Zmiany hiperpigmentacyjne jako niepożądany efekt działania wybranych leków

W pracy przedstawiono mechanizm powstawania pigmentu skóry – melaniny oraz przemiany tego barwnika, które pod wpływem czynników wewnętrznych i zewnętrznych, mogą predysponować do powstania zmian hiperpigmentacyjnych w obrębie skóry. Zmiany barwnikowe będące efektem niepożądanym działania leków stanowią 10–20% wszystkich zmian hiperpigmentacyjnych. Defekt ten związany jest ze zwiększoną syntezą melaniny, zwiększoną produkcją lipofuscyny, odkładaniem się w skórze związków farmakologicznych, a także bardzo często stanowią efekt ustępowania stanu zapalnego. Czynnikiem o istotnym znaczeniu w mechanizmie powstawania tego typu zmian jest współdziałanie promieniowania UV. Istnieje bardzo duża grupa leków oraz substancji pochodzenia roślinnego, które uwrażliwiają skórę na działanie promieniowania. Zaliczyć można tu głównie antybiotyki, leki przeciwarytmiczne, hormonalne, cytostatyki oraz suplementy diety zawierające w swoim składzie dziurawiec, seler, arcydzięgiel czy rutę zwyczajną.The work shows the mechanism of creating pigmentation i.e. melanin as well as its transformation which due to external or internal factors could predispose to skin hyperpigmentation. The changes in the skin color that are the side eff ect of drugs are 10–20% of all hyperpigmentations. It is a result of hypersynthesis of melanin, increased formation of lipofuscin, cumulating pharmacological compounds and often it can outgoing infl ammatory condition. UV radiation has been found an important concomitant factor in causing this type of skin change. There is a large group of pharmaceutical drugs and botanical extracts that could sensitize skin to UV radiation. This includes mainly antibiotics, antiarrhythmic drugs, hormonal drugs, cytostatic as well as supplements containing St John’s wort, celery, Angelica archangelica or rue

Hyperpigmentation as a side effect of the selected pharmaceuticals activity

The work shows the mechanism of creating pigmentation i.e. melanin as well as its transformation which due to external or internal factors could predispose to skin hyperpigmentation. The changes in the skin color that are the side effect of drugs are 10–20% of all hyperpigmentations. It is a result of hypersynthesis of melanin, increased formation of lipofuscin, cumulating pharmacological compounds and often it can outgoing inflammatory condition. UV radiation has been found an important concomitant factor in causing this type of skin change. There is a large group of pharmaceutical drugs and botanical extracts that could sensitize skin to UV radiation. This includes mainly antibiotics, antiarrhythmic drugs, hormonal drugs, cytostatic as well as supplements containing St John’s wort, celery, Angelica archangelica or rue.W pracy przedstawiono mechanizm powstawania pigmentu skóry – melaniny oraz przemiany tego barwnika, które pod wpływem czynników wewnętrznych i zewnętrznych, mogą predysponować do powstania zmian hiperpigmentacyjnych w obrębie skóry. Zmiany barwnikowe będące efektem niepożądanym działania leków stanowią 10–20% wszystkich zmian hiperpigmentacyjnych. Defekt ten związany jest ze zwiększoną syntezą melaniny, zwiększoną produkcją lipofuscyny, odkładaniem się w skórze związków farmakologicznych, a także bardzo często stanowią efekt ustępowania stanu zapalnego. Czynnikiem o istotnym znaczeniu w mechanizmie powstawania tego typu zmian jest współdziałanie promieniowania UV. Istnieje bardzo duża grupa leków oraz substancji pochodzenia roślinnego, które uwrażliwiają skórę na działanie promieniowania. Zaliczyć można tu głównie antybiotyki, leki przeciwarytmiczne, hormonalne, cytostatyki oraz suplementy diety zawierające w swoim składzie dziurawiec, seler, arcydzięgiel czy rutę zwyczajną

Interaction of serum amyloid A with human cystatin Cuidentification of binding sites

Serum amyloid A (SAA) is a multifunctional acute-phase protein whose natural role seems to be participation in many physiologic and pathological processes. Prolonged increased SAA level in a number of chronic inflammatory and neoplastic diseases gives rise to reactive systemic amyloid A amyloidosis, where the N-terminal 76-amino acid residue-long segment of SAA is deposited as amyloid fibrils. Recently, a specific interaction between SAA and the ubiquitous inhibitor of cysteine proteaseshuman cystatin C (hCC)has been described. Here, we report further evidence corroborating this interaction, and the identification of the SAA and hCC binding sites in the SAAhCC complex, using a combination of selective proteolytic excision and high-resolution mass spectrometry. The shortest binding site in the SAA sequence was determined as SAA(86104), whereas the binding site in hCC sequence was identified as hCC(96102). Binding specificities of both interacting sequences were ascertained by affinity experiments (ELISA) and by registration of mass spectrum of SAAhCC complex. Copyright (c) 2012 John Wiley & Sons, Ltd

BTLA-derived peptides as inhibitors of BTLA/HVEM complex formation – design, synthesis and biological evaluation

Immune checkpoints can be divided into co-stimulatory and co-inhibitory molecules that regulate the activation and effector functions of T cells. The co-inhibitory pathways mediated by ICPs are used by cancer cells to escape from immune surveillance, and therefore the blockade of these receptor/ligand interactions is one of the strategies used in the treatment of cancer. The two main pathways currently under investigation are CTLA-4/CD80/CD86 and PD-1/PD-L1, and the monoclonal Abs targeting them have shown potent immunomodulatory effects and activity in clinical environments. Another interesting target in cancer treatment is the BTLA/HVEM complex. Binding of BTLA protein on T cells to HVEM on cancer cells leads to inhibition of T cell proliferation and cytokine production. In the presented work, we focused on blocking the HVEM protein using BTLA-derived peptides. Based on the crystal structure of the BTLA/HVEM complex and MM/GBSA analysis performed here, we designed and synthesized peptides, specifically fragments of BTLA protein. We subsequently checked the inhibitory capacities of these compounds using ELISA and a cellular reporter platform. Two of these peptides, namely BTLA(35−43) and BTLA(33−64)C58Abu displayed the most promising properties, and we therefore performed further studies to evaluate their affinity to HVEM protein, their stability in plasma and their effect on viability of human PBMCs. In addition, the 3D structure for the peptide BTLA(33−64)C58Abu was determined using NMR. Obtained data confirmed that the BTLA-derived peptides could be the basis for future drugs and their immunomodulatory potential merits further examination

Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses

International audienceAntibody based immune-checkpoint blockade therapy is a major breakthrough in oncology, leading to clinical benefit for cancer patients. Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), which interacts with herpes virus entry mediator (HVEM), is a promising target for immunotherapy. Indeed, BTLA inhibits T-cell proliferation and cytokine production. The crystal structure of the BTLA/HVEM complex has shown that the HVEM(26-38) fragment is directly involved in protein binding. We designed and analyzed the capacity of several analogs of this fragment to block the ligation between BTLA and HVEM, using competitive ELISA and cellular assay. We found that the HVEM(23-39) peptide can block BTLA/HVEM ligation. However, the blocking ability was due to the Cys encompassed in this peptide and that even free cysteine targeted the BTLA protein and blocked its interaction with HVEM. These data highlight a Cys-related artefact in vitro, which should be taken in consideration for future development of BTLA/HVEM blocking compounds

African Viper Poly-His Tag Peptide Fragment Efficiently Binds Metal Ions and Is Folded into an α‑Helical Structure

Snake venoms are complex mixtures of toxic and often spectacularly biologically active components. Some African vipers contain polyhistidine and polyglycine peptides, which play a crucial role in the interaction with metal ions during the inhibition of snake metalloproteases. Polyhistidine peptide fragments, known as poly-His tags, play many important functions, e.g., in metal ion transport in bacterial chaperon proteins. In this paper, we report a detailed characterization of Cu²⁺, Ni²⁺, and Zn²⁺ complexes with the EDDHHHHHHHHHG peptide fragment (pHG) derived from the venom of the rough scale bush viper (Atheris squamigera). In order to determine the thermodynamic properties, stoichiometry, binding sites, and structures of the metal–pHG complexes, we used a combination of experimental techniques (potentiometric titrations, electrospray ionization mass spectrometry, UV–vis spectroscopy, circular dichroism spectroscopy, and electron paramagnetic resonance spectroscopy) and extensive computational tools (molecular dynamics simulations and density functional theory calculations). The results showed that pHG has a high affinity toward metal ions. The numerous histidine residues located along this sequence are efficient metal ion chelators with high affinities toward Cu²⁺, Ni²⁺, and Zn²⁺ ions. The formation of an α-helical structure induced by metal ion coordination and the occurrence of polymorphic binding states were observed. It is proposed that metal ions can “move along” the poly-His tag, which serves as a metal ion transport pathway. The coordination of Cu²⁺, Ni²⁺, and Zn²⁺ ions to the histidine tag is very effective in comparison with other histidine-rich peptides. The stabilities of the metal–pHG complexes increase in the order Zn²⁺ < Ni²⁺≪ Cu²⁺