Study of the impurity profile of photodegradation in lomefloxacin hydrochloride ear drops using liquid chromatography combined with ion trap/time-of-flight mass spectrometry.

RATIONALE: Lomefloxacin hydrochloride ear drops are highly unstable to light and prone to produce photodegradation impurities. These impurities might be related to the phototoxicity of lomefloxacin, which could seriously threaten the health of patients. In this article, the photodegradation impurity profile in lomefloxacin hydrochloride ear drops was studied for further improvement of quality control of the drug. METHODS: By studying the chromatographic behavior of photodegradation impurities, the photodegradation impurities in lomefloxacin hydrochloride ear drops were separated and detected effectively. Liquid chromatography combined with ion trap/time-of-flight mass spectrometry was applied to characterize the structures of the photodegradation impurities in lomefloxacin hydrochloride ear drops. RESULTS: The structures of 17 impurities in lomefloxacin hydrochloride ear drops were elucidated based on high-resolution MSn data in positive ion mode, 12 of them being unknown impurities. CONCLUSIONS: The structural characteristics and fragmentation patterns of the photodegradation impurities were also studied. The study of the photodegradation impurity profile in lomefloxacin hydrochloride ear drops provides a scientific basis for quality control of these ear drops and ensures the safety of drug use by the public.

An Ellagic Acid Coordinated Copper-Based Nanoplatform for Efficiently Overcoming Cancer Chemoresistance by Cuproptosis and Synergistic Inhibition of Cancer Cell Stemness.

Drug resistance is one of the leading causes of treatment failure in current cancer chemotherapy. In addition to the classical drug efflux transporter-mediated chemoresistance, cancer cells with stemness features play a crucial role in escaping the maximum impact of chemotherapy. To sensitize cancer chemotherapy, in a novel approach, the hedgehog pathway inhibitor ellagic acid (EA) is coordinated with Cu2+ to develop nanoscale metal-organic frameworks (EA-Cu), which are then loaded with doxorubicin (DOX) and modified with targeted chondroitin sulfate (CS) to form the CS/E-C@DOX nanoplatform (CS/NPs). Notably, EA inhibits stemness maintenance by suppressing the hedgehog pathway, while Cu2+ further decreases stemness features of tumor cells by disrupting mitochondrial metabolism, effectively enhancing DOX-mediated chemotherapy. Meanwhile, EA can act synergistically with Cu2+ to cause mitochondrial dysfunction and cuproptosis, which effectively decreases ATP levels and subsequently suppresses the activity of P-glycoprotein (P-gp), thus reducing drug efflux and sensitizing DOX-mediated chemotherapy. Additionally, the attached CS endows CS/NPs with specific tumor targeting properties, whereas EA-Cu endows this nanoplatform with pH/glutathione (GSH) dual-responsive release behavior. Taken together, CS/NPs exhibited excellent antitumor effects by inducing cuproptosis and significantly inhibiting cancer cell stemness, which has great potential for overcoming cancer chemoresistance.

Percutaneous transluminal pulmonary angioplasty for Takayasu arteritis-associated pulmonary hypertension: A single-arm meta-analysis.

BACKGROUND: The efficacy and safety of percutaneous transluminal pulmonary angioplasty (PTPA) for Takayasu arteritis-associated pulmonary hypertension (TA-PH) remain unclear. OBJECTIVES: To examine the efficacy and safety of PTPA in TA-PH. METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials Library were searched from inception to August 18, 2022, for articles investigating the efficacy and safety of PTPA for TA-PH. The primary efficacy outcomes were pulmonary vascular resistance (PVR) changes from baseline to re-evaluation and 6-minute walking distance (6MWD). The safety outcome was procedure-related complications. RESULTS: Five articles comprising 104 patients with TA-PH who underwent PTPA were included. The scores of article quality, as assessed using the methodological index for nonrandomized studies tool, were high, ranging from 13 to 15 points. The pooled treatment effects of PVR (weighted mean difference [WMD]: -4.8 WU; 95% confidence interval [CI]: -6.0 to -3.5 WU; I2 = 0.0%), 6MWD (WMD: 101.9 m; 95% CI: 60.3-143.6 m; I2 = 70.4%) significantly improved. Procedure-related complications, which predominantly present as pulmonary artery injury and pulmonary injury, occurred in 32.0% of the included patients. Periprocedural death occurred in one patient (1.0%, 1/100). CONCLUSIONS: Patients with TA-PH could benefit from PTPA in terms of hemodynamics and exercise tolerance, at the expense of procedure-related complications. PTPA should be encouraged to enhance the treatment response in TA-PH. These findings need to be confirmed by further studies, ideally, randomized controlled trials. REGISTRATION: PROSPERO CRD42022354087.

Protein O-GlcNAcylation in cardiovascular diseases.

O-GlcNAcylation is a post-translational modification of protein in response to genetic variations or environmental factors, which is controlled by two highly conserved enzymes, i.e. O-GlcNAc transferase (OGT) and protein O-GlcNAcase (OGA). Protein O-GlcNAcylation mainly occurs in the cytoplasm, nucleus, and mitochondrion, and it is ubiquitously implicated in the development of cardiovascular disease (CVD). Alterations of O-GlcNAcylation could cause massive metabolic imbalance and affect cardiovascular function, but the role of O-GlcNAcylation in CVD remains controversial. That is, acutely increased O-GlcNAcylation is an adaptive heart response, which temporarily protects cardiac function. While it is harmful to cardiomyocytes if O-GlcNAcylation levels remain high in chronic conditions or in the long run. The underlying mechanisms include regulation of transcription, energy metabolism, and other signal transduction reactions induced by O-GlcNAcylation. In this review, we will focus on the interactions between protein O-GlcNAcylation and CVD, and discuss the potential molecular mechanisms that may be able to pave a new avenue for the treatment of cardiovascular events.

Testicular orphan receptor 4 induced hepatic stellate cells activation via the regulation of TGF-ß receptor â /Smad2/3 signaling pathway.

INTRODUCTION AND OBJECTIVES: Liver fibrosis is a common pathological change in many chronic liver diseases. Activation of hepatic stellate cells (HSCs) is the core event in liver fibrosis. This study aimed to investigate the role of testicular orphan receptor 4 (TR4) in the activation of HSCs. MATERIALS AND METHODS: In vivo, bile duct ligation (BDL)-induced rat liver fibrosis model was established, and the expressions of TR4 and α-smooth muscle actin (α-SMA) in liver tissues were detected. In vitro, TR4 knockdown and overexpression in JS-1 cells using lentiviral vectors were constructed, and the expressions of TR4, α-SMA, Col-I, and TGF-ß1/smads and retinoid X receptor (RXR) pathway-related genes were detected. RESULTS: TR4 was highly expressed in BDL-induced fibrotic liver, accompanied by increased expression of α-SMA. Knockdown of TR4 significantly inhibited the expressions of α-SMA, Col-I, p-TßRI, and p-Smad2/3, and up-regulated the expression of RXRα in HSCs in vitro. In contrast, TR4 overexpression significantly increased the expressions of α-SMA, Col-I, p-TßRI, and p-Smad2/3, and inhibited the expression of RXRα. CONCLUSIONS: TR4 may promote the activation of HSCs by up-regulating TßR I/Smad2/3 signaling pathway and down-regulating RXRα signaling, thereby promoting the progression of liver fibrosis. Our findings may provide a new therapeutic target against hepatic fibrosis.

The steroid hormone estriol (E3) regulates epigenetic programming of fetal mouse brain and reproductive tract.

BACKGROUND: Estriol (E3) is a steroid hormone formed only during pregnancy in primates including humans. Although E3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E3 on fetal development using mouse as a model system. RESULTS: We administered E3 to pregnant mice, exposing the fetus to E3. Adult females exposed to E3 in utero (E3-mice) had increased fertility and superior pregnancy outcomes. Female and male E3-mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E3-mice were distinct from controls. E3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. CONCLUSIONS: We identify an unexpected functional role for E3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.

Gut microbiome: New biomarkers in early screening of colorectal cancer.

BACKGROUND: Certain "star intestinal bacteria" have been found to act as a contributor to the development of colorectal cancer (CRC). Besides, given that the gut microbiome can be detected in a diverse range of samples (stool, tissue, blood, etc), it is categorized into fecal microbiome, blood microbiome, and tissue microbiome. METHODS: To provide an overview of the recent research progress, this review summarizes the characteristics of the gut microbiome in different samples at each stage of CRC and their screening efficiency. RESULTS: The screening models constructed from different sample microbiomes (healthy/colorectal adenoma, healthy/CRC, and colorectal adenoma/CRC) have both strengths and constraints in terms of biomarker reproducibility and area under the receiver-operating characteristic curve (AUC) of the screening models. Many bacteria, such as Bifidobacteria, Fusobacterium nucleatum (F. n), Geotrichum candidum, Porphyromonas asaccharolytica, Escherichia coli, Rhodococcus, Anaerostipes caccae, Enhydrobacter, Lachnoclostridiumsp. m3, Bacteroides clarus, Clostridium hathewayi, Ruminococcaceae, Bacteroides thetaiotaomicron, Culinariside, and enterotoxigenic Bacteroides fragilis (ETBF), show favorable diagnostic efficacy in early screening of colorectal cancer. CONCLUSIONS: This review highlights stool, blood, tissue, and bowel fluid are the main sample sources for biomarkers, each with its own advantages and limitations. Moreover, other samples such as extracellular vesicles and biofilms also should been deserved further attention.

Alterations of gut microbiota-derived metabolites in gestational diabetes mellitus and clinical significance.

BACKGROUND: The change in the characteristics of the gut microbiota is linked to gestational diabetes mellitus (GDM). However, whether and how the gut microbiota-derived metabolites change in GDM is uncertain. Here, we aimed to determine associations between the gut microbiota-derived metabolites and GDM. METHODS: Using targeted metabolomics approaches, 7 types of short-chain fatty acids (SCFAs), 38 types of bile acids (BAs), and 5 types of trimethylamine N-oxide (TMAO), and its derivatives of serum samples were obtained from pregnant women with GDM (n = 24), and healthy pregnant controls (HC, n = 28) were detected to identify the metabolic signature of GDM to investigate the potential biomarkers. Moreover, we assessed the associations between gut microbiota-derived metabolites and clinical parameters. RESULTS: In our study, the gut microbiota-derived metabolites signatures were significantly different between GDM and HC. Quantitative results showed the levels of isobutyric acid, isovaleric acid, valeric acid, caproic acid, GUDCA, THDCA + TUDCA, and LCA-3S were significantly higher in GDM, but the level of TMAO and its derivatives did not change significantly. Some altered gut microbiota-derived metabolites were significantly correlated with glucose and lipid levels. Receiver-operating characteristic (ROC) analysis of generalized linear models showed that gut microbiota-derived metabolites may be potential biomarkers of GDM. CONCLUSION: This study highlights gut microbiota-derived metabolites alterations in GDM and correlation of the clinical indicators, which provides a new direction for future studies aiming to novel serum biomarker for early detection or target of drug therapy of GDM.

Clinical features and survival in Takayasu's arteritis-associated pulmonary hypertension: a nationwide study.

AIMS: This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu's arteritis-associated pulmonary hypertension (TA-PH). METHODS AND RESULTS: We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu's arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77-16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03-1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01-1.13), P = 0.015]. CONCLUSION: Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators' personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.

Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling.

The conversion of skeletal muscle fiber from fast twitch to slow-twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber-type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss-of-function models generated by phospholipase Cß antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations.

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension.

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

The Calmodulin-Binding Protein IQM1 Interacts with CATALASE2 to Affect Pathogen Defense.

Calmodulin (CaM) regulates plant disease responses through its downstream calmodulin-binding proteins (CaMBPs) often by affecting the biosynthesis or signaling of phytohormones, such as jasmonic acid (JA) and salicylic acid. However, how these CaMBPs mediate plant hormones and other stress resistance-related signaling remains largely unknown. In this study, we conducted analyses in Arabidopsis (Arabidopsis thaliana) on the functions of AtIQM1 (IQ-Motif Containing Protein1), a Ca2+-independent CaMBP, in JA biosynthesis and defense against the necrotrophic pathogen Botrytis cinerea using molecular, biochemical, and genetic analyses. IQM1 directly interacted with and promoted CATALASE2 (CAT2) expression and CAT2 enzyme activity and indirectly increased the activity of the JA biosynthetic enzymes ACX2 and ACX3 through CAT2, thereby positively regulating JA content and B. cinerea resistance. In addition, in vitro assays showed that in the presence of CaM5, IQM1 further enhanced the activity of CAT2, suggesting that CaM5 may affect the activity of CAT2 by combining with IQM1 in the absence of Ca2+ Our data indicate that IQM1 is a key regulatory factor in signaling of plant disease responses mediated by JA. The study also provides new insights that CaMBP may play a critical role in the cross talk of multiple signaling pathways in the context of plant defense processes.

Inhibition of miR-103a-3p suppresses lipopolysaccharide-induced sepsis and liver injury by regulating FBXW7 expression.

Inflammation, apoptosis, and oxidative stress are involved in septic liver dysfunction. Herein, the role of miR-103a-3p/FBXW7 axis in lipopolysaccharides (LPS)-induced septic liver injury was investigated in mice. Hematoxylin-eosin staining was used to evaluate LPS-induced liver injury. Quantitative real-time polymerase chain reaction was performed to determine the expression of microRNA (miR) and messenger RNA, and western blot analysis was conducted to examine the protein levels. Dual-luciferase reporter assay was used to confirm the binding between miR-103a-3p and FBXW7. Both annexin V-fluoresceine isothiocyanate/propidium iodide staining and caspase-3 activity were employed to determine cell apoptosis. First, miR-103a-3p was upregulated in the septic serum of mice and patients with sepsis, and miR-103a-3p was elevated in the septic liver of LPS-induced mice. Then, interfering miR-103a-3p significantly decreased apoptosis by suppressing Bax expression and upregulating Bcl-2 levels in LPS-induced AML12 and LO2 cells, and septic liver of mice. Furthermore, inhibition of miR-103a-3p repressed LPS-induced inflammation by downregulating the expression of tumor necrosis factor, interleukin 1ß, and interleukin 6 in vitro and in vivo. Meanwhile, interfering miR-103a-3p obviously attenuated LPS-induced overactivation of oxidation via promoting expression of antioxidative enzymes, including catalase, superoxide dismutase, and glutathione in vitro and in vivo. Moreover, FBXW7 was a target of miR-103a-3p, and overexpression of FBXW7 significantly ameliorated LPS-induced septic liver injury in mice. Finally, knockdown of FBXW7 markedly reversed anti-miR-103a-3p-mediated suppression of septic liver injury in mice. In conclusion, interfering miR-103a-3p or overexpression of FBXW7 improved LPS-induced septic liver injury by suppressing apoptosis, inflammation, and oxidative reaction.

Circular RNA MTO1 suppresses tumorigenesis of gastric carcinoma by sponging miR-3200-5p and targeting PEBP1.

Gastric carcinoma (GC) is one of the most common cancers with the fifth highest incidence of malignant tumors and the second highest death rate in the world. Ever-increasing investigations have shown that circular RNAs (circRNAs) are involved in the development of numerous cancers. But so far, the recognization for circMTO1 that is realized and studied as a cancer-suppressing gene is a small part and the regulatory mechanism of circMTO1 in GC has yet to be further explored. In this study, our experimental results delineated that circMTO1 exhibited much lower expression level in GC tissues and cells. CircMTO1 overexpression slowed down GC progression via inhibiting cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. Besides, circMTO1 acted as a sponge for miR-3200-5p as well as it could negatively regulate the expression of miR-3200-5p. Moreover, circMTO1 was verified to compete with PEBP1 to bind to miR-3200-5p, thus decelerating the development of GC. In a word, this study was the first to indagate the underlying mechanism of circMTO1 in GC and confirmed circMTO1 exerted its anti-cancer effects by miR-3200-5p/PEBP1 axis, implying that circMTO1 may become a new promising therapeutic target for GC patients.

Forecasting incidence of hand, foot and mouth disease using BP neural networks in Jiangsu province, China.

BACKGROUND: Hand, foot and mouth disease (HFMD) is a rising public health problem and has attracted considerable attention worldwide. The purpose of this study was to develop an optimal model with meteorological factors to predict the epidemic of HFMD. METHODS: Two types of methods, back propagation neural networks (BP) and auto-regressive integrated moving average (ARIMA), were employed to develop forecasting models, based on the monthly HFMD incidences and meteorological factors during 2009-2016 in Jiangsu province, China. Root mean square error (RMSE) and mean absolute percentage error (MAPE) were employed to select model and evaluate the performance of the models. RESULTS: Four models were constructed. The multivariate BP model was constructed using the HFMD incidences lagged from 1 to 4 months, mean temperature, rainfall and their one order lagged terms as inputs. The other BP model was fitted just using the lagged HFMD incidences as inputs. The univariate ARIMA model was specified as ARIMA (1,0,1)(1,1,0)12 (AIC = 1132.12, BIC = 1440.43). And the multivariate ARIMAX with one order lagged temperature as external predictor was fitted based on this ARIMA model (AIC = 1132.37, BIC = 1142.76). The multivariate BP model performed the best in both model fitting stage and prospective forecasting stage, with a MAPE no more than 20%. The performance of the multivariate ARIMAX model was similar to that of the univariate ARIMA model. Both performed much worse than the two BP models, with a high MAPE near to 40%. CONCLUSION: The multivariate BP model effectively integrated the autocorrelation of the HFMD incidence series. Meanwhile, it also comprehensively combined the climatic variables and their hysteresis effects. The introduction of the climate terms significantly improved the prediction accuracy of the BP model. This model could be an ideal method to predict the epidemic level of HFMD, which is of great importance for the public health authorities.

Differential expression of circular RNAs in hepatic tissue in a model of liver fibrosis and functional analysis of their target genes.

AIM: To measure the expression profile of circular RNA (circRNA) in hepatic tissues in a liver fibrosis model and to explore their function using molecular biology and bioinformatic techniques. METHODS: The classic CCl4 mouse liver fibrosis model was established alongside a normal control group. The circRNA expression profile of hepatic tissue from the two groups was compared using a high-throughput circRNA microarray. The differentially expressed circRNAs were identified, and real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify a subset of the differentially expressed circRNAs (target genes). At the same time, the mouse oxidative stress injury, macrophage inflammation, and hepatic stellate cell activation models were established, and the expression of target circRNA in the above cells was measured by RT-qPCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the biological functions of target genes. Finally, one of the circRNAs was selected and its cellular function was verified using siRNA. RESULTS: A total of 10 389 circRNAs were analyzed by microarray. Compared with the normal group, there were 69 circRNAs that were differentially expressed in the liver fibrosis model group (>2-fold differential expression, P < 0.05), of which 14 were upregulated and 55 were downregulated. Five circRNAs and their differential expression were verified by RT-qPCR, and the findings were consistent with the microarray results. Of these, three circRNAs were differentially expressed (P < 0.05) in the JS1 model, one circRNA was differentially expressed (P < 0.05) in the AML12 model, and four circRNAs were differentially expressed (P < 0.05) in the RAW264.7 model. The GO analysis showed that the differentially expressed circRNAs might be involved in cell autophagy, composition of extracellular matrix components, synthesis and metabolism of retinoic acid, retinol dehydrogenase activity, ubiquitin-like protein ligase activity, histone methylation, and other biological functions. The KEGG analysis showed that the target genes of the differentially expressed circRNAs might be involved in transforming growth factor-ß1/smads, Hippo, Rap1, vascular endothelial growth factor, and other signaling pathways. Lipofection experiments showed that the expression of α-smooth muscle actin (α-SMA) in JS1 cells increased significantly after the expression of mmu_circ_34116 was decreased. CONCLUSION: The circRNA expression profile in liver fibrosis tissue shows significant changes. Partially differentially expressed circRNA could be involved in hepatic fibrosis related to hepatic oxidative stress injury, macrophage inflammation, and stellate cell activation. For instance, mmu_circ_34116 can significantly inhibit the activation of hepatic stellate cells.

Astragaloside IV Regulates the PI3K/Akt/HO-1 Signaling Pathway and Inhibits H9c2 Cardiomyocyte Injury Induced by Hypoxia-Reoxygenation.

Astragaloside IV (AS-IV) is one of the main pharmacologically active compounds found in Astragalus membranaceus. AS-IV has protective effects against ischemia-reperfusion injury (IRI), but its mechanism of action has not yet been determined. This study aims to investigate the effect of AS-IV on IRI and its effect on the phosphadylinositol 3-kinase (PI3K)/Akt/heme oxygenase (HO-1) signaling pathway through in vitro experiments. Firstly, a cell culture model of myocardiocyte hypoxia-reoxygenation (H/R) injury was replicated. After AS-IV treatment, cell viability, reactive oxygen species (ROS) levels, as well as the content or activity of the cellular factors lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), were measured to evaluate the effect of treatment with AS-IV. The effect of AS-IV on HO-1 protein expression and nuclear factor E2-related factor 2 (Nrf2) and Bach1 protein expression was determined by Western blotting. Finally, a reversal of the effect of AS-IV treatment was observed following co-incubation with a PI3K inhibitor. Our results show that AS-IV has good protective effect on H/R injury and has anti-oxidative stress and anti-inflammatory effects. It can regulate the expression of Nrf2 and Bach1 proteins in the nucleus and promote the expression of HO-1 protein, while a PI3K inhibitor can partially reverse the above effects. This study suggests that the PI3K/Akt/HO-1 signaling pathway may be a key signaling pathway for the anti-IRI effect of AS-IV.

[Astragaloside â £ regulates Nrf2/Bach1/HO-1 signaling pathway and inhibits H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation].

Astragaloside Ⅳ(AS-Ⅳ) has protective effects against ischemia-reperfusion injury(IRI), but its mechanism of action has not yet been determined. This study aims to investigate the protective effects and mechanism of AS-Ⅳ on H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation(H/R). The H/R model of myocardial cells was established by hypoxic culture for 12 hours and then reoxygenation culture for 8 hours. After AS-Ⅳ treatment, cell viability, the reactive oxygen species(ROS) levels, as well as the content or activity of superoxide dismutase(SOD), malondialdehyde(MDA), interleukin 6(IL-6), and tumor necrosis factor alpha(TNF-α), were measured to evaluate the effect of AS-Ⅳ treatment. The effect of AS-Ⅳ on HO-1 protein expression and nuclear Nrf2 and Bach1 protein expression was determined by Western blot. Finally, siRNA was used to knock down HO-1 gene expression to observe its reversal effect on AS-Ⅳ intervention. The results showed that as compared with the H/R model group, the cell viability was significantly increased(P<0.01), ROS level in the cells, MDA, hs-CRP and TNF-α in cell supernatant and nuclear protein Bach1 expression in the cells were significantly decreased(P<0.01), while SOD content, HO-1 protein expression in cells and expression of nuclear protein Nrf2 were significantly increased(P<0.01) in H/R+AS-Ⅳ group. However, pre-transfection of HO-1 siRNA into H9c2 cells by liposome could partly reverse the above effects of AS-Ⅳ after knocking down the expression of HO-1. This study suggests that AS-Ⅳ has significant protective effect on H/R injury of H9c2 cardiomyocytes, and Nrf2/Bach1/HO-1 signaling pathway may be a key signaling pathway for the effect.

Endotoxin Tolerant Dendritic Cells Suppress Inflammatory Responses in Splenocytes via Interleukin-1 Receptor Associated Kinase (IRAK)-M and Programmed Death-Ligand 1 (PDL-1).

BACKGROUND Sepsis causes the highest mortality in non-cardiovascular intensive care units worldwide. Recent research has demonstrated that the late phase of sepsis, characterized as septic immunosuppression, is the central pathophysiological mechanism of immune dysfunction. Investigating the suppressive mechanism of immune cells may identify possible targets for therapy. MATERIAL AND METHODS We used LPS 2-hit model for dendritic cells (DCs) to establish endotoxin tolerance, and co-cultured with splenocytes. Co-culture responses and gene expressions were evaluated. RESULTS Endotoxin tolerant DCs showed irresponsiveness in pro-inflammatory cytokine production and expressed negative regulator genes of inflammation. When co-cultured with splenocytes, suppression of inflammatory responses and T cells apoptosis were observed with elevated expression of IRAK-M and PDL-1, and interference and neutralization of these 2 molecules led to partly reversed suppression of inflammation. CONCLUSIONS Our research found direct regulation of endotoxin tolerant DCs to other immune cells and suggested a possible mechanism via IRAK-M and PDL-1. This may inform research on septic immunosuppression and suggests possible therapeutic targets for sepsis.