The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (ob) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin’s pleiotropic effects, playing a crucial role in regulating body mass via a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.

Mycobacterium tuberculosis truncated hemoglobin, HbN, is endowed with a potent nitric-oxide dioxygenase activity and has been found to relieve nitrosative stress and enhance in vivo survival of a heterologous host, Salmonella enterica Typhimurium, within the macrophages. These findings implicate involvement of HbN in the defense of M. tuberculosis against nitrosative stress. The protein carries a tunnel system composed of a short and a long tunnel branch that has been proposed to facilitate diatomic ligand migration to the heme and an unusual Pre-A motif at the N terminus, which does not contribute significantly to the structural integrity of the protein, as it protrudes out of the compact globin fold. Strikingly, deletion of Pre-A region from the M. tuberculosis HbN drastically reduces its ability to scavenge nitric oxide (NO), whereas its insertion at the N terminus of Pre-A lacking HbN of Mycobacterium smegmatis improved its nitric-oxide dioxygenase activity. Titration of the oxygenated adduct of HbN and its mutants with NO indicated that the stoichiometric oxidation of protein is severalfold slower when the Pre-A region is deleted in HbN. Molecular dynamics simulations show that the excision of Pre-A motif results in distinct changes in the protein dynamics, which cause the gate of the tunnel long branch to be trapped into a closed conformation, thus impeding migration of diatomic ligands toward the heme active site. The present study, thus, unequivocally demonstrates vital function of Pre-A region in NO scavenging and unravels its unique role by which HbN might attain its efficient NO-detoxification ability.Unlike many pathogens that are overtly harmful to their host, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. The success of tubercle bacillus to establish long term persistent infection within the human host lies in its ability to survive and resist hazardous environment of its intracellular niche. Early infection events involve entry and multiplication within the bacteriostatic environment of macrophages (1, 2), where an inducible nitric-oxide synthase generates copious amounts of nitric oxide (NO), which plays an important role in the host defense against microbial pathogens (3, 4) and restricts their growth and survival by inhibiting key enzymes such as the terminal respiratory oxidases (5) and ironsulfur centers of key enzymes such as aconitase (6, 7). In addition, NO combines with superoxide produced by respiring cells to form the highly oxidizing agent peroxynitrite (8). An efficient NO scavenging system, therefore, is required by microbial pathogens to cope with NO poisoning during their intracellular regime.M. tuberculosis has evolved resistance mechanisms by which toxic effects of NO and nitrosative stress can be evaded. One of the unique defense mechanisms by which it can protect itself from reactive nitrogen species relies on the oxygenated form of a group I truncated hemoglobin, HbN, which very efficiently converts NO into harmless nitrate (9 -11)...

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In mammalian blood plasma, serum albumin acts as a transport protein for free fatty acids, other lipids and hydrophobic molecules including neurodegenerative peptides, and essential metal ions such as zinc to allow their systemic distribution. Importantly, binding of these chemically extremely diverse entities is not independent, but linked allosterically. One particularly intriguing allosteric link exists between free fatty acid and zinc binding. Albumin thus mediates crosstalk between energy status/metabolism and organismal zinc handling. In recognition of the fact that even small changes in extracellular zinc concentration and speciation modulate the function of many cell types, the albumin-mediated impact of free fatty acid concentration on zinc distribution may be significant for both normal physiological processes including energy metabolism, insulin activity, heparin neutralisation, blood coagulation, and zinc signalling, and a range of disease states, including metabolic syndrome, cardiovascular disease, myocardial ischemia, diabetes, and thrombosis.

Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly and systemic side" of drusen. 6.2. Nineteen drusen proteins out of 89 were not assigned. 6.3. Blood proteins are an important source of drusen proteins. 7. Drusen and hydroxyapatite. 8. Drusen and plaques: age-related macular degeneration and atherosclerosis. 8.1. Clinical and epidemiological studies. 8.2. Histological and pathobiological similarities. 8.3. Genetics and molecular biology. 9. Future directions and conclusions.

HighlightsA molecular mechanism underlying the albumin-cobalt binding assay.Free fatty acid binding interferes with Co(II) binding to albumin.Ischemia-modified albumin corresponds to albumin with increased FFA bound.Increased FFA levels are sufficient to explain high ACB readings.Clinical data are consistent with FFA as the trigger for high ACB/high IMA levels.

Pulse-dipolar EPR is an appealing strategy for structural characterization of complex systems in solution that complements other biophysical techniques. Significantly, the emergence of genetically encoded self-assembling spin labels exploiting exogenously introduced double-histidine motifs in conjunction with Cu II -chelates offers high precision distance determination in systems nonpermissive to thiol-directed spin labeling. However, the noncovalency of this interaction exposes potential vulnerabilities to competition from adventitious divalent metal ions, and pH sensitivity. Herein, a combination of room-temperature isothermal titration calorimetry (ITC) and cryogenic relaxation-induced dipolar modulation enhancement (RIDME) measurements are applied to the model protein Streptococcus sp. group G. protein G, B1 domain (GB1). Results demonstrate double-histidine motif spin labeling using Cu II -nitrilotriacetic acid (Cu II –NTA) is robust against the competitor ligand Zn II –NTA at >1000-fold molar excess, and high nM binding affinity is surprisingly retained under acidic and basic conditions even though room temperature affinity shows a stronger pH dependence. This indicates the strategy is well-suited for diverse biological applications, with the requirement of other metal ion cofactors or slightly acidic pH not necessarily being prohibitive.

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