The Inhibition of Fibrosis and Inflammation in Obstructive Kidney Injury via the miR-122-5p/SOX2 Axis Using USC-Exos.

Background: Fibrosis and inflammation due to ureteropelvic junction obstruction substantially contributes to poor renal function. Urine-derived stem-cell-derived exosomes (USC-Exos) have therapeutic effects through paracrine. Methods: In vitro, the effects of USC-Exos on the biological functions of HK-2 and human umbilical vein endothelial cells were tested. Cell inflammation and fibrosis were induced by transforming growth factor-ß1 and interleukin-1ß, and their anti-inflammatory and antifibrotic effects were observed after exogenous addition of USC-Exos. Through high-throughput sequencing of microRNA in USC-Exos, the pathways and key microRNAs were selected. Then, the antifibrotic and anti-inflammatory effects of exosomal miR-122-5p and target genes were verified. The role of the miR-122-5p/SOX2 axis in anti-inflammatory and antifibrotic effects was verified. In vivo, a rabbit model of partial unilateral ureteral obstruction (PUUO) was established. Magnetic resonance imaging recorded the volume of the renal pelvis after modeling, and renal tissue was pathologically analyzed. Results: We examined the role of USC-Exos and their miR-122-5p content in obstructive kidney injury. These Exos exhibit antifibrotic and anti-inflammatory activities. SOX2 is the hub gene in PUUO and negatively related to renal function. We confirmed the binding relationship between miR-122-5p and SOX2. The anti-inflammatory and antifibrotic effects of miR-122-5p were inhibited, indicating that miR-122-5p has anti-inflammatory and antifibrotic effects by inhibiting SOX2 expression. In vivo, the PUUO group showed typical obstructive kidney injury after modeling. After USC-Exo treatment, the shape of the renal pelvis shown a remarkable improvement, and inflammation and fibrosis decreased. Conclusions: We confirmed that miR-122-5p from USC-Exos targeting SOX2 is a new molecular target for postoperative recovery treatment of obstructive kidney injury.

Drug-induced hypoglycemia: a disproportionality analysis of the FAERS database.

BACKGROUND: Hypoglycemia is an adverse event (AE) that cannot be ignored in clinical practice. This study aimed to identify the most common and top drugs associated with the risk of hypoglycemia based on the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. RESEARCH DESIGN AND METHODS: We used OpenVigil 2.1 pharmacovigilance analytics platform to query FAERS database and data from 2004 to 2023 were retrieved. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify hypoglycemia cases, and DrugBank database was used to determine drug generic names. RESULTS: A total of 11,155,106 AEs reports were identified, of which 28,443 (0.25%) were related to hypoglycemia. Metformin (6926 cases) was associated with most cases of hypoglycemia. According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were penamecillin, nikethamide, sotagliflozin, norethandrolone, glimepiride/pioglitazone. Nineteen of the top 50 drugs did not have hypoglycemia indicated in the package insert. CONCLUSIONS: By analyzing the FAERS database, we listed drugs with a strong hypoglycemic signal for which the label does not provide a reminder. Notably, the potential hypoglycemia risks are of great importance and should be closely monitored in medical practice.

Protective Effect of Alkaline Mineral Water on Calcium Oxalate-Induced Kidney Injury in Mice.

Background: Kidney stone disease induces chronic renal insufficiency by crystal-induced renal tubular epithelial cell injury. It has been reported that the prevalence of kidney stone disease is increasing, accompanied by the high recurrence rate. Alkaline mineral water has been reported to possess beneficial effects to attenuate inflammation. Here, we explored the potential protective effects and underlying mechanisms of alkaline mineral water against calcium oxalate-induced kidney injury. Methods: We performed the mice kidney stone model by administering glyoxylate at 100 mg/kg once daily for 7 days. To assess the effects of alkaline mineral water on oxalate-induced kidney injury, mice drank different water (distilled water, natural mineral water at pH = 8.0, as well as natural mineral water at pH = 9.3) for 7 days, respectively, followed by glyoxylate exposure. After collection, crystal formation, kidney injury and cell apoptosis, fibrosis, oxidative stress, as well as inflammation were measured. Results: Our results showed that glyoxylate treatment led to kidney crystal formation and fibrosis, which can be attenuated by drinking alkaline mineral water. Furthermore, alkaline mineral water also reduced kidney injury and cell apoptosis, oxidative stress, and inflammation. Conclusion: Alkaline mineral water supplement prevents progression of glyoxylate-induced kidney stones through alleviating oxidative stress and inflammation.

The mechanism of linear ubiquitination in regulating cell death and correlative diseases.

Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases. Cell death is a fundamental physiological process and responsible for embryonic development, organ maintenance, and immunity response. Therefore, it is worth speculating that linear ubiquitin mediated signaling pathway would participate in different diseases. The relative literature search was done from core collection of electronic databases such as Web of Science, PubMed, and Google Scholar using keywords about main regulators of linear ubiquitination pathway. Here, we summarize the regulatory mechanism of linear ubiquitination on cellular signaling pathway in cells with apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Intervening generation of linear ubiquitin chains in relative signaling pathway to regulate cell death might provide novel therapeutic insights for various human diseases.

Sarmentosin Induces Autophagy-dependent Apoptosis via Activation of Nrf2 in Hepatocellular Carcinoma.

Background and Aims: Hepatocellular carcinoma (HCC) is a common and deadly cancer. Accumulating evidence supports modulation of autophagy as a novel approach for determining cancer cell fate. The aim of this study to evaluate the effectiveness of sarmentosin, a natural compound, on HCC in vitro and in vivo and elucidated the underlying mechanisms. Methods: Cell functions and signaling pathways were analyzed in HepG2 cells using western blotting, real-time PCR, siRNA, transmission electron microscopy and flow cytometry. BALB/c nude mice were injected with HepG2 cells to produce a xenograft tumour nude mouse model for in vivo assessments and their tumors, hearts, lungs and kidneys were isolated. Results: We found that autophagy was induced by sarmentosin in a concentration- and time-dependent manner in human HCC HepG2 cells by western blot assays and scanning electron microscopy. Sarmentosin-induced autophagy was abolished by the autophagy inhibitors 3-methyladenine, chloroquine, and bafilomycin A1. Sarmentosin activated Nrf2 in HepG2 cells, as shown by increased nuclear translocation and upregulated expression of Nrf2 target genes. Phosphorylation of mTOR was also inhibited by sarmentosin. Sarmentosin stimulated caspase-dependent apoptosis in HepG2 cells, which was impaired by silencing Nrf2 or chloroquine or knocking down ATG7. Finally, sarmentosin effectively repressed HCC growth in xenograft nude mice and activated autophagy and apoptosis in HCC tissues. Conclusions: This study showed sarmentosin stimulated autophagic and caspase-dependent apoptosis in HCC, which required activation of Nrf2 and inhibition of mTOR. Our research supports Nrf2 as a therapeutic target for HCC and sarmentosin as a promising candidate for HCC chemotherapy.

[Mechanism of Jiaotai Pills in treatment of depression based on quantitative proteomics].

This study aimed to investigate the effect of Jiaotai Pills on protein expression in the hippocampus of the rat model of chronic unpredictable mild stress(CUMS)-induced depression by quantitative proteomics and explore the anti-depression mechanism of Jiaotai Pills. The SD rats were randomized into control, model, Jiaotai Pills, and fluoxetine groups(n=8). Other groups except the control group were subjected to CUMS modeling for 4 weeks. After 4 weeks of continuous administration, the changes of behavior and pathological morphology of the hippocampal tissue were observed. Proteins were extracted from the hippocampal tissue, and bioinformatics analysis was performed for the differentially expressed proteins(DEPs) identified by quantitative proteomics. Western blot was employed to verify the key DEPs. The results showed that Jiaotai Pills significantly alleviated the depression behaviors and hippocampal histopathological changes in the rat model of CUMS-induced depression. A total of 5 412 proteins were identified in the hippocampus of rats, including 65 DEPs between the control group and the model group and 35 DEPs between the Jiaotai Pills group and the model group. There were 16 DEPs with the same trend in the Jiaotai Pills group and the control group, which were mainly involved in sphingolipid, AMPK, and dopaminergic synapse signaling pathways. The Western blot results of Ppp2r2b, Cers1, and Ndufv3 in the hippocampus were consistent with the results of proteomics. In conclusion, Jiaotai Pills may play an anti-depression role by modulating the levels of Ppp2r2b, Cers1, Ndufv3 and other proteins and regulating sphingolipid, AMPK, and dopaminergic synapse signaling pathways.

Sarmentosin promotes USP17 and regulates Nrf2-mediated mitophagy and cellular oxidative stress to alleviate APAP-induced acute liver failure.

BACKGROUND: An overdose of acetaminophen (APAP), the main cause of acute liver failure (ALF), induces oxidative stress that ultimately causes mitochondrial impairment and hepatotoxicity. The nuclear factor erythroid 2-related factor 2 (Nrf2) was widely recognized as an anti-oxidative stress mechanism. The present study was aimed at investigating whether sarmentosin, extract from traditional Chinese medicine, protects the liver against APAP-induced injury via activating Nrf2 and subsequently decreasing oxidative stress. METHODS: Male ICR mice were treated with sarmentosin oral administration for 1 week and injected APAP (300 mg/kg. i.p.) for acute liver injury model. The liver and serum of mice for histological and biochemistry analysis. AML12 and LO2 cells were used in vitro assays. RESULTS: We found that sarmentosin moderately increased accumulation of Nrf2 via upregulating USP17-mediated ubiquitin inhibition at the early stage of hepatocytes damage. The Nrf2 separating from bonding protein Keap1 translocated into nucleus and activated downstream gene of antioxidants. Mitophagy, a unique autophagy can remove Reactive Oxygen Species (ROS) damaged mitochondria, was elevated in this progress to maintain mitochondria function and ROS homeostasis. CONCLUSION: In summary, our research revealed that sarmentosin could alleviate APAP-induced liver acute injury through USP17-mediated Nrf2 overexpression and PINK1-dependent mitophagy.

[Mechanism of Qingwei Powder in treatment of periodontitis based on UPLC-Q-TOF-MS, GC-MS, network pharmacology and molecular docking].

The present study explored the mechanism of Qingwei Powder(QP) in the treatment of periodontitis based on chromatography-mass spectrometry and network pharmacology-molecular docking techniques. UPLC-Q-TOF-MS and GC-MS were used to identify the chemical constituents of QP. The active components and targets were screened out through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and their targets were predicted using SwissTargetPrediction. Targets related to periodontitis were obtained from GeneCards, OMIM, and DisGeNET. Venn diagram was constructed using Venny 2.1 to obtain the intersection targets. Cytoscape 3.7.2 was used to construct the "chemical component-target-disease" network. The targets were analyzed for Gene Ontology(GO) function and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment by clusterProfiler R, and the "chemical component-target-pathway" network was constructed. The binding activity of the active components to the target proteins was verified by molecular docking. A total of 189 chemical components were obtained by UPLC-Q-TOF-MS and GC-MS, including 39 active components with 180 potential targets related to periodontitis. Target enrichment analysis of the active components yielded 92 KEGG pathways. Twenty KEGG pathways, 34 active components, and 99 targets were involved in the "chemical component-target-pathway" network. Molecular docking verified a good binding ability of the key targets to the key compounds. This study preliminarily indicates that QP is effective in treating periodontitis through multiple components, multiple targets, and multiple pathways, which reflects the complex system of Chinese medicine. This study provides the theoretical foundation for the subsequent research on the material basis and key quality attributes of QP.

Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Promote Peritoneal Healing by Activating MAPK-ERK1/2 and PI3K-Akt to Alleviate Postoperative Abdominal Adhesion.

Peritoneal regeneration and repair can alleviate postoperative intraperitoneal adhesions, and mesenchymal stem cells (MSCs) have demonstrated the potential for peritoneal repair and regeneration. However, extracellular vesicles (EVs) are the main carriers for the MSC activity. Thus far, the roles of MSC-derived EVs on peritoneal repair are not well understood. To investigate the therapeutic effect of adipose-derived mesenchymal stem cell-derived EVs (ADSC-EVs) in peritoneal injuries, ADSC-EVs were injected in vivo via the tail vein of rats. The antiadhesion effects were evaluated following abdominal surgery. In addition, the levels of the peritoneal fibrinolysis system were determined via enzyme-linked immunosorbent assay. Expression differences in inflammatory and apoptotic markers were detected using immunofluorescence. The expression of extracellular matrix-related indexes and peritoneal healing were observed using immunohistochemistry. In vitro, rat peritoneal mesothelial cell proliferation was assessed via a 5-ethynyl-2-deoxyuridine assay. Cell migration was determined using scratch wound and transwell assays. Related signaling networks were estimated based on sequencing and bioinformatics analyses. The roles of the MAPK-ERK1/2 and PI3K-Akt signaling networks were analyzed using immunoblotting. This is the first report of the effectiveness of ADSC-EVs in the treatment of postoperative adhesions. ADSC-EVs were incorporated in vitro and induced rat peritoneal mesothelial cell proliferation and migration. This was mediated by stimulation of the MAPK-ERK1/2 and PI3K-Akt axes. ADSC-EVs promote the healing of the injured peritoneum, suggesting a promising therapeutic approach for peritoneal adhesions.

Non-coding RNAs regulating epithelial-mesenchymal transition: Research progress in liver disease.

Chronic liver injury could gradually progress to liver fibrosis, cirrhosis, and even hepatic carcinoma without effective treatment. The massive production and activation of abnormal cell differentiation is vital to the procession of liver diseases. Epithelial-mesenchymal transformation (EMT) is a biological process in which differentiated epithelial cells lose their epithelial characteristics and acquire mesenchymal cell migration capacity. Emerging evidence suggests that EMT not only occurs in the process of hepatocellular carcinogenesis, but also appears in liver cells transforming to myofibroblasts, a core event of liver disease. Non-coding RNA (ncRNA) such as microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) are important regulatory factors in EMT, which can regulate target gene expression by binding with RNA single-stranded. Various studies had shown that ncRNA regulation of EMT plays a key role in liver disease development, and many effective ncRNAs have been identified as promising biomarkers for the diagnosis and treatment of liver disease. In this review, we focus on the relationship between the different ncRNAs and EMT as well as the specific molecular mechanism in the liver diseases to enrich the pathological progress of liver diseases and provide reference for the treatment of liver diseases.

Regulation of Pyroptosis by ncRNA: A Novel Research Direction.

Pyroptosis is a novel form of programmed cell death (PCD), which is characterized by DNA fragmentation, chromatin condensation, cell swelling and leakage of cell contents. The process of pyroptosis is performed by certain inflammasome and executor gasdermin family member. Previous researches have manifested that pyroptosis is closely related to human diseases (such as inflammatory diseases) and malignant tumors, while the regulation mechanism of pyroptosis is not yet clear. Non-coding RNA (ncRNA) such as microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) have been widely identified in the genome of eukaryotes and played a paramount role in the development of cell function and fate after transcription. Accumulating evidences support the importance of ncRNA biology in the hallmarks of pyroptosis. However, the associations between ncRNA and pyroptosis are rarely reviewed. In this review, we are trying to summarize the regulation and function of ncRNA in cell pyroptosis, which provides a new research direction and ideas for the study of pyroptosis in different diseases.

Sedum sarmentosum Bunge Attenuates Drug-Induced Liver Injury via Nrf2 Signaling Pathway: An Experimental Verification Based on Network Pharmacology Prediction.

Purpose: Using network pharmacology and in vivo experiments, we investigated the antidrug-induced liver injury components and functional processes of Sedum sarmentosum Bunge (SSBE). Methods: The effective components, primary active ingredients, and possible target in the therapy of DILI were predicted using network pharmacology and bioinformatics. APAP was inducing the DILI model. In vivo testing of the pharmacodynamic foundation of SSBE in the treatment of DILI was performed. Results: The TCMSP database evaluated five main active components and 299 related targets. In addition, 707 differential genes for DILI were obtained from the DisGeNET database, DigSee database, and OMIM database. 61 related targets were mapped to predict the targets of SSBE acting on DILI. The protein-protein interaction (PPI) core network contained 59 proteins, including IL-ß, MARK14, SSP1, and MMP9. These genes are closely related to the Nrf2/ARE signaling pathway, and they may play a key role in the hepatoprotective effect of SSBE. Verification experiment results showed that, in the DILI mouse model, SSBE promoted inflammation diminution and regulation of Nrf2-ARE cascade. SSBE protected normal hepatocyte growth and inhibited apoptosis of normal liver cells induced by APAP. SSBE inhibited the expression of Nrf2 and ARE proteins in the liver tissue of the DILI mouse model in vivo. Conclusion: By modulating the Nrf2 signaling pathway, the active components in SSBE may protect against drug-induced liver damage.

Recent Progress of SERS Nanoprobe for pH Detecting and Its Application in Biological Imaging.

As pH value almost affects the function of cells and organisms in all aspects, in biology, biochemical and many other research fields, it is necessary to apply simple, intuitive, sensitive, stable detection of pH and base characteristics inside and outside the cell. Therefore, many research groups have explored the design and application of pH probes based on surface enhanced Raman scattering (SERS). In this review article, we discussed the basic theoretical background of explaining the working mechanism of pH SERS sensors, and also briefly described the significance of cell pH measurement, and simply classified and summarized the factors that affected the performance of pH SERS probes. Some applications of pH probes based on surface enhanced Raman scattering in intracellular and extracellular pH imaging and the combination of other analytical detection techniques are described. Finally, the development prospect of this field is presented.

Caffeic Acid Phenethyl Ester Prevents Colitis-Associated Cancer by Inhibiting NLRP3 Inflammasome.

Long-lasting inflammation in the intestinal tract renders individuals susceptible to colitis-associated cancer (CAC). The NOD-like receptor protein 3 (NLRP3) inflammasome plays a key role in the progression of inflammatory bowel disease and CAC. Therefore, identifying effective drugs that prevent CAC by targeting NLRP3 inflammasome is of great interest. Here, we aimed to evaluate the anti-inflammatory effect of caffeic acid phenethyl ester (CAPE) on bone marrow-derived macrophages (BMDMs), THP-1 cells, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon cancer mouse model. We also investigated the anti-tumor mechanism of CAPE. We found that CAPE decreased NLRP3 inflammasome activation in BMDMs and THP-1 cells and protected mice from colorectal cancer induced by AOM/DSS. CAPE regulated NLRP3 at the post-transcriptional level by inhibiting reactive oxygen species (ROS) production. However, CAPE did not affect NLRP3 or IL-1ß transcription, but instead enhanced NLRP3 binding to ubiquitin molecules, promoting NLRP3 ubiquitination, and contributing to the anti-tumor effect in the AOM/DSS mouse model. Moreover, CAPE suppressed the interaction between NLRP3 and CSN5 but enhanced that between NLRP3 and Cullin1 both in vivo and in vitro. Altogether, our findings demonstrate that CAPE prevents CAC by post-transcriptionally inhibiting NLRP3 inflammasome. Thus, CAPE may be an effective candidate for reducing the risk of CAC in patients with inflammatory bowel disease.

Simultaneous determination of eight flavonoids in Sedum sarmentosum Bunge from different areas by UHPLC with triple quadrupole MS/MS.

Sedum sarmentosum Bunge (SSB) is a traditional Chinese herbal medicine containing multiple components that has been extensively used clinically to treat chronic viral hepatitis and some inflammatory diseases. Total flavonoids are major pharmacologically active components of SSB. To gain a deeper understanding of SSB resources, we analyzed eight chemical constituents in 33 batches of SSB from 11 regions in China. An accurate, precise and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry method was developed for the determination of eight flavonoids in SSB. Under the optimized chromatographic conditions, good separation for the eight target components was obtained on an Agilent Zobax SB C18 (50 × 2.1 mm, 5 µm) column within 4 min. The established methods were validated with good linearity (r ≥ 0.9988), precision (RSD ≤ 2.68%), stability (1.43-3.28%) and repeatability (1.14-2.89%). Moreover, the average recoveries were 95.91-100.68%, and the RSDs were 1.50-3.80%. In addition, the analytical conditions of UPLC-ESI-MS/MS provided better sensitivity with a shorter analysis time when compared with the HPLC-DAD method. Hierarchical clustering analysis and principal component analysis were performed to estimate and classify these samples based on the contents of the eight chemical constituents. This study provided the theoretical basis and scientific evidence for the development and utilization of SSB resources.

Down Regulation of the Expression of ELMO3 by COX2 Inhibitor Suppresses Tumor Growth and Metastasis in Non-Small-Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies. Studies have shown that engulfment and cell motility 3 (ELMO3) is highly expressed in NSCLC and can be used as a novel biomarker, but its underlying mechanism remains to be explored. The aim of this study was to investigate the mechanism by which ELMO3 may be down-regulated by COX-2 inhibitors to inhibit NSCLC. NSCLC tissue and adjacent normal lung tissue from 24 patients were used to detect the mRNA and protein expression of ELMO3, COX-2, and other related proteins by Western blot, RT-PCR, and Immunohistochemical analysis. Lewis Lung carcinoma (LLC) cells were used to investigate the effects and the mechanism of siELMO3 and COX-2 inhibitor. C57BL/6 mice inoculated with LLC cells by subcutaneous (s.c.) injection were used to detect the in vivo effects of cox-2 inhibitor. The expression of ELMO3 and cyclooxygenase-2 (COX-2) in human NSCLC tissues was significantly increased compared with that in the adjacent normal tissues. ELMO3 exhibited a positive correlation with COX-2 expression. Moreover, knockdown of ELMO3 suppressed the epithelial-mesenchymal transition (EMT), adhesion, and metastasis of Lewis lung carcinoma (LLC) cells. Importantly, Parecoxib, a selective inhibitor of COX-2, significantly reduced the expression of ELMO3 and EMT in LLC cells and LLC-bearing mice. Furthermore, it could inhibit the growth, adhesion and metastasis of LLC cells in vitro. Our results demonstrate that down regulation of ELMO3 suppressed growth and metastasis of lung cancer by inhibiting EMT. Parecoxib could reduce ELMO3 expression and suppress growth and metastasis of lung cancer, which might be a useful chemotherapeutic agent for inhibiting metastasis and recurrence of NSCLC.

Celastrol inhibits colorectal cancer through TGF-ß1/Smad signaling.

BACKGROUND: There are few clinical challenges associated with the treatment of colorectal cancer (CRC). Studies have shown that TGF-ß plays a crucial role in CRC. Importantly, celastrol, a major components of the root extract of the traditional Chinese herb Tripterygium wilfordii Hook F, has been shown to inhibit the growth, adhesion, and metastasis of human CRC cells through the inhibition of TGF-ß1/Smad signaling. MATERIALS AND METHODS: Real-time PCR and Western blot tests were proceeded to present TGF-ß1, TGF-ß receptor type I (TGFßRI), TGF-ß receptor type II (TGFßRII), Smad2/3, p-Smad2/3, Smad4, and glyceraldehyde-3-phosphate dehydrogenase expression in human colon cancer cell samples. RESULTS: Our results indicated that celastrol can reduce the expression levels of TGF-ß1, TGFßRI, and TGFßRII in HCT116 and SW620 cells. Furthermore, celastrol could also prevent the increase in Smad4 and p-Smad2/3 in HCT116 and SW620 cells. CONCLUSION: Celastrol could inhibit tumor growth through TGF-ß1/Smad signaling and might be a promising therapeutic component against CRC.

Hyperoside alleviated N-acetyl-para-amino-phenol-induced acute hepatic injury via Nrf2 activation.

N-acetyl-para-amino-phenol (APAP) acute hepatic injury is receiving increasing attention. In the present study, we examined the effects of Hyperoside (Hype) on APAP-induced acute hepatic injury. Oral administration of Hype dose-dependently attenuated the index of hepatic injury, including the production of AST, ALT, and ALP. Increased glutathione (GSH) and decreased ROS production induced by Hype demonstrated its potential antioxidant capacity. In addition, Nrf2 and its downstream genes were markedly activated by Hype. Furthermore, enhanced levels of SOD, GST, and GSH-Px were markedly suppressed by Hype in a dose-dependent manner. At the same time, decreased LPO was also detected in Hype-treated mice. The in vitro study verified a protective effect of Hype on APAP-induced injuries in LO2 cells. Moreover, the regulatory effect was found to be mostly dependent on Nrf2 which decreased LDH and ALT generation and increased cell viability. Nrf2-silenced LOS cells were sensitive to APAP-induced injury, while Hype did not exhibit any further effects on LO2 cells, which demonstrate the critical role of Nrf2 in this process. Taken together, our results demonstrated the ability of Hype to inhibit APAP-induced acute hepatic injury and its potential use in the treatment of Nrf2-associated diseases.

[Nasal resorption of prim-O-glucosylcimifugin and 5-O-methylvisammioside in rats].

In this experiment, rat nasal mucosa absorption characteristics of prim-O-glucosylcimifugin and 5-O-methylvisammioside were studied to provide a basis for drug delivery of Toutongning nasal spray. The nasal mucosa absorption test in rats was conducted with in situ nasal perfusion method after pH 6 buffer solution was used to prepare high, medium and low concentrations of prim-O-glucosylcimifugin, 5-O-methylvisammioside mixed solution as liquid circulation in nasal cavity. Then the concentrations of the circulating liquid compositions to be measured were determined by HPLC, and the absorption rates of prim-O-glucosylcimifugin and 5-O-methylvisammioside under different pH conditions were also investigated. According to the results, the absorption rate constant was (0.588±0.041)×10⁻³, (0.547±0.023)×10⁻³, (0.592±0.063)×10⁻³ min⁻¹ for prim-O-glucosylcimifugin high, middle and low concentrations, and (0.438±0.041)×10⁻³, (0.407±0.023)×10⁻³, and (0.412±0.063)×10⁻³ min⁻¹ for 5-O-methylvisammioside high, middle and low concentrations. There was no significant difference among high, middle and low concentration groups, and the absorption under pH 6 was better than that under other pH conditions. Therefore, we can get the conclusion that the main active ingredient of Toutongning nasal sprays can be absorbed through the nasal mucosa, and it is feasible to make nasal spray; in addition, pH 6 of nasal spray is scientific and reasonable.

[Screen absorption enhancer for intranasal administration preparations of paeoniflorin based on nasal perfusion method in rats].

This experiment was aimed to screen the absorption enhancer for intranasal administration preparations of paeoniflorin. In this study, HPLC method for determination of paeoniflorin in perfusion liquid was established and the improved model of nasal perfusion in rats was used to screen out the species and amounts of absorption enhancer. In order to avoid the influence of the secretion and absorption of nasal cavity on the volume of perfusion fluid, the residual dose was calculated by using the volume correction method. Linear regression was carried out between the logarithm to the percentage of the residual dose and the corresponding time, and the slope of the regression line was exactly the absorption rate constant. Experimental results showed that hydroxypropyl-ß-cyclodextrin and water-soluble azone can significantly improve the nasal absorption of paeoniflorin. Furthermore, water-soluble azone had the highest absorption rate constant and the best promoting penetration effect on intranasal administration preparations of paeoniflorin. It was also found that when the mass concentration of water-soluble azone in the perfusion liquid increased from 5 g•L⁻¹ to 20 g•L⁻¹, the absorption rate constant was gradually increased and peaked at 20 g•L⁻¹. When the mass concentration was increased to 30 g•L⁻¹, the absorption rate constant was decreased, indicating that the best mass concentration of water-soluble azone was 20 g•L⁻¹.