follicular fluid (FF) contains a variety...
The proliferation and death of granulosa cells (GCs) in poultry play a decisive role in follicular fate and egg production. The follicular fluid (FF) contains a variety of nutrients and genetic substances to ensure the communication between follicular cells. Exosomes, as a new intercellular communication, could carry and transport the proteins, RNA, and lipids to react on GCs, which had been found in FF of various domestic animals. Whether exosomes of FF in poultry play a similar role is unclear. In this study, geese, a poultry with low egg production, were chosen, and the effect of FF exosomes on the proliferation and death of GCs was investigated. Firstly, there were not only a large number of healthy small yellow follicles (HSYFs) but also some atresia small yellow follicles (ASYFs) in the egg-laying stage. Also, the GC layers of ASYFs became loose interconnections, inward detachment, and diminished survival rate than that of HSYFs. Besides, compared to HSYFs, the contents of E2, P4, and the mRNA expression levels of ferroptosis-related genes GPX4, FPN1, and FTH1 were significantly decreased, while COX2, NCOA4, VDAC3 mRNA were significantly increased, and the structure of mitochondrial cristae disappeared and the outer membrane broke in the GC layers of ASYFs. Moreover, the ROS, MDA, and oxidation levels in the GC layers of ASYFs were significantly higher than those of HSYFs. All these hinted that ferroptosis might result in a large number of GCs death and involvement in follicle atresia. Secondly, FF exosomes were isolated from HSYFs and ASYFs, respectively, and identified by TEM, NTA, and detection of exosome marker proteins. Also, we found the exosomes were phagocytic by GCs by tracking CM-Dil. Moreover, the addition of ASYF-FF exosomes significantly elevated the MDA content, Fe levels, and the mitochondrial membrane potential (MMP) in GCs, thus significantly inhibiting the proliferation of GCs, which was restored by the ferroptosis inhibitor ferrostatin-1. Thirdly, the proteomic sequencing was performed between FF-derived exosomes of HSYFs and ASYFs. We obtained 1615 differentially expressed proteins, which were mainly enriched in the protein transport and ferroptosis pathways. Among them, HMOX1 was enriched in the ferroptosis pathway based on differential protein-protein interaction network analysis. Finally, the role of HMOX1 in regulating ferroptosis in GCs was further explored. The highly expressed HMOX1 was observed in the exosomes of ASYF-FF than that in HSYF-FF. Overexpression of HMOX1 increased ATG5, LC3II, and NCOA4 expression and reduced the expression of FTH1, GPX4, PCBP2, FPN1 in the ferroptosis pathway, also promoted intracellular Fe accumulation and MDA surge, which drove ferroptosis in GCs. The effects of HMOX1 on ferroptosis could be blocked by its inhibitor Znpp. Taken together, the important protein HMOX1 was identified in FF, which could be delivered to GCs via exosomes, triggering ferroptosis and thus determining the fate of follicles.
PubMed: 38943808
DOI: 10.1016/j.psj.2024.103912 -
Molekuliarnaia Biologiia 2024Murine gammaherpesvirus 68 (MHV68) establishes latency mainly in B cells and causes lymphomas reminiscent of human gammaherpesvirus diseases in laboratory mice. To study...
Murine gammaherpesvirus 68 (MHV68) establishes latency mainly in B cells and causes lymphomas reminiscent of human gammaherpesvirus diseases in laboratory mice. To study the molecular mechanism of virus infection and how the viral determinants control cell and eventually cause tumorigenesis, readily available latently infected cell lines are essential. For in vitro MHV68 latency studies, only two cell culture systems have been available. Gammaherpesviruses are known to infect developing B cells and macrophages, therefore we aimed to expand the MHV68 latently infected cell line repertoire. Here, several latently infected immature B cell and macrophage-like cell line clones were generated. Hygromycin-resistant recombinant MHV68 was isolated from a laboratory-made latent cell line, HE2.1, and propagated to develop stable cell lines that carry the viral genome under hygromycin selection. Subclones of these cells lines were analyzed for viral miRNA expression by TaqMan qPCR and assessed for expression of a lytic viral transcript M3. The cell lines maintain the viral genome as an episome shown by the digestion-circularization PCR assay. Latently infected cell lines generated here do not express viral miRNAs higher than the parental cell line. However, these cell lines may provide an alternative tool to study latency mechanisms and miRNA target identification studies.
Topics: Animals; Mice; MicroRNAs; Virus Latency; Genome, Viral; Hygromycin B; Macrophages; Rhadinovirus; RNA, Viral; Cell Line; Gene Expression Regulation, Viral; Precursor Cells, B-Lymphoid; Herpesviridae Infections; Cinnamates
PubMed: 38943586
DOI: No ID Found -
BMC Cancer Jun 2024Exploring the predictive value of NLR, PLR, MLR, and SII for the severity of cervical cancer screening abnormalities in patients.
OBJECTIVE
Exploring the predictive value of NLR, PLR, MLR, and SII for the severity of cervical cancer screening abnormalities in patients.
METHODS
A retrospective analysis was conducted on the data of 324 patients suspected of cervical lesions due to abnormal TCT and/or HPV in our hospital from January 2023 to December 2023, who underwent colposcopy. The pathological results of colposcopic biopsy confirmed that there were 140 cases of chronic cervicitis, which classified as the group without cervical lesions. The cervical lesion group included 184 cases, including 91 cases of LSIL, 71 cases of HSIL, and 22 cases of cervical cancer. Compared the differences in preoperative peripheral blood NLR, PLR, MLR, and SII among different groups of patients, and evaluated their predictive value for the severity of cervical lesions using Receiver Operating Characteristic (ROC) curves.
RESULTS
The levels of NLR, PLR, and SII in the group without cervical lesions were lower than those in the group with cervical lesions (p < 0.05), and there was no statistically significant difference in MLR (p > 0.05). The comparison of NLR among LSIL, HSIL, and cervical cancer groups showed statistically significant differences (p < 0.05), while PLR, MLR, and SII showed no statistically significant differences (p > 0.05). The AUC of peripheral blood NLR, PLR, and SII for predicting cervical lesions were 0.569, 0.582, and 0.572, respectively. The optimal cutoff values were 2.3,176.48, and 603.56. The sensitivity and specificity were 38.6% and 73.6%, 28.8% and 85.7%, 37.5% and 76.4%, respectively. At the same time, the joint testing of the three had the highest efficiency, with sensitivity of 69% and specificity of 45%.
CONCLUSION
Although the peripheral blood NLR, PLR, and SII of the cervical lesions patients were higher than those without cervical lesions in cervical cancer screening abnormal patients, the predictive ROC curve discrimination was low. Therefore, it is not recommended to use preoperative peripheral blood inflammatory markers as markers for cervical cancer screening abnormal patient diversion.
Topics: Humans; Female; Uterine Cervical Neoplasms; Retrospective Studies; Adult; Middle Aged; ROC Curve; Predictive Value of Tests; Uterine Cervical Dysplasia; Early Detection of Cancer; Colposcopy; Severity of Illness Index; Biomarkers, Tumor; Neutrophils; Inflammation
PubMed: 38943072
DOI: 10.1186/s12885-024-12561-7 -
Translational Stroke Research Jun 2024Blood components released by erythrolysis play an important role in secondary brain injury and posthemorrhagic hydrocephalus (PHH) after intraventricular hemorrhage...
Blood components released by erythrolysis play an important role in secondary brain injury and posthemorrhagic hydrocephalus (PHH) after intraventricular hemorrhage (IVH). The current study examined the impact of N-acetylheparin (NAH), a complement inhibitor, on early erythrolysis, PHH and iron accumulation in aged rats following IVH. This study, on 18-months-old male Fischer 344 rats, was in 3 parts. First, rats had an intracerebroventricular injection of autologous blood (IVH) mixed with NAH or saline, or saline alone. After MRI at four hours, Western blot and immunohistochemistry examined complement activation and electron microscopy choroid plexus and periventricular damage. Second, rats had an IVH with NAH or vehicle, or saline. Rats underwent serial MRI at 4 h and 1 day to assess ventricular volume and erythrolysis. Immunohistochemistry and H&E staining examined secondary brain injury. Third, rats had an IVH with NAH or vehicle. Serial MRIs on day 1 and 28 assessed ventricular volume and iron accumulation. H&E staining and immunofluorescence evaluated choroid plexus phagocytes. Complement activation was found 4 h after IVH, and co-injection of NAH inhibited that activation. NAH administration attenuated erythrolysis, reduced ventricular volume, alleviated periventricular and choroid plexus injury at 4 h and 1 day after IVH. NAH decreased iron accumulation, the number of choroid plexus phagocytes, and attenuated hydrocephalus at 28 days after IVH. Inhibiting complement can reduce early erythrolysis, attenuates hydrocephalus and iron accumulation after IVH in aged animals.
PubMed: 38943026
DOI: 10.1007/s12975-024-01273-6 -
Scientific Reports Jun 2024The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through...
The tobacco alkaloid nicotine is known for its activation of neuronal nicotinic acetylcholine receptors. Nicotine is consumed in different ways such as through conventional smoking, e-cigarettes, snuff or nicotine pouches. The use of snuff has been associated with several adverse health effects, such as inflammatory reactions of the oral mucosa and oral cavity cancer. We performed a metabolomic analysis of nicotine-exposed THP-1 human monocytes. Cells were exposed to 5 mM of the alkaloid for up to 4 h, and cell extracts and medium subjected to untargeted liquid chromatography high-resolution mass spectrometry. Raw data processing revealed 17 nicotine biotransformation products. Among these, cotinine and nornicotine were identified as the two major cellular biotransformation products. The application of multi- and univariate statistical analyses resulted in the annotation, up to a certain level of identification, of 12 compounds in the cell extracts and 13 compounds in the medium that were altered by nicotine exposure. Of these, four were verified as methylthioadenosine, cytosine, uric acid, and L-glutamate. Methylthioadenosine levels were affected in both cells and the medium, while cytosine, uric acid, and L-glutamate levels were affected in the medium only. The effects of smoking on the pathways involving these metabolites have been previously demonstrated in humans. Most of the other discriminating compounds, which were merely tentatively or not fully identified, were amino acids or amino acid derivatives. In conclusion, our preliminary data suggest that some of the potentially adverse effects related to smoking may also be expected when nicotine is consumed via snuff or nicotine pouches.
Topics: Humans; Nicotine; Metabolomics; Monocytes; Mass Spectrometry; THP-1 Cells; Cotinine; Chromatography, Liquid; Metabolome; Glutamic Acid
PubMed: 38942832
DOI: 10.1038/s41598-024-65733-7 -
Cell Death & Disease Jun 2024S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory...
S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9 neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.
Topics: Calgranulin A; Neutrophils; Sepsis; Humans; Calgranulin B; Mitochondria; Electron Transport Complex I; Endothelial Cells; Animals; Mice; Male; Human Umbilical Vein Endothelial Cells; Mitophagy; Mice, Inbred C57BL; Apoptosis
PubMed: 38942784
DOI: 10.1038/s41419-024-06849-6 -
Science Immunology Jun 2024Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require...
Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.
Topics: Animals; Immunological Synapses; Single-Cell Analysis; Mice; T-Lymphocytes, Cytotoxic; Biomechanical Phenomena; Cytotoxicity, Immunologic; Macrophages; Mice, Inbred C57BL
PubMed: 38941478
DOI: 10.1126/sciimmunol.adj2898 -
Science Advances Jun 2024Oral medication for ulcerative colitis (UC) is often hindered by challenges such as inadequate accumulation, limited penetration of mucus barriers, and the intricate...
Oral medication for ulcerative colitis (UC) is often hindered by challenges such as inadequate accumulation, limited penetration of mucus barriers, and the intricate task of mitigating excessive ROS and inflammatory cytokines. Here, we present a strategy involving sodium alginate microspheres (SAMs) incorporating M2 macrophage membrane (M2M)-coated Janus nanomotors (denominated as Motor@M2M) for targeted treatment of UC. SAM provides a protective barrier, ensuring that Motor@M2M withstands the harsh gastric milieu and exhibits controlled release. M2M enhances the targeting precision of nanomotors to inflammatory tissues and acts as a decoy for the neutralization of inflammatory cytokines. Catalytic decomposition of HO by MnO in the oxidative microenvironment generates O bubbles, propelling Motor@M2M across the mucus barrier into inflamed colon tissues. Upon oral administration, Motor@M2M@SAM notably ameliorated UC severity, including inflammation mitigation, ROS scavenging, macrophage reprogramming, and restoration of the intestinal barrier and microbiota. Consequently, our investigation introduces a promising oral microsphere formulation of macrophage-biomimetic nanorobots, providing a promising approach for UC treatment.
Topics: Colitis, Ulcerative; Microspheres; Macrophages; Animals; Administration, Oral; Mice; Alginates; Humans; Disease Models, Animal; Reactive Oxygen Species; Nanoparticles; Drug Delivery Systems; Hydrogen Peroxide
PubMed: 38941458
DOI: 10.1126/sciadv.ado6798 -
Medicine Jun 2024Neutrophil to lymphocyte ratio (NLR) has been considered a prognostic biomarker of mortality and other major cardiac events. This study investigates NLR's efficacy in... (Meta-Analysis)
Meta-Analysis
Neutrophil to lymphocyte ratio as a prognostic marker for cardiovascular outcomes in patients with ST-segment elevation myocardial infarction after percutaneous coronary intervention: A systematic review and meta-analysis.
BACKGROUND
Neutrophil to lymphocyte ratio (NLR) has been considered a prognostic biomarker of mortality and other major cardiac events. This study investigates NLR's efficacy in predicting in-hospital and long-term outcomes in patients with ST-segment elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI).
METHODS
Electronic databases (PUBMED, Cochrane CENTRAL, ERIC, Embase, Ovid, and Google Scholar) were searched till June 2022 to identify studies having STEMI patients who underwent PCI. Risk ratios and mean differences (MDs), along with their corresponding 95% confidence intervals (Cis) and standard deviations (SDs), were pooled using a random-effect model. This meta-analysis has been registered on Prospero (ID: CRD42022344072).
RESULTS
A total of 35 studies with 28,756 patients were included. Pooled estimates revealed an increased incidence of primary outcomes; in-hospital all-cause mortality (RR = 3.52; 95% CI = 2.93-4.24), long-term all-cause mortality (HR = 1.07; 95% CI = 1.00-1.14), (RR = 3.32; 95% CI = 2.57-4.30); in-hospital cardiovascular mortality (RR = 2.66; 95% CI = 2.04-3.48), long-term cardiovascular mortality (RR = 6.67; 95% CI = 4.06-10.95); in-hospital major adverse cardiovascular events (MACE) (RR = 1.31; 95% CI = 1.17-1.46), long-term MACE (RR = 2.92; 95% CI = 2.16-3.94); length of hospital stay (WMD = 0.60 days; 95% CI = 0.40-0.79) in patients with high NLR compared to those with a low NLR.
CONCLUSION
NLR might be a valuable tool for prognostication (in-hospital) and stratification of patients with STEMI who underwent PCI.
Topics: Humans; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Neutrophils; Prognosis; Lymphocytes; Biomarkers; Lymphocyte Count; Hospital Mortality
PubMed: 38941418
DOI: 10.1097/MD.0000000000038692