Mechanism of directed activation of peroxymonosulfate by Fe-N/O unsymmetrical coordination-modulated polarized electric field.

Iron-nitrogen co-doped carbon materials as heterogeneous catalysts have attracted much attention in advanced oxidation processes involving peroxymonosulfate (PMS) due to their unique structure and enormous catalytic potential. However, there is limited research on the influence of different coordination structures on the central iron atoms. Through simple pyrolysis, we introduced oxygen atoms into the Fe-N coordination structure, constructing Fe-N/O@C catalysts with Fe-N2O2 coordination structure, and achieved efficient degradation of bisphenol A (BPA). Quenching experiments, electron paramagnetic resonance, and electrochemical analysis indicate that compared to the free radical activation pathway of Fe-N@C, high-valent iron-oxo species (≡Fe(Ⅳ) = O) are the main reactive oxygen species (ROS) in the Fe-N/O@C/PMS system. Meanwhile, we compared the differences in the oxidation states of Fe atoms and electron density in different coordination structures, revealing the formation of high-valent iron-oxo species and the mechanism of interfacial electron transfer. Therefore, this study provides new insights into the design and development of Fe-N co-doped catalysts for resource-efficient and environmentally friendly catalytic oxidation systems.

Comparative study of Fe2+/H2O2 and Fe2+/persulfate systems on the pre-treatment process of real pharmaceutical wastewater.

Advanced oxidation technologies based on hydroxyl radical (•OH) and sulfate radical (SO4-•) are two common types of advanced oxidation technologies, but there are not many reports on the application of advanced oxidation methods in actual wastewater pretreatment. This article compares the pre-treatment performance of Fe2+/H2O2 and Fe2+/Persulfate systems in actual pharmaceutical wastewater, and combines EEM, GC-MS, and toxicity testing results to explore the differences in TOC, COD, and NH3-N removal rates, optimal catalyst dosage, applicable pH range, toxicity of effluent after reaction, and pollutant structure between the two systems. The results indicate that the Fe2+/H2O2 system has a higher pollutant removal rate (TOC: 71.9%, COD: 66.9%, NH3-N: 34.1%), but also requires a higher catalyst (Fe2+) concentration (6.0 g/L), and its effluent exhibits characteristic peaks of aromatic proteins. The Fe2+/Persulfate system has a wider pH range (pH ≈ 3-7) and is more advantageous in treating wastewater containing more cyclic organic compounds, but the effluent contains some sulfur-containing compounds. In addition, toxicity tests have shown that the toxicity reduction effect of the Fe2+/Persulfate system is stronger than that of the Fe2+/H2O2 system.

Homoplantaginin attenuates high glucose-induced vascular endothelial dysfunction via inhibiting store-operated calcium entry channel and endoplasmic reticulum stress.

OBJECTIVES: The activation of store-operated calcium entry (SOCE) channel and endoplasmic reticulum stress (ERS) induced by high glucose (HG) is recognized as a major cause of vascular endothelial dysfunction. This study aims to investigate the protective effect of homoplantaginin (Hom) on HG-induced endothelial dysfunction. METHODS: HG-induced vascular endothelial dysfunction model in human umbilical vein endothelial cells (HUVECs) and rat-isolated thoracic aortas were established to observe the protective effect of Hom, further evaluated the mechanism of SOCE channel and ERS in the pathogenesis. KEY FINDINGS: Hom increased the levels of nitric oxide (NO) and phospho-endothelial nitric oxide synthase (p-eNOS) in HUVECs and isolated rat thoracic aortas in a dose-dependent manner, restored acetylcholine-mediated endothelium-dependent vasodilation. Network pharmacology showed that the pathogenesis of diabetic vascular complications may involve calcium (Ca2+) signal pathway. Hom reduced Ca2+ concentration via blocking SOCE channel in HUVECs, and resisted ERS activation by down-regulating ERS-related proteins expression. Importantly, SKF96365 (SOCE inhibitor) intervention experiment showed that Hom inhibited ERS activation by blocking the SOCE channel, further increased the levels of NO and p-eNOS. CONCLUSION: Hom could alleviate HG-induced vascular endothelial dysfunction by inhibiting SOCE channel and ERS. This provided a potential pharmacological intervention strategy for the treatment of vascular endothelial dysfunction.

Homoplantaginin attenuates high glucose-induced vascular endothelial cell apoptosis through promoting autophagy via the AMPK/TFEB pathway.

Vascular endothelial cell (VEC) injury is a key factor in the development of diabetic vascular complications. Homoplantaginin (Hom), one of the main flavonoids from Salvia plebeia R. Br. has been reported to protect VEC. However, its effects and mechanisms against diabetic vascular endothelium remain unclear. Here, the effect of Hom on VEC was assessed using high glucose (HG)-treated human umbilical vein endothelial cells and db/db mice. In vitro, Hom significantly inhibited apoptosis and promoted autophagosome formation and lysosomal function such as lysosomal membrane permeability and the expression of LAMP1 and cathepsin B. The antiapoptosis effect of Hom was reversed by autophagy inhibitor chloroquine phosphate or bafilomycin A1. Furthermore, Hom promoted gene expression and nuclear translocation of transcription factor EB (TFEB). TFEB gene knockdown attenuated the effect of Hom on upregulating lysosomal function and autophagy. Moreover, Hom activated adenosine monophosphate-dependent protein kinase (AMPK) and inhibited the phosphorylation of mTOR, p70S6K, and TFEB. These effects were attenuated by AMPK inhibitor Compound C. Molecular docking showed a good interaction between Hom and AMPK protein. Animal studies indicated that Hom effectively upregulated the protein expression of p-AMPK and TFEB, enhanced autophagy, reduced apoptosis, and alleviated vascular injury. These findings revealed that Hom ameliorated HG-mediated VEC apoptosis by enhancing autophagy via the AMPK/mTORC1/TFEB pathway.

Geniposide suppresses liver injury in a mouse model of DDC-induced sclerosing cholangitis.

Sclerosing cholangitis, characterized by biliary inflammation, fibrosis, and stricturing, remains one of the most challenging conditions of clinical hepatology. Geniposide (GE) has anti-inflammatory, hepatoprotective, and cholagogic effects. Whether GE provides inhibition on the development of sclerosing cholangitis is unknown. Here, we investigated the role of GE in a mouse model in which mice were fed with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 4 weeks to induce sclerosing cholangitis. The results demonstrated that the increased hepatic gene expressions of pro-inflammatory (IL-6, VCAM-1, MCP-1, and F4/80) and profibrogenic markers (Col1α1, Col1α2, TGF-ß, and α-SMA) in DDC feeding mice were reversed after treatment with GE. GE also suppressed expressions of CK19 and Ki67 in DDC-fed mice, suggesting that GE could ameliorate DDC-induced hepatocytes and cholangiocytes proliferation. In addition, GE significantly increased bile acids (BAs) secretion in bile, which correlated with induced expressions of hepatic FXR, BAs secretion transporters (BSEP, MRP2, MDR1, and MDR2), and reduced CYP7A1 mRNA expression. Furthermore, higher expressions of ileal FXR-FGF15 signaling and reduced ASBT were also observed after GE treatment. Taken together, these data showed that GE could modulate inflammation, fibrosis, and BAs homeostasis in DDC-fed mice, which lead to efficiently delay the progression of sclerosing cholangitis.

Clinopodium chinense Attenuates Palmitic Acid-Induced Vascular Endothelial Inflammation and Insulin Resistance through TLR4-Mediated NF- κ B and MAPK Pathways.

Elevated palmitic acid (PA) levels are associated with the development of inflammation, insulin resistance (IR) and endothelial dysfunction. Clinopodium chinense (Benth.) O. Kuntze has been shown to lower blood glucose and attenuate high glucose-induced vascular endothelial cells injury. In the present study we investigated the effects of ethyl acetate extract of C. chinense (CCE) on PA-induced inflammation and IR in the vascular endothelium and its molecular mechanism. We found that CCE significantly inhibited PA-induced toll-like receptor 4 (TLR4) expression in human umbilical vein endothelial cells (HUVECs). Consequently, this led to the inhibition of the following downstream adapted proteins myeloid differentiation primary response gene 88, Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon- ß and TNF receptor-associated factor 6. Moreover, CCE inhibited the phosphorylation of Ikappa B kinase ß , nuclear factor kappa-B (NF- κ B), c-Jun N-terminal kinase, extracellular regulated protein kinases, p38-mitogen-activated protein kinase (MAPK) and subsequently suppressed the release of tumor necrosis factor- α , interleukin-1 ß (IL-1 ß ) and IL-6. CCE also inhibited IRS-1 serine phosphorylation and ameliorated insulin-mediated tyrosine phosphorylation of IRS-1. Moreover, CCE restored serine/threonine kinase and endothelial nitric oxide synthase (eNOS) activation and thus increased insulin-mediated nitric oxide (NO) production in PA-treated HUVECs. This led to reverse insulin mediated endothelium-dependent relaxation, eNOS phosphorylation and NO production in PA-treated rat thoracic aortas. These results suggest that CCE can significantly inhibit the inflammatory response and alleviate impaired insulin signaling in the vascular endothelium by suppressing TLR4-mediated NF- κ B and MAPK pathways. Therefore, CCE can be considered as a potential therapeutic candidate for endothelial dysfunction associated with IR and diabetes.

Mechanistic insights into geniposide regulation of bile salt export pump (BSEP) expression.

Geniposide (GE) is a major component isolated from Gardenia jasminoides Ellis, which has been used to treat cholestasis liver diseases. Our previous study has shown that GE could notably increase mRNA and protein expressions of BSEP in cholestatic rats. BSEP plays a critical role in maintenance of the enterohepatic circulation of bile acids. BSEP could be regulated by the transactivation pathway of farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor (Nrf2). Here the mechanisms for BSEP regulation by GE were investigated. GE induced the mRNA levels of BSEP in HepG2 cells and cholestatic mice, and knockdown of FXR and Nrf2 reduced the mRNA expression of BSEP at varying degrees after treatment of GE. FXR acts as the major regulator of BSEP transcription. The involvement of FXR regulated BSEP expression by GE was further investigated. An enhancement was observed in FXR-dependent BSEP promoter activation using luciferase assay. ChIP assay further confirmed the interaction between FXR and BSEP after GE treatment. Using siRNA and ChIP assays, we demonstrated that peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) and co-activator-associated arginine methyltransferase 1 (CARM1) were predominantly recruited to the BSEP promoter upon FXR activation by GE. In conclusion, GE regulated the expression of BSEP through FXR and Nrf2 signaling pathway. The FXR transactivation pathway was enhanced by increasing recruitment of coactivators PGC-1α and CARM1 upon GE treatment, coupled with an increased binding of FXR to the BSEP promoter.

The Association of Uric Acid Calculi with Obesity, Prediabetes, Type 2 Diabetes Mellitus, and Hypertension.

OBJECTIVES: To disclose the link between the composition of urolithiasis, especially that of uric acid calculi, and obesity, prediabetes, type 2 diabetes mellitus, and hypertension. MATERIALS AND METHODS: Patients who had urinary calculi and underwent surgical treatment were registered in the study. The composition of urinary calculi was analyzed and correlated with clinical features and biomedical profiles of the patients before surgical intervention. RESULTS: A total of 666 patients with urolithiasis who underwent surgical management were registered and analyzed. In those who had uric acid calculi, there was a significant association with prediabetic (OR: 20.11, 95% CI: 7.40-54.63, P < 0.001) and diabetic states (OR: 11.55, 95% CI: 4.41-29.97, P < 0.001). It also seemed that uric acid calculi were related to obesity but there was no statistical significance (OR: 2.45, 95% CI: 0.91-6.62, P = 0.078). There was no association of uric acid calculi with hypertension (OR: 1.08, 95% CI: 0.54-2.17, P = 0.822) and concurrent urinary tract infection (OR: 0.93, 95% CI: 0.44-1.96, P = 0.841). CONCLUSION: There was a remarkable association of uric acid calculi with prediabetic and diabetic states. The uric acid calculi were also seemingly associated with obesity in patients with urolithiasis undergoing surgical management.

Novel Magnetic-Luminescent Janus Nanoparticles for Cell Labeling and Tumor Photothermal Therapy.

Magnetic-luminescent nanocomposites have multiple uses including multimodal imaging, magnetic targeted drug delivery, and cancer imaging-guided therapies. In this work, dumbbell-like MnFe2 O4 -NaYF4 Janus nanoparticles are synthesized via a two-step thermolysis approach. These synthesized nanoparticles exhibit stability in aqueous solutions and very low cytotoxicity after poly(acryl amide) modification. High cellular uptake efficiency is observed for the folic acid-conjugated MnFe2 O4 -NaYF4 in human esophagus carcinoma cells (Eca-109) due to the upconversion luminescence properties as well as the folate targeting potential. The MnFe2 O4 -NaYF4 also strongly absorbs light in the near-infrared range and rapidly converts to heat energy. It is demonstrated that Eca-109 cells incubated with MnFe2 O4 -NaYF4 are killed with high efficiency after 808 nm laser irradiation. Furthermore, the growth of tumors in mice (grown from Eca-109 cells) is highly inhibited by the photothermal effects of MnFe2 O4 -NaYF4 efficiently. Histological analysis reveals no pathological change and inflammatory response in heart, liver, spleen, lung, or kidney. The low toxicity, excellent luminescence, and highly efficient photothermal therapy properties of MnFe2 O4 -NaYF4 Janus nanoparticles illustrated in this work support their vast potential for nanomedicine and cancer therapy.

Geniposide attenuates ANIT-induced cholestasis through regulation of transporters and enzymes involved in bile acids homeostasis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Geniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by α-naphthylisothiocyanate (ANIT) remain unclear. AIM OF THE STUDY: The purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats. MATERIALS AND METHODS: Sprague-Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT-induced rats. RESULTS: GE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTß (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down-regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration. CONCLUSION: GE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis.

Homoplantaginin Inhibits Palmitic Acid-induced Endothelial Cells Inflammation by Suppressing TLR4 and NLRP3 Inflammasome.

Palmitic acid (PA)-induced vascular endothelial inflammation plays a pivotal role in the occurrence and development of vascular diseases. The present study was conducted to examine the effect of homoplantaginin, a main flavonoid from a traditional Chinese medicine Salvia plebeia R. Br., on PA-treated human umbilical vein endothelial cells inflammation and the underlying molecular mechanism. Firstly, we found that homoplantaginin (0.1, 1, 10 µM) dose-dependently reduced expression of toll-like receptor-4 evoked by PA (100 µM). The inhibitory effect of homoplantaginin was further confirmed under lipopolysaccharide challenge. In addition, downstream adapted proteins including myeloid differentiation primary response gene 88, toll/interleukin-1 receptor-domain containing adaptor-inducing interferon-ß and tumor necrosis factors receptor associated factor-6 were successfully inhibited by homoplantaginin under PA treatment. Also, we found that homoplantaginin tightly controlled PA-induced reactive oxygen species to prevent nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome activation by suppressing reactive oxygen species-sensitive thioredoxin-interacting protein, NLRP3, and caspase-1. Meanwhile, protein and mRNA levels of inflammatory mediators (interleukin-1ß, intercellular cell adhesion molecule-1, and monocyte chemotactic protein-1) were decreased by homoplantaginin. Furthermore, homoplantaginin restored PA-impaired nitric oxide generation. Taken together, these results indicated that homoplantaginin protected endothelial cells from ameliorating PA-induced endothelial inflammation via suppressing toll-like receptor-4 and NLRP3 pathways, and restoring nitric oxide generation, suggesting it may be a potential candidate for further development in the prevention and treatment of vascular diseases.

Simultaneous determination of four alkaloids in mice plasma and brain by LC-MS/MS for pharmacokinetic studies after administration of Corydalis Rhizoma and Yuanhu Zhitong extracts.

A sensitive and selective liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of tetrahydropalmatine, coptisine, palmatine and dehydrocorydaline in mice plasma and brain after intraperitoneal administration of the extracts of Yuanhu Zhitong (YZ) and Corydalis Rhizoma (CR). Biological samples were processed with ethyl acetate extraction. The mobile phase consisted of acetonitrile and water (containing 10mM ammonium acetate, adjusted with acetic acid to pH 4.25) with gradient elution at a flow rate of 0.4mL/min. Detection was performed on a triple quadrupole mass spectrometer using positive ion ESI in the multiple reaction monitoring (MRM) mode. The calibration curves for all analytes had good linearity (r(2)>0.9910). The intra- and inter-day precisions (RSD) were within 13.9%, and accuracy (RE) was between -12.0% and 13.7%. This method was successfully applied to the pharmacokinetic and brain distribution study after administration of the extracts of YZ and CR. The pharmacokinetic study indicated that the AUC of plasma and brain increased, and the CL of the two matrixes decreased after administration of YZ when compared with CR (p<0.05). The four analytes could cross the blood-brain barrier in vivo and elucidate the potentials for the treatment of diseases of the central nervous system.

Comparative pharmacokinetic study of chlorogenic acid after oral administration of Lonicerae Japonicae Flos and Shuang-Huang-Lian in normal and febrile rats.

Shuang-Huang-Lian (SHL), a famous traditional Chinese medicine recipe containing Lonicerae Japonicae Flos (LJF), Forsythiae Fructus, and Scutellariae Radix, is clinically used for the treatment of fever and acute upper respiratory tract infection. In this research, a comparative study was conducted to compare the pharmacokinetic difference of chlorogenic acid (ChA) after oral administration of LJF and SHL to normal and febrile rats with approximately the same dose of 60 mg/kg, and the antipyrexia effect of LJF and SHL on rectal temperature changes induced by Baker's yeast was investigated. The results indicated that AUC(0-t) and plasma concentrations of ChA in the febrile rats were significantly higher than normal rats whether in the extract of LJF or SHL. In addition, SHL increased the values of AUC of ChA in both febrile and normal rats compared with LJF alone (p < 0.05), and SHL showed better antipyrexia effect than LJF. These results indicate that fever could play an important role in pharmacokinetic process of ChA. Meanwhile, the combined formula SHL exhibits higher bioavailability of ChA and superior antipyrexia effect than the single herb.

Reactive oxygen species are the cause of the enhanced cardiorespiratory response induced by intermittent hypoxia in conscious rats.

This study was carried out to investigate the role of reactive oxygen species (ROS) in the elevation of cardiorespiratory responses during the development of intermittent hypoxia (IH)-induced hypertension. Rats were exposed to either 30 days of IH [(30s N2)+(45 s room air (RA)] or RA for 6 h/day. After 5 days of exposure, stable mean arterial pressure, normalized low-frequency power of pulses interval spectrogram (a marker of cardiac sympathetic outflow), and minute ventilation (an index for arterial chemoreflex activation) were significantly increased throughout the observation period in IH-exposed rats, but not in RA-exposed rats. FosB expression in rostral ventrolateral medulla was elevated after IH exposure for 5 days. Intraperitoneal injection of MnTMPyP (a superoxide scavenger) or N-acetylcysteine (an antioxidant) prevented IH-induced elevation of the cardiorespiratory responses and lipid peroxidation of lung tissues. These results suggest that ROS are essential for IH-induced elevation of arterial chemoreflex activation and sympathetic outflow, which may, in turn, contribute to IH-induced hypertension.

Characterization of homoisoflavonoids in different cultivation regions of Ophiopogon japonicus and related antioxidant activity.

Homoisoflavonoids were identified in Ophiopogon japonicus of two cultivation regions in China: Hang-maidong (grown in Zhejiang province) and Chuan-maidong (grown in Sichuan province). Liquid chromatography (LC), coupled with electrospray ionization (ESI) tandem mass spectrometry (MS), was developed to analyze homoisoflavonoids in these two areas. Based on LC-MS/MS data, 24 homoisoflavonoid compounds--19 in Hang-maidong and 17 in Chuan-maidong--were identified or tentatively characterized. The homoisoflavonoids in the two regions were similar in chemical profile, but distinctive in their combination and ratio. Methylophiopogonanone A and methylophiopogonanone B were the major contributors to the total homoisoflavonoid content. Hang-maidong had a higher total homoisoflavonoid content and better DPPH (2,2-diphenyl-1-picryl-hydrazyl) radical-scavenging activity than that of Chuan-maidong. The total phenolic content showed no significant difference between the two regions. This study allows a clear chemical differentiation of Hang-maidong from Chuan-maidong.

Determination of ruscogenin in crude Chinese medicines and biological samples by immunoassay.

Ruscogenin is a major bioactive steroidal aglycone found in the Chinese medicine, Ophiopogon japonicus. We have developed a quantitative determination of ruscogenin with an indirect enzyme-linked immunosorbent (ELISA) assay using polyclonal antibodies against ruscogenin conjugated with bovine serum albumin. This assay was highly sensitive, and it had considerably less cross-reactivity to diosgenin and sarsasapogenin, but high cross-reactivity to ruscogenin glycosides. The assay was successfully used for the measurement of ruscogenin concentrations in crude Chinese medicines and in biological samples from a pharmacokinetics study of ruscogenin.

Adsorption of a polymeric siloxane surfactant on carbon black particles dispersed in mixtures of water with polar organic solvents.

The adsorption of a rake-type polymeric siloxane surfactant (polydimethylsiloxane-graft-polyether copolymer) on carbon black (CB) particles dispersed in mixtures of water with polar organic solvents (ethanol, formamide, or glycerol) has been investigated. The adsorption obeys the Langmuir isotherm at low surfactant concentrations (below the critical micelle concentration, CMC). At these conditions, the average surface area occupied by one siloxane surfactant follows the sequence water+glycerol mixture >plain water >water+ethanol mixture. At higher surfactant concentrations in the solution in contact with the particles, a sharp increase in the adsorbed amount is observed. The adsorbed layer thickness has been determined by dynamic light scattering. Below the CMC the adsorbed layer thickness is less than 10 nm. Above the CMC, the adsorbed layer thickness increases to 20-30 nm, a length scale comparable to the diameter of the siloxane surfactant micelles in aqueous solution. This fact, together with SANS data that we have obtained in the absence of added polar organic solvent, indicates that the structure of the adsorbed layer is similar to that of micelles. The findings presented here are relevant to waterborne coatings and ink formulations, where polymeric surfactants are used in conjunction with polar organic solvents.