Heteroleptic complexes of cocaine/TMEDA with some f block metals: Synthesis, DFT studies, spectral, thermal, cytotoxicity and antimetastatic properties.

A series of new three heteroleptic complexes of the general formula [Ln(Cn)(TMEDA)Cl(OH2)]·2Cl·xH2O, (where Ln = La(III), Er(III) and Yb(III), Cn = cocaine and TMEDA = N,N,N',N'-tetramethylethylenediamine) were synthesized, structurally characterized by elemental analysis, spectroscopic methods, molar conductivity and mass spectrometry. Thermal properties of the synthesized complexes and their kinetic thermodynamic parameters were studied. Theoretical calculations including geometry optimization, electronic structure and electronic and thermal energies were carried out using DFT and TD-DFT calculations at B3LYP/LANL2DZ level of theory and the different quantum chemical parameters were calculated. The in vitro antiproliferative activity of the newly synthesized complexes was assessed by MTT assay on MCF-7 and HepG-2 cancer cell lines. Yb(III) complex showed promising cytotoxic activity comparable to that of cisplatin on both cell lines with minimum effect on human normal cells. Further molecular mechanistic investigations showed that Yb(III) complex is an apoptotic inducer as it raises the caspase-3 and caspase-9 cellular level in the MCF-7 cell line. Furthermore, it showed an elevating effect on the level of the tumor suppressor nuclear proteins P21 and P27 concentrations in MCF-7 cells. Moreover, Yb(III) complex hindered the cellular scavenger system of the reactive oxygen species through reducing the glutathione peroxidase (GPx) cellular level imperiling MCF-7 cells by unmanageable oxidative stress. In addition to its cytotoxic effect, Yb(III) complex showed antimetastatic properties as it decreased the cellular levels of matrix metalloproteinases MMP-3 and MMP-9. These results showed that the Yb(III) complex is a promising cytotoxic metal-based agent that exerts its action through various molecular mechanisms with minimum effects on normal cells and with additional antimetastatic properties.

Molecular Patterns of MEFV Gene Mutations in Egyptian Patients with Familial Mediterranean Fever: A Retrospective Cohort Study.

BACKGROUND: Familial Mediterranean Fever (FMF) is a hereditary autosomal recessive disease which is mainly seen in the Turks, Armenians, Arabs, and Jews. It is characterized by recurrent episodes of fever, polyserositis, and rash. MEFV gene, encoding pyrin protein, is located on the short arm of chromosome 16. FMF is associated with a broad mutational spectrum in this gene. Certain mutations are more common in particular ethnic groups. To date, different mutations of MEFV were observed in studies carried out in different regions worldwide. However, most of these studies did not extensively investigate the Egyptian population, in spite of the high prevalence of FMF in this geographical region. AIM: To identify the frequency of MEFV gene mutations among the patients who presented with FMF like symptoms and, to characterize the different genetic mutations and their association with increased Amyloid A among Egyptian patients. METHODS: FMF Strip Assay (Vienna Lab Diagnostics, Vienna, Austria) was used. This test is based on reverse hybridization of biotinylated PCR products on immobilized oligonucleotides for mutations and controls in a parallel array of allele-specific oligonucleotides. RESULTS: Among the 1387 patients presenting with signs and symptoms suggestive of FMF, 793 (57.2%) were of undefined mutations, whereas 594 had MEFV gene mutations. 363 patients (26.2%) were heterozygous mutants, 175 patients (12.6%) were compound heterozygous mutants, and 56 patients (4%) were homozygous mutants. The most commonly encountered gene mutations in heterozygous and homozygous groups were E148Q (38.6%), M694I (18.1%), and V726A (15.8%). The most commonly encountered gene mutations in the compound heterozygous groups were E148Q+M694I observed in 20.6% of the patients, followed by M694I+V726A and M6801+V726A found in 18.9% and 11.4 %, respectively. The most commonly encountered gene mutation associated with abdominal pain, fever, and high serum Amyloid A was E148Q allele (37.5%). CONCLUSIONS: Unlike all previous publications, E148Q allele was found to be the most frequent in the studied patients. Moreover, this allele was associated with increased Amyloid A. 793 patients were free of the 12 studied Mediterranean mutations, which implies the necessity to perform future sequencing studies to reveal other mutations.

Melatonin charge transfer complex with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone: Molecular structure, DFT studies, thermal analyses, evaluation of biological activity and utility for determination of melatonin in pure and dosage forms.

A simple, accurate and fast spectrophotometric method for the quantitative determination of melatonin (ML) drug in its pure and pharmaceutical forms was developed based on the formation of its charge transfer complex with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an electron acceptor. The different conditions for this method were optimized accurately. The Lambert-Beer's law was found to be valid over the concentration range of 4-100µgmL-1 ML. The solid form of the CT complex was structurally characterized by means of different spectral methods. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) calculations were carried out. The different quantum chemical parameters of the CT complex were calculated. Thermal properties of the CT complex and its kinetic thermodynamic parameters were studied, as well as its antimicrobial and antifungal activities were investigated. Molecular docking studies were performed to predict the binding modes of the CT complex components towards E. coli bacterial RNA and the receptor of breast cancer mutant oxidoreductase.

Clinical, electrophysiological and immunological study of peripheral nerves in Egyptian patients with monoclonal gammopathies.

Monoclonal antibodies are found in approximately 10% of patients with peripheral neuropathy (PN) of unknown etiology. Several autoantibodies, including anti-MAG (myelin-associated glycoprotein) antibodies, have been reported to induce neuropathy. It has been suggested that over 50% of patients with PN and IgM monoclonal gammopathy (MG) have anti-MAG IgM antibodies in their sera. This work aimed at studying the frequency and characteristics of PN in a group of Egyptian patients with MGs and to estimate the serum level of anti-MAG antibodies and its relationship to peripheral nerve dysfunction. Forty patients with MGs were enrolled in the study. Their mean age was 56.65 ± 8.55 years. There were 17 males and 23 females. Patients were subjected to complete general and neurological examination, laboratory investigations including serum LDH, ß2 microglobulin, serum protein electrophoresis, urinary Bence-Jones protein, bone marrow aspiration and/or trephine biopsy, quantitative estimation of serum IgM and IgG by nephelometry, detection of anti-MAG antibodies by indirect immunofluorescence, radiological assessment and nerve conduction study of both upper and lower limbs. Clinical and electrophysiological evidences of PN were found in 32 (80%) out of the 40 patients with MG. Twenty-five patients (62.5%) had distal symmetrical polyneuropathy and seven (17.5%) had mononeuritis or mononeuritis multiplex. The majority of patients (65%) had sensory or predominantly sensorimotor polyneuropathy. The neuropathy was mainly demyelinating in 22 patients (55%) and axonal in the other 10 (25%) patients. Anti-MAG antibodies were positive in nine patients (22.5%) and six of them (66.6%) had PN. The latter was predominantly demyelinating motor neuropathy in 4 and axonal in the remaining 2. However, the relationship between the presence of anti-MAG antibodies and the development and type of PN was not statistically significant. Anti-MAG showed significant association with IgM level (P = 0.003**) and the MG subtypes: Waldenström's macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) (P = 0.004**). The present study showed high frequency (>60%) of distal symmetrical polyneuropathy in Egyptian patients with MG. The neuropathy was predominantly sensory and demyelinating. Anti-MAG antibodies were detected only in 22.5% of the patients, especially those with WM and MGUS and were associated with more motor and demyelinating neuropathy. We recommend that patients with chronic polyneuropathies should be evaluated for underlying plasma cell dyscrasia.

Alterations of immune functions in heroin addicts.

The alteration of peripheral blood T-and B-lymphocyte proliferative responses were determined during different periods of withdrawal in heroin (Hw) and heroin / bhang (HBw) addicts. The results clearly demonstrated a significant decrease in the response of T- lymphocytes to PHA-stimulation and secretion of IL-2 in both Hw and HBw addicts. The in vitro presence of naloxone induced further inhibition of the PHA proliferative response and IL-2 production. Our data also indicated a significant suppression of IFN-gamma levels by human blood lymphocytes from Hw and HBw addicts. Additionally, a significant suppression of IFN-gamma production was demonstrated in the presence of naloxone. Moreover, IL-4 production was suppressed in Hw, but not in HBw groups and the in vitro presence of naloxone did not affect the level of IL-4 in both groups. However, IL-10 production was significantly increased in both groups accompanied by a significant suppression of IL-10 secretion in the presence of naloxone. In contrast, IL-5 levels stimulated by PHA showed a significant increase in both groups, while no significant effect of naloxone could be observed. Our results suggested that heroin administration can cause measurable suppression of some components of the human cellular immune system. The results further demonstrated that the immunsuppressive effect observed after heroin use are naloxone-mediated and suggested that activation of the adrenal gland is one potential mechanism for this effect.