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Background: Obesity and its co-morbidities are characterized by a chronic low-grade in amatory state, uncontrolled expression of metabolic measurements and dis-regulation of various forms of stress response. However, the contribution and correlation of in ammation, metabolism and stress responses to the disease are not fully elucidated. In this paper a cross-sectional case study was conducted on clinical data comprising 117 human male and female subjects with and without Type 2 Diabetes (T2D). Characteristics such as anthropometric, clinical and biochemical measurements were collected. Methods: Association of these variables with T2D and BMI were assessed using penalized hierarchical linear and logistic regression. In particular, elastic net, hdi and glinternet were used as regularization models to distinguish between cases and controls. Differential network analysis using closed-form approach was performed to identify pairwise-interaction of variables that influence prediction of the phenotype. Results: For the 117 participants, physical variables such as PBF, HDL and TBW had absolute coefficients 0.75, 0.65 and 0.34 using the glinternet approach, biochemical variables such as MIP, ROS and RANTES were identified as determinants of obesity with some interaction between inflammatory markers such as IL-4, IL-6, MIP, CSF, Eotaxin and ROS. Diabetes was associated with a significant increase in Thiobarbituric Acid Reactive Substances (TBARS) which are considered as an index of endogenous lipid peroxidation and an increase in two inflammatory markers, MIP-1 and RANTES. Furthermore, we obtained 13 pairwise effects. The pairwise effects include pairs from and within physical, clinical and biochemical features, in particular metabolic, inflammatory, and oxidative stress markers. Conclusion: We showcase those markers of oxidative stress (derived from lipid peroxidation) such as MIP-1 and RANTES participate in the pathogenesis of diseases such as diabetes and obesity in the Arab population.

Control of the intrinsic apoptotic pathway is exercised through the interplay of a 20-member family of proteins related to the founding member, Bcl-2. These proteins are confined to the vicinity of two membrane surfaces, the endoplasmic reticulum and the mitochondrial outer membrane. Like most of cellular biochemistry, reactions are confined in nano time and space which do not allow the approach to equilibrium seen at the macro level of the test tube, motivating us to initiate a dynamic systems biology approach to these non-equilibrium reactions. Our laboratory has investigated the mechanism of action of a non-peptide small molecule TW-37, which represents a new chemical class of compounds like ABT-737 (Abbott) useful in the induction of apoptosis in tumor cells. The drug induces apoptotic death in lymphoma cells with an observed EC50 of 290 nM (Mohammad et al., Clin. Cancer Res.13, 2226 (2007)). TW-37 binds with nanomolar affinity to the hydrophobic groove on the surface of the pro-survival Bcl-2 proteins which can accommodate the hydrophobic face of the amphipathic α-helix of BH3-only family members such as Bid. To model how the drug perturbs the Bcl-2 system, we have immobilized a highly-helical 24-mer Bid-derived BH3-domain peptide via its N-terminus to the surface of a CM5 chip (ligand) and analyzed peptide-protein interaction with flowing analyte proteins Bcl-2, Bcl-XL, Mcl-1, Bcl-w, and Bfl-1/A1 using the Biacore 3000. Using an analysis of Langmuir binding, we observe that the analyte proteins bind Bid with ON-rates (ka) varying modestly (3.01–7.72 E+05 1/Ms), but dissociate from Bid with 17-fold variation in OFF-rate (kd). The Bcl-w complex with Bid is the slowest to dissociate with a kd of 0.0015 (1/s); the most rapid dissociation is seen with Bcl-2 and Bid, where the kd is 0.0385. We find that Bid interacts with the multidomain proteins with dissociation constants (KD) between 4 and 82 nM, intermediate between earlier determinations (J. Med. Chem.49, 6139 (2006)); Molec. Cell17, 393 (2005)), but significantly lower than the KD for the drug TW-37 and the multidomain proteins (260–1100 nM reported previously; 79-333 nM measured here). Contrary to the suggestion of Shangary and Johnson (Biochemistry41, 9485 (2002)), our BH3-mimetic TW-37 is unable to disrupt already-formed Bid heterodimers with the mutidomain survival proteins; when heterodimers on the Biacore chip are challenged with doses of TW-37 up to 10000 nM. Consequently, the only opportunity the drug might have to perturb the Bcl-2 system is to locate the hydrophobic groove before Bid. Thus, a new picture emerges of drug action in which the dynamics of pre-apoptotic protein-protein interactions creates a temporal window for drug binding to the hydrophobic groove. In this light, attempts to develop small molecule inhibitors of protein-protein interaction (Current Topics in Medicinal Chem7(10), 922–927 (2007)) should incorporate surface plasmon resonance measurements of ka and kd into preclinical drug discovery programs in addition to KD estimates of drug binding to target. Figure Figure