Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties

Tumor cells have the ability to exploit stromal cells to facilitate metastasis. By using malignant melanoma as a model, we show that the stroma adjacent to metastatic lesions is enriched in the known metastasis-promoting protein S100A4. S100A4 stimulates cancer cells to secrete paracrine factors, such as inflammatory cytokines IL8, CCL2 and SAA, which activate stromal cells (endothelial cells and monocytes) so that they acquire tumor-supportive properties. Our data establishes S100A4 as an inducer of a cytokine network enabling tumor cells to engage angiogenic and inflammatory stromal cells, which might contribute to pro-metastatic activity of S100A4.     

Effects of dietary fruits,vegetables and a herbal tea on the in vitro transport of cimetidine: Comparing the Caco-2 model with porcine jejunum tissue

Context: Dietary botanicals are often consumed together with allopathic medicines, which may give rise to pharmacokinetic interactions. In vitro intestinal models are useful to identify botanical-drug interactions, but they may exhibit different expressions of transporters or enzymes.

Objective: To compare the effects of selected dietary botanical extracts on cimetidine transport across two in vitro intestinal models.

Materials and Methods: Bi-directional transport of cimetidine was measured across Caco-2 cell monolayers and excised porcine jejunum tissue in the absence (control) as well as the presence of verapamil (positive control) and selected plant extracts.

Results: Sclerocarya birrea Hochst. (Anacardiaceae) (marula) and Psidium guajava L. (Myrtaceae) (guava) crude extracts significantly decreased cimetidine efflux in both in vitro models resulting in increased absorptive transport of the drug. On the other hand, Dovyalis caffra Sim. (Flacourtiaceae) (Kei-apple), Prunus persica (L.) Batsch (Rosaceae) (peach), Aspalathus linearis (Burm. f.) R. Dahlgren (Fabaceae) (rooibos tea), Daucus carota L. (Apiaceae) (carrot), Prunus domestica A. Sav. (Rosaceae) (plum), Beta vulgaris L. (Chenopodiaceae) (beetroot) and Fragaria x ananassa (Weston) Duchesne ex Rozier. (Rosaceae) (strawberry) crude extracts exhibited different effects on cimetidine transport between the two models.

Discussion: Caco-2 cells were more sensitive to changes in cimetidine transport by the plant extracts and therefore may overestimate the effects of co-administered plant extracts on drug transport compared to the excised pig tissue model, which is congruent with findings from previous studies.

Conclusions: The excised porcine jejunum model seemed to provide a more realistic estimation of botanical-drug pharmacokinetic interactions than the Caco-2 cell model.     

Tumor necrosis factor‐like weak inducer of apoptosis and its receptor fibroblast growth factor‐inducible 14 are expressed in urticarial vasculitis

Tumor necrosis factor (TNF)‐like weak inducer of apoptosis (TWEAK), a member of the TNF family, has been implicated as a pro‐inflammatory cytokine in many types of autoimmune and infectious diseases. However, information about TWEAK in dermatological diseases is limited. To date, no studies have investigated the roles of TWEAK in patients with urticarial vasculitis (UV). This study aimed to assess serum TWEAK levels, together with TWEAK and fibroblast growth factor‐inducible 14 (Fn14) expressions of skin lesions in patients with UV. Serum TWEAK levels in patients with UV, together with patients with cutaneous leukocytoclastic angiitis (CLA) and healthy controls were detected by enzyme‐linked immunosorbent assay; TWEAK and Fn14 expressions of skin lesions were analyzed by immunohistochemistry. Results showed that TWEAK and Fn14 were abundantly expressed in the dermal vessel wall of lesional skin in patients with UV but not healthy controls. Serum TWEAK levels in the acute stage in patients with UV were significantly higher than those in the convalescent stage and healthy controls. Serum TWEAK levels were elevated significantly in patients with CLA compared with those in healthy controls. Our previous study indicated that TWEAK may be an important mediator for the development of vascular inflammation in skin. In addition, we also found that TWEAK blockade substantially reduced vascular damage and perivascular leukocyte infiltrates in lipopolysaccharide‐induced cutaneous vasculitis. Our study shows that TWEAK may be associated with the pathogenesis of UV; it is therefore suggested that TWEAK may be a potential therapeutic target for UV and other types of cutaneous vasculitis.