Hepatoprotective effect of Ginkgo biloba extract against methotrexate-induced hepatotoxicity via targeting STAT3/miRNA-21 axis.

The usage of the chemotherapeutic agent methotrexate (MTX) was associated with hepatotoxicity that minimized its clinical use. The Ginkgo biloba extract (GBE) was used before to alleviate the MTX-induced liver injury through its antioxidant activity. This work was carried out to elucidate other molecular hepatoprotective mechanisms of GBE via examining the IL-6/STAT3 pathway in addition to the miRNA-21 expression in hepatic tissue. Sprague Dawley rats were allocated into four groups: normal control (NC); Ginkgo biloba extract control (GBEC); methotrexate (MTX); and Ginkgo biloba extract and methotrexate (GBE + MTX) group. GBE was administered orally 60 mg/kg/day for 10 days while MTX was intraperitoneally injected with 20 mg/kg on day 5. After the experiment, the serum was separated for liver enzyme determination while liver tissues were collected for biochemical and histopathological examinations. MTX induced marked elevation in the liver enzymes, hepatic IL-6, and HGF mRNA expressions, phospho-STAT3/STAT3 ratio, and miRNA-21 hepatic expression when compared with the NC group. Liver injury was observed histopathologically after MTX. The GBE administration reversed these biochemical alterations and improved liver histopathology. The hepatoprotective mechanism of GBE against MTX-induced hepatotoxicity via the modulation of the IL-6/STAT3 signaling pathway and the downregulation of the miRNA-21 hepatic expression was reported for the first time.

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11ß-HSD1 Inhibitors.

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P21/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO2/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11ß-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11ß-HSD1 inhibitors were able to accurately dock within the 11ß-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11ß-HSD1 binding affinity scores as well as interactions to a known potent 11ß-HSD1 inhibitor.

Renoprotective effect of vildagliptin following hepatic ischemia/reperfusion injury.

Remote renal injury is a drastic consequence of hepatic ischemia/reperfusion (IR) injury. Vildagliptin (V) is a dipeptidyl peptidase-4 inhibitor that has a hepatorenal protective effect against models of liver and renal IR. This research was done to explore the protective role of vildagliptin against renal injury following hepatic IR injury as well as the possible involvement of transforming growth factor-beta (TGF-ß)/Smad/alpha-smooth muscle actin (α-SMA) expressions in the pathophysiological mechanism of the remote renal injury. Three groups of male Wistar rats were organized into: sham group, IR group, and V + IR group in which 10 mg/kg/day of vildagliptin was pretreated for 10 days intraperitoneally. Blood in addition to renal and hepatic tissue samples was used for biochemical and histopathological studies. Hepatic IR induced a marked increase in serum creatinine, blood urea nitrogen, liver enzymes, renal nitric oxide, malondialdehyde, tumor necrosis factor-alpha levels with a marked upregulation of renal mRNA expressions of TGF-ß, Smad2, Smad3, and α-SMA in addition to a marked decline in renal catalase content comparing to the sham group. Abnormal histopathological findings of hepatic and renal injury were detected in the IR group. Vildagliptin significantly improved these biochemical markers as well as the histopathological changes. The upregulation of renal TGF-ß/Smad/α-SMA mRNA expressions was involved for the first time in the pathogenesis of the renal injury following hepatic IR and vildagliptin ameliorated this renal injury through blocking these expressions.

The therapeutic and antineoplastic effects of vitamin B17 against the growth of solid-form Ehrlich tumours and the associated changes in oxidative stress, DNA damage, apoptosis and proliferation in mice.

Many cancer therapies indirectly activate apoptosis by chemical or physical damage of DNA. This study was performed to evaluate protective potential of vitamin B17 (VitB17) against Ehrlich solid tumor (EST) induced changes in the oxidative stress, DNA damage, apoptosis and proliferation in mice. In the experiment, 60 female CD1 mice were randomly and allocated to the following four equal-sized groups [G1, negative control; G2, positive control (VitB17); G3, untreated EST; G4, EST treated with VitB17 (EST+VitB17)]. The untreated EST group displayed major increases in tumor volume, significant increase in the levels of MDA, H2O2, NO, PCNA, TNF-α, AFP and dsDNA and notable reductions in the catalase, GSH, P53 and SOD activities. By contrast, reduced levels of TNF-α, AFP, MDA, H2O2, NO, PCNA and dsDNA, along with enhanced levels of P53 and the antioxidant indicators catalase, GSH and SOD were observed in the EST+VitB17 group. These results indicate the antineoplastic and antioxidant properties of vitamin B17 with the potential to decrease the oxidative stress associated with ESTs by augmenting the antioxidant defence system.

Dispersive liquid-liquid microextraction of lead(II) as 5-(4-dimethylaminobenzylidene) rhodanine chelates from food and water samples.

A dispersive liquid-liquid microextraction procedure for lead(II) as its 5-(4-dimethylaminobenzylidene) rhodanine complex has been established prior to its microsampling flame atomic absorption spectrometric determination. The influences of various analytical parameters including pH, solvent type and volume, dispersive solvent type and volume, 5-(4-dimethylaminobenzylidene) rhodanine amount, salt effect, and centrifugation time and speed were investigated. The effects of certain alkali, alkaline earth, and transition metal ions on the quantitative extraction of lead(II) were also studied. Quantitative recoveries were obtained at pH 6. The enrichment factor was calculated as 125. The detection limit for lead is 1.1 µg/L. The accuracy of the method was tested with the additions recovery test and analysis of the standard reference materials (SPS-WW2 waste water, NIST SRM 1515 apple leaves, and TMDA-51.3 fortified water). Applications of the present procedure were tested by analyzing water and food samples.

SERS study of classical and newly ß-lactams-metal complexation based on in situ laser-induced coral reefs-like silver photomicroclusters: In vitro study of antibacterial activity.

The influence of metal complexation of two polar ß-lactam antibiotics was investigated using surface enhanced Raman spectroscopy (SERS) technique. SERS method was applied to track the structural changes and the degradation behaviour of the studied compounds upon Zinc (II) ions-complexation. In situ laser-induced coral reefs-like photomicroclusters have been utilized as a SERS platform. The produced coral reefs-like photomicroclusters were characterized using scanning electron microscopy (SEM) and transmission electron microscope (TEM). The antibacterial efficiency of the antibiotics was investigated and compared before and after metal complexation using two techniques; agar well diffusion and growth curve. To provide a detailed elucidation of the complexation reaction, mass fragmentation of metal- antibiotics complexes was investigated using liquid chromatography/mass spectrometric (LC/MS) technique. It was found that metal complexation of classical ß-lactam antibiotic (Ticarcillin) promoted the rate of its degradation, leading to a decrease of the antibacterial efficiency. On the other side, the antibacterial activity of the newly developed ß-lactam (Faropenem) has been greatly enhanced via metal-complexation reaction.

Alleviation of chemotherapy-induced acute lung injury via NLRP3/ ASC/ Caspase-1 signaling pathway.

Acute lung injury has been reported following various chemotherapeutic agents administration. Several pathways for lung injury have been speculated however, the exact mechanism of the lung injury induced by methotrexate (MTX) is yet to be defined. The potential protective effect of Ginkgo biloba extract (GB), a Chinese herbal medicine, against MTX-induced lung injury is still not reported. Therefore, this study was performed to examine the possible implication of NLRP3 inflammasome and miRNA-21 in the pathogenesis of the MTX-induced lung injury as well as the protective role of GB in ameliorating the induced lung injury. Rats received GB (100 mg/kg/day, orally) for 10 days and MTX (20 mg/kg single dose, intraperitoneally) on the fifth day. MTX-induced lung injury was manifested by lung histopathology. MTX exhibited a marked increase in lung malondialdehyde beside a notable decrease in lung reduced glutathione. Moreover, MTX injection activated the lung NLRP3 inflammasome by significant upregulation of the NLRP3, ASC, caspase-1 lung mRNA expressions and protein levels in addition to lung NF-kBp65 protein expression, and miRNA-21 expression when compared with the normal control group. However, GB administration mitigated lung injury and inhibited the NLRP3 activation. This study is the first report to reveal the involvement of NLRP3 inflammasome in the pathogenesis of MTX-induced lung injury and also to show that the administration of GB alleviates the lung injury induced by MTX via suppressing the oxidative stress, restoring the antioxidant activity, blocking the NLRP3/ASC/Caspase-1 signaling and downregulating the NF-kBp65 protein expression ae well as miRNA-21 expression in lung tissue.

Inspection of antimicrobial remains in bovine milk in Egypt and Saudi Arabia employing a bacteriological test kit and HPLC-MS/MS with estimation of risk to human health.

Veterinary medicine uses antibiotics randomly for treatment and growth promotion. Milk of dairy animals contains substantial quantities of antibiotics that have harmful effects on health. It is therefore necessary to test commercially available milk using immunological, chromatographic, or microbiological methods to confirm the absence of antibiotic residues. This study aims to perform a microbiological test, followed by a quantitative confirmation analysis, on raw milk to assess the presence of antibiotic residues. Tests were conducted on 200 milk samples collected from markets and farms in Saudi Arabia and Egypt. The microbial inhibitor test (Delvotest SP-NT) revealed that 40 samples were positive for antibiotic residues. The positive samples were further tested using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a confirmatory quantitative test for 29 antibiotics that belong to five groups: tetracyclines, sulfonamides, fluoroquinolones, macrolides, and lactamases. Only four samples tested positive for oxytetracycline residues above the maximum residue limit. Based on these results, researchers suggest a monitoring system that considers both microbial and HPLC-MS/MS methods when detecting antibiotic residues in bovine milk. The analysis of risk to human health revealed that antibiotic residues at the detected levels do not pose any health risks to consumers.

Supramolecular Self-Assembly Mediated by Multiple Hydrogen Bonds and the Importance of C-S···N Chalcogen Bonds in N'-(Adamantan-2-ylidene)hydrazide Derivatives.

The present article comprehensively examines six N'-(adamantan-2-ylidene)hydrazide derivatives using the Hirshfeld surface analysis, PIXEL energy for molecular dimers, lattice energies for crystal packing, and topological analysis for intramolecular and intermolecular interactions. The crystal structure of one of the N'-(adamantan-2-ylidene)hydrazide derivatives, namely, N'-(adamantan-2-ylidene)-5-bromothiophene-2-carbohydrazide 1, C15H17N2OSBr, has been determined and analyzed in detail along with five closely related structures. The molecular conformation of 1 is locked by an intramolecular C-S···N chalcogen bond as found in one of its closely related structure, namely, N'-(adamantan-2-ylidene)thiophene-2-carbohydrazide. Furthermore, a detailed potential energy surface scan analysis has been performed to highlight the importance of a chalcogen bond. Two of these compounds possess syn-orientation for amide units, whereas the corresponding moiety exhibits anti-conformations in the remaining four structures. The Hirshfeld surface and its decomposed fingerprint plots provide a qualitative picture of acyl substituent effects on the intermolecular interactions toward crystal packing of these six structures. Intermolecular interaction energies for dimers observed in these structures calculated by density functional theory (B97D3/def2-TZVP) and PIXEL (MP2/6-31G**) methods are comparable. This study also identifies that multiple hydrogen bonds, including N/C-H···O/N and C-H···π interactions, are collectively responsible for a self-assembled synthon. The nature and strength of these interactions have been studied using atoms in molecule topological analysis. The in vitro antiproliferative activity of compound 1 was assessed against five human tumor cell lines and showed marked antiproliferative activity.

Synthesis, characterization and biological activities of Cu(II), Co(II), Mn(II), Fe(II), and UO2(VI) complexes with a new Schiff Base hydrazone: O-hydroxyacetophenone-7-chloro-4-quinoline hydrazone.

The Schiff base hydrazone ligand HL was prepared by the condensation reaction of 7-chloro-4-quinoline with o-hydroxyacetophenone. The ligand behaves either as monobasic bidentate or dibasic tridentate and contain ONN coordination sites. This was accounted for be the presence in the ligand of a phenolic azomethine and imine groups. It reacts with Cu(II), Ni(II), Co(II), Mn(II), UO(2) (VI) and Fe(II) to form either mono- or binuclear complexes. The ligand and its metal complexes were characterized by elemental analyses, IR, NMR, Mass, and UV-Visible spectra. The magnetic moments and electrical conductance of the complexes were also determined. The Co(II), Ni(II) and UO(2) (VI) complexes are mononuclear and coordinated to NO sites of two ligand molecules. The Cu(II) complex has a square-planar geometry distorted towards tetrahedral, the Ni(II) complex is octahedral while the UO(2) (VI) complex has its favoured heptacoordination. The Co(II), Mn(II) complexes and also other Ni(II) and Fe(III) complexes, which were obtained in the presence of Li(OH) as deprotonating agent, are binuclear and coordinated via the NNNO sites of two ligand molecules. All the binuclear complexes have octahedral geometries and their magnetic moments are quite low compared to the calculated value for two metal ions complexes and thus antiferromagnetic interactions between the two adjacent metal ions. The ligand HL and metal complexes were tested against a strain of Gram +ve bacteria (Staphylococcus aureus), Gram -ve bacteria (Escherichia coli), and fungi (Candida albicans). The tested compounds exhibited high antibacterial activities.

Alleviation of remote lung injury following liver ischemia/reperfusion: Possible protective role of vildagliptin.

Lung injury is a serious condition encountered following hepatic ischemia/reperfusion (IR). This study aimed to explore whether a dipeptidyl peptidase-4 inhibitor agent vildagliptin (V) could alleviate the lung injury caused by hepatic IR in a rat model and if so elucidate its molecular protective mechanism. Three groups of rats were used. Sham group: received normal saline and exposed to a sham operation, IR group: received normal saline and subjected to the operation of hepatic I (45 min)/ R (180 min), V+IR group: received for 10 days intraperitoneal injection of V (10 mg/kg/day). After reperfusion, liver and lung were collected for biochemical and histological evaluation. Hepatic IR exhibited significant elevation in serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) enzyme levels, serum and lung malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) in addition to lung nitric oxide (NO) levels, hypoxia-inducible factor 1-alpha (HIF-1α) mRNA and protein levels, hepatocyte growth factor (HGF) mRNA expression, and inducible nitric oxide synthase (iNOS) mRNA and protein expressions in lung tissue along with a marked reduction in the serum and lung content of catalase in comparison to the sham group. Moreover, liver and lung injury in the IR group was detected by histopathological examination. Vildagliptin ameliorated markedly the biochemical changes as well as liver and lung architecture in comparison to the IR group. Vildagliptin mitigated the induced lung injury by hepatic IR via suppression of oxidative stress markers, pro-inflammatory cytokine TNF-α as well as the HIF1-α/iNOS/HGF expressions in lung tissue.

Neuroprotective Potential of Bone Marrow-Derived Mesenchymal Stem Cells Following Chemotherapy.

Cisplatin (CP) is extensively used in the medical oncology field for malignancy treatment, but its use is associated with neurological side effects that compromise the patients' quality of life. Cytotherapy is a new treatment strategy for tissue damage that has recently emerged. The use of bone marrow-derived mesenchymal stem cells (BM-MSCs) was investigated for its therapeutic potential against CP-induced chemobrain as well as various models of brain damage. This study was carried out to elucidate, for the first time, the role of the intravenous injection (IV) of BM-MSCs against CP-induced neurotoxicity in a rat model through investigation of the parameters of oxidative stress, inflammation, and apoptosis in brain tissue. A rat model of neurotoxicity was generated by intraperitoneal injection of 7.5 mg/kg CP while 2 × 106 BM-MSCs was given by IV as a therapeutic dose. Injection of CP led to a significant rise in malondialdehyde and nitric oxide levels accompanied by a marked depletion of superoxide dismutase and reduced glutathione content in brain tissue in comparison to the normal control (NC) rats. Furthermore, a remarkable rise in the brain levels of inflammatory cytokines interleukin (IL)-1ß and IL-6, together with the expression of apoptotic marker caspase-3, and the downregulation of the brain expression of proliferating marker Ki-67 in brain tissue were detected in the CP group compared to the NC group. Histopathological alterations were observed in the brain tissue of the CP group. BM-MSCs mitigated the biochemical and histopathological alterations induced by CP without affecting brain cell proliferation. BM-MSCs could be used as a promising neuroprotective agent against CP-induced neurotoxicity.

Probing the Effect of Halogen Substituents (Br, Cl, and F) on the Non-covalent Interactions in 1-(Adamantan-1-yl)-3-arylthiourea Derivatives: A Theoretical Study.

The effect of halogen substituents (X = Br, Cl, and F) on the crystal packing and intra- and intermolecular interactions in four adamantane-thiourea hybrid derivatives is investigated using different theoretical tools. The bromo and chloro derivatives exhibit 3D isostructurality as evident from lattice parameters, molecular conformation, and crystal packing. The density functional theory study suggests that the molecular conformation of the parent (unsubstituted) and fluoro derivatives exhibits a stable low energy anti-syn conformation. In contrast, bromo and chloro derivatives adopt stable and relatively high energy minima on their potential energy surfaces. Hirshfeld surface analysis reveals the effect of halogen substituents on the intermolecular contacts. The halogen atoms mainly reduce the contribution of H···H contacts toward crystal packing. PIXEL energy analysis indicates the strong dimer formed by N-H···S hydrogen bonds in all four structures. It also revealed that a vast number of H···H contacts observed in different dimers of these structures either presented along with other conventional interactions or solely stabilize the dimeric topology. The topological parameters for intermolecular interactions in these structures suggest an intermediate bonding character between shared and closed-shell interactions for N-H···S hydrogen bonds in the parent and chloro derivatives. In contrast, the N-H···S hydrogen bond in other structures is of a closed-shell interaction. Among four derivatives, the fluoro derivative is weakly packed in the solid state based on the PIXEL method's lattice energy calculation.

Quantitative assessment of the nature of noncovalent interactions in N-substituted-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amines: insights from crystallographic and QTAIM analysis.

Three adamantane-1,3,4-thiadiazole hybrid derivatives namely; N-ethyl-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amine I, N-(4-fluorophenyl)-5-(adamantan-1-yl)-1,3,4-thiadiazole-2-amine II and (4-bromophenyl)-5-(adamantan-1-yl)-N-1,3,4-thiadiazole-2-amine III, have been synthesized and crystal structures have been determined at low temperature. The structures revealed that the orientation of the amino group is different in non-halogenated structures. Intra- and intermolecular interactions were characterized on the basis of the quantum theory of atoms-in-molecules (QTAIM) approach. Intermolecular interaction energies for different molecular pairs have been obtained using the PIXEL method. Hirshfeld surface analysis and 2D-fingerprint plots revealed that the relative contributions of different non-covalent interactions are comparable in compounds with halogen (Br and F) substitutions. Crystal structures of II and III show isostructural behaviour with 1D supramolecular constructs. In all three structures, the N-H⋯N hydrogen bond was found to be stronger among other noncovalent interactions. The H-H bonding showed a closed shell in nature and played significant roles in the stabilization of these crystal structures.

Quantitative analysis of hydrogen and chalcogen bonds in two pyrimidine-5-carbonitrile derivatives, potential DHFR inhibitors: an integrated crystallographic and theoretical study.

Two potential bioactive pyrimidine-5-carbonitrile derivatives have been synthesized and characterized by spectroscopic techniques (1H and 13C-NMR) and the three dimensional structures were elucidated by single crystal X-ray diffraction at low temperature (160 K). In both structures, the molecular conformation is locked by an intramolecular C-H⋯C interaction involving the cyano and CH of the thiophene and phenyl rings. The intermolecular interactions were analyzed in a qualitative manner based on the Hirshfeld surface and 2D-fingerprint plots. The results suggest that the phenyl and thiophene moieties have an effect on the crystal packing. For instance, the chalcogen bonds are only preferred in the thiophene derivative. However, both structures uses a common N-H⋯O hydrogen bond motif. Moreover, the structures of 1 and 2 display 1D isostructurality and molecular chains stabilize by intermolecular N-H⋯O and N-H⋯N hydrogen bonds. The nature and extent of different non-covalent interactions were further characterized by the topological parameters derived from the quantum theory of atoms-in-molecules approach. This analysis indicates that apart from N-H⋯O hydrogen bonds, other non-covalent interactions are closed-shell in nature. A strong and linear N-H⋯O hydrogen bond shows intermediate bonding character between shared and closed-shell interactions. The molecular docking analysis suggests that both compounds display potential inhibitory effect against the dihydrofolate reductase (DHFR) enzyme from humans and Staphylococcus aureus.

Ginkgo Biloba Extract Alleviates Methotrexate-Induced Renal Injury: New Impact on PI3K/Akt/mTOR Signaling and MALAT1 Expression.

Renal injury induced by the chemotherapeutic agent methotrexate (MTX) is a serious adverse effect that has limited its use in the treatment of various clinical conditions. The antioxidant activity of Ginkgo biloba extract (GB) was reported to mitigate renal injury induced by MTX. Our research was conducted to examine the nephroprotective role of GB versus MTX-induced renal injury for the first time through its impact on the regulation of phosphatidylinositol 3-kinase/protein kinase B/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling together with the renal level of TGF-ß mRNA and long non-coding RNA-metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) expression. A group of adult rats was intraperitoneally (ip) injected with MTX 20 mg/kg as a single dose to induce kidney injury (MTX group). The other group of rats was orally administered with GB 60 mg/kg every day for 10 days (GB+ MTX group). The MTX increased the serum creatinine and urea levels, renal TGF-ß mRNA and MALAT1 expression, in addition to dysregulation of the PI3K/Akt/mTOR signaling when compared with normal control rats that received saline only (NC group). Moreover, renal damage was reported histopathologically in the MTX group. The GB ameliorated the renal injury induced by MTX and reversed the changes of these biochemical analyses. The involvement of PI3K/Akt/mTOR signaling and downregulation of TGF-ß mRNA and MALAT1 renal expressions were firstly reported in the nephroprotective molecular mechanism of GB versus MTX-induced renal injury.

Crystal structure, Hirshfeld surface analysis and DFT studies of 5-(adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole, a potential 11ß-HSD1 inhibitor.

5-(Adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole (4) was identified as a potential 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor and this paper describes the in-depth structural analysis thereof. Compound 4 was synthesized in a 92% yield and its 3D-structure confirmed by single-crystal X-ray diffraction. Hirshfeld surface analysis indicated that H…H, C-H…C, C-H…Cl and especially C-H…N hydrogen bond interactions are the primary contributors to the intermolecular stabilisation in the crystal. In order to explore the properties of 4, free from the influence of the crystal field, density functional theory (DFT) calculations were conducted. Results indicated that the DFT optimized geometry of 4 produced a conformer (4a) that is significantly different from the crystal structure. Further experiments confirmed that the crystal structure is not the absolute minimum conformation. This indicated that the crystal packing forces has significantly influenced the conformation thereof. Frontier molecular orbital energies and net atomic charges were also calculated to elucidate the electronic properties of 4a. These results provided insight into areas of the molecule that may present with the ability to form binding interactions at the 11ß-HSD1 active site. Molecular docking experiments revealed important intermolecular interactions between 4a and 11ß-HSD1. These results indicate that 4 may be considered for further drug design endeavors.

Vildagliptin Attenuates Hepatic Ischemia/Reperfusion Injury via the TLR4/NF-κB Signaling Pathway.

The Toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway is vital in the pathogenesis of hepatic ischemia/reperfusion (HIR) injury. Dipeptidyl peptidase-4 (DPP4) inhibitors exert protective effects on IR injury of the kidney, heart, and lung; however, their effect on the liver is still unknown. Thus, the purpose of this study was to examine whether pretreatment with vildagliptin (Vilda), a DPP4 inhibitor, produces hepatic protection against IR injury and to investigate its influence on TLR4/NF-κB signaling in a rat model. Thirty male Wistar rats were divided into 3 groups: the sham group: subjected to a sham operation and received normal saline; the HIR group: subjected to HIR and received normal saline; and the Vilda + HIR group: subjected to HIR with pretreatment of 10 mg/kg/day Vilda for 10 days intraperitoneally. Hepatic ischemia lasted for 45 minutes followed by 3-hour reperfusion; then blood and liver samples were collected for biochemical and histopathological examination. The HIR group produced a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA), nitric oxide (NO), and tumor necrosis factor alpha (TNF-α) levels and a significant reduction in the hepatic catalase level in comparison to the sham group. Moreover, a significant upregulation of gene and protein expressions of TLR4, NF-κB, and high-mobility group box-1 (HMGB1) along with caspase-3 protein expression was observed in the HIR group when compared with the sham group. Histopathological examination of the liver from the HIR group showed necrosis, sinusoidal congestion, hemorrhage, and hepatocyte degeneration. Administration of Vilda ameliorated the biochemical and histopathological changes caused by HIR. Vildagliptin showed for the first time a hepatoprotective effect in HIR injury through downregulation of TLR4/NF-κB/HMGB1 and caspase-3 hepatic expressions.

Simultaneous determination of monosaccharides and oligosaccharides in dates using liquid chromatography-electrospray ionization mass spectrometry.

Ultra performance liquid chromatography coupled to mass spectrometry was used for the simultaneous separation and determination of reducing monosaccharides (fructose and glucose), a non-reducing disaccharide (sucrose) and oligosaccharides (kestose and nystose) in HILIC mode. The chromatographic separation of all saccharides was performed on a BEH amide column using an acetonitrile-water gradient elution. The detection was carried out using selected ion recording (SIR) acquisition mode. The validation of the proposed method showed that the limit of detection and limit of quantification values for the five analyzed compounds were in the range of 0.25-0.69µg/mL and 0.82-3.58µg/mL, respectively; while the response was linear in the range of 1-50µg/mL. The developed method showed potential usefulness for a rapid and sensitive analysis of underivatized saccharides and was used for determination of sugars in three date samples (Sefri, Mabroom, Ghassab) which were soxhlet extracted by ethanol.

High-performance liquid chromatography analysis of phenolic acid, flavonoid, and phenol contents in various natural Yemeni honeys using multi-walled carbon nanotubes as a solid-phase extraction adsorbent.

A simple method has been described for simultaneous determination of phenolic acid, flavonoid, and other phenol contents in various natural honey samples collected from various regions of Yemen. Multi-walled carbon nanotubes were used as a solid-phase adsorbent for extraction of the polyphenols from honey samples. The total contents of phenolic acids, flavonoids, and phenolic components of the 12 different samples were found in the range of 363-2658, 261-1646, and 224-1355 µg/100 g of honey samples, respectively. The major phenolic acid, flavonoid, and phenolic compound in these samples were found to be 4-hydroxybenzoic acid (1410 µg/100 g), chrysin (850 µg/100 g), and cinnamic acid (1336 µg/100 g), respectively. A total of 25 compounds (10 phenolic acids, 9 flavonoids, and 6 phenols) were analyzed, and a total of 24 were detected, while only 23 compounds were determined quantitatively in the honey samples. The developed method showed potential usefulness for the analysis of honey and was used for the determination of polyphenols in honey extracts.