Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.

Obesity is an increasing problem worldwide. It is often associated with co-morbidities such as type II diabetes, atherosclerotic diseases, and non-alcoholic fatty liver disease. The risk of these diseases can be lowered by relieving the systemic low-grade inflammation associated with obesity, even without noticeable weight loss. Bilberry is an anthocyanin-rich wild berry with known antioxidant and anti-inflammatory properties. In the present study, a high-fat-diet-induced mouse model of obesity was used to investigate the effects of air-dried bilberry powder on weight gain, systemic inflammation, lipid and glucose metabolism, and changes in the gene expression in adipose and hepatic tissues. The bilberry supplementation was unable to modify the weight gain, but it prevented the increase in the hepatic injury marker ALT and many inflammatory factors like SAA, MCP1, and CXCL14 induced by the high-fat diet. The bilberry supplementation also partially prevented the increase in serum cholesterol, glucose, and insulin levels. In conclusion, the bilberry supplementation alleviated the systemic and hepatic inflammation and retarded the development of unwanted changes in the lipid and glucose metabolism induced by the high-fat diet. Thus, the bilberry supplementation seemed to support to retain a healthier metabolic phenotype during developing obesity, and that effect might have been contributed to by bilberry anthocyanins.

Metabolic diseases linked to obesity are an increasing problem globally. They are associated with systemic inflammation, which can be triggered by nutrients such as saturated fatty acids. Cloudberry is rich in ellagitannin and its derivatives, which are known to have anti-inflammatory properties. In the present study, a high-fat-diet-induced mouse model of obesity was used to study the effects of air-dried cloudberry powder on weight gain, systemic inflammation, lipid and glucose metabolism, and changes in gene expression in hepatic and adipose tissues. Cloudberry supplementation had no effect on weight gain, but it prevented the rise in the systemic inflammation marker serum amyloid A (SAA) and the hepatic inflammation/injury marker alanine aminotransferase (ALT), as well as the increase in the expression of many inflammation-related genes in the liver and adipose tissue, such as Mcp1, Cxcl14, Tnfa, and S100a8. In addition, cloudberry supplementation impeded the development of hypercholesterolemia and hyperglycemia. The results indicate that cloudberry supplementation helps to protect against the development of metabolic inflammation and provides partial protection against disturbed lipid and glucose metabolism. These results encourage further studies on the effects of cloudberry and cloudberry-derived ellagitannins and support the use of cloudberries as a part of a healthy diet to prevent obesity-associated metabolic morbidity.

Type 2 inflammation‒related cytokine IL-13 plays a protective role in experimental papilloma induction in mice. To understand the mechanisms by which IL-13 contributes to papilloma formation, we utilized Il13rα1-knockout (KO) mice in a widely used 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl phorbol-13-acetate two-stage skin carcinogenesis protocol that mimics the development of squamous cell carcinoma. KO mice developed more papillomas and significantly faster than wild-type mice. Papilloma development reduced regulatory T cells in wild-type mice but substantially less in KO mice. In line with this, IL-2 and IL-10 levels decreased in wild-type mice but not in KO mice. Furthermore, systemic IL-5 and TSLP levels were elevated, whereas IL-22 was decreased during papilloma formation in the skin of KO mice. Polymorphonuclear myeloid‒derived suppressor cells were decreased in the KO mice at the early phase of papilloma induction. We show that IL-13Rα1 protects from papilloma development in chemically induced skin carcinogenesis, and our results provide further insights into the protective role of functional IL-4 and IL-13 signaling through type II IL-4 receptor in tumor development.

In vivo phage display is a method used for identification of organ- or disease-specific vascular homing peptides for targeted delivery of pharmaceutics. It is agnostic as to the nature and identity of the target molecules. The current in vivo biopanning lacks inbuilt mechanisms to select for peptides capable of vascular homing that would also be capable of tissue penetration to reach therapeutically relevant cells in the tissue parenchyma. Here, we combined in vivo phage display with microdialysis-based parenchymal recovery and high-throughput sequencing to select for peptides that, besides vascular homing, facilitate extravasation and tissue penetration. We first demonstrated in skin wounds that the method can selectively separate known homing peptides from those with additional tissue-penetrating ability. Screening of a naïve peptide library identifies peptides that home and extravasate to extravascular granulation tissue in vascularized and diabetic wounds and cross blood–retina barrier in retinopathy. Our work suggests that in vivo phage display combined with microdialysis can be used for the discovery of vascular homing peptides capable of extravasation and tissue penetration.

Carbonic anhydrases (CAs) contribute to tumor cell migration by generating an acidic environment through the conversion of carbon dioxide to bicarbonate and a proton. CA VI is secreted to milk and saliva, and it could contribute to wound closure, as a potential trophic factor, in animals that typically lick their wounds. Our aim was to investigate whether human CA VI improves skin-wound healing in full-thickness skin-wound models. The effect was studied in Car6 ^−/− knockout mice and wild type littermates. Half of both mice strains were given topically administered, milk-derived CA VI after wounding and eight hours later. The amount of topically given CA VI exceeded the predicted amount of natural saliva-delivered CA VI. The healing was followed for seven days and studied from photographs and histological sections. Our results showed no significant differences between the treatment groups in wound closure, re-epithelization, or granulation tissue formation, nor did the Car6 genotype affect the healing. Our results demonstrate that CA VI does not play a major role in skin-wound healing and also suggest that saliva-derived CA VI is not responsible for the licking-associated improved wound healing in animals.