Alpha lipoic acid and diabetes mellitus: potential effects on peripheral neuropathy and different metabolic parameters

Introduction: Alpha lipoic acid (ALA) is an antioxidant used in the treatment of neuroinflammation, diabetes and diabetic nephropathy. The current study aiming to gauge the effect of oral ALA on diabetic peripheral neuropathy, glycemic control, LDL-C, and HDL-C. Methods: This is a prospective, interventional study carried out on patients with type 2 diabetes mellitus (DM) who were following at the outpatient internal medicine & diabetes clinics at Benha University Hospital. Treatment with ALA for 3 months was given to patient with diabetic peripheral neuropathy. Data in the form of age, sex, body mass index (BMI), duration & treatment of DM, manifestations of peripheral neuropathy were collected. LDL-C, HDL-C, HbA1c, TSH, ALT, AST were measured before and after intervention. Peripheral neuropathy symptoms, nerve conduction velocities, cardiovascular (CV) tests of autonomic neuropathy, and cross-section area of the posterior tibial nerve were performed before and after treatment intervention. Results: 90 adult diabetic patients were recruited in the study, 42.2% were females and 57.8% were males with a median age of 50–60.3 years (IQR = 52). A statistically significant improvements of neuropathic symptoms, nerve conduction velocity, and cardiovascular autonomic neuropathy were noted after 3 months of administration of ALA (p ˂0.001). However, the cross-section area of the posterior tibial nerve at baseline and after treatment did not change significantly (p value of 0.84). There was a significant improvement in the BMI, HDLC, LDL-C, HbA1c (p ˂ 0.001). Conclusion: Oral treatment with ALA might cause ameliorations of peripheral neuropathy, HbA1c, and LDL-C & HDL-C levels in diabetic patients. Our result failed to proof effect of ALA on nerve cross-section area. The global data encourage further studies with this medication as an ancillary treatment of DM2.Clinical trial registration: It was registered in clinical trial website; ClinicalTrials.gov Identifier(NCT number): NCT04322240

Kinetic Simulation of He radio frequency capacitive coupled plasma

Radiofrequency capacitively coupled plasma is studied theoretically using a Particle-in-Cell code. For He discharge, the time-averaged sheaths are in the range of few centimeters. The sheath potential, ion, and electron energy and angular distributions, discharge current, and dissipated power depend on the driven potentials and frequencies. Increasing the amplitude of the high radio frequencies increases the bulk density and the sheath potential and, consequently, increases the plasma processing rate. Increasing the intermediate radio frequency amplitude allows a wider sheath with a broad ion energy distribution and a narrower ion angular distribution. Changing the amplitude and the phase shift between driven frequencies provide different energies and angular distribution allowing performing various processes. The interplay between the sheath and bulk dynamics in the intermediate radiofrequency regime and the high-frequency regime may excite harmonics in the discharge current

A comparative study of the effects of different low-level lasers on the proliferation, viability, and migration of human melanocytes in vitro.

The aim of this study was to investigate the effects of different low-level laser therapies (LLLTs) of various wavelengths and energies on normal cultured human melanocytes. Various studies have shown the effects of LLLs on various types of cultured cells. Presently, little is known about the biological effects of LLLTs on melanocytes. Melanocytes were exposed to LLLT at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 J/cm(2) using a blue (457 nm), red (635 nm), or ultraviolet (UV) (355 nm) laser. Melanocyte viability, proliferation, and migration were monitored at 72 h after irradiation. The blue (P < 0.001) and red (P < 0.001 and P < 0.01) lasers significantly enhanced viability at 0.5 to 2.0 J/cm(2), whereas the UV laser (P < 0.001) could significantly enhance viability only at 0.5 and 1.0 J/cm(2) compared with controls. The blue and red lasers also significantly enhanced the proliferation of the melanocytes at 0.5 to 2.0 J/cm(2) (P < 0.001), and the UV laser significantly enhanced proliferation at 0.5 to 1.5 J/cm(2) (P < 0.001 and P < 0.01) compared with controls. The blue laser significantly enhanced melanocyte migration at 0.5 to 4.0 J/cm(2) (P < 0.001 to P < 0.05), but the red (P < 0.001 and P < 0.01) and UV (P < 0.001 to P < 0.05) lasers could significantly enhance such migration at 0.5 to 1.0 J/cm(2) and 0.5 to 2.0 J/cm(2), respectively, compared with controls. LLLT at low energy densities is able to significantly increase melanocyte viability, proliferation, and migration in vitro, and at higher energy densities, it gives non-stimulatory results. Additionally, the blue laser was the best among the three lasers. These findings might have potential application in vitiligo treatment in future

Physical pegylation enhances the cytotoxicity of 5-fluorouracil-loaded PLGA And PCL nanoparticles.

Purpose : The main goal of this study is to evaluate the impact of physical incorporation of polyethylene glycol (PEG) into 5-fluorouracil (5-FU)-loaded polymeric nanoparticles (NPs). METHODS: The 5-FU-loaded NPs were prepared utilizing a simple double emulsion method using polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA) with or without PEG 6000. The surface charge, particle size, and shape of NPs were evaluated by standard procedures. Both Fourier Transform Infrared Spectroscopy and X-ray diffraction spectra of the 5-FU loaded NPs were compared against the pure 5-FU. The in vitro release profile of 5-FU from the NPs was monitored by the dialysis tubing method. Cell death and apoptosis induction in response to 5-FU NP exposure were measured by MTT and Annexin-V/7-amino-actinomycin D (7-AAD) assays, respectively, in Daoy, HepG2, and HT-29 cancer cell lines. RESULTS: The 5-FU loaded NPs were found to be spherical in shape with size ranging between 176±6.7 and 253.9±8.6 nm. The zeta potential varied between -7.13± 0.13 and -27.06±3.18 mV, and the entrapment efficiency was between 31.96% and 74.09%. The in vitro release of the drug followed a two-phase mode characterized by rapid release in the first 8 hrs followed by a period of slow release up to 72 hrs with composition-based variable extents. Cells exposed to NPs demonstrated a significant cell death which correlated with the ratio of PEG in the formulations in Daoy and HepG2 cells but not in HT-29 cells. Formulations (F1-F3) significantly induced early apoptosis in HT-29 cell lines. CONCLUSION: The physical PEGylation significantly enhanced the entrapment and loading efficiencies of 5-FU into NPs formulated with PLGA and PCL. It also fostered the in vitro cytotoxicity of 5-FU-loaded NPs in both Daoy and HepG2 cells. Induction of early apoptosis was confirmed for some of the formulations

Novel docetaxel chitosan-coated PLGA/PCL nanoparticles with magnified cytotoxicity and bioavailability

In the present study, docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) nanoparticles were successfully prepared and coated with chitosan (CS). The prepared nanoparticles (NPs) were evaluated for their particle size, zeta potential, particle morphology, drug entrapment efficiency (EE%), and in vitro drug release profile. The anticancer activity of DTX-loaded NPs was assessed in human HT29 colon cancer cell line utilizing MTT assay. The pharmacokinetics of DTX-loaded NPs was monitored in Wistar rats in comparison to DTX solution. The prepared NPs exhibited particle sizes in the range 177.1 ± 8.2-287.6 ± 14.3 nm. CS decorated NPs exhibited a significant increase in particle size and a switch of zeta potential from negative to positive. In addition, high EE% values were obtained for CS coated PCL NPs and PLGA NPs as 67.1 and 76.2%, respectively. Moreover, lowering the rate of DTX in vitro release was achieved within 48 h by using CS coated NPs. Furthermore, a tremendous increase in DTX cytotoxicity was observed by CS-decorated PLGA NPs compared to all other NPs including DTX-free-NPs and pure DTX. The in vivo study revealed significant enhancement in DTX bioavailability from CS-decorated PLGA NPs with more than 4-fold increase in AUC compared to DTX solution. In conclusion, CS-decorated PLGA NPs are a considerable DTX-delivery carrier with magnificent antitumor efficacy

Stimulation of the histamine 4 receptor with 4-methylhistamine modulates the effects of chronic stress on the Th1/Th2 cytokine balance.

Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune-related diseases such as cancer and autoimmune disorders. We investigated the potential anti-stress effects of the histamine 4 receptor (H4R) agonist, 4-methylhistamine (4-MeH), in a murine stress model. Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest. The effects of treatment with 4-MeH (30mg/kg, i.p., twice daily) for 2 days were assessed. At 2 days after physical restraint, mice were sacrificed and tissues harvested. We evaluated the effects of 4-MeH treatment on CD4(+) T cell production, and intracellular IFN-γ and IL-4 expression in these cells. We also assessed IL-1β, IFN-γ, TNF-α, and IL-4 mRNA expression as well as IFN-γ, TNF-α, GITR, Ox40 and IL-4 protein expression in the spleen. The results showed that 4-MeH treatment of stressed mice results in a substantial increase in the CD4(+) T cells as well as in IFN-γ production by these cells. Compared to both untreated and stressed controls. In contrast, IL-4 expression decreased significantly following 4-MeH treatment of mice. Moreover, stimulation of the H4R resulted in up-regulated expression of IL-1β, IFN-γ and TNF-α mRNAs and decreased the expression of IL-4. Western blot analysis confirmed decreased protein expression of IFN-γ, TNF-α, GITR, Ox40 and increased IL-4 in the SC group and treatment of mice with 4-MeH reversed these effects. Our results confirm the significant impact of chronic stress on T cell function and production of Th1/Th2 mediators H4R

Ligating Behavior Of Some Sulphur Containing Benzotriazole Derivatives Towards Some Transition Metal Ions And Their Biological Effect

Abstract: New Cu 2+ and Ni 2+ complexes of N 1 -phenyl-2-[1H-1,2,3-bezotriazol-1-yl] 3-phenyl-3-oxopropane thioamide, HL, has been synthesized and characterized by different spectral and magnetic measurements and elemental analysis. The spectral studies indicated that HL exist in the thion form in the solid state and the IR spectra of the complexes indicated that the ligand act as monobasic bidentate ligand giving distorted tetragonal structure in case of Cu 2+ and square planar structure in case of Ni 2+ , which was the reason of their different antimicrobial activity. Thermal decomposition of both complexes showed similar steps

Regulation of TNF-α and NF-κB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation.

Histamine 4 receptor (H4R) is a novel target for the pharmacological modulation of histamine-mediated immune signals during inflammatory diseases. The purpose of this study was to assess the effects of the H4R agonist 4-methylhistamine dihydrochloride (4-MeH) and antagonist JNJ7777120 (JNJ) in the inflamed rat knee. Animals were fasted for 18h before a single dose of 4-MeH or JNJ (30mg/kg) was administered intraperitoneally (i.p.), both followed by intra-articular (i.a.) injection of LPS 2h later. Blood and synovial fluid were collected after a short incubation period and TNF-α, NF-κB, and IkB-α levels were measured via flow cytometry. Additionally, we assessed the effects of H4R engagement on the expression of IL-1β, TNF-α, and NF-κB mRNAs and the protein levels of TNF-α, NF-κB, JAK-1, and STAT-3 in the inflamed knee tissue. These results revealed increased TNF-α and NF-κB expression and decreased IkB-α levels in both the LPS alone and 4-MeH treated groups in whole blood and synovial fluid. Further, IL-1β, TNF-α, and NF-κB mRNA levels were significantly increased and western blot analysis confirmed increased expression of TNF-α, NF-κB, JAK-1, and STAT-3 in both LPS and 4-MeH treatment groups. Furthermore, these increases were completely inhibited in the inflamed knee tissue of the JNJ-treated group. Thus, the inhibition of inflammatory mediators and signaling pathways by the H4R antagonist JNJ suggests the anti-arthritic importance of this molecule

Development of certain novel N-(2-(2-(2-oxoindolin-3-ylidene)hydrazinecarbonyl)phenyl)-benzamides and 3-(2-oxoindolin-3-ylideneamino)-2-substituted quinazolin-4(3H)-ones as CFM-1 analogs: design, synthesis, QSAR analysis and anticancer activity.

The reaction of N-(2-(hydrazinecarbonyl)aryl)benzamides 2a, b with indoline-2,3-diones 4ae in acidified ethanolic solution furnished the corresponding N-(2-(2-(2-oxoindolin-3-ylidene)hydrazinecarbonyl)phenyl)benzamides 5aj, respectively. Furthermore, 3-(2-oxoindolin-3-ylideneamino)-2-substituted quinazolin-4(3H)-ones 6aj were prepared by the reaction of 3-amino-2-arylquinazolin-4(3H)-one 3a, b with 4ae. Six derivatives of the twenty newly synthesized compounds showed remarkable antitumor activity against most of the tested cell lines, Daoy, UW228-2, Huh-7, Hela and MDA-MB231. Although these six compounds were more potent than the standard drug (CFM-1), indeed compounds 5b, 5d and 6b were the best candidates with IC50 values in the range 1.866.87, 4.4210.89 and 1.468.60 μg/ml and percentage inhibition in the range 77.188.7, 59.4184.8 and 75.488.0%, respectively. QSAR analyses on the current series of derivatives also have been performed for all five cancer cell lines and thus 10 statistically significant models were developed and internally cross validated

Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis

Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug