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Biomacromolecules Feb 2024As a biodegradable and biocompatible protein derived from collagen, gelatin has been extensively exploited as a fundamental component of biological scaffolds and drug... (Review)
Review
As a biodegradable and biocompatible protein derived from collagen, gelatin has been extensively exploited as a fundamental component of biological scaffolds and drug delivery systems for precise medicine. The easily engineered gelatin holds great promise in formulating various delivery systems to protect and enhance the efficacy of drugs for improving the safety and effectiveness of numerous pharmaceuticals. The remarkable biocompatibility and adjustable mechanical properties of gelatin permit the construction of active 3D scaffolds to accelerate the regeneration of injured tissues and organs. In this Review, we delve into diverse strategies for fabricating and functionalizing gelatin-based structures, which are applicable to gene and drug delivery as well as tissue engineering. We emphasized the advantages of various gelatin derivatives, including methacryloyl gelatin, polyethylene glycol-modified gelatin, thiolated gelatin, and alendronate-modified gelatin. These derivatives exhibit excellent physicochemical and biological properties, allowing the fabrication of tailor-made structures for biomedical applications. Additionally, we explored the latest developments in the modulation of their physicochemical properties by combining additive materials and manufacturing platforms, outlining the design of multifunctional gelatin-based micro-, nano-, and macrostructures. While discussing the current limitations, we also addressed the challenges that need to be overcome for clinical translation, including high manufacturing costs, limited application scenarios, and potential immunogenicity. This Review provides insight into how the structural and chemical engineering of gelatin can be leveraged to pave the way for significant advancements in biomedical applications and the improvement of patient outcomes.
Topics: Humans; Gelatin; Tissue Scaffolds; Tissue Engineering; Collagen; Polyethylene Glycols; Biocompatible Materials
PubMed: 38174643
DOI: 10.1021/acs.biomac.3c01021 -
Archives of Oral Biology Mar 2024To assess the outcomes of several rodent animal models for studying tooth extraction-related medication-related osteonecrosis of the jaw (MRONJ). (Review)
Review
OBJECTIVE
To assess the outcomes of several rodent animal models for studying tooth extraction-related medication-related osteonecrosis of the jaw (MRONJ).
DESIGN
After a search of the databases, 2004 articles were located, and 118 corroborated the inclusion factors (in vivo studies in rodents evaluating tooth extraction as a risk factor for the development of MRONJ).
RESULTS
Numerous studies attempting to establish an optimal protocol to induce MRONJ were found. Zoledronic acid (ZA) was the most used drug, followed by alendronate (ALN). Even when ZA did not lead to the development of MRONJ, its effect compromised the homeostasis of the bone and soft tissue. The association of other risk factors (dexamethasone, diabetes, and tooth-related inflammatory dental disease) besides tooth extraction also played a role in the development of MRONJ. In addition, studies demonstrated a relationship between cumulative dose and MRONJ.
CONCLUSIONS
Both ZA and ALN can lead to MRONJ in rodents when equivalent human doses (in osteoporosis or cancer treatment) are used. Local oral risk factors and tooth-related inflammatory dental disease increase the incidence of MRONJ in a tooth extraction-related rodent model.
Topics: Animals; Humans; Diphosphonates; Bone Density Conservation Agents; Bisphosphonate-Associated Osteonecrosis of the Jaw; Rodentia; Zoledronic Acid; Tooth Extraction; Models, Animal; Alendronate
PubMed: 38160519
DOI: 10.1016/j.archoralbio.2023.105875 -
Osteoporosis International : a Journal... Apr 2024
Topics: Humans; Female; Alendronate; Denosumab; Osteoporosis; Bone Density Conservation Agents; Osteoporosis, Postmenopausal
PubMed: 38147135
DOI: 10.1007/s00198-023-07000-5 -
European Journal of Cell Biology Dec 2023Alendronate (ALN) is a second-generation bisphosphonate widely used for osteoporosis and cancer-induced bone lesions. Many studies have confirmed a strong relationship...
Alendronate (ALN) is a second-generation bisphosphonate widely used for osteoporosis and cancer-induced bone lesions. Many studies have confirmed a strong relationship between osteonecrosis of the jaws (ONJ) development and oral bisphosphonates, especially ALN, although the molecular mechanisms underlying this pathology have not yet been elucidated. The reduction in bone turnover and vascularization usually observed in ONJ are the result of ALN action on different cell types harboured in oral microenvironment, such as osteoclasts, endothelial cells, and periodontal ligament stem cells (PDLSCs). In this perspective, the present study aims to investigate the effects of different ALN concentrations (2 μM, 5 μM, 10 μM, 25 μM, 50 μM) on the phenotype and functional properties of human PDLSCs (hPDLSCs). hPDLSCs showed a decrease in cell viability (MTT assay) only when treated with ALN concentration of 10 μM or larger for 48 h and 72 h. Cell cycle analysis revealed a moderate increase in proportion of S-phase cells after exposure to low ALN concentration (2-5 μM), an effect that was reverted after exposure to 10-50 μM ALN. Conversely, cell death was evidenced via Annexin V/PI assay at very high concentration of ALN (50 μM) after 4 days of treatment. In addition, we explored whether the effects of ALN on hPDLSCs growth and survival can be mediated by its ability to modulate oxidative stress. To this, we quantified the intracellular ROS amount and lipid peroxidation by using DCF probe and Bodipy staining, respectively. Flow cytometry analysis showed that ALN induced a dose-dependent reduction of intracellular oxidative stress and lipid peroxidation upon treatment with low concentrations at both 48 h and 72 h. Increased levels of oxidative stress was reported at 50 μM ALN and was also confirmed via TEM analysis. Despite the stability of the cellular immunophenotype, hPDLSCs showed impaired mobility after ALN exposure. Chronic exposure (7-14 days) to ALN in the range of 2-10 μM significantly decreased the expression of the differentiation-related factors ALP, RUNX2, COLI, and OPN as well as the osteogenic ability of hPDLSCs compared with untreated cells. Conversely, higher doses were found to be neutral. Our findings indicated that the effects of ALN on hPDLSCs behavior are dose-dependent and suggest a role for oxidative stress in ALN-induced cell death that may lead to novel therapeutic approaches for ONJ.
Topics: Humans; Periodontal Ligament; Alendronate; Diphosphonates; Endothelial Cells; Cell Differentiation; Stem Cells; Cells, Cultured; Cell Proliferation
PubMed: 37604089
DOI: 10.1016/j.ejcb.2023.151354 -
International Journal of Gynaecology... Feb 2024Nabhan, A.F. and Rabie, N.H. (2008), Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis. International Journal of Gynecology & Obstetrics, 103:...
Nabhan, A.F. and Rabie, N.H. (2008), Isosorbide mononitrate versus alendronate for postmenopausal osteoporosis. International Journal of Gynecology & Obstetrics, 103: 213-216. https://doi.org/10.1016/j.ijgo.2008.07.011 The above article, published online on 21 September 2008 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Professor Michael Geary, the International Federation of Gynecology and Obstetrics, and John Wiley and Sons Ltd. Concerns were raised by a number of third parties regarding the authenticity of the data and results presented in this study. In light of these concerns, the authors were asked to provide the raw data for the study. The authors cooperated fully and provided the raw data. Following review of the raw data by the journal's research integrity team, it was found that there were highly similar sequences of values of in the data for the two study groups, suggesting duplication of data. Since the data of are incompatible with randomisation, this invalidates the study results and gives rise to considerable uncertainty around the observed effect of the intervention. As a result, the journal is issuing this retraction.
PubMed: 38084820
DOI: 10.1002/ijgo.15297 -
Osteoporosis International : a Journal... May 2024Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative... (Review)
Review
Denosumab and bisphosphonates for primary osteoporosis are generally well-tolerated, but their comparative safety remains unclear. We aimed to explore the comparative safety of denosumab and bisphosphonates in primary osteoporosis. Databases such as PubMed and Google Scholar were searched for relevant peer-reviewed randomized controlled trials published in English (as of December 2023). Trials comparing adverse events (AE) between denosumab and bisphosphonates in patients with primary osteoporosis were investigated. Data were pooled using a fixed- or random-effects model to determine the risk ratios (RR) and 95% confidence intervals (CIs) for various AEs in patients treated with denosumab in comparison to patients treated with bisphosphonates. Eleven trials (5,545 patients; follow-up period: 12-24 months) were included in this meta-analysis. All trials had a risk of bias (e.g., reporting bias linked to secondary endpoints and selection bias linked to random allocation). In comparison to bisphosphonates, denosumab was significantly associated with less withdrawal due to AEs (RR = 0.49; 95% CI 0.34-0.71), more five-point major adverse cardiovascular events (RR = 2.05; 95% CI 1.03-4.09), more cardiovascular AEs (RR = 1.61; 95% CI 1.07-2.41), more infections (RR = 1.14; 95% CI 1.02-1.27), more upper respiratory tract infections (RR = 1.56; 95% CI 1.08-2.25), less vertebral fractures (RR = 0.54; 95% CI 0.31-0.93), and less abdominal pain (RR = 0.44;95% CI 0.22-0.87). We explored the comparative safety of denosumab and bisphosphonates for primary osteoporosis, some of which could be attributed to their beneficial effects. However, all trials had a risk of bias. Further investigations are required to confirm our results.
PubMed: 38733394
DOI: 10.1007/s00198-024-07118-0 -
Acta Pharmaceutica Sinica. B Feb 2024Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It...
Boosting synergism of chemo- and immuno-therapies switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules.
Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs. It is critical to inspire new potential to remodel the value of this classical therapeutic strategy. Here, we fabricate bisphosphonate coordination lipid nanogranules (BC-LNPs) and load paclitaxel (PTX) to boost the chemo- and immuno-therapeutic synergism of cytotoxic drugs. Alendronate in BC-LNPs@PTX, a bisphosphonate to block mevalonate metabolism, works as both the structure and drug constituent in nanogranules, where alendronate coordinated with calcium ions to form the particle core. The synergy of alendronate enhances the efficacy of paclitaxel, suppresses tumor metastasis, and alters the cytotoxic mechanism. Differing from the paclitaxel-induced apoptosis, the involvement of alendronate inhibits the mevalonate metabolism, changes the mitochondrial morphology, disturbs the redox homeostasis, and causes the accumulation of mitochondrial ROS and lethal lipid peroxides (LPO). These factors finally trigger the ferroptosis of tumor cells, an immunogenic cell death mode, which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy. Therefore, by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis, BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.
PubMed: 38322346
DOI: 10.1016/j.apsb.2023.08.029 -
Phytomedicine : International Journal... Jul 2024Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various...
BACKGROUND
Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various components with anti-PMOP activities. Morinda Officinalis-derived extracellular vesicle-like particles (MOEVLPs) are new active components isolated from MO, and no relevant studies have investigated their anti-osteoporosis effect and mechanism.
PURPOSE
To investigate the alleviating effect of MOEVLPs on PMOP and the underlying mechanism.
METHODS
Differential centrifugation and ultracentrifugation were used to isolate MOEVLPs from MO. Transmission electron microscopy (TEM), flow nano analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), agarose gel electrophoresis, and thin-layer chromatography were employed to characterize MOEVLPs. PMOP mouse models were utilized to examine the anti-PMOP effect of MOEVLPs. H&E and immunohistochemical staining were used for drug safety and osteogenic effect assessment. Mouse embryo osteoblast precursor cells (MC3T3-E1) were used in vitro experiments. CCK-8 kit, alizarin red staining, proteomic, bioinformatic analyses, and western blot were used to explore the mechanism of MOEVLPs.
RESULTS
In this study, MOEVLPs from MO were successfully isolated and characterized. Animal experiments demonstrated that MOEVLPs exhibited specific femur targeting, were non-toxic to the heart, liver, spleen, lung, kidney, and aorta, and possessed anti-PMOP properties. The ability of MOEVLPs to strengthen bone formation was better than that of alendronate. In vitro experiments, results revealed that MOEVLPs did not significantly enhance osteogenic differentiation in MC3T3-E1 cells. Instead, MOEVLPs promoted the proliferation of MC3T3-E1 cells. Proteomic and bioinformatic analyses suggested that the proliferative effect of MOEVLPs was closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway, particularly the altered expression of cAMP response element-binding protein (CREB) and ribosomal S6 kinase 1 (RSK1). Western blot results further confirmed these findings.
CONCLUSION
Our studies successfully isolated high-quality MOEVLPs and demonstrated that MOEVLPs can alleviate PMOP by promoting osteoblast proliferation through the MAPK pathway. MOEVLPs have the potential to become a novel and natural anti-PMOP drug.
Topics: Animals; Extracellular Vesicles; Morinda; Mice; MAP Kinase Signaling System; Female; Osteoporosis, Postmenopausal; Osteoblasts; Osteogenesis; Humans; Disease Models, Animal
PubMed: 38663117
DOI: 10.1016/j.phymed.2024.155628 -
Biomaterials Advances Jun 2024Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution...
Chronic myeloid leukemia is a hematological cancer, where disease relapse and drug resistance are caused by bone-hosted-residual leukemia cells. An innovative resolution is bone-homing and selective-active targeting of anticancer loaded-nanovectors. Herein, ivermectin (IVM) and methyl dihydrojasmonate (MDJ)-loaded nanostructured lipid carriers (IVM-NLC) were formulated then dually decorated by lactoferrin (Lf) and alendronate (Aln) to optimize (Aln/Lf/IVM-NLC) for active-targeting and bone-homing potential, respectively. Aln/Lf/IVM-NLC (1 mg) revealed nano-size (73.67 ± 0.06 nm), low-PDI (0.43 ± 0.06), sustained-release of IVM (62.75 % at 140-h) and MDJ (78.7 % at 48-h). Aln/Lf/IVM-NLC afforded substantial antileukemic-cytotoxicity on K562-cells (4.29-fold lower IC), higher cellular uptake and nuclear fragmentation than IVM-NLC with acceptable cytocompatibility on oral-epithelial-cells (as normal cells). Aln/Lf/IVM-NLC effectively upregulated caspase-3 and BAX (4.53 and 15.9-fold higher than IVM-NLC, respectively). Bone homing studies verified higher hydroxyapatite affinity of Aln/Lf/IVM-NLC (1 mg; 22.88 ± 0.01 % at 3-h) and higher metaphyseal-binding (1.5-fold increase) than untargeted-NLC. Moreover, Aln/Lf/IVM-NLC-1 mg secured 1.35-fold higher in vivo bone localization than untargeted-NLC, with lower off-target distribution. Ex-vivo hemocompatibility and in-vivo biocompatibility of Aln/Lf/IVM-NLC (1 mg/mL) were established, with pronounced amelioration of hepatic and renal toxicity compared to higher Aln doses. The innovative Aln/Lf/IVM-NLC could serve as a promising nanovector for bone-homing, active-targeted leukemia therapy.
PubMed: 38875802
DOI: 10.1016/j.bioadv.2024.213924 -
Proceedings (Baylor University. Medical... 2024Approximately 70% of multiple myeloma patients develop pathologic fractures. Osteoclast inhibitors can provide reduction in vertebral fractures with an increased risk of...
BACKGROUND
Approximately 70% of multiple myeloma patients develop pathologic fractures. Osteoclast inhibitors can provide reduction in vertebral fractures with an increased risk of osteonecrosis of the jaw (ONJ). ONJ associated with currently used osteoclast inhibitors causes significant morbidity, often from delayed diagnosis and ineffective treatment.
METHODS
The TriNetX Diamond Network was used to create patient cohorts for each medication: alendronate, pamidronate, zoledronic acid, and denosumab. All patients had a diagnosis of multiple myeloma as identified by International Classification of Disease-10 (ICD-10) code C90.0. Pamidronate, zoledronic acid, and denosumab were each compared to alendronate for 5-year incidence of pathologic vertebral fracture (ICD-10 M48.50XA) and development of ONJ.
RESULTS
The 5-year risk of pathologic vertebral fracture was not statistically different between alendronate versus pamidronate, zoledronic acid, and denosumab. However, the 5-year risk of ONJ was significantly higher for both zoledronic acid and denosumab (relative risk 4.85 and 2.9, respectively).
CONCLUSION
This study shows that fracture reduction risk is comparable for all four treatments in multiple myeloma patients, but ONJ risk is lowest for alendronate and pamidronate. Overall, these data support the continued use of pamidronate and alendronate in multiple myeloma patients.
PubMed: 38343457
DOI: 10.1080/08998280.2023.2298667