P-glycoprotein-mediated herb-drug interaction evaluation between Tenacissoside G and paclitaxel.

P-glycoprotein (P-gp)-mediated herb-drug interactions (HDIs) may impact drug efficacy and safety. Tenacissoside G (Tsd-G), a major active component of Marsdenia tenacissima, exhibits anticancer activity. To analyze the effect of Tsd-G on the pharmacokinetics of paclitaxel (PTX), researchers selected 30 Sprague-Dawley (SD) rats, randomized into a solvent control group, a verapamil positive control group, and 20, 40, and 60 mg/kg Tsd-G groups. After seven consecutive days of intraperitoneal injection of verapamil or Tsd-G, a single dose of 6 mg/kg PTX was injected intravenously. Plasma samples were collected at different time points, and proteins were precipitated using a methanol-acetonitrile solution. An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed, with docetaxel as an internal standard, and quantified using positive ion multiple reaction monitoring (MRM) mode. This analytical method's specificity, accuracy, precision, recovery, matrix effect, and sample stability meet the requirements for biological sample determination. After Tsd-G administration in rats, the mean residence time of PTX was significantly prolonged. And Tsd-G can stably bind to P-gp by forming hydrogen bonds and inhibiting the expression of P-gp in rat liver. Although the metabolites of PTX were not detected in this study, the above results still indicate the existence of HDIs between Tsd-G and PTX, and P-gp may be the main target to mediate HDIs.

Plasma SARS-CoV-2 N antigen is a powerful molecular marker for early detection of severe COVID-19 in patients and monitoring disease progression.

BACKGROUND AND AIMS: Clear and effective indicators for early detection of severe coronavirus disease 2019 (COVID-19) are insufficient. We investigated the clinical value of the plasma SARS-CoV-2 N antigen (plasma N antigen) for severe COVID-19 early identification and disease progression monitoring. MATERIALS AND METHODS: A cross-sectional study compared the diagnostic value of plasma N antigen levels detected within two days after hospital admission in 957 patients with COVID-19 during the BA2.2 outbreak in Shanghai (April 6-June 15, 2022). A follow-up study analyzed the plasma N antigen prognostic value in 274 non-severe patients, and a longitudinal study evaluated its continuous monitoring value in 16 patients with COVID-19 grade changes. RESULTS: Plasma N antigen concentrations were significantly higher in severely ill than in non-severely ill patients. The plasma N antigen was superior to nasopharyngeal nucleic acid CT values and established COVID-19 blood biomarkers in identifying severe COVID-19. Patients with high plasma N-antigen concentrations at initial admission were more prone to developing severe COVID-19. The changes in plasma N antigen concentrations were consistent with disease progression. Two logistic regression models, including and excluding plasma N antigen, were established, with model 1 (including plasma N antigen) (AUC = 0.971, 0.958-0.980) yielding a better diagnostic value for severe COVID-19 than Model 2 (plasma N antigen excluded). CONCLUSION: The plasma N antigen is superior to nasopharyngeal nucleic acids and established COVID-19 blood biomarkers for severe COVID-19 early recognition and progression monitoring, enabling the most accurate patient triaging and efficient utilization of medical resources.

Tongguanteng injection reverses paclitaxel resistance via upregulation of TAB1 expression in ovarian cancer in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguanteng injection (TGT), the water extract from the stem of the Traditional Chinese hebal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as anticancer remedy for decades. TGT was not only used in the treatment of many malignant cancers extensively, but also an adjuvant anticancer drug with chemotherapeutics clinically. AIM OF THE STUDY: To evaluate the effects of TGT on reversing paclitaxel (PTX) resistance and investigate the potential mechanism related to TAB1 in ovarian cancer (OC) in vitro and in vivo. MATERIALS AND METHODS: The synergistic effect and reversal ratio were determined by CCK8 assay and median-effect principle after the combination of TGT and PTX in OC A2780 and its PTX-resistant (A2780/T) cells. The biological functions in cell apoptosis, migration and invasion of A2780/T cells treated by PTX 4 µM with TGT 20, 40, 80 mg⋅mL-1 for 24 h were evaluated by colony formation, flow cytometry, wound healing and transwell assays. Proteomics technique and bioinformatic analysis were used to indentify the change of TAB1 expression in A2780/T cells induced by TGT. The association between TAB1 expression and human OC was analyzed by gene expression databases. In A2780/T cells, western blotting and colony formation assays were used to investigate the relationship between TAB1 expression and PTX resistance after TAB1 overexpression by TAB1 plasmids. The mechanism of TGT and PTX regulating TAB1 and its related proteins were explored by western blotting and flow cytometry assays after TAB1 knock-down using siTAB1. Moreover, TUNEL staining, immunohistochemistry (IHC) and histopathology were used to observe the antitumor effects, TAB1 and p-p38 expression and the tissues impairments in nude mice xenograft model established by A2780/T cells after the co-treatment with TGT and PTX by in vivo. RESULTS: TGT combined with PTX showed the synergistic effect (CI<1), which could reverse the IC50 values of PTX in OC A2780 and A2780/T cells about 23.50 and 6.44 times, respectively. Besides, TGT combined with PTX could significantly inhibit the migration, invasion and promote apoptosis of A2780/T cells. We identified that TGT could induce TAB1 expression in A2780/T cells by proteomics analysis. TAB1 downregulation was significantly associated with tumorigenesis and poor prognosis in OC patients and PTX resistance in A2780/T cells. Furthermore, TGT could activate TAB1/TAK1/p38 MAPK signaling pathway targeting TAB1 and regulate the expression of Bax, Bcl-2 proteins to improve the sensitivity of A2780/T cells to PTX. TGT combined with PTX also showed a greater inhibition in tumor growth than PTX monotherapy in vivo. These promising results show the efficacy of TGT in reversing PTX resistance and provide a potential strategy that targeting TAB1/TAK1/p38 MAPK signaling pathway may improve the chemotherapy sensitivity in OC. CONCLUSIONS: Our results revealed that Tongguanteng injection could reverse paclitaxel resistance and the potential mechanism might be associated with the activation of TAB1/TAK1/p38 MAPK signaling pathway in OC in vitro and in vivo. TAB1 might be a pivotal target for reversing PTX resistance. This study will provide a theoretical basis for the combination of Tongguanteng injection and paclitaxel in clinic.

Effect of Xiao-Ai-Ping injection on paclitaxel pharmacokinetics in rats by LC-MS/MS method.

Xiao-Ai-Ping injection (XAP) has been shown to be clinically effective in treatment of gastric carcinoma, liver cancer and lung cancer, when it was combined with anticancer drug paclitaxel (PTX). To analyze the effect of XAP on the pharmacokinetics of PTX, a liquid chromatography-tandem mass spectroscopy (LCMS/MS) assay method was developed and validated to quantify PTX simultaneously and its main metabolite 3'-p-hydroxypaclitaxel (C3'-OHP) in rat plasma. PTX and C3'-OHP were quantified using positive MRM mode. The analysis method was validated for specificity, recovery, carry-over, accuracy, precision, sample stability and dilution integrity under various storage conditions. The pharmacokinetic parameters were determined in rats after tail intravenous administration of 6 mg/mL PTX in the absence (control group) or presence of intraperitoneal administration of 10 mL/kg、20 mL/kg XAP (study groups). Compared to control group, the area under the plasma concentration-time curve (AUC) of PTX and C3'-OHP in study groups increased significantly following consecutive administration with XAP for 10 days. In conclusion, pretreatment with XAP enhanced the exposure of PTX and C3'-OHP. There would be herb-drug interaction happening between XAP and PTX in rats.