Dual­directional effect of vinorelbine combined with cisplatin or fluorouracil on tumor growth and metastasis in metronomic chemotherapy in breast cancer.

Metronomic chemotherapy (MCT) regimens may be associated with risks to the patient due to the ambiguity surrounding low dosages and schedules. In the present study, metronomic regimens of vinorelbine (NVB) combined with cisplatin (CDDP) or fluorouracil (5­FU) were chosen to study the dose­response associations with tumor growth and metastasis, along with the underlying mechanisms in angiogenesis, apoptosis and tumor immunity, using experimental techniques such as immunofluorescence, immunohistochemistry, western blotting and flow cytometry. The results demonstrated a dual­directional pharmacological action of promoting and suppressing tumor growth or metastasis in BALB/c mice bearing a 4T1 tumor at certain low and high doses of the drugs. Low doses of NVB combined with CDDP or 5­FU accelerated tumor growth by enhancing angiogenesis, increasing the expression of angiogenic proteins, NF­κB and osteopontin in tumor tissues, and inducing the accumulation of myeloid­derived suppressor cells and macrophages. By contrast, higher doses inhibited tumor growth by suppressing these effects. Notably, the upregulation of apoptotic proteins was observed after low­ and high­dose treatments. Furthermore, at low concentrations, NVB combined with CDDP or 5­FU stimulated certain functions of endothelial and tumor cells, including migration and invasion, whereas at higher concentrations they suppressed proliferation and induced apoptosis. Therefore, the results of the present study suggested the potential risks of metronomic combination chemotherapy by demonstrating that, at certain low doses, tumor growth or metastasis was promoted, and emphasized the existence of an effective dose interval that changes with different drug combinations. However, further studies are needed before a specific metronomic combination regimen can be administered clinically for cancer treatment.

Protective role of baicalin in the dynamic progression of lung injury to idiopathic pulmonary fibrosis: A meta-analysis.

BACKGROUND AND PURPOSE: The pathological progression of lung injury (LI) to idiopathic pulmonary fibrosis (IPF) is a common feature of the development of lung disease. At present, effective strategies for preventing this progression are unavailable. Baicalin has been reported to specifically inhibit the progression of LI to IPF. Therefore, this meta-analysis aimed to assess its clinical application and its potential as a therapeutic drug for lung disease based on integrative analysis. METHODS: We systematically searched preclinical articles in eight databases and reviewed them subjectively. The CAMARADES scoring system was used to assess the degree of bias and quality of evidence, whereas the STATA software (version 16.0 software) was used for statistical analysis, including a 3D analysis of the effects of dosage frequency of baicalin in LI and IPF. The protocol of this meta-analysis is documented in the PROSPERO database (CRD42022356152). RESULTS: A total of 23 studies and 412 rodents were included after several rounds of screening. Baicalin was found to reduce the levels of TNF-α, IL-1ß, IL-6, HYP, TGF-ß and MDA and the W/D ratio and increase the levels of SOD. Histopathological analysis of lung tissue validated the regulatory effects of baicalin, and the 3D analysis of dosage frequency revealed that the effective dose of baicalin is 10-200 mg/kg. Mechanistically, baicalin can prevent the progression of LI to IPF by modulating p-Akt, p-NF-κB-p65 and Bcl-2-Bax-caspase-3 signalling. Additionally, baicalin is involved in signalling pathways closely related to anti-apoptotic activity and regulation of lung tissue and immune cells. CONCLUSION: Baicalin at the dose of 10-200 mg/kg exerts protective effects against the progression of LI to IPF through anti-inflammatory and anti-apoptotic pathways.

Simultaneous Determination of Multiple Active Components from Bushen Pills and Application in a Pharmacokinetic Study in Rats.

Bushen Pills (BSPs), as a traditional Chinese medicine (TCM), is widely used in clinic to enrich Yang, nourish Yin, stem essence, and strengthen kidneys. Two chromatographic methods, liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), were applied to analyze the multiple active components of BSPs in dosage form for quality evaluation and in rat plasma for pharmacokinetics study, respectively. Three active constituents of BSPs, including paeoniflorin (PF), berberine hydrochloride (BBR), and schizandrin (SCH), were simultaneously determined by the established LC-MS method with electrospray ionization (ESI) in positive selected ion monitoring (SIM) mode at m/z 503.1, 336.0, and 455.2. The contents of PF, BBR, and SCH were (6.112 ± 0.166) mg/g, (335.1 ± 14.95) µg/g, and (5.867 ± 0.136) µg/g in BSPs. On this basis, PF and BBR were selected as targeted analytes for the pharmacokinetic study of BSPs in rats. Memantine hydrochloride was used as an internal standard (IS), and the plasma samples were processed by liquid-liquid extraction with ethyl acetate. All the analytes were separated on a C18 reversed phase column, eluted with a mobile phase consisting of acetonitrile-formic acid (0.01%) (25 : 75, v/v), and detected by ESI in the selected ion mode with multiple reaction monitoring (MRM). The target fragment ions were m/z 525.3 ⟶ 449.5 for PF, 336.2 ⟶ 320.2 for BBR, and 180.1 ⟶ 163.1 for IS. The linear ranges of PF and BBR were 5-500 ng/mL and 0.1-20 ng/mL with good linearity (r 2 > 0.99). No obvious matrix effect was observed, and acceptable accuracy, precision, recovery, and stability were obtained. The proposed method has been successfully applied to the pharmacokinetic study of BSPs in rats after a single dose.

The effect of Astragalus as an adjuvant treatment in type 2 diabetes mellitus: A (preliminary) meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalus is a traditional Chinese medicine that is widely used for tonifying Qi (Qi mainly means life energy) to treat diabetes mellitus and its complications. AIM OF THE STUDY: We performed a meta-analysis to evaluate the effect of Astragalus in adjuvant treatment of type 2 diabetes mellitus (T2DM), and to provide novel information to improve clinical decision-making. MATERIALS AND METHODS: We conducted an exhaustive database search (PubMed, EMbase, Cochrane Library, China Knowledge Resource Integrated Database (CNKI), Wanfang data and SinoMed) of studies associated with "Astragalus" and "type 2 diabetes mellitus" until December 2015. Following quality assessment of study eligibility, the extracted data were statistically analyzed using STATA, ver. 12.0 (Stata Corp.). RESULTS: A total of 13 studies with 1054 participants were included in this meta-analysis. Two subgroups were identified, based on Astragalus dosing regimens: control group vs. Astragalus injection (AI); control group vs. Astragalus aqueous decoction (AAD). The pooled results showed that, in comparison with control group, Astragalus administration significantly reduced fasting plasma glucose (FPG) in both the AI group (WMD=-0.28, 95% CI=-0.46 to -0.10, P=0.002, I(2)=18.5%) and the AAD group (WMD=-0.83, 95% CI=-1.07 to -0.58, P=0.000, I(2)=0.0%); postprandial plasma glucose (PPG) was also significantly reduced in the AI group (WMD=-0.47, 95% CI=-0.77 to -0.17, P=0.002, I(2)=46.8%) and the AAD group (WMD=-1.19, 95% CI=-1.63 to -0.75, P=0.000, I(2)=49.3%). Fasting insulin (Fins) was significantly reduced only in the AAD treatment group (SMD=-0.33, 95% CI=-0.55 to -0.10, P=0.005, I(2)=1.0%) as was the homeostasis model assessment insulin resistance index (HOMA-IRI) levels (SMD=-1.66, 95% CI=-3.24 to -0.09, P=0.038, I(2)=94.0%). Although AAD treatment significantly reduced levels of glycated hemoglobin A1c (HbA1c) (WMD=-1.77, 95% CI=-3.06 to -0.47, P=0.007, I(2)=90.8%), AI treatment failed to show significant efficacy (WMD=-0.28, 95% CI=-0.63 to 0.06, P=0.102, I(2)=83.8%). Sensitivity analysis failed to detect outliers in all studies while Egger's linear regression test revealed a lack of publication bias in this meta-analysis (P=0.771, 95%CI =-3.51 to 4.56). CONCLUSIONS: Astragalus may be beneficial as an adjuvant therapy in the treatment of type 2 diabetes. However, due to the limited quality of existing studies, further high-quality studies are warranted before definitive conclusions may be reached.

Vasorelaxant activities of Danhong injection and their differential effects on the rat abdominal aorta and mesenteric artery.

Previous studies have found that Danhong injection (DHI), an extensively used herbal extract preparation in China, might be a powerful vasodilator. The aims of this study were to determine the vascular activity of DHI and its effects on arteries of different sizes. The results showed that DHI significantly inhibited rat-hindquarters and rabbit-ear vasoconstriction elicited by norepinephrine (NE) perfusion and markedly relaxed KCl-contracted and NE-contracted rat abdominal aortic and mesenteric artery rings. The endothelium made only a minor contribution to the vasorelaxant effect of DHI on artery segments. The vasorelaxant effect of DHI varied with the artery size, with larger arteries exhibiting a more sensitive and potent vasodilator response. DHI relaxed NE-induced vasoconstriction probably through inhibition of the intracellular Ca2+ release through the inositol triphosphate receptor system in the abdominal aorta and mesenteric artery, along with blockage of extracellular Ca2+ influx through the receptor-linked Ca2+ channels in the mesenteric artery. In addition, DHI completely relaxed KCl-induced contraction in both of the arteries, suggesting that inhibition of Ca2+ influx through voltage-gated Ca2+ channels is involved in the vasorelaxant effect of DHI. This elucidation of the vascular effects of DHI and the underlying mechanisms could lead to improved clinical applications.

Highly selective screening of the bioactive compounds in Huoxue capsule using immobilized ß(2)-adrenoceptor affinity chromatography.

A highly selective assay was developed for screening compounds that bind to the porcine recombinant ß2-adrenoceptor (ß2-AR) with affinity chromatography coupled to quadrupole time-of-flight mass spectrometry (Q-TOF-MS). The methodology involved selective screening with immobilized ß2-AR, a highly accurate identification via Q-TOF-MS, and a functional evaluation of the screened compounds with a sensitive myograph system. Ferulic acid, hydroxysafflor yellow A (HSYA), and naringin were confirmed to be the bioactive compounds in Huoxue capsule that specifically bound to the ß2-AR. These compounds produced a concentration-dependent relaxation of arteries that were contracted by treatment with phenylephrine, and the relaxation caused by these compounds was attenuated in the presence of ICI 118551, a type of ß2-AR antagonist. Our data indicate that the use of an immobilized receptor is potentially an alternative method for the rapid screening of bioactive compounds in a complex matrix because of its high specificity. ß2-AR affinity chromatography was valuable in focusing attention on the further investigation of ferulic acid, HSYA, and naringin as ß2-AR agonists.

[Pro-angiogenic effects of four Chinese medicines and three herbal prescription in chicken chorioallantoic membrane model].

OBJECTIVE: To observe the pro-angiogenic effect of four Chinese medicines and three herbal prescriptions, screen the effective components from them. METHODS: Chicken chorioallantoic membrane (CAM) model was employed to observe the pro-angiogenic activities of Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix, Notoginseng Radix, Astragali Radix, Xuefuzhuyu decoction, Dangguibuxue decoction and Taohongsiwu decoction, all of them were claimed to promote angiogenesis. The effective components were screened from the extracts. RESULTS: Compared with negative control group, the blood vessel densities in Angelicae Sinensis Radix and Notoginseng Radix groups were not increased significantly (P > 0.05). However, blood vessel densities in Astragali Radix group, Salviae Miltiorrhizae Radix group, Xuefuzhuyu decoction group, Dangguibuxue decoction group and Taohongsiwu decoction group were notably enhanced (P < 0.05). Dangguibuxue decoction showed a more than 90% of increase in blood vessel densities as compared with the negative control group (P < 0.01), and components contained ferulic acid and astragaloside from Dangguibuxue decoction displayed significantly pro-angiogenic effect (P < 0.05). CONCLUSION: Dangguibuxue decoction and its extract, components contained ferulic acid and astragaloside, can improve angiogenesis in CAM model significantly.

[Effect and mechanism of Danhong injection on isolated mesenteric arterial rings in rats].

OBJECTIVE: To study the effect and mechanism of Danhong injection on isolated mesenteric arterial rings in rats. METHOD: An isolated vascular ring experiment was conducted to determine the changes in tension of vascular rings with a biological signal collection and analytical system. RESULT: Danhong injection had no impact on the tension of vascular rings. Danhong injection showed a significant vasodilatation effect on treated arteria rings of norepinephrine, and no remarkable impact was made on the effect without endothium. It showed notable effect on blood vessels treated with Ca(2+) and no significant impact on those treated with caffeine. It could inhibit NE-induced intracellular calcium from releasing and external calcium from inflowing. No effects of potassium channel blockers on aorta ring tensile force were found. CONCLUSION: Danhong injection shows significant vasodilation effect, which mainly works through vascular smooth muscle. Its vasodilation effect may be related to inhibitory receptor, voltage-dependent Ca(2+)-release and IP3 receptor-mediated Ca(2 +)-influx.