BACKGROUND Background diabetic nephropathy(DN),a major complication of diabetes,is linked to gut microbiota dysbiosis.Elevated trimethylamine N-oxide(TMAO),a microbiota-derived metabolite,plays a central role in induc...BACKGROUND Background diabetic nephropathy(DN),a major complication of diabetes,is linked to gut microbiota dysbiosis.Elevated trimethylamine N-oxide(TMAO),a microbiota-derived metabolite,plays a central role in inducing renal injury during DN pathogenesis.AIM To investigate the role of TMAO in renal dysfunction and intestinal microbiota alterations associated with DN,hypothesizing that TMAO exacerbates renal injury and fibrosis through gut microbiota-dependent mechanisms.METHODS A DN model was successfully established using Zucker diabetic fatty(ZDF)rats.Blood samples were analyzed for renal function parameters,and serum TMAO levels were quantified via high-performance liquid chromatography-tandem mass spectrometry.Renal tissue morphology and fibrosis were assessed using hematoxylin and eosin and Masson staining,respectively.Additionally,16S rRNA sequencing was employed to profile fecal bacterial communities in rats with diabetes and DN.Fecal microbiota transplantation was conducted to verify alterations in TMAO production capacity in the gut microbiota of DN rats.RESULTS After 8 weeks of modeling,the ZDF rat model group exhibited blood glucose levels surpassing 16.7 mmol/L,and compared to the control group,renal function indicators,includingβ2-microglobulin,cystatin C,uric acid,and creatinine,were significantly elevated(P<0.05).Renal fibrosis was more pronounced in the ZDF model group,accompanied by heightened P-smad3 expression,in contrast to the TMAO inhibition group.Although Masson staining results did not reach statistical significance(P>0.05),notable alterations in intestinal flora structure were observed in DN rats,and fecal microbiota transplantation led to increased TMAO production within the intestinal flora of DN rats compared to controls(P>0.05).CONCLUSION DN is associated with gut microbiota alterations that potentiate TMAO generation,contributing to renal injury and fibrotic progression.While TMAO’s role in fibrosis warrants further validation,these findings implicate the gutkidney axis in DN pathogenesis.展开更多
BACKGROUND Diabetic nephropathy(DN)is one of the most serious microvascular complications of type 2 diabetes mellitus(T2DM),and its incidence increases with the global rise in diabetes prevalence.It is the leading cau...BACKGROUND Diabetic nephropathy(DN)is one of the most serious microvascular complications of type 2 diabetes mellitus(T2DM),and its incidence increases with the global rise in diabetes prevalence.It is the leading cause of chronic kidney disease and end-stage kidney disease.Patients with DN often experience complex metabolic disorders and chronic inflammatory states,which not only accelerate the decline of renal function but are also closely related to complications such as cardiovascular events and osteoporosis(OP),seriously compromising quality of life.With the in-depth research on the gut microbiota and the emergence of concepts such as the"gut-kidney axis"and the"enteric-bone axis",the key roles of the gut microbiota and its metabolites in metabolic disorders,inflammatory responses,and target organ damage have been increasingly recognized.However,the specific role of gut microbiota in the pathogenesis of DN remains to be further explored.The results obtained may provide evidence to better understand the pathogenesis of DN and to identify high-risk populations at an early stage.This research direction is of strategic significance.AIM To assess the correlation of the gut microbiota metabolite trimethylamine N-oxide(TMAO)with inflammatory marker levels and OP in patients with DN.METHODS A total of 115 patients diagnosed with type 2 DN and treated at the Department of Endocrinology,Second Affiliated Hospital of Shandong First Medical University from August 2022 to December 2024 were enrolled in the DN group,and 115 patients with T2DM without nephropathy were included in the T2DM group.The two groups were compared in terms of gastrointestinal microbiota abundance and relative abundance at the genus level;levels of TMAO,inflammatory markers[including C-reactive protein(CRP),interleukin-6(IL-6),interleukin-8(IL-8),and tumor necrosis factor-α(TNF-α)],and bone metabolism markers[including procollagen type I N-terminal propeptide(PINP),β-CrossLaps(β-CTX),and alkaline phosphatase(ALP)];and lumbar spine and hip bone mineral density(BMD).The correlation of TMAO level with inflammatory factor and bone metabolism indicator levels was further analyzed.RESULTS The DN group had higher Chao1 and Simpson indices of gastrointestinal microbiota diversity than the T2DM group,whereas the ACE and Shannon indices were lower(P<0.05).The relative abundance of Firmicutes was higher,and the relative abundances of Bacteroidetes,Proteobacteria,and Actinobacteria were lower in the DN group than in the T2DM group(P<0.05).CRP,IL-6,IL-8,TNF-α,and TMAO levels were considerably elevated in the DN group compared to the T2DM group(P<0.05).Moreover,the DN group had higher levels of bone turnover markers-including PINP,β-CTX,and ALP-but lower lumbar spine and hip BMDs than the T2DM group(P<0.05).TMAO level positively correlated with the Chao1 and Simpson indices and negatively correlated with the ACE and Shannon indices of gut microbiota diversity.TMAO level also negatively correlated with the relative abundances of Bacteroidetes,Proteobacteria,and Actinobacteria and positively correlated with the abundance of Firmicutes.Additionally,TMAO level positively correlated with the inflammatory markers CRP,IL-6,IL-8,and TNF-α,as well as with the bone turnover markers PINP,β-CTX,and ALP.It negatively correlated with lumbar spine and hip BMDs(P<0.05).CONCLUSION Inflammatory and bone metabolic levels in patients with DN were found to be associated with the gut microbiota–derived metabolite TMAO.Elevated TMAO levels may mediate inflammatory responses and bone metabolism disorders in patients with DN,thereby contributing to the progression of systemic inflammation and OP.展开更多
An ishemic ventricular tachyarrhythmias canine model was established in open-chest dogs subjected to programmed electrical stimulation (PES)for 5-8 days after acute myocardial infarction. The electrophysiologic effect...An ishemic ventricular tachyarrhythmias canine model was established in open-chest dogs subjected to programmed electrical stimulation (PES)for 5-8 days after acute myocardial infarction. The electrophysiologic effects of neferine (Nef) and procainamide (PA) were observed in this model. With routine methods of PES,ventricular tachycardia (VT)and ventricular fibrillation (VF) could be reproducibly initiated. Both drugs lengthened the QTc interval (P【0.01) and effective refractory period(ERP)of normal and ischemic ventricular myocardia (NERP and IERP) respectively (P【0.01), decreased the dispersion of ERP in ischemic myocardium and the dispersion of ERP in left ventricle (P【0.01), and increased the diastolic excitability threshold of normal and ischemic ventricular myocardia (P【0.01). The two compounds prevented the PES-induced VT or VF (Nef group P【0.01, PA group P【0.05) and ischemia-induced VF (P【0.05). The results indicated that neferine and procainamide may be effective in preventing the onset of reentrant ventricular tachyarrhythmias after myocardial ischemic damage in dogs.展开更多
Based on the parent tetrazole 2N-oxide, six series of novel carbon-linked ditetrazole 2N- oxides with different energetic substituent groups （-NH2, -Na, -NO2, NF2, -NHNO2） and energetic bridge groups （-CH2-, -CH2-C...Based on the parent tetrazole 2N-oxide, six series of novel carbon-linked ditetrazole 2N- oxides with different energetic substituent groups （-NH2, -Na, -NO2, NF2, -NHNO2） and energetic bridge groups （-CH2-, -CH2-CH2-, -NH-, -N=N-, -NH-NH-） were designed. The overall performance and the effects of different energetic substituent groups and energetic bridge groups on the performance were investigated by density functional theory and electrostatic potential methods. The results showed that most of designed compounds have oxygen balance around zero, high heats of formation, high density, high energy, and acceptable sensitivity, indicating that tetrazole N-oxide is a useful parent energetic compound employed for obtaining high energy compounds, even only combined with some very common energetic substituent groups and bridge groups. Comprehensively considering the effects on energy and sensitivity, the -NO2, -NF2, -NH- and-NH-NH- are appropriate substituent groups for combining tetrozale N-oxide to design new energetic compounds, while -NH2, -Na, -CH2-CH2-, and -N=N- are inappropriate.展开更多
Objective: To study the reversal effect of neferine on adriamycin (ADM) resistant human breast cancer cell line MCF-7/ADM. Methods: The cytotoxic effect of Nef or ADM was determined by 3-[4, 5-dimethylthiazol-2.-yl], ...Objective: To study the reversal effect of neferine on adriamycin (ADM) resistant human breast cancer cell line MCF-7/ADM. Methods: The cytotoxic effect of Nef or ADM was determined by 3-[4, 5-dimethylthiazol-2.-yl], 5-diphenyl tetraxolium bromid (MTT) assay. Apoptosis and the expression of P-glycoprotein (P-gp) were detected by flow cytometry (FCM). The intracellular ADM concentration was measured by HPLC. Results: Nef at 1, 5, 10 mol/L decreased the IC50 of ADM to MCF-7/ADM from 11.63 g/mL to 4.59, 2.44, 0.27 g/mL respectively. MCF-7/ADM could resist the apoptosis induced by ADM while Nef (1-10 mol/L) could augment ADR-mediated apoptosis. Nef (10 mol/L) increased the accumulation of ADM up to 2.88 fold in MCF-7/ADM but not in sensitive cells MCF-7/S and reduced the expression of P-gp in MCF-7/ADM cells. Conclusion: Nef can circumvent multidrug resistance (MDR) of MCF-7/ADM cells and the mechanism was associated with the increase of intracellular accumulation of ADM and the reduced expression of P-gp in MCF-7/ADM cells.展开更多
Doxorubicin is one of the anthracycline anti-neoplastic drugs widely used to treat leukemia, liver, breast, and ovarian cancers and other solid tumors. However, its clinical applications have been limited by its serio...Doxorubicin is one of the anthracycline anti-neoplastic drugs widely used to treat leukemia, liver, breast, and ovarian cancers and other solid tumors. However, its clinical applications have been limited by its serious cardio-cytotoxic effects. The aim of this study was to investigate the effect of neferine, a bisbenzylisoquinoline alkaloid extracted from the green embryo in the mature lotus seed, on the pharmacokinetics of doxorubicin. The levels of doxorubicin in plasma and tissues were measured using the high performance liquid chromatography（HPLC） method. The chromatographic separation was completed on a reversed-phase C18 column using acetonitrile–phosphate buffer（30：70, v/v） as the mobile phase at a flow rate of 1 mL /min and ultraviolet detection wave length was set at 233 nm. The pharmacokinetic study found that the co-administration of neferine and doxorubicin significantly affected the pharmacokinetics of doxorubicin. There were evident changes in area under the curve（AUC）, clearance（CL） and t1/2β in group of pretreatment neferine as compared with those in group treated with doxorubicin alone. Tissue distribution analysis showed that the concentrations of doxorubicin distributed to heart, liver and kidney were statistically significant higher in group of pretreatment with neferine plus doxorubicin than those in the doxorubicin alone-group at 0.5 h and 2 h after drug administration, respectively. While the doxorubicin concentrations in spleen and lung drug were slightly increased in the group of pretreatment with neferine plus doxorubicin as compared to that of group of doxorubicin alone, the difference between two groups were not statistically significant. Therefore, the dose of doxorubicin needs to be taken into consideration when it is administrated in combination with neferine.展开更多
Multidrug resistance（MDR） plays a major obstacle to successful gastric cancer chemotherapy.The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with nefe...Multidrug resistance（MDR） plays a major obstacle to successful gastric cancer chemotherapy.The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine（Nef） in adriamycin（ADM） resistant human SGC7901/ADM gastric cancer cells.The MDR cells were heated at 42℃ and 45℃ for 30 min alone or combined with 10 μg/mL Nef.The cytotoxic effect of ADM was evaluated by MTT assay.Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique.Intracellular accumulation of ADM was monitored with high performance liquid chromatography.Mdr-1 mRNA,P-glycoprotein（P-gp）,γH2AX expression and γH2AX foci formation were determined by real-time PCR,Western blot and immunocytochemical staining respectively.It was found that different heating methods induced different cytotoxic effects.Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells.The water submerged hyperthermia increased the cell membrane fluidity.Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM.The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp.The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells.The higher temperature was,the worse effect was.Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells.展开更多
Aim： To further investigate the relaxation mechanism of neferine （NED, a bis-benzylisoquinoline alkaloid extracted （isolated） from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavern...Aim： To further investigate the relaxation mechanism of neferine （NED, a bis-benzylisoquinoline alkaloid extracted （isolated） from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavernosum tissue in vitro. Methods： The effects of Nef on the concentrations of cyclic adenosine monophosphate （cAMP） and cyclic guanosine monophosphate （cGMP） in isolated and incubated rabbit corpus cavernosum tissue were recorded using ^125I radioimmunoassay. Results： The basal concentration of cAMP in corpus cavernosum tissue was 5.67 ± 0.97 pmol/mg. Nef increased the cAMP concentration in a dose-dependent manner （P 〈 0.05）, but this effect was not inhibited by an adenylate cyclase inhibitor （cis-N-[2-phenylcyclopentyl]azacyclotridec-1-en-2-amine, MDL-12, 330A） （P 〉 0.05）. The accumulation of cAMP induced by prostaglandin Et （PGEt, a stimulator of cAMP production） was also augmented by Nef in a dose-dependent manner （P 〈 0.05）. The basal concentration of cGMP in corpus cavernosum tissue is 0.44 ± 0.09 pmol/mg. Nef did not affect this concentration of cGMP, either in the presence or in the absence of a guanyl cyclase inhibitor （1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ） （P 〉 0.05）. Also, sodium nitroprusside （SNP, a stimulator of cGMP production）-induced cGMP production was not enhanced by Nef （P 〉 0.05）. Conclusion： Nef, with its relaxation mechanism, can enhance the concentration of cAMP in rabbit corpus cavernosum tissue, probably by inhibiting phosphodiesterase activity. （Asian JAndro12008 Mar; 10： 307-312）展开更多
BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the p...BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.展开更多
Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch-clamp technique, we investigated the effects of nefer...Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch-clamp technique, we investigated the effects of neferine on Nav1.5 channels that are stably expressed in HEK 293 cells. We found that neferine potently and reversibly inhibited Nav1.5 currents in a concentration dependent manner with a half-maximal inhibition（IC50） being 26.15 μmol/L. The inhibitory effects of neferine on Nav1.5 currents were weaker than those of quinidine at the same concentration. The steady-state inactivation curve was significantly shifted towards hyperpolarizing direction in the presence of 30 μmol/L neferine, while the voltage-dependent activation was unaltered. Neferine prolonged the time to peak of activation, increased the inactivation time constants of Nav1.5 currents and markedly slowed the recovery from inactivation. The inhibitory effect of neferine could be potentiated in a frequency-dependent manner. These results suggested that neferine can block Nav1.5 channels under the open state and inactivating state and it is an open channel blocker of Nav1.5 channels.展开更多
An eco-friendly protocol for the synthesis of various 2-sulfonyl quinolines/pyridines through sulfonylation of heteroaromatic N-oxides with sodium sulfinates in water at ambient temperature under metal-and oxidant-fre...An eco-friendly protocol for the synthesis of various 2-sulfonyl quinolines/pyridines through sulfonylation of heteroaromatic N-oxides with sodium sulfinates in water at ambient temperature under metal-and oxidant-free conditions has been developed.The mild reaction conditions,high reaction efficiency,operational simplicity,short reaction time and remarkable functional-group compatibility make the developed protocol very attractive for the preparation of 2-sulfonyl N-heteroaromatic compounds.展开更多
Oxidatively modified low density lipoprtein (LDL) plays an important role in atheroslerosis (AS) development. To investigate the role of neferine (Nef) in anti-LDL oxidation and foam cell formation, the lipoprotein wa...Oxidatively modified low density lipoprtein (LDL) plays an important role in atheroslerosis (AS) development. To investigate the role of neferine (Nef) in anti-LDL oxidation and foam cell formation, the lipoprotein was derived and subjected to three different treatments: N-LDL (normal LDL), Cu(2+) +LDL and Cu(2+)+Nef+LDL. The LDLs were put at 25℃ for 24 h and the thiobarbituric acid reactive substance (TBARS) values were determined. They were 0. 57 ±0. 02, 6.01±0. 22 and 2. 26±0. 13 nmol/mg protein, respectively. The difference was very significant (P<0.01) for each two groups by t test. Mouse peritoneal macrophage (MΦ) were exposed to 50 μg protein/ml of Cu(2+) + LDL and Cu(2+)+Nef+LDL at 37℃ for 60 h. The tryglyceride (TG) and total cholesterol (TC) content in Mad were assayed. The results showed that Cu(2+) + LDL was more efficient than Cu(2+)+Nef+LDL in stimulating lipid accumulation in MΦ(P <0. 001). The study demonstrated that Nef could inhibit Cu(2+)-mediated LDL oxidation and thereby inhibiting macrophage-derived foam cell formation.展开更多
OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.S...OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.Serum creatinine(Crea),blood urea(UREA)and urinary albumin were measured in mice by kits,and renal histopathological changes and fibrosis were observed by hematoxylin-eosin staining and Masson staining.Renal tissue superoxide dismutase(SOD),malondialdehyde(MDA)and glutathione peroxidase(GSH-Px)activities were measured by enzyme-linked immunosorbent assay(ELISA).Western blotting was used to detect the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)signaling pathway-related proteins in kidney tissues.Quantitative reverse transcription-polymerase chain reaction(q RT-PCR)was used to detect the expression of miR-17-5p in kidney tissues.Subsequently,a DN in vitro model was constructed by high glucose culture of human mesangial cells(HMCs),cells were transfected with miR-17-5p mimic and/or treated with Nef,and we used q RTPCR to detect cellular miR-17 expression,flow cytometry to detect apoptosis,ELISAs to detect cellular SOD,MDA,and GSH-Px activities,Western blots to detect Nrf2/HO-1 signaling pathway-related protein expression,and dual luciferase reporter gene assays to verify the targeting relationship between Nrf2 and miR-17-5p.RESULTS:Administration of Nef significantly reduced the levels of blood glucose,Crea,and UREA and the expression of miR-17-5p,improved renal histopathology and fibrosis,significantly reduced MDA levels,elevated SOD and GSH-Px activities,and activated Nrf2 expression in kidney tissues from mice with DN.Nrf2 is a post-transcriptional target of miR-17-5p.In HMCs transfected with miR-17-5p mimics,the m RNA and protein levels of Nrf2 were significantly suppressed.Furthermore,miR-17-5p overexpression and Nef intervention resulted in a significant increase in high glucose-induced apoptosis and MDA levels in HMCs and a significant decrease in the protein expression of HO-1 and Nrf2.CONCLUSION:Collectively,these results indicate that Nef has an ameliorative effect on DN,and the mechanism may be through the miR-17-5p/Nrf2 pathway.展开更多
AIM: The application of strychnine(S) is limited due to its toxicity; strychnine N-oxide(SNO) is a derivative of strychnine. The aim was to employ zebrafish embryos to investigate and compare the developmental toxicit...AIM: The application of strychnine(S) is limited due to its toxicity; strychnine N-oxide(SNO) is a derivative of strychnine. The aim was to employ zebrafish embryos to investigate and compare the developmental toxicity induced by S and SNO. METHODS: The toxicity of S and SNO was examined through the hatching rate and survival rate. Morphological changes of the zebrafish were observed with a dissecting microscope. Apoptosis was detected through acridine orange(AO) staining and flow cytometry. Apoptotic genes were measured by RT-PCR. RESULTS: Embryo malformation was observed in the embryos exposed to S at 200 μmol·L–1. When SNO concentration was increased to 1 mmol·L–1, scoliolosis, and pericardial edema could be seen in some embryos. Results from fluorescence microscopy and flow cytometry analysis showed that S at 200 μmol·L–1 induced apoptosis, whereas the apoptotic rate in the SNO-treated group(200 μmol·L–1) was much lower than that in the S group. RT-PCR analysis showed that p53 mRNA expression and the ratio of Bax/Bcl-2 in the S group were significantly altered compared with the control group(*P < 0.05). Moreover, Bax mRNA expression in both S and SNO group were significantly different from that in the control group(**P <0.01). CONCLUSION: These results lead to the conclusion that SNO has significantly lower toxicity than S in zebrafish embryos.展开更多
The title zinc（Ⅱ） complex salt [Zn（H2O）6]（ClO4）2-（PNOS）4, where PNOS is derived from picolinaldehyde N-oxide with semicarbazone, has been prepared and structurally characterized by X-ray single-crystal analys...The title zinc（Ⅱ） complex salt [Zn（H2O）6]（ClO4）2-（PNOS）4, where PNOS is derived from picolinaldehyde N-oxide with semicarbazone, has been prepared and structurally characterized by X-ray single-crystal analysis. It crystallizes in triclinic, space group PI with a = 7.529（3）, b = 10.206（4）, c = 14.678（6）A, a = 86.293（6）, β= 87.686（7）, γ= 81.382（6）°, C28H44Cl2N16O22Zn, Mr = 1093.06, V = 1112.3（8） ,A^3 Z = 1, Dc = 1.632 g/cm^3, S = 1.089, μ（MoKa） = 0.773 mm^-1, F（000） = 564, the final R = 0.0438 and wR = 0.1076 for 3888 independent reflections with Rint = 0.0224. The crystal structure possesses a [Zn（H2O）6]^2＋ cation, two ClO4^- anions and four PNOSs. In the crystal structure, Zn^2＋ cation is located at the symcenter and coordinated by six water molecules. In [Zn（H2O）6]^2＋, an elongate octahedral complex cation, the average Zn-O bond length is 2.087（2） A. There exist a lot of H bonds in the structure, linking the cation [Zn（H2O）6]^2＋, anion ClO4^- and PNOS to form a 3D network.展开更多
AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biolog...AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells(HRMEC)under high glucose conditions was tested by a cell counting kit,wound healing,a transwell and a tube formation assay.The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction(RT-PCR).The expression of the cell junction was measured by Western blotting(WB)and immunofluorescence staining.In addition,two groups of rat models,diabetic and non-diabetic,were fed with normal or 0.1%TMAO for 16wk,and their plasma levels of TMAO,vascular endothelial growth factor(VEGF),interleukin(IL)-6 and tumor necrosis factor(TNF)-αwere tested.The vascular permeability of rat retinas was measured using FITC-Dextran,and the expression of zonula occludens(ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining.RESULTS:TMAO administration significantly increased the cell proliferation,migration,and tube formation of primary HRMEC either in normal or high-glucose conditions.RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation,while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment.Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage,which were even higher in TMAO-feeding diabetic rats.Furthermore,TMAO administration increased the rat plasma levels of VEGF,IL-6 and TNF-αwhile decreasing the retinal expression levels of ZO-1 and claudin-5.CONCLUSION:TMAO enhances the proliferation,migration,and tube formation of HRMEC,as well as destroys their vascular integrity and tight connection.It also regulates the expression of VEGF,IL-6,and TNF-α.展开更多
A new complex [Cd（H2biim）2（H2O）2]·（ino）2·4H2O （H2biim = 2,2＇-biimidazole, ino = isonicotinate-N-oxide） has been prepared and characterized by single-crystal X-ray diffraction analysis, IR and fluore...A new complex [Cd（H2biim）2（H2O）2]·（ino）2·4H2O （H2biim = 2,2＇-biimidazole, ino = isonicotinate-N-oxide） has been prepared and characterized by single-crystal X-ray diffraction analysis, IR and fluorescence spectra analysis. The crystal is of triclinic system, space group P1 with a = 7.5380（6）, b = 8.0402（7）, c = 13.5094（11） , α = 104.269（1）, β = 93.604（1）, γ = 98.349（1）°, V = 780.93（11） 3, Mr = 765.00, Dc = 1.627 g/cm3, F（000） = 390, μ = 0.776 mm-1 and Z = 1. The final R = 0.0322 and wR = 0.0825 for 7038 observed reflections with I 2σ（I） and R = 0.0341 and wR = 0.0832 for all data. The title complex exhibits an infinite chain-like structure through bridging isonicotinate-N-oxide. Strong interchain hydrogen bonds between isonicotinate-N-oxide and H2biim result in the robust 3-D supramolecular architecture. Moreover, the complex shows strong photoluminescence with emission maximum at λ = 401 nm upon λex = 330 nm.展开更多
We report a practical and highly efficient protocol for the arylation of pyridine N-oxides with arylboronic acid through palladium-catalyzed Suzuki reaction in water.This ligand-free Suzuki reaction is performed in th...We report a practical and highly efficient protocol for the arylation of pyridine N-oxides with arylboronic acid through palladium-catalyzed Suzuki reaction in water.This ligand-free Suzuki reaction is performed in the presence of diisopropylamine and gives 2-or 3-arylated pyridyl N-oxide derivatives in good to excellent yields within 1 h.展开更多
Sophoridine N-oxide was synthesized and characterized by 1H-NMR,EI-MS,IR and elemental analysis,together with X-ray single-crystal diffraction analysis,and its crystal structure was reported for the first time.The cry...Sophoridine N-oxide was synthesized and characterized by 1H-NMR,EI-MS,IR and elemental analysis,together with X-ray single-crystal diffraction analysis,and its crystal structure was reported for the first time.The crystal belongs to the orthorhombic system,space group P212121 with a = 8.321（2）,b = 15.650（3）,c = 24.352（5） ,V = 3171.1（11） 3,Z = 8,Dc = 1.258 g/cm3,λ（CuKα） = 1.54178,F（000） = 1440,the final R = 0.0351 and wR = 0.0970.The crystal structure shows Sophoridine N-oxide crystallizes with two host molecules of similar conformation and four water solvent molecules in the asymmetric unit.In the crystal structure,intermolecular O-H…O hydrogen bonds link the constituent molecules into a 2D layer structure,which further extends to a 3D supramolecular architecture via Van der Waals interactions and intermolecular O-H…O hydrogen bonds.展开更多
The complex Mn(apo)6Cl2 (apo=2-aminopyridine N-oxide) was obtained by the reaction of MnCl2(4H2O with apo(HCl and NaOH in ethanol. A single-crystal X-ray study shows that the complex is mononuclear with octahedral coo...The complex Mn(apo)6Cl2 (apo=2-aminopyridine N-oxide) was obtained by the reaction of MnCl2(4H2O with apo(HCl and NaOH in ethanol. A single-crystal X-ray study shows that the complex is mononuclear with octahedral coordination environment (MnC30H36N12O6Cl2). The oxygen atoms from apo ligands coordinate to the manganese atom forming Mn(apo)6Cl2. The compound Mn(apo)6Cl2 is hexagonally symmetric with space group R3, lattice constants: a = 12.010(2), b = 12.010(2), c = 20.232(4) ?, ( = 120(, V= 2527.4(7) ?3, Z=3, Mr =786.55, Dc=1.550 g/cm3, (= 0.614mm-1, F(000) = 1221, R = 0.0541, Rw = 0.0580 for 1229 reflections with I>2((I). The distances between Mn(II) and O atoms are in the range from 2.171(5) to 2.184(5) ?, and the distance between the chlorine anion and N atom of amido group is 3.3 ?. The dihedral angle between two adjacent pyridine ring planes is 59.19 (0.17)°.展开更多
基金Supported by the Chinese People’s Liberation Army,No.2021yxky056.
文摘BACKGROUND Background diabetic nephropathy(DN),a major complication of diabetes,is linked to gut microbiota dysbiosis.Elevated trimethylamine N-oxide(TMAO),a microbiota-derived metabolite,plays a central role in inducing renal injury during DN pathogenesis.AIM To investigate the role of TMAO in renal dysfunction and intestinal microbiota alterations associated with DN,hypothesizing that TMAO exacerbates renal injury and fibrosis through gut microbiota-dependent mechanisms.METHODS A DN model was successfully established using Zucker diabetic fatty(ZDF)rats.Blood samples were analyzed for renal function parameters,and serum TMAO levels were quantified via high-performance liquid chromatography-tandem mass spectrometry.Renal tissue morphology and fibrosis were assessed using hematoxylin and eosin and Masson staining,respectively.Additionally,16S rRNA sequencing was employed to profile fecal bacterial communities in rats with diabetes and DN.Fecal microbiota transplantation was conducted to verify alterations in TMAO production capacity in the gut microbiota of DN rats.RESULTS After 8 weeks of modeling,the ZDF rat model group exhibited blood glucose levels surpassing 16.7 mmol/L,and compared to the control group,renal function indicators,includingβ2-microglobulin,cystatin C,uric acid,and creatinine,were significantly elevated(P<0.05).Renal fibrosis was more pronounced in the ZDF model group,accompanied by heightened P-smad3 expression,in contrast to the TMAO inhibition group.Although Masson staining results did not reach statistical significance(P>0.05),notable alterations in intestinal flora structure were observed in DN rats,and fecal microbiota transplantation led to increased TMAO production within the intestinal flora of DN rats compared to controls(P>0.05).CONCLUSION DN is associated with gut microbiota alterations that potentiate TMAO generation,contributing to renal injury and fibrotic progression.While TMAO’s role in fibrosis warrants further validation,these findings implicate the gutkidney axis in DN pathogenesis.
文摘BACKGROUND Diabetic nephropathy(DN)is one of the most serious microvascular complications of type 2 diabetes mellitus(T2DM),and its incidence increases with the global rise in diabetes prevalence.It is the leading cause of chronic kidney disease and end-stage kidney disease.Patients with DN often experience complex metabolic disorders and chronic inflammatory states,which not only accelerate the decline of renal function but are also closely related to complications such as cardiovascular events and osteoporosis(OP),seriously compromising quality of life.With the in-depth research on the gut microbiota and the emergence of concepts such as the"gut-kidney axis"and the"enteric-bone axis",the key roles of the gut microbiota and its metabolites in metabolic disorders,inflammatory responses,and target organ damage have been increasingly recognized.However,the specific role of gut microbiota in the pathogenesis of DN remains to be further explored.The results obtained may provide evidence to better understand the pathogenesis of DN and to identify high-risk populations at an early stage.This research direction is of strategic significance.AIM To assess the correlation of the gut microbiota metabolite trimethylamine N-oxide(TMAO)with inflammatory marker levels and OP in patients with DN.METHODS A total of 115 patients diagnosed with type 2 DN and treated at the Department of Endocrinology,Second Affiliated Hospital of Shandong First Medical University from August 2022 to December 2024 were enrolled in the DN group,and 115 patients with T2DM without nephropathy were included in the T2DM group.The two groups were compared in terms of gastrointestinal microbiota abundance and relative abundance at the genus level;levels of TMAO,inflammatory markers[including C-reactive protein(CRP),interleukin-6(IL-6),interleukin-8(IL-8),and tumor necrosis factor-α(TNF-α)],and bone metabolism markers[including procollagen type I N-terminal propeptide(PINP),β-CrossLaps(β-CTX),and alkaline phosphatase(ALP)];and lumbar spine and hip bone mineral density(BMD).The correlation of TMAO level with inflammatory factor and bone metabolism indicator levels was further analyzed.RESULTS The DN group had higher Chao1 and Simpson indices of gastrointestinal microbiota diversity than the T2DM group,whereas the ACE and Shannon indices were lower(P<0.05).The relative abundance of Firmicutes was higher,and the relative abundances of Bacteroidetes,Proteobacteria,and Actinobacteria were lower in the DN group than in the T2DM group(P<0.05).CRP,IL-6,IL-8,TNF-α,and TMAO levels were considerably elevated in the DN group compared to the T2DM group(P<0.05).Moreover,the DN group had higher levels of bone turnover markers-including PINP,β-CTX,and ALP-but lower lumbar spine and hip BMDs than the T2DM group(P<0.05).TMAO level positively correlated with the Chao1 and Simpson indices and negatively correlated with the ACE and Shannon indices of gut microbiota diversity.TMAO level also negatively correlated with the relative abundances of Bacteroidetes,Proteobacteria,and Actinobacteria and positively correlated with the abundance of Firmicutes.Additionally,TMAO level positively correlated with the inflammatory markers CRP,IL-6,IL-8,and TNF-α,as well as with the bone turnover markers PINP,β-CTX,and ALP.It negatively correlated with lumbar spine and hip BMDs(P<0.05).CONCLUSION Inflammatory and bone metabolic levels in patients with DN were found to be associated with the gut microbiota–derived metabolite TMAO.Elevated TMAO levels may mediate inflammatory responses and bone metabolism disorders in patients with DN,thereby contributing to the progression of systemic inflammation and OP.
文摘An ishemic ventricular tachyarrhythmias canine model was established in open-chest dogs subjected to programmed electrical stimulation (PES)for 5-8 days after acute myocardial infarction. The electrophysiologic effects of neferine (Nef) and procainamide (PA) were observed in this model. With routine methods of PES,ventricular tachycardia (VT)and ventricular fibrillation (VF) could be reproducibly initiated. Both drugs lengthened the QTc interval (P【0.01) and effective refractory period(ERP)of normal and ischemic ventricular myocardia (NERP and IERP) respectively (P【0.01), decreased the dispersion of ERP in ischemic myocardium and the dispersion of ERP in left ventricle (P【0.01), and increased the diastolic excitability threshold of normal and ischemic ventricular myocardia (P【0.01). The two compounds prevented the PES-induced VT or VF (Nef group P【0.01, PA group P【0.05) and ischemia-induced VF (P【0.05). The results indicated that neferine and procainamide may be effective in preventing the onset of reentrant ventricular tachyarrhythmias after myocardial ischemic damage in dogs.
基金This work was supported by the Natural Science Foundation of Nanjing Institute of Technology （YKJ201507, CKJA201603） and the Youth Natural Sci- ence Foundation of Jiangsu Province （BK20160774）, and Outstanding Scientific and Technological Innovation Team in Colleges and Universities of Jiangsu Province.
文摘Based on the parent tetrazole 2N-oxide, six series of novel carbon-linked ditetrazole 2N- oxides with different energetic substituent groups （-NH2, -Na, -NO2, NF2, -NHNO2） and energetic bridge groups （-CH2-, -CH2-CH2-, -NH-, -N=N-, -NH-NH-） were designed. The overall performance and the effects of different energetic substituent groups and energetic bridge groups on the performance were investigated by density functional theory and electrostatic potential methods. The results showed that most of designed compounds have oxygen balance around zero, high heats of formation, high density, high energy, and acceptable sensitivity, indicating that tetrazole N-oxide is a useful parent energetic compound employed for obtaining high energy compounds, even only combined with some very common energetic substituent groups and bridge groups. Comprehensively considering the effects on energy and sensitivity, the -NO2, -NF2, -NH- and-NH-NH- are appropriate substituent groups for combining tetrozale N-oxide to design new energetic compounds, while -NH2, -Na, -CH2-CH2-, and -N=N- are inappropriate.
文摘Objective: To study the reversal effect of neferine on adriamycin (ADM) resistant human breast cancer cell line MCF-7/ADM. Methods: The cytotoxic effect of Nef or ADM was determined by 3-[4, 5-dimethylthiazol-2.-yl], 5-diphenyl tetraxolium bromid (MTT) assay. Apoptosis and the expression of P-glycoprotein (P-gp) were detected by flow cytometry (FCM). The intracellular ADM concentration was measured by HPLC. Results: Nef at 1, 5, 10 mol/L decreased the IC50 of ADM to MCF-7/ADM from 11.63 g/mL to 4.59, 2.44, 0.27 g/mL respectively. MCF-7/ADM could resist the apoptosis induced by ADM while Nef (1-10 mol/L) could augment ADR-mediated apoptosis. Nef (10 mol/L) increased the accumulation of ADM up to 2.88 fold in MCF-7/ADM but not in sensitive cells MCF-7/S and reduced the expression of P-gp in MCF-7/ADM cells. Conclusion: Nef can circumvent multidrug resistance (MDR) of MCF-7/ADM cells and the mechanism was associated with the increase of intracellular accumulation of ADM and the reduced expression of P-gp in MCF-7/ADM cells.
基金The Scientific Research Fund Project of Heilongjiang University of Chinese Medicine(Grant No.201420)
文摘Doxorubicin is one of the anthracycline anti-neoplastic drugs widely used to treat leukemia, liver, breast, and ovarian cancers and other solid tumors. However, its clinical applications have been limited by its serious cardio-cytotoxic effects. The aim of this study was to investigate the effect of neferine, a bisbenzylisoquinoline alkaloid extracted from the green embryo in the mature lotus seed, on the pharmacokinetics of doxorubicin. The levels of doxorubicin in plasma and tissues were measured using the high performance liquid chromatography（HPLC） method. The chromatographic separation was completed on a reversed-phase C18 column using acetonitrile–phosphate buffer（30：70, v/v） as the mobile phase at a flow rate of 1 mL /min and ultraviolet detection wave length was set at 233 nm. The pharmacokinetic study found that the co-administration of neferine and doxorubicin significantly affected the pharmacokinetics of doxorubicin. There were evident changes in area under the curve（AUC）, clearance（CL） and t1/2β in group of pretreatment neferine as compared with those in group treated with doxorubicin alone. Tissue distribution analysis showed that the concentrations of doxorubicin distributed to heart, liver and kidney were statistically significant higher in group of pretreatment with neferine plus doxorubicin than those in the doxorubicin alone-group at 0.5 h and 2 h after drug administration, respectively. While the doxorubicin concentrations in spleen and lung drug were slightly increased in the group of pretreatment with neferine plus doxorubicin as compared to that of group of doxorubicin alone, the difference between two groups were not statistically significant. Therefore, the dose of doxorubicin needs to be taken into consideration when it is administrated in combination with neferine.
基金supported by grants from Natural Science Foundation of Hunan Province(No.07JJ4009)Project of the Department of Science and Technology of Hunan Province(No. 2010FJ6029)+2 种基金Research and Innovation Conditions Project of Hunan Province(No.2010TT2034)125 Talent Project of the Third Xiangya Hospital of Central South Universitythe Freedom Explore Program of Central South University(No. 2011QNZT193),China
文摘Multidrug resistance（MDR） plays a major obstacle to successful gastric cancer chemotherapy.The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine（Nef） in adriamycin（ADM） resistant human SGC7901/ADM gastric cancer cells.The MDR cells were heated at 42℃ and 45℃ for 30 min alone or combined with 10 μg/mL Nef.The cytotoxic effect of ADM was evaluated by MTT assay.Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique.Intracellular accumulation of ADM was monitored with high performance liquid chromatography.Mdr-1 mRNA,P-glycoprotein（P-gp）,γH2AX expression and γH2AX foci formation were determined by real-time PCR,Western blot and immunocytochemical staining respectively.It was found that different heating methods induced different cytotoxic effects.Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells.The water submerged hyperthermia increased the cell membrane fluidity.Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM.The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp.The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells.The higher temperature was,the worse effect was.Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells.
基金Acknowledgment The authors thank Prof. Jia-Ling Wang for kindly supplying the neferine. The technical support from Prof. Bo-Hua Shu is also greatly appreciated. This study was sponsored by the National Natural Science Foundation of China （No. 30471736） and China Postdoctoral Science Foundation （No. 20070410176）.
文摘Aim： To further investigate the relaxation mechanism of neferine （NED, a bis-benzylisoquinoline alkaloid extracted （isolated） from the green seed embryo of Nelumbo nucifera Gaertn in China, on rabbit corpus cavernosum tissue in vitro. Methods： The effects of Nef on the concentrations of cyclic adenosine monophosphate （cAMP） and cyclic guanosine monophosphate （cGMP） in isolated and incubated rabbit corpus cavernosum tissue were recorded using ^125I radioimmunoassay. Results： The basal concentration of cAMP in corpus cavernosum tissue was 5.67 ± 0.97 pmol/mg. Nef increased the cAMP concentration in a dose-dependent manner （P 〈 0.05）, but this effect was not inhibited by an adenylate cyclase inhibitor （cis-N-[2-phenylcyclopentyl]azacyclotridec-1-en-2-amine, MDL-12, 330A） （P 〉 0.05）. The accumulation of cAMP induced by prostaglandin Et （PGEt, a stimulator of cAMP production） was also augmented by Nef in a dose-dependent manner （P 〈 0.05）. The basal concentration of cGMP in corpus cavernosum tissue is 0.44 ± 0.09 pmol/mg. Nef did not affect this concentration of cGMP, either in the presence or in the absence of a guanyl cyclase inhibitor （1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ） （P 〉 0.05）. Also, sodium nitroprusside （SNP, a stimulator of cGMP production）-induced cGMP production was not enhanced by Nef （P 〉 0.05）. Conclusion： Nef, with its relaxation mechanism, can enhance the concentration of cAMP in rabbit corpus cavernosum tissue, probably by inhibiting phosphodiesterase activity. （Asian JAndro12008 Mar; 10： 307-312）
基金Supported by National Key R and D Program of China,No.2017YFC0908903National Natural Science Foundation of China,No.81873565,No.81470840,and No.81800510Shanghai Sailing Program,No.18YF1415900
文摘BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.
文摘Neferine, a bisbenzylisoquinoline alkaloid in Lotus Plumule, was proved to have a wide range of biological activities. In the present study, using whole-cell patch-clamp technique, we investigated the effects of neferine on Nav1.5 channels that are stably expressed in HEK 293 cells. We found that neferine potently and reversibly inhibited Nav1.5 currents in a concentration dependent manner with a half-maximal inhibition（IC50） being 26.15 μmol/L. The inhibitory effects of neferine on Nav1.5 currents were weaker than those of quinidine at the same concentration. The steady-state inactivation curve was significantly shifted towards hyperpolarizing direction in the presence of 30 μmol/L neferine, while the voltage-dependent activation was unaltered. Neferine prolonged the time to peak of activation, increased the inactivation time constants of Nav1.5 currents and markedly slowed the recovery from inactivation. The inhibitory effect of neferine could be potentiated in a frequency-dependent manner. These results suggested that neferine can block Nav1.5 channels under the open state and inactivating state and it is an open channel blocker of Nav1.5 channels.
基金financial support from the Hunan Provincial Natural Science Foundation of China (No.2019JJ20008)
文摘An eco-friendly protocol for the synthesis of various 2-sulfonyl quinolines/pyridines through sulfonylation of heteroaromatic N-oxides with sodium sulfinates in water at ambient temperature under metal-and oxidant-free conditions has been developed.The mild reaction conditions,high reaction efficiency,operational simplicity,short reaction time and remarkable functional-group compatibility make the developed protocol very attractive for the preparation of 2-sulfonyl N-heteroaromatic compounds.
文摘Oxidatively modified low density lipoprtein (LDL) plays an important role in atheroslerosis (AS) development. To investigate the role of neferine (Nef) in anti-LDL oxidation and foam cell formation, the lipoprotein was derived and subjected to three different treatments: N-LDL (normal LDL), Cu(2+) +LDL and Cu(2+)+Nef+LDL. The LDLs were put at 25℃ for 24 h and the thiobarbituric acid reactive substance (TBARS) values were determined. They were 0. 57 ±0. 02, 6.01±0. 22 and 2. 26±0. 13 nmol/mg protein, respectively. The difference was very significant (P<0.01) for each two groups by t test. Mouse peritoneal macrophage (MΦ) were exposed to 50 μg protein/ml of Cu(2+) + LDL and Cu(2+)+Nef+LDL at 37℃ for 60 h. The tryglyceride (TG) and total cholesterol (TC) content in Mad were assayed. The results showed that Cu(2+) + LDL was more efficient than Cu(2+)+Nef+LDL in stimulating lipid accumulation in MΦ(P <0. 001). The study demonstrated that Nef could inhibit Cu(2+)-mediated LDL oxidation and thereby inhibiting macrophage-derived foam cell formation.
基金the Chengdu Health and Wellness Commission:Exploring the Mechanism of Neferine on Diabetic Nephropathy Based on mi R-17/Nrf2 Axis(No.2021127)。
文摘OBJECTIVE:To investigate the effect of Neferine(Nef)on diabetic nephropathy(DN)and to explore the mechanism of Nef in DN based on miRNA regulation theory.METHODS:A DN mouse model was constructed and treated with Nef.Serum creatinine(Crea),blood urea(UREA)and urinary albumin were measured in mice by kits,and renal histopathological changes and fibrosis were observed by hematoxylin-eosin staining and Masson staining.Renal tissue superoxide dismutase(SOD),malondialdehyde(MDA)and glutathione peroxidase(GSH-Px)activities were measured by enzyme-linked immunosorbent assay(ELISA).Western blotting was used to detect the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1)signaling pathway-related proteins in kidney tissues.Quantitative reverse transcription-polymerase chain reaction(q RT-PCR)was used to detect the expression of miR-17-5p in kidney tissues.Subsequently,a DN in vitro model was constructed by high glucose culture of human mesangial cells(HMCs),cells were transfected with miR-17-5p mimic and/or treated with Nef,and we used q RTPCR to detect cellular miR-17 expression,flow cytometry to detect apoptosis,ELISAs to detect cellular SOD,MDA,and GSH-Px activities,Western blots to detect Nrf2/HO-1 signaling pathway-related protein expression,and dual luciferase reporter gene assays to verify the targeting relationship between Nrf2 and miR-17-5p.RESULTS:Administration of Nef significantly reduced the levels of blood glucose,Crea,and UREA and the expression of miR-17-5p,improved renal histopathology and fibrosis,significantly reduced MDA levels,elevated SOD and GSH-Px activities,and activated Nrf2 expression in kidney tissues from mice with DN.Nrf2 is a post-transcriptional target of miR-17-5p.In HMCs transfected with miR-17-5p mimics,the m RNA and protein levels of Nrf2 were significantly suppressed.Furthermore,miR-17-5p overexpression and Nef intervention resulted in a significant increase in high glucose-induced apoptosis and MDA levels in HMCs and a significant decrease in the protein expression of HO-1 and Nrf2.CONCLUSION:Collectively,these results indicate that Nef has an ameliorative effect on DN,and the mechanism may be through the miR-17-5p/Nrf2 pathway.
基金supported by The Opening Project of Jiangsu Key Laboratory for Chinese Medicine Processing(ZYPZ010)the National Natural Science Foundation of China(81373295)
文摘AIM: The application of strychnine(S) is limited due to its toxicity; strychnine N-oxide(SNO) is a derivative of strychnine. The aim was to employ zebrafish embryos to investigate and compare the developmental toxicity induced by S and SNO. METHODS: The toxicity of S and SNO was examined through the hatching rate and survival rate. Morphological changes of the zebrafish were observed with a dissecting microscope. Apoptosis was detected through acridine orange(AO) staining and flow cytometry. Apoptotic genes were measured by RT-PCR. RESULTS: Embryo malformation was observed in the embryos exposed to S at 200 μmol·L–1. When SNO concentration was increased to 1 mmol·L–1, scoliolosis, and pericardial edema could be seen in some embryos. Results from fluorescence microscopy and flow cytometry analysis showed that S at 200 μmol·L–1 induced apoptosis, whereas the apoptotic rate in the SNO-treated group(200 μmol·L–1) was much lower than that in the S group. RT-PCR analysis showed that p53 mRNA expression and the ratio of Bax/Bcl-2 in the S group were significantly altered compared with the control group(*P < 0.05). Moreover, Bax mRNA expression in both S and SNO group were significantly different from that in the control group(**P <0.01). CONCLUSION: These results lead to the conclusion that SNO has significantly lower toxicity than S in zebrafish embryos.
基金Natural Science Foundation and Education Department Foundation of Guangxi Province
文摘The title zinc（Ⅱ） complex salt [Zn（H2O）6]（ClO4）2-（PNOS）4, where PNOS is derived from picolinaldehyde N-oxide with semicarbazone, has been prepared and structurally characterized by X-ray single-crystal analysis. It crystallizes in triclinic, space group PI with a = 7.529（3）, b = 10.206（4）, c = 14.678（6）A, a = 86.293（6）, β= 87.686（7）, γ= 81.382（6）°, C28H44Cl2N16O22Zn, Mr = 1093.06, V = 1112.3（8） ,A^3 Z = 1, Dc = 1.632 g/cm^3, S = 1.089, μ（MoKa） = 0.773 mm^-1, F（000） = 564, the final R = 0.0438 and wR = 0.1076 for 3888 independent reflections with Rint = 0.0224. The crystal structure possesses a [Zn（H2O）6]^2＋ cation, two ClO4^- anions and four PNOSs. In the crystal structure, Zn^2＋ cation is located at the symcenter and coordinated by six water molecules. In [Zn（H2O）6]^2＋, an elongate octahedral complex cation, the average Zn-O bond length is 2.087（2） A. There exist a lot of H bonds in the structure, linking the cation [Zn（H2O）6]^2＋, anion ClO4^- and PNOS to form a 3D network.
基金Supported by the National Natural Science Foundation in China(No.81671641)Jiangsu Provincial Medical Innovation Team(No.CXTDA2017039)Gusu Health Talents Program(No.GSWS 2022018).
文摘AIM:To provide the direct evidence for the crucial role of trimethylamine N-oxide(TMAO)in vascular permeability and endothelial cell dysfunction under diabetic condition.METHODS:The role of TMAO on the in vitro biological effect of human retinal microvascular endothelial cells(HRMEC)under high glucose conditions was tested by a cell counting kit,wound healing,a transwell and a tube formation assay.The inflammation-related gene expression affected by TMAO was tested by real-time polymerase chain reaction(RT-PCR).The expression of the cell junction was measured by Western blotting(WB)and immunofluorescence staining.In addition,two groups of rat models,diabetic and non-diabetic,were fed with normal or 0.1%TMAO for 16wk,and their plasma levels of TMAO,vascular endothelial growth factor(VEGF),interleukin(IL)-6 and tumor necrosis factor(TNF)-αwere tested.The vascular permeability of rat retinas was measured using FITC-Dextran,and the expression of zonula occludens(ZO)-1 and claudin-5 in rat retinas was detected by WB or immunofluorescence staining.RESULTS:TMAO administration significantly increased the cell proliferation,migration,and tube formation of primary HRMEC either in normal or high-glucose conditions.RT-PCR showed elevated inflammation-related gene expression of HRMEC under TMAO stimulation,while WB or immunofluorescence staining indicated decreased cell junction ZO-1 and occludin expression after high-glucose and TMAO treatment.Diabetic rats showed higher plasma levels of TMAO as well as retinal vascular leakage,which were even higher in TMAO-feeding diabetic rats.Furthermore,TMAO administration increased the rat plasma levels of VEGF,IL-6 and TNF-αwhile decreasing the retinal expression levels of ZO-1 and claudin-5.CONCLUSION:TMAO enhances the proliferation,migration,and tube formation of HRMEC,as well as destroys their vascular integrity and tight connection.It also regulates the expression of VEGF,IL-6,and TNF-α.
基金supported by the National Natural Science Foundation of China (No. 20772042)
文摘A new complex [Cd（H2biim）2（H2O）2]·（ino）2·4H2O （H2biim = 2,2＇-biimidazole, ino = isonicotinate-N-oxide） has been prepared and characterized by single-crystal X-ray diffraction analysis, IR and fluorescence spectra analysis. The crystal is of triclinic system, space group P1 with a = 7.5380（6）, b = 8.0402（7）, c = 13.5094（11） , α = 104.269（1）, β = 93.604（1）, γ = 98.349（1）°, V = 780.93（11） 3, Mr = 765.00, Dc = 1.627 g/cm3, F（000） = 390, μ = 0.776 mm-1 and Z = 1. The final R = 0.0322 and wR = 0.0825 for 7038 observed reflections with I 2σ（I） and R = 0.0341 and wR = 0.0832 for all data. The title complex exhibits an infinite chain-like structure through bridging isonicotinate-N-oxide. Strong interchain hydrogen bonds between isonicotinate-N-oxide and H2biim result in the robust 3-D supramolecular architecture. Moreover, the complex shows strong photoluminescence with emission maximum at λ = 401 nm upon λex = 330 nm.
基金financial support from the National Natural Science Foundation of China(No.21276043)
文摘We report a practical and highly efficient protocol for the arylation of pyridine N-oxides with arylboronic acid through palladium-catalyzed Suzuki reaction in water.This ligand-free Suzuki reaction is performed in the presence of diisopropylamine and gives 2-or 3-arylated pyridyl N-oxide derivatives in good to excellent yields within 1 h.
基金supported by Tianjin key Technology R&D Program (No. 07ZCKFSH00200)
文摘Sophoridine N-oxide was synthesized and characterized by 1H-NMR,EI-MS,IR and elemental analysis,together with X-ray single-crystal diffraction analysis,and its crystal structure was reported for the first time.The crystal belongs to the orthorhombic system,space group P212121 with a = 8.321（2）,b = 15.650（3）,c = 24.352（5） ,V = 3171.1（11） 3,Z = 8,Dc = 1.258 g/cm3,λ（CuKα） = 1.54178,F（000） = 1440,the final R = 0.0351 and wR = 0.0970.The crystal structure shows Sophoridine N-oxide crystallizes with two host molecules of similar conformation and four water solvent molecules in the asymmetric unit.In the crystal structure,intermolecular O-H…O hydrogen bonds link the constituent molecules into a 2D layer structure,which further extends to a 3D supramolecular architecture via Van der Waals interactions and intermolecular O-H…O hydrogen bonds.
文摘The complex Mn(apo)6Cl2 (apo=2-aminopyridine N-oxide) was obtained by the reaction of MnCl2(4H2O with apo(HCl and NaOH in ethanol. A single-crystal X-ray study shows that the complex is mononuclear with octahedral coordination environment (MnC30H36N12O6Cl2). The oxygen atoms from apo ligands coordinate to the manganese atom forming Mn(apo)6Cl2. The compound Mn(apo)6Cl2 is hexagonally symmetric with space group R3, lattice constants: a = 12.010(2), b = 12.010(2), c = 20.232(4) ?, ( = 120(, V= 2527.4(7) ?3, Z=3, Mr =786.55, Dc=1.550 g/cm3, (= 0.614mm-1, F(000) = 1221, R = 0.0541, Rw = 0.0580 for 1229 reflections with I>2((I). The distances between Mn(II) and O atoms are in the range from 2.171(5) to 2.184(5) ?, and the distance between the chlorine anion and N atom of amido group is 3.3 ?. The dihedral angle between two adjacent pyridine ring planes is 59.19 (0.17)°.
