Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.

Frequently, subcellular-targeted drugs tend to accumulate in lysosomes after cellular absorption, a process termed the lysosomal trap. This accumulation often interferes with the drug's ability to bind to its target, resulting in decreased efficiency. Existing methods for addressing lysosome-induced drug resistance mainly involve improving the structures of small molecules or enveloping drugs in nanomaterials. Nonetheless, these approaches can lead to changes in the drug structure or potentially trigger unexpected reactions within organisms. To address these issues, we introduced a strategy that involves inactivating the lysosome with the use of Ag nanoparticles (Cy3.5@Ag NPs). In this method, the Cy3.5@Ag NPs gradually accumulate inside lysosomes, leading to permeation of the lysosomal membrane and subsequent lysosomal inactivation. In addition, Cy3.5@Ag NPs also significantly affected the motility of lysosomes and induced the occurrence of lysosome passivation. Importantly, coincubating Cy3.5@Ag NPs with various subcellular-targeted drugs was found to significantly increase the efficiency of these treatments. Our strategy illustrates the potential of using lysosomal inactivation to enhance drug efficacy, providing a promising therapeutic strategy for cancer.

Repeat dose and reproductive toxicity of thrombopoietin mimic peptide in Sprague-Dawley rats.

Thrombopoietin mimic peptide (TMP) is a novel thrombopoietin receptor agonist. In this report, we evaluated the potential toxicity of TMP in repeat-dose toxicity and reproductive/developmental toxicity studies (segment Ⅰ, Ⅱ, Ⅲ). TMP was administered subcutaneously to Sprague-Dawley (SD) rats at 5, 15 or 50 mcg/kg. In repeat-dose toxicity study, the rats were administrated three times a week for 26 week with a 4-week recovery. TMP could produce anti-drug antibodies and induce platelet counts increase, megakaryocyte proliferation. While platelet counts decreased gradually and returned to normal after 4 weeks in male rats. Other significant findings included myelofibrosis of bone marrow, hepatic extramedullary hematopoiesis, splenic lymphocytic depletion and bone hyperostosis. All treatment-related effects were reversed following recovery. The NOAEL of repeat-dose toxicity in female rats is 5 mcg/kg. In the reproductive/developmental toxicity (segment Ⅰ, Ⅲ), no deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed. In embryo-fetal developmental toxicity study (segment Ⅱ), the number of resorbed fetuses in the 50 mcg/kg group was significantly increased. The NOAEL as related to reproductive/developmental toxicity in these rats was 15 mcg/kg.

Acute, subchronic toxicity and genotoxicity studies of JointAlive, a traditional Chinese medicine formulation for knee osteoarthritis.

AIM: In vivo and in vitro toxicity tests of JointAlive® were studied in animal models to support the safe use of JointAlive® as a drug for knee osteoarthritis treatment. METHODS: The acute toxicity study in Sprague Dawley (SD) rats was conducted at a 20 g/kg bw/day dose of JointAlive®. For 13-week subchronic toxicity tests, SD rats were orally dosed daily with 0.5, 1.5 and 5 g/kg bw/day of JointAlive®. To assess the potential genotoxicity, Ames test, cellular chromosome aberration and mouse micronucleus test in vivo were carried out. RESULTS: Based on a lack of notable findings other than histopathology finding of co-incidental prostate inflammation at the high dose, the "No Observed Adverse Effect Level (NOAEL)" of JointAlive® was concluded as 5 g/kg bw/day in males and females. Results also indicated that JointAlive® has no risk of genotoxicity. CONCLUSIONS: General toxicity and genotoxicity studies empirically demonstrated that JointAlive® poses a low risk of potential health risks, providing safety supports for the application of JointAlive® as a potential drug candidate to treat knee osteoarthritis.

Bioprinted Notch ligand to function as stem cell niche improves muscle regeneration in dystrophic muscle.

299In Duchenne muscular dystrophy, dystrophic muscle phenotypes are closely associated with the exhaustion of muscle stem cells. Transplantation of muscle stem cells has been widely studied for improving muscle regeneration, but poor cell survival and self-renewal, rapid loss of stemness, and limited dispersion of grafted cells following transplantation have collectively hindered the overall success of this strategy. Optimized mechanisms for maintaining and improving stem cell function are naturally present in the microenvironment of the stem cell niche in healthy muscles. Therefore, one logical strategy toward improving stem cell function and efficiency of stem cell transplantation in diseased muscles would be the establishment of a microenvironment mimicking some key aspects of healthy native stem cell niches. Here, we applied inkjet-based bioprinting technology to engineer a mimicked artificial stem cell niche in dystrophic muscle, comprising stem cell niche regulating factors (Notch activator DLL1) bioprinted onto 3D DermaMatrix construct. The recombinant DLL1 protein, DLL1 (mouse): Fc (human) (rec), was applied here as the Notch activator. Bioprinted DermaMatrix construct was seeded with muscle stem cells in vitro, and increased stem cell maintenance and repressed myogenic differentiation process was observed. DLL1 bioprinted DermaMatrix construct was then engrafted into dystrophic muscle of mdx/scid mice, and the improved cell engraftment and progression of muscle regeneration was observed 10 days after engraftment. Our results demonstrated that bioprinting of Notch activator within 3D construct can be applied to serve as muscle stem cell niche and improve the efficacy of muscle stem cell transplantation in diseased muscle.

Nuclear softening mediated by Sun2 suppression delays mechanical stress-induced cellular senescence.

Nuclear decoupling and softening are the main cellular mechanisms to resist mechanical stress-induced nuclear/DNA damage, however, its molecular mechanisms remain much unknown. Our recent study of Hutchinson-Gilford progeria syndrome (HGPS) disease revealed the role of nuclear membrane protein Sun2 in mediating nuclear damages and cellular senescence in progeria cells. However, the potential role of Sun2 in mechanical stress-induced nuclear damage and its correlation with nuclear decoupling and softening is still not clear. By applying cyclic mechanical stretch to mesenchymal stromal cells (MSCs) of WT and Zmpset24-/- mice (Z24-/-, a model for HGPS), we observed much increased nuclear damage in Z24-/- MSCs, which also featured elevated Sun2 expression, RhoA activation, F-actin polymerization and nuclear stiffness, indicating the compromised nuclear decoupling capacity. Suppression of Sun2 with siRNA effectively reduced nuclear/DNA damages caused by mechanical stretch, which was mediated by increased nuclear decoupling and softening, and consequently improved nuclear deformability. Our results reveal that Sun2 is greatly involved in mediating mechanical stress-induced nuclear damage by regulating nuclear mechanical properties, and Sun2 suppression can be a novel therapeutic target for treating progeria aging or aging-related diseases.

Comparative pharmacokinetics of four major compounds after oral administration of Mori Cortex total flavonoid extract in normal and diabetic rats.

Introduction: Mori Cortex has been used in traditional Chinese Medicine as an antidiabetic agent. The aim of this study was to establish a UPLC-MS/MS method for simultaneous determination of morin, morusin, umbelliferone and mulberroside A in rat plasma and investigate the pharmacokinetics differences between normal and diabetic rats following oral administration of Mori Cortex total flavonoid extract. Methods: Samples were pre-treated by protein precipitation and genkwanin was used as internal standard. Chromatographic separation was performed using a Hypersil GOLD C18 column (50 mm × 2.1 mm, 3 µm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) in gradient mode at a flow rate of 0.5 ml/min. The transitions of m/z 300.9→107.1, m/z 419.3→297.1, m/z 160.9→77.0, m/z 567.1→243.2 and m/z 283.1→268.2 were selected for morin, morusin, umbelliferone, mulberroside A and internal standard, respectively. Results: The intra- and inter-day precision for analytes were less than 12.5% and the accuracy ranged from -8.1% to 3.5%. The extraction recovery was >88.5% and no obvious matrix effect was observed. The AUC (0-t) and C max of morin were 501.3 ± 115.5 ng/mL*h and 127.8 ± 56.0 ng/mL in normal rats and 717.3 ± 117.4 ng/ml*h and 218.6 ± 33.5 ng/ml in diabetic rats. Meanwhile, the AUC (0-t) and C max of morusin were 116.4 ± 38.2 ng/ml*h and 16.8 ± 10.1 ng/mL in normal rats and 325.0 ± 87.6 ng/mL*h and 39.2 ± 5.9 ng/ml in diabetic rats. For umbelliferone and mulberroside A, the AUC (0-t) and C max also increased significantly in diabetic rats (p < 0.05). Discussion: The validated method was successfully applied to the pharmacokinetic study in normal and diabetic rats.

Developmental and reproduction toxicity studies of Biolimus A9 in SD rats.

Biolimus A9 (BA9) is a novel rapamycin derivative. In this report we evaluated the potential toxicity of BA9 in a developmental and reproduction toxicity study (segment Ⅰ, Ⅱ, Ⅲ). In segment I, body weight gains in F0 rats receiving 0.80 mg/kg/day were decreased. A lower fertility index of males was observed and females failed to become pregnant in the 0.80 mg/kg/day group. The number of live fetuses and implantations were decreased while the number of dead fetuses, resorptions, and implantation losses were increased in the 0.12 mg/kg/day group. In segment Ⅱ, maternal toxicity: body weight gains in F0 females receiving 0.036 and 0.090 mg/kg/day group were decreased. Embryo toxicity: In the 0.090 mg/kg/day group, weights and body lengths of fetuses were decreased, the numbers of viable fetuses was decreased and resorbed fetuses increased. Teratogenic effects: The percent of visceral variations and skeletal variations were both increased in the 0.090 mg/kg/day group. In segment Ⅲ, dosing F0 rats with BA9 at dose levels of 0.12 and 0.80 mg/kg/day resulted in reproductive and maternal toxicity, consisting of prolonged labor, dystocia, increased mortality, along with reductions in lactation food consumption. F1 rats in the 0.12 mg/kg/day group showed reproductive and developmental toxicity consisting of body weight decreases, decreased food consumption after weaning and a reduction in the gestation index of pregnant rats. Based on these findings, the no-observed-adverse-effect-level (NOAEL) of BA9 toxicity in segment Ⅰ and Ⅲ was 0.02 mg/kg/day. The NOAEL in segment Ⅱ was 0.015 mg/kg/day.

Fabrication of polydopamine reduced CuO nanoparticle-alginate composite nanogels for management of Pseudomonas synringae pv. tabaci in tobacco.

BACKGROUND: The wildfire disease on tobacco can seriously hinder plants. Meanwhile, its pathogen, Pseudomonas syringae, can also infect over 200 plants and threat agriculture production. However, the disease usually occurs after summer rains which washes away most copper (Cu)-based bactericides, allowing the disease to invade. Therefore, we fabricate a new nanogel with high disease control and anti-erosion ability and study the effects of the reductant on the performance of the copper oxide nanoparticle (CuONP) composite nanogel. RESULTS: Polydopamine (PDA) is a polycation for both in situ reduction of CuONP in alginate nanogels and for adjusting the copper ion (Cu2+ ) releasing rate in this work. The composite nanogel fabricated by PDA (PDA-CuONP@ALGNP@CTAC) had a higher Cu2+ releasing rate, damaging the pathogen membrane more efficiently, allowing for better disease control and plant growth promotion when compared to sodium borohydride (SBH)-fabricated nanogel (SBH-CuONP@ALGNP@CTAC) or the commercial bactericide, thiodiazole copper. The PDA-CuONP@ALGNP@CTAC had a high anti-erosion ability and could remain adhered to the leaf surface even after five rain event simulations. CONCLUSION: The addition of polycations (like PDA) into CuONP composite nanogel could increase the Cu2+ releasing rate, resulting in improved disease management when compared to SBH-CuONP@ALGNP@CTAC or thiodiazole copper. The PDA containing gel had an improved anti-erosion ability and water resistance. This new composite nanogel has a high potential for wildfire disease control, improving agricultural production. © 2022 Society of Chemical Industry.

Fabrication of CuO nanoparticles composite ε-polylysine-alginate nanogel for high-efficiency management of Alternaria alternate.

Although ε-poly-l-lysine (ε-PL) has a good potential as a green fungicide, high concentration is usually required during its controlling of plant disease. On the other hand, same problems also appeared in the study of CuONP based nano pesticides. In this manuscript, a new composite alginate nanogel (ALGNP) that containing CuONP and ε-PL was fabricated via in situ reduction of CuONP in nanogel and ε-PL surface coating. Based on the chelation of amide bond of ε-PL and Cu2+ released by CuONP, the synergy effect between Cu2+ and ε-PL layer of the nanogel make the nanogel (CuONP@ALGNP@PL) performed high anti-fungal activity under low Cu2+ and ε-PL concentration (Cu concentration was 40.09 µg/mL, ε-PL concentration was 11.90 µg/mL). Study showed that the nanogel could more significantly destroy the fungal cell membrane than CuONP@ALGNP and ALGNP@PL, also better than commercial fungicide CuCaSO4 (Cu concentration was 120 µg/mL). Furthermore, CuONP@ALGNP@PL could seriously affect the spore production, spore germination rate and bud tube elongation length of Alternaria alternate. Moreover, CuONP@ALGNP@PL also inhibit Botrytis cinerea, Phytophthora, Thanatephorus cucumeris and Fusarium graminearum. These results showed that composite of CuONP and ε-PL based on nanogel can decrease the raw materials application amount, and achieve a high disease controlling ability, which provides a new perspective for preventing fungal diseases.

Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage.

Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.

3-Arylcoumarin inhibits vascular calcification by inhibiting the generation of AGEs and anti-oxidative stress.

OBJECTIVE: This work aims to screen drugs for preventing and treating vascular calcification. Method: We screened a series of 3-arylcoumarins for the detection of vascular calcification-associated factors using human aortic vascular smooth muscle cells. RESULTS: We found that compounds 14 and 32 significantly inhibited alkaline phosphatase (ALP) activity similar to aminoguanidine hydrochloride (AGH) in a cellular model of AGEs-induced calcification. We also found that compounds 14 and 32 could significantly decrease the levels of factors such as AGEs, intracellular calcium ions, and total ROS in the calcified cell model. Further study indicates that compound 14 could significantly inhibit the expression of P-ERK1/2, PKC, NF-κB, RAGE and OPN proteins and increased the expression of SM22-α and PPAR-γ proteins in the calcified cells. CONCLUSION: We speculate that compound 14 inhibits vascular calcification by inhibiting oxidative stress and inhibiting AGEs production, suggesting that 3-arylcoumarin derivatives are potential candidates for the treatment of vascular calcification.

Vascular calcification is a process similar to bone formation, which is highly adjustable and active. Currently, there are no specific drugs to delay or reverse vascular calcification. Through the screening of 44 coumarin compounds synthesised by our group, compound 14 was obtained to dose-dependently inhibit the calcification of vascular smooth muscle cells without affecting the normal proliferation of cells, decreasing the intracellular calcium concentration, inhibiting the activity of ALP enzyme. In conclusion, the calcium lowering effect of compound 14 is a potential candidate for drugs for the treatment of vascular calcification.

Neuroprotective Effects of Chlorogenic Acid in a Mouse Model of Intracerebral Hemorrhage Associated with Reduced Extracellular Matrix Metalloproteinase Inducer.

Chlorogenic acid (CGA) has been reported to have various biological activities, such as anti-inflammatory, anti-oxidant and anti-apoptosis effects. However, the role of CGA in intracerebral hemorrhage (ICH) and the underlying mechanisms remain undiscovered. The current study aims to investigate the effect of CGA on neuroinflammation and neuronal apoptosis after inhibition of EMMPRIN in a collagenase-induced ICH mouse model. Dose optimization data showed that intraperitoneal administration of CGA (30 mg/kg) significantly attenuated neurological impairments and reduced brain water content at 24 h and 72 h compared with ICH mice given vehicle. Western blot and immunofluorescence analyses revealed that CGA remarkably decreased the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in perihematomal areas at 72 h after ICH. CGA also reduced the expression of matrix metalloproteinases-2/9 (MMP-2/9) at 72 h after ICH. CGA diminished Evans blue dye extravasation and reduced the loss of zonula occludens-1 (ZO-1) and occludin. CGA-treated mice had fewer activated Iba-1-positive microglia and MPO-positive neutrophils. Finally, CGA suppressed cell death around the hematoma and reduced overall brain injury. These outcomes highlight that CGA treatment confers neuroprotection in ICH likely by inhibiting expression of EMMPRIN and MMP-2/9, and alleviating neuroinflammation, blood-brain barrier (BBB) disruption, cell death and brain injury.

Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease.

Phytotherapy offers obvious advantages in the intervention of Coronary Artery Disease (CAD), but it is difficult to clarify the working mechanisms of the medicinal materials it uses. DGS is a natural vasoprotective combination that was screened out in our previous research, yet its potential components and mechanisms are unknown. Therefore, in this study, HPLC-MS and network pharmacology were employed to identify the active components and key signaling pathways of DGS. Transgenic zebrafish and HUVECs cell assays were used to evaluate the effectiveness of DGS. A total of 37 potentially active compounds were identified that interacted with 112 potential targets of CAD. Furthermore, PI3K-Akt, MAPK, relaxin, VEGF, and other signal pathways were determined to be the most promising DGS-mediated pathways. NO kit, ELISA, and Western blot results showed that DGS significantly promoted NO and VEGFA secretion via the upregulation of VEGFR2 expression and the phosphorylation of Akt, Erk1/2, and eNOS to cause angiogenesis and vasodilation. The result of dynamics molecular docking indicated that Salvianolic acid C may be a key active component of DGS in the treatment of CAD. In conclusion, this study has shed light on the network molecular mechanism of DGS for the intervention of CAD using a network pharmacology-driven strategy for the first time to aid in the intervention of CAD.

A Pyridazinone Compound for Effectively Treating Non-alcoholic Steatohepatitis by Targeting THRß.

Developing effective therapies and medicines to conquer nonalcoholic steatohepatitis (NASH) is of great significance for public health and is faced with a major challenge. The activation of the thyroid hormone receptor agonist THRß could be regulated by target drugs that has brought huge potential to the treatment of NASH. In this work, pyridazinone compound YWS01125 was synthesized for the first time. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for YWS01125 determination was established, and the pharmacokinetics of YWS01125 was evaluated. The half-life values (t1/2)of three different doses of YWS01125 was 189.12 ± 95.27, 152.64 ± 37.98, and 181.95 ± 64.25 min, respectively, and the tissue distribution studies demonstrated that YWS01125 was quickly distributed to various tissues. With successful application in the pharmacokinetics study of YWS01125, the UPLC-MS/MS method has shown characteristics of high sensitivity, rapidity, and good selectivity.

Design, Synthesis and Biological Activity Testing of Library of Sphk1 Inhibitors.

Our team discovered a moderate SphK1 inhibitor, SAMS10 (IC50 = 9.8 µM), which was screened by computer-assisted screening. In this study, we developed a series of novel diaryl derivatives with improved antiproliferative activities by modifying the structure of the lead compound SAMS10. A total of 50 new compounds were synthesized. Among these compounds, the most potent compound, named CHJ04022Rb, has significant anticancer activity in melanoma A375 cell line (IC50 = 2.95 µM). Further underlying mechanism studies indicated that CHJ04022R exhibited inhibition effect against PI3K/NF-κB signaling pathways, inhibited the migration of A375 cells, promoted apoptosis and exerted antiproliferative effect by inducing G2/M phase arrest in A375 cells. Furthermore, acute toxicity experiment indicated CHJ04022R exhibited good safety in vivo. Additionally, it showed a dose-dependent inhibitory effect on the growth of xenograft tumor in nude mice. Therefore, CHJ04022R may be a potential candidate for the treatment of melanoma.

Pharmacokinetics and pharmacodynamics of Astragali Radix-Corni Fructus Herb-pair Extract, in kidney-yin deficiency model

Abstract To investigate the pharmacokinetics and pharmacodynamics of Astragali Radix-Corni Fructus herb-pair in kidney-yin deficiency model, which was made by continuously oral gavage of thyroxine. A simple and rapid LC-MS/MS method was developed and validated for the determination of loganin and morroniside in rat plasma and used for the pharmacokinetics study. The kidney-yin deficiency significantly changed the AUC(0-∞), Cmax and CLz/F of loganin and morroniside. The T1/2z of morroniside increased significantly in the kidney-yin deficiency rats. For the pharmacodynamics study, the liver index, kidney index, and ALT, TBIL, UREA, CREA level in the kidney-yin deficiency mice were examined. The herb-pair had been proved to be effective for the treatment of kidney-yin deficiency by affecting the liver, kidney, ALT, UREA and CREA, which showed positively correlated with the dose. The pharmacokinetics and pharmacodynamics studies in the pathological status could offer more valuable information for the future application of Astragali Radix-Corni Fructus herb-pair.

Animal models for analysis of hypersensitivity reactions to Shuanghuanglian injection.

Among a variety of traditional Chinese medicines, Shuanghuanglian injection (SHLI), has the highest incidence of injection-induced immediate hypersensitivity reactions (IHRs). However, the precise mechanisms of SHLI-induced IHRs remain to be understood. In the present study, we characteriszed IHRs as induced by SHLI by recording changes in physiological and hemodynamic indicators following intravenous injections of SHLI in rats and dogs. The results indicate that SHLI induced the release of histamine, decreased mean arterial blood pressure (MAP), increased SC5b-9 in rats and dogs, increased C4d and Bb in dogs without any changes in IgE. n vitro incubation of SHLI with serum from dogs in the presence of an inhibitor of complement activation (EGTA/Mg2+) resulted in an increase in C4d. These results suggest that SHLI induces anaphylactoid reactions in rats and dogs. Furthermore, SHLI appears to activate the complement system through classical and alternative pathways in dogs in vivo. Additional experiments in mice demonstrated that SHLI induces locus coeruleus infiltration and results in significant increase in vascular permeability within the skin of mice. We established a reliable method for the evaluation of anaphylactoid reactions induced by complex compounds, using multiple physiological indicators, different experimental models in vivo and in vitro.

Inhibition of NF-κB and Wnt/ß-catenin/GSK3ß Signaling Pathways Ameliorates Cardiomyocyte Hypertrophy and Fibrosis in Streptozotocin (STZ)-induced Type 1 Diabetic Rats.

Type 1 diabetes mellitus (T1DM) is associated with an increased risk of diabetic cardiomyopathy (DCM). Nuclear factor kappa B (NF-κB) and Wnt/ß-catenin/GSK3ß have been demonstrated to play pathogenic roles in diabetes. In this study, we evaluated the roles of these two pathways in T1DM-induced cardiomyopathy in rats. Streptozotocin (STZ)-induced type 1 diabetic rats were treated with pyrrolidine dithiocarbamate (PDTC) or meisoindigo (Me) to inhibit NF-κB and Wnt/ß-catenm/GSK3ß respectively for 4 or 8 weeks. As compared with untreated diabetic rats, treatment with either PDTC or Me partly attenuated the myocardial hypertrophy and interstitial fibrosis, improved cardiac function, and exhibited reduction in inflammatory reaction. In addition, we found that inhibiting NF-κB and Wnt/ß-catenin/GSK3ß pathways could regulate glucose and lipid metabolism. The effects were associated with the decrease of NF-κB activity and the downregulation of some proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-2. Our data suggested that the activities of NF-κB and Wnt/ß-catenin/GSK3ß pathways were both increased and inhibiting NF-κB and Wnt/ß-catenin/GSK3ß signaling pathways might improve myocardial injury in T1DM rats.

A new indole alkaloid with anti-inflammatory from the branches of Nauclea officinalis.

A new indole alkaloid, 17-oxo-19-(Z)-naucline, and six known alkaloids 2-7 were isolated from the branches of Nauclea officinalis. The structure of the new compound 1 was characterised mainly by analysing its physical data including IR, 1 D, 2 D NMR, and HR-ESI-MS. Other compounds were identified by comparisons their data with those reported in the literature. Compound1, 4, 5, 6, 7 showed in vitro anti-inflammatory activity decrease the LPS-stimulated production of nitric oxide in RAW264.7 cell, while all compounds exhibited weak cytotoxicity against human tumour cell lines (LOVO, A549 and HepG2).