Haixia Liu

Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety

&NA; Cinnamaldehyde, one of the active components derived from Cinnamon, has been used as a natural flavorant and fragrance agent in kitchen and industry. Emerging studies have been performed over the past decades to evaluate its beneficial role in management of diabetes and its complications. This review highlights recent advances of cinnamaldehyde in its glucolipid lowering effects, its pharmacokinetics, and its safety by consulting the Pubmed, China Knowledge Resource Integrated, China Science and Technology Journal, National Science and Technology Library, Wanfang Data, and the Web of Science Databases. For the inquiries, keywords such as Cinnamon, cinnamaldehyde, property, synthesis, diabetes, obesity, pharmacokinetics, and safety were used in various combinations. Accumulating evidence supports the notion that cinnamaldehyde exhibits glucolipid lowering effects in diabetic animals by increasing glucose uptake and improving insulin sensitivity in adipose and skeletal muscle tissues, improving glycogen synthesis in liver, restoring pancreatic islets dysfunction, slowing gastric emptying rates, and improving diabetic renal and brain disorders. Cinnamaldehyde exerts these effects through its action on multiple signaling pathways, including PPARs, AMPK, PI3K/IRS‐1, RBP4‐GLUT4, and ERK/JNK/p38MAPK, TRPA1‐ghrelin and Nrf2 pathways. In addition, cinnamaldehyde seems to regulate the activities of PTP1B and &agr;‐amylase. Furthermore, cinnamaldehyde has the potential of metalizing into cinnamyl alcohol and methyl cinnamate and cinnamic acid in the body. Finally, there is a potential toxicity concern about this compound. In summary, cinnamaldehyde supplementation is shown to improve glucose and lipid homeostasis in diabetic animals, which may provide a new option for diabetic intervention. To this end, further scientific evidences are required from clinical trials on its glucose regulating effects and safety. Graphical abstract Figure. No caption available.

Rehmanniae Radix in osteoporosis: A review of traditional Chinese medicinal uses, phytochemistry, pharmacokinetics and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE Emerging clinical usage and pharmacological effects have been achieved in using Rehmanniae Radix either singly or in combination with other herbs to treat skeletal diseases in traditional Chinese medicine (TCM) in the recent years. This study is aimed to provide a comprehensive review about the historical TCM interpretation of the action of Rehmanniae Radix in osteoporosis, its usage in clinical trials and osteoporotic models, its main phytochemical constituents, and its pharmacokinetics. MATERIALS AND METHODS Several databases included PubMed, China Knowledge Resource Integrated Database, China Science and Technology Journal Database, National Science and Technology Library and the Web of Science Database were consulted to locate the publications pertaining to Rehmanniae Radix. The initial inquiry was conducted for the presence of the following terms combinations in the abstracts: Rehmanniae Radix, Dihuang, phytochemistry, pharmacokinetics, osteoporosis, bone, osteoclast and osteoblast. About 330 research papers and reviews were consulted. RESULTS In TCM, Rehmanniae Radix exerts the anti-osteoporotic effect via regulating the functions of kidney and liver as well as improving blood circulation. 107 clinical trials are identified that used Rehmanniae Radix in combination with other herbs to treat post-menopausal, senile and secondary osteoporosis. Most of the clinical trials are characterized by high efficacy and no obvious adverse effects. However, the efficacies of these clinical trials are limited because of small patient sample size, short treatment duration and poor clinical design. In addition, TCM herbs under the clinical study are not clear because of a lack of standardization and authentication. The pharmacokinetics data demonstrate that the ingredients of Rehmanniae Radix are widely distributed after administration, and that catalpol and ajugol as well as acetoside are supposed to be the active constituents. More than 140 individual compounds have been currently isolated from this plant and reported to show pleiotropic effects on various diseases. Rehmanniae Radix displays bone protecting features in the osteoporosis models via the delicate balance between osteoclastogenesis and osteoblastogenesis through single herb extracts and its isolated compounds. CONCLUSIONS The successful inclusion of Rehmanniae Radix in clinical trials and preclinical studies for the management of osteoporosis has attracted rising attentions for identifying potential anti-osteoporotic candidates from this plant and clinical existing TCM formulas, which will further speed up anti-osteoporosis drug discovery processes. Properly designed and well controlled prospective studies are still needed to further demonstrate bone protective actions and safe use of this herb and its ingredients.

Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis

Curcumin, a polyphenol derived from the turmeric, has received attention as a potential treatment for renal fibrosis primarily because it is a relatively safe and inexpensive compound that contributes to kidney health. Here, we review the literatures on the applications of curcumin in resolving renal fibrosis in animal models and summarize the mechanisms of curcumin and its analogs (C66 and (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one(B06)) in preventing inflammatory molecules release and reducing the deposition of extracellular matrix at the priming and activation stage of renal fibrosis in animal models by consulting PubMed and Cnki databases over the past 15 years. Curcumin exerts antifibrotic effect through reducing inflammation related factors (MCP-1, NF-κB, TNF-α, IL-1β, COX-2, and cav-1) and inducing the expression of anti-inflammation factors (HO-1, M6PRBP1, and NEDD4) as well as targeting TGF-β/Smads, MAPK/ERK, and PPAR-γ pathways in animal models. As a food derived compound, curcumin is becoming a promising drug candidate for improving renal health.

Salvia miltiorrhiza: A Potential Red Light to the Development of Cardiovascular Diseases

Salvia miltiorrhiza Bunge, also known as Danshen in Chinese, has been widely used to treat cardiovascular diseases (CVD) in China and other Asia countries. Here, we summarize literatures of the historical traditional Chinese medicine (TCM) interpretation of the action of Salvia miltiorrhiza, its use in current clinical trials, its main phytochemical constituents and its pharmacological findings by consulting Pubmed, China Knowledge Resource Integrated, China Science and Technology Journal, and the Web of Science Databases. Since 2000, 39 clinical trials have been identified that used S. miltiorrhiza in TCM prescriptions alone or with other herbs for the treatment of patients with CVD. More than 200 individual compounds have been isolated and characterized from S. miltiorrhiza, which exhibited various pharmacological activities targeting different pathways for the treatment of CVD in various animal and cell models. The isolated compounds may provide new perspectives in alternative treatment regimes and reveal novel chemical scaffolds for the development of anti-CVD drugs. Meanwhile, there are also some rising concerns of the potential side effects and drug-drug interactions of this plant. The insights gained from this study will help us to better understanding of the actions of this herb for management of cardiovascular disorders. As an herb of red root, S. miltiorrhiza will act as a potential red light to prevent the development of CVD.

Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-κB Pathway

Purpose: This study is designed to explore whether Fructus ligustri lucidi (FLL) exhibits antioxidant effect in ovariectomized (OVX) rats, and to identify the signaling pathway involved in this process. Methods: OVX rats were treated with FLL aqueous extract (3.5 g/kg) for 12 weeks. Serum, uteri, and tibias were harvested from the rats and the levels of total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), 8-hydroxy-desoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were determined. Changes in the levels of NF-κB-p65, phosphorylation of NF-κB-p65 (NF-κB-pp65), NF-κB inhibitor alpha (IκBα), phosphorylation of IκBα (p-IκBα), and NADPH oxidase 4 (Nox4) in uteri and tibias were determined by western blot, immunofluorescent and immunohistochemical analysis, respectively. In addition, the expression of cytochrome C (Cyto-C) and B-cell lymphoma-2 (Bcl-2) were determined in the tibias of rats. Histopathological changes in the bones were evaluated by hematoxylin-eosin staining. Bone mineral density (BMD) was determined in rat femurs by dual X-ray absorptiometry. Results: Treatment of OVX rats with FLL aqueous extract improved redox homeostasis by increasing the levels of TAC and NO as well as decreasing the levels of MDA and 8-OHdG in serum, tibias, and uteri. Further, FLL extract also downregulated the expression of Nox4, NF-κB-p65, NF-κB-pp65, and p-IκBα in the uteri and tibias. Furthermore, administration of FLL–OVX rats increased Bcl-2 expression and prevented cytoplasmic release of mitochondrial Cyto-C in the tibias. In addition, FLL treatment also improved bone microstructure and increased cortical bone thickness as well as increased BMD values in the femurs of OVX rats. Conclusions: FLL treatment may suppress oxidative stress response in OVX rats via regulating the Nox4/ROS/NF-κB signaling pathway. These results suggest the potential of using FLL as a natural antioxidant agent in preventing the development of osteoporosis.

Diabetes Perturbs Bone Microarchitecture and Bone Strength through Regulation of Sema3A/IGF-1/β-Catenin in Rats

Purpose: Increasing evidence supported that semaphorin 3A (Sema3A), insulin-like growth factor (IGF)-1 and β-catenin were involved in the development of osteoporosis and diabetes. This study is aimed to evaluate whether Sema3A/IGF-1/β-catenin is directly involved in the alterations of bone microarchitecture and bone strength of diabetic rats. Methods: Diabetic rats were induced by streptozotocin and high fat diet exposure. Bone microarchitecture and strength in the femurs were evaluated by micro-CT scanning, three-point bending examination and the stainings of HE, alizarin red S and safranin O/fast green, respectively. The alterations of lumbar spines microarchitecture were also determined by micro-CT scanning. Western blot and immunohistochemical analyses were used to examine the expression of Sema3A, β-catenin, IGF-1, peroxisome proliferator-activated receptor γ (PPARγ) and cathepsin K in rat tibias. Results: Diabetic rats exhibited decreased trabecular numbers and bone formation, but an increased trabecular separation in the femurs and lumbar spines. Moreover, the increased bone fragility and decreased bone stiffness were evident in the femurs of diabetic rats. Diabetic rats also exhibited a pronounced bone phenotype which manifested by decreased expression of Sema3A, IGF-1 and β-catenin, as well as increased expression of cathepsin K and PPARγ. Conclusions: This study suggests that diabetes could perturb bone loss through the Sema3A/IGF-1/β-catenin pathway. Sema3A deficiency in bone may contribute to upregulation of PPARγ and cathepsin K expression, which further disrupts bone remodeling in diabetic rats.

Evaluation of Decalcification Techniques for Rat Femurs Using HE and Immunohistochemical Staining

Aim. In routine histopathology, decalcification is an essential step for mineralized tissues. The purpose of this study is to evaluate the effects of different decalcification solutions on the morphological and antigenicity preservation in Sprague Dawley (SD) rat femurs. Materials and Methods. Four different decalcification solutions were employed to remove the mineral substances from rat femurs, including 10% neutral buffered EDTA, 3% nitric acid, 5% nitric acid, and 8% hydrochloric acid/formic acid. Shaking and low temperature were used to process the samples. The stainings of hematoxylin-eosin (HE) and immunohistochemical (IHC) were employed to evaluate the bone morphology and antigenicity. Key Findings. Different decalcification solutions may affect the quality of morphology and the staining of paraffin-embedded sections in pathological examinations. Among four decalcifying solutions, 3% nitric acid is the best decalcifying agent for HE staining. 10% neutral buffered EDTA and 5% nitric acid are the preferred decalcifying agents for IHC staining. Significance. The current study investigated the effects of different decalcifying agents on the preservation of the bone structure and antigenicity, which will help to develop suitable protocols for the analyses of the bony tissue.

Diabetic Osteoporosis: A Review of Its Traditional Chinese Medicinal Use and Clinical and Preclinical Research

Aim. The incidence of diabetic osteoporosis (DOP) is increasing due to lack of effective management over the past few decades. This review aims to summarize traditional Chinese medicine (TCM) suitability in the pathogenesis and clinical and preclinical management of DOP. Methods. Literature sources used were from Medline (Pubmed), CNKI (China Knowledge Resource Integrated Database), and CSTJ (China Science and Technology Journal Database) online databases. For the consultation, keywords such as diabetic osteoporosis (DOP), TCM, clinical study, animal experiment, toxicity, and research progress were used in various combinations. Around 100 research papers and reviews were visited. Results. Liver-spleen-kidney insufficiency may result in development of DOP. 18 clinical trials are identified to use TCM compound prescriptions for management of patients with DOP. TCM herbs and their active ingredients are effective in preventing the development of DOP in streptozotocin (STZ) and alloxan as well as STZ combined with ovariectomy insulted rats. Among them, most frequently used TCM herbs in clinical trials are Radix Astragali, Radix et Rhizoma Salviae Miltiorrhizae, Radix Rehmanniae Preparata, and Herba Epimedii. Some of TCM herbs also exhibit toxicities in clinical and preclinical research. Conclusions. TCM herbs may act as the novel sources of anti-DOP drugs by improving bone and glucolipid metabolisms. However, the pathogenesis of DOP and the material base of TCM herbs still merit further study.

Fructus Ligustri Lucidi in Osteoporosis: A Review of its Pharmacology, Phytochemistry, Pharmacokinetics and Safety

Background: Fructus Ligustri Lucidi (FLL) has now attracted increasing attention as an alternative medicine in the prevention and treatment of osteoporosis. This study aimed to provide a general review of traditional interpretation of the actions of FLL in osteoporosis, main phytochemical constituents, pharmacokinetics, pharmacology in bone improving effect, and safety. Materials and Methods: Several databases, including PubMed, China National Knowledge Infrastructure, National Science and Technology Library, China Science and Technology Journal Database, and Web of Science were consulted to locate publications pertaining to FLL. The initial inquiry was conducted for the presence of the following keywords combinations in the abstracts: Fructus Ligustri Lucidi, osteoporosis, phytochemistry, pharmacokinetics, pharmacology, osteoblasts, osteoclasts, salidroside. About 150 research papers and reviews were consulted. Results: FLL is assumed to exhibit anti-osteoporotic effects by improving liver and kidney deficiencies and reducing lower back soreness in Traditional Chinese Medicine (TCM). The data from animal and cell experiments demonstrate that FLL is able to improve bone metabolism and bone quality in ovariectomized, growing, aged and diabetic rats through the regulation of PTH/FGF-23/1,25-(OH)2D3/CaSR, Nox4/ROS/NF-κB, and OPG/RANKL/cathepsin K signaling pathways. More than 100 individual compounds have been isolated from this plant. Oleanolic acid, ursolic acid, salidroside, and nuzhenide have been reported to exhibit the anti-osteoporosis effect. The pharmacokinetics data reveals that salidroside is one of the active constituents, and that tyrosol is hard to detect under physiological conditions. Acute and subacute toxicity studies show that FLL is well tolerated and presents no safety concerns. Conclusions: FLL provides a new option for the prevention and treatment of osteoporosis, which attracts rising interests in identifying potential anti-osteoporotic compounds and fractions from this plant. Further scientific evidences are expected from well-designed clinical trials on its bone protective effects and safety.

Cinnamaldehyde Ameliorates Diet-Induced Obesity in Mice by Inducing Browning of White Adipose Tissue

Background/Aims: Obesity has become a major health concern with few effective medications. Cinnamaldehyde (CA) has been reported to exhibit anti-diabetic and anti-inflammatory properties. However, whether CA shows anti-obesity activity remains unknown. Therefore, the present study aimed to investigate the potential anti-obesity effects of CA on mice fed a high-fat diet (HFD) and to explore the possible mechanisms involved. Methods: Male C57BL/6J mice fed an HFD for 12 weeks were supplemented with CA (40 mg/kg/day) via gavage for an additional 8 weeks. Mice fed a standard diet were used as normal controls. Results: The results revealed that CA treatment decreased body weight, fat mass, food intake, and serum lipid, free fatty acid and leptin levels. CA administration also improved insulin sensitivity in HFD-induced obese mice. Additionally, CA inhibited the hypertrophy of adipose tissue and induced browning of white adipose tissue. Uncoupling protein 1 (UCP1) was expressed in white adipose tissue after the oral administration of CA. Furthermore, CA enhanced the expression of the peroxisome proliferator-activated receptor γ (PPARγ), PR domain-containing 16 (PRDM16) and PPARγ coactivator 1α (PGC-1α) proteins in both brown and white adipose tissues. Conclusions: The results suggest that CA exhibits therapeutic potency against obesity by inducing the browning of white adipose tissue in HFD-fed mice.