Glycogen Synthase Kinase-3 Beta (GSK3ß) as a Potential Drug Target in Regulating Osteoclastogenesis: An Updated Review on Current Evidence.

Glycogen synthase kinase 3-beta (GSK3ß) is a highly conserved protein kinase originally involved in glucose metabolism, insulin activity, and energy homeostasis. Recent scientific evidence demonstrated the significant role of GSK3ß in regulating bone remodelling through involvement in multiple signalling networks. Specifically, the inhibition of GSK3ß enhances the conversion of osteoclast progenitors into mature osteoclasts. GSK3ß is recognised as a pivotal regulator for the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT), nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1), canonical Wnt/beta (ß)-catenin, and protein kinase C (PKC) signalling pathways during osteoclastogenesis. Conversely, the inhibition of GSK3ß has been shown to prevent bone loss in animal models with complex physiology, suggesting that the role of GSK3ß may be more significant in bone formation than bone resorption. Divergent findings have been reported regarding the efficacy of GSK3ß inhibitors as bone-protecting agents. Some studies demonstrated that GSK3ß inhibitors reduced osteoclast formation, while one study indicated an increase in osteoclast formation in RANKL-stimulated bone marrow macrophages (BMMs). Given the discrepancies observed in the accumulated evidence, further research is warranted, particularly regarding the use of GSK3ß silencing or overexpression models. Such efforts will provide valuable insights into the direct impact of GSK3ß on osteoclastogenesis and bone resorption.

The effects of E'Jiao on body composition, bone marrow adiposity and skeletal redox status in ovariectomised rats.

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.

The Effects of Tocotrienol on Gut Microbiota: A Scoping Review.

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.

Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.

A Review of the Application of Natural and Synthetic Scaffolds in Bone Regeneration.

The management of bone defects is complicated by the presence of clinical conditions, such as critical-sized defects created by high-energy trauma, tumour resection, infection, and skeletal abnormalities, whereby the bone regeneration capacity is compromised. A bone scaffold is a three-dimensional structure matrix serving as a template to be implanted into the defects to promote vascularisation, growth factor recruitment, osteogenesis, osteoconduction, and mechanical support. This review aims to summarise the types and applications of natural and synthetic scaffolds currently adopted in bone tissue engineering. The merits and caveats of natural and synthetic scaffolds will be discussed. A naturally derived bone scaffold offers a microenvironment closer to in vivo conditions after decellularisation and demineralisation, exhibiting excellent bioactivity, biocompatibility, and osteogenic properties. Meanwhile, an artificially produced bone scaffold allows for scalability and consistency with minimal risk of disease transmission. The combination of different materials to form scaffolds, along with bone cell seeding, biochemical cue incorporation, and bioactive molecule functionalisation, can provide additional or improved scaffold properties, allowing for a faster bone repair rate in bone injuries. This is the direction for future research in the field of bone growth and repair.

Normalisation of High Bone Remodelling due to Oestrogen Deficiency by Traditional Chinese Formulation Kang Shuai Lao Pian in Ovariectomised Rats.

Postmenopausal osteoporosis transpires due to excessive osteoclastic bone resorption and insufficient osteoblastic bone formation in the presence of oestrogen insufficiency. Kang Shuai Lao Pian (KSLP) is a red ginseng-based traditional Chinese medicine known for its anti-ageing properties. However, studies on its effect on bone loss are lacking. Thus, the current study examined the skeletal protective effects of KSLP in an ovariectomised rodent bone loss model. Three-month-old female Sprague Dawley rats (n=42) were randomised into baseline, sham and ovariectomised (OVX) groups. The OVX rats were supplemented with low- (KSLP-L; 0.15 g/kg), medium- (KSLP-M; 0.30 g/kg), high-dose KSLP (KSLP-H; 0.45 g/kg) or calcium carbonate (1% w/v). The daily supplementation of KSLP was performed via oral gavage for eight weeks. Gavage stress was stimulated in the ovariectomised control with distilled water. The rats were euthanised at the end of the study. Whole-body and femoral bone mineral content and density scans were performed at baseline and every four weeks. Blood samples were obtained for the determination of bone remodelling markers. Histomorphometry and biomechanical strength testing were performed on femurs and tibias. High bone remodelling typically due to oestrogen deficiency, indicated by the elevated bone formation and resorption markers, osteoclast surface, single-labelled surface and mineralising surface/bone surface ratio, was observed in the untreated OVX rats. Whole-body BMD adjusted to body weight and Young's modulus decreased significantly in the untreated OVX rats. High-dose KSLP supplementation counteracted these degenerative changes. In conclusion, KSLP improves bone health by normalising bone remodelling, thereby preventing bone loss and decreased bone strength caused by oestrogen deficiency. Its anti-osteoporosis effects should be validated in patients with postmenopausal osteoporosis.

Suppression of high bone remodelling by E'Jiao in ovariectomised rats.

The current prevention options for postmenopausal osteoporosis are very limited. E'Jiao is a collagen-rich traditional Chinese medicine with the potential to prevent osteoporosis but more comprehensive investigations are lacking. This study aimed to investigate the skeletal protective effects of E'Jiao in a rat model of osteoporosis caused by ovariectomy. Female Sprague Dawley rats (n = 42) were randomly assigned into baseline, sham, ovariectomised (OVX) control, OVX-treated with low-dose (0.26 g/kg), medium dose (0.53 g/kg) and high dose E'Jiao (1.06 g/kg), as well as calcium carbonate (1% w/v) groups. Daily treatment through oral gavage was initiated 7 days after OVX. The rats were euthanised after eight weeks of treatment. Bone mineral density and content were measured at baseline, 1 and 2 months after treatment. Blood was collected for the measurement of bone remodelling markers. Femur and tibial bones were collected for histomorphometry and biomechanical strength analysis. Untreated OVX rats showed high bone remodelling marked by the increased bone formation and bone resorption markers, as well as increased mineralising surface/bone surface ratio. In addition, osteoclast surface and single-labelled surface were increased while mineral apposition rate was reduced in the untreated OVX rats. These changes were antagonised by E'Jiao at all doses. However, the structural, cellular and biomechanical parameters were not affected by ovariectomy and treatment. In conclusion, E'Jiao prevented high bone remodelling during oestrogen deficiency but a long-term study will be required to establish its effects on structural and biomechanical changes due to oestrogen deficiency.

A Review on the Enhancement of Calcium Phosphate Cement with Biological Materials in Bone Defect Healing.

Calcium phosphate cement (CPC) is a promising material used in the treatment of bone defects due to its profitable features of self-setting capability, osteoconductivity, injectability, mouldability, and biocompatibility. However, the major limitations of CPC, such as the brittleness, lack of osteogenic property, and poor washout resistance, remain to be resolved. Thus, significant research effort has been committed to modify and reinforce CPC. The mixture of CPC with various biological materials, defined as the materials produced by living organisms, have been fabricated by researchers and their characteristics have been investigated in vitro and in vivo. This present review aimed to provide a comprehensive overview enabling the readers to compare the physical, mechanical, and biological properties of CPC upon the incorporation of different biological materials. By mixing the bone-related transcription factors, proteins, and/or polysaccharides with CPC, researchers have demonstrated that these combinations not only resolved the lack of mechanical strength and osteogenic effects of CPC but also further improve its own functional properties. However, exceptions were seen in CPC incorporated with certain proteins (such as elastin-like polypeptide and calcitonin gene-related peptide) as well as blood components. In conclusion, the addition of biological materials potentially improves CPC features, which vary depending on the types of materials embedded into it. The significant enhancement of CPC seen in vitro and in vivo requires further verification in human trials for its clinical application.

Effects of tocotrienols supplementation on markers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials.

Studies investigating the effects of tocotrienols on inflammation and oxidative stress have yielded inconsistent results. This systematic review and meta-analysis aimed to evaluate the effects of tocotrienols supplementation on inflammatory and oxidative stress biomarkers. We searched PubMed, Scopus, and Cochrane Central Register of Controlled Trials from inception until 13 July 2020 to identify randomized controlled trials supplementing tocotrienols and reporting circulating inflammatory or oxidative stress outcomes. Weighted mean difference (WMD) and corresponding 95% confidence interval (CI) were determined by pooling eligible studies. Nineteen studies were included for qualitative analysis, and 13 studies were included for the meta-analyses. A significant reduction in C-reactive protein levels (WMD: -0.52 mg/L, 95% CI: -0.73, -0.32, p < 0.001) following tocotrienols supplementation was observed, but this finding was attributed to a single study using δ-tocotrienols, not mixed tocotrienols. There were no effects on interleukin-6 (WMD: 0.03 pg/mL, 95% CI: -1.51, 1.58, p = 0.966), tumor necrosis factor-alpha (WMD: -0.28 pg/mL, 95% CI: -1.24, 0.68, p = 0.571), and malondialdehyde (WMD: -0.42 µmol/L, 95% CI: -1.05, 0.21, p = 0.189). A subgroup analysis suggested that tocotrienols at 400 mg/day might reduce malondialdehyde levels (WMD: -0.90 µmol/L, 95% CI: -1.20, -0.59, p < 0.001). Future well-designed studies are warranted to confirm the effects of tocotrienols on inflammatory and oxidative stress biomarkers, particularly on different types and dosages of supplementation. PROSPERO registration number: CRD42020198241.

Relationship Between Metabolic Syndrome and Bone Health - An Evaluation of Epidemiological Studies and Mechanisms Involved.

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.

The Skeletal-Protecting Action and Mechanisms of Action for Mood-Stabilizing Drug Lithium Chloride: Current Evidence and Future Potential Research Areas.

Lithium, the lightest natural-occurring alkali metal with an atomic number of three, stabilizes the mood to prevent episodes of acute manic and depression. Multiple lines of evidence point to lithium as an anti-suicidal, anti-viral, anti-cancer, immunomodulatory, neuroprotective and osteoprotective agent. This review article provides a comprehensive review of studies investigating the bone-enhancing effects of lithium and its possible underlying molecular mechanisms. Most of the animal experimental studies reported the beneficial effects of lithium in defective bones but not in healthy bones. In humans, the effects of lithium on bones remain heterogeneous. Mechanistically, lithium promotes osteoblastic activities by activating canonical Wingless (Wnt)/beta (ß)-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and bone morphogenetic protein-2 (BMP-2) transduction pathways but suppresses osteoclastic activities by inhibiting the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and calcium signaling cascades. In conclusion, lithium confers protection to the skeleton but its clinical utility awaits further validation from human clinical trials.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence.

Tocotrienol (T3) is a subfamily of vitamin E known for its wide array of medicinal properties. This review aimed to summarize the health benefits of T3, particularly in prevention or treatment of non-communicable diseases (NCDs), including cardiovascular, musculoskeletal, metabolic, gastric, and skin disorders, as well as cancers. Studies showed that T3 could prevent various NCDs, by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the mevalonate pathway, inflammatory response, oxidative stress, and alternating hormones. The efficacy of T3 in preventing/treating these NCDs is similar or greater compared to tocopherol (TF). TF may lower the efficacy of T3 because the efficacy of the combination of TF and T3 was lower than T3 alone in some studies. Data investigating the effects of T3 on osteoporosis, arthritis, and peptic ulcers in human are limited. The positive outcomes of T3 treatment obtained from the preclinical studies warrant further validation from clinical trials.

Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecular mechanisms.

BACKGROUND: Musculoskeletal disorders are a group of disorders that affect the joints, bones, and muscles, causing long-term disability. Berberine, an isoquinoline alkaloid, has been previously established to exhibit beneficial properties in preventing various diseases, including musculoskeletal disorders. PURPOSE: This review article aims to recapitulate the therapeutic potential of berberine and its mechanism of action in treating musculoskeletal disorders. METHODS: A wide range of literature illustrating the effects of berberine in ameliorating musculoskeletal disorders was retrieved from online electronic databases (PubMed and Medline) and reviewed. RESULTS: Berberine may potentially retard the progression of osteoporosis, osteoarthritis and rheumatoid arthritis. Limited studies reported the effects of berberine in suppressing the proliferation of osteosarcoma cells. These beneficial properties of berberine are mediated in part through its ability to target multiple signaling pathways, including PKA, p38 MAPK, Wnt/ß-catenin, AMPK, RANK/RANKL/OPG, PI3K/Akt, NFAT, NF-κB, Hedgehog, and oxidative stress signaling. In addition, berberine exhibited anti-apoptotic, anti-inflammatory, and immunosuppressive properties. CONCLUSION: The current evidence indicates that berberine may be effective in preventing musculoskeletal disorders. However, findings from in vitro and in vivo investigations await further validation from human clinical trial.

The Osteoprotective Effects Of Kaempferol: The Evidence From In Vivo And In Vitro Studies.

Kaempferol is a dietary bioflavonoid ubiquitously found in various types of plant. It possesses a wide range of medicinal properties suggesting its potential clinical utility that requires further investigation. The present review intends to highlight the efficacy of kaempferol and its molecular mechanisms of action in regulating bone metabolism. Many reports have acknowledged the bone-protecting property of kaempferol and kaempferol-containing plants using in vitro and in vivo experimental models. Kaempferol supplementation showed bone-sparing effects in newborn rats, glucocorticoid-induced and ovariectomy-induced osteoporotic models as well as bone fracture models. It achieves the bone-protective effects by inhibiting adipogenesis, inflammation, oxidative stress, osteoclastic autophagy and osteoblastic apoptosis while activating osteoblastic autophagy. The anti-osteoporotic effects of kaempferol are mediated through regulation of estrogen receptor, bone morphogenetic protein-2 (BMP-2), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways. In summary, kaempferol exhibits beneficial effects on skeleton, thus is potentially effective for the prophylaxis and treatment of osteoporosis.

The Effects of Tocotrienol on Bone Peptides in a Rat Model of Osteoporosis Induced by Metabolic Syndrome: The Possible Communication between Bone Cells.

A positive association between metabolic syndrome (MetS) and osteoporosis has been demonstrated in previous animal studies. The mechanisms of MetS in orchestrating the bone remodelling process have traditionally focused on the interactions between mature osteoblasts and osteoclasts, while the role of osteocytes is unexplored. Our earlier studies demonstrated the bone-promoting effects of tocotrienol using a rat model of osteoporosis induced by MetS. This study aimed to investigate the expression of osteocyte-derived peptides in the bone of rats with MetS-induced osteoporosis treated with tocotrienol. Age-matched male Wistar rats (12-week-old; n = 42) were divided into seven experimental groups. Two groups served as the baseline and normal group, respectively. The other five groups were fed with a high-carbohydrate high-fat (HCHF) diet to induce MetS. The five groups of HCHF animals were treated with tocopherol-stripped corn oil (vehicle), annatto tocotrienol (60 and 100 mg/kg), and palm tocotrienol (60 and 100 mg/kg) starting from week 8. At the end of the study, the rats were sacrificed and their right tibias were harvested. Protein was extracted from the metaphyseal region of the proximal right tibia and levels of bone peptides, including osteoprotegerin (OPG), soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH), were measured. The vehicle-treated animals displayed higher levels of sRANKL, SOST, DKK-1, FGF-23, and PTH as compared to the normal animals. Oral supplementation of annatto and palm tocotrienol (60 and 100 mg/kg) reduced the levels of sRANKL and FGF-23 in the HCHF animals. Only 100 mg/kg annatto and palm tocotrienol lowered SOST and DKK-1 levels in the HCHF animals. In conclusion, tocotrienol exerts potential skeletal-promoting benefit by modulating the levels of osteocytes-derived bone-related peptides.

Prostate Cancer and Bone Metastases: The Underlying Mechanisms.

Patients with advanced prostate cancer often develop bone metastases, leading to bone pain, skeletal fracture, and increased mortality. Bone provides a hospitable microenvironment to tumor cells. The disease manifestation is driven by the interaction between invading tumor cells, bone-forming osteoblasts, and bone-resorbing osteoclasts. The increased level of osteoclast-activating factor (parathyroid hormone-related peptide, PTHrP) is believed to induce bone resorption by upregulating receptor activator of nuclear factor-kappa B ligand (RANKL) and the release of various growth factors into the bone microenvironment to enhance cancer cell growth. However, the underlying molecular mechanisms remain poorly understood. This review outlines the possible molecular mechanisms involved in governing bone metastases driven by prostate cancer, which further provide the basis in searching for new molecular targets for the development of potential therapy.

Toll-like Receptor as a Molecular Link between Metabolic Syndrome and Inflammation: A Review.

Metabolic Syndrome (MetS) involves a cluster of five conditions, i.e. obesity, hyperglycaemia, hypertension, hypertriglyceridemia and low High-Density Lipoprotein (HDL) cholesterol. All components of MetS share an underlying chronic inflammatory aetiology, manifested by increased levels of pro-inflammatory cytokines. The pathogenic role of inflammation in the development of MetS suggested that toll-like receptor (TLR) activation may trigger MetS. This review summarises the supporting evidence on the interactions between MetS and TLR activation, bridged by the elevation of TLR ligands during MetS. The regulatory circuits mediated by TLR activation, which modulates signal propagation, leading to the state of chronic inflammation, are also discussed. Taken together, TLR activation could be the molecular basis in the development of MetS-induced inflammation.

The use of selective estrogen receptor modulators on bone health in men.

Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.

The relationship between circulating testosterone and inflammatory cytokines in men.

Testosterone is the predominant gonadal androgen in men. Low testosterone levels are found to be associated with an increased in metabolic risk and systematic inflammation. Since adipose tissue is a source of inflammatory cytokines, testosterone may regulate inflammation by acting on adipose tissue. This review aimed to explore the role of testosterone in inflammation and its mechanism of action. Both animal studies and human studies showed that (1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines. The suppression of inflammation by testosterone were observed in patients with coronary artery disease, prostate cancer and diabetes mellitus through the increase in anti-inflammatory cytokines (IL-10) and the decrease in pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α). Despite these, some studies also reported a non-significant relationship. In conclusion, testosterone may possess anti-inflammatory properties but its magnitude is debatable. More evidence is needed to validate the use of testosterone as a marker and in the management of chronic inflammatory diseases.

Wound Healing Properties of Selected Natural Products.

Wound healing is a complex process of recovering the forms and functions of injured tissues. The process is tightly regulated by multiple growth factors and cytokines released at the wound site. Any alterations that disrupt the healing processes would worsen the tissue damage and prolong repair process. Various conditions may contribute to impaired wound healing, including infections, underlying diseases and medications. Numerous studies on the potential of natural products with anti-inflammatory, antioxidant, antibacterial and pro-collagen synthesis properties as wound healing agents have been performed. Their medicinal properties can be contributed by the content of bioactive phytochemical constituents such as alkaloids, essential oils, flavonoids, tannins, saponins, and phenolic compounds in the natural products. This review highlights the in vitro, in vivo and clinical studies on wound healing promotions by the selected natural products and the mechanisms involved.