Novel IMB16-4 Compound Loaded into Silica Nanoparticles Exhibits Enhanced Oral Bioavailability and Increased Anti-Liver Fibrosis In Vitro

Background: Liver fibrosis, as a common and refractory disease, is challenging to treat due to the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide (IMB16-4), which is expected to have good potential effects against liver fibrosis. However, IMB16-4 is water-insoluble and has very low bioavailability. Methods: Mesoporous silica nanoparticles (MSNs) were selected as drug carriers for the purpose of increasing the dissolution of IMB16-4, as well as improving its oral bioavailability and inhibiting liver fibrosis. The physical states of IMB16-4 and IMB16-4-MSNs were investigated using nitrogen adsorption, thermogravimetric analysis (TGA), HPLC, UV-Vis, X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results: The results show that MSNs enhanced the dissolution rate of IMB16-4 significantly. IMB16-4-MSNs reduced cytotoxicity at high concentrations of IMB16-4 on human hepatic stellate cells LX-2 cells and improved oral bioavailability up to 530% compared with raw IMB16-4 on Sprague–Dawley (SD) rats. In addition, IMB16-4-MSNs repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers, including α-smooth muscle actin (α-SMA), transforming growth factor-beta (TGF-β1) and matrix metalloproteinase-2 (MMP2) in LX-2 cells. Conclusions: These results provided powerful information on the use of IMB16-4-MSNs for the treatment of liver fibrosis in the future.     

Efficiency of Biodegradable and pH‐Responsive Polysuccinimide Nanoparticles (PSI‐NPs) as Smart Nanodelivery Systems in Grapefruit: In Vitro Cellular Investigation

Biodegradable pH‐responsive polysuccinimide nanoparticles (PSI‐NPs) are synthesized for directly delivering agrochemicals to plant phloem to improve their efficacy. The PSI‐NPs have an average size of 20.6 nm with negative charge on the surface. The desired responsiveness to changes in pH is demonstrated by release efficiency of the model molecule (Coumarin 6), which increases with increasing pH over 24 h. The internalization of PSI‐NPs into grapefruit cells occurs in 10 min, and into nucleus in 2 h, with most of the PSI‐NPs being distributed in cytoplasm and nucleus. The proportion of PSI‐NPs in plant cells significantly increases with time, from 19.1% at 10 min to 55.5% at 2 h of administering. The PSI‐NPs do not show significant inhibitory effects on soil microbial growth and activity. These results indicate that this smart nanodelivery system has potential of application in agriculture for mitigating phloem‐limited diseases, such as citrus huanglongbing.     

Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT

Obacunone, a limonin triterpenoid extracted from Phellodendronchinense Schneid or Dictamnus dasycarpusb Turcz plant, elicits a variety of pharmacological effects such as anti-inflammatory, anti-neoplastic, anti-oxidation, and anti-lung-fibrosis ones. However, the anti-fibrotic effect of obacunone and the detailed underlying mechanism in liver fibrosis remain unclear. Liver fibrosis is a debilitating disease threatening human health. Transforming growth factor (TGF)-β/P-Smad is a major pathway of fibrosis featured with epithelia mesenchymal transformations (EMT) and collagen depositions, accompanying with excessive oxygen-free radicals. Nrf-2 acts as a key anti-oxidative regulator driving the expressions of various antioxidant-related genes. Glutathionperoxidase-4 (GPx-4) is a member of the glutathione peroxidase family that directly inhibits phospholipid oxidation to alleviate oxidative stress. In the present study, we aimed to explore the role of obacunone in mouse liver fibrosis model induced by carbon tetrachloride (CCl4) and in hepatic stellate cells (LX2 cell line) challenging with TGF-β. Obacunone demonstrated potent ameliorative effects on liver fibrosis both in activated LX2 and in mice liver tissues with reduced levels of α-SMA, collagen1, and vimentin. Obacunone also remarkably suppressed the TGF-β/P-Smad signals and EMT process. Meanwhile, obacunone exerted a potent anti-oxidation effect by reducing the levels of reactive oxygen species (ROS) in both models. The antioxidant effect of obacunone was attributed to the activation of GPx-4 and Nrf-2. In addition, the therapeutic effect of obacunone on LX2 cells was significantly removed in vitro plus with GPx-4 antagonist RSL3, in parallel with the re-elevated levels of ROS. Thus, we demonstrate that obacunone is able to attenuate liver fibrosis via enhancing GPx-4 signal and inhibition of the TGF-β/P-Smad pathway and EMT process.     

5-(4-硝基苯偶氮)-8-(4-甲苯磺酰氨基)-喹啉的合成及在钴的测定中的应用研究

首次合成了5-(4-硝基苯偶氮)-8-(4-甲苯磺酰氨基)-喹啉,测量了其酸离解常数。在非离子型表面活性剂存在下,试剂与钴(Ⅱ)在pH9.0～11.2范围内形成配合物,ε_(645)=1.01×10~5L·mol~(-1)cm~(-1),在H_2o_2作用下,于λ_((?)m)/λ_((?)x)=420nm/345nm产生强荧光,建立了一个操作简便快速、灵敏度高、选择性好的荧光分析新方法,线性范围2～32ppb,检测极限0.1ngCo(Ⅱ)/ml,用以测量了维生素B_(12)及生物样品中的痕量钴(Ⅱ)。探讨了H_2O_2对荧光增敏的机理。     

One‐Step Synthesis of Small‐Sized and Water‐Soluble NaREF4 Upconversion Nanoparticles for In Vitro Cell Imaging and Drug Delivery

Small (2–28 nm) NaREF₄ (rare earth (RE)=Nd–Lu, Y) nanoparticles (NPs) were prepared by an oil/water two‐phase approach. Meanwhile, hydrophilic NPs can be obtained through a successful phase‐transition process by introducing the amphiphilic surfactant sodium dodecylsulfate (SDS) into the same reaction system. Hollow‐structured NaREF₄ (RE=Y, Yb, Lu) NPs can be fabricated in situ by electron‐beam lithography on solid NPs. The MTT assay indicates that these hydrophilic NPs with hollow structures exhibit good biocompatibility. The as‐prepared hollow‐structured NPs can be used as anti‐cancer drug carriers for drug storage/release investigations. Doxorubicin hydrochloride (DOX) was taken as model drug. The release of DOX from hollow α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ exhibits a pH‐sensitive release patterns. Confocal microscopy observations indicate that the NPs can be taken up by HeLa cells and show obvious anti‐cancer efficacy. Furthermore, α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ NPs show bright‐red emission under IR excitation, making both the excitation and emission light fall within the “optical window” of biological tissues. The application of α‐NaLuF₄:20 % Yb³⁺, 2 % Er³⁺ in the luminescence imaging of cells was also investigated, which shows a bright‐red emission without background noise.     

4-{[(2-Hydroxyphenyl)imino]methyl}-1,2-benzenediol (HIMB) anchored Amberlite XAD-16: Preparation and applications as metal extractants

Amberlite XAD-16 was loaded with 4-{[(2-hydroxyphenyl)imino]methyl}-1,2-benzenediol (HIMB) via azo linker and the resulting resin AXAD-16-HIMB explored for enrichment of Zn(II), Mn(II), Ni(II), Pb(II), Cd(II), Cu(II), Fe(III) and Co(II) in the pH range 5.0-8.0. The sorption capacity was found between 56 and 415 μmol g⁻¹ and the preconcentration factors from 150 to 300. Tolerance limits for foreign species are reported. The kinetics of sorption is not slow, as t_1/2 is ≤15 min. The chelating resin can be reused for seventy cycles of sorption-desorption without any significant change (<2.0%) in the sorption capacity. The limit of detection values (blank + 3 s) are 1.72, 1.30, 2.56, 2.10, 0.44, 2.93, 2.45 and 3.23 μg l⁻¹ for Zn, Mn, Ni, Pb, Cd, Cu, Fe and Co, respectively. The enrichment on AXAD-16-HIMB coupled with flame atomic absorption spectrometry (FAAS) monitoring is used to determine the metal ion ions in river and synthetic water samples, Co in vitamin tablets and Zn in powdered milk samples.     

Tuning the Surface of Nanoparticles: Impact of Poly(2‐ethyl‐2‐oxazoline) on Protein Adsorption in Serum and Cellular Uptake

Due to the adsorption of biomolecules, the control of the biodistribution of nanoparticles is still one of the major challenges of nanomedicine. Poly(2‐ethyl‐2‐oxazoline) (PEtOx) for surface modification of nanoparticles is applied and both protein adsorption and cellular uptake of PEtOxylated nanoparticles versus nanoparticles coated with poly(ethylene glycol) (PEG) and non‐coated positively and negatively charged nanoparticles are compared. Therefore, fluorescent poly(organosiloxane) nanoparticles of 15 nm radius are synthesized, which are used as a scaffold for surface modification in a grafting onto approach. With multi‐angle dynamic light scattering, asymmetrical flow field‐flow fractionation, gel electrophoresis, and liquid chromatography‐mass spectrometry, it is demonstrated that protein adsorption on PEtOxylated nanoparticles is extremely low, similar as on PEGylated nanoparticles. Moreover, quantitative microscopy reveals that PEtOxylation significantly reduces the non‐specific cellular uptake, particularly by macrophage‐like cells. Collectively, studies demonstrate that PEtOx is a very effective alternative to PEG for stealth modification of the surface of nanoparticles.

     

Ultrasound Assisted Synthesis and In Silico Modelling of 1,2,4-Triazole Coupled Acetamide Derivatives of 2-(4-Isobutyl phenyl)propanoic acid as Potential Anticancer Agents

The development of an economical method for the synthesis of biologically active compounds was the major goal of this research. In the present study, we have reported the ultrasound-radiation-assisted synthesis of a series of novel N-substituted 1,2,4-triazole-2-thiol derivatives. The target compounds 6a–f were efficiently synthesized in significant yields (75–89%) by coupling 1,2,4-triazole of 2-(4-isobutylphenyl) propanoic acid 1 with different electrophiles using ultrasound radiation under different temperatures. The sonication process accelerated the rate of the reaction as well as yielded all derivatives compared to conventional methods. All derivatives were confirmed by spectroscopic (FTIR, ¹HNMR, ¹³CNMR, HRMS) and physiochemical methods. All derivatives were further screened for their anticancer effects against the HepG2 cell line. Compound 6d containing two electron-donating methyl moieties demonstrated the most significant anti-proliferative activity with an IC₅₀ value of 13.004 µg/mL, while compound 6e showed the lowest potency with an IC₅₀ value of 28.399 µg/mL. The order of anticancer activity was found to be: 6d > 6b > 6f > 6a > 6c > 6e, respectively. The in silico modelling of all derivatives was performed against five different protein targets and the results were consistent with the biological activities. Ligand 6d showed the best binding affinity with the Protein Kinase B (Akt) pocket with the lowest ∆G value of −176.152 kcal/mol. Compound 6d has been identified as a promising candidate for treatment of liver cancer.     

藉聚2-丙烯胺缩-3-(4-甲酰基苯偶氮)-4,5-二羟基-2,7-萘二磺酸分光光度法测定生物体液、食品和饮品中的镁

聚2-丙烯胺缩3－（4-甲酰基苯偶氮）-4，5-二羟基-2，7-萘二磺酸（PA-FPNS）在pH11．5的磷酸盐介质中．与镁（Ⅱ）形成一蓝色络合物，其最大吸收位于604nm，表观摩尔吸光系数ε=5．7×104L·mol-1·cm-1，线性范围为0．01～0．35mg／L，至少稳定12h。考察了30多种共存离子的影响，在所测样品中它们不干扰，无需掩蔽或分离即可直接测得其中的镁。     

Synthesis and In Vitro Testing of YVO4:Eu3+@silica-NH-GDA-IgG Bio-Nano Complexes for Labelling MCF-7 Breast Cancer Cells

We present a visual tool and facile method to detect MCF-7 breast cancer cells by using YVO₄:Eu³⁺@silica-NH-GDA-IgG bio-nanocomplexes. To obtain these complexes, YVO₄:Eu³⁺ nanoparticles with a uniform size of 10–25 nm have been prepared firstly by the hydrothermal process, followed by surface functionalization to be bio-compatible and conjugated with cancer cells. The YVO₄:Eu³⁺@silica-NH-GDA-IgG nanoparticles exhibited an enhanced red emission at 618 nm under an excitation wavelength of 355 nm and were strongly coupled with MCF-7 breast cancer cells via biological conjugation. These bio-nanocomplexes showed a superior sensitiveness for MCF-7 cancer cell labelling with a detection percentage as high as 82%, while no HEK-293A healthy cells were probed under the same conditions of in vitro experiments. In addition, the detection percentage of MCF-7 breast cancer cells increased significantly via the functionalization and conjugation of YVO₄:Eu³⁺ nanoparticles. The experimental results demonstrated that the YVO₄:Eu³⁺@silica-NH-GDA-IgG bio-nanocomplexes can be used as a promising labelling agent for biomedical imaging and diagnostics.     

2-(4-甲氧羰基苯基)-5-硝基-6-羟基苯并噁唑的热分解机理及动力学

顺式聚对苯撑苯并二噁唑(cis-poly-paraphenyl enebenzobisoxazole,简称PBO)引起了人们的重视[1-3]。由PBO制得的高性能纤维的商品名为Zylon[2],Zylon不仅具有高的机械强度,而且具有高的热氧化稳定性[2,4-5]。PBO纤维和PBO复合材料在宇航、武器装备等领域中有广阔的应用前景[1-     

Synthesis and properties of aromatic polyamides with oligobenzamide pendent groups. I. Poly-5-(4-benzoylamino-1-benzoylamino)isophthalamides

A series of polyisophthalamides having pendent oligomeric benzamide groups were prepared by the Yamazaki reaction from common aromatic diamines and 5-(4-benzoylamino-1-benzoylamino)isophthalic acid. The latter was synthesized from 5-aminoisophthalic acid in a three-step synthesis by successive incorporation of benzamido groups. The new polymers were characterized by NMR, DSC, TGA, and WAXD and the properties were compared to those of corresponding unsubstituted polyisophthalamides. All of the polymers were essentially amorphous and their T_gs were about 20°C higher than the reference polymers. Initial thermal decomposition temperatures ranged from 375 to 420°C. All of the polymers were soluble in aprotic polar solvents without added salts. Properties of particular note were: the water uptake, which was particularly high, ranging from 7.5 to 18.2%, and the temporary insolubilization in concentrated sulfuric acid of films of the polymers heated for a short time to ≥ 200°C. © 1995 John Wiley & Sons, Inc.     

Sustainable and Efficacy Approach of Green Synthesized Cobalt Oxide (Co3O4) Nanoparticles and Evaluation of Their Cytotoxicity Activity on Cancerous Cells

In this study, rosemary leaf extract was effectively used to synthesize cobalt oxide nanoparticles (Co₃O₄ NPs) using a rapid, low-cost, and environmentally friendly approach. The prepared Co₃O₄ NPs were examined using various analytical techniques. However, UV spectrum analysis displayed two sharp absorption peaks at ~350 and 745 nm. The dynamic light scattering and zeta potential measurements were used to evaluate the particle size and the effective stabilization of the synthetic nanoparticles in the suspensions. A semi-triangular pyramidal shape of the Co₃O₄ NPs with a wide particle-size distribution could be observed in the scanning electron microscopy images. The energy-dispersive X-ray spectrum confirmed their successful synthesis, as the experimental atomic percentages agreed with the theoretical values. Moreover, X-ray diffraction analysis revealed that the synthesized Co₃O₄ NPs had a cubic crystalline structure corroborating that of theoretical Co₃O₄. Additionally, the Co₃O₄ NPs were not toxic at ≤62.5 µg/mL for Hep G2 and at ≤31.25 µg/mL for Mcf7. Therefore, these unique environmentally friendly Co₃O₄ NPs at this safe concentration could be studied in the future for their therapeutic activity.     

Group 13 Metal Halide Based Coordination Polymers of Al,Ga, In and 2,4,6-Tri(4-pyridyl)-1,3,5-triazine

Four isotypic one-dimensional coordination polymers (CP) were synthesized using the group 13 metal halides AlBr₃, GaCl₃, GaBr₃, and InI₃ and the tridentate ligand 2,4,6-tri(4-pyridyl)-1,3,5-triazine (tpt) serving as bidentate linker. The neutral one-dimensional CPs ¹_∞[AlBr₃(tpt)], ¹_∞[GaCl₃(tpt)], ¹_∞[GaBr₃(tpt)], and ¹_∞[InI₃(tpt)] are constituted by zigzag-shaped chains in the crystal structure, in which one coordination site of the tpt ligand remains uncoordinated. All CPs were characterized by SCXRD, PXRD, simultaneous DTA/TG, elemental-analysis and IR spectroscopy. Furthermore, three complexes of the composition [(AlBr₃)₃(tpt)], [(GaCl₃)₃(tpt)], and [(GaBr₃)₃(tpt)] were structurally characterized by SCXRD, being preliminary and side products of the formation of the coordination polymers.     

Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC₅₀) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.