How ceramides affect the development of colon cancer: from normal colon to carcinoma.

The integrity of the colon and the development of colon cancer depend on the sphingolipid balance in colon epithelial cells. In this review, we summarize the current knowledge on how ceramides and their complex derivatives influence normal colon development and colon cancer development. Ceramides, glucosylceramides and sphingomyelin are essential membrane components and, due to their biophysical properties, can influence the activation of membrane proteins, affecting protein-protein interactions and downstream signalling pathways. Here, we review the cellular mechanisms known to be affected by ceramides and their effects on colon development. We also describe which ceramides are deregulated during colorectal carcinogenesis, the molecular mechanisms involved in ceramide deregulation and how this affects carcinogenesis. Finally, we review new methods that are now state of the art for studying lipid-protein interactions in the physiological environment.

How sphingolipids affect T cells in the resolution of inflammation.

The concept of proper resolution of inflammation rather than counteracting it, gained a lot of attention in the past few years. Re-assembly of tissue and cell homeostasis as well as establishment of adaptive immunity after inflammatory processes are the key events of resolution. Neutrophiles and macrophages are well described as promotors of resolution, but the role of T cells is poorly reviewed. It is also broadly known that sphingolipids and their imbalance influence membrane fluidity and cell signalling pathways resulting in inflammation associated diseases like inflammatory bowel disease (IBD), atherosclerosis or diabetes. In this review we highlight the role of sphingolipids in T cells in the context of resolution of inflammation to create an insight into new possible therapeutical approaches.

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model.

To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.

Incidence of Ultrathin Descemet Stripping Endothelial Keratoplasty Corneal Graft Rejection following Steroid Discontinuation.

Purpose/Aims: To determine the incidence of corneal graft rejection in patients with approximately 1 year of steroid therapy following uDSEK. A shortened course of corticosteroids may be beneficial and a viable option in Ultrathin Descemet's Stripping Endothelial Keratoplasty (uDSEK).Materials and Methods: This retrospective cohort study evaluated corneal graft rejection rate in 170 cases of uDSEK that met inclusion criteria with approximately 1 year of steroid therapy. Corneal graft rejection was defined by anterior chamber cell/flare, keratic precipitates with/without corneal edema, and/or a rejection line. The following were collected retrospectively from January 1, 2005 through January 1, 2013: gender, age, race, indication for uDSEK, length of follow-up, length of steroid therapy. Continuous data were compared using Wilcoxon Rank Sum Test and categorical data were compared using Fisher's Exact Test.Results: The included eyes had an average length of steroid therapy of 431 days (range 85-720 days) with an average follow-up of 1274 days (range 395-3186 days). During the follow-up period without steroid, 5 of the 170 eyes were diagnosed with rejection (2.94%). Of the five eyes that experienced rejection, four eyes resolved after topical prednisone was reinstituted alone and did not require repeat uDSEK. The other eye was lost to follow-up. The cumulative probability of rejection after steroid cessation was calculated at 0.67% after 12 months, 2.20% after 18 months, 3.08% after 24 months, and 4.55% after 36 months.Conclusion: Discontinuation of topical steroid at approximately 1 year after uDSEK results in a low rate of corneal graft rejection and may prove extended use unnecessary.

Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation.

Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3+ immune cells in the spleen, colon, and blood, especially of intraepithelial CD8+ T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1ß, IFNγ, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect.

Current and future evidence-based acne treatment: a review.

INTRODUCTION: Current acne treatment guidelines, as well as, treatment efficacy, safety, tolerability and patient preferences must all be considered in determining appropriate treatment regimes. Literature can assist physicians' evidence-based recommendations according to these factors. AREAS COVERED: To determine the current and future direction of pharmacotherapy for treatment of acne, a PubMed search was conducted to identify all clinical trials involving the treatment of acne from 2009 to 2012. A total of 65 publications met inclusion criteria and were reviewed. Literature was heavily focused on the efficacy and tolerability of topical combination therapies and supported their use compared with monotherapy. A few studies on topical antiandrogens and antioxidants showed an alternative approach to targeting acne. Studies on oral monotherapy provided some evidence for the use of pulsed azithromycin for acne in adolescents. Literature also supports the use of low-dose isotretinoin for moderate acne, which was comparable in efficacy to high-dose regimes and better tolerated. EXPERT OPINION: Combination acne therapy, whether it be combination topical therapy or combination oral and topical therapy, is well supported by recent studies. Given the multifactorial pathogenesis of acne and the hurdles of adherence to treatment, we anticipate greater development of and reliance on combination acne products in the future.