We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.

Mesenchymal stromal cells (MSCs) are rare progenitor cells that can be isolated from various tissues. They exhibit multilineage differentiation potential, support regenerative processes, and interact with various immune cells. Therefore, MSCs represent a promising tool for regenerative medicine. However, source-dependent and donor-dependent differences of MSC properties, including implications on their clinical application are still largely unknown. We evaluated MSCs derived from perinatal tissues umbilical cord (UC) and amniotic membrane (AM) in comparison to adult MSCs from bone marrow (BM), which were used as gold standard. We found genetic background-independent differences between MSCs from UC and AM. While AM-and UC-MSCs were closer to each other than to BM-MSCs, they also exhibited differences between each other. AM-MSCs from different donors but not UC-MSCs displayed high interdonor variability. In addition, we show that although all MSCs expressed similar surface markers, MSC populations from UC and AM showed differential profiles of gene expression and paracrine factor secretion to BM-derived MSCs. Notably, pathway analysis of gene expression data revealed intriguing differences between MSCs suggesting that MSCs from UC and AM possess in general a higher potential of immunomodulatory capacity, whereas BM-MSCs showed a higher potential of supporting regenerative processes as exemplified by neuronal differentiation and development. These differences between perinatal and BM-derived MSCs may be relevant for clinical applications.

Dietary supplementation with very-long-chain n-3 fatty acids was no better than corn-oil supplementation in treating psoriasis. Clinical improvement was not correlated with an increase in the concentration of n-3 fatty acids in serum phospholipids among the patients in the fish-oil group, whereas there was a significant correlation between clinical improvement and an increase in eicosapentaenoic acid and total n-3 fatty acids in the corn-oil group.

The purpose of this study was to investigate whether fish oil and/or corn oil had a beneficial effect on the clinical state of atopic dermatitis, and to evaluate the dietary intake of nutrients in this group of patients. In a double-blind, multicentre study lasting 4 months, during wintertime, 145 patients with moderate to severe atopic dermatitis were randomly assigned to receive either 6 g/day of concentrated n-3 fatty acids, or an isoenergetic amount of corn oil. As local treatment, only an emollient cream or hydrocortisone cream was allowed. The fatty acid pattern in serum phospholipids, and the dietary intake of nutrients were monitored in a subgroup of patients, and the results were compared with a group of patients with psoriasis. The overall clinical score, as evaluated by the physicians, improved during the trial by 30% in the fish oil (P < 0.001) and 24% in the corn oil group (P < 0.001). This was also consistent with the results from a selected skin area, and it was further confirmed by the total subjective clinical score reported by the patients. There were no significant differences in the clinical scores between the two groups at baseline, and at the end of the study. In the fish oil group, the amount of n-3 fatty acids in serum phospholipids was significantly increased at the end of the trial, compared with pretreatment values (P < 0.001), whereas the level of n-6 fatty acids was decreased (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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