Targeting bone homeostasis regulation: potential of traditional Chinese medicine flavonoids in the treatment of osteoporosis.

Osteoporosis is a systemic metabolic disease characterized by disrupted bone formation/resorption and homeostasis. Flavonoids extracted from traditional Chinese medicinal plants regulate bone homeostasis by intervening in differentiating bone marrow mesenchymal stem cells, balancing the bone immune system, inhibiting oxidative stress response, and reversing iron overload. The target molecules and signaling pathways, such as Wnt/ß-catenin and OPG/RANKL/RANK, directly affect osteoblast/osteoclast activity, exhibiting significant potential in the treatment of OP. Therefore, this study presents a systematic review of the recent literature to provide comprehensive information on the traditional Chinese medicine flavonoids involved in the regulation of bone homeostasis. Also, the molecular mechanisms and pharmacological uses of these metabolites are summarized, and their clinical translation and development potential are discussed.

An evidence-based guideline on treating lumbar disc herniation with traditional Chinese medicine.

BACKGROUND: Lumbar disc herniation (LDH), as one of the most common causes of lower back pain, imposes a heavy economic burden on patients and society. Conservative management is the first-line choice for the majority of LDH patients. Traditional Chinese medicine (TCM) is an important part of conservative treatment and has attracted more and more international attention. STUDY DESIGN: Evidence-based guideline. METHODS: We formed a guideline panel of multidisciplinary experts. The clinical questions were identified on the basis of a systematic literature search and a consensus meeting. We searched the literature for direct evidence on the management of LDH and assessed its certainty-generated recommendations using the grading of recommendations, assessment, development, and evaluation (GRADE) approach. RESULTS: The guideline panel made 20 recommendations, which covered the use of Shentong Zhuyu decoction, Shenzhuo decoction, Simiao San decoction, Duhuo Jisheng decoction, Yaobitong capsule, Yaotongning capsule, Osteoking, manual therapy, needle knife, manual acupuncture, electroacupuncture, Chinese exercise techniques (Tai Chi, Baduanjin, or Yijinjing), and integrative medicine, such as combined non-steroidal anti-inflammatory drugs, neural nutrition, and traction. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. CONCLUSION: This is the first LDH treatment guideline for TCM and integrative medicine with a systematic search, synthesis of evidence, and using the GRADE method to rate the quality of evidence. We hope these recommendations can help support healthcare workers caring for LDH patients.

Exploring the mechanism of traditional Chinese medicine in regulating gut-derived 5-HT for osteoporosis treatment.

Osteoporosis is a systemic bone disease characterized by an imbalance in the relationship between osteoblasts, osteocytes, and osteoclasts. This imbalance in bone metabolism results in the destruction of the bone's microstructure and an increase in bone brittleness, thereby increasing the risk of fractures. Osteoporosis has complex causes, one of which is related to the dysregulation of 5-hydroxytryptamine, a neurotransmitter closely associated with bone tissue metabolism. Dysregulation of 5-HT directly or indirectly promotes the occurrence and development of osteoporosis. This paper aims to discuss the regulation of 5-HT by Traditional Chinese Medicine and its impact on bone metabolism, as well as the underlying mechanism of action. The results of this study demonstrate that Traditional Chinese Medicine has the ability to regulate 5-HT, thereby modulating bone metabolism and improving bone loss. These findings provide valuable insights for future osteoporosis treatment.

Targeting different phenotypes of macrophages: A potential strategy for natural products to treat inflammatory bone and joint diseases.

BACKGROUND: Macrophages, a key class of immune cells, have a dual role in inflammatory responses, switching between anti-inflammatory M2 and pro-inflammatory M1 subtypes depending on the specific environment. Greater numbers of M1 macrophages correlate with increased production of inflammatory chemicals, decreased osteogenic potential, and eventually bone and joint disorders. Therefore, reversing M1 macrophages polarization is advantageous for lowering inflammatory factors. To better treat inflammatory bone disorders in the future, it may be helpful to gain insight into the specific mechanisms and natural products that modulate macrophage polarization. OBJECTIVE: This review examines the impact of programmed cell death and different cells in the bone microenvironment on macrophage polarization, as well as the effects of natural products on the various phenotypes of macrophages, in order to suggest some possibilities for the treatment of inflammatory osteoarthritic disorders. METHODS: Using 'macrophage polarization,' 'M1 macrophage' 'M2 macrophage' 'osteoporosis,' 'osteonecrosis of femoral head,' 'osteolysis,' 'gouty arthritis,' 'collagen-induced arthritis,' 'freund's adjuvant-induced arthritis,' 'adjuvant arthritis,' and 'rheumatoid arthritis' as search terms, the relevant literature was searched using the PubMed, the Cochrane Library and Web of Science databases. RESULTS: Targeting macrophages through different signaling pathways has become a key mechanism for the treatment of inflammatory bone and joint diseases, including HIF-1α, NF-κB, AKT/mTOR, JAK1/2-STAT1, NF-κB, JNK, ERK, p-38α/ß, p38/MAPK, PI3K/AKT, AMPK, AMPK/Sirt1, STAT TLR4/NF-κB, TLR4/NLRP3, NAMPT pathway, as well as the programmed cell death autophagy, pyroptosis and ERS. CONCLUSION: As a result of a search of databases, we have summarized the available experimental and clinical evidence supporting herbal products as potential treatment agents for inflammatory osteoarthropathy. In this paper, we outline the various modulatory effects of natural substances targeting macrophages in various diseases, which may provide insight into drug options and directions for future clinical trials. In spite of this, more mechanistic studies on natural substances, as well as pharmacological, toxicological, and clinical studies are required.

Huogu injection alleviates SONFH by regulating adipogenic differentiation of BMSCs via targeting the miR-34c-5p/MDM4 pathway.

Although the precise pathogenesis of steroid-induced osteonecrosis of femoral head (SONFH) is not yet fully understood, evidence shows miRNAs-mediated posttranscription control directs the adipogenesis of bone marrow mesenchymal stem cells (BMSCs) and plays a pivotal role in the SONFH processes. Huogu injection formulated according to traditional Chinese medicine (TCM) theory has been used to treat SONFH by intra-articular injection. In this study, we asked whether the therapeutic effects of Huogu injection might depend on the inhibition of adipogenic differentiation of BMSCs, and if so, the pathway might be a therapeutic target to promote bone repair. Consequently, miR-34c-5p was upregulated in the dexamethasone (DEX)-treated BMSCs and might participate in the adipogenesis of BMSCs. TargetScan database and the luciferase reporter assay showed miR-34c-5p targeted on the MDM4 and negatively regulated its expression. Huogu injection in vitro inhibited the adipogenesis in the DEX-treated BMSCs by inhibiting the expression levels of PPARγ and C/EBPα, as well as reducing miR-34c-5p to prevent the degradation of MDM4. Moreover, miR-34c-5p mimic or MDM4 knockdown using shRNA neutralized the anti-adipogenesis of Huogu injection in BMSCs. In vivo, the results of X-ray imaging confirmed that Huogu injection alleviated the bone loss in rat SONFH. Consistent with results in vitro, Huogu injection reduced the lipid accumulation, removed the suppression of MDM4 by downregulating the expression of miR-34c-5p, and inhibited the expression of C/EBPα and PPARγ in bone tissues. When the lentivirus encoding miR-34c-5p was conducted by intra-articular injection, the overexpression of miR-34c-5p antagonized the therapeutic effects of Huogu injection. Our results underline the critical importance of the miR-34c-5p/MDM4 pathway in regulating the adipogenic outcome of BMSCs, suggesting the miR-34c-5p as a potentially effective therapeutic target in SONFH. These results further reinforce the potential of Huogu injection as an alternative approach in SONFH.

Tanshinone I Mitigates Steroid-Induced Osteonecrosis of the Femoral Head and Activates the Nrf2 Signaling Pathway in Rats.

Steroid-induced osteonecrosis of the femoral head (SIONFH) is a frequent orthopedic disease caused by long-term or high-dose administration of corticosteroids. Tanshinone I (TsI), a flavonoid compound isolated from Salvia miltiorrhiza Bunge, has been reported to inhibit osteoclastic differentiation in vitro. This study aimed to investigate whether TsI can ameliorate SIONFH. Herein, SIONFH was induced by intraperitoneal injection of 20 µg/kg lipopolysaccharide every 24 h for 2 days, followed by an intramuscular injection of 40 mg/kg methylprednisolone every 24 h for 3 days. Four weeks after the final injection of methylprednisolone, the rats were intraperitoneally administrated with low-dose (5 mg/kg) and high-dose (10 mg/kg) TsI once daily for 4 weeks. Results showed that TsI significantly alleviated osteonecrotic lesions of the femoral heads as determined by micro-CT analysis. Furthermore, TsI increased alkaline phosphatase activity and expressions of osteoblastic markers including osteocalcin, type I collagen, osteopontin, and Runt-related transcription factor 2 and decreased tartrate-resistant acid phosphatase activity and expressions of osteoclastic markers including cathepsin K and acid phosphatase 5. TsI also reduced inflammatory response and oxidative stress and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in the femoral heads. Taken together, our findings show that TsI can relieve SIONFH, indicating that it may be a candidate for preventing SIONFH.

Identification of narciclasine from Lycoris radiata (L'Her.) Herb. and its inhibitory effect on LPS-induced inflammatory responses in macrophages.

Lycoris radiata (L'Her.) Herb. (L. radiata) was traditionally used as a folk medicine in China for treatment of Alzheimer's disease. However, the specific component responsible for its considerable toxicity remained unclear thus restricting its clinical trials. Narciclasine (NCS) was isolated from L. radiata and treatment of NCS for 72 h exhibited significant antiproliferative effects against L02, Hep G2, HT-29 and RAW264.7 cells. However, what needs to be emphasized is that at safe working concentrations of 0.001-0.016 µM, administration of NCS for 24 h inhibited the mRNA expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-ɑ), interleukin-1beta (IL-1ß) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced macrophages thereby suppressing production of nitric oxide (NO), IL-6, TNF-ɑ and IL-1ß. NCS supplementation also inhibited nuclear factor-kappa B (NF-κB) activation by suppressing NF-κB P65 phosphorylation and nuclear translocation, IκBɑ degradation and phosphorylation, and IκKɑ/ß phosphorylation. The phosphorylation of c-Jun N-terminal kinase (JNK) and P38, and expression of COX-2 was also attenuated by NCS. These results suggested that NCS might exert anti-inflammatory effects through inhibiting NF-κB and mitogen-activated protein kinase (MAPK) pathways even at very low doses.

Danshen attenuates cartilage injuries in osteoarthritis in vivo and in vitro by activating JAK2/STAT3 and AKT pathways.

Articular cartilage degradation is a main feature of osteoarthritis (OA). The effects of Danshen, a traditional Chinese herb, in mitigating cartilage damage have been reported before. This study was conducted to investigate the effects of Danshen on cartilage injuries in OA. Rabbit OA models were established by surgical destabilization of the medial meniscus and the anterior and posterior cruciate ligaments in the left knee joint. Injection of Danshen into the articular cavity attenuated OA cartilage destruction in vivo. The levels of phosphorylated Janus kinase 2 (JAK2) and phosphorylated signal transducer and activator of transcription 3 (STAT3) were decreased in osteoarthritic cartilage, while they were rescued upon Danshen treatment. Furthermore, chondrocytes isolated from normal rabbit cartilage were exposed to 2 mM sodium nitroprusside (SNP) to establish an OA model in vitro. We found that the oxidative stress and chondrocyte apoptosis induced by SNP were suppressed by Danshen. The phosphorylation levels of JAK2 and STAT3 were decreased in response to SNP treatment, whereas they were rescued by Danshen. Additionally, AG490, a specific JAK2 inhibitor, counteracted the anti-apoptotic effect of Danshen. The phosphorylation level of protein kinase B (AKT) was also altered in response to SNP and reversed by Danshen. The anti-apoptotic effect of Danshen was counteracted by AKT pathway inhibitor LY194002. Taken together, Danshen attenuates OA cartilage destruction by regulating the JAK2/STAT3 and AKT signaling pathways.

Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-κB signaling pathway in vivo and in vitro.

Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine herb that can alleviate the symptoms of osteoarthritis (OA) (Söder et al. 2006) in animals. However, the underlying mechanisms remain poorly understood and require further investigation. In this study, rabbits with experimentally induced OA were given an intra-articular injection of danshen (0.7 mL/day) for 5 weeks. In addition to attenuating the cartilage degeneration of OA in the rabbits, danshen decreased the expression and activity of matrix metalloproteinase 9 (MMP-9) and MMP-13, and increased the expression of their natural inhibitors: tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and TIMP-2. Apoptosis in osteoarthritic cartilage tissues was attenuated by danshen, accompanied with increased expression of B cell lymphoma 2 (Bcl-2) and decreased levels of Bcl-2-associated X protein (Bax). Further, danshen inhibited the nuclear accumulation of nuclear factor kappa-B (NF-κB) p65 in osteoarthritic cartilage. The therapeutic effects of danshen in vivo were comparable to that of sodium hyaluronate, which is a drug used clinically for the treatment OA. In vitro, sodium nitroprusside (SNP) was used to stimulate apoptosis in primary rabbit chondrocytes. We found that the SNP-induced apoptosis was mitigated by danshen. BAY11-7028, an inhibitor of the NF-κB pathway, augmented danshen's anti-apoptotic effects in cells exposed to SNP. When these results are considered together, they indicate that danshen alleviates the cartilage injury in rabbit OA through inhibition of the NF-κB signaling pathway.

Study of Guanxinning Injection on Regulatory Mechanism of Bcl-2 and Bax by Liquid Nitrogen Freezing-Mediated Femoral Head Necrosis.

The objective of this study was to investigate the impact of femoral head perfusion by traditional Chinese medicine Guanxinning injection promoting blood circulation for removing blood stasis on the expression of Bcl-2 and Bax induced by liquid nitrogen freezing-mediated femoral head necrosis. 90 rabbits were randomized into three groups. Normal control group was not subjected to any medication. Saline and Guanxinning group were perfused with 0.9% saline and Guanxinning injection once every three days through the hip joint, respectively. Six animals in each group were sacrificed at weeks 1, 3, 6, 9, and 12. PCR and Western blot measured the expressions of Bcl-2 and Bax in the femoral head. The bax expression in the Guanxinning group reduced at the third week significantly compared to the normal control group (P < 0.01). The Bcl-2 expression in the Guanxinning group increased substantially at the third week (P < 0.05 or P < 0.01). Prolonged treatment elevated the expression of Bcl-2 in the Guanxinning group while that of Bax reduced remarkably (P < 0.01). Moreover, the ratio of Bcl-2 to Bax increased gradually in the Guanxinning group with prolonged drug administration. Guanxinning injection can inhibit the cell apoptosis of femoral head necrosis through the treatment by femoral head perfusion.

Chinese medicines with sedative-hypnotic effects and their active components.

The main pharmacological effects of sedative agents are sedation, hypnosis, antianxiety, and antidepression. Traditional Chinese medicine (TCM) has a long history of clinical experience in treating insomnia. This review focuses mainly on the role of active ingredients from TCM in the treatment of insomnia. Single herbs and their active ingredients from TCM with hypnotic effects are summarized through reviewing the relevant literature published in the past 20 y. The active ingredients are divided into alkaloids, terpenoids, and volatile oils, flavonoids, lignanoids and coumarins, saponins, and others. Current studies on TCM in treating insomnia are described from the aspects of active ingredients, sources, experimental models and methods, results, and mechanisms. In addition, Chinese compound prescriptions developed from a variety of single herbs with sedative-hypnotic effects are introduced. The acting pathways of TCM are covered from the perspectives of regulating central neurotransmitters, influencing sleep-related cytokines, and improving the structure of the central nervous system.

Plant species forbidden in health food and their toxic constituents, toxicology and detoxification.

Many plants with pharmacological efficacies are widely used as ingredients in so-called "health foods", but many of them are toxic. In order to ensure the safety of "health food", the Chinese Ministry of Health has listed 59 materials that are forbidden from being used in health food and are called health food forbidden species (HFFS). This review focuses on 47 plants among the HFFS to discuss research regarding their pharmacology, toxicology, and detoxification methods. According to the literature published in the last 2 decades, the main constituents and the pharmacology of such plants are described here, especially their toxic constituents and toxicology. The toxicity mechanisms of several typical toxic components from the 47 plants are outlined and some effective detoxification methods are introduced. Although all HFFS are poisonous, they are considered to be useful in the treatment of many diseases. How to keep their pharmacological effects and at the same time decrease their toxicity is a great challenge. In the future, more attention should be paid to the application of modern science and technology in the exploration of the toxicology and detoxification of HFFS.

Renal toxic ingredients and their toxicology from traditional Chinese medicine.

INTRODUCTION: There have been increasing concerns regarding adverse reactions and toxicity incidents caused by traditional Chinese medicines (TCMs), among which the nephrotoxicity is particularly worrying. AREAS COVERED: This review summarizes the ingredients with renal toxicity from some TCMs through searching the relevant literature published over the past two decades. Renal toxicity components from TCMs include aristolochic acids (AAS), alkaloids, anthraquinones and others. TCM renal toxicity is most commonly caused by AAS and some alkaloids. AAS mainly come from Aristolochia contorta Bunge, Aristolochia manshuriensis Kom, Clematis Chinensis Osbeck, Aristolochia cathcartii Hook. Some renal toxic alkaloids are derived from Tripterygium regelii Sprague et Takeda, Stephania tetrandra S. Moore, Strychnos nux-vomica Linn. and Aconitum carmichaeli Debx. A few kinds of anthraquinones, flavonoids, and glycosides from TCMs also cause renal toxicity. All of these renal toxicity components and their associated renal toxicity, structures and toxic mechanism are introduced in detail in this review. EXPERT OPINION: Given the complexity of the toxic components, a lot of work needs to be done to analyze the specific modes of action of toxic components in vivo and in vitro, in particular, to elucidate the molecular mechanism of toxicity, in order to reduce the occurrence of renal toxicity of TCM.

Efficacy evaluation of a Chinese bitter tea (Ilex latifolia Thunb.) via analyses of its main components.

In order to evaluate the health effects of Ilex latifolia Thunb., a Chinese bitter tea widely consumed as a health beverage, flavonoids, saponins, polysaccharides and alkaloids were extracted from its leaves and their in vitro antioxidant activity, anticomplement system activity, antiproliferative effects against human cervical carcinoma Hela cells, and anti-inflammatory effects against mouse macrophage RAW 264.7 cells were analyzed. Results showed that the polysaccharides exhibited a considerable inhibition of the complement system, the hemolysis inhibition rate reached 98% at a concentration of 0.8 mg mL(-1), which was clearly higher than that of the positive control (heparin sodium). The total flavonoids displayed significant DPPH scavenging activity and an inhibition effect on the generation of NO in LPS-induced RAW 264.7 macrophages. In addition, the total saponins showed a better antiproliferative effect against Hela cells, and the total alkaloids exhibited a high reducing power. It is obvious that I. latifolia has a variety of nutritional and health functions which are attributed to its different components. The analysis method presented in this research can suggest lessons for analysis of other plant foods.

Hydroxytyrosol and its potential therapeutic effects.

As olive oil is the main source of calories in the Mediterranean diet, a large number of studies have been carried out to characterize its role in various diseases and exploitation for the prevention and treatment of hypertension, carcinogenesis, diabetes, atherosclerosis, and other diseases. As one of the major polyphenols present in virgin olive oil, hydroxytyrosol shows a variety of pharmacological activities such as antioxidant properties, anticancer, anti-inflammatory, and neuroprotective activities, and beneficial effects on the cardiovascular system, which show its potentiality for the development of dietary supplements. In the future, more attention should be paid to its action mechanism in vivo and synergistic effect. Further research will be performed to provide the theoretical basis for hydroxytyrosol and its derivatives use as health supplements.

Antioxidant and anticomplement functions of flavonoids extracted from Penthorum chinense Pursh.

Penthorum chinense Pursh is rich in flavonoids, which have strong antioxidant and anticomplement activities. In order to optimize their extraction conditions, various extraction parameters were chosen to identify their effects on flavonoids extraction. Single factor and Box-Behnken experimental designs consisting of 24 experimental runs and five replicates at zero point were applied to obtain the optimal extraction yield. The optimization conditions for flavonoids extraction were determined as follows: ethanol concentration 60.89%, extraction time 68.15 min, temperature 52.89 °C and liquid/solid ratio 19.70 : 1. The corresponding flavonoids content was 7.19%. The regression equation was found to fit well with the actual situation. Furthermore, the antioxidant activity (the free radical scavenging ability and ferric reducing/antioxidant power) and anticomplement ability of the flavonoids from P. chinense were determined. Results showed that the flavonoids of P. chinense displayed significant antioxidant and anticomplement activities. Its antioxidant activity can compete with ascorbic acid (Vc), whereas its anticomplement activity (IC50 = 111.6 µg ml(-1)) surpassed the effect of heparin (IC50 = 399.7 µg ml(-1)) which was used as the positive control, suggesting that P. chinense flavonoids and their related products could potentially be used as a promising natural agent in the treatment of humoral effector inflammation.

Hepatoprotective function of Penthorum chinense Pursh.

This research was to figure out the hepatoprotective constituents of Penthorum chinense Pursh, a typical species both for food and medicine, using carbon tetrachloride-induced chronic hepatotoxicity in HL-7702 cells. Cell viability, levels of microsomal enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and the concentration of malondialdehyde (MDA) were determined in homogenates of the liver cells. Results showed that the cell viability increased significantly in all test groups in a concentration-dependent manner and the content of the peroxidation product MDA decreased significantly, similar to the serum levels of hepatic enzyme biomarkers (ALT and AST). The effects of 70% ethanol extracts and Vc were better than 95% ethanol and water extracts, and the ethyl acetate extracts further obtained from 70% ethanol fraction showed the highest hepatoprotective activity, even better than Vc. The ethyl acetate fraction from 70% ethanol extracts is responsible for the hepatoprotective function of P. chinense.

Protective effect of compounds from the flowers of Citrus aurantium L. var. amara Engl against carbon tetrachloride-induced hepatocyte injury.

5-Hydroxy-6,7,3',4'-tetramethoxyflavone (HTF), limonexic acid (LA) are two compounds isolated from the flowers of Citrus aurantium L. var. amara Engl with various biological activities. This study was designed to investigate their protective effects against carbon tetrachloride (CCl4)-induced hepatocyte injury, using human hepatic cell line HL-7702 to determine the cell cytotoxicity, cell viability, levels of hepatic marker enzymes, malondialdehyde (MDA). Results showed that pretreatment with HTF, LA could significantly reverse CCl4-induced HL-7702 cell viability decrease, LA displayed a higher activity. HTF, LA also showed their capability of decreasing the CCl4-induced leakage of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), inhibiting the lipid peroxidation, HTF showed more significant activity. Given that HTF, LA were not toxic, it is concluded that HTF, LA could effectively protect hepatocyte against CCl4-induced injury.