2-Formyl-komarovicine promotes adiponectin production in human mesenchymal stem cells through PPARγ partial agonism.

Adiponectin is a major adipocytokine secreted from mammalian adipocytes. Relatively low expression of adiponectin is associated with various human metabolic diseases and some cancers. Adiponectin-secreting compounds have therapeutic potential for these diseases. Adipogenesis of human bone marrow-mesenchymal stem cells (hBM-MSCs) has been used as a phenotypic assay to find adiponectin secreting compounds. In a phytochemical library screen, 2-formyl-komarovicine, 1-(quinolin-8-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbaldehyde, isolated from Nitraria komarovii was identified as a potential adiponectin-secreting compound. To validate the results of the impure phytochemical, we synthesized 2-formyl-komarovicine. The synthetic 2-formyl-komarovicine significantly promoted adiponectin production during adipogenesis in hBM-MSCs. In a target identification experiment, 2-formyl-komarovicine bound to peroxisome proliferator-activated receptor γ (PPARγ) in a concentration-dependent manner. Notably, 2-formyl-komarovicine competitively inhibited the adiponectin-promoting activity of a full PPARγ agonist, troglitazone, in hBM-MSCs, which is a pharmacological feature of a partial agonist. The ligand-docking model showed that 2-formyl-komarovicine interacted with the hydrophobic pocket of the PPARγ ligand-binding domain, but lacked an interaction to stabilize helix H12, which is one of the major binding themes of PPARγ partial agonists. We concluded that 2-formyl-komarovicine provides a novel pharmacophore for PPARγ partial agonists to increase adiponectin production.

Synthesis and Structure Revision of Dimeric Tadalafil Analogue Adulterants in Dietary Supplements.

A number of phosphodiesterase 5 (PDE5) inhibitors approved by authorities have been used successfully in the treatment of erectile dysfunction. These medicines must be prescribed carefully due to their adverse effects, but they and their analogues are being illegally added to dietary supplements. These illegal dietary supplements pose a significant risk to public health. Several dimeric tadalafil analogues have been synthesized for use as reference standards in the inspection of functional foods that are mainly advertised as sexual enhancement products. During the course of this synthesis, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) was proven to be the reagent of choice for amide coupling to produce these dimeric tadalafil analogues. Moreover, the trans-isomer structures tentatively assigned for the isolated dimeric tadalafil analogues (bisprehomotadalafil and bisprecyclopentyltadalafil) found in dietary supplements are now revised to cis-isomer structures.

Soluble terminal complement activation fragment sC5b-9: a new serum biomarker for traumatic brain injury?

PURPOSE: Terminal complement pathway activation after traumatic brain injury (TBI) leads to formation of the membrane attack complex (MAC/C5b-9) which induces neuronal cell death and host-mediated secondary brain injury. Serum levels of soluble MAC (sC5b-9) have not been previously determined in patients with isolated TBI. METHODS: A prospective observational cohort study was performed during a 5-year time-period on adult patients with isolated TBI admitted to an academic level I trauma center in the United States. Controls consisted of patients with femur shaft fractures with or without TBI to mitigate the effect of systemic complement activation by peripheral trauma. Healthy volunteers served as internal controls. The sC5b-9 serum concentrations were measured on the day of admission by enzyme-linked immunosorbent assay (ELISA) and compared between the study cohorts. Univariate analysis was performed to determine independent predictive variables of major complications during hospital admission. RESULTS: Serum sC5b-9 levels were significantly elevated in patients with isolated TBI (n = 42), compared to patients with isolated femoral shaft fractures (n = 36) or combined TBI and femoral shaft fractures (n = 30; p < 0.05). There was no significant difference in serum sC5b-9 levels between the femur group and the combined injury group, compared to the healthy volunteers (n = 21). Univariate analysis revealed serum sC5b-9 levels as an independent predictor of major postinjury complications after isolated TBI (p < 0.01). CONCLUSION: The soluble terminal complement complex sC5b-9 represents a potential novel serum biomarker specific for isolated head injuries, since peripheral trauma did not appear to affect the serum sC5b-9 levels.