The Involvement of Semaphorins in the Pathogenesis of Skin Diseases.

Semaphorins belong to a group of membrane and secretory proteins that act as ligands for several receptor families and are involved in modulating cell signaling pathways. They bind multimeric receptor complexes on the cell membrane to exert their effects and initiate unique intracellular signal transduction cascades. These proteins can influence several processes that are very important for cell function, such as cell division and differentiation. Semaphorins are involved in cell migration, apoptosis, cell adhesion, aggregation, and numerous immune processes due to their immunoregulatory effects. Semaphorins are expressed in keratinocytes, which is why they have become a target for studies on the pathogenesis of skin diseases. Most studies to date on the role of semaphorins in the pathogenesis of skin diseases have been carried out in cellular or animal models, and there are few clinical studies evaluating the role of semaphorins in the pathogenesis and therapy of skin diseases. In this narrative review, we summarized the current state of knowledge on the role of semaphorins in the pathogenesis of skin diseases and their potential importance as targets for therapy. We also tried to present the key findings and weaknesses of previous research in this field. The novelty of this article lies in the comprehensive presentation of the role of semaphorins in the pathogenesis of skin diseases, including the results of studies on cell cultures and animal models, elucidating the mechanisms and signaling pathways through which semaphorins affect the development of skin diseases, as well as on the presentation of the results of existing clinical trials evaluating the role of semaphorins in the pathogenesis of skin diseases, and as potential therapeutic targets.

Targeting cyclin-dependent kinases in rheumatoid arthritis and psoriasis - a review of current evidence.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with synovial proliferation and bone erosion, which leads to the structural and functional impairment of the joints. Immune cells, together with synoviocytes, induce a pro-inflammatory environment and novel treatment agents target inflammatory cytokines. Psoriasis is a chronic immune-mediated skin disease, and several cytokines are considered as typical mediators in the progression of the disease, including IL-23, IL-22, and IL-17, among others. AREA COVERED: In this review, we try to evaluate whether cyclin-dependent kinases (CDK), enzymes that regulate cell cycle and transcription of various genes, could become novel therapeutic targets in RA and psoriasis. We present the main results of in vitro and in vivo studies, as well as scarce clinical reports. EXPERT OPINION: CDK inhibitors seem promising for treating RA and psoriasis because of their multidirectional effects. CDK inhibitors may affect not only the process of osteoclastogenesis, thereby reducing joint destruction in RA, but also the process of apoptosis of neutrophils and macrophages responsible for the development of inflammation in both RA and psoriasis. However, assessing the efficacy of these drugs in clinical practice requires multi-center, long-term clinical trials evaluating the effectiveness and safety of CDK-blocking therapy in RA and psoriasis.

The Role of Sirtuins in the Pathogenesis of Psoriasis.

Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient's physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1-SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.

Adiponectin, Leptin and Resistin in Patients with Psoriasis.

Psoriasis is a common chronic, inflammatory skin disease characterised by keratinocyte hyperproliferation, parakeratosis, and T-cell infiltration. Adipose tissue has an endocrine function, producing an abundance of cytokines and adipokines. It has also been described that the major adipokines, leptin, resistin, and adiponectin, may be involved in the pathogenesis of psoriasis. The aim of the study was to examine the plasma levels of adiponectin, leptin, and resistin in patients with psoriasis and their correlations with disease activity parameters: Psoriasis Activity Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Body Surface Area (BSA) index, as well as selected clinical parameters. The study included 53 patients with the plaque type and 31 healthy controls. The plasma concentrations of adiponectin were significantly lower in patients with psoriasis (p < 0.001) than in the control group. The plasma concentrations of leptin were higher in patients with psoriasis, however, due to high intra-patient variability of leptin plasma concentrations these differences did not reach statistical significance (p = 0.2). The plasma concentrations of resistin were significantly increased in patients with psoriasis compared to healthy controls (p = 0.02). There were no statistically significant correlations between adiponectin and leptin plasma concentrations and values of PASI, DLQI, and BSA. The resistin plasma concentrations correlated significantly with DLQI values. Additionally, we examined the correlations between adiponectin, leptin, and resistin plasma concentrations, and selected clinical parameters. Plasma concentrations of adiponectin correlated significantly with CRP values and ALT values. Leptin plasma concentrations correlated significantly with creatinine values. The results of our study confirm the role of adiponectin, leptin, and resistin in the pathogenesis of psoriasis.

Plasma Levels of Interleukins 36α, 36ß, and 37 in Patients with Psoriasis and Their Correlation with Disease Activity Parameters.

Psoriasis is a chronic, proliferative, inflammatory skin disease characterised by skin lesions and systemic symptoms. Numerous cytokines are produced in psoriasis as a result of inflammation. The aim of this study was to examine the plasma concentrations of IL-36α, IL-36ß, and IL-37 in psoriasis and their correlations with disease activity parameters. This study recruited 84 individuals, 53 with plaque-type psoriasis and 31 healthy controls. The plaque type of psoriasis is the most common type and is typically characterized by circular-to-oval red plaques distributed over body surfaces of the extremities and scalp. In patients with psoriasis, we observed statistically significantly decreased plasma concentrations of IL-36ß and IL-37. The concentrations of IL-36α were increased in comparison with control group. The plasma concentrations of IL-36α and IL-36ß were statistically significantly correlated with all tested parameters of disease activity: the Psoriasis Activity Severity Index, Dermatology Life Quality Index, and Body Surface Area Index. There were no statistically significant correlations between plasma levels of IL-37 and the tested parameters of disease activity. These results indicate a role of IL36α, IL-36ß, and IL-37 in the pathogenesis of psoriasis.

IL17A and IL17F genes polymorphisms are associated with histopathological changes in transplanted kidney.

BACKGROUND: Interleukin 17 is a proinflammatory cytokine involved in immune response after allograft transplantation. IL-17 family of proinflammatory cytokines includes IL-17A and IL-17F. Previous studies have demonstrated that the rs2275913 IL17A and the rs11465553 IL17F gene polymorphism are associated with kidney allograft function. Because of the association between these polymorphisms and post-transplant immune response, we assume that these single nucleotide polymorphisms may affect morphological structure of transplanted kidney. The aim of this study was to examine the association of rs2275913 IL17A and rs2397084, rs11465553 and rs763780 IL17F gene polymorphisms with histopathological changes in transplanted kidney biopsies such as: glomerulitis, tubulitis, arteritis, cell infilitration and fibrosis. METHODS: The study enrolled 82 patients after renal graft transplantation in whom a kidney biopsy was performed because of impaired graft function. The rs2397084 T > C (Glu126Gly), rs11465553 G > A (Val155Ile) and rs763780 T > C (His167Arg) polymorphisms within the IL17F gene and the rs2275913 A > G (- 197 A > G) polymorphism within the IL17A gene promoter were genotyped using TaqMan genotyping assays on a 7500 FAST Real-Time PCR System (Applied Biosystems, USA). RESULTS: There was a significant association between the rs2275913 IL17A gene polymorphism and the grade of tubulitis, which was more severe among patients with the A allele, compared to recipients with the GG genotype (GG vs. AG + AA, P = 0.02), and with the grade of arteriolar hyaline thickening and mesangial matrix increase, which were more severe among patients with the G allele compared to recipients with the AA genotype (AA vs. AG + GG, P = 0.01 and P = 0.04, respectively). Tubular atrophy and interstitial fibrosis were more severe among individuals with the C allele at the rs763780 IL17F gene polymorphism (TT vs. TC, P = 0.09 and P = 0.017, respectively). However, it should be taken into account that the statistical significance was achieved without correction for multiple testing, and no significant association would remain significant after such correction. CONCLUSIONS: The results of this study may suggest a possible association between the rs2275913 IL17A and rs2275913 IL17A gene polymorphisms and some histopathological changes in transplanted kidney biopsies.

Plasma concentration of urokinase plasminogen activator receptor is a marker of kidney allograft function.

BACKGROUND: Urokinase-type plasminogen activator receptor (uPAR) is found in a variety of cell types including monocytes, lymphocytes, macrophages, and endothelial cells and plays an important role in fibrinolysis and in the activation and chemotaxis of neutrophils and lymphocytes. In this study, we examined the correlation between uPAR plasma concentration and kidney allograft function. AIMS: This study enrolled 78 Caucasian deceased-donor renal transplant recipients. METHODS: Plasma concentrations of uPAR were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: We observed elevated with borderline significance (p = 0.095) uPAR plasma concentrations in patients with tubular atrophy. Plasma concentrations of uPAR showed strong statistically significant positive correlations with serum creatinine or urea and strong negative correlation with estimated glomerular filtration rate (eGFR). There was also a borderline positive correlation between uPAR plasma concentration and protein concentration in urine as well as the duration of hemodialysis. CONCLUSIONS: The results of our study indicate that uPAR plasma concentrations in kidney allograft recipients are significantly negatively correlated with graft function and may be elevated in patients with tubular atrophy.

TNF-α and IL10 gene polymorphisms in women with postmenopausal osteoporosis.

OBJECTIVE: Postmenopausal osteoporosis is a common disorder characterized by decreased bone mineral density (BMD). Proinflammatory cytokines are among the significant factors involved in bone turnover. They are the stimulants of bone resorption, acting directly on osteoclasts and osteoclast precursors. In this study, we examined the TNF-α (-308G>A) (rs1800629) and IL10 (-1082G>A) (rs1800896), (-592C>A) (rs1800872) polymorphisms in postmenopausal women with BMD T-scores less than and greater than or equal to -2.5 SD. STUDY DESIGN: This study included 224 postmenopausal women with BMD T-scores lower than -2.5 SD (mean: -3.02±0.53) and 238 postmenopausal women with BMD T-scores -2.5 SD and greater (mean: -1.33±0.51). RESULTS: There was a decrease in the frequency of IL10 1082 G allele carriers (GG and GA genotypes) in women with T-scores below -2.5 SD (GG+GA vs AA: OR=0.65, 95% CI=0.44-0.97, p=0.037). With regard to the TNF-α -308 G>A polymorphism, in the women with T-scores below -2.5 SD, the increased frequency of GG homozygotes and G allele carriers was detected (AA+GA vs GG: OR=0.54, 95% CI=0.35-0.82, p=0.004). CONCLUSIONS: The results of our study suggest an association between TNF-α -308G>A and IL10 -1082G>A polymorphisms and postmenopausal osteoporosis.

Role of prometastatic factors in gastric cancer development.

The second half of the 20th century has seen a sharp worldwide decline in both the incidence and mortality of gastric cancer. Despite this, gastric cancer is the most common cause of mortality in the world. It is closely related to the commonly asymptomatic course at the beginning and delayed diagnosis. Approximately 90­97% of stomach cancers are adenocarcinomas, which may be subdivided histologically into two categories - intestinal type, and diffuse type. Cancer metastasis is a complex multi­step process that is closely associated with tumor phenotype. The most important steps in the metastasis process are proteolytic activity, migration, adhesion, proliferation, and neovascularization. In this review we focus on mechanisms regulating gastric cancer metastasis.

Stem cells and skin regeneration.

Stem cells represent a great hope for regenerative medicine. In adult life, stem cell deposits are kept in organ niches; the need for tissue or organ regeneration mobilizes stem cells via the SDF-1-CXCR4 regulation axis. Constant regeneration of the skin is achieved due to stem cell differentiation within the epidermis and the hair follicle; thus, skin may serve as an excellent source of stem cells. This is of paramount importance in the treatment of chronic skin wounds and burns.

Aldehyde dehydrogenase (ALDH) - a promising new candidate for use in preclinical and clinical selection of pluripotent very small embryonic-like stem cells (VSEL SCs) of high long-term repopulating hematopoietic potential.

BACKGROUND: In the field of stem cells (SCs) biology there is great need for a universal marker that can effectively identify the rare populations of SCs in order to characterize and isolate them for research and therapeutic purposes. In line with this idea, the measurement of aldehyde dehydrogenase (ALDH) activity shows promising potential as a common marker for the identification of SCs. Recently discovered very small embryonic-like stem cells (VSEL SCs) have a pluripotent nature and high long-term repopulating hematopoietic potential. The aim of the present study was to determine whether VSEL SCs isolated from umbilical cord blood (CB) and different murine organs express high ALDH activity. MATERIAL/METHODS: To address this issue, 12 CB units were analyzed by employing flow cytometry to detect the following populations: (i) CXCR4(+)/Lin(-)/CD45(-)/ALDH(high), (ii) CD34(+)/Lin(-)/CD45(-)/ALDH(high) and (iii) CD133(+)/Lin(-)/CD45(-)/ALDH(high). Additionally, selected organs from 16 5-week-old female inbred C57BL/6J mice and 16 7-month-old female C57BL/6J mice were analyzed for detection of the following populations: (i) Sca-1(+)/Lin(-)/CD45(-) and (ii) Sca-1(+)/Lin(-)/CD45(+). All these populations were assessed for ALDH activity. RESULTS: We found that CB contains VSEL SCs with high ALDH activity. We also observed that ALDH(high) cells constitute a modest percentage of VSEL SCs present in selected murine organs. CONCLUSIONS: We demonstrated that CB and adult murine organs possess a subpopulation of ALDH(high) VSEL SCs. Above all, the observed high level of ALDH activity can be considered a functional marker of organ-derived pluripotent SCs and allows for simple, efficient isolation of cells with primitive features for their utility in targeted cell therapies.

[The effect of hyperbaric air exposure on concentrations of malondialdehyde and some parameters of the antioxidant system in rat blood]. / Wplyw powietrznej ekspozycji hiperbarycznej na stezenie malonylodialdehydu i wybrane wskazniki systemu antyoksydacyjnego we krwi szczura.

UNLABELLED: Hyperbaric air exposure (ExH) produces potentially harmful effects in organisms due to increased oxygen pressure and creates the risk of gas emboli during decompression. The effect of hyperbaric air exposure on free radical generation can be studied by varying the dynamics of tissue desaturation and total time of exposure to hyperbaric oxygen. The aim of the present study in rats was to (1) assess the effect of hyperbaric air exposures with accelerated decompression on free radical generation by measuring serum concentrations of malondialdehyde produced during beta-elimination of polyunsaturated fatty and by determining the serum antioxidant status; and (2) examine the effect of hyperbaric air exposures on activities of the main antioxidant enzymes. The study was performed in 50 male Wistar rats dividet into one control (n=10) and two study groups (II and III, n=20 each). The study groups were divided into two equal subgroups (IIa, IIb, IIIa, IIIb) and exposed to hyperbaric air under maximal pressure of 6 ata, with a single session in group II and three session 60 minutes apart in group III. Subgroups IIa and IIIa underwent stepwise decompression during 101 minutes, while subgroups IIb and IIIb during 67 minutes. Serum concentrations of malondialdehyde (MDA), total antioxidant serum status (TAS), activities of antioxidant enzymes in serum (glutathione peroxidase (GPx)) and in erythrocytes (superoxide dismutase (SOD) and catalase (CAT)) were measured 30 min. from decompression. Mean MDA concentration in the control group was 0.691 +/- 0.154 nmol/l. MDA concentrations in the study groups were higher by 22.2% in subgroup IIa (p<0.001), 8.8% in IIb (n.s.), 44.5% in IIIa (p<0.0005), and 14.7% in IIIb (n.s.). Concentrations of MDA in subgroups that underwent decompression for 101 minutes (IIa and IIIa) were higher than in subgroups that underwent decompression for 67 minutes (IIb and IIIb). Mean serum TAS values in the control group was 0.580 +/- 0.077 nmol/l. TAS values in the study animals were as follows: subgroup IIa--94% of control value (n.s.), IIb--104% (n. s.), IIIa--85% (p<0.05), and IIIb--76% (p<0.0005). Mean serum TAS were lower in subgroups IlIa and IIIb than in subgroups IIa and IIb (n. s., p<0.0001, respectively). Activities of serum antioxidant enzymes were not altered after hyperbaric air exposure. CONCLUSIONS: 1. Hyperbaric air exposure of 6 ata with decompression that did not offer safe tissue desaturation enhanced lipid peroxidation and increased serum levels of malondialdehyde in rats. Concentration changes were related to the decompression regimen. 2. Three consecutive hyperbaric air exposures with 60-minute intervals and accelerated decompression produced deterioration in the antioxidant status of serum. 3. Hyperbaric air exposure with accelerated decompression did not affect activities of the main serum antioxidant enzymes, namely superoxide dismutase, glutathione peroxidase, and catalase.