Xanthoceras sorbifolium leaves alleviate hyperuricemic nephropathy by inhibiting the PI3K/AKT signaling pathway to regulate uric acid transport.

ETHNOPHARMACOLOGICAL RELEVANCE: In China, Xanthoceras sorbifolium Bunge was first documented as "Wen Guan Hua" in the "Jiu Huang Ben Cao" in 1406 A.D. According to the "National Compilation of Chinese Herbal Medicine," X. sorbifolium leaves are sweet and flat in nature and can dispel wind and dampness, suggesting that their extract can be used to treat rheumatoid arthritis. X. sorbifolium Bunge has also been used to treat arteriosclerosis, hyperlipidemia, hypertension, chronic hepatitis, and rheumatism, complications associated with hyperuricemic nephropathy (HN), a condition characterized by kidney damage resulting from high levels of uric acid (UA) in the blood. AIM OF THE STUDY: The purpose of this study was to investigate the effects and underlying mechanisms of a 70% ethanol extract from X. sorbifolium leaves (EX) in alleviating HN. MATERIALS AND METHODS: A mouse model of hyperuricemia was established to initially evaluate the hypouricemic effects and determine the effective dose of EX. Phytochemical analyses were conducted using ultra high-performance liquid chromatography and liquid chromatography-mass spectroscopy. The potential key pathways of EX in the alleviation of HN were inferred using network pharmacology and bioinformatics. An HN rat model was then established, and experiments including biomarker detection, western blotting, reverse transcription quantitative polymerase chain reaction, immunohistochemical and Masson's trichrome staining, and transmission electron microscopy were conducted to evaluate the effect of EX on UA transporter expression in vitro. RESULTS: Network pharmacology and bioinformatics analyses revealed that the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway was the key pathway for the alleviation of HN progression by EX. EX treatment reduced serum biomarkers in HN rats, downregulated the expression of p-PI3K, p-AKT, glucose transporter 9 (GLUT9), urate transporter 1 (URAT1), Collagen I, matrix metalloproteinase (MMP)-2, and MMP-9, and upregulated the expression of ATP binding cassette subfamily G member 2 (ABCG2) to improve renal interstitial fibrosis in HN rats. A high content of both quercitrin and cynaroside were identified in EX; their administration inhibited the increased expression of GLUT9 and URAT1 in damaged HK-2 cells. CONCLUSION: Our study provides evidence that EX alleviates HN. The potential mechanism underlying this effect may be the regulation of UA transporters, such as GLUT9 and URAT1, by limiting the activation of the PI3K/AKT signaling pathway to improve renal injury.

Advances in the Mechanism of Luteolin against Hepatocellular Carcinoma Based on Bioinformatics and Network Pharmacology.

As one of the most common malignant tumors, hepatocellular carcinoma (HCC) has a rising incidence rate and also seriously endangers human life and health. According to research reports, hepatitis B, hepatitis C, intake of aflatoxin in the diet, and the effects of alcohol and other chemicals can induce an increase in the incidence of liver cancer. However, in the current clinical treatment of HCC, most of the drugs are chemical drugs, which have relatively large side effects and are prone to drug resistance. Therefore, the development of natural compounds to treat HCC has become a new treatment strategy. Several studies have shown that flavonoids have shown outstanding effects and exhibit strong tumor growth inhibitory effects in vivo experimental studies. Luteolin, as a natural flavonoid, has anti-tumor, anti-inflammatory, anti-viral, anti-oxidation, immune regulation, and other pharmacological effects. The anti-cancer mechanism of luteolin mainly directly acts on tumor cells to inhibit their growth, induce cell apoptosis, reduce tumor tissue angiogenesis, regulate long non-coding RNA, affect immunogenic cell death, and regulate autophagy. As well as improving the curative effect of radiotherapy and chemotherapy and chemoprevention. In this study, we evaluated the function of luteolin in regulating cancer cell proliferation, migration, and invasion will summarize and analyze luteolin and its mechanism of regulating HCC to improve the role of luteolin in the clinical prevention and treatment of HCC.

Induction of polyploid Malus prunifolia and analysis of its salt tolerance.

The apple rootstock Malus prunifolia (Willd.) Borkh. is widely used for apple production. Because polyploid plants are often more tolerant to abiotic stress than diploids, we wondered whether polyploidy induction in M. prunifolia might improve its stress tolerance, particularly to high salinity. We used a combination of colchicine and dimethyl sulfoxide (DMSO) to induce chromosome doubling in M. prunifolia and identified the resulting polyploids by stomatal observations and flow cytometry. We found the best way to induce polyploidy in M. prunifolia was to use 2% DMSO and 0.05% colchicine for 2 days for leaves or 0.02% colchicine for stem segments. The results of hydroponic salt treatment showed that polyploid plants were more salt tolerant and had greater photosynthetic efficiency, thicker leaf epidermis and palisade tissues, and shorter but denser root systems than diploids. During salt stress, the polyploid leaves and roots accumulated less Na+, showed upregulated expression of three salt overly sensitive (SOS) pathway genes, and produced fewer reactive oxygen species. The polyploid plants also had considerably higher ABA and jasmonic acid levels than diploid plants under salt stress. Under normal growth conditions, gibberellins (GAs) levels were much lower in polyploid leaves than in diploid leaves; however, after salt treatment, polyploid leaves showed upregulation of essential GAs synthesis genes. In summary, we developed a system for the induction of polyploidy in M. prunifolia and response to salt stress of the resulting polyploids, as reflected in leaf and root morphology, changes in Na+ accumulation, antioxidant capacity and plant hormone levels.

CT-721, a Potent Bcr-Abl Inhibitor, Exhibits Excellent In Vitro and In Vivo Efficacy in the Treatment of Chronic Myeloid Leukemia.

Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl. It functioned as a typically ATP-competitive inhibitor, superior to other existing Bcr-Abl inhibitors. CT-721 also demonstrated time-dependent inhibition of Bcr-Abl activation and the resultant downstream signaling transduction pathways in Bcr-Abl positive cells. Furthermore, CT-721 induced cell apoptosis and cell cycle arrest, and efficaciously inhibited tumor growth in Bcr-Abl-expressed K562 and KU812 xenograft models in a mechanism-based manner. Further PK/PD studies revealed a positive in vivo correlation between the compound concentration and inhibition of Bcr-Abl activity. Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other Bcr-Abl kinase inhibitors already approved and current in development for the treatment of CML.