Palladium(ii), platinum(ii), and silver(i) complexes with 3-acetylcoumarin benzoylhydrazone Schiff base: Synthesis, characterization, biomolecular interactions, cytotoxic activity, and computational studies.

New Pd(ii) (C1), Pt(ii) (C2), and Ag(i) (C3) complexes derived from 3-acetylcoumarin benzoylhydrazone (HL) Schiff base were synthesized and characterized by FTIR, 1H NMR, UV-visible spectroscopies along with elemental analysis (C, H, N), magnetic, molar conductivity measurements, and DFT calculations. The obtained results suggested that the ligand had different behaviors in the complexes: mono-negative tridentate (C1) and neutral tridentate (C2) as an ONO-donor and neutral bidentate (C3) as an ON-donor. Quantum chemistry calculations were performed to validate the stability of the suggested geometries and indicated that all the complexes possess tetra-coordinated metal ions. The binding affinity of all the compounds toward calf thymus (ctDNA), yeast (tRNA), and bovine serum albumin (BSA) was evaluated by absorption/emission spectral titration studies, which revealed the intercalative binding to ctDNA and tRNA and static binding upon complex formation with BSA. Molecular insights into the binding affinity of the characterized complexes were provided through conducting molecular docking analysis. Moreover, the cytotoxic activity (in vitro) of the compounds was screened against human cancerous cell lines and a non-cancerous lung fibroblast (WI38) one using cis-platin as a reference drug. The IC50 and selective index (SI) values indicated the higher cytotoxic activity of all the metal complexes compared to their parent ligand. Among all the compounds, the complex C2 showed the highest activity. These results confirmed the improvement of the anticancer activity of the ligand by incorporating the metal ions. In addition, flow cytometry results showed that complexes C1 and C2 induced cell cycle arrest at S and G1/S, respectively.

Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades.

AIMS: This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. MAIN METHODS: To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. KEY FINDINGS: The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-ß1 pathway. SIGNIFICANCE: The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis.

Synthesis, characterization of ruthenium(II), nickel(II), palladium(II), and platinum(II) triphenylphosphine-based complexes bearing an ONS-donor chelating agent: Interaction with biomolecules, antioxidant, in vitro cytotoxic, apoptotic activity and cell cycle analysis.

Four new transition metal complexes, [M(PPh3)(L)].CH3OH (M = Ni(II) (1), Pd(II) (2)) [Pt (PPh3)2(HL)]Cl (3) and [Ru(CO)(PPh3)2(L)] (4) (H2L = 2,4-dihydroxybenzaldehyde-S-methyldithiocarbazate, PPh3 = triphenylphosphine) have been synthesized and characterized by elemental analyses (C, H, N), FTIR, NMR (1H, 31P), ESI-MS and UV-visible spectroscopy. The molecular structure of (1) and (2) complexes was confirmed by single-crystal X-ray crystallography. It showed a distorted square planar geometry for both complexes around the metal center, and the H2L adopt a bi-negative tridentate chelating mode. The interaction with biomolecules viz., calf thymus DNA (ct DNA), yeast RNA (tRNA), and BSA (bovine serum albumin) was examined by both UV-visible and fluorescence spectroscopies. The antioxidant activity of all compounds is discussed on basis of DPPH• (2,2-diphenyl-1-picrylhydrazyl) scavenging activity and showed better antioxidant activity for complexes compared to the ligand. The in vitro cytotoxicity of the compounds was tested on human (breast cancer (MCF7), colon cancer (HCT116), liver cancer (HepG2), and normal lung fibroblast (WI38)) cell lines, showing that complex (1) the most potent against MCF7 and complex (4) against HCT116 cell lines based on IC50 and selective indices (SI) values. So, both complexes were chosen for further studies such as DNA fragmentation, cell apoptosis, and cell cycle analyses. Complex (1) induced MCF7 cell death by cellular apoptosis and arrest cells at S phase. Complex (4) induced HCT116 cell death predominantly by cellular necrosis and arrested cell division at G2/M phase due to DNA damage.

Bioavailability of paracetamol with/without caffeine in Egyptian patients with hepatitis C virus.

PURPOSE: This study investigates the involvement of liver dysfunction in the modulation of paracetamol pharmacokinetic profile in genotype-4 HCV patients treated with either paracetamol alone (Para) or in combination with caffeine (Para-Caf). METHODS: Twenty healthy volunteers and 20 Child-Pugh B HCV patients, each divided into two equal subgroups, were examined, whose liver/kidney functions were correlated with their main clinical manifestation. After an overnight fasting, healthy and hepatic subjects received either a single dose of Para (1000 mg paracetamol) or Para-Caf (1000 mg paracetamol/130 mg caffeine). Two milliliters of saliva samples were collected prior to and at different time-intervals after drug administration and analyzed using HPLC. RESULTS: There was a noticeable increase in the mean concentration time profile of salivary paracetamol concentrations in hepatic patients, with concomitant decrease in paracetamol clearance (CLT), along with induction in the primary pharmacokinetic (PK) parameters, C max, AUC(0-8 h) and AUC(0-∞) (by about 95, 82, and 64 %, respectively, after treatment with Para, and 98, 96, and 101 %, respectively, after treatment with Para-Caf), when compared with the corresponding parameters in healthy subjects. Additionally, the healthy subjects treated with Para-Caf exhibited bioinequivalent increase in C max, K a, and t 1/2 with decrease in T max when compared with the healthy individuals treated with Para alone. A similar pattern was recorded in hepatic patients after addition of caffeine to paracetamol, with even augmented significant increase in K a and t 1/2 (by 100 and 32 %, respectively). CONCLUSIONS: Liver dysfunction modified the PK of paracetamol expressed as earlier effective paracetamol concentration, with obvious decrease in its clearance. Caffeine induced faster absorption (evidenced by shorter T max and higher K a) and prolonged t 1/2 of paracetamol, the effects that were more profound in hepatic patients. Further studies are needed to evaluate the influence of liver damage on paracetamol pharmacokinetics whenever repeated dosing is applied, to avoid possible drug accumulation.

Complexes of cis-dioxomolybdenum(VI) and oxovanadium(IV) with a tridentate ONS donor ligand: synthesis, spectroscopic properties, X-ray crystal structure and catalytic activity.

New cis-dioxomolybdenum(VI) and oxovanadium(IV) complexes of the Schiff base, derived from S-methyl dithiocarbazate and 2,3-dihydroxybenzaldehyde (H2dhsm), have been synthesized. The complexes of the type cis-[MoO2(dhsm)] (1a), cis-[MoO2(dhsm)(D)] (1b-1d) [D=neutral monodentate ligand; EtOH, pyridine (py) or imidazole (imz)], [VO(dhsm)(NN)] (2a, 2b) [NN=2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen)] and [VO(dhsm)] (2c) have been isolated, characterized by (1)H NMR, IR, UV-Vis and EPR spectral studies and investigated by cyclic voltammetry. The X-ray crystal structure of cis-[MoO2(dhsm)(EtOH)] (1b) has been determined and shows that the complex has a distorted octahedral geometry in which the H2dhsm behaves as a dianionic ONS tridentate ligand coordinating via phenoxide oxygen, hydrazinic nitrogen and thiolate sulfur. The oxomolybdenum(IV) complex [MoO(dhsm)] (1e) has obtained from dioxomolybdenum(VI) complex (1b) by oxo abstraction with PPh3. The reactivity of the complexes toward catalytic oxidation of alcohols in the presence of H2O2 and t-BuOOH as co-oxidants under solvent free conditions is reported.

Antineoplastic Activity of New Transition Metal Complexes of 6-Methylpyridine-2-carbaldehyde-N(4)-ethylthiosemicarbazone: X-Ray Crystal Structures of [VO(2)(mpETSC)] and [Pt(mpETSC)Cl].

New complexes of dioxovanadium(V), zinc(II), ruthenium(II), palladium(II), and platinum(II) with 6-methylpyridine-2-carbaldehyde-N(4)-ethylthiosemicarbazone (HmpETSC) have been synthesized. The composition of these complexes is discussed on the basis of elemental analyses, IR, Raman, NMR ((1)H, (13)C, and (31)P), and electronic spectral data. The X-ray crystal structures of [VO(2)(mpETSC)] and [Pt(mpETSC)Cl] are also reported. The HmpETSC and its [Zn(HmpETSC)Cl(2)] and [Pd(mpETSC)Cl] complexes exhibit antineoplastic activity against colon cancer human cell lines (HCT 116).

Non-histological assessment of liver fibrosis in HCV infection.

This study found a correlation between some serum markers [AST/ALT ratio, level of matrix metalloproteinase 9 (MMP9), level of viraemia and HCV serotype] and severity of liver fibrosis in HCV-infected patients. The study included 72 human cases referred to the Early Cancer Detection Unit, for liver biopsy assessment. The severity of liver fibrosis was staged using the METAVIR scoring system into 4 stages. The level of viraemia did not differ significantly in the different stages of liver fibrosis. Also, the type of HCV had no effect on the severity of liver fibrosis. However, the transaminases ratio differed significantly in the different fibrosis stages (P < 0.01). This serum test has a relatively high sensitivity and specificity (92.6% and 94.3%, respectively) in diagnosing severe fibrosis and cirrhosis. The level of MMP9 was, however, inversely correlated with the fibrosis stages and was found to have an 88.9% sensitivity and an 88.6% specificity when diagnosing severe fibrosis and cirrhosis. Although, the sensitivity of these serum markers did not reach 100%, yet their use can reduce the number of liver biopsies when diagnosing and treating HCV-infected patients.