The aim of this study was to establish an efficient and stable mouse model of hyperuricemic nephropathy (HN) by testing different modes of administration of potassium oxonate (PO) combined with hypoxanthine (Hx). Animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Guangdong Pharmaceutical University. Male C57BL/6 mice were randomly divided into a control group, a PO+Hx group (i.g.; 100 mg·kg^-1·d^-1 and 500 mg·kg^-1·d^-1, respectively), and a PO+Hx group (i.p.; 100 mg·kg^-1·d^-1, and 500 mg·kg^-1·d^-1). This HN model was induced by combination of PO and Hx administration once daily for 21 days. The results of serum biochemistry showed that the levels of serum creatinine and 24 h albuminuria were increased compared with the normal group in intragastric administration of PO combined with Hx (P < 0.05), but there was no significant difference in serum uric acid and hepatic levels of xanthine oxidase. The maximum value of serum uric acid and creatinine was 349.3 μmol·L^-1 and 26.4 μmol·L^-1, respectively, in mice injected with PO combined with Hx. The levels of liver xanthine oxidase and 24 h albuminuria were significantly increased in mice injected with PO combined with Hx (P < 0.01). Pathological data showed that renal tubules were dilated, the epithelial cells of renal tubules were disordered, and the production of collagen fibers, reactive oxygen species (ROS) and lipid peroxidase 4-hydroxynonenal (4-HNE) were slightly increased after intragastric administration of PO combined with Hx mice. Obvious infiltration of inflammatory cells and large area of collagen deposition, with a large amount of ROS and the lipid peroxide 4-HNE were produced in mice injected with PO combined with Hx. Western blot analysis showed that the expression of fibronectin (FN) and urate transporter 1 (URAT1) was increased after intragastric administration of PO combined with Hx in mice and further increased in mice injected with PO combined with Hx. This study demonstrates that injection with 100 mg·kg^-1 potassium oxonate combined with 500 mg·kg^-1 hypoxanthine establishes a stable and efficient mouse HN model.

Oxygen is vital for life. Redox stress is important in cell signal transduction, mediating many physiological and pathological processes such as aging, neurodegenerative diseases, metabolic diseases and tumors. Redox homeostasis maintainance is critical for promoting life health. In this paper, the lasting challenges during antioxidant research and development and the beyond main reasons were analyzed: including insufficient understanding of the physiological function of redox stress; excessive antioxidant, causing reductive stress; antioxidant strategies lacking specificity. Here the author proposed that cells and the body own precise redox nature, therefore, redox intervention strategies such as anti-oxidation should consider the "5R" principle, i.e. right species, right time, right place, right level, right target. Precision redox regulation is the future direction and precise redox medicine development is opening.

In recent years, the use of the body's immune system for anti-tumor immunotherapy has received extensive attention. However, the immunosuppressive tumor microenvironment (TME) limits the effect of immunotherapy. Therefore, overcoming the limitations of TME and immunosuppressive cells plays an important role in tumor immunotherapy. Nano agents have great potential to reprogram the immunosuppressive microenvironment and provide an effective strategy for immunotherapy. With the continuous development of active targeting nano carrier technology and the deepening of the research on drug action sites, subcellular organ targeting nano carrier materials with more accurate active targeting function have also attracted more and more attention. This review will briefly introduce the relationship between subcellular organelles and tumor, summarize the design strategy and research progress of targeted nano drug delivery system based on the characteristics of acidity, reactive oxygen species (ROS) activity, immunogenicity, and TME of immunosuppressive cells, to provide reference for the construction of subcellular pathway targeted drug delivery system in tumor immunotherapy.

There is a broad and urgent need for the clinical application of anticancer nanomedicine in tumor therapy, but the complex biological barrier in solid tumors has always been the main obstacle to infiltrating nanomedicine into the tumor. The traditional design of nanomedicine based on enhanced permeability and retention (EPR) effect still has some limitations in tumor permeability, it is urgent to find other design theories. Therefore, this review summarizes two novel strategies, active transcytosis and immune cell-mediated tumor penetration, for promoting tumor penetration of anticancer nanomedicine.

The abnormal lipids metabolism is a critical pathological feature of coronary heart disease (CHD). Additional supplemental intake of polyunsaturated fatty acid (PUFA) has long been considered to be an effective strategy for preventing CHD, but more and more clinical trials have denied this view. Still, it is ambiguity for the specific mechanism of PUFA in CHD. The experimental programs are compliant with ethical principles for animal use and have been approved by the Animal Experiment Ethics Committee of Jinan University. In the present study, we established an animal model by intake of omega-6 PUFA combined acute myocardial ischemia to explore the mechanism of CHD. Intragastric administration of linoleic acid (LA) for 14 days, intraperitoneal injection of isoprenaline (ISO) was applied to induce acute myocardial ischemia for the animal model establishment. The animal ultrasound imaging system was used to detect cardiac function in vivo after ISO injection for 24 h. Serum and heart tissue samples were collected for the myocardial enzyme, phospholipidomics analysis and molecular biological detection. Compared to the LA group, the cardiac function showed that the left ventricular ejection fraction (EF%) and the left ventricular shortening fraction (FS%) decreased, aspaetate aminotransferase (AST), creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH) increased in the LA + ISO mice. Compared to the ISO group, the phospholipidomics analysis showed that the PUFAs significantly were raised in the LA + ISO myocardium, and the content of oxidized phosphatidylethanolamine (ox-PE) changed most remarkable. Compared with the ISO group, the molecular biology detection showed that glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were depleted, the end-products of ox-PE were increased, and the level of arachidonic acid 12/15-lipoxygenase (ALOX15) protein expression increased obviously. We suggest that ALOX15 mediated phospholipid peroxidation might be the critical mechanism of LA increased the susceptibility of myocardial ischemia injury. This study provides an experimental basis for whether PUFA could be used as an alternative treatment strategy for CHD prevention and provides a new intervention target for the early prevention strategy of CHD.

The high mortality of tumor is one of the most urgent problems to be solved. However, the current clinical trials provide limited quantitative descriptions on dynamic changes of drug efficacy, which restrict the selection of dosing regimens. Quantitative systems pharmacology (QSP) is a new approach for precise treatment of tumors. It quantifies the network relationship between drug action and diseases by integrating the tumor growth and molecules, cells in vivo, thereby predicting the efficacy, toxicity, and mechanism of antitumor drugs as well as identifying predictive biomarkers. In this review, we provide an overview of definition of QSP, current approaches and typical applications in research of antitumor drugs to enhance our understanding of QSP.

Four compounds were isolated from the 70% EtOH extract of Ardisia crispa by using various chromatographic techniques, including silica gel, ODS and semi-preparative HPLC. The structures of 1-4 were elucidated based on physicochemical properties and spectroscopic data. These compounds were defined as crispalactone A (1), (+)-pinoresinol (2), 3, 5-dimethoxy-4- hydroxyphenol-1-O-β-D-glucopyranoside (3) and (+)-schizandriside (4). Compound 1 is a new γ-valerolactone derivative, and compounds 2-4 are firstly isolated from Ardisia crispa.

The aim of this study is to investigate the role of fibroblast growth factor 21 (FGF21) in empagliflozin (EMP) in treatment of heart failure and the related mechanisms. FGF21 knockout (FGF21 KO) and littermate wild-type (WT) mice induced by doxorubicin (Dox) were used to establish heart failure mouse model in vivo. The experiment process and animal welfare follow the regulations of Animal Ethics Committee of Hefei University of Technology strictly. The results suggest that Dox (5 mg·kg^-1) induced typical heart failure symptoms in both WT and FGF21 KO mice. In WT mice, EMP (10 mg·kg^-1) significantly improved Dox-induced cardiac atrophy, decreased myocardial systolic function, decreased left ventricular ejection fraction and shortened fraction; EMP treatment also significantly inhibited the increase of Dox-induced cardiotoxicity indexes (aspartate amino transferase, creatine kinase, hydroxybutyrate dehydrogenase, lactate dehydrogenase) in mice. Dox induced cardiac fibrosis, inflammation and oxidative stress were also significantly improved by EMP. However, in FGF21 KO mice, the therapeutic effects of EMP on heart failure was significantly inhibited. The results suggest that the function of EMP in treating heart failure partly depends on the presence of FGF21, and the mechanism may be related to the effect of FGF21 on improving fibrosis, inflammation and oxidative stress.

In this study, according to TCM theory of "liver qi stagnation forming fire", emotional stress mice model was employed to evaluate the protective effects of Qingre Xiaoyanning on herpes simplex virus type 1 (HSV-1) induced reactivation. The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Jinan University, in compliance with the Institutional Animal Care Guidelines. BALB/c mice were divided into six groups, including mock group, HSV-1 latency group, HSV-1 reactivation group (HSV-1 latency + stress), low (0.658 g·kg^-1·day^-1) and high dose (1.316 g·kg^-1·day^-1) of Qingre Xiaoyanning groups and positive control group (acyclovir, 0.206 g·kg^-1·day^-1). Except for the normal group and HSV-1 latency group, all mice in other groups received a daily 12-h restraint stress for 4 days. After 7-day treatment of drugs, body weight and recurrent eye infections of mice were recorded. Brain tissues were harvested to monitor HSV-1 antigen distribution by immunohistochemical staining and detect virus titer by plaque assay. In the meantime, the mRNA and protein levels of infected cell polypeptide (ICP27) and glycoprotein B (gB) in the brain tissues were detected by RT-PCR and Western blot, respectively. The level of 4-hydroxynonenal (4-HNE) and expressions of ferroptosis-related proteins were measured by Western blot. The evaluation of malondialdehyde (MDA) content in the brain tissues was conducted by MDA assay commercial kit. The results showed that Qingre Xiaoyanning significantly retarded the decline of body weight of mice induced by HSV-1 reactivation, reduced the activation rate of HSV-1 and recurrent eye infections, declined virus titer of HSV-1, down-regulated gene and protein expressions of ICP27 and gB, and hindered the distribution of HSV-1 antigen in the brain of mice. Meanwhile, Qingre Xiaoyanning also decreased the protein expression of ferroptosis-related proteins, including DMT1, TFR1 and ALOX15 in the brain tissue of HSV-1 reactivated mice. The levels of lipid peroxidation products, 4-HNE and MDA, were also reduced by Qingre Xiaoyanning treatment. All the above results indicate that Qingre Xiaoyanning significantly inhibited HSV-1 reactivation by restraint stress, which might be related to the regulation of ferroptosis. Our findings provide a theoretical basis for the application of "clearing liver-fire" TCM on treatmenting HSV-1 reactivation-related symptoms.

In order to reveal the molecular mechanism of the small heat shock proteins (sHSPs) involved in stress resistance and active ingredients accumulation in Salvia miltiorrhiza, a small heat shock protein gene was cloned from Salvia miltiorrhiza by reverse transcription PCR according to the transcriptome data of orange root Salvia miltiorrhiza. The gene is named SmHSP21.8 based on the molecular weight of the protein, and it contains an open reading frame of 585 bp, which encodes 194 amino acids. The results of phylogenetic analysis and amino acid sequence alignment showed that SmHSP21.8 protein belongs to the endoplasmic reticulum (ER) subfamily, and contains a conserved endoplasmic reticulum-specific DPFR-I/V-LE-H/Q-x-P motif at N-terminus. The prokaryotic expression vector pMAL-c2X-SmHSP21.8 was constructed and transformed into E. coli BL21 competent cells. The recombinant protein was successfully expressed after inducted. Temporal and spatial expression analysis showed that SmHSP21.8 gene was the highest expressed in flowers and had significant tissue specificity. The relative expression of the gene was significantly increased in seedlings after induction by 38 ℃, PEG6000, abscisic acid(ABA), and indole-3-acetic acid (IAA), indicating that SmHSP21.8 gene may be involved in abiotic stress such as high temperature and drought, as well as the response to exogenous hormones ABA and IAA. These results lay the foundation for further research on the molecular mechanism of small heat shock proteins involved in adversity stress.