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Journal of Molecular Medicine (Berlin,... May 2023The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST...
The most common cause for prosthetic revision surgery is wear particle-induced periprosthetic osteolysis, which leads to aseptic loosening of the prosthesis. Both SOST gene and its synthetic protein, sclerostin, are hallmarks of osteocytes. According to our previous findings, blocking SOST induces bone formation and protects against bone loss and deformation caused by titanium (Ti) particles by activating the Wnt/β-catenin cascade. Although SOST has been shown to influence osteoblasts, its ability to control wear-particle-induced osteolysis via targeting osteoclasts remains unclear. Mice were subjected to development of a cranial osteolysis model. Micro CT, HE staining, and TRAP staining were performed to evaluate bone loss in the mouse model. Bone marrow-derived monocyte-macrophages (BMMs) made from the C57BL/6 mice were exposed to the medium of MLO-Y4 (co-cultured with Ti particles) to transform them into osteoclasts. Bioinformatics methods were used to predict and validate the interaction among SOST, Wnt/β-catenin, RANKL/OPG, TNF-α, and IL-6. Local bone density and bone volume improved after SOST inhibition, both the number of lysis pores and the rate of skull erosion decreased. Histological research showed that β-catenin and OPG expression were markedly increased after SOST inhibition, whereas TRAP and RANKL levels were markedly decreased. In-vitro, Ti particle treatment elevated the expression of sclerostin, suppressed the expression of β-catenin, and increased the RANKL/OPG ratio in the MLO-Y4 cell line. TNF-α and IL-6 also elevated after treatment with Ti particles. The expression levels of NFATc1, CTSK, and TRAP in osteoclasts were significantly increased, and the number of positive cells for TRAP staining was increased. Additionally, the volume of bone resorption increased at the same time. In contrast, when SOST expression was inhibited in the MLO-Y4 cell line, these effects produced by Ti particles were reversed. All the results strongly show that SOST inhibition triggered the osteocyte Wnt/β-catenin signaling cascade and prevented wear particle-induced osteoclastogenesis, which might reduce periprosthetic osteolysis. KEY MESSAGES: SOST is a molecular regulator in maintaining bone homeostasis. SOST plays in regulating bone homeostasis through the Wnt/β-catenin signaling pathway. SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis.
Topics: Animals; Mice; Osteolysis; Osteocytes; Wnt Signaling Pathway; Tumor Necrosis Factor-alpha; beta Catenin; Interleukin-6; Mice, Inbred C57BL; Bone Resorption; Osteoclasts; Osteogenesis; Skull; RANK Ligand; Adaptor Proteins, Signal Transducing
PubMed: 37121919
DOI: 10.1007/s00109-023-02319-2 -
Cancers Feb 2020Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%-57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC.
PubMed: 32092952
DOI: 10.3390/cancers12020481 -
Nuclear Medicine and Biology 2021In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable,... (Review)
Review
In oncology, the holy grail of radiotherapy is specific radiation dose deposition in tumours with minimal healthy tissue toxicity. If used appropriately, injectable, systemic radionuclide therapies could meet these criteria, even for treatment of micrometastases and single circulating tumour cells. The clinical use of α and β particle-emitting molecular radionuclide therapies is rising, however clinical translation of Auger electron-emitting radionuclides is hampered by uncertainty around their exact subcellular localisation, which in turn affects the accuracy of dosimetry. This review aims to discuss and compare the advantages and disadvantages of various subcellular localisation methods available to localise radiopharmaceuticals and radionuclides for in vitro investigations.
Topics: Alpha Particles; Radiation Dosage; Radiopharmaceuticals
PubMed: 33964707
DOI: 10.1016/j.nucmedbio.2021.03.010 -
Frontiers in Medicine 2021Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of RaCl for patients with metastatic castration-resistant... (Review)
Review
Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of RaCl for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50-230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.
PubMed: 34386508
DOI: 10.3389/fmed.2021.692436 -
Frontiers in Pharmacology 2019Glioblastoma is the most common malignant adult brain tumor and has a very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10 to... (Review)
Review
Glioblastoma is the most common malignant adult brain tumor and has a very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10 to 14 months despite an aggressive current therapeutic approach known as Stupp's protocol, which consists of debulking surgery followed by radiotherapy and chemotherapy. Despite several clinical trials using anti-angiogenic targeted therapies, glioblastoma medical care remains without major progress in the last decade. Recent progress in nuclear medicine, has been mainly driven by advances in biotechnologies such as radioimmunotherapy, radiopeptide therapy, and radionanoparticles, and these bring a new promising arsenal for glioblastoma therapy. For therapeutic purposes, nuclear medicine practitioners classically use β particle emitters like I, Y, Re, or Lu. In the glioblastoma field, these radioisotopes are coupled with nanoparticles, monoclonal antibodies, or peptides. These radiopharmaceutical compounds have resulted in a stabilization and/or improvement of the neurological status with only transient side effects. In nuclear medicine, the glioblastoma-localized and targeted internal radiotherapy proof-of-concept stage has been successfully demonstrated using β emitting isotopes. Similarly, α particle emitters like Bi, At, or Ac appear to be an innovative and interesting alternative. Indeed, α particles deliver a high proportion of their energy inside or at close proximity to the targeted cells (within a few micrometers from the emission point versus several millimeters for β particles). This physical property is based on particle-matter interaction differences and results in α particles being highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting of isolated tumor cells. The first clinical trials confirmed this idea and showed good therapeutic efficacy and less side effects, thus opening a new and promising era for glioblastoma medical care using α therapy. The objective of this literature review is focused on the developing field of nuclear medicine and aims to describe the various parameters such as targets, vectors, isotopes, or injection route (systemic and local) in relation to the clinical and preclinical results in glioblastoma pathology.
PubMed: 31354487
DOI: 10.3389/fphar.2019.00772 -
Nature Communications Oct 2020Unconventional oil and natural gas development (UOGD) expanded extensively in the United States from the early 2000s. However, the influence of UOGD on the radioactivity...
Unconventional oil and natural gas development (UOGD) expanded extensively in the United States from the early 2000s. However, the influence of UOGD on the radioactivity of ambient particulate is not well understood. We collected the ambient particle radioactivity (PR) measurements of RadNet, a nationwide environmental radiation monitoring network. We obtained the information of over 1.5 million wells from the Enverus database. We investigated the association between the upwind UOGD well count and the downwind gross-beta radiation with adjustment for environmental factors governing the natural emission and transport of radioactivity. Our statistical analysis found that an additional 100 upwind UOGD wells within 20 km is associated with an increase of 0.024 mBq/m (95% confidence interval [CI], 0.020, 0.028 mBq/m) in the gross-beta particle radiation downwind. Based on the published health analysis of PR, the widespread UOGD could induce adverse health effects to residents living close to UOGD by elevating PR.
PubMed: 33051463
DOI: 10.1038/s41467-020-18226-w -
Environmental Health : a Global Access... Jun 2021Exposure to ionizing radiation has been associated with insulin resistance and type 2 diabetes. In light of recent work showing an association between ambient...
BACKGROUND
Exposure to ionizing radiation has been associated with insulin resistance and type 2 diabetes. In light of recent work showing an association between ambient particulate matter (PM) gross β-activity and gestational diabetes mellitus (GDM) among pregnant women, we examined pregnancy glucose levels in relation to PM gross β-activity to better understand this pathway.
METHODS
Our study included 103 participants receiving prenatal care at Beth Israel Deaconess Medical Center in Boston, MA. PM gross β-activity was obtained from US Environmental Protection Agency's RadNet program monitors, and blood glucose levels were obtained from the non-fasting glucose challenge test performed clinically as the first step of the 2-step GDM screening test. For each exposure window we examined (i.e., moving average same-day, one-week, first-trimester, and second-trimester PM gross β-activity), we fitted generalized additive models and adjusted for clinical characteristics, socio-demographic factors, temporal variables, and PM with an aerodynamic diameter ≤ 2.5 μm (PM). Subgroup analyses by maternal age and by body mass index were also conducted.
RESULTS
An interquartile range increase in average PM gross β-activity during the second trimester of pregnancy was associated with an increase of 17.5 (95% CI: 0.8, 34.3) mg/dL in glucose concentration. Associations were stronger among younger and overweight/obese participants. Our findings also suggest that the highest compared to the lowest quartile of one-week exposure was associated with 17.0 (95% CI: - 4.0, 38.0) mg/dL higher glucose levels. No associations of glucose were observed with PM gross β-activity during same-day and first-trimester exposure windows. PM was not associated with glucose levels during any exposure window in our data.
CONCLUSIONS
Exposure to higher levels of ambient PM gross β-activity was associated with higher blood glucose levels in pregnant patients, with implications for how this novel environmental factor could impact pregnancy health.
Topics: Adult; Air Pollutants; Beta Particles; Blood Glucose; Female; Humans; Maternal Exposure; Particulate Matter; Pregnancy
PubMed: 34126994
DOI: 10.1186/s12940-021-00744-9 -
Cardiovascular Diabetology Jul 2021Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described.... (Observational Study)
Observational Study
BACKGROUND
Triglyceride-rich lipoproteins particles (TRLP) and low density lipoprotein particles (LDLP) vary in size. Their association with β-cell function is not well described. We determined associations of TRLP and LDLP subfractions with β-cell function, estimated as HOMA-β, and evaluated their associations with incident T2D in the general population.
METHODS
We included 4818 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study without T2D at baseline. TRLP and LDLP subfraction concentrations and their average sizes were measured using the LP4 algorithm of the Vantera nuclear magnetic resonance platform. HOMA-IR was used as measure of insulin resistance. HOMA-β was used as a proxy of β-cell function.
RESULTS
In subjects without T2D at baseline, very large TRLP, and LDL size were inversely associated with HOMA-β, whereas large TRLP were positively associated with HOMA-β when taking account of HOMA-IR. During a median follow-up of 7.3 years, 263 participants developed T2D. In multivariable-adjusted Cox regression models, higher concentrations of total, very large, large, and very small TRLP (reflecting remnants lipoproteins) and greater TRL size were associated with an increased T2D risk after adjustment for relevant covariates, including age, sex, BMI, HDL-C, HOMA-β, and HOMA-IR. On the contrary, higher concentrations of large LDLP and greater LDL size were associated with a lower risk of developing T2D.
CONCLUSIONS
Specific TRL and LDL particle characteristics are associated with β-cell function taking account of HOMA-IR. Moreover, TRL and LDL particle characteristics are differently associated with incident T2D, even when taking account of HOMA-β and HOMA-IR.
Topics: Adult; Aged; Biomarkers; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Incidence; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lipoproteins, LDL; Longitudinal Studies; Male; Middle Aged; Netherlands; Particle Size; Prognosis; Risk Assessment; Risk Factors; Triglycerides
PubMed: 34321006
DOI: 10.1186/s12933-021-01348-w -
Frontiers in Immunology 2023Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the...
BACKGROUND
Intestinal epithelial cells (IECs) are the first to encounter luminal microorganisms and actively participate in intestinal immunity. We reported that IECs express the β-glucan receptor Dectin-1, and respond to commensal fungi and β-glucans. In phagocytes, Dectin-1 mediates LC3-associated phagocytosis (LAP) utilizing autophagy components to process extracellular cargo. Dectin-1 can mediate phagocytosis of β-glucan-containing particles by non-phagocytic cells. We aimed to determine whether human IECs phagocytose β-glucan-containing fungal particles LAP.
METHODS
Colonic (n=18) and ileal (n=4) organoids from individuals undergoing bowel resection were grown as monolayers. Fluorescent-dye conjugated zymosan (β-glucan particle), heat-killed- and UV inactivated were applied to differentiated organoids and to human IEC lines. Confocal microscopy was used for live imaging and immuno-fluorescence. Quantification of phagocytosis was carried out with a fluorescence plate-reader.
RESULTS
zymosan and particles were phagocytosed by monolayers of human colonic and ileal organoids and IEC lines. LAP was identified by LC3 and Rubicon recruitment to phagosomes and lysosomal processing of internalized particles was demonstrated by co-localization with lysosomal dyes and LAMP2. Phagocytosis was significantly diminished by blockade of Dectin-1, actin polymerization and NAPDH oxidases.
CONCLUSIONS
Our results show that human IECs sense luminal fungal particles and internalize them LAP. This novel mechanism of luminal sampling suggests that IECs may contribute to the maintenance of mucosal tolerance towards commensal fungi.
Topics: Humans; beta-Glucans; Epithelial Cells; Fungi; Phagocytosis; Zymosan
PubMed: 36969163
DOI: 10.3389/fimmu.2023.1142492 -
Cell Death & Disease Jun 2017Wear debris-induced osteogenic inhibition and bone destruction are critical in the initiation of peri-prosthetic osteolysis. However, the molecular mechanism underlying...
Wear debris-induced osteogenic inhibition and bone destruction are critical in the initiation of peri-prosthetic osteolysis. However, the molecular mechanism underlying this phenomenon is poorly understood. In this study, we analyzed the involvement of the GSK-3β/β-catenin signal pathway, which is important for bone formation in this pathological condition. We established a titanium (Ti) particle-stressed murine MC3T3-E1 cell culture system and calvariae osteolysis model to test the hypothesis that Ti particle-induced osteogenic inhibition and bone destruction are mediated by the GSK-3β/β-catenin signal pathway. Our findings showed that Ti particles reduced osteogenic differentiation induced by osteogenesis-related gene expression, alkaline phosphatase activity and matrix mineralization, as well as pSer9-GSK-3β expression and β-catenin signal activity. Downregulation of GSK-3β activity attenuated Ti particle-induced osteogenic inhibition, whereas the β-catenin inhibitor reversed this protective effect. Moreover, the GSK-3β/β-catenin signal pathway mediated the upregulation of RANKL and downregulation of OPG in Ti particle-stressed MC3T3-E1 cells. In addition, our in vivo results showed that Ti particles induced bone loss via regulating GSK-3β and β-catenin signals. Based on these results, we concluded that the GSK-3β/β-catenin signal pathway mediates the adverse effects of Ti particles on osteoblast differentiation and bone destruction, and can be used as a potential therapeutic target for the treatment of peri-prosthetic osteolysis.
Topics: 3T3 Cells; Alkaline Phosphatase; Animals; Bone and Bones; Cell Differentiation; Cell Proliferation; Cell Survival; Down-Regulation; Female; Glycogen Synthase Kinase 3 beta; Mice; Mice, Inbred C57BL; Osteoblasts; Osteogenesis; RANK Ligand; Signal Transduction; Titanium; X-Ray Microtomography; beta Catenin
PubMed: 28617442
DOI: 10.1038/cddis.2017.275