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Fabrication of dicalcium phosphate dihydrate-coated β-TCP granules and evaluation of their osteoconductivity using experimental rats

Shariff KA, Tsuru K, Ishikawa K

Mater Sci Eng C Mater Biol Appl, 2017 Jun 01;75:1411-1419.
PMID: 28415432 DOI: 10.1016/j.msec.2017.03.004

β-Tricalcium phosphate (β-TCP) has attracted much attention as an artificial bone substitute owing to its biocompatibility and osteoconductivity. In this study, osteoconductivity of β-TCP bone substitute was enhanced without using growth factors or cells. Dicalcium phosphate dihydrate (DCPD), which is known to possess the highest solubility among calcium phosphates, was coated on β-TCP granules by exposing their surface with acidic calcium phosphate solution. The amount of coated DCPD was regulated by changing the reaction time between β-TCP granules and acidic calcium phosphate solution. Histomorphometry analysis obtained from histological results revealed that the approximately 10mol% DCPD-coated β-TCP granules showed the largest new bone formation compared to DCPD-free β-TCP granules, approximately 2.5mol% DCPD-coated β-TCP granules, or approximately 27mol% DCPD-coated β-TCP granules after 2 and 4weeks of implantation. Based on this finding, we demonstrate that the osteoconductivity of β-TCP granules could be improved by coating their surface with an appropriate amount of DCPD.
Celastrol attenuates inflammatory responses in adipose tissues and improves skeletal muscle mitochondrial functions in high fat diet-induced obese rats via upregulation of AMPK/SIRT1 signaling pathways

Abu Bakar MH, Shariff KA, Tan JS, Lee LK

Eur J Pharmacol, 2020 Sep 15;883:173371.
PMID: 32712089 DOI: 10.1016/j.ejphar.2020.173371

Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment in vivo remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol in vivo against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.
Effect of strontium substitution on structural, sinterability, physicomechanical and biological properties of akermanite ceramic

Mohammadi H, Baba Ismail YM, Shariff KA, Mohd Noor AF

J Mech Behav Biomed Mater, 2021 04;116:104379.
PMID: 33561674 DOI: 10.1016/j.jmbbm.2021.104379

Despite the excellent in vitro and in vivo performance of akermanite ceramic, its poor toughness and strength limit the biomedical application, particularly under load. Herein, the incorporation of strontium enhanced the physicomechanical properties of akermanite and this is ascribed to the decrease in grain size and better sinterability. To investigate the biological performance, the bone-cell interaction with sintered pellets was assessed by in vitro biocompatibility with human fetal osteoblast cell (hFOB). The cell viability using MTT assay revealed that the Ca1.9Sr0.1MgSi2O7 pellets with finer grain size provided better interaction between the cells compared to the unsubstituted counterpart with larger grain size. Our findings highlighted that the synergistic effect of controlled degradation rate and release of Sr2+ into the medium enhanced the in vitro biological properties of akermanite-based materials.
Withaferin A Protects Against High-Fat Diet-Induced Obesity Via Attenuation of Oxidative Stress, Inflammation, and Insulin Resistance

Abu Bakar MH, Azmi MN, Shariff KA, Tan JS

Appl Biochem Biotechnol, 2019 May;188(1):241-259.
PMID: 30417321 DOI: 10.1007/s12010-018-2920-2

Withaferin A (WA), a bioactive constituent derived from Withania somnifera plant, has been shown to exhibit many qualifying properties in attenuating several metabolic diseases. The current investigation sought to elucidate the protective mechanisms of WA (1.25 mg/kg/day) on pre-existing obese mice mediated by high-fat diet (HFD) for 12 weeks. Following dietary administration of WA, significant metabolic improvements in hepatic insulin sensitivity, adipocytokines with enhanced glucose tolerance were observed. The hepatic oxidative functions of obese mice treated with WA were improved via augmented antioxidant enzyme activities. The levels of serum pro-inflammatory cytokines and hepatic mRNA expressions of toll-like receptor (TLR4), nuclear factor κB (NF-κB), tumor necrosis factor-α (TNF-α), chemokine (C-C motif) ligand-receptor, and cyclooxygenase 2 (COX2) in HFD-induced obese mice were reduced. Mechanistically, WA increased hepatic mRNA expression of peroxisome proliferator-activated receptors (PPARs), cluster of differentiation 36 (CD36), fatty acid synthase (FAS), carnitine palmitoyltransferase 1 (CPT1), glucokinase (GCK), phosphofructokinase (PFK), and phosphoenolpyruvate carboxykinase (PCK1) that were associated with enhanced lipid and glucose metabolism. Taken together, these results indicate that WA exhibits protective effects against HFD-induced obesity through attenuation of hepatic inflammation, oxidative stress, and insulin resistance in mice.
Celastrol attenuates high-fructose diet-induced inflammation and insulin resistance via inhibition of 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose tissues

Abu Bakar MH, Mohamad Khalid MSF, Nor Shahril NS, Shariff KA, Karunakaran T

Biofactors, 2022 Jan;48(1):111-134.
PMID: 34676604 DOI: 10.1002/biof.1793

High fructose consumption has been linked to low-grade inflammation and insulin resistance that results in increased intracellular 11ß-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. Celastrol, a pentacyclic triterpene, has been demonstrated to exhibit multifaceted targets to attenuate various metabolic diseases associated with inflammation. However, the underlying mechanisms by which celastrol exerts its attributive properties on high fructose diet (HFrD)-induced metabolic syndrome remain elusive. Herein, the present study was aimed to elucidate the mechanistic targets of celastrol co-administrations upon HFrD in rats and evaluate its potential to modulate 11β-HSD1 activity. Celastrol remarkably improved glucose tolerance, lipid profiles, and insulin sensitivity along with suppression of hepatic glucose production. In rat adipose tissues, celastrol attenuated nuclear factor-kappa B (NF-κB)-driven inflammation, reduced c-Jun N-terminal kinases (JNK) phosphorylation, and mitigated oxidative stress via upregulated genes expression involved in mitochondrial biogenesis. Furthermore, insulin signaling pathways were significantly improved through the restoration of Akt phosphorylation levels at Ser473 and Thr308 residues. Celastrol exhibited a potent, selective and specific inhibitor of intracellular 11β-HSD1 towards oxidoreductase activity (IC50 value = 4.3 nM) in comparison to other HSD-related enzymes. Inhibition of 11β-HSD1 expression in rat adipose microsomes reduced the availability of its cofactor NADPH and substrate H6PDH in couple to upregulated mRNA and protein expressions of glucocorticoid receptor. In conclusion, our results underscore the most likely conceivable mechanisms exhibited by celastrol against HFrD-induced metabolic dysregulations mainly through attenuating inflammation and insulin resistance, at least via specific inhibitions on 11β-HSD1 activity in adipose tissues.
Fulltext Bioactive Carbonate Apatite Cement with Enhanced Compressive Strength via Incorporation of Silica Calcium Phosphate Composites and Calcium Hydroxide

Cahyanto A, Liemidia M, Karlina E, Zakaria MN, Shariff KA, Sukotjo C, et al.

Materials (Basel), 2023 Mar 03;16(5).
PMID: 36903186 DOI: 10.3390/ma16052071

Carbonate apatite (CO3Ap) is a bioceramic material with excellent properties for bone and dentin regeneration. To enhance its mechanical strength and bioactivity, silica calcium phosphate composites (Si-CaP) and calcium hydroxide (Ca(OH)2) were added to CO3Ap cement. The aim of this study was to investigate the effect of Si-CaP and Ca(OH)2 on the mechanical properties in terms of the compressive strength and biological characteristics of CO3Ap cement, specifically the formation of an apatite layer and the exchange of Ca, P, and Si elements. Five groups were prepared by mixing CO3Ap powder consisting of dicalcium phosphate anhydrous and vaterite powder added by varying ratios of Si-CaP and Ca(OH)2 and 0.2 mol/L Na2HPO4 as a liquid. All groups underwent compressive strength testing, and the group with the highest strength was evaluated for bioactivity by soaking it in simulated body fluid (SBF) for one, seven, 14, and 21 days. The group that added 3% Si-CaP and 7% Ca(OH)2 had the highest compressive strength among the groups. SEM analysis revealed the formation of needle-like apatite crystals from the first day of SBF soaking, and EDS analysis indicated an increase in Ca, P, and Si elements. XRD and FTIR analyses confirmed the presence of apatite. This combination of additives improved the compressive strength and showed the good bioactivity performance of CO3Ap cement, making it a potential biomaterial for bone and dental engineering applications.
Fulltext Ellagic acid and hydroxyapatite promote angiogenesis marker in bone defect

Nirwana I, Munadziroh E, Yuliati A, Fadhila AI, Nurliana, Wardhana AS, et al.

J Oral Biol Craniofac Res, 2022;12(1):116-120.
PMID: 34840942 DOI: 10.1016/j.jobcr.2021.11.008

The combination of hydroxyapatite and the herbal extract ellagic acid is expected to accelerate the bone healing process (osteogenesis) due to the extract's anti-inflammatory and antioxidant properties. The osteogenesis process is closely associated with angiogenesis markers, such as fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF) and alkali phosphatase (ALP). The objective of this study is to analyse the combination of ellagic acid and hydroxyapatite to promote FGF-2, VEGF and ALP expression as angiogenesis markers in a bone defect model. The research sample comprised 30 male Wistar rats with a defect introduced on the left femur; these were divided into three groups for treatment with ellagic acid and hydroxyapatite, hydroxyapatite and polyethylene glycol (PEG) (control). On days 7 and 14 days after treatment, the Wistar rats were euthanised, and the femoral bone tissue was removed for the immunohistochemical analysis of FGF-2, VEGF and ALP expression. FGF-2 and ALP expression increased in the group treated with ellagic acid and hydroxyapatite on days 7 and 14 post treatment (p
Fulltext The Cytokine and Bone Protein Expression by Ellagic Acid-Hydroxyapatite in Bone Remodelling Model

Primasari DN, Nirwana I, Budi HS, Wardhana AS, Sari AF, Novita N, et al.

ScientificWorldJournal, 2022;2022:6740853.
PMID: 36561943 DOI: 10.1155/2022/6740853

OBJECTIVE: Ellagic acid, a phenolic compound with anti-inflammatory potential, can be used to accelerate the bone healing process and affect human health, while hydroxyapatite is the most commonly used bone graft material. Using a combination of the two materials results in reduced inflammation and increased osteogenesis. This study aimed to determine the effects of combining ellagic acid and hydroxyapatite in bone marker remodelling by analysing the expression of tumour necrosis factor-α (TNF-α), interleukin 10 (IL-10), bone morphogenetic 4 protein (BMP-4), and osteopontin (OPN).
METHODS: Thirty Wistar rats were used in the study. A defect was created in each animal's femur using a low-speed diamond bur. In the control group, the bone was then treated with polyethylene glycol (PEG). In one of the other groups, the bone was treated with hydroxyapatite, and in the other, with ellagic acid-hydroxyapatite. The femur was biopsied 7 days after the procedure and again 14 days after the procedure, and an indirect immunohistochemical (IHC) examination was performed for TNF-α, IL-10, BMP-4, and OPN expression.
RESULTS: The ellagic acid-hydroxyapatite decreased TNF-α expression in the bone tissue after 7 days and again after 14 days (p
Anti-Inflammatory Effects of Calcium Hydroxide Combined with Ellagic Acid as Pulp Capping Material: In Vivo Study

Sari AF, Nirwana I, Yuliati A, Meizarini A, Rahayu RP, Palupi R, et al.

Eur J Dent, 2024 Nov 07.
PMID: 39510525 DOI: 10.1055/s-0044-1791243

OBJECTIVES: Pulp capping is a pivotal treatment in dentistry aimed at preserving pulp vitality. While calcium hydroxide has long been considered the gold standard in pulp capping materials, its long-term use can induce chronic inflammation, ultimately leading to pulp necrosis and affecting human health. In this context, ellagic acid, a natural compound with potent anti-inflammatory properties, emerged as a promising adjunct to mitigate inflammation associated with calcium hydroxide application, thereby sustaining pulp vitality. This study aimed to investigate the inflammatory response by alterations in neutrophil, macrophage, lymphocyte, and tumor necrosis factor-α (TNF-α) expression following the treatment with a combination of calcium hydroxide and ellagic acid.
MATERIALS AND METHODS: Dental pulp perforation was made on 27 male Wistar rats on the upper first molar and then pulp capped with calcium hydroxide and ellagic acid. The pulp of the control positive group was capped with calcium hydroxide, and the control group was not capped. The teeth were then extracted after 1, 3, and 7 days posttreatment. The differences in the number of neutrophils, macrophages, lymphocytes, and TNF-α expression were analyzed using one-way analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) test.
RESULTS: The treatment combination of calcium hydroxide and ellagic acid showed the lowest neutrophil number and TNF-α expression compared with the other groups (p