Serum Levels of Soluble CD26/Dipeptidyl Peptidase-IV in Type 2 Diabetes Mellitus and Its Association with Metabolic Syndrome and Therapy with Antidiabetic Agents in Malaysian Subjects

BackgroundA soluble form of CD26/dipeptidyl peptidase-IV (sCD26/DPP-IV) induces DPP-IV enzymatic activity that degrades incretin. We investigated fasting serum levels of sCD26/DPP-IV and active glucagon-like peptide-1 (GLP-1) in Malaysian patients with type 2 diabetes mellitus (T2DM) with and without metabolic syndrome (MetS), as well as the associations between sCD26/DPP-IV levels, MetS, and antidiabetic therapy.MethodsWe assessed sCD26/DPP-IV levels, active GLP-1 levels, body mass index (BMI), glucose, insulin, A1c, glucose homeostasis indices, and lipid profiles in 549 Malaysian subjects (including 257 T2DM patients with MetS, 57 T2DM patients without MetS, 71 non-diabetics with MetS, and 164 control subjects without diabetes or metabolic syndrome).ResultsFasting serum levels of sCD26/DPP-IV were significantly higher in T2DM patients with and without MetS than in normal subjects. Likewise, sCD26/DPP-IV levels were significantly higher in patients with T2DM and MetS than in non-diabetic patients with MetS. However, active GLP-1 levels were significantly lower in T2DM patients both with and without MetS than in normal subjects. In T2DM subjects, sCD26/DPP-IV levels were associated with significantly higher A1c levels, but were significantly lower in patients using monotherapy with metformin. In addition, no significant differences in sCD26/DPP-IV levels were found between diabetic subjects with and without MetS. Furthermore, sCD26/DPP-IV levels were negatively correlated with active GLP-1 levels in T2DM patients both with and without MetS. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-cholesterol (LDL-c) levels.ConclusionSerum sCD26/DPP-IV levels increased in T2DM subjects with and without MetS. Active GLP-1 levels decreased in T2DM patients both with and without MetS. In addition, sCD26/DPP-IV levels were associated with Alc levels and negatively correlated with active GLP-1 levels. Moreover, metformin monotherapy was associated with reduced sCD26/DPP-IV levels. In normal subjects, sCD26/DPP-IV levels were associated with increased BMI, cholesterol, and LDL-c.     

Activity of salivary glands in secreting honey‐elaborating enzymes in two subspecies of honeybee (Apis mellifera L)

The activity of invertase, glucose oxidase and amylase in the cephalic (post‐cerebral) and thoracic salivary glands is determined in Egyptian and Carniolan honeybees (Apis mellifera L). For this purpose, three ages of worker bees are selected for enzyme assays. The results show that the three target enzymes are detected in the two glands during the three worker ages, except invertase, which cannot be detected in the cephalic gland of newly emerged bees of both subspecies. In both glands, the secretion of invertase is highest, followed by amylase and then glucose oxidase. In Carniolan bees, invertase secretion of the cephalic and thoracic glands increases gradually with age. In Egyptian bees, invertase increases with age only in the cephalic gland, whereas, in the thoracic gland, the highest secretion activity is detected in 10–15‐day‐old bees. The highest amounts of glucose oxidase and amylase in the cephalic gland are detected in newly emerged individuals of both Egyptian and Carniolan bees. In the thoracic gland, however, the highest activity of both enzymes is recorded only in newly emerged Egyptian bees. The results are discussed in the light of bee management and biological aspects of the two subspecies.     

Technical Study of a Standalone Photovoltaic–Wind Energy Based Hybrid Power Supply Systems for Island Electrification in Malaysia

Energy is one of the most important factors in the socioeconomic development of a country. In a developing country like Malaysia, the development of islands is mostly related to the availability of electric power. Power generated by renewable energy sources has recently become one of the most promising solutions for the electrification of islands and remote rural areas. But high dependency on weather conditions and the unpredictable nature of these renewable energy sources are the main drawbacks. To overcome this weakness, different green energy sources and power electronic converters need to be integrated with each other. This study presents a battery storage hybrid standalone photovoltaic-wind energy power supply system. In the proposed standalone hybrid system, a DC-DC buck-boost bidirectional converter controller is used to accumulates the surplus hybrid power in the battery bank and supplies this power to the load during the hybrid power shortage by maintaining the constant dc-link voltage. A three-phase voltage source inverter complex vector control scheme is used to control the load side voltage in terms of the voltage amplitude and frequency. Based on the simulation results obtained from MATLAB/Simulink, it has been found that the overall hybrid framework is capable of working under variable weather and load conditions.     

The non-equivalence of binding sites of coenzyme quinone and rotenone in mitochondrial NADH-CoQ reductase

The fluorescent probe erythrosine 5′-iodoacetamide (ER) binds to mitochondrial NADH-CoQ reductase (Complex-I) accompanied by an enhancement of the fluorescence intensity. The binding of the CoQ analogue, 2,3-dimethoxy-5-methyl-6-decyl-1,4-benzoquinone (DB), decreased the fluorescence intensity of the ER:Complex-I system. The ‘site 1’ inhibitor rotenone did not decrease the fluorescence intensity showing the non-identical nature of the binding sites of DB and rotenone. Also, the reduced form of DB did not decrease the fluorescence intensity. The decrease of the fluorescence intensity by DB was shown to be due to the removal of bound ER by DB. The rapid kinetics of ER binding was studied by temperature-jump relaxation. While DB caused complete elimination of the relaxation process in the ER:Complex-I system, rotenone caused only a decrease in the relaxation rate, suggesting conformational change. The relaxation rate showed a pH dependence with a maximum around pH 7.5.     

Estrogen induces normal murine CD5+ B cells to produce autoantibodies

Females have better humoral immune responses and are more susceptible to autoimmune diseases than males. Normal female mice (C57BL/6J, C3H/HeJ, and NZW) have significantly increased spontaneous autoimmune plaque-forming cells (APFC) to mouse erythrocytes pretreated with bromelain (Br-ME) in spleen, peritoneal exudate cell, and bone marrow compared to their male counterparts. A minor subpopulation of B cells, CD5+ B, is thought to produce this autoantibody. As determined by dual color flow cytometry, increased APFC to Br-ME in females is not due to quantitative increase of CD5+ B cells. Rather, it is due to increased numbers or percentages) of CD5+ B cells producing these autoantibodies, because CD5+ B cells from females produced greater numbers of APFC to Br-ME than equal numbers of cells derived from males. The increased autoantibody production in females can be attributed to the effect of estrogen on the immune response because this hormone markedly augments APFC to Br-ME in intact or orchidectomized males. Male hormone had little effect. Importantly, estrogen did not increase the numbers of B or CD5+ B cells but augmented the ability of B cells to produce this response. This was verified when a T cell-depleted B cell fraction or fluorescence-activated cell sorter purified CD5+ B cells from estrogen-treated mice proved more efficient in the production of APFC to Br-ME. These results suggest that the number of CD5+ B cells committed to produce autoantibodies to Br-ME is increased under the influence of estrogen. This is the first demonstration that estrogen can augment the production of natural autoantibodies in normal mice. The overall augmented humoral immune responses in females and the B cell hyperactivity in female predominant autoimmune diseases appears to be due to estrogen.     

Infant mortality in Bangladesh: a review of recent evidence

Estimates of child mortality are mainly based on reports by mothers on the survival status of their children. Infant mortality estimates from such data do not seem to have declined in recent years. The Bangladesh Bureau of Statistics sample registration infant mortality estimates appear to be suspiciously low.     

Catalytic properties of streptococcal NADH oxidase containing artificial flavins.

The flavoprotein NADH oxidase from Streptococcus faecalis 10C1, which catalyzes the tetravalent reduction of O2-->2H2O, has been purified as the apoenzyme to allow reconstitution studies with both native and artificial flavins. Turnover numbers for the enzyme containing 1-deaza-, 2-thio-, and 4-thio-FAD range from 51 to 4% of that of the native FAD enzyme; these reconstituted oxidases also catalyze the four-electron reduction of oxygen. Dithionite and NADH titrations of the native FAD oxidase require 1.7 eq of reductant/FAD and follow spectral courses very similar to those previously reported for the purified holoenzyme. Azide is a linear mixed-type inhibitor with respect to NADH, and dithionite titrations in the presence of azide yield significant stabilization of the neutral blue semiquinone. Redox stoichiometries for the oxidase containing modified flavins range from 1.1 to 1.4 eq of reductant/FAD. Spectrally distinct reduced enzyme.NAD+ complexes result with all but the 2-thio-FAD enzyme on titration with NADH. The reduced 4-thio-FAD oxidase shows little or no evidence of desulfurization to native FAD on reduction and reoxidation. Both the 8-mercapto- (E'o = -290 mV) and 8-hydroxy-FAD (E'o = -335 mV) oxidase are readily reduced by excess NADH. These results offer a further basis for analysis of the active-site structure and oxygen reactivity of this unique flavoprotein oxidase.     

Dynamics and modulation studies of human voltage gated Kv1.5 channel

The voltage gated Kv1.5 channels conduct the ultrarapid delayed rectifier current (IK_ur) and play critical role in repolarization of action potential duration. It is the most rapidly activated channel and has very little or no inactivated states. In human cardiac cells, these channels are expressed more extensively in atrial myocytes than ventricle. From the evidences of its localization and functions, Kv1.5 has been declared a selective drug target for the treatment of atrial fibrillation (AF). In this present study, we have tried to identify the rapidly activating property of Kv1.5 and studied its mode of inhibition using molecular modeling, docking, and simulation techniques. Channel in open conformation is found to be stabilized quickly within the dipalmitoylphosphatidylcholine membrane, whereas most of the secondary structure elements were lost in closed state conformation. The obvious reason behind its ultra-rapid property is possibly due to the amino acid alteration in S4–S5 linker; the replacement of Lysine by Glutamine and vice versa. The popular published drugs as well as newly identified lead molecules were able to inhibit the Kv1.5 in a very similar pattern, mainly through the nonpolar interactions, and formed sable complexes. V512 is found as the main contributor for the interaction along with the other important residues such as V505, I508, A509, V512, P513, and V516. Furthermore, two screened novel compounds show surprisingly better inhibitory potency and can be considered for the future perspective of antiarrhythmic survey.     

Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases

Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL-6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen–antibody (Ag???Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag???Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases.