Osteoprotective Effects in Postmenopausal Osteoporosis Rat Model: Oral Tocotrienol vs. Intraosseous Injection of Tocotrienol-Poly Lactic-Co-Glycolic Acid Combination

Osteoporosis, the most common bone disease, is associated with compromised bone strength and increased risk of fracture. Previous studies have shown that oxidative stress contributes to the progression of osteoporosis. Specifically, for postmenopausal osteoporosis, the reduction in estrogen levels leads to increased oxidative stress in bone remodeling. Tocotrienol, a member of vitamin E that exhibits antioxidant activities, has shown potential as an agent for the treatment of osteoporosis. Most studies on the osteoprotective effects of tocotrienols had used the oral form of tocotrienols, despite their low bioavailability due the lack of transfer proteins and high metabolism in the liver. Several bone studies have utilized tocotrienol combined with a nanocarrier to produce a controlled release of tocotrienol particles into the system. However, the potential of delivering tocotrienol–nanocarrier combination through the intraosseous route has never been explored. In this study, tocotrienol was combined with a nanocarrier, poly lactic-co-glycolic acid (PLGA), and injected intraosseously into the bones of ovariectomized rats to produce targeted and controlled delivery of tocotrienol into the bone microenvironment. This new form of tocotrienol delivery was compared with the conventional oral delivery in terms of their effects on bone parameters. Forty Sprague–Dawley rats were divided into five groups. The first group was sham operated, while other groups were ovariectomized (OVX). Following 2 months, the right tibiae of all the rats were drilled at the metaphysis region to provide access for intraosseous injection. The estrogen group (OVX + ESTO) and tocotrienol group (OVX + TTO) were given daily oral gavages of Premarin (64.5 mg/kg) and annatto-tocotrienol (60 mg/kg), respectively. The locally administered tocotrienol group (OVX + TTL) was given a single intraosseous injection of tocotrienol–PLGA combination. After 8 weeks of treatment, both OVX + TTO and OVX + TTL groups have significantly lower bone markers and higher bone mineral content than the OVX group. In terms of bone microarchitecture, both groups demonstrated significantly higher trabecular separation and connectivity density than the OVX group (p < 0.05). Both groups also showed improvement in bone strength by the significantly higher stress, strain, stiffness, and Young’s modulus parameters. In conclusion, daily oral tocotrienol and one-time intraosseous injection of tocotrienol–PLGA combination were equally effective in offering protection against ovariectomy-induced bone changes.

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Bone Sclerostin and Dickkopf-related protein-1 are positively correlated with bone mineral density, bone microarchitecture, and bone strength in postmenopausal osteoporosis

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04365-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Jia Peng ◽

Zhang Dong ◽

Zhang Hui ◽

Wang Aifei ◽

Deng Lianfu ◽

...

Keyword(s):

Bone Mineral Density ◽

Yield Strength ◽

Postmenopausal Osteoporosis ◽

Bone Strength ◽

Bone Microarchitecture ◽

Compressive Force ◽

Related Protein ◽

Mineral Density ◽

Ionised Calcium

Abstract Background Wnt-catenin signaling antagonists sclerostin and dickkopf-related protein-1 (Dkk-1) inhibit bone formation and are involved in the pathogenesis of postmenopausal osteoporosis (PO). However, the association between sclerostin and Dkk-1 and bone mineral density (BMD) in women with PO remains unclear. Objective This study aimed to determine the association between sclerostin and Dkk-1 and BMD, bone microarchitecture, and bone strength in PO. Methods Trabecular bone specimens were obtained from the femoral heads of 76 Chinese women with PO who underwent hip arthroplasty for femoral neck fractures. Micro-computed tomography (Micro-CT) was used to assess the BMD and bone microarchitecture of the trabecular bone. Subsequently, a mechanical test was performed. Finally, sclerostin and Dkk-1 in the bone were measured by enzyme-linked immunosorbent (Elisa) assay. Serum ionized serum ionised calcium, propeptide of type 1 collagen, C-terminal β-telopeptide of type-1 collagen, sclerostin, and Dkk-1 were also detected. Results Bone sclerostin was positively correlated with serum ionised calcium, serum sclerostin, BMD, bone volume/tissue volume (BV/TV), trabecular number (Tb.N), maximum compressive force, and yield strength (r = 0.32, 0.906, 0.355, 0.401, 0.329, 0.355, and 0.293, respectively, P < 0.05) and negatively correlated with age and trabecular separation (Tb.Sp) (r = − 0.755 and − 0.503, respectively, P < 0.05). Bone Dkk-1 was positively correlated with serum ionised calcium, serum Dkk-1, BMD, BV/TV, trabecular thickness, Tb.N, maximum compressive force, yield strength, and Young’s modulus (r = 0.38, 0.809, 0.293, 0.293, 0.228, 0.318, 0.352, 0.315, and 0.266, respectively, P < 0.05) and negatively correlated with age and Tb.Sp (r = − 0.56 and − 0.38, respectively, P < 0.05). Serum levels of sclerostin and Dkk-1 reflected the levels of sclerostin and Dkk-1 in the bone. Conclusion Bone sclerostin and Dkk-1 were positively correlated with BMD in women with PO, and higher levels of bone sclerostin and Dkk-1 might predict better BMD, bone microarchitecture, and bone strength. The potential molecular mechanisms still require further study.

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Consumption of Rabbiteye Blueberry Results in Accumulation of Hippuric Acid in the Bone Marrow and Increased Bone Deposition in Ovariectomized Rats but Few Other Bone Benefits (P06-064-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.p06-064-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Maria Maiz ◽

Hawi Debelo ◽

Pamela Lachcik ◽

Mary Lila ◽

Teresita Bellido ◽

...

Keyword(s):

Bone Marrow ◽

Cortical Bone ◽

Bone Strength ◽

Phenolic Acid ◽

Hippuric Acid ◽

Bone Microarchitecture ◽

Ovariectomized Rats ◽

Calcium Balance ◽

Calcium Kinetics ◽

Bone Deposition

Abstract Objectives Determine the effects of an 8-wk chronic consumption of two different blueberry varieties at varying doses on calcium balance, calcium kinetics, bone microarchitecture and polyphenol metabolism and distribution in ovariectomized rats. Methods Eighty 5-mo old ovariectomized rats were sorted by weight and block-randomized to an 8-wk chronic feeding treatment of a polyphenol-free (control), 2.5% or 5% `Montgomery ́ (Mont) rabbiteye blueberry (V. ashei) or 5% wild lowbush blueberry (Wild BB) (V. angustifolium) (% w/w). During week 0 and week 8, rats went through a calcium balance study to determine calcium absorption and retention. At the end of week 8, rats were dosed with 45Ca and serial blood draws were done from baseline up to 48 h post-dose to map Ca kinetics. At sacrifice, the right femur was collected to determine differences in bone strength and microarchitecture of trabecular and cortical bone through MicroCT and a three-point bending test. A 24 h urine collection was done at baseline and during week 8 of treatment to determine urinary phenolic acid excretion and the left femur bone marrow phenolic acid accumulation through UPLC-MS/MS. Results A blueberry enriched diet had no effect on cortical bone microarchitecture, with a trend towards increased trabecular bone protection (p = 0.08). No differences were observed in bone strength. During baseline, a 2.5% Mont diet significantly increased Ca retention, but the effect was lost after the 8 weeks of treatment when rats had stabilized to treatment. Calcium kinetics showed that Mont 5% significantly increased Ca absorption and bone turnover (p < 0.05), while Mont 2.5% and Wild BB 5% did not. An accumulation of hippuric acid in the bone marrow was detected with the Mont blueberry treatments and it was significantly and positively correlated with bone deposition. The metabolism of phenolic acids was significantly affected by a chronic consumption of the treatment diets, resulting in significant phenolic acid profiles and excretion shifts. Conclusions A blueberry-enriched diet had minimal effects on bone after stabilized to ovariectomy and the effects differ depending on blueberry variety and dose. Funding Sources National Institute of Health (NIH) and National Center for Complementary and Integrative Health (NCCIH).

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In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength, and Low Bone Turnover

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab061 ◽

2021 ◽

Author(s):

Francesca Vigevano ◽

Giulia Gregori ◽

Georgia Colleluori ◽

Rui Chen ◽

Vimlin Autemrongsawat ◽

...

Keyword(s):

Bone Turnover ◽

Bone Strength ◽

Type I Collagen ◽

Failure Load ◽

Bone Microarchitecture ◽

Enzyme Linked Immunosorbent Assay ◽

Type I ◽

Mineral Density ◽

Trabecular Microarchitecture ◽

Increased Risk

Abstract Introduction Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture and strength in the obese population remains unknown. Methods Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay (ELISA), body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry (DXA), whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography (HR-pQCT). Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D. Results Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49±3.0 and 6.03±2.47, vs 4.24±2.72 ng/ml, respectively, p=0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28±0.10 and 0.29±0.13 vs. 0.21±0.15 ng/ml, respectively, p=0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (p=0.003) and CTx (p=0.005), greater trabecular separation at the tibia and radius (p=0.03 and p=0.04, respectively) and lower tibial failure load and stiffness (both p=0.04), relative to obese men without T2D. Conclusion In men, the combination of obesity and T2D is associated with reduced bone turnover, poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D suggesting worse bone disease.

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Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year longitudinal study

Acta Endocrinologica ◽

10.1530/eje-17-0014 ◽

2017 ◽

Vol 176 (6) ◽

pp. 685-693 ◽

Cited By ~ 44

Author(s):

Vikram V Shanbhogue ◽

René Klinkby Støving ◽

Katrine Hartmund Frederiksen ◽

Stine Hanson ◽

Kim Brixen ◽

...

Keyword(s):

Weight Loss ◽

Gastric Bypass ◽

Bone Strength ◽

Structural Changes ◽

Bone Microarchitecture ◽

Clinical Importance ◽

Morbidly Obese ◽

Mineral Density ◽

Quantitative Ct ◽

Increased Risk

Objective, design and methods Roux-en-Y gastric bypass (RYGB) has proved successful in attaining sustained weight loss but may lead to metabolic bone disease. To assess impact on bone mass and structure, we measured a real bone mineral density at the hip and spine by dual-energy X-ray absorptiometry, and volumetric BMD (vBMD) and bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative CT in 25 morbidly obese subjects (15 females, 10 males) at 0, 12 and 24 months after RYGB. Bone turnover markers (BTMs), calciotropic and gut hormones and adipokines were measured at the same time points. Results After a 24.1% mean weight loss from baseline to month 12 (P < 0.001), body weight plateaued from month 12 to 24 (−0.9%, P = 0.50). However, cortical and trabecular vBMD and microarchitecture deteriorated through the 24 months, such that there was a 5 and 7% reduction in estimated bone strength at the radius and tibia respectively (both P < 0.001). The declines observed in the first 12 months were matched or exceeded by declines in the 12- to 24-month period. While a significant increase in BTMs and decrease in leptin and insulin were seen at 24 months, these changes were maximal at month 12 and stabilized from month 12 to 24. Conclusions Despite weight stabilization and maintenance of metabolic parameters, bone loss and deterioration in bone strength continued and were substantial in the second year. The clinical importance of these changes in terms of increased risk of developing osteoporosis and fragility fractures remain an important concern.

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Determination of Tissue Protective and Antioxidant Activities of Two Medicinal Mushrooms from Turkey against CCl4-lnduced Experimental Oxidative Stress in Rats

International Journal of Medicinal Mushrooms ◽

10.1615/intjmedmushrooms.2020035054 ◽

2020 ◽

Vol 22 (7) ◽

pp. 671-681

Author(s):

Songul Hasar ◽

Abdulahad Dogan ◽

Kenan Demirel

Keyword(s):

Oxidative Stress ◽

Antioxidant Activities ◽

Medicinal Mushrooms

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Oxidative Stress Levels, JAK2V617F Mutational Status and Thrombotic Complications in Patients with Essential Thrombocythemia

Revista de Chimie ◽

10.37358/rc.19.8.7435 ◽

2019 ◽

Vol 70 (8) ◽

pp. 2822-2825 ◽

Cited By ~ 6

Author(s):

Cornel Moisa ◽

Mihnea Alexandru Gaman ◽

Camelia Cristina Diaconu ◽

Amelia Maria Gaman

Keyword(s):

Oxidative Stress ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasm ◽

Oxygen Species ◽

Mutational Status ◽

Increased Risk ◽

Stress Levels ◽

Total Antioxidant ◽

Thrombotic Complications ◽

The Relationship

Essential thrombocythemia (ET) is a BCR-ABL1-negative myeloproliferative neoplasm associated with thrombotic and haemorrhagic complications. Reactive oxygen species (ROS) overexpression induces a growth advantage to JAK2V617F-positive clones and, in association with a higher number of immature platelets, leukocytosis, and additional cardiovascular risk factors, leads to an increased risk for thrombotic events. We evaluated oxidative stress by measuring ROS levels and the total antioxidant capacity (TAC) in 62 ET patients and investigated the relationship between oxidative stress, JAK2V617F mutational status and the development of thrombotic events. We found higher oxidative stress levels in JAK2V617F-positive vs. JAK2V617F-negative ET cases with no significant differences between homozygous and heterozygous genotypes. Increased ROS levels and thrombotic events were more frequent in ET patients with old age at diagnosis, higher haematocrit levels or leukocytosis.

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Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

Current Vascular Pharmacology ◽

10.2174/1570161118666200317151553 ◽

2020 ◽

Vol 19 (1) ◽

pp. 41-54 ◽

Cited By ~ 1

Author(s):

Stefanos Roumeliotis ◽

Athanasios Roumeliotis ◽

Xenia Gorny ◽

Peter R. Mertens

Keyword(s):

Oxidative Stress ◽

Renal Disease ◽

End Stage Renal Disease ◽

Close Association ◽

Omega 3 ◽

Endstage Renal Disease ◽

Increased Risk ◽

Underlying Mechanisms ◽

Stage Renal Disease ◽

End Stage

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

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Eudragit L-100 Capsules Aromatize and Quaternerize Chitosan for Insulin Nanoparticle Oral Delivery During Toxic Oxidative Stress in Rat Liver and Kidney

Pharmaceutical Nanotechnology ◽

10.2174/2211738508666200628033442 ◽

2020 ◽

Vol 8 (3) ◽

pp. 239-254 ◽

Cited By ~ 2

Author(s):

Reza Mahjub ◽

Farzane K. Najafabadi ◽

Narges Dehkhodaei ◽

Nejat Kheiripour ◽

Amir N. Ahmadabadi ◽

...

Keyword(s):

Oxidative Stress ◽

Oral Administration ◽

Oral Delivery ◽

Biochemical Parameters ◽

Kidney Injury ◽

Regular Insulin ◽

Treated Group ◽

Histopathological Change ◽

Diabetic Rats ◽

Liver And Kidney

Background: Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome. Objective: In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied. Methods: INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining . Results: Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups. Conclusion: Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe. Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.

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5-Fluorouracil Loaded Orally Administered WGA-decorated Poly(lactic-co-glycolic acid) Nanoparticles for Treatment of Colorectal Cancer: In Vivo Evaluation

Current Nanomedicine ◽

10.2174/2468187310999201123195233 ◽

2020 ◽

Vol 10 ◽

Author(s):

Aditya Nath Pandey ◽

Kuldeep Rajpoot ◽

Sunil K. Jain

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Oral Delivery ◽

Wheat Germ ◽

Glycolic Acid ◽

Organ Distribution ◽

In Vivo Evaluation ◽

Distribution Study ◽

Prolonged Retention

Background:: Several studies have suggested potential aptitude of polylactic-co-glycolic acid (PLGA)-derived nanoparticles (NPs) to improve the antitumor efficacy of anticancer drugs against colon cancer. Further, conjugation of lectins over the surface of the NPs may ameliorate interaction and thus enhance attachment of NPs with receptors. Objective:: The main goal of the study was to prepare and evaluate targeting potential (in vivo) of the optimized NPs against colorectal cancer. Methods:: The 5-fluorouracil (5-FU) loaded and wheat germ agglutinin (WGA)-conjugated PLGA-NPs (WFUNPs) were prepared and then they were evaluated in vivo for targeting aptitude of formulation using gamma scintigraphy after oral delivery. The WGA-conjugated and non-conjugated optimized NPs were compared for any significant results. Further, optimized formulations were also assessed for different parameters such as radiolabeling efficiency, sodium pertechnetate uptake, stability of NPs, and organ distribution study. Results:: Findings suggested prolonged retention of 99mTc-tagged WFUNPs in the colonic region after 24 h study. Eventually, the outcome from conjugated formulation revealed enhanced bioavailability of the drug in blood plasma for up to 24 h. Conclusion:: In conclusion, WGA-conjugation to NPs could improve the performance of the PLGA-NPs in the treatment of colorectal cancer.

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