Anti-inflammatory and anti-bacterial properties of tetramethylhexadecenyl succinyl cysteine (TSC): a skin-protecting cosmetic functional ingredient.

BACKGROUND: The skin is the first line of defence against exposure to microbial, physical, environmental and chemical insults. In mobilizing a protective response, several different cell types located in our skin release and respond to pro-inflammatory cytokines ensuring skin homeostasis and health. However, chronic activation of this response eventually causes damage resulting in premature ageing. Diosodium tetramethylhexadecenyl succinyl cysteine (TSC or SIG1273), an isoprenylcysteine small molecule, down modulates these inflammatory signalling pathways in various cell types (keratinocytes, peripheral blood mononuclear cells (PBMCs) and endothelial cells) and possesses anti-bacterial properties. Thus, TSC represents a novel cosmetic functional ingredient that provides a broad spectrum of benefits for the skin. OBJECTIVE: To assess the anti-inflammatory properties of TSC in several cutaneous cell types and further investigate its anti-microbial activity. METHODS: Cultured normal human epidermal keratinocytes were exposed to chemical irritant phorbol 12-myrisate 13-acetate (TPA) or ultraviolet-B light (UVB) to induce pro-inflammatory cytokine (IL-6, IL-8 and TNF-α) production. T-cell receptor (TCR) activation of PBMCs and nickel (Ni(2+) ) treatments of human dermal microvascular endothelial cells (HDMECs) were performed resulting in IL-4, IL-6, IL-8 and IL-17 production. Streptococcus pyogenes were cultured to determine minimal inhibitory concentration values. RESULTS: In vitro studies demonstrate TSC blocks TPA and UVB-induced cytokine production in cultured keratinocytes. Similarly, TSC inhibits overproduction of IL-4 and IL-17 in T-cell receptor (TCR)-activated PBMCs as well as nickel induction of IL-6 and IL-8 in HDMECs. Lastly, TSC demonstrated anti-microbial properties, inhibiting cell growth of S. pyogenes. CONCLUSIONS: Tetramethylhexadecenyl succinyl cysteine represents a novel cosmetic functional ingredient that provides a dual modulating benefit of skin protection to individuals by reducing inflammation in keratinocytes, endothelial and mononuclear cell types and S. pyogenes counts.

Extra-anatomic arterial reconstruction with ligation of common iliac arteries and embolization of the aneurysm for the treatment of abdominal aortic aneurysms in high-risk patients.

PURPOSE: The mortality of an unrepaired abdominal aortic aneurysm (AAA) generally exceeds the mortality associated with surgical repair. However, as our longevity increases, more frequently we see patients whose risk of surgical repair approximates the risk of rupture. We present an extra-anatomic bypass graft with complete aneurysm exclusion by iliac ligation and coil embolization of the aneurysm as an alternative for these high-risk patients. METHODS: An extra-anatomic bypass graft, followed by bilateral iliac artery ligation (retroperitoneal approach) and complete coil embolization of the AAA, was performed in eight patients (mean age, 77 years) found to be at prohibitive operative risk because of multiple comorbidities (American Society of Anesthesiologists class IV). Most patients (5 of 8) were symptomatic on presentation with a mean AAA diameter of 7 cm (range, 6.7-9.5 cm). We repair approximately 30 infrarenal aneurysms per year electively at our institution. RESULTS: All patients tolerated the surgical procedures. The average hospital stay was 8 days. All but two aneurysms demonstrated complete thrombosis by 48 hours. After 48 months there was no incidence of graft thrombosis, peripheral ischemia, visceral ischemia or thrombus infection. There was one perioperative death from aspiration pneumonia. Seventy-five percent (6 of 8) of patients have survived at least 1 year without surgical complications. No patient has had a ruptured aneurysm. CONCLUSION: Combining an extra-anatomic bypass graft and complete exclusion of the AAA by ligation of the common iliac arteries and a coil embolization is an effective, less invasive treatment option for patients with AAA and prohibitive operative risk. We emphasize the need for complete embolization documented by decreased aneurysm size.

Zinc metabolism and metallothionein expression in bone marrow during erythropoiesis.

Zinc metabolism and metallothionein induction in rat bone marrow were investigated during induced erythropoiesis. Redistribution of body zinc was measured with 65Zn after acute blood loss in rats fed zinc-restricted or zinc-adequate diets. Uptake of 65Zn by bone marrow was related to time after blood loss, metallothionein induction, and dietary zinc status. Increased 65Zn uptake by marrow of zinc-restricted rats suggests a minimal amount of zinc is necessary to support expansion of the erythrocytic compartment. Zinc induction of marrow metallothionein also occurred in rats in which anemia was produced using phenylhydrazine. Anemic rats which were administered zinc had higher concentrations of marrow metallothionein compared with control rats. Induction of marrow metallothionein by zinc in nonanemic rats required prior treatment with erythropoietin. Percoll fractionation showed marrow metallothionein was most abundant in erythroblasts. These experiments suggest metallothionein synthesis occurs in erythropoietin-sensitive precursor cells in the marrow in response to increased zinc accessibility.

Metallothionein expression in rat bone marrow is dependent on dietary zinc but not dependent on interleukin-1 or interleukin-6.

The comparative influence of dietary zinc status and recombinant human interleukin-1 alpha (rhIL-1 alpha) and recombinant human interleukin-6 (rhIL-6) on metallothionein (MT) gene expression was examined in rat bone marrow and liver. Growing male rats were fed a diet with 5 (restricted), 30 (control), or 180 (supplemented) mg Zn/kg for 14 d. On d 15, rats were injected with 5 micrograms of rhIL-1 alpha or rhIL-6. Marrow metallothionein responded directly to dietary zinc but did not respond to these cytokines. Significantly less zinc accumulated in marrow from the zinc-restricted rats compared with control or supplemented rats. Analysis of metallothionein isoform mRNA expression showed MT-1 is the primary gene expressed in marrow. A significant interaction between dietary zinc and cytokine treatment was observed in the liver. Hepatic metallothionein induction following both rhIL-1 alpha and rhIL-6 injection was directly related to dietary zinc intake. Expression of hepatic metallothionein isoform mRNAs suggested MT-1 responded to zinc and MT-2 responded to cytokines. These results indicate that metallothionein gene expression in both the marrow and the liver responds to dietary zinc status. In contrast, liver metallothionein expression can be altered by these cytokines, which are known to act on many cell types. Furthermore, these results suggest that bone marrow metallothionein could be of importance in the development of marrow cells.

Maternal zinc deprivation and interleukin-1 influence metallothionein gene expression and zinc metabolism of rats.

The influence of maternal dietary zinc intake and recombinant human interleukin-1 alpha (rhIL-1 alpha) administration on metallothionein gene expression and the distribution of 65Zn were investigated. Pregnant rats were fed diets containing 1, 5, 30 or 180 mg Zn/kg diet in an equalized regime from d 13-20 of gestation. Metallothionein gene expression was examined by Northern blot and dot blot hybridization using combined 60-mer oligonucleotides specific for rat metallothionein-1 and -2 genes. Expression was progressively depressed in the fetal livers and livers and kidneys of dams fed diets marginal (5 mg/kg) and deficient (1 mg/kg) in zinc content. Administration of rhIL-1 alpha increased expression in maternal liver, placenta and in fetal liver of dams fed adequate or deficient diets. Kinetics of intravenously administered 65Zn showed that in response to rhIL-1 alpha, there was a higher uptake by the maternal liver and bone marrow with less 65Zn uptake by bone, intestine and plasma activity compared to controls. No change was observed in 65Zn taken up by the placenta or transferred to the fetus. Alteration of metallothionein gene expression could represent, in part, the mechanism whereby altered effects of zinc metabolism and function are mediated during fetal development.