The Importance of 6-Aminohexanoic Acid as a Hydrophobic, Flexible Structural Element.

6-aminohexanoic acid is an ω-amino acid with a hydrophobic, flexible structure. Although the ω-amino acid in question is mainly used clinically as an antifibrinolytic drug, other applications are also interesting and important. This synthetic lysine derivative, without an α-amino group, plays a significant role in chemical synthesis of modified peptides and in the polyamide synthetic fibers (nylon) industry. It is also often used as a linker in various biologically active structures. This review concentrates on the role of 6-aminohexanoic acid in the structure of various molecules.

Cannabidiol Decreases Metalloproteinase Activity and Normalizes Angiogenesis Factor Expression in UVB-Irradiated Keratinocytes from Psoriatic Patients.

The development of psoriasis is associated with the consequences of oxidative stress and inflammation leading to metabolic changes locally, in the skin cells, and systemically, in the blood. Therefore, the aim of this study was to analyze the effect of psoriasis vulgaris (PsV) and psoriatic arthritis (PsA) on the basal plasma/keratinocyte levels of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and angiogenesis factors, as well as to evaluate the effect of CBD on these parameters in keratinocytes isolated from psoriatic/healthy individuals with and without in vitro irradiation by UVB. A quantitative chemiluminescent method of detection based on an ELISA protocol and zymography technique was used during analysis. It was shown that activity levels of MMP-9 and TIMP-2 in PsA plasma were higher than in PsV. Changes in the proteolytic activity were accompanied by an increase in markers of angiogenesis (angiopoietin-2, HGF, VEGF, TNFα, PDGF, FGF), where in the specific case of angiopoietin-2 and TNFα, the overexpression in PsV was significantly stronger than in PsA. CBD application to keratinocytes partially restored levels of MMP-1/2/3/7 and TIMP-1/2 (in an effect which was particularly enhanced by UVB irradiation), as well as levels of the examined angiogenic factors except TNFα (levels of which were increased in psoriatic keratinocytes and decreased in healthy keratinocytes). Presented results indicate that CBD may be suggested as an antiangiogenic factor that reduces the proinflammatory action of UVB in psoriatic keratinocytes and partially has a protective effect for healthy keratinocytes.

Therapeutic Potential of Jasmonic Acid and Its Derivatives.

A modern method of therapeutic use of natural compounds that would protect the body are jasmonates. The main representatives of jasmonate compounds include jasmonic acid and its derivatives, mainly methyl jasmonate. Extracts from plants rich in jasmonic compounds show a broad spectrum of activity, i.e., anti-cancer, anti-inflammatory and cosmetic. Studies of the biological activity of jasmonic acid and its derivatives in mammals are based on their structural similarity to prostaglandins and the compounds can be used as natural therapeutics for inflammation. Jasmonates also constitute a potential group of anti-cancer drugs that can be used alone or in combination with other known chemotherapeutic agents. Moreover, due to their ability to stimulate exfoliation of the epidermis, remove discoloration, regulate the function of the sebaceous glands and reduce the visible signs of aging, they are considered for possible use in cosmetics and dermatology. The paper presents a review of literature data on the biological activity of jasmonates that may be helpful in treatment and prevention.

Oxidative Stress and Its Consequences in the Blood of Rats Irradiated with UV: Protective Effect of Cannabidiol.

UVA/UVB radiation disturbs the redox balance of skin cells, and metabolic consequences can be transferred into the blood and internal tissues, especially after chronic skin exposure to UV radiation. Therefore, the aim of this study was to evaluate the effect of cannabidiol (CBD), an antioxidant and anti-inflammatory phytocannabinoid, on oxidative stress and its consequences in the blood of nude rats whose skin was exposed to UVA/UVB radiation for 4 weeks. It was shown that CBD penetrated the blood and in UVB-irradiated rats was preferentially located in the membranes of polymorphonuclear leukocytes, which promoted reduction of ROS generation and up-regulation of antioxidant ability by increasing the activity of glutathione reductase and thioredoxin reductase, while the level of reduced glutathione decreased by UV radiation. Consequently, reduction in UV-induced lipid peroxidation, assessed as 4-hydroxynonenal (4-HNE) and 8-isoprostane (8-isoPGF2α) as well as protein modifications, estimated as 4-HNE-protein adducts and protein carbonyl groups, was observed. CBD, by countering the UV-induced down-regulation of 2-arachidonylglycerol, promoted its antioxidant/anti-inflammatory effects by reducing CB1 and increasing PPARγ receptor activation and consequently ROS and TNF-α down-regulation. The results suggest that CBD applied topically to the skin minimizes redox changes not only at the skin level, but also at the systemic level.

Jasmonate Compounds and Their Derivatives in the Regulation of the Neoplastic Processes.

Cancer is a serious problem in modern medicine, mainly due to the insufficient effectiveness of currently available therapies. There is a particular interest in compounds of natural origin, which can be used in the prophylaxis, as well as in the treatment and support of cancer treatment. One such compound is jasmonic acid (3-oxo-2-(pent-2'-enyl)cyclopentane acetic acid; isolated active form: trans-(-)-(3R,7R)- and cis-(+)-(3R,7S)-jasmonic acid) and its derivatives, which, due to their wide range of biological activities, are also proposed as potential therapeutic agents. Therefore, a review of literature data on the biological activity of jasmonates was prepared, with particular emphasis on the mechanisms of jasmonate action in neoplastic diseases. The anti-tumor activity of jasmonate compounds is based on altered cellular ATP levels; induction of re-differentiation through the action of Mitogen Activated Protein Kinases (MAPKs); the induction of the apoptosis by reactive oxygen species. Jasmonates can be used in anti-cancer therapy in combination with other known drugs, such as cisplatin, paclitaxel or doxorubicin, showing a synergistic effect. The structure-activity relationship of novel jasmonate derivatives with anti-tumor, anti-inflammatory and anti-aging effects is also shown.

Ceramides Profile Identifies Patients with More Advanced Stages of Colorectal Cancer.

Much attention is paid to different sphingolipid pathways because of their possible use in diagnostics and treatment. However, the activity status and significance of ceramide pathways in colorectal cancer are still unclear. We analyzed colorectal cancer patients to evaluate sphingolipid profiles in the blood, colorectal cancer (CRC) tissues, and healthy surrounding colorectal tissues of the same patient, simultaneously, using liquid chromatography coupled with triple quadrupole mass spectrometry. Furthermore, we measured protein expression of de novo ceramide synthesis enzymes and mitochondrial markers in tissues using western blot. We confirmed the different sphingolipid contents in colorectal cancer tissue compared to healthy surrounding tissues. Furthermore, we showed changed amounts of several ceramides in more advanced colorectal cancer tissue and found a prominently higher circulating level of several of them. Moreover, we observed a relationship between the amounts of some ceramide species in colorectal cancer tissue and plasma depending on the stage of colorectal cancer according to TNM (tumors, nodes, metastasis) classification. We think that the combined measurement of several ceramide concentrations in plasma can help distinguish early-stage lesions from advanced colorectal cancer and can help produce a screening test to detect early colorectal cancer.

Correction to: Methods for 20S Immunoproteasome and 20S Constitutive Proteasome Determination Based on SPRI Biosensors.

[This corrects the article DOI: 10.1007/s12195-017-0478-7.].

The Effects of a Novel Series of KTTKS Analogues on Cytotoxicity and Proteolytic Activity.

KTTKS is a matrikine that originates from the proteolytic hydrolysis of collagen. This peptide stimulates ECM production and types I and III collagen expression in vitro. A more stable form of KTTKS is pal-KTTKS, known as Matrixyl® or palmitoyl pentapeptide-3. A series of novel pentapeptides, analogues of KTTKS with the general formula X-KTTKS-OH(NH2), where X = acetyl, lipoyl, palmitoyl residues, was designed and synthesized. Their effect on amidolytic activity of urokinase, thrombin, trypsin, plasmin, t-PA, and kallikrein were tested. Cytotoxic tests on fibroblasts, as well as collagen and DNA biosynthesis tests for selected peptides, were also carried out. The test results showed that the most active plasmin inhibitors were palmitoyl peptides, whether in acid or amide form. No biological effects of lysine modification to arginine in the synthesized peptides were found. None of the synthesized peptides was not cytotoxic on fibroblasts, and three of them showed cell growth. These three compounds showed no concentration-activity relationship in the collagen and DNA biosynthesis assays.

The Possible Pre- and Post-UVA Radiation Protective Effect of Amaranth Oil on Human Skin Fibroblast Cells.

BACKGROUND: The health effects of Amaranth Oil (AO) are attributed to its specific chemical composition. That makes it an outstanding natural product for the prevention and treatment of ultraviolet (UV) irradiation-related pathologies such as sunburn, photoaging, photoimmunosuppression, and photocarcinogenesis. Most of the studies are taken on animal model, and there is a lack of research on the endogenous effect of AO on fibroblast level, where UVA takes it harmful place. OBJECTIVE: The aim of this study was evaluation if AO can protect or abolish UVA exposure effect on human skin fibroblast. MATERIALS AND METHODS: The 0.1% AO, 0.25% AO, and 0.5% AO concentration and irradiation for 15 min under UVA-emitting lamp were studied in various condition. In all experiments, the mean values for six assays ± standard deviations were calculated. RESULTS: Pretreatment with various concentrations of AO was tested. The highest concentration of AO where cell survival was observed was 0.5%. Cytotoxicity assays provided evidence for pre- and post-UVA protective effect of 0.1% AO among three tested concentrations. The results also provide evidence that UVA has inhibitory effect on collagen biosynthesis in confluent skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effect comparing to other used AO concentration. The assessment results on DNA biosynthesis show the significant abolished post-UVA effect when 0.1% and 0.5% of AO were added. CONCLUSION: AO gives pre- and post-UVA protection in low concentration. This provides the evidence for using it not as a main protective factor against UV but as one of the combined components in cosmetic formulation. SUMMARY: The recommended Amaranth Oil (AO) concentration in cosmetic formulation is between 0.1 and 5%Pretreatment with various concentrations of AO suggests to use the highest 0.5% concentration of AO in human skin fibroblast culturesThe 0.1% of AO in fibroblast cultures, protects and abolishes effect of ultraviolet A (UVA) exposureUVA has inhibitory effect on collagen biosynthesis in skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effectThe abolished post-UVA effect occurs when 0.1% and 0.5% of AO were added on DNA biosynthesis. Abbreviations used: AO: Amaranth Oil.

Peptides with 6-Aminohexanoic Acid: Synthesis and Evaluation as Plasmin Inhibitors.

Fifteen new peptide derivatives of ɛ-aminocaproic acid (EACA) containing the known fragment -Ala-Phe-Lys- with an affinity for plasmin were synthesised in the present study. The synthesis was carried out a solid phase. The following compounds were synthesised: H-Phe-Lys-EACA-X, H-d-Ala-Phe-Lys-EACA-X, H-Ala-Phe-Lys-EACA-X, H-d-Ala-Phe-EACA-X and H-Ala-Phe-EACA-X, where X = OH, NH2 and NH-(CH2)5-NH2. All peptides, except for those containing the sequence H-Ala-Phe-EACA-X, displayed higher inhibitory activity against plasmin than EACA. The most active and selective inhibitor of plasmin was the compound H-d-Ala-Phe-Lys-EACA-NH2 which inhibited the amidolytic activity of plasmin (IC50 = 0.02 mM), with the antifibrinolytic activity weaker than EACA. The resulting peptides did not affect the viability of fibroblast cells, colon cancer cell line DLD-1, breast MCF-7 and MDA-MB-231 cell lines.

Methods for 20S Immunoproteasome and 20S Constitutive Proteasome Determination Based on SPRI Biosensors.

The 20S proteasome, released into the circulation, is a novel cancer biomarker. It exists in two forms: the constitutive proteasome (20Sc) and the immunoproteasome (20Si), which both have separate diagnostic significance. The aim of this work was to develop new methods for 20Si and 20Sc determination. Five alternative specific biosensors usable with the surface plasmon resonance imaging (SPRI) technique for 20Si determination have been developed. Specific 20Si entrapment on the biosensor surface from an analyzed solution was achieved by means of an immobilized specific 20Si receptor. Four of the biosensors contain newly synthesized specific 20Si receptors, while the fifth contains the inhibitor ONX 0914. A method for 20Sc determination using an SPRI biosensor containing PSI inhibitor has been developed. By the introduction of an inhibitor blocking 20Si, 20Sc is selectively determined. All of the methods developed for 20Si and 20Sc determination exhibit good selectivity and satisfactory precision, recoveries and dynamic response ranges. 20Si and 20Sc were determined in blood plasma samples from healthy donors and patients with acute leukemia. In the case of these patients 20Si was the major component, and its level was more than one order of magnitude higher than in the healthy donors.

Pathophysiological and clinical aspects of gastric hyperplastic polyps.

Gastric polyps become a major clinical problem because of high prevalence and tendency to malignant transformation of some of them. The development of gastric hyperplastic polyps results from excessive proliferation of foveolar cells accompanied by their increased exfoliation, and they are macroscopically indistinguishable from other polyps with lower or higher malignant potential. Panendoscopy allows detection and differentiation of gastric polyps, usually after obtaining histopathological biopsy specimens. Unremoved gastric hyperplastic polyps may enlarge and sometimes spontaneously undergo a sequential progression to cancer. For this reason, gastric hyperplastic polyps larger than 5 mm in size should be removed in one piece. After excision of polyps with atypical focal lesion, endoscopic surveillance is suggested depending on histopathological diagnosis and possibility of confirming the completeness of endoscopic resection. Because of the risk of cancer development also in gastric mucosa outside the polyp, neighboring fragments of gastric mucosa should undergo microscopic investigations. This procedure allows for identification of patients who can benefit most from oncological endoscopic surveillance. If Helicobacter pylori (H. pylori) infection of the gastric mucosa is confirmed, treatment strategies should include eradication of bacteria, which may prevent progression of intestinal metaplasia. The efficacy of H. pylori eradication should be checked 3-6 mo later.

ANTIPROLIFERATIVE EFFECTS ON BREAST CANCER CELLS AND SOME INTERACTIONS OF NEW DISTAMYCIN ANALOGUES WITH DNA, ENDONUCLEASES AND DNA TOPOISOMERASES.

The evaluation of a new group of distamycin analogues 1-6 as potential minor groove binders for the treatment of cancer were investigated. The activity of the new compounds against several restriction enzymes was examined. The studied compounds did not block GC-rich sequences regions of DNA but inhibited catalytic action of endonucleases in AA, AT, TT and AG restriction sites. Determination of association constants using calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 have confirmed that the tested compounds bind within minor groove of B-DNA. All of the compounds demonstrated activity against DNA topoisomerases II at the concentration 10 µM, but they did not inhibit activity of topoisomerase I. The studied derivatives were evaluated in human MCF-7 breast cancer cells and showed antiproliferative and cytotoxic effects in the range of 81.70 µM and 200.00 µM.

Morphological and Functional Evaluation of Meibomian Gland Dysfunction in Rosacea Patients.

PURPOSE: Skin rosacea is a chronic inflammatory disease affecting up to 10% of the population in some European countries. Although considered a skin disease, acne rosacea may involve the eyes, causing eyelid and ocular surface inflammation. This study investigated the relationship between skin rosacea and various signs of ocular involvement and evaluated severity of meibomian gland dysfunction in rosacea patients. METHODS: The ocular surface and meibomian gland parameters were evaluated in 41 patients with diagnosed skin rosacea and 44 age-matched healthy controls. We analyzed meibomian gland function (meibum quality and meibum expressibility) and morphology (meibography) and lid margin alterations. We correlated our findings with self-reported ocular symptoms and tear film abnormalities (tear film breakup time, Schirmer test). RESULTS: The prevalence of ocular erythema and lid margin alterations was significantly higher in rosacea patients compared with controls. We found that rosacea is accompanied with significant loss of meibomian gland tissue defined as reduced meibomian gland area and decreased meibomian gland density. A positive correlation between margin abnormality score and the extent of meibomian gland loss in rosacea group was observed (rs = +0.30, p = 0.005), suggesting that ocular rosacea is accompanied by meibomian gland dropout. CONCLUSION: Skin rosacea is associated with ocular erythema and lid margin abnormalities. Our results suggest that ocular signs of rosacea may influence meibomian gland morphology, causing meibomian gland loss.

Antimicrobial peptides and their analogs: searching for new potential therapeutics.

Antimicrobial peptides (AMPs) are an essential part of innate immunity. These compounds have been considered as potential therapeutics because of their broad-spectrum activities and proven ability to avoid antimicrobial resistance, but their clinical and commercial developments have some limitations, such as susceptibility to proteases and a high cost of peptide production. To overcome these problems, many researchers have tried to develop short active peptides, their modifications and mimics with better properties while retaining their basic features of natural AMPs such as cationic charge and the amphipathic structure.

[Lunasin--a novel chemopreventive peptide]. / Lunazyna--peptyd o wlasciwosciach przeciwnowotworowych.

Lunasin is a bioactive peptide originally isolated from soybean and has demonstrated chemopreventive and anticancer properties against: skin, colon, prostate and breast cancers. Lunasin by binding to the receptors of colon cancer cells prevents its adhesion to the liver tissue. When the receptor is blocked, new blood vessels cannot differentiate which prevent the spread of cancer. In the model estrogen-independent breast cancer, lunasin and aspirin administration inhibits cell proliferation, arrest cell cycle in S-phase as well as a decreases expression of cancer genes. Lunasin has also been found to exert potent antioxidant properties, reducing lipopolysaccharide induced production of ROS by macrophage cells, and acting as a potent free radical scavenger. Using the modifying the of DNA method it has been demonstrated that CpG islands were hypomethylated in RWPE-1 cell lines and hypermethylated RWPE-2 in cell line.Despite of numerous and promising evidence of antitumor activity of lunasin, there are still not explained all the mechanisms of its action in the processes of carcinogenesis.

Synthesis and Biological Activity of N-Sulfonyltripeptides with C-Terminal Arginine as Potential Serine Proteases Inhibitors.

Tripeptides of the general X-SO2-d-Ser-AA-Arg-CO-Y formula, where X = α-tolyl, p-tolyl, 2,4,6-triisopropylphenyl; AA = alanine, glycine, norvaline and Y = OH, NH-(CH2)5NH2 were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. The most active compound towards urokinase was PhCH2SO2-d-Ser-Gly-Arg-OH with Ki value 5.4 µM and the most active compound toward thrombin was PhCH2SO2-d-Ser-NVa-Arg-OH with Ki value 0.82 µM. The peptides were nontoxic against porcine erythrocytes in vitro. PhCH2SO2-d-Ser-Gly-Arg-OH showed cytotoxic effect against DLD cell lines with IC50 values of 5 µM. For the highly selective determination of the interaction of some of the synthesised acids of tripeptides with urokinase and plasmin the Surface Plasmon Resonance Imaging sensor has been applied. These compounds bind to urokinase and plasmin in 0.05 mM concentration.

Effect of short peptides containing lysine and epsilon-aminocaproic acid on fibrinolytic activity of plasmin and topoisomerase II action on supercoiled DNA.

Effects of eight short peptides containing lysine and epsilon-aminocaproic acid (EACA) on prolongation of the clot lysis time, as well as hemolytic and antibacterial activities were investigated. Interaction with plasmids pBR322 and pUC19 with the use of ethidium bromide assay and determination of influence on the activity of topoisomerase I and II were also tested. Examined compounds inhibited fibrinolytic activity of plasmin and five of them were more active than EACA. Amides of dipeptides were most active antifibrinolytics (IC50 < 0.2 mM). According to the obtained data, the significant inhibition of fibrinolytic activity of plasmin was not associated with hemolytic effects. Examined compounds did not show antibacterial activity (MIC > 512 mg/L). DNA binding effects determined with the use of ethidium bromide were weak for all peptides and similar to those observed with EACA. Six compounds inhibited topoisomerase II action on supercoiled DNA.

Tripeptides with non-code amino acids as potential serine proteases inhibitors.

Eight peptides of the general H-D-Ser-AA-Arg-OH formula, where AA = phenylglycine, phenylalanine, homophenylalanine, cyclohexylglycine, cyclohexylalanine, homocyclohexylalanine, α-methylphenylalanine and 1-aminocyclohexyl carboxylic acid were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. We tested the hemolytic activity of the peptides against porcine erythrocytes and the antitumor activity against the human breast cancer cells, standard MCF-7 and estrogen-independent MDA-MB-231. The most active compounds were H-D-Ser-Chg-Arg-OH towards thrombin and H-D-Ser-Phg-Arg-OH towards plasmin with K(i) value 5.02 µM and 5.7 µM, respectively.

Municipal wastewater treatment in Poland - efficiency, costs and returns to scale.

This paper reports the costs of municipal wastewater collection and treatment in Poland. Our study provides detailed cost estimates for the collection and treatment of municipal wastewater, based on an empirical sample of 1,400 operators, who jointly collect and treat over 80% of wastewater in Poland. The unit costs of collection and treatment, and the nitrogen and phosphorus treatment efficiency were investigated, and the effects of plant capacity on unit costs (scale effects) were explored. Primary, secondary and tertiary treatment cost functions were analysed econometrically using the Box-Cox regression model, indicating high non-linearity and significant scale effects. We found that wastewater treatment costs were increasing with technology efficiency (moving from the primary, through the secondary, to the tertiary treatment), and decreasing with higher wastewater treatment plant capacity. Our results provide a comprehensive picture of municipal wastewater treatment in Poland but potentially, as the technology is fairly generic, they can also be used for applications in other countries, after accounting for capital and labour cost differences. The paper thus provides a valuable input into cost-benefit analyses of nutrient loading reduction achieved by extending or intensifying municipal wastewater treatment.