Macrophage migration inhibitory factor (MIF) is an enzyme-active pleiotropic cytokine that is expressed in various immune cells and tumor cells. MIF plays diverse roles in inflammation and tumor progression. It acts as a cytokine involved in immune response and inflammatory lesions. Additionally, MIF is closely associated with tumor proliferation, metastasis, and other tumor hallmarks, exerting a multifaceted influence on tumor occurrence and progression. MIF not only functions by being secreted into the extracellular space as a cytokine but can also be localized within the cytoplasm and nucleus, exhibiting diverse biological functions. As MIF in promoting tumor progression becomes increasingly recognized, MIF-based therapeutic strategies have become a hot research topic in oncology. Here, we provide a comprehensive review of MIF with different subcellular localization about their pro-tumoral functions. A better understanding of MIF in tumor biology will bring broader perspectives for the development of novel MIF targeting strategies and give promising direction for future tumor treatments.

Radiation enteritis (RE) is a common syndrome in the radiotherapy of abdominal and pelvic malignant tumors, heavy influencing living quality, but no specific clinical regimens are available. Long oil (LO) is composed of the fat components from cuttlebone, safflower, walnut oil and rapeseed oil and has been clinically used for wound healing. In this study, oral LO was applied for the prevention and treatment of RE and the mechanisms were explored. Animal experiments were approved by the Ethics Committee of the Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, and the experiments were conducted in accordance with relevant guidelines and regulations. An RE mouse model was established after single whole abdominal γ-ray radiation of 13 Gy. LO (8 mL·kg^-1) was intragastrically administered to the mice 1 h pre-radiation. Compared to the models, the mice of the LO group had more regenerated intestinal crypts and longer villus on day 3.5, and remarkable increase in the abundance of gut microbiota on day 7, especially the amounts of probiotics including Eubacterium and Lactobacillus. Moreover, the mice of the LO group showed longer total movement distance, shorter immobility time, and higher speed than the model mice on day 7. On day 14, the mice of the LO group showed the high descending of proinflammatory factors including tumor necrosis factor-α and interleukin-6, close to the normal levels. Therefore, oral LO can alleviate the inflamed syndromes of RE and improve the repair of damaged intestinal tissues. Moreover, the mice of the LO group had highly low permeability of intestinal mucosa according to the fluorescence labeling experiment, which was close to the normal level. Oral LO can protect intestine mucosa and prevent RE by modification of the intestinal microenvironment, alleviation of the inflammatory response, and promotion of tissue repair.

Non-alcoholic fatty liver disease (NAFLD) is a very common chronic liver disease in clinic, which can further develop into liver fibrosis, cirrhosis, eventually hepatocellular carcinoma and liver failure. Limonin is a natural triterpenoid compound containing furan rings. Previous studies have found that limonin has good anti-inflammatory, analgesic and liver protective functions. However, the mechanism of action of limonin on NAFLD has not been clarified. Based on the background, C57BL/6J male mice were fed with high fat diet (HFD) to establish NAFLD model (the experiment was approved by the Animal Ethics Committee of Hefei University of Technology, the approval number is HFUT20220429001), and limonin was added to the mice for administration by intragastric administration (i.g.). The results showed that HFD can induce typical NAFLD phenotypes, including impaired liver function, increased fat accumulation, and increased serum aspartate amino transferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) levels in mice. Mice were treated with limonin (50 and 100 mg·kg^-1) for 10 weeks, and it was found that limonin could restore dyslipidemia and improve fat accumulation in liver cells of mice. In addition, we conducted in vitro experiments with human hepatoma cell line HepG2 cells, and found that limonin can promote the expression of oxidative metabolism and autophagy related genes and inhibit apoptosis in HepG2 cells. Mechanistically, limonin improves high-fat food-induced NAFLD by promoting the expression of oxidative metabolism genes transcriptional coactivator of peroxisome proliferator activating receptor γ (PPARγ) (PGC1α) and carnitine palmitoyl transferase 1 alpha (CPT1α) through peroxisome proliferator activates receptor alpha (PPARα). These results indicate that limonin can inhibit apoptosis, promote autophagy and improve NAFLD by promoting oxidative metabolism of fatty acids through PPARα.

Blood stasis syndrome is one of the core clinical syndrome of rheumatoid arthritis (RA), but the biological connotation of this syndrome is not clear, and there is a lack of disease improved animal models that match the characteristics of this disease and syndrome. The aim of this study was to screen the candidate biomarker gene set of blood stasis syndrome of RA, reveal the biological connotation of this syndrome, and explore and evaluate the preparation method of the improved animal model based on the characteristics of "disease-syndrome-symptom". The study was approved by the ethics committee of Guang'anmen Hospital, Chinese Academy of Traditional Chinese Medicine (No. 2019-073-KY-01) and the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine (No. TYLL2021[K]018), and the study subjects gave their informed consent. Animal welfare and experimental procedures followed the regulations of the Experimental Animal Ethics Committee of the Chinese Academy of Traditional Chinese Medicine (No. IBTCMCACMS21-2207-01). The whole blood samples were collected clinically from RA patients with blood stasis syndrome (3 cases) or other syndromes (7 types, 3 cases/type), and healthy volunteers (4 cases), and then transcriptome sequencing, KEGG, gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) analysis were performed. 126 pivotal genes were screened, and their functional annotation results were significantly enriched in "immune-inflammation" related pathways and lipid metabolism regulation (sphingolipids, ether lipid metabolism and steroid biosynthesis). Syndrome-symptom mapping of hub gene set to the TCM primary and secondary symptoms, Western phenotypic symptoms and pathological links showed that joint tingling, abnormal joint morphology, petechiae and abnormal blood circulation are representative of blood stasis syndrome of RA. The results of the improved animal model showed that the rats in the collagen-induced arthritis + adrenaline hydrochloride (CIA+Adr) 3 model group had increased blood rheology, coagulation, platelet function and endothelial function abnormalities compared with the CIA-alone model group, suggesting that the rats with blood stasis syndrome of RA may be in a state of "blood stasis". The results of the study can help to advance the objective study of the evidence of blood stasis syndrome in RA, and provide new ideas for the establishment of an animal model that reflects the clinical characteristics of the disease and syndrome.

The most toxic DNA damage is DNA double strand breaks (DSBs), which are mainly repaired by non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK) belongs to phosphatidylinositol-3-kinase-related protein kinase family (PIKK) and plays a key role in NHEJ. DNA-PK is overexpressed in a variety of cancer cells and is related to the occurrence, development and drug resistance of malignant tumors. In this article, the representative DNA-PK inhibitors with anticancer effects are reviewed, in order to provide a reference to discovery novel DNA-PK inhibitors.

Lipid-based nanocarrier is a classic drug delivery system with great biocompatibility and biodegradability. It can effectively reduce the toxicity of anti-tumor and anti-infective drugs in clinical practice. However, it has not yet met the clinical demand for enhanced therapeutic efficacy, and the clinical application is still very limited. The complex in vivo delivery process of lipid-based nanomedicine and the reciprocal interactions with body lead to unexpected changes in in vivo performance of nanomedicine and seriously hinder clinical translation. Therefore, the in-depth study of the relationships among intrinsic properties of lipid-based nanomedicine, the in vivo delivery process, and the regulatory mechanisms will not only provide guidance for the rational design of nanocarriers, but also promote the clinical translation and precision medicine of new lipid-based nanomedicine. In this review, we summarize the in vivo delivery process, regulating factors and intervention strategies for the in vivo delivery of lipid-based nanomedicine.

Bupleuri Radix is commonly used in the traditional Chinese medicine, and saikosaponins are the important active ingredients. In this study, we first established a relative quantitative method for 25 saikosaponins using ultra high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-QTrap-MS) in the scheduled multiple reaction monitoring (sMRM) mode. The established method showed good intra-day and intra-day precision, linearity, repeatability and stability. Then the method was applied to compare 37 batches of Bupleuri Radix from different planting areas. The results showed that there was no significant difference in the saikosaponins composition of Bupleuri Radix from different planting areas in Shanxi Province, which indicating that Bupleuri Radix is well adapted to the environment, so it is suitable for widely planting. However, Bupleuri Radix harvested at spring and autumn were differed from those harvested at summer, which indicated that the traditional harvesting experience was reasonable. Correlation analysis showed that saikosaponins a and d were positively correlated with some saponins, and 4 saponins (such as clinoposaponin Ⅻ) showed bigger content variation were identified by coefficient of variation analysis. The LC-MS based pseudotargeted metabonomic method established in this study can be applied to the comprehensive detection of saikosaponins, which providing new method for the quality evaluation of Bupleuri Radix.

This study used metabolomics to explore the improvement effect of raw and honey-processed Glycyrrhizae Radix et Rhizoma on acute kidney injury (AKI) in rats. All animal experiments were approved by the Animal Ethics Committee of Shandong Academy of Chinese Medicine (approval No.: SDZYY20200101001). SD rats were randomly divided into normal group, model group, raw Glycyrrhizae Radix et Rhizoma group (0.9 g·kg^-1) and honey-processed Glycyrrhizae Radix et Rhizoma group (0.9 g·kg^-1), 6 rats in each group. The rats model of acute kidney injury was established by single intraperitoneal injection of cisplatin (CP) and treated with raw and honey-processed Glycyrrhizae Radix et Rhizoma. The pathological changes of renal tissue were evaluated by hematoxylin and eosin (HE) and PAS staining, the contents creatinine (Cr), blood urea nitrogen (BUN) and superoxide dismutase (SOD) in serum were detected. UPLC-Q-TOF/MS was used to study tissue metabolomics to screen the biomarkers affected by raw and honey-processed Glycyrrhizae Radix et Rhizoma and analyz the metabolic pathways. The results showed that compared with the model group, raw and honey-processed Glycyrrhizae Radix et Rhizoma can significantly improve the pathological changes of renal tissue and decrease the content of Cr, BUN and increase the activity of SOD. In addition, honey-processed Glycyrrhizae Radix et Rhizoma can also significantly reduce the kidney index. In tissue samples, 45 biomarkers were measured in AKI rats. Raw Glycyrrhizae Radix et Rhizoma and honey-processed Glycyrrhizae Radix et Rhizoma could simultaneously call back 11 differential metabolites, which were involved in the regulation of glycerophospholipid metabolism, tryptophan metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glutathione metabolism. In addition, raw Glycyrrhizae Radix et Rhizoma is also involved in the regulation of glycine, serine and threonine metabolism and pyrimidine metabolism. In summary, raw and honey-processed Glycyrrhizae Radix et Rhizoma can participate in the regulation of different metabolic pathways, and play an improvement role in AKI rats by regulating amino acid, lipid metabolism, energy metabolism and oxidative stress.

This study aimed to explore the effects of Ziziphi Spinosae Seme (ZSS) and Fried Ziziphi Spinosae Semen (FZSS) on metabolites and intestinal flora structure in insomnia mice by combining metabolomics analysis and 16S rRNA gene sequencing. Animal experimentation was approved according to the Committee on the Ethics of Animal Experiments of Shanxi University of Chinese Medicine (approval number: 2021DW172). The prediction targets were validated in para-chlorophenylalanine (PCPA) induced insomnia mice with administration of ZSS and FZSS for 5 days, respectively. Then pentobarbital sodium induced sleeping test were performed to evaluate the synergistic sleep-aiding effect of ZSS and FZSS. The metabolic profile of serum from insomnia mice was analyzed by UPLC-Q-Orbitrap MS. Different metabolites were screened combined with multivariate statistical analysis. The relevant metabolic pathways and networks were constructed by MetaboAnalyst 5.0. Intestinal flora changes were detected by 16S rRNA sequencing technology. Animal study indicated that, compared to PCPA-induced insomnia model, ZSS and FZSS shortened the sleeping latency and increased the sleeping duration. The serum metabolomics results showed that, there are 36 potential biomarkers associated with insomnia were identified. Compared with the model group, 25 and 27 differential metabolites were identified in the ZSS and FZSS groups, respectively. Both ZSS and FZSS groups could significantly adjust to the common 20 differential metabolites. A total of 10 pathways are closely related to insomnia, which including amino acid metabolism, energy metabolism and lipid metabolism. 5 metabolic pathways are shared in ZSS and FZSS, including phenylalanine, tyrosine and tryptophan biosynthesis, cysteine and methionine metabolism and so on. Arachidonic acid metabolism is the unique metabolic pathway for ZSS to improve sleep; 3 metabolic pathways including glutamate and glutamine are the unique regulatory pathway for FZSS to improve sleep. PCoA analysis showed that the structure of ZSS and FZSS recovered to blank group, ZSS and FZSS can decrease the abundance of Pvotella and increase the abundance of Lactobacillus. LEfSe and correlation analysis between metabolites and differential intestinal flora showed that kynurenic acid, L-glutamic acid, D-proline are significantly positively associated with Gammaproteobacteria in ZSS and 5-HT, acetylcholine, L-methionine are significantly positively associated with Lactobacillus in FZSS. In conclusion, both ZSS and FZSS can influence metabolic pathways such as amino acids, energy and lipids and regulate the structure of intestinal flora, and then play a part in treating insomnia. However, ZSS and FZSS improve the quality of sleeping by regulating different metabolic pathways and regulating gut microbiota structure. The results of this study provide an experimental basis for illustrating the action mechanism of ZSS and FZSS in treating insomnia and provide a scientific basis for clinical rational medication guidance.

The purpose of this study was to investigate the effects of ethanol extract of Scutellaria baicalensis Georgi (SGE) on endogenous metabolites in toes of rats with inflammatory pain induced by complete Freund's adjuvant (CFA) based on ¹H NMR metabolomics, which would provide foundation for revealing the effects and mechanisms of SGE in improving inflammatory pain. This animal experiment was approved by the Committee on the Ethics of Animal Experiments of Shanxi University (SXULL2022062). The rats model of inflammatory pain was induced by subcutaneous injection of CFA (0.1 mL), and the effect of low, medium and high doses of SGE (1.5, 3, 6 g·kg^-1) on inflammatory pain were explored. The effects of SGE on relieving inflammatory pain was evaluated by mechanical nociceptive thresholds (MNTs) test. Western blot was used to detect the effects of SGE on protein expression of cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB) and phospho-NF-κB (p-NF-κB). ¹H NMR metabolomics was used to analyze the regulatory effects of SGE on endogenous metabolites in the toes of rats with inflammatory pain. The results showed that SGE (6 g·kg^-1) could significantly relieve CFA-induced inflammatory pain, and also notably inhibit the protein expression of COX-2, NF-κB and p-NF-κB. SGE could markedly reverse the changes of 8 differential metabolites, such as glycine, glutamine, succinate, phosphorylcholine, etc. The metabolites were involved in eight metabolic pathways, such as glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, glutathione metabolism, glycerophospholipid metabolism. These results suggest that SGE may relieve inflammatory pain by regulating NF-κB signaling pathway and metabolic abnormality.