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  1. Ekeuku SO, Chin KY
    Molecules, 2021 May 25;26(11).
    PMID: 34070497 DOI: 10.3390/molecules26113156
    Chronic inflammation and oxidative stress are two major mechanisms leading to the imbalance between bone resorption and bone formation rate, and subsequently, bone loss. Thus, functional foods and dietary compounds with antioxidant and anti-inflammatory could protect skeletal health. This review aims to examine the current evidence on the skeletal protective effects of propolis, a resin produced by bees, known to possess antioxidant and anti-inflammatory activities. A literature search was performed using Pubmed, Scopus, and Web of Science to identify studies on the effects of propolis on bone health. The search string used was (i) propolis AND (ii) (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes). Eighteen studies were included in the current review. The available experimental studies demonstrated that propolis could prevent bone loss due to periodontitis, dental implantitis, and diabetes in animals. Combined with synthetic and natural grafts, it could also promote fracture healing. Propolis protects bone health by inhibiting osteoclastogenesis and promoting osteoblastogenesis, partly through its antioxidant and anti-inflammatory actions. Despite the promising preclinical results, the skeletal protective effects of propolis are yet to be proven in human studies. This research gap should be bridged before nutraceuticals based on propolis with specific health claims can be developed.
  2. Ekeuku SO, Pang KL, Chin KY
    Molecules, 2021 Apr 16;26(8).
    PMID: 33923673 DOI: 10.3390/molecules26082319
    BACKGROUND: Osteoporosis results from excessive bone resorption and reduced bone formation, triggered by sex hormone deficiency, oxidative stress and inflammation. Tanshinones are a class of lipophilic phenanthrene compounds found in the roots of Salvia miltiorrhiza with antioxidant and anti-inflammatory activities, which contribute to its anti-osteoporosis effects. This systematic review aims to provide an overview of the skeletal beneficial effects of tanshinones.

    METHODS: A systematic literature search was conducted in January 2021 using Pubmed, Scopus and Web of Science from the inception of these databases. Original studies reporting the effects of tanshinones on bone through cell cultures, animal models and human clinical trials were considered.

    RESULTS: The literature search found 158 unique articles on this topic, but only 20 articles met the inclusion criteria and were included in this review. The available evidence showed that tanshinones promoted osteoblastogenesis and bone formation while reducing osteoclastogenesis and bone resorption.

    CONCLUSIONS: Tanshinones modulates bone remodelling by inhibiting osteoclastogenesis and osteoblast apoptosis and stimulating osteoblastogenesis. Therefore, it might complement existing strategies to prevent bone loss.

  3. Ekeuku SO, Pang KL, Chin KY
    Drug Des Devel Ther, 2020;14:4963-4974.
    PMID: 33235437 DOI: 10.2147/DDDT.S280520
    Palmatine is a naturally occurring isoquinoline alkaloid with various pharmacological properties. Given its antioxidant and anti-inflammatory properties, palmatine may be able to impede the effects of metabolic syndrome (MetS) and its related diseases triggered by inflammation and oxidative stress. This review summarises the existing literature about the effects of palmatine supplementation on MetS and its complications. The evidence shows that palmatine could protect against MetS, and cardiovascular diseases, osteoporosis and osteoarthritis, which might be associated with MetS. These protective effects are mediated by the antioxidant and anti-inflammatory properties of palmatine. Although preclinical experiments have demonstrated the efficacy of palmatine against MetS and its related diseases, no human clinical trials have been performed to validate these effects. This research gap should be bridged to validate the efficacy and safety of palmatine supplementation in protecting humans against MetS and its related diseases.
  4. Pang KL, Ekeuku SO, Chin KY
    Risk Manag Healthc Policy, 2021;14:2715-2732.
    PMID: 34194253 DOI: 10.2147/RMHP.S316429
    Air pollution is associated with inflammation and oxidative stress, which predispose to several chronic diseases in human. Emerging evidence suggests that the severity and progression of osteoporosis are directly associated with inflammation induced by air pollutants like particulate matter (PM). This systematic review examined the relationship between PM and bone health or fractures. A comprehensive literature search was conducted from January until February 2021 using the PubMed, Scopus, Web of Science, Google Scholar and Cochrane Library databases. Human cross-sectional, cohort and case-control studies were considered. Of the 1500 papers identified, 14 articles were included based on the inclusion and exclusion criteria. The air pollution index investigated by most studies were PM2.5 and PM10. Current studies demonstrated inconsistent associations between PM and osteoporosis risk or fractures, which may partly due to the heterogeneity in subjects' characteristics, study design and analysis. In conclusion, there is an inconclusive relationship between osteoporosis risk and fracture and PM exposures which require further validation.
  5. Ekeuku SO, Pang KL, Chin KY
    Drug Des Devel Ther, 2021;15:259-275.
    PMID: 33519191 DOI: 10.2147/DDDT.S287280
    PURPOSE: Caffeic acid is a metabolite of hydroxycinnamate and phenylpropanoid, which are commonly synthesized by all plant species. It is present in various food sources that are known for their antioxidant properties. As an antioxidant, caffeic acid ameliorates reactive oxygen species, which have been reported to cause bone loss. Some studies have highlighted the effects of caffeic acid against bone resorption.

    METHODS: A systematic review of the literature was conducted to identify relevant studies on the effects of caffeic acid on bone. A comprehensive search was conducted from July to November 2020 using PubMed, Scopus, Cochrane Library and Web of Science databases. Cellular, animal and human studies reporting the effects of caffeic acid, as a single compound, on bone cells or bone were considered.

    RESULTS: The literature search found 226 articles on this topic, but only 24 articles met the inclusion criteria and were included in this review. The results showed that caffeic acid supplementation reduced osteoclastogenesis and bone resorption, possibly through its antioxidant potential and increased expression of osteoblast markers. However, some studies showed that caffeic acid did not affect bone resorption in ovariectomized rats and might impair bone mechanical properties in normal rats.

    CONCLUSION: Caffeic acid potentially regulates the bone remodelling process by inhibiting osteoclastogenesis and bone resorption, as well as osteoblast apoptosis. Thus, it has medicinal values against bone diseases.

  6. Nor Muhamad ML, Ekeuku SO, Wong SK, Chin KY
    Nutrients, 2022 Nov 16;14(22).
    PMID: 36432535 DOI: 10.3390/nu14224851
    BACKGROUND: Osteoporosis is caused by the deterioration of bone density and microstructure, resulting in increased fracture risk. It transpires due to an imbalanced skeletal remodelling process favouring bone resorption. Various natural compounds can positively influence the skeletal remodelling process, of which naringenin is a candidate. Naringenin is an anti-inflammatory and antioxidant compound found in citrus fruits and grapefruit. This systematic review aims to present an overview of the available evidence on the skeletal protective effects of naringenin.

    METHOD: A systematic literature search was conducted using the PubMed and Scopus databases in August 2022. Original research articles using cells, animals, or humans to investigate the bone protective effects of naringenin were included.

    RESULTS: Sixteen eligible articles were included in this review. The existing evidence suggested that naringenin enhanced osteoblastogenesis and bone formation through BMP-2/p38MAPK/Runx2/Osx, SDF-1/CXCR4, and PI3K/Akt/c-Fos/c-Jun/AP-1 signalling pathways. Naringenin also inhibited osteoclastogenesis and bone resorption by inhibiting inflammation and the RANKL pathway.

    CONCLUSIONS: Naringenin enhances bone formation while suppressing bone resorption, thus achieving its skeletal protective effects. It could be incorporated into the diet through fruit intake or supplements to prevent bone loss.

  7. Ekeuku SO, Chin KY, Mohd Ramli ES
    PMID: 36453484 DOI: 10.2174/1871530323666221130152737
    BACKGROUND: Piper sarmentosum (PS) is a traditional herb used by Southeast Asian communities to treat various illnesses. Recent pharmacological studies have discovered that PS possesses antioxidant and anti-inflammatory activities. Since oxidative stress and inflammation are two important processes driving the pathogenesis of bone loss, PS may have potential therapeutic effects against osteoporosis.

    OBJECTIVE: This review systematically summarised the therapeutic effects of PS on preventing osteoporosis and promoting fracture healing.

    METHODS: A systematic literature search was performed in November 2021 using 4 electronic databases and the search string "Piper sarmentosum" AND (bone OR osteoporosis OR osteoblasts OR osteoclasts OR osteocytes).

    RESULTS: Nine unique articles were identified from the literature. The efficacy of PS has been studied in animal models of osteoporosis induced by ovariectomy and glucocorticoids, as well as bone fracture models. PS prevented deterioration of bone histomorphometric indices, improved fracture healing and restored the biomechanical properties of healed bone in ovariectomised rats. PS also prevented osteoblast/osteocyte apoptosis, increased bone formation and mineralisation and subsequently improved trabecular bone microstructures and strength of rats with osteoporosis induced by glucocorticoids. Apart from its antioxidant and anti-inflammatory activity, PS also suppressed circulating and skeletal expression of corticosterone and skeletal expression of 11β hydroxysteroid dehydrogenase type 1 but increased the enzyme activity in the glucocorticoid osteoporosis model. This review also identified several research gaps about the skeletal effects of PS and suggested future studies to bridge these gaps.

    CONCLUSION: PS may be of therapeutic benefit to bone health. However, further research is required to validate this claim.

  8. Chin KY, Wong SK, Ekeuku SO, Pang KL
    Diabetes Metab Syndr Obes, 2020;13:3667-3690.
    PMID: 33116718 DOI: 10.2147/DMSO.S275560
    Metabolic syndrome (MetS) and osteoporosis are two medical problems plaguing the ageing populations worldwide. Though seemingly distinctive to each other, metabolic derangements are shown to influence bone health. This review summarises the relationship between MetS and bone health derived from epidemiological studies and explains the mechanistic basis of this relationship. The discourse focuses on the link between MetS and bone mineral density, quantitative sonometric indices, geometry and fracture risk in humans. The interesting sex-specific trend in the relationship, probably due to factors related to body composition and hormonal status, is discussed. Mechanistically, each component of MetS affects the bone distinctly, forming a complex interacting network influencing the skeleton. Lastly, the effects of MetS management, such as pharmacotherapies, exercise and bariatric surgery, on bone, are presented. This review aims to highlight the significant relationship between MetS and bone, and proper management of MetS with the skeletal system in mind could prevent cardiovascular and bone complications.
  9. Okechukwu PN, Ekeuku SO, Chan HK, Eluri K, Froemming GRA
    Curr Pharm Biotechnol, 2021;22(2):288-298.
    PMID: 32744968 DOI: 10.2174/1389201021666200730124208
    BACKGROUND: Diabetes Mellitus (DM) is characterized by hyperglycemia (high blood glucose levels) which is due to the destruction of insulin-producing β-cells in the islets of Langerhans in the pancreas. It is associated with oxidative and endoplasmic reticulum stress. The plant alkaloid Palmatine has been previously reported to possess antidiabetic and antioxidant properties as well as other protective properties against kidney and liver tissue damage.

    OBJECTIVE: Here, we investigated the ability of Palmatine to reduce the up-regulation of chaperone proteins Glucose Regulatory Protein 78 (GRP78), and Calreticulin (CALR) protein in a Streptozotocin (STZ)-induced diabetic rat model.

    METHODS: Streptozotocin (STZ) induced diabetes in Sprague Dawley rats treated with 2mg/kg of Palmatine for 12 weeks after the elevation of plasma glucose levels above 11mmol/L post-STZ administration. Proteins were extracted from the pancreas after treatment and Two-Dimensional gel electrophoresis (2-DE), PDQuest 2-D analysis software genomic solutions and mass spectrometer were used to analyze differentially expressed protein. Mass Spectrometry (MS/MS), Multidimensional Protein Identification Technology (MudPIT) was used for protein identification.

    RESULTS: There was an up-regulation of the expression of chaperone proteins CALR and GRP78 and down-regulation of the expression of antioxidant and protection proteins peroxidoxin 4 (Prdx4), protein disulfide isomerase (PDIA2/3), Glutathione-S-Transferase (GSTs), and Serum Albumin (ALB) in non-diabetic rats. Palmatine treatment down-regulated the expression of chaperone proteins CALR and GRP78 and up-regulated the expression of Prdx4, PDIA2/3, GST, and ALB.

    CONCLUSION: Palmatine may have activated antioxidant proteins, which protected the cells against reactive oxygen species and endoplasmic stress. The result is in consonance with our previous report on Palmatine.

  10. Ekeuku SO, Thong BKS, Quraisiah A, Annuar F, Hanafiah A, Nur Azlina MF, et al.
    Drug Des Devel Ther, 2020;14:5359-5366.
    PMID: 33324037 DOI: 10.2147/DDDT.S287239
    Purpose: Triple therapy is the standard therapy to eradicate Helicobacter pylori (H.pylori) infection. Chronic use of proton pump inhibitors (PPIs), a component of triple therapy, is associated with osteoporosis. However, the skeletal effects of short-term triple therapy containing PPI remain elusive. This study aims to determine the skeletal effect of short-term triple therapy in a rat model of gastric ulcer induced by H. pylori.

    Methods: Three-month-old male Sprague Dawley rats were assigned to normal control, H. pylori-inoculated group (negative control) and H. pylori-inoculated group receiving triple therapy consisting of omeprazole [2.035 mg/kg body weight (b.w)], amoxicillin (102.80 mg/kg b.w) and clarithromycin (51.37 mg/kg b.w) (n=6/group). H. pylori infection developed for four weeks after inoculation, followed by two-week triple therapy. At the end of the treatment period, femoral bones of the rats were harvested for analysis. Bone mineral density and content of the femurs were determined using dual-energy X-ray absorptiometry, while bone strength was measured with a universal mechanical tester.

    Results: Bone mineral content was significantly lower in the negative control group compared to the triple therapy group (p=0.014). Triple therapy decreased strain (vs negative control, p=0.002) and displacement of the femur (vs normal control, p=0.004; vs untreated control, p=0.005). No significant difference was observed in other parameters among the study groups (p>0.05).

    Conclusion: Short-term triple therapy increases bone mineral content but decreases bone strength of rats. Skeletal prophylaxis should be considered for patients on short-term triple therapy containing PPI.

  11. Tejpal Singh HS, Aminuddin AA, Pang KL, Ekeuku SO, Chin KY
    Pharmaceuticals (Basel), 2023 Mar 02;16(3).
    PMID: 36986484 DOI: 10.3390/ph16030385
    Arthritis is a cluster of diseases impacting joint health and causing immobility and morbidity in the elderly. Among the various forms of arthritis, osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common. Currently, satisfying disease-modifying agents for arthritis are not available. Given the pro-inflammatory and oxidative stress components in the pathogenesis of arthritis, tocotrienol, a family of vitamin E with both anti-inflammatory and antioxidant properties, could be joint-protective agents. This scoping review aims to provide an overview of the effects of tocotrienol on arthritis derived from the existing scientific literature. A literature search using PubMed, Scopus and Web of Science databases was conducted to identify relevant studies. Only cell culture, animal and clinical studies with primary data that align with the objective of this review were considered. The literature search uncovered eight studies investigating the effects of tocotrienol on OA (n = 4) and RA (n = 4). Most of the studies were preclinical and revealed the positive effects of tocotrienol in preserving joint structure (cartilage and bone) in models of arthritis. In particular, tocotrienol activates the self-repair mechanism of chondrocytes exposed to assaults and attenuates osteoclastogenesis associated with RA. Tocotrienol also demonstrated strong anti-inflammatory effects in RA models. The single clinical trial available in the literature showcases that palm tocotrienol could improve joint function among patients with OA. In conclusion, tocotrienol could be a potential anti-arthritic agent pending more results from clinical studies.
  12. Ekeuku SO, Etim EP, Pang KL, Chin KY, Mai CW
    World J Gastrointest Oncol, 2023 Jun 15;15(6):943-958.
    PMID: 37389119 DOI: 10.4251/wjgo.v15.i6.943
    Pancreatic cancer is the leading cause of cancer mortality worldwide. Research investigating effective management strategies for pancreatic cancer is ongoing. Vitamin E, consisting of both tocopherol and tocotrienol, has demonstrated debatable effects on pancreatic cancer cells. Therefore, this scoping review aims to summarize the effects of vitamin E on pancreatic cancer. In October 2022, a literature search was conducted using PubMed and Scopus since their inception. Original studies on the effects of vitamin E on pancreatic cancer, including cell cultures, animal models and human clinical trials, were considered for this review. The literature search found 75 articles on this topic, but only 24 articles met the inclusion criteria. The available evidence showed that vitamin E modulated proliferation, cell death, angiogenesis, metastasis and inflammation in pancreatic cancer cells. However, the safety and bioavailability concerns remain to be answered with more extensive preclinical and clinical studies. More in-depth analysis is necessary to investigate further the role of vitamin E in the management of pancreatic cancers.
  13. Ekeuku SO, Mohd Murshid N, Shukri SN, Mohd Sahardi NFN, Makpol S
    Int J Mol Sci, 2023 Aug 03;24(15).
    PMID: 37569747 DOI: 10.3390/ijms241512372
    Research into ageing is focused on understanding why some people can maintain cognitive ability and others lose autonomy, affecting their quality of life. Studies have revealed that age-related neurodegenerative disorders like Alzheimer's disease (AD) are now major causes of death among the elderly, surpassing malignancy. This review examines the effects of vitamin E on transcriptomic changes in ageing and neurodegenerative diseases, using AD as an example, and how different transcriptome profiling techniques can shape the results. Despite mixed results from transcriptomic studies on AD patients' brains, we think advanced technologies could offer a more detailed and accurate tool for such analysis. Research has also demonstrated the role of antioxidant modifiers in preventing AD. This review will explore the key findings regarding AD and its modulation by vitamin E, emphasizing the shift in its epidemiology during the ageing process.
  14. Chin KY, Ng BN, Rostam MKI, Muhammad Fadzil NFD, Raman V, Mohamed Yunus F, et al.
    J Clin Med, 2022 Oct 30;11(21).
    PMID: 36362662 DOI: 10.3390/jcm11216434
    Osteoporosis refers to excessive bone loss as reflected by the deterioration of bone mass and microarchitecture, which compromises bone strength. It is a complex multifactorial endocrine disease. Its pathogenesis relies on the presence of several endogenous and exogenous risk factors, which skew the physiological bone remodelling to a more catabolic process that results in net bone loss. This review aims to provide an overview of osteoporosis from its biology, epidemiology and clinical aspects (detection and pharmacological management). The review will serve as an updated reference for readers to understand the basics of osteoporosis and take action to prevent and manage this disease.
  15. Ekeuku SO, Chin KY, Qian J, Zhang Y, Qu H, Ahmad F, et al.
    Int J Med Sci, 2023;20(13):1711-1721.
    PMID: 37928881 DOI: 10.7150/ijms.84604
    Background: Menopause is accompanied by increased oxidative stress, partly contributing to weight gain and bone marrow adiposity. Traditional Chinese medication, E'Jiao, has been demonstrated to reduce excessive bone remodelling during oestrogen deprivation, but its effects on body composition and bone marrow adiposity during menopause remain elusive. Objective: To determine the effects of E'Jiao on body composition, bone marrow adiposity and skeletal redox status in ovariectomised (OVX) rats. Methods: Seven groups of three-month-old female Sprague Dawley rats were established (n=6/group): baseline, sham, OVX control, OVX-treated with low, medium or high-dose E'Jiao (0.26, 0.53, 1.06 g/kg, p.o.) or calcium carbonate (1% in tap water, ad libitum). The supplementation was terminated after 8 weeks. Whole-body composition analysis was performed monthly using dual-energy X-ray absorptiometry. Analysis of bone-marrow adipocyte numbers and skeletal antioxidant activities were performed on the femur. Results: Increased total mass, lean mass, and bone marrow adipocyte number were observed in the OVX control versus the sham group. Low-dose E'Jiao supplementation counteracted these changes. Besides, E'Jiao at all doses increased skeletal catalase and superoxide dismutase activities but lowered glutathione levels in the OVX rats. Skeletal malondialdehyde level was not affected by ovariectomy but was lowered with E'Jiao supplementation. However, peroxisome proliferator-activated receptor gamma protein expression was not affected by ovariectomy or any treatment. Conclusion: E'Jiao, especially at the low dose, prevented body composition changes and bone marrow adiposity due to ovariectomy. These changes could be mediated by the antioxidant actions of E'Jiao. It has the potential to be used among postmenopausal women to avoid adiposity.
  16. Ekeuku SO, Nor Muhamad ML, Aminuddin AA, Ahmad F, Wong SK, Mark-Lee WF, et al.
    Biomed Pharmacother, 2024 Jan;170:115998.
    PMID: 38091638 DOI: 10.1016/j.biopha.2023.115998
    Postmenopausal women are susceptible to osteoporosis and osteoarthritis. Tocotrienol, a bone-protective nutraceutical, is reported to prevent osteoarthritis in male rats. However, its efficacy on joint health in oestrogen deficiency has not been validated. Besides, data on the use of emulsification systems in enhancing bioavailability and protective effects of tocotrienol are limited. Ovariectomised adult female Sprague-Dawley rats (3 months old) were treated with refined olive oil, emulsified (EPT, 100 mg/kg/day with 25% vitamin E content), non-emulsified palm tocotrienol (NEPT, 100 mg/kg/day with 50% vitamin E content) and calcium carbonate (1% w/v in drinking water) plus glucosamine sulphate (250 mg/kg/day) for 10 weeks. Osteoarthritis was induced with monosodium iodoacetate four weeks after ovariectomy. Baseline control was sacrificed upon receipt, while the sham group was not ovariectomised and treated with refined olive oil. EPT and NEPT prevented femoral metaphyseal and subchondral bone volume decline caused by ovariectomy. EPT decreased subchondral trabecular separation compared to the negative control. EPT preserved stiffness and Young's Modulus at the femoral mid-shaft of the rats. Circulating RANKL was reduced post-treatment in the EPT group. Joint width was reduced in all the treatment groups vs the negative control. The EPT group's grip strength was significantly improved over the negative control and NEPT group. EPT also preserved cartilage histology based on several Mankin's subscores. EPT performed as effectively as NEPT in preventing osteoporosis and osteoarthritis in ovariectomised rats despite containing less vitamin E content. This study justifies clinical trials for the use of EPT in postmenopausal women with both conditions.
  17. Ekeuku SO, Tan JK, Al-Saadi HM, Ahmad F, Elvy Suhana MR, Arlamsyah AM, et al.
    Life (Basel), 2023 Dec 15;13(12).
    PMID: 38137944 DOI: 10.3390/life13122343
    Osteoarthritis (OA) is a degenerative joint condition with limited disease-modifying treatments currently. Palm tocotrienol-rich fraction (TRF) has been previously shown to be effective against OA, but its mechanism of action remains elusive. This study aims to compare serum metabolomic alteration in Sprague-Dawley rats with monosodium iodoacetate (MIA)-induced OA which were treated with palm TRF, glucosamine sulphate, or a combination of both. This study was performed on thirty adult male rats, which were divided into normal control (n = 6) and OA groups (n = 24). The OA group received intra-articular injections of MIA and daily oral treatments of refined olive oil (vehicle, n = 6), palm TRF (100 mg/kg, n = 6), glucosamine sulphate (250 mg/kg, n = 6), or a combination of TRF and glucosamine (n = 6) for four weeks. Serum was collected at the study's conclusion for metabolomic analysis. The findings revealed that MIA-induced OA influences amino acid metabolism, leading to changes in metabolites associated with the biosynthesis of phenylalanine, tyrosine and tryptophan as well as alterations in the metabolism of phenylalanine, tryptophan, arginine and proline. Supplementation with glucosamine sulphate, TRF, or both effectively reversed these metabolic changes induced by OA. The amelioration of metabolic effects induced by OA is linked to the therapeutic effects of TRF and glucosamine. However, it remains unclear whether these effects are direct or indirect in nature.
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