Safety Evaluation of Natural Drugs in Chronic Skeletal Disorders: A Literature Review of Clinical Trials in the Past 20 years

Chronic skeletal disorders (CSDs), including degenerative diseases such as osteoporosis (OP) and autoimmune disorders, have become a leading cause of disability in an ageing society, with natural drugs being indispensable therapeutic options. The clinical safety evaluation (CSE) of natural drugs in CSDs has been given priority and has been intensively studied. To provide fundamental evidence for the clinical application of natural drugs in the elderly population, clinical studies of natural drugs in CSDs included in this review were selected from CNKI, Web of Science, PubMed, Science Direct and Google Scholar since 2001. Seventeen randomized controlled trials (RCTs) met our inclusion criteria: four articles were on OP, seven on osteoarthritis (OA), four on rheumatoid arthritis (RA) and two on gout. Common natural drugs used for the treatment of OP include Epimedium brevicornu Maxim [Berberidaceae], Dipsacus asper Wall ex DC [Caprifoliaceae] root, and Phalaenopsis cornu-cervi (Breda) Blume & Rchb. f[ Orchidaceae], which have been linked to several mild adverse reactions, such as skin rash, gastric dysfunction, abnormal urine, constipation and irritability. The safety of Hedera helix L [Araliaceae] extract, Boswellia serrata Roxb [Burseraceae] extract and extract from perna canaliculus was evaluated in OA and upper abdominal pain, and unstable movements were obsrerved as major side effects. Adverse events, including pneumonia, vomiting, diarrhoea and upper respiratory tract infection, were reported when RA was treated with Tripterygium wilfordii, Hook. F [Celastraceae][TwHF] polyglycosides and quercetin (Capsella bursa-pastoris (L.) Medik [Brassicaceae]). The present review aimed to summarize the CSE results of natural drugs in CSDs and could provide evidence-based information for clinicians.

The Combination of Low-Temperature Plasma and Tripterygium wilfordii Hook F on Ameliorating Imiquimod-Induced Psoriasiform Dermatitis in Mice

Improving the transdermal delivery efficiency of medicine is a crucial measure to improve the treatment efficiency of psoriasis. This paper developed a low-cost, highly active, and large-action-area low-temperature plasma (LTP) jet array. The two components of plasma—the high concentration of reactive oxygen and nitrogen species and the strong electric field—easily changed the structural integrity of the stratum corneum, which enhanced the transdermal delivery of the medicine. Tripterygium wilfordii Hook F (TwHF) is a medicine used to treat autoimmune and inflammatory conditions. The enhanced transdermal delivery of TwHF significantly alleviated the severed psoriasiform dermatitis induced by the imiquimod. Unlike the TwHF treatment alone, the LTP + TwHF treatment was more efficient at suppressing epidermal thickening and inhibiting systemic inflammation without noticeable side effects. LTP + TwHF treatment provides a potential new solution for psoriasis treatment.

Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1

Triptolide (TP), the main active compound extracted from medicine— tripterygium wilfordii Hook f. (TWHF). It has anti-tumor and immunomodulatory properties. Our study aimed to investigate the mechanisms of hepatotoxicity treated with TP in vivo and in vitro, as well as their relationship with the NF-κB (p65) signal pathway; and to assess TP-induced hepatotoxicity after CYP2E1 modulation by the known inhibitor, clomethiazole, and the known inducer, pyrazole. Mice were given TP to cause liver injury and IHHA-1 cells were given TP to cause hepatocyte injury. The enzyme activity and hepatotoxicity changed dramatically when the CYP2E1 inhibitor and inducer were added. In comparison to the control group, the enzyme inducer increased the activity of CYP2E1, whereas the enzyme inhibitor had the opposite effect. Our findings suggest that TP is an inducer of CYP2E1 via a time-dependent activation mechanism. In addition, TP can promote oxidative stress, inflammatory and involving the NF-κB (p65) signal pathway. Therefore, we used triptolide to stimulate C57 mice and IHHA-1 cells to determine whether TP can promote oxidative stress and inflammation by activating CYP2E1 in response to exacerbated liver damage and participate in NF-κB (p65) signaling pathway.

Therapeutic potential of triptolide in autoimmune diseases and strategies to reduce its toxicity

With the increasing epidemiology of autoimmune disease worldwide, there is an urgent need for effective drugs with low cost in clinical treatment. Triptolide, the most potent bioactive compound from traditional Chinese herb Tripterygium Wilfordii Hook F, possesses immunosuppression and anti-inflammatory activity. It is a potential drug for the treatment of various autoimmune diseases, but its clinical application is still restricted due to severe toxicity. In this review, the pharmacodynamic effects and pharmacological mechanisms of triptolide in autoimmune diseases are summarized. Triptolide exerts therapeutic effect by regulating the function of immune cells and the expression of cytokines through inflammatory signaling pathways, as well as maintaining redox balance and gut microbiota homeostasis. Meanwhile, the research progress on toxicity of triptolide to liver, kidney, reproductive system, heart, spleen, lung and gastrointestinal tract has been systematically reviewed. In vivo experiments on different animals and clinical trials demonstrate the dose- and time- dependent toxicity of triptolide through different administration routes. Furthermore, we focus on the strategies to reduce toxicity of triptolide, including chemical structural modification, novel drug delivery systems, and combination pharmacotherapy. This review aims to reveal the potential therapeutic prospect and limitations of triptolide in treating autoimmune diseases, thus providing guiding suggestions for further study and promoting its clinical translation.

The Active Compounds and Therapeutic Target of Tripterygium wilfordii Hook. f. in Attenuating Proteinuria in Diabetic Nephropathy: A Review

Tripterygium wilfordii Hook. f. (TWHF) is a traditional Chinese herbal medicine and widely used to treat diabetic kidney disease in China. Emerging evidences have revealed its ability to attenuate diabetic nephropathy (DN). Tripterygium wilfordii polyglycosides (TWPs), triptolide (TP), and celastrol are predominantly active compounds isolated from TWHF. The effects and molecular mechanisms of TWHF and its active compounds have been investigated in recent years. Currently, it is becoming clearer that the effects of TWHF and its active compounds involve in anti-inflammation, anti-oxidative stress, anti-fibrosis, regulating autophagy, apoptosis, and protecting podocytes effect. This review presents an overview of the current findings related to the effects and mechanisms of TWHF and its active compounds in therapies of DN, thus providing a systematic understanding of the mechanisms and therapeutic targets by which TWHF and its active compounds affect cells and tissues in vitro and in vivo.

Novel Therapies for Kidney Disease in People with Diabetes

Aim The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies. This review aims to summarise the results of recent clinical trials that test the efficacy of potential therapies for DKD. Methods A systematised narrative review was performed utilising PubMed, Embase (Ovid), CINAHL and Cochrane databases (January 2010-January 2021). Trials included assessed the efficacy of specific medications using renal endpoints in adult participants with either type 1 or 2 diabetes. Results 53 trials were identified. Large, multinational and high-powered trials investigating sodium-glucose cotransporter-2 inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid-receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints, but with need for further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, praliciguat, palosuran, benfotiamine and diacerein were not associated with improved renal outcomes. Conclusion Trials have yielded promising results in the search for new therapies to manage DKD. Sodium-glucose cotransporter-2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid-receptor antagonists are another class of agents with increasing evidence of benefits.

Exploring the Pharmacological Mechanisms of Tripterygium wilfordii Hook F against Cardiovascular Disease Using Network Pharmacology and Molecular Docking

Background. Tripterygium wilfordii Hook F (TwHF) has been used in traditional Chinese medicine (TCM) for treating cardiovascular disease (CVD). However, the underlying pharmacological mechanisms of the effects of TwHF on CVD remain elusive. This study revealed the pharmacological mechanisms of TwHF acting on CVD based on a pharmacology approach. Materials and Methods. The active compounds were selected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database according to the absorption, distribution, metabolism, and excretion (ADME). The potential targets of TwHF were obtained from the SwissTargetPrediction database. The CVD-related therapeutic targets were collected from the DrugBank, the GeneCards database, and the OMIM database. Protein–protein interaction (PPI) network was generated by the STITCH database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed by R package. The network of drug-targets-diseases-pathways was constructed by the Cytoscape software. Results. The 41 effective ingredients of TwHF and the 178 common targets of TwHF and CVD-related were collected. Furthermore, AKT1, amyloid precursor protein (APP), mitogen-activated protein kinase 1 (MAPK), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA), and cellular tumor antigen p53 (TP53) were identified as the core targets involved in the mechanism of TwHF on CVD. Top ten GO (biological processes, cellular components, and molecular functions) and KEGG pathways were screened with a P value ≤0.01. Finally, we constructed the network of TwHF-targets-CVD-GO-KEGG. Conclusions. These findings demonstrate that the main active compound of TwHF, the core targets, and pathways maybe provide new insights into the development of a natural therapy for the prevention and treatment of CVD.