A continuing quest for specific inhibitors of proinflammatory cytokines brings promise for effective therapies designed for inflammatory and autoimmune disorders. Cefazolin, a safe, first-generation cephalosporin antibiotic, has been recently shown to specifically interact with interleukin 15 (IL-15) receptor subunit α (IL-15Rα) and to inhibit IL-15-dependent TNF-α and IL-17 synthesis. The aim of this study was to elucidate cefazolin activity against IL-2, IL-4, IL-15 and IL-21, i.e. four cytokines sharing the common cytokine receptor γ chain (γ c). In silico, molecular docking unveiled two potential cefazolin binding sites within the IL-2/IL-15Rβ subunit and two within the γ c subunit. In vitro, cefazolin decreased proliferation of PBMC (peripheral blood mononuclear cells) following IL-2, IL-4 and IL-15 stimulation, reduced production of IFN-γ, IL-17 and TNF-α in IL-2-and IL-15-treated PBMC and in IL-15 stimulated natural killer (NK) cells, attenuated IL-4-dependent expression of CD11c in monocyte-derived dendritic cells and suppressed phosphorylation of JAK3 in response to IL-2 and IL-15 in PBMC, to IL-4 in TF-1 (erythroleukemic cell line) and to IL-21 in NK-92 (NK cell line). The results of the study suggest that cefazolin may exert inhibitory activity against all of the γ c receptor-dependent cytokines, i.e. IL

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The Parkes Weber syndrome (PWS), first described in 1907 [1], is characterized by triad of arteriovenous fistulas (AVF), varicose veins and bone and soft tissue hypertrophy leading to limb enlargement. The symptoms of PWS are congenital and present at birth. Vascular anomalies usually affect a limb, most commonly a leg, and less often a trunk. Capillary malformations, forming geographic patterns, are typically located on lateral side of the limb, buttocks or trunk. The appearance of varicose veins and dilated superficial veins in older age is triggered by arteriovenous shunt, venous hypertension and insufficiency of the deep venous system. The enlargement of a limb is present at birth, and the axial overgrowth can enlarge in postnatal period [2,3]. Cases of shortened lower extremity and pelvis malformations have also been described [4]. Arteriovenous leak may also lead to cardiac system failure or to limb ischemia. Not surprisingly, PWS, similarly to other vascular malformations, significantly reduces the quality of life of the affected patients [5].The treatment of patients with PWS is mainly symptomatic. Compression therapy is used to reduce symptoms of chronic venous insufficiency and lymphatic edema. In selected cases invasive procedures are performed. Surgical treatment is difficult and may require several intravascular procedures, such as embolization, sclerotherapy or classic open operations involving arteriovenous fistula ligation. In severe cases of ischemic extremities amputation is the only therapy. Therefore, there is an ever-existing need to develop a safe and effective pharmacological therapy for PWS patients.For the purpose of the study we have established the first animal model reproducing complex manifestations of PWS and applicable for research on etiology, treatment and prevention of the disease. The model mimics major clinical features characteristic for the human PWS: venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy [6] [7].Cellular biology tools were applied to examine protective effect of ca. 30 new semi-synthetic compounds derived from the main aglycone of escin saponins, on the vascular endothelium under inflammatory conditions. The in vitro tests evaluated i.a. cell proliferation, migration, endothelial monolayer permeability, and the effect on NFκB signal transduction. One paricular molecule (1), obtained in 5 steps as illustrated on the Scheme below, showing promising biological characteristics and favorable physicochemical properties has been selected for in vivo studies [8]. The obtained results confirmed valuable pharmacological properties of the tested compound as all the animals treated with the selected compound showed significantly reduced symptoms of PWS as compared to untreated control. Furthermore, we believe that the molecule should be considered as a promising candidate for the prevention and treatment of other, more common vascular disorders.PeerJ PrePrints | https://doi.org/10.7287/peerj.preprints.1598v1 | CC-BY 4.0 Open Access | rec:

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The Parkes Weber syndrome (PWS), first described in 1907, is characterized by triad of arteriovenous fistulas (AVF), varicose veins and bone and soft tissue hypertrophy leading to limb enlargement. The symptoms of PWS are congenital and present at birth. Vascular anomalies usually affect a limb, most commonly a leg, and less often a trunk. Capillary malformations, forming geographic patterns, are typically located on lateral side of the limb, buttocks or trunk. The appearance of varicose veins and dilated superficial veins in older age is triggered by arteriovenous shunt, venous hypertension and insufficiency of the deep venous system. The enlargement of a limb is present at birth, and the axial overgrowth can enlarge in postnatal period. Cases of shortened lower extremity and pelvis malformations have also been described. Arteriovenous leak may also lead to cardiac system failure or to limb ischemia. Not surprisingly, PWS, similarly to other vascular malformations, significantly reduces the quality of life of the affected patients. The treatment of patients with PWS is mainly symptomatic. Compression therapy is used to reduce symptoms of chronic venous insufficiency and lymphatic edema. In selected cases invasive procedures are performed. Surgical treatment is difficult and may require several intravascular proce-dures, such as embolization, sclerotherapy or classic open operations involving arteriovenous fistula ligation. In severe cases of ischemic extremities amputation is the only therapy. Therefore, there is an ever-existing need to develop a safe and effective pharmacological therapy for PWS patients. For the purpose of the study we have established the first animal model reproducing complex manifestations of PWS and applicable for research on etiology, treatment and prevention of the disease. The model mimics major clinical features characteristic for the human PWS: venous hypertension and dilatation, varicose veins formation, and the limb hypertrophy. Cellular biology tools were applied to examine protective effect of ca. 30 new semi-synthetic compounds derived from the main aglycone of escin saponins, on the vascular endothelium under inflammatory conditions. The in vitro tests evaluated i.a. cell proliferation, migration, endothelial monolayer permeability, and the effect on NFκB signal transduction. One paricular molecule (1), obtained in 5 steps as illustrated on the Scheme below, showing promising biological characteristics and favorable physicochemical properties has been selected for in vivo studies. The obtained results confirmed valuable pharmacological properties of the tested compound as all the animals treated with the selected compound showed signifi-cantly reduced symptoms of PWS as compared to untreated control. Furthermore, we believe that the molecule should be considered as a promising candidate for the prevention and treatment of other, more common vascular disorders.

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