Diosmetin alleviates neuropathic pain by regulating the Keap1/Nrf2/NF-κB signaling pathway.

BACKGROUND: Neuropathic pain, a chronic condition with a high incidence, imposes psychological burdens on both patients and society. It is urgent to improve pain management and develop new analgesic drugs. Traditional Chinese medicine has gained popularity as a method for pain relief. Diosmetin (Dio) is mainly found in Chinese herbal medicines with effective antioxidant, anti-cancer, and anti-inflammatory properties. There are few known mechanisms underlying the effectiveness of Dio in treating neuropathic pain. However, the complete understanding of its therapeutic effect is missing. PURPOSE: This study aimed to evaluate Dio's therapeutic effects on neuropathic pain models and determine its possible mechanism of action. We hypothesized that Dio may activate antioxidants and reduce inflammation, inhibit the activation of Kelch-like epichlorohydrin-associated protein 1 (Keap1) and nuclear factor-k-gene binding (NF-κB), promote the metastasis of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of heme oxygenase 1 (HO-1), thus alleviating the neuropathic pain caused by spinal nerve ligation. METHODS: Chronic nociceptive pain mouse models were established in vivo by L4 spinal nerve ligation (SNL). Different dosages of Dio (10, 50, 100 mg/kg) were intragastrically administered daily from the third day after the establishment of the SNL model. Allodynia, caused by mechanical stimuli, and hyperalgesia, caused by heat, were assessed using the paw withdrawal response frequency (PWF) and paw withdrawal latency (PWL), respectively. Cold allodynia were assessd by acetone test. RT-PCR was used to detect the content of interleukin-(IL)- 1ß, IL-6 and tumor necrosis factor (TNF)-a. Immunofluorescence and western blotting were employed to assess the expression levels of Glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule (Iba1), Keap1, Nrf2, HO-1, and NF-κB p-p65 protein. RESULTS: Dio administration relieved SNL-induced transient mechanical and thermal allodynia in mice. The protective effect of Dio in the SNL model was associated with its anti-inflammatory and anti-glial responses in the spinal cord. Dio inhibited both inflammatory factors and macrophage activation in the DRG. Furthermore, Dio regulated the Keap1/Nrf2/NF-κB signaling pathway. HO-1 and Nrf2 were upregulated following Dio administration, which also decreased the levels of Keap1 and NF-κB p65 protein. CONCLUSION: Mice with SNL-induced neuropathic pain were therapeutically treated with Dio. Dio may protect against pain by inhibiting inflammatory responses and improved Keap1/Nrf2/NF-κB pathway. These results highlight the potential therapeutic effect of Dio for the development of new analgesic drugs.

Identification of Nrf2/Keap1 pathway and its transcriptional regulation of antioxidant genes after exposure to microcystins in freshwater mussel Cristaria plicata.

Microcystins (MC) are one of the most abundant and widely distributed cyanotoxins in aquatic systems. MC inhibits the functions of protein phosphatase 1 and 2A (PP1/2A), which can seriously affect ecosystem integrity. The NF-E2-related nuclear factor 2 (Nrf2)/Kelch-like epichlorohydrin-related protein-1 (Keap1) signaling pathway protects against oxidative damage by activating phase II detoxification/antioxidant enzymes. Our previous study revealed that MC upregulates the expression and enhances the activities of the antioxidant enzymes by stimulating the CpNrf2 signaling pathway. In the current study, to further clarify the regulatory role of Keap1 in response to MC-induced oxidative stress in shellfish, we cloned the full-length cDNA of Keap1a and Keap1b from Cristaria plicata (designated CpKeap1a and CpKeap1b), which are 2952 and 3710 bp peptides, respectively. The amino acid sequence of CpKeap1a and CpKeap1b contained Tram-track and Bric-a-brac (BTB), Intervening region (IVR), and Double glycine repeat (DGR) domain. Additionally, CpKeap1a contained two cysteine residues analogous to Cys-273 and -288 in zebrafish, but CpKeap1b did not. Moreover, CpKeap1a and -1b formed a homodimer and heterodimer, respectively, and also formed a heterodimer with CpNrf2. In the hepatopancreas, the expression levels of CpKeap1a and -1b were the highest, but MC treatment down-regulated the expression of these proteins. Moreover, the transcription of antioxidant enzymes with antioxidant response element (ARE-driven enzymes), including CpMnSOD, CpCu/ZnSOD, CpTRX, CpPrx, CpSe-GPx, and Cpsigma-GST was upregulated by CpNrf2 in the hepatopancreas. Compared with the MC-induced group, CpKeap1a-siRNA1117 injection significantly increased the transcription of mRNAs for ARE-driven enzymes and Nrf2. CpKeap1a-siRNA1117 also enhanced the activities of antioxidation enzymes. These findings demonstrated that Keap1a negatively regulated the expression of Nrf2 protein and MC-induced oxidative stress response in C. plicata. Therefore, we speculated that CpKeap1a promoted CpNrf2 by recognizing and binding MC. These events then protected molluscs from MC-induced oxidative damage.

Epoxy-functionalized polyethyleneimine modified epichlorohydrin-cross-linked cellulose aerogel as adsorbents for carbon dioxide capture.

Developing affordable and effective carbon dioxide (CO2) capture technology has attracted substantial intense attention due to the continued growth of global CO2 emissions. The low-cost and biodegradable cellulosic materials are developed into CO2 adsorbent recently. Epoxy-functionalized polyethyleneimine modified epichlorohydrin-cross-linked cellulose aerogel (EBPCa) was synthesized from alkaline cellulose solution, epoxy-functionalized polyethyleneimine (EB-PEI), and epichlorohydrin (ECH) through the freezing-thawing processes and freeze-drying. The Fourier transform infrared spectroscopy confirmed that the cellulose aerogel was successfully modified by EB-PEI. The X-ray photoelectron spectroscopy analyses confirmed the presence of N 1s and Cl 2p in EBPCa, meaning that the chlorine of ECH and the amino groups of EB-PEI exist in the cellulose surface. The obtained sample has a rich porous structure with a specific surface area in the range of 97.5-149.5 m2/g. Owing to its uniformly three-dimensional porous structure, the sample present preferable rigidity and carrying capacity, which 1 g of sample could easily carry the weight of a 3000 ml Erlenmeyer flask filled with water (total 4 kg). The sample showed good adsorption performance, with a maximum adsorption capacity of 6.45 mmol/g. This adsorbent has broad prospects in the CO2 capture process.

Sustainable, High-Performance, and Biodegradable Plastics Made from Chitin.

A high-performance biodegradable plastic was made from a chitin KOH/urea solution. The solution was transferred into a hydrogel by cross-linking using epichlorohydrin and ethanol immersion, and a chitin bioplastic was finally prepared by drying in a mold at 40 °C. The solution concentration positively impacts viscosity, crystallinity, and smoothness. A 4% chitin bioplastic exhibits high barrier properties, flame retardancy, high-temperature resistance, mechanical properties (tensile strength up to 107.1 MPa), and soil degradation properties. The chitin bioplastic can be completely degraded by microorganisms in 7 weeks. In addition, biosafety tests suggest that chitin is safe for cells and crops (wheat and mung beans). The chitin bioplastic was further applied to containers, straws, cups, and photoprotection, and it was found that the water resistance and transparency were comparable to those of commercial polypropylene plastics. Due to the excellent performance, safety, and sustainability of the chitin bioplastic, it is expected to become a good substitute for conventional fossil fuel-based plastics.

Asymmetric Synthesis of Methoxylated Ether Lipids: A Glyceryl Glycidyl Ether Key Building Block Design, Preparation, and Synthetic Application.

The report describes the preparation and use of a double-C3 building block intended as a head group synthon in the synthesis of saturated, mono-, and polyunsaturated 1-O-alkyl-sn-glycerol type methoxylated ether lipids (MELs). The resulting head piece, an enantiopure isopropylidene-protected glyceryl glycidyl ether diastereomer, was accomplished in 49% yield (max 50%) from a 1:1 diastereomeric mixture obtained from R-solketal and racemic epichlorohydrin after treatment with the Jacobsen (S,S)-Co(III)salen catalyst for the hydrolytic kinetic resolution of terminal epoxides. The diol hydrolytic product obtained in 47% yield from the unwanted diastereomer was reconverted into epoxide with an inversion of configuration in a three-step operation involving a highly regioselective lipase. This enabled the recovery of a substantial amount of diastereopure material after a subsequent treatment with the Jacobsen catalyst to furnish the oxirane head piece in altogether 72% yield of higher than 99% diastereomeric purity. A modified synthesis of a monounsaturated 16:1 MEL confirmed the correct stereochemistry and excellent enantiopurity of the head piece and resulted in a dramatic improvement in yields, efficiency, and economy of the synthesis.

Development of a SAW poly(epichlorohydrin) gas sensor for detection of harmful chemicals.

The uniformity and compactness of the surface of a viscoelastic sensitive film are among the most important factors that influence the characteristics of a surface acoustic wave (SAW) gas sensor, directly affecting the detection sensitivity of a SAW sensor on a target gas. In this paper, poly(epichlorohydrin) (PECH) with viscoelastic properties was used as sensitive film for the detection of 2-chloroethyl ethyl sulfide (CEES), a common simulant of the chemical agent mustard gas. Nanoscale films were prepared using a spin coating technology on a SAW delay line of 200 MHz. Films were evaluated using polarizing microscopy and atomic force microscopy and observed with uniform surface states and particle diameter in the cluster region of 4.52-5.22 µm. The interface parameters, including contact angle, surface tension, Gibbs free energy, work of adhesion, work of immersion, and spreading coefficient values were 9.31° to 39.63°, 22.475 to 29.945 mN m-1, -85.70 to -78.08 J m-2, 78.08 to 85.70 J m-2, -42.62 to -35.00 J m-2, and 0.46 to 8.08 J m-1, respectively. These values were obtained by experiments combined with the Young T equation and Gibbs adsorption isotherm, and the surface analysis was carried out theoretically. The glass transition temperature (-22.4 °C), viscosity, pyrolysis, and other physical characteristics of the prepared PECH were discussed. Five SAW sensors prepared at the same time were used to test the repeatability of CEES measurements at one concentration, where the consistency of the sensor preparation was confirmed. At a concentration of 13.6 mg m-3 for CEES, 10 consecutive detection results showed good repeatability (i.e., standard deviation = 0.295, coefficient of variance = 0.021, and population mean deviation = 0.364). At room temperature (20 °C ± 5 °C), different concentrations of CEES were detected using the developed sensor, which showed good linearity in the concentration range of 1.9-19.6 mg m-3 (y = 0.0309 + 1.13x, r = 0.99478). The limit of detection was 0.85 mg m-3, the limit of quantitation was 1.91 mg m-3, and the sensitivity of the SAW sensor was 1.13 mV (mg m-3). The adsorption mechanism related to PECH in the detection of CEES was also discussed.

Antioxidant and antibacterial properties of essential oils-loaded ß-cyclodextrin-epichlorohydrin oligomer and chitosan composite films.

Chitosan (CS) is becoming increasingly popular in food packaging due to its natural degradability and great film-forming properties. Nevertheless, its poor antibacterial properties and inadequate antioxidant properties prevent it from being used effectively. In this study, ß-cyclodextrin-epichlorohydrin (ß-CD-EP) oligomers were prepared and encapsulated with natural essential oils cinnamaldehyde and thymol, and then the inclusion complexes (IC) were incorporated into chitosan in various contents to afford a series of CS-IC composite films. The impacts of IC on the morphological, mechanical, thermal, and water resistance properties, antioxidant and antibacterial activities of chitosan films, as well as the loading and sustained release behavior of IC, were thoroughly examined. The results turned out that the essential oils were well-loaded with high encapsulation efficiency and showed a significant slow-release effect. It was also found that the tensile strength and the elongation at break decreased with increasing IC contents, while the thermal stability was enhanced. The incorporation of IC dramatically promoted the antioxidant and antibacterial properties of the chitosan films towards Gram-positive bacteria. Based on our findings, chitosan films containing essential oils-loaded ß-CD-EP oligomers may serve as an effective food packaging material.

Synthesis of the Alkylsulfonate Metabolites Cysteinolic Acid, 3-Amino-2-hydroxypropanesulfonate, and 2,3-Dihydroxypropanesulfonate.

Chiral hydroxy- and aminohydroxysulfonic acids are widespread in the marine and terrestrial environment. Here we report simple methods for the synthesis of d- and l-cysteinolic acid (from (Boc-d-Cys-OH)2 and (Boc-l-Cys-OH)2, respectively), R- and S-3-amino-2-hydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively), and R- and S-2,3-dihydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively). d-Cysteinolate bile salts were generated by coupling with cholic and chenodeoxycholic acids. A series of single-crystal 3D X-ray structures confirmed the absolute configurations of the aminosulfonates. By comparison of optical rotation, we assign naturally occurring 3-amino-2-hydroxypropanesulfonate from Gateloupia livida as possessing the R-configuration. This simple synthetic approach will support future studies of the occurrence, chemotaxonomic distribution, and metabolism of these alkylsulfonates.

Epichlorohydrin and tripolyphosphate-crosslinked chitosan-kaolin composite for Auramine O dye removal from aqueous solutions: Experimental study and DFT calculations.

Chitosan (Ch, a natural polymer) and kaolin (K, a natural mineral) composite (Ch-K) was produced with the help of two crosslinkers, epichlorohydrin and tripolyphosphate, and then moulded into uniform beads in tripolyphosphate solution. The synthesis was proved by the analyses involving FT-IR and SEM-EDX. The beads were then used as the natural adsorbent for removal of the auramine O (AO), a frequently-used industrial dye, in aqueous solutions. Adsorbent performance of the Ch-K composite for AO dye molecules was optimized: 500 mg L-1 at pH 7.5 at 25 °C. The Langmuir model found 0.118 mol kg-1 for the maximum adsorption capacity of the Ch-K and the D-R isotherm model showed that the nature of the adsorption process was physical. Kinetics of the adsorption could be explained by using both IPD (intraparticle diffusion) and PSO (pseudo second order) models. Thermodynamic parameters demonstrated that the behaviour of the adsorption was an endothermic and spontaneous. The activity of the composite adsorbent was recovered (88%) after the five sequential adsorption/desorption cycles. Supported by experimental findings, the results obtained from in silico modeling at M06-2X/6-31+G (d,p) level helped hypothesise a mechanism for the formation of the Ch-K composite, and shed some light onto the adsorption behaviour of AO dye by assuming several favourable intermolecular interactions.

Preparation, Characterization and Evaluation of the Anti-Inflammatory Activity of Epichlorohydrin-ß-Cyclodextrin/Curcumin Binary Systems Embedded in a Pluronic®/Hyaluronate Hydrogel.

Curcumin (Cur) is an anti-inflammatory polyphenol that can be complexed with polymeric cyclodextrin (CD) to improve solubility and bioavailability. The aim of the present work was to prepare a CurCD hydrogel to treat inflammatory skin conditions. Epichlorohydrin-ß-CD (EpißCD) was used as polymeric CD. To characterize the binary system, solid-state and in-solution studies were performed. Afterwards, an experimental design was performed to optimize the hydrogel system. Finally, the CurEpißCD hydrogel system was tested for anti-inflammatory activity using a HaCat psoriasis cell model. Co-grinded Cur/EpißCD binary system showed a strong interaction and Curcumin solubility was much improved. Its combination with Pluronic® F-127/hyaluronate hydrogel demonstrated an improvement in release rate and Curcumin permeation. After testing its anti-inflammatory activity, the system showed a significant reduction in IL-6 levels. Hydrogel-containing CurEpißCD complex is a great alternative to treat topical inflammatory diseases.

Highly selective removal and recovery of Ni(II) from aqueous solution using magnetic ion-imprinted chitosan nanoparticles.

Nickel (Ni) is one of the most common heavy metals. In this study, nano-sized magnetic ion-imprinted polymers (MIIPs) were synthesized using chitosan as the functional monomer, and used for selective adsorption and recovery of Ni(II) from solutions. The results showed MIIPs possessed high sorption selectivity for Ni(II), and the change in pH (5.0-9.0) exerted insignificant influence on the ion adsorption, allowing almost complete elution and recovery of adsorbed Ni(II) ions by using 0.5% EDTA-Na solution. Moreover, the sorption capacity of the recycled MIIPs decreased by only about 10% after 15 adsorption-desorption cycles. The time required for establishing the adsorption equilibrium was less than 1 h. The sorption process was predominant and endothermic, and could be well described by both Langmuir isotherm model and pseudo-second-order kinetic model. Therefore, the synthesized MIIPs was a suitable adsorbent for highly selective, fast and efficient removal and recovery of low-concentration Ni(II) ions from wastewaters.

Chitin-hydroxyapatite-collagen composite scaffolds for bone regeneration.

Bone defect is usually difficult to recover quickly, and bone scaffold transplantation is considered to be an effective method. Biomaterials have a wide range of application prospects in bone tissue repair, and the two key problems are the selection of materials and cells. The object of this study was to discuss the structural characteristics of bone scaffold materials and their effects on bone repair in vivo. The chitin-hydroxyapatite (HAP)-collagen composite scaffolds (CHCS) was prepared with epichlorohydrin (ECH) as crosslinking agent. The structure was characterized and the compressive strength, porosity, water absorbency and stability were investigated. The biocompatibility and osteogenic differentiation of CHCS in vitro were detected, and the effect of defect repair in vivo was evaluated. The results suggested that HAP not only enhanced the compressive strength of CHCS, but also promoted the formation of calcium nodules due to its bone conductivity. Histological staining showed that collagen promoted collagen deposition and new bone formation. X-ray images also indicated that CHCS transplantation accelerated bone repair. Therefore, CHCs has immense potential in bone regeneration.

[Determination of 1-chloro-2,3-epoxypropane in order to assess the working environment]. / Oznaczanie 1-chloro-2,3-epoksypropanu dla potrzeb oceny srodowiska pracy.

BACKGROUND: 1-Chloro-2,3-epoxypropane, known as epichlorohydrin (ECH), is a colorless liquid used in the production of epoxy resins, synthetic glycerine, elastomers, glycidyl ethers, surfactants, polyamide-epichlorohydrin resins and others. Epichlorohydrin may cause cancer. The aim of this study was to develop a new method for determining concentrations of ECH in workplace air in the range of 1/10-2 values of the maximum admissible concentration (MAC). MATERIAL AND METHODS: The paper presents a method for the determination of ECH in workplace air using a gas chromatograph coupled with a mass spectrometer (GC-MS). The developed method is based on the adsorption of ECH on an activated charcoal, extraction with acetone, and a chromatographic analysis of the resulting solution. RESULTS: The method developed makes it possible to determine ECH in the concentration range of 0.1-2 mg/m3, i.e., 1/10-2 values of MAC established in Poland. The limit of detection (LOD) is 0.24 µg/m3 and the limit of quantification (LOQ) is 0.71 µg/m3. CONCLUSIONS: The method is characterized by good precision and accuracy; it meets the requirements of the European standard PN-EN 482, and can be used by occupational hygiene laboratories to measure concentrations of ECH in workplace air, with a view to assessing workers' exposure to this substance. Med Pr. 2020;71(6):715-23.

Fabrication of a novel nontoxic trichlorophenol-epichlorohydrin-based compound with high antimicrobial activity and thermal stability.

The aim of this study was to modify a discontinued, toxic antiseptic agent 2,4,5-trichlorophenol (TCP) by reacting it with epichlorohydrin (ECH) to obtain a nontoxic novel compound with similar antimicrobial effectiveness. A novel compound named {[1,3-bis(2,4,5-trichlorophenoxy) propan-2-yl] oxy}-3-(2,4,5-trichlorophenoxy) hexan-2-ol (TPTH) was synthesized from this reaction. Chemical and physical structures of the product were characterized by FTIR, MS, Uv-vis, NMR, SEM and TEM. The thermal stability of TPTH was evaluated by conducting thermogravimetric analysis. Biological interactions of the compound were investigated by performing antimicrobial activity and cytotoxicity assays. The compound displayed a good antimicrobial activity where minimum inhibitor concentrations were found to be 0.02, 0.08, and 0.15 µg mL-1 against Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) respectively. Additionally, well diffusion assay demonstrated that, the zone of inhibitions for S. aureus, MRSA and E. coli were 24 mm, 22 mm and 18 mm, respectively. Cytotoxicity assay results revealed that TPTH is nontoxic against cells at effective anti-microbial concentrations. TPTH shows thermal stability up to 220 °C. Results here demonstrate the successful conversion of toxic TCP to a nontoxic form; TPTH with a good anti-microbial activity and thermal stability.

Inflammation targeted chitosan-based hydrogel for controlled release of diclofenac sodium.

Inflammation is a key challenge in the treatment of chronic diseases. Spurred by topical advancement in polymer chemistry and drug delivery, hydrogels that release a drug in temporal, spatial and dosage controlled fashion have been trendy. This research focused on the fabrication of hydrogels with controlled drug release properties to control inflammation. Chitosan and polyvinyl pyrrolidone were used as base polymers and crosslinked with epichlorohydrin to form hydrogel films by solution casting technique. Prepared hydrogels were analyzed by swelling analysis in deionized water, buffer and electrolyte solutions and gel fraction. Functional groups confirmation and development of new covalent and hydrogen bonds, thermal stability (28.49%) and crystallinity were evaluated by FTIR, TGA and WAXRD, respectively. Rheological properties including gel strength and yield stress, elasticity (2309 MPa), porosity (75%) and hydrophilicity (73°) of prepared hydrogels were also evaluated. In vitro studies confirmed that prepared hydrogels have good biodegradability, excellent antimicrobial property and admirable cytotoxicity. Drug release profile (87.56% in 130 min) along with the drug encapsulation efficiency (84%) of prepared hydrogels was also studied. These results paved the path towards the development of hydrogels that can release the drugs with desired temporal patterns.

[THE CELLULAR COMPOSITION OF THE EPITHELIUM OF THE VILLUS OF THE MUCOUS MEMBRANE OF THE DUODENUM OF RATS IN THE CONDITIONS OF EPICHLOROHYDRIN AND DRUG INFLUENCE].

Purpose of the research is to study the nature of the disorders of the villi of the duodenal mucous membrane (MM) in conditions of long-acting ECH as well as to substantiate experimentally the effectiveness of the use of the extract of Echinacea purpurea (EP) and thiotriazoline for the purpose of these disorders correction. The withdrawal of the rats from the experiment was carried out on the 1st, 7th, 15th, 30th and 60th day after the completion of the administration of ECH, EP extract and thiotriazoline. Histological processing of duodenum fragments was performed according to the standard method. The cell composition of the villus epithelium of duodenal MM was evaluated using a laboratory microscope of the MC 100 (Micros, Austria) and the Microvisible software (version 1.11.10). The determination of the significance of differences was carried out according to the Mann-Whitney U criterion. Differences were considered significant at p<0.05. Prolonged action of ECH led to a decrease in the number of cells in one villus of duodenal MM. This decrease persisted after the end of the administration of this chemical. There was a decrease in the number of columnar epithelial cells, goblet exocrinocytes and argyrophil endocrinocytes. In rats that did not receive ECH, administration of an EP extract was accompanied by a short-term increase in the number of columnar epithelial cells in one villus of duodenal MM. The administration of thiotriazolin to rats that did not receive ECH caused a short-term increase in the number of cells in one villus of duodenal MM and the number of columnar epithelial cells in the one villus of duodenal MM. The use of EP extract on the background of inhalations of ECH reduced the degree of decrease in the number of cells in one villus of duodenal MM and the number of columnar epitheliocytes in one villus of duodenal MM, reduced the degree and duration of reduction in the number of goblet exocrinocytes in one villus of duodenal MM, reduced the duration of reduction in the number of argyrophil endocrinocytes in one villus of duodenal MM. The use of thiotriazolin during the administration of ECH led to a decrease in the degree and duration of a decrease in the number of cells in one villus of duodenal MM and the number of columnar epithelial cells in one villus of duodenal MM, and also prevented the occurrence of a decrease in the number of goblet exocrinocytes and argyrophil endocrinocytes in one villus of duodenal MM.

Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their ß-adrenoceptor blocking property.

The design, synthesis, antinociceptive and ß-adrenoceptor blocking activities of several eugenyloxy propanol azole derivatives have been described. In this synthesis, the reaction of eugenol with epichlorohydrin provided adducts 3 and 4 which were N-alkylated by diverse azoles to obtain the eugenyloxy propanol azole analogues in good yields. Adducts 3 and 4 were also reacted with azide ion to obtain the corresponding azide 6. The 'Click' Huisgen cycloaddition reaction of 6 with diverse alkynes afforded the title compounds in good yields. The synthesized eugenyloxy propanol azole derivatives were in vivo studied for the acute antinociception on male Spargue Dawley rats using tail-flick test. Compounds 5f, 5g, 7b and 11a exhibited potent analgesic properties in comparison with eugenol as a standard drug. In addition, all compounds were ex vivo tested for ß-adrenoceptor blocking properties on isolated left atrium of male rats which exhibited partial antagonist or agonist behaviour compared to the standard drugs. The molecular docking study on the binding site of transient receptor potential vanilloid subtype 1 (TRPV1) has indicated that like capsaicin, eugenyloxy propanol azole analogues exhibited the strong affinity to bind at site of TPRV1 in a "tail-up, head-down" conformation and the presence of triazolyl moieties has played undeniable role in durable binding of these ligands to TRPV1. The in silico pharmacokinetic profile, drug likeness and toxicity predictions carried out for all compounds determined that 5g can be considered as potential antinociceptive drug candidate for future research.

Investigation of inclusion behaviour of gefitinib with epichlorohydrin-ß-cyclodextrin polymer: preparation of binary complex, stoichiometric determination and characterization.

Gefitinib is anticancer drug which is sparingly soluble in water. This limits its dissolution and bioavailability. Binary inclusion complex of gefitinib with Epi-ß-CD was prepared by freeze-drying method. Stoichiometric ratio of 1:1 M was established by continuous variation (Job's) plot. The stability constant of complex as determined by phase solubility study was found to be 15,871.3 M-1. Complex was characterized by FTIR, DSC, DTA and dissolution study. Results revealed that in complex the drug no longer exist in crystalline state and is converted into amorphous form; which shows higher dissolution efficiency as compared to crystalline drug. The solubilizing efficiency for freeze dried complex was found to be 175.57 and the relative drug crystallinity degree was 87.91% as estimated by thermal analysis. Complexation led to decrease in surface tension; from 54.8 dynes/cm (pure gefitinib) to 40.3 dynes/cm (FD complex) due to adsorption phenomenon. The results obtained in this study confirmed that complexation of gefitinib with Epi-ß-CD is a prominent approach and suitable tool for tailoring the issue related to its delivery and can be explored for development of an effective delivery system.

Cross-linking by epichlorohydrin and diepoxybutane correlates with cytotoxicity and leads to apoptosis in human leukemia (HL-60) cells.

The bifunctional alkylating agents epichlorohydrin (ECH) and diepoxybutane (DEB) have been linked to increased cancer risks in industrial workers. These compounds react with DNA and proteins, leading to genotoxic effects. We used the comet assay to monitor formation of cross-links in HL-60 cells treated with ECH, DEB, and the structurally related anti-cancer drug mechlorethamine (HN2). We report a time- and dose-dependent cytotoxicity that correlated with cross-linking activity, following the order HN2 > DEB > ECH. The rate of cross-link repair also varied with drug, with ECH-induced lesions the fastest to repair. High drug doses led to the formation of saturating amounts of HN2 cross-links that were repaired inefficiently. DEB and ECH produced fewer overall cross-links, but some were also resistant to repair. These persistent cross-links may activate cell-cycle arrest to allow repair of damage, with prolonged arrest triggering apoptosis. Quantitative reverse transcription polymerase chain reaction experiments revealed that treatment of HL-60 cells with DEB and ECH results in up-regulation of several genes involved in the intrinsic (mitochondrial) apoptosis pathway, including BAX, BAK1, CASP-9, APAF-1, and BCL-2. These findings contribute to our understanding of the principles underlying the carcinogenic potentials of these xenobiotics.

Rubbery Chitosan/Carrageenan Hydrogels Constructed through an Electroneutrality System and Their Potential Application as Cartilage Scaffolds.

In the present work, the bulk and homogeneous composite hydrogels were successfully constructed from positively charged chitosan (CS) and negatively charged carrageenan (CG) in alkali/urea aqueous solution via a simple one-step approach for the first time. An electroneutral CS solution was achieved in alkali/urea, leading to a homogeneous solution blended by CS and CG, which could not be realized in acidic medium because of the agglomeration caused by polycation and polyanion. Subsequently, the CS/CG composite hydrogels with multiple cross-linked networks were prepared from blend solution by using epichlorohydrin (ECH) as the cross-linking agent. The composite hydrogels exhibited hierarchically porous architecture, excellent mechanical properties as well as pH- and salt-responsiveness. Importantly, the composite hydrogels were successfully applied for spreading ATDC5 cells, showing high attachment and proliferation of cells. The results of fluorescent micrographs and scanning electronic microscope images revealed that the CS/CG composite hydrogels enhanced the adhesion and viability of ATDC5 cells. The alcian blue staining, glycosaminoglycan quantification, and real-time PCR analysis proved that the CS/CG composite hydrogels could induce chondrogenic differentiation of ATDC5 cells in vitro, exhibiting great potential for application in cartilage repair. This work provides a facile and fast fabrication pathway for the construction of ampholytic hydrogel from polycation and polyanion in an electroneutrality system.