ß-Elemene in zedoary turmeric oil injection induces dyspnea by binding to hemoglobin and upregulating HIF-1α.

ETHNOPHARMACOLOGICAL RELEVANCE: Zedoary turmeric oil injection (ZTOI) extracted from the rhizome extract of Curcuma phaeocaulis Valeton, Curcuma wenyujin Y. H. Chen et C. Ling or Curcuma kwangsiensis S. G. Lee et C. F. Liang, is widely used for the treatment of virus-induced upper respiratory tract infections, peptic ulcers, viral pneumonia, etc. However, it has attracted widespread attention because it often causes adverse drug reactions (ADRs), including dyspnea. However, little is known about the mechanism underlying dyspnea caused by ZTOI, which limits its clinical application. AIM OF THE STUDY: To investigate the major pathophysiologic signatures and underlying mechanism of ZTOI-related dyspnea. METHODS: Respiratory function detection was used to explore the pathophysiologic signature of dyspnea induced by ZTOI. UV-vis absorption spectroscopy and isothermal titration calorimetry were applied to test the interaction between ZTOI and hemoglobin (Hb). GC‒MS was used to identify the main components in ZTOI. Molecular docking, surface plasmon resonance, and circular dichroism spectroscopy were employed to test the reaction between ß-elemene and Hb. Western blot was performed to investigate the effect of ß-elemene on the hypoxia signaling pathway. RESULTS: The results showed that ZTOI-induced dyspnea was related to a decreased oxygen carrying capacity of Hb. The molecular interaction between ZTOI and Hb was proven. Notably, ß-elemene in ZTOI exhibited high binding affinity to Hb and altered its secondary structure. Furthermore, it was found that ß-elemene downregulated the expression of prolyl hydroxylase-domain protein 2 and upregulated the expression of hypoxia-inducible factor-1α. CONCLUSIONS: Our study is valuable for better understanding the pathophysiological characteristics and underlying mechanism of ZTOI to ensure its safe clinical application. We also provided a strategy to elucidate the underlying mechanism based on inspiration from clinical ADR phenotypes for investigating other medical products with ADRs in the clinic.

Network pharmacology-based dissection of the underlying mechanisms of dyspnoea induced by zedoary turmeric oil.

Zedoary turmeric oil (ZTO) has been widely used in clinic. However, the unpleasant induced dyspnoea inevitably impedes its clinical application. Thus, it is urgent to elucidate the mechanism underlying the ZTO-induced dyspnoea. In this study, network pharmacology was firstly performed to search the clue of ZTO-induced dyspnoea. The key target genes of ZTO-induced dyspnoea were analysed using GO enrichment analysis and KEGG pathway analysis. GO analysis suggested that haem binding could be a key molecular function involved in ZTO-induced dyspnoea. Hence, the haemoglobin (Hb) was focused for its oxygen-carrying capacity with haem as its critical component binding to the oxygen. Ultraviolet-visible absorption spectrum indicated that the ZTO injection (ZTOI) perturbed the Soret band of Hb, suggesting an interaction between ZTO and Hb. GC-MS analysis revealed that ß-elemene, germacrone, curdione and furanodiene were main components of ZTOI. Molecular docking was used to illustrate the high affinity between representative sesquiterpenes and Hb, which was finally confirmed by surface plasmon resonance, suggesting their potential roles in dyspnoea by ZTO. Following a network pharmacology-driven strategy, our study revealed an intervened Hb-based mechanism underlying the ZTO-induced dyspnoea, providing a reference for elucidating mechanism underlying adverse drug reactions of herbal medicines in clinic.

Deviating from clinical practice: Pharmacokinetics of Chinese materia medica faces a substantial challenge.

The pharmacokinetics of Chinese materia medica (PCMM) has made a great contribution to investigations of the in vivo process of various components in Chinese materia medica (CMM), intending to provide useful information for clinical guidance related to CMM. However, some issues are worthy of further consideration, and current PCMM studies face a substantial challenge. First, high-dosage administration is prevalent in PCMM studies, and the obtained results might be meaningless and inappropriate for guiding the clinical application of CMM, as they deviate from clinical practice. Improvements in instrument sensitivity have not reduced the prevalence of high-dosage administration. In addition, the selection of components for detection in PCMM studies is usually uncertain, lacking sufficient scientific support, especially for components without clarified bioactivities. Therefore, the scientific value of current PCMM studies is limited. We believe that these abnormalities can be attributed to the poor recognition of the characteristics of CMM and the improper application of research approaches from Western medicines. Currently, the more pressing key scientific issues for CMM should be clinical effectiveness, quality control and bioactivity discovery, which are closely related to its own characteristics and are beneficial to its modern developments.

Renoprotective effects of Gushen Jiedu capsule on diabetic nephropathy in rats.

Gushen Jiedu capsule (GSJD) is a formula that has been widely used in traditional Chinese medicine for the prevention and treatment of diabetic nephropathy (DN). However, the mechanism underlying the protective effects of GSJD on DN is still unclear. This study was performed to clarify the therapeutic effects of GSJD on DN and its underlying mechanisms. High-fat diet- and streptozotocin-induced DN rats were treated with or without GSJD suspension by gavage for 8 weeks, and biochemical changes in blood and urine were analysed. Kidneys were isolated for histological, TUNEL and Western blot analysis. Compared to the DN group, the GSJD-treated groups exhibited decreased urinary albumin, ameliorated renal dysfunction, including serum creatinine and blood urea nitrogen, and attenuated total cholesterol, triglyceride and total protein levels. However, there were no significant effects of GSJD on body weight, fasting blood glucose or albuminuria. Histology showed that GSJD could retard the progression of DN and decrease the apoptosis rate from 52% to less than 20%. Western blot analysis showed that GSJD could regulate the mitochondrial apoptotic pathway by downregulating the expression of Bax and upregulating the expression of BCL-2 in the kidneys of DN rats. Moreover, the Akt pathway, an upstream signalling pathway of the BCL-2 family, was also ameliorated by GSJD. Further, the podocyte foot process markers podocin and nephrin were upregulated by GSJD in DN rats. This study demonstrated that GSJD might play a renoprotective role by inhibiting apoptosis and regulating the mitochondrial apoptotic and Akt pathways during pathological changes in DN.

A Chinese medicine formula (Jinqi Jiangtang Tablet): A review on its chemical constituents, quality control, pharmacokinetics studies, pharmacological properties and clinical applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes belongs to the category of "Xiao Ke Zheng" in the field of traditional Chinese medicine (TCM) and has been listed as one of the predominant diseases of TCM. Jinqi Jiangtang Tablet (JQJTT), a Chinese medicine formula composed of three herbs (Coptis chinensis, Astragalus membranaceus and Lonicera japonica), is an effective prescription for diabetes proved by randomized, double-blind, placebo-controlled trials. AIM OF THE REVIEW: To analyze systematic and up-to-date classification information on the study of JQJTT, explain the problems existing in the current research of classics formulas, and further propose the solution, providing a reference for future study. MATERIALS AND METHODS: Literatures on JQJTT were collected from a variety of databases, including PubMed, Google Scholar, Science Direct, Wiley, Web of Science, China National Knowledge Infrastructure, and WanFang Data. Information was also collected from books and reports, such as Chinese Pharmacopoeia, Chinese herbal classic books and reports of re-evaluation on post-marketing drugs conducted by companies. RESULTS: There are some problems for JQJTT: the quality control system is not perfect, the pharmacological functional mechanism is not fully explained, and clinical applications need to be reevaluated. A few of research directions for future research are proposed: (i) the chemical quality evaluation combined with bioassay to evaluate quality; (ii) interaction based on gut microbiota in vivo; (iii) the effects of interaction between components of the polypharmacy on pharmacokinetic studies; (iv) interaction mechanism between drugs and endogenous small molecules and biomacromolecules; (v) evidence-based medicine reconfirmation for clinical evaluation. CONCLUSIONS: The recent research status of JQJTT was summarized and analyzed from the aspects of chemical constituents, quality control, pharmacokinetics studies, pharmacological properties and clinical applications. This review takes JQJTT as an example, points out some typical problems and opinions about the TCM formulas, highlights the importance of the secondary development of classical formula, and lays a foundation for the further research.

[Exploring research ideas of mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine].

The prescription of clinical curative effect has promoted the formation and development of the dominant diseases in traditional Chinese medicine, but it has been controversial for a long time because its mechanism has not been effectively explained. Breaking the gap between animal/cell research and clinical research, and understanding the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine has become an important breakthrough in this scientific issue. Therefore, based on evidence-based medicine, we established the research concept that "originating from clinic, testing in experiment, returning to clinic". Taking the classic formula (Jinqi Jiangtang formula) treating diabetes as an example to find characteristic markers of diabetes supported by evidence-based medicine from clinic. We used the reverse analysis strategy of the response of characteristic markers to explore the intervention mechanism of Jinqi Jiangtang formula on characteristic markers. Then, we verified the key signaling molecules of the metabolic regulation of the Jinqi Jiangtang formula in clinic. The research ideas and key technologies for the mechanism of treatment of diabetes by Jinqi Jiangtang formula based on evidence-based medicine are formed, and it is expected to provide research reference for explaining the mechanism of dominant diseases in traditional Chinese medicine based on evidence-based medicine.

San-Cao Granule () Ameliorates Hepatic Fibrosis through High Mobility Group Box-1 Protein/Smad Signaling Pathway.

OBJECTIVE: To investigate the possible mechanism of San-Cao Granule (SCG, ) mediating antiliver fibrosis. METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid (UDCA, 60 mg/kg), SCG (3.6 g/kg) group, SCG (1.8 g/kg) group and SCG (0.9 g/kg) group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), albumin (ALB), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN), and type IV collagen (IVC) were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein (HMGB1), transforming growth factor ß1 (TGF-ß1), phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3), Smad7, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) and α-smooth muscle actin (α-SMA) were determined by western blot, immunohistochemistry and real time quantitative-reverse transcription polymerase. RESULTS: Both SCG (3.6 and 1.8 g/kg) and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and IVC and preventing the serum level reducing of ALB compared with the model group (all P<0.01). Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-ß1, p-Smad3, TLR4, MyD88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group (all P<0.01). CONCLUSION: SCG ameliorates hepatic fibrosis possibly through inhibiting HMGB1, TLR4/NF-κB and TGF-ß1/Smad signaling pathway.

Kushenin Combined with Nucleos(t)ide Analogues for Chronic Hepatitis B: A Systematic Review and Meta-Analysis.

Objective. To evaluate the efficacy and safety of Kushenin (KS) combined with nucleoside analogues (NAs) for chronic hepatitis B (CHB). Methods. Randomized controlled trials (RCTs) of KS combined with NAs for CHB were identified through 7 databases. Frequencies of loss of serum HBeAg, HBeAg seroconversion, undetectable serum HBV-DNA, ALT normalization, and adverse events at 48 weeks were abstracted by two reviewers. The Cochrane software was performed to assess the risk of bias in the included trials. Data were analyzed with Review Manager 5.3 software. Results. 18 RCTs involving 1684 subjects with CHB were included in the analysis. KS combined with NAs including lamivudine (LAM), entecavir (ETV), adefovir dipivoxil (ADV), and telbivudine (TLV) showed different degree of improvement in CHB indices. KS combined with NAs increased the frequency of loss of serum HBeAg, HBeAg seroconversion, undetectable HBV-DNA levels, and ALT normalization compared with single agents. It also decreased serum ALT and AST level after one-year treatment. However, KS combined with TLV did not show a significant difference in CHB indices. The side-effects of KS combined with NAs were light and of low frequency. Conclusion. KS combined with NAs improves the efficacy of NAs in CHB.