Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

FDA Approval Summary: Tremelimumab in Combination with Durvalumab for the Treatment of Patients with Unresectable Hepatocellular Carcinoma.

On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma. The approval was based on the results from the HIMALAYA study, in which patients with unresectable hepatocellular carcinoma who were naïve to previous systemic treatment were randomly assigned to receive one of three study arms: tremelimumab in combination with durvalumab (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared with sorafenib met statistical significance with a stratified HR of 0.78 [95% confidence interval (CI), 0.66-0.92; P = 0.0035]. The median OS was 16.4 months (95% CI, 14.2-19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3-16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg, i.v., as a single dose in combination with durvalumab 1,500 mg at cycle 1/day 1, followed by durvalumab 1,500 mg, i.v., every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg, i.v., as a single dose in combination with durvalumab 20 mg/kg, i.v., followed by durvalumab 20 mg/kg, i.v., every 4 weeks.

Protective effect of vitamin B6 against doxorubicin-induced cardiotoxicity by modulating NHE1 expression.

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.

Dose Correlation of Panax ginseng and Atractylodes macrocephala Koidz. Drug Pairs in the Chinese Medicine Prescription Based on the Copula Function.

OBJECTIVE: Panax ginseng and Atractylodes macrocephala Koidz. (AMK) are widely used in treating various diseases; however, research is insufficient on measuring the relationship that exists by combining this drug pair using the copula function. METHODS: In this study, 279 traditional Chinese medicine prescriptions containing the Panax ginseng and AMK drug pair were extracted from the prescription database for three types of screened indications, namely, diabetes mellitus, diarrhea, and insomnia. Following the principle of dose conversion, each dynasty unit was uniformly converted into a modern unit. Then, the kernel density distribution of Panax ginseng and AMK was fitted with their empirical distribution functions. Finally, the optimal copula function was selected from the copula function family as a t-copula function. RESULTS: The empirical distribution and probability density functions of Panax ginseng and AMK were obtained. From the results, their Kendall rank correlation coefficients with indications of diabetes mellitus, insomnia, and diarrhea were 0.8689, 0.7858, and 0.7403, whereas their Spearman rank correlation coefficients were 0.9563, 0.9276, and 0.8958. Results also indicated that the use of the t-copula function can better reflect the correlation between Panax ginseng and AMK doses. CONCLUSION: From the three indications, the dose between Panax ginseng and AMK was positively correlated. This study, therefore, confirms the medicinal principle of Chinese medicine "combining" from the perspective of mathematical statistics. Results from this study are practical to evaluate the correlation between the drug pair doses, Panax ginseng and AMK, using the copula function model, which provides a new model for the scientific explanation of compatibility for Chinese medicines. This study also provides a methodological basis for more drug measurement studies and clinical medications.

[Study on relationship between efficacy against lung cancer and different parts of Schizonepeta tenuifolia based on microfluidic chip technology].

In order to further clarify the rational use of different medicinal parts of Schizonepeta, microfluidic technology was used in this study to investigate the differences in drug efficacy against lung cancer in vitro. The ethanol extracts were examined with HPLC to establish their fingerprints in order to analyze the relationship between the spectrum and efficacy index through Grey Correlation software, and a rapid HPLC-Q-TOF/MS method was established. The result in vitro shows that the effect and components of different medicinal parts had a certain differences, and apoptosis and necrosis rate from big to small in turn is leaf, flower, root, stem. The chromatographic peaks of the 26, 12, 2, 6 and 15th are the luteolin, icynaroside, rosmarinic, caffeic acid, and hesperidin, while the 20 and 10th may be dan phenolic acid L and benzoic acid. On the one hand, preliminary study reflects that the root of Schizonepeta tenuifolia may be developed into the medicinal parts in future. On the other hand, the major chemical composition of S. tenuifolia was found to have the anti-lung-tumor effects. This new method was established for the quality control and the rational use of different parts of traditional Chinese medicine.

Mechanism of modulation through PI3K-AKT pathway about Nepeta cataria L.'s extract in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is regarded as one of the major intractable diseases, which was cured mainly by chemotherapeutics in the clinical treatment at present. But it is still a vital mission for the current medical and researchers that hunting a natural medicine which have little side effects and high-efficiency against the NSCLC on account of the shortcomings on current drugs. Nepeta cataria L. plays an important role in anti-cancer treatment according to the reports which was recorded in the Chinese Pharmacopoeia of version 2015 and belongs to one of the Traditional Chinese medicine (TCM). Microfluidic chip technology is widely used in scientific research field due to its high-throughput, high sensitivity and low cost with the continuous progress of science and technology. In this study, we investigate the effect of total flavonoid extracted from Nepeta cataria L. (TFS) through human lung cancer cell line A549 based on the microfluidic device and Flow Cytometry. So we detected the mRNA expression of MicroRNA-126 (miR-126), VEGF, PI3K, PTEN and proteins expression respectively to explore the partial PI3K-AKT pathway molecular mechanisms through Quantitative Real-time PCR (qRT-PCR) and Western Blot. The results showed that TFS can disturb the expression of miR-126 and regulate the PI3K-AKT signaling pathway to meet the effect of anti-cancer. Taking all these results into consideration we can draw a conclusion that TFS may be used as a novel therapeutic agent for NSCLC in the near future.

[Study of cancer cell apoptosis induced by Schizonepeta tenuifolia with microfluidic chip technology].

This study was designed to elucidate the chemical composition and anti-cancer effects of Schizonepeta tenuifolia's ethanol extracts. Microfluidic technology was used in the study of Schizonepeta tenuifolia from 9 different geographic regions. The ethanol extracts were examined with HPLC to establish their Fingerprints in order to analyze the relationship between the spectrum and efficacy index through Grey Correlation software, and a rapid HPLC-Q-TOF/MS method was established. The result shows that chromatographic peaks of the 19, 6, 11, 16, 18th are the representative diosmetin, luteoloside, hesperidin, luteolin, and apigenin. The 10, 12, 20th peaks may be naringenin-7-O-glucuronide or quercitrin, rosmarinate or acetylcorynoline, and 5,7-dihydroxy-6,4-dimethoxy flavone. The major chemical composition of Schizonepeta tenuifolia was found to have the anti-lung-tumor effects. A new method was established for the quality control of traditional Chinese medicine.