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European Journal of Cell Biology May 2024Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While...
Nuclear receptor Nur77 plays a pivotal role in immune regulation across various tissues, influencing pro-inflammatory signaling pathways and cellular metabolism. While cellular mechanics have been implicated in inflammation, the contribution of Nur77 to these mechanical processes remains elusive. Macrophages exhibit remarkable plasticity in their morphology and mechanics, enabling them to adapt and execute essential inflammatory functions, such as navigating through inflamed tissue and pathogen engulfment. However, the precise regulatory mechanisms governing these dynamic changes in macrophage mechanics during inflammation remain poorly understood. To establish the potential correlation of Nur77 with cellular mechanics, we compared bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Nur77-deficient (Nur77-KO) mice and employed cytoskeletal imaging, single-cell acoustic force spectroscopy (AFS), migration and phagocytosis assays, and RNA-sequencing. Our findings reveal that Nur77-KO BMDMs exhibit changes to their actin networks compared to WT BMDMs, which is associated with a stiffer and more rigid phenotype. Subsequent in vitro experiments validated our observations, showcasing that Nur77 deficiency leads to enhanced migration, reduced adhesion, and increased phagocytic activity. The transcriptomics data confirmed altered mechanics-related pathways in Nur77-deficient macrophage that are accompanied by a robust pro-inflammatory phenotype. Utilizing previously obtained ChIP-data, we revealed that Nur77 directly targets differentially expressed genes associated with cellular mechanics. In conclusion, while Nur77 is recognized for its role in reducing inflammation of macrophages by inhibiting the expression of pro-inflammatory genes, our study identifies a novel regulatory mechanism where Nur77 governs macrophage inflammation through the modulation of expression of genes involved in cellular mechanics. Our findings suggest that immune regulation by Nur77 may be partially mediated through alterations in cellular mechanics, highlighting a potential avenue for therapeutic targeting.
PubMed: 38763048
DOI: 10.1016/j.ejcb.2024.151419 -
Lancet (London, England) May 2024Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the...
Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
BACKGROUND
Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.
METHODS
The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.
FINDINGS
Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).
INTERPRETATION
Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Humans; Global Burden of Disease; Risk Factors; Global Health; Female; Male; Risk Assessment; Adult; Middle Aged; Aged; Disability-Adjusted Life Years; Adolescent; Young Adult; Quality-Adjusted Life Years
PubMed: 38762324
DOI: 10.1016/S0140-6736(24)00933-4 -
Journal of Nanobiotechnology May 2024Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for...
Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.
Topics: Animals; Mice; Mesenchymal Stem Cells; Nanoparticles; Cell Differentiation; Histone Deacetylases; NF-E2-Related Factor 2; Mice, Inbred C57BL; Osteoclasts; Osteoblasts; Signal Transduction; Heme Oxygenase-1; Male; Bone Regeneration; Osteogenesis; Cell Nucleus; Fracture Healing; Humans; Membrane Proteins
PubMed: 38760744
DOI: 10.1186/s12951-024-02436-1 -
Frontiers in Oncology 2024Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by variable risk of evolution to acute myeloid leukemia; to date, allogeneic stem...
Chronic myelomonocytic leukemia (CMML) is a rare hematological disorder characterized by variable risk of evolution to acute myeloid leukemia; to date, allogeneic stem cell transplantation is the only curative treatment. We report a case of choroidal involvement in a woman affected by CMML and presenting only with visual impairment. The patient was initially evaluated for an intensive therapeutic approach, but after biopsy the ocular lesion spontaneously regressed. Thus a "watch and wait" strategy was preferred. One year and a half after initial diagnosis, the patient is alive, with stable hematological disease and without any ocular involvement. Therefore, a close, not invasive follow up could be useful to tailor treatment for patients affected by single ocular lesions in CMML.
PubMed: 38756666
DOI: 10.3389/fonc.2024.1399894 -
HemaSphere May 2024Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings...
Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.
PubMed: 38756352
DOI: 10.1002/hem3.64 -
Open Medicine (Warsaw, Poland) 2024Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver...
Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver fibrosis. To explore the effect and mechanism of MSC-derived exosomal miR-26a on liver fibrosis, exosomes were separated from bone marrow-derived MSCs (BMSCs) and used to treat with LX2 cells. The miR-26a level was decreased in BMSC-derived exosomes. Treatment with exosomes isolated from human BMSCs transfected with miR-26a mimics (miR-26a mimic-Exo) decreased the 5-ethynyl-2'-deoxyuridine-positive cell rate, the protein level of α-SMA and collagen I, and the glutathione (GSH) level but enhanced the apoptosis rate and the reactive oxide species (ROS) level in LX2 cells, which were reversed by the treatment of deferoxamine. Mechanically, miR-26a directly bound SLC7A11 mRNA and negatively modulated the level of SLC7A11 in LX2 cells. Overexpression of SLC7A11 reversed the miR-26a mimic-Exo-induced alterations in the level of ROS, Fe, malonaldehyde, and GSH in LX2 cells. , miR-26a mimic-Exo decreased the level of SLC7A11 and attenuated CCL4-induced liver fibrosis. Collectively, miR-26a mimic-Exo induced ferroptosis to alleviate liver fibrosis by regulating SLC7A11, which may provide new strategies for the treatment of liver fibrosis, and even other relevant diseases.
PubMed: 38756248
DOI: 10.1515/med-2024-0945 -
Allergologie Select 2024None.
None.
PubMed: 38756207
DOI: 10.5414/ALX02444E -
JPGN Reports May 2024Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by...
Shwachman-Diamond syndrome (SDS) is a genetic disorder caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. The syndrome is characterized by multiorgan dysfunction primarily involving the bone marrow and exocrine pancreas. Frequently overlooked is the hepatic dysfunction seen in early childhood which tends to improve by adulthood. Here, we report a child who initially presented with failure to thrive and elevated transaminases, and was ultimately diagnosed with SDS. A liver biopsy electron micrograph revealed hepatocytes crowded with numerous small mitochondria, resembling the hepatic architecture from patients with inborn errors of metabolism, including mitochondrial diseases. To our knowledge, this is the first report of the mitochondrial phenotype in an SDS patient. These findings are compelling given the recent cellular and molecular research studies which have identified SBDS as an essential regulator of mitochondrial function and have also implicated SBDS in the maintenance of mitochondrial DNA.
PubMed: 38756125
DOI: 10.1002/jpr3.12064 -
ELife May 2024A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered...
Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.
A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed or (K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the (K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of (K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the (K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.
Topics: Animals; Kruppel-Like Transcription Factors; Mice; Longevity; Killer Cells, Natural; Neoplasms; Genetic Engineering; Bone Marrow Transplantation; Female; Gene Expression Profiling; Male; Mice, Transgenic
PubMed: 38752723
DOI: 10.7554/eLife.88275 -
Technology in Cancer Research &... 2024The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow...
Dose-Volume Parameters of Spared Magnetic Resonance Imaging-Defined Active Bone Marrow Predict Hematologic Toxicity in Pelvic Malignancies Patients Undergoing Radiotherapy: A Cohort Study.
The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow (ABM) over those based on total bone marrow (TBM) contoured via CT in the prediction of hematologic toxicity (HT) occurrence among patients with pelvic malignancies undergoing radiotherapy. The clinical data of 116 patients with pelvic malignancies treated with pelvic radiotherapy were analyzed retrospectively. The ABM areas on T1-weighted MRI were contoured. The statistical significance between TBM and ABM dose-volume measures was assessed through the utilization of either Student's t-test or Wilcoxon signed rank test. Logistic and linear regression models were employed to analyze the correlation between dose-volume parameters (V5-V50) and HT occurrence in pelvic ABM and TBM. Receiver operating characteristic (ROC) curves were used to compare predictors of HT2+. There were significant differences in dosimetric parameters between ABM and TBM. Logistic regression analysis showed that ABM V5, ABM V10, ABM V15, ABM V20, and TBM V5 were significantly associated with the occurrence of HT2+ in pelvic malignancies. Linear regression analysis showed that ABM V5, ABM V10, and ABM V15 were significantly associated with white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), and lymphocyte (Lym) nadir. ABM V5, ABM V10, ABM V15, and ABM V30 were predictive of HT2+. More accurate prediction of HT in patients receiving pelvic radiotherapy may be achieved by relying on dose-volume parameters of MRI-based ABM. Further prospective studies are needed to confirm this.
Topics: Humans; Female; Bone Marrow; Magnetic Resonance Imaging; Male; Middle Aged; Radiotherapy Dosage; Pelvic Neoplasms; Aged; Adult; Retrospective Studies; Radiotherapy Planning, Computer-Assisted; Radiation Injuries; ROC Curve; Aged, 80 and over; Hematologic Diseases
PubMed: 38752234
DOI: 10.1177/15330338241255283