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Sophia Ogechi Ekeuku, Kok-Lun Pang, Kok-Yong Chin Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence: Kok-Yong ChinDepartment of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, MalaysiaTel +60 3-9145 9573Email chinkokyong@ppukm.ukm.edu.myPurpose: 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.Keywords: antioxidant, bone, osteoclast, osteoblast, osteoporosis

Sophia Ogechi Ekeuku,1 Benjamin Ka Seng Thong,1,2 Adam Quraisiah,1 Fazalda Annuar,1 Alfizah Hanafiah,3 Mohd Fahami Nur Azlina,1 Kok-Yong Chin1 1Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Malaysia; 2Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Medical Microbiology & Immunology Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, MalaysiaCorrespondence: Kok-Yong ChinDepartment of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Level 17, Preclinical Building, Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Kuala Lumpur, MalaysiaTel +60 3-9145-9573Email chinkokyong@ppukm.ukm.edu.myPurpose: 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.Keywords: bone, gastric ulcer, omeprazole, osteoporosis, osteopenia, proton pump inhibitor

Sophia Ogechi Ekeuku,1 Kok-Lun Pang,1 Kok-Yong Chin1,2 1Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia; 2State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Kok-Yong ChinDepartment of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras 56000, Kuala Lumpur, MalaysiaTel +60 3-9145 9573Email chinkokyong@ppukm.ukm.edu.myAbstract: 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.Keywords: anti-inflammation, antioxidant, myocardial reperfusion injury, obesity, osteoporosis, osteoarthritis

Kok-Yong Chin,1,2 Sok Kuan Wong,1 Sophia Ogechi Ekeuku,1 Kok-Lun Pang1 1Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia; 2State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Kok-Yong ChinDepartment of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, MalaysiaTel +60 3-9145 9573Email chinkokyong@ppukm.ukm.edu.myAbstract: 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.Keywords: bone mineral density, diabetes, dyslipidemia, fracture, hypertension, obesity

Chlorella vulgaris is renowned for its rich nutritional composition and has been associated with various health benefits. This study aimed to look into the effect of CV on liver metabolomes and metabolic pathways in aged Sprague Dawley (SD) rats. Three and 21-month-old male SD rats were divided into control and treated groups. Results showed that carbohydrates such as maltose/lactose and mannose/fructose were downregulated in old rats. These metabolites were downregulated in young rats supplemented with CV. Interestingly, taurine was upregulated in old rats, while the trend was reversed in old rats supplemented with CV at 300 mg/kg/d. The differentially expressed metabolites in different age groups and CV supplementation were mapped to starch and sucrose metabolism, galactose metabolism, and taurine and hypotaurine metabolism. Further research is needed to understand the long-term effects of CV supplementation on ageing and determine optimal dosage levels, especially regarding its potential to mitigate age-related diseases.

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.

Gut dysbiosis has been associated with many chronic diseases, such as obesity, inflammatory bowel disease, and cancer. Gut dysbiosis triggers these diseases through the activation of the immune system by the endotoxins produced by gut microbiota, which leads to systemic inflammation. In addition to pre-/pro-/postbiotics, many natural products can restore healthy gut microbiota composition. Tocotrienol, which is a subfamily of vitamin E, has been demonstrated to have such effects. This scoping review presents an overview of the effects of tocotrienol on gut microbiota according to the existing scientific literature. A literature search to identify relevant studies was conducted using PubMed, Scopus, and Web of Science. Only original research articles which aligned with the review’s objective were examined. Six relevant studies investigating the effects of tocotrienol on gut microbiota were included. All of the studies used animal models to demonstrate that tocotrienol altered the gut microbiota composition, but none demonstrated the mechanism by which this occurred. The studies induced diseases known to be associated with gut dysbiosis in rats. Tocotrienol partially restored the gut microbiota compositions of the diseased rats so that they resembled those of the healthy rats. Tocotrienol also demonstrated strong anti-inflammatory effects in these animals. In conclusion, tocotrienol could exert anti-inflammatory effects by suppressing inflammation directly or partially by altering the gut microbiota composition, thus achieving its therapeutic effects.

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.

E’Jiao is a traditional Chinese medicine derived from donkey skin. E’Jiao is reported to suppress elevated bone remodelling in ovariectomised rats but its mechanism of action is not known. To bridge this research gap, the current study aims to investigate the effects of E’Jiao on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. Female Sprague–Dawley rats (3 months old) were ovariectomised and supplemented with E’Jiao at 0.26 g/kg, 0.53 g/kg and 1.06 g/kg, or 1% calcium carbonate (w/v) in drinking water. The rats were euthanised after two months of supplementation and their bones were collected for Fourier-transform infrared spectroscopy, histomorphometry and protein analysis. Neither ovariectomy nor treatment affected the skeletal mineral/matrix ratio, osteocyte number, empty lacunar number, and Dickkopf-1 and sclerostin protein levels (p > 0.05). Rats treated with calcium carbonate had a higher Dickkopf-1 level than baseline (p = 0.002) and E’Jiao at 0.53 g/kg (p = 0.002). In conclusion, E’Jiao has no significant effect on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. The skeletal effect of E’Jiao might not be mediated through osteocytes.

Glucocorticoid-induced osteogenic dysfunction is the main pathologyical mechanism underlying the development of glucocorticoid-induced osteoporosis. Glucocorticoids promote adipogenic differentiation and osteoblast apoptosis through various pathways. Various ongoing studies are exploring the potential of natural products in preventing glucocorticoid-induced osteoporosis. Preclinical studies have consistently shown the bone protective effects of tocotrienol through its antioxidant and anabolic effects. This review aims to summarise the potential mechanisms of tocotrienol in preventing glucocorticoid-induced osteoporosis based on existing in vivo and in vitro evidence. The current literature showed that tocotrienol prevents oxidative damage on osteoblasts exposed to high levels of glucocorticoids. Tocotrienol reduces lipid peroxidation and increases oxidative stress enzyme activities. The reduction in oxidative stress protects the osteoblasts and preserves the bone microstructure and biomechanical strength of glucocorticoid-treated animals. In other animal models, tocotrienol has been shown to activate the Wnt/β-catenin pathway and lower the RANKL/OPG ratio, which are the targets of glucocorticoids. In conclusion, tocotrienol enhances osteogenic differentiation and bone formation in glucocorticoid-treated osteoblasts while improving structural integrity in glucocorticoid-treated rats. This is achieved by preventing oxidative stress and osteoblast apoptosis. However, these preclinical results should be validated in a randomised controlled trial.

Background: The uptake of human papillomavirus vaccines (HPVV) among men who have sex with men (MSM) remains unsatisfactory. Healthcare providers play a crucial role in improving HPVV acceptability and uptake among MSM. This scoping review aims to provide an overview of (1) the perceived role of healthcare providers by MSM, and (2) the knowledge, beliefs and practices of healthcare providers themselves in promoting HPVV uptake. Methods: A literature search was performed with PubMed and Scopus databases using a specific search string. The relevant original research articles on this topic were identified, and the major findings were charted and discussed. Results: The literature search identified 18 studies on the perceived role of healthcare providers by MSM, and 6 studies on the knowledge, beliefs and practices of healthcare providers in promoting HPVV uptake among MSM. Recommendations by healthcare providers and disclosure of sexual orientation were important positive predictors of higher HPVV acceptability and uptake. Sexual healthcare providers were more confident in delivering HPVV to MSM clients compared to primary practitioners. Conclusion: Recommendation from, and disclosure of sexual orientation to healthcare providers are important in promoting HPVV uptake among MSM. The competency of healthcare providers in delivering HPVV to MSM can be improved by having clearer guidelines, education campaigns and better incentives.

Piper sarmentosum (PS) is a traditional medicinal herb used by South East Asians. It demonstrates promising properties against various non-communicable diseases and infectious agents due to its antioxidant and anti-inflammatory properties. Given that oxidative stress and inflammation are involved in developing and exacerbating metabolic syndrome (MetS) and its principal components (central obesity, hyperglycaemia, hypertension, and dyslipidaemia), PS could manage MetS and its complications. This review summarises the available literature on the effects of PS on principal components of MetS and their complications. The accumulated evidence suggests that PS prevented adiposity, hyperglycaemia, hypertension, and dyslipidaemia in preclinical studies mainly through its antioxidant and anti-inflammatory properties. It also protected against MetS-associated cardiovascular complications. This review has identified research gaps in this field and suggested future studies to guide interested researchers to explore further or affirm the therapeutic potential of PS. One of the most significant challenges to the medical use of PS is the absence of randomised controlled trials in humans. This study gap must be bridged before PS supplementation could be used to manage MetS in humans.

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.

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.