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Objectives Ferroptosis is a unique process of cell death that specifically requires iron. We investigated ferroptosis genes and their function in lung adenocarcinoma (LUAD) patients. Methods Data on the expression levels of genes associated with ferroptosis were collected from the FerrDb and the Cancer Genome Atlas database. Kaplan-Meier Plotter was employed to generate the survival curves of LUAD patients with high vs low expression of ferroptosis genes. The relationship between immune cell infiltration and ferroptosis genes was analyzed via TIMMER. Immunohistochemical staining was employed to quantitatively evaluate gene expression in 43 LUAD patients. Results A total of 89 ferroptosis genes were found to have significant differential expression between LUAD and normal tissues (pALOX5 and FTL3 demonstrated a positive correlation with sets of immune markers. The expression of ALOX5 exhibited a positive correlation with the levels of infiltration of dendritic cells, macrophages, neutrophils, and CD4+ T cells, while FLT3 expression correlated with the infiltration of B cells, CD4+ T cells, neutrophils, and dendritic cells. Furthermore, ALOX5 was confirmed to be downregulated in lung tumor tissues (p Conclusions Our findings show that the ferroptosis genes FLT3 and ALOX5 play prominent roles in immune cell infiltration during LUAD progression and may serve as prognostic biomarkers for LUAD.

Background: Long-term intake of a high-fat diet is a crucial factor contributing to obesity, which has become a global public health problem. Progressive obesity subsequently leads to hepatic injury, renal damage and intestinal atrophy. Transporters expressed in the liver, kidney and intestine play important roles in the deposition of nutrients and drugs, but researchers have not clearly determined whether/how the expression of transporters changes after long-term administration of a High-Fat Diet (HFD). This study aims to explore the effects of the long-term administration of a HFD on the expression of drug transporters in the liver, kidney and intestine in mice and to provide useful information for medical applications in the clinic. Methods: Male C57BL/6J mice were fed either a basal diet or HFD for 24 weeks, and oral glucose tolerance tests were performed after 3, 11 and 23 weeks. Serum was obtained to measure lipid metabolism, inflammatory mediators, renal function and hepatic function. Adipose tissues, kidney, pancreas and liver were collected for hematoxylin and eosin (H&E) staining after 4, 12 and 24 weeks. The mRNA and proteins expression of drug transporters in the liver, kidney and intestine were detected using real-time PCR and western blot, respectively. Results: Compared with the control group, long-term HFD administration significantly increased the adipose index. The serum lipid levels, including Total Cholesterol (TC), Triglyceride (TG), and Low-Density Lipoprotein Cholesterol (LDL-C), as well as the levels of the inflammatory cytokines Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) were significantly elevated in HFD-induced obese mice. H&E staining revealed pathological changes in the adipose cells, liver, kidney and pancreas from the obese group following the long-term administration of the HFD. The liver of the obese group presented increased mRNA expression of the efflux transporter Mrp2 and uptake transporter Oat2 at 24 weeks. The relative expression of Oat2 increased 4.08-fold and the protein expression of Oat2 was upregulated at 24 weeks in HFD-fed mice, while the mRNA expression of the uptake transporters Oct1, Oatp1b2 and Oatp1a4 decreased by 79%, 61% and 19%, respectively. The protein expression of Oct1 was significantly downregulated in obese mice at 12 weeks. The mRNA expression of the efflux transporter Mdr1a was significantly reduced in HFD-fed mice compared with the control group at 24 weeks. Western blot showed that the trend of protein level of Mdr1 was consistent with the mRNA expression. In the kidney, the level of the Oct2 mRNA increased 1.92- and 2.46-fold at 4 and 12 weeks in HFD-fed mice, respectively. The expression of the Oat1 and Oat3 mRNAs was markedly downregulated in the kidneys of mice with HFD-induced obesity at 4 weeks. The decrease of 72% and 21% in Mdr1a mRNA expression was observed in the obese model at 4 weeks and 12 weeks, respectively. Western blot showed that the protein levels of Mdr1 and Oat1 were consistent with the mRNA expression. The qPCR experiments showed a 2.87-fold increase in Bcrp mRNA expression at 24 weeks, and the expression of the Pept1 mRNA increased 2.84-fold in intestines of obese mice subjected to long-term administration of the HFD compared with control mice at 12 weeks. Western blot showed that the trend of protein levels of Mdr1 and Mrp2 were consistent with the mRNA expression. Conclusion: The expression of uptake and efflux transporters mRNAs and protein levels were altered in obese mice compared with control mice, providing scientific evidence for future medical applications in the clinic.

Background Nephrotic syndrome (NS) is a common nephropathy with a complex and diverse aetiology. Both Imperatae rhizoma and Hedyotis diffusa Willd. are herbs that are widely used as medicine and functional food. In traditional Chinese medicine theory, they are used as an herbal pair (HP) to treat inflammation-related diseases in the clinic, especially disorders of the kidney. Purpose This study aimed to investigate the anti-inflammatory and hypolipidaemic effects of HP in an NS rat model and provide scientific data for its clinical application. Methods An NS model was established by two-dose injection of Sprague-Dawley rats with adriamycin. Seven groups, including the sham, model, HP treatment (0.25, 0.5 and 1.0 g/kg/d), prednisone (positive control, 5 mg/kg/d), and atorvastatin (positive control, 4 mg/kg/d) groups, were tested. The biochemical indexes of renal function and inflammatory cytokines were determined by ELISA kits and/or qPCR assays, and the crucial protein involved in the signalling pathway were subsequently tested by qPCR and/or Western blotting. Based on specific compounds identified by LC-Q-TOF-MS, network pharmacological study was carried out. Results The levels of BUN, Scr, Upro, UA, Alb, TC, TG, and LDL-C were significantly elevated in model rats. HP treatment for four weeks improved the renal function and the dyslipidaemia by decreasing the levels of all parameters, except BUN and Scr. HP treatment (0.5 and 1.0 g/kg/d) upregulated the expression of PPARγ, CYP7b1, and LDLR in the liver, while it down-regulated PCSK9, showing a regulatory effect on lipid metabolism disorder. The levels of TNF-α and IL-1β in the plasma and the mRNA expression of TNF-α, IL-1β, MCP-1, and TGF-β1 in the kidney were decreased in HP groups, revealing its anti-inflammatory effect in NS rats. The HP exerted an alleviation effect on the inflammatory response through the NF-κB pathway by inhibiting the mRNA and protein expression of p50 and p65. There were 34 compounds identified or tentatively characterized in HP. In the network pharmacological study, PPARG(PPARγ), PCSK9, RELA(p65), and NF-κB1(p50) were the top 20 targets for HP, supporting the animal experimental results. Conclusion : HP exhibited protective effects on NS rats. These effects might be closely related to the inhibition of NF-κB and PCSK9-LDLR and activation of the PPARγ-CYP7B1 signalling pathways.

Ethnopharmacological relevance Herba Patriniae has been used for thousands of years in China as a traditional Chinese medicine with heat-clearing and detoxicating effects. It is applied widly for the treatment of rheumatoid arthritis, diarrhea, acute hepatitis, pelvic inflammatory disease and ulcerative colitis in clinic. Two species, namely Patrinia scabiosaefolia Fisch. (PS) and Patrinia villosa Juss. (PV) from the Caprifoliaceae family, are considered as Herba Patriniae in the pharmaceutical industry. Aim of the review This paper aims to comprehensively outline the traditional uses, botanical description, phytochemistry, pharmacology, toxicology, quality control, pharmacokinetics and patents of Herba Patriniae, and elaborate the same/different characteristics between PS and PV. Materials and methods Detailed information of Herba Patriniae was collected from various online databases (Pubmed, Web of Science, Google Schola, China National Knowledge Infrastructure Database, National Intellectual Property Administration, PRC National Medical Products Administration), and those published resources (M.Sc. Thesis and books). Results A total of 233 compounds have been identified in Herba Patriniae, including triterpenoid saponins, flavonoids, organic acids, iridoids, and volatiles. A very distinct difference was observed, that PS is rich in triterpenoid saponins and volatiles, while PV contains more flavonoids. Two source species of Herba Patriniae gave similar pharmacological effects on anti-cancer, anti-inflammatory, antioxidant, antimicrobial, sedative and hypnotic effects. But there were no reports were on antipruritic, proangiogenic and anti-diarrheal effects for PS, and no studies on anti-diabetic effects for PV. Generally, Herba Patriniae showed non-toxic in the clinical dose, but mild side effects, such as temporary leukopenia, dizziness and nausea, could be found when large and excessive dosage is used. A variety of compounds have been quantified for the quality control of PS and PV. The variety, growth environment, growth time, and harvest time not only affected the contents but also the pharmacological activities of the bioactive compounds. In the past year, patents for compositions containing PV and PS have been filed, mainly involving human health, hygiene, agriculture, and animal husbandry. Unfortunately, the research on pharmacokinetics is insufficient. Only the prototype components and metabolites were repored after intragastric administration of total flavonoids extract from PV in rats. Conclusion Herba Patriniae has displayed a significant medicinal value in clinic, but the differences in phytochemistry, pharmacological effects and the content of compounds have been found between two official recorded species. About side effects and pharmacokinetic characteristics, the differeces between two species have not been well studied. For a better clinical use of Herba Patriniae, it is urgent to establish systematic pharmacology, quality control, pharmacokinetics, and clinical researches on the same/different characteristics between PS and PV., Graphical abstract Image 1

Background: Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear. Objective: Our study was to investigate the changes in the expression of main enzymes and drug transporters distributed in Adriamycin nephropathy rat liver, kidney, and intestine. Methods: An intravenous injection with a single dose of Adriamycin (6mg/kg) was made to establish Adriamycin nephropathy (AN) model and normal groups were injected with normal saline. Serum was collected for lipid metabolism, renal, and hepatic function measurement. The real-time PCR and western blot were applied to determine the mRNA and protein expression of drug enzymes and transporters. Results: In the kidney, a greater expression of Mdr1, Mrp2, Mrp4 Oat2 and Oct2 mRNA was found in AN rats as compared with control rats. In the liver, the expression of Bcrp mRNA was more doubled or tripled than control groups and downregulation of Mdr1, Mrp2, Mrp4 and Bsep gene expression was found in AN rats. Besides, we observed a downward trend of Cyp1a2, Cyp3a4 and Cyp2c9 mRNA levels in AN groups. In the duodenum, the expression of Mdr1 and Mrp3 mRNA level was decreased, while Bcrp and Mrp2 mRNA were increased. Conclusion: The changes in drug-metabolizing enzymes and transporters expression in AN rats were clarified, which may be beneficial for understanding the altered pharmacokinetics and pharmacodynamics of clinical drugs and reduce unexpected clinical findings for nephropathy patients.

Ethnopharmacological relevance Penyanling is made up of Smilacis Glabrae Rhizoma (SG, from Smilar glabra Roxb.), Angelicae Sinensis Radix (AS, from Angelica sinensis (Oliv.) Diels), Salviae Miltiorrhizae Radix et Rhizoma (SM, from Salvia miltiorrhiza Bunge), Sargentodoxae Caulis (SC, from Sargentodoxa cuneata (Oliv.) Rehd.et Wils.), Linderae Radix (LR, from Lindera aggregata (Sims) Kosterm.), Paeoniae Radix Rubra (PR, from Paeonia lactiflora Pall.), Sparganii Rhizoma (SR, from Sparganium stoloniferum (Graebn.) Buch.-Ham.), Corydalis Rhizoma (CoR, from Corydalis yanhusuo W. T. Wang), Cyperi Rhizoma (CyR, from Cyperus rotundus Linn.), Glycyrrhizae Radix et Rhizoma (GR, from Glycyrrhiza uralensis Fisch.), and Patrinia Scabiosaefolia (PS, from Patrinia scabiosaefolia Fisch. ex Trev.) recorded in Chinese Pharmacopoeia. It has been used on pelvic inflammatory disease (PID) for more than twenty years. Aim of the study: This study was carried out to illustrate its pharmacological action and clarify its substantial composition. Materials and methods The anti-inflammatory effects of Penyanling were studied on a PID rat model and a lipopolysaccharides (LPS)-stimulated THP-1 cell line. Histological changes and levels of inflammatory factors in the uterine tube of the PID rat were examined. Levels of nuclear factor-kappa B (NF-κB) in the nuclear of THP-1 cells and NF-κB, IκB-α, and FPR2 in the cytoplasm were tested by Western blot analysis. Substances within Penyanling were scanned with liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-Q-TOF-MS). The contents of total flavonoids, phenolics, and saponins were quantified. Results The anti-inflammatory effects of Penyanling were observed on PID rats, such as suppressing the infiltrations of lymphocytes and neutrophils in the uterine tube, decreasing the release of interleukin (IL)-1β, IL-6, IL-8, and monocyte chemotactic protein (MCP)-1, and promoting the production of lipoxin A4 (LXA4). On the other hand, Penyanling regulated the activity of NF-κB signal pathway on the LPS-stimulated THP-1 cell line, which suggested the potential mechanism of its anti-inflammatory effect. Besides, it could promote the expression of formyl peptide receptor 2 (FPR2), which suggested its effect on enhancing the resolution of inflammation. Seventy-six substances were identified by their accurate molecular weights, mass fragment patterns, retention times, and standards if available. Most of these substances were flavonoids, phenolics, saponins, and alkaloids. The contents of total flavonoids, phenolics, and saponins within Penyanling were 0.186, 1.371, and 4.321 mg/mL, respectively. Conclusion Penyanling showed an anti-inflammatory effect on PID, and its potential mechanism involved suppressing NF-κB signal pathway and promoting the resolution of inflammation. The main substances within it were flavonoids, phenolics, saponins, and alkaloids.