Molecular Pro-Apoptotic Activities of Flavanone Derivatives in Cyclodextrin Complexes: New Implications for Anticancer Therapy.

This study evaluates the antiproliferative potential of flavanones, chromanones and their spiro-1-pyrazoline derivatives as well as their inclusion complexes. The main goal was to determine the biological basis of molecular pro-apoptotic activities and the participation of reactive oxygen species (ROS) in shaping the cytotoxic properties of the tested conjugates. For this purpose, changes in mitochondrial potential and the necrotic/apoptotic cell fraction were analyzed. Testing with specific fluorescent probes found that ROS generation had a significant contribution to the biological anticancer activity of complexes of flavanone analogues. TT (thrombin time), PT (prothrombin time) and APTT (activated partial tromboplastin time) were used to evaluate the influence of the compounds on the extrinsic and intrinsic coagulation pathway. Hemolysis assays and microscopy studies were conducted to determine the effect of the compounds on RBCs.

An Overview of the Potential Medicinal and Pharmaceutical Properties of Ru(II)/(III) Complexes.

This review examines the existing knowledge about Ru(II)/(III) ion complexes with a potential application in medicine or pharmacy, which may offer greater potential in cancer chemotherapy than Pt(II) complexes, which are known to cause many side effects. Hence, much attention has been paid to research on cancer cell lines and clinical trials have been undertaken on ruthenium complexes. In addition to their antitumor activity, ruthenium complexes are under evaluation for other diseases, such as type 2 diabetes, Alzheimer's disease and HIV. Attempts are also being made to evaluate ruthenium complexes as potential photosensitizers with polypyridine ligands for use in cancer chemotherapy. The review also briefly examines theoretical approaches to studying the interactions of Ru(II)/Ru(III) complexes with biological receptors, which can facilitate the rational design of ruthenium-based drugs.

Mechanistic Studies of Arene-Ruthenium(II) Complexes with Carbothioamidopyrazoles as Alternative Cancer Drugs.

Arene-ruthenium(II) complexes with carbothioamidopyrazoles at the C-2 and C-5 positions have been recognized as chemotherapeutic agent alternatives to cisplatin and its oxaliplatin analogs. The aim of this study was to continue research on the biological aspect of arene-ruthenium(II) complexes and their anticancer activity. The present paper includes an additional 12 new tumor cells, analyzed by MTT, and employs a series of extended bioassays to better understand their potential mechanism of antitumor activity. The following tests were conducted: membrane permeability studies, intramolecular reactive oxygen and nitrogen species (ROS/RNS) assays, mitochondrial potential changes, DNA analysis by comet assay using the electrophoresis method, measurement of cleaved PARP protein levels, and determination of apoptotic and necrotic cell fractions by fluorescence microscopy. Additionally, the article presents lipophilicity studies based on RP-TLC and molecular docking studies. We hope that the presented data will prove useful in practical treatment, especially for patients with cancer.

Long-term effect of azelaic acid peel on sebum production in acne.

Seborrhea and the associated oily skin are undoubtedly the problem of women and men around the world. The pathogenesis of acne vulgaris involves excessive activity of sebaceous glands, as well as disturbances in the composition of sebum. The aim of the study was to assess the severity of seborrhea in a group of acne vulgaris patients and to determine the effect of a 20% azelaic acid solution on the activity of sebaceous glands. Twenty seven women, aged 19-25 years, underwent a series of six treatments with the application of a 20% solution of azelaic acid to the face. The mean values of sebum level showed a decreasing tendency. On the forehead, the results were as follows-195.5 before the treatment and 162.7 2 weeks after the last treatment. Measurements of the right cheek decreased from 175.3 to 141.3 The measurements taken 3 months after the study were 151.3 on the forehead and 138.9 on the cheek. Similarly, the values determining the total number of acne lesions and the severity of the disease according to the IGA scale also changed significantly. Chemical peel with 20% azelaic acid shows long-term sebostatic action, which inhibits the formation of new acne lesions.

Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives.

In this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound I demonstrated promising antiproliferative properties, especially toward the HL60 cell line, for which IC50 was equal to 9.4 µM/L. The analysis of DNA damage by the comet assay showed that compound II caused DNA damage to tumor lineage cells to a greater extent than compound I. The level of damage to tumor cells of the HEC-1-A lineage was 23%. The determination of apoptotic and necrotic cell fractions by fluorescence microscopy indicated that cells treated with spiropyrazoline-based analogues were entering the early phase of programmed cell death. Compounds I and II depolarized the mitochondrial membranes of cancer cells. Furthermore, we performed simple docking calculations, which indicated that the obtained compounds are able to bind to the PARP1 active site, at least theoretically (the free energy of binding values for compound I and II were -9.7 and 8.7 kcal mol-1, respectively). In silico studies of the influence of the studied compounds on PARP1 were confirmed in vitro with the use of eight cancer cell lines. The degradation of the PARP1 enzyme was observed, with compound I characterized by a higher protein degradation activity.

Arene-Ruthenium(II) Complexes with Carbothiamidopyrazoles as a Potential Alternative for Antibiotic Resistance in Human.

To meet the demand for alternatives to commonly used antibiotics, this paper evaluates the antimicrobial potential of arene-ruthenium(II) complexes and their salts, which may be of value in antibacterial treatment. Their antimicrobial activity (MIC, MBC/MFC) was examined in vitro against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus vulgaris and Candida albicans and compared with classic antibiotics used as therapeutics. Selected arene-ruthenium(II) complexes were found to have synergistic effects with oxacillin and vancomycin against staphylococci. Their bactericidal effect was found to be associated with cell lysis and the ability to cut microbial DNA. To confirm the safety of the tested arene-ruthenium(II) complexes in vivo, their cytotoxicity was also investigated against normal human foreskin fibroblasts (HFF-1). In addition, the antioxidant and thus pro-health potential of the compounds, i.e., their nonenzymatic antioxidant capacity (NEAC), was determined by two different methods: ferric-TPTZ complex and DPPH assay.

Overview of the Antioxidant and Anti-Inflammatory Activities of Selected Plant Compounds and Their Metal Ions Complexes.

Numerous plant compounds and their metal-ion complexes exert antioxidative, anti-inflammatory, anticancer, and other beneficial effects. This review highlights the different bioactivities of flavonoids, chromones, and coumarins and their metal-ions complexes due to different structural characteristics. In addition to insight into the most studied antioxidative properties of these compounds, the first part of the review provides a comprehensive overview of exogenous and endogenous sources of reactive oxygen and nitrogen species, oxidative stress-mediated damages of lipids and proteins, and on protective roles of antioxidant defense systems, including plant-derived antioxidants. Additionally, the review covers the anti-inflammatory and antimicrobial activities of flavonoids, chromones, coumarins and their metal-ion complexes which support its application in medicine, pharmacy, and cosmetology.

A blinded study assessment of the efficacy of an original formula with retinol in combination with sonophoresis.

An appropriately designed cosmetic product and regimen of treatment can improve facial skin appearance and provide good tolerability. The aim of the study was to evaluate the effect of 0.3 and 0.5% retinol in liquid crystal formula, applied with sonophoresis, on mature skin. Serum with various concentrations of retinol was applied to the left and right sides of the face and treated with ultrasound. The treatments were performed once a week for a period of 7 weeks. The skin condition before and after treatment was compared using the Fotomedicus system. The Visual Analogue Scale method enabled the results to be assessed by three independent specialists. The Multi Probe Adapter system was used to evaluate the efficacy of a series of treatments. Subjective assessment of volunteers identified perceived improvement of skin conditions. In addition, treatment was associated with greater skin moisture level, reduced wrinkling and decreased skin discoloration. Mild side effects appeared mainly after the first treatment and on the left side of the face with 0.5% retinol. More significant results may be obtained by extending the treatment duration in longer-term studies. Nonetheless, the findings confirmed the effectiveness of the procedures.

A Clinical Anti-Ageing Comparative Study of 0.3 and 0.5% Retinol Serums: A Clinically Controlled Trial.

BACKGROUND: Retinol influences the process of keratinization of the epidermis, which improves stratum corneum structure and reduces transepidermal water loss. It also significantly enhances mature skin by brightening hyperpigmentation and reducing the signs of photoageing. Cosmeceuticals are intended to both provide aesthetic effects for the skin and allow dermatological treatment. The aim of the study was to assess the rejuvenating effect of retinol serum on facial skin at concentrations of 0.3 and 0.5%, as well as any improvements in skin brightening and elasticity. MATERIALS AND METHODS: Thirty-seven volunteers were included in the study, after confirming tolerance. The novel formula was applied once daily to the face for a period of 12 weeks: one retinol concentration on the left side and the other on the right. The initial study with liquid crystal formula (study vehicle) was carried out for 8 weeks on 28 volunteers. Treatment efficiency was evaluated at baseline, and 56 and 84 days following treatment using the multi probe adapter and Fotomedicus imaging system. PRIMOS was used to measure skin surface roughness. The visual analogue scale method enabled the results to be determined by 3 independent specialists. RESULTS: Skin hyperpigmentation, unevenness, and wrinkles gradually decreased over the course of treatment, both on the left and right parts of the face. Adverse events were predominantly mild or moderate skin irritation. More frequent and more intense symptoms were observed on the left side (0.5%). CONCLUSION: Retinol in liquid crystal formulation is safe and provides significant clinical benefits associated with unification of skin colour, overall skin tone, skin elasticity, and moisture. Regular use of retinol typically results in brightening of the skin and reduced signs of ageing. The objective findings confirmed the effectiveness of the procedures.

Antagonists of Vitamin K-Popular Coumarin Drugs and New Synthetic and Natural Coumarin Derivatives.

Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.

Biological Evaluation of 3-Benzylidenechromanones and Their Spiropyrazolines-Based Analogues.

A series of 3-benzylidenechrmanones 1, 3, 5, 7, 9 and their spiropyrazoline analogues 2, 4, 6, 8, 10 were synthesized. X-ray analysis confirms that compounds 2 and 8 crystallize in a monoclinic system in P21/n space groups with one and three molecules in each asymmetric unit. The crystal lattice of the analyzed compounds is enhanced by hydrogen bonds. The primary aim of the study was to evaluate the anti-proliferative potential of 3-benzylidenechromanones and their spiropyrazoline analogues towards four cancer cell lines. Our results indicate that parent compounds 1 and 9 with a phenyl ring at C2 have lower cytotoxic activity against cancer cell lines than their spiropyrazolines analogues. Analysis of IC50 values showed that the compounds 3 and 7 exhibited higher cytotoxic activity against cancer cells, being more active than the reference compound (4-chromanone or quercetin). The results of this study indicate that the incorporation of a pyrazoline ring into the 3-arylideneflavanone results in an improvement of the compounds' activity and therefore it may be of use in the search of new anticancer agents. Further analysis allowed us to demonstrate the compounds to have a strong inhibitory effect on the cell cycle. For instance, compounds 2, 10 induced 60% of HL-60 cells to be arrested in G2/M phase. Using a DNA-cleavage protection assay we also demonstrated that tested compounds interact with DNA. All compounds at the concentrations corresponding to cytotoxic properties are not toxic towards red blood cells, and do not contribute to hemolysis of RBCs.

Retinoids: active molecules influencing skin structure formation in cosmetic and dermatological treatments.

Vitamin A is the first vitamin approved by the Food and Drug Administration as an anti-wrinkle agent that changes appearance of the skin surface and has anti-aging effects. Vitamin A is in a group of fat-soluble substances and belongs to the category of retinoids. Apart from retinol, that group includes structurally related substances with the biological properties of retinol. Since the biological activity of the substances differs, for the purpose of standardization, it is given in retinol equivalents. Vitamin A and its derivatives are among the most effective substances slowing the aging process. Retinoids regulate the cell apoptosis, differentiation and proliferation. Anti-wrinkle properties of retinoids promote keratinocytes proliferation, strengthen the protective function of the epidermis, restrain transepidermal water loss, protect collagen against degradation and inhibit metalloproteinases activity. Retinoid activity is related to high affinity for nuclear receptors: RAR - retinoid acid receptors and RXR - retinoid X receptors.

Interaction of Arylidenechromanone/Flavanone Derivatives with Biological Macromolecules Studied as Human Serum Albumin Binding, Cytotoxic Effect, Biocompatibility Towards Red Blood Cells.

The aim of this study was to determine the cytotoxic effect of 3-arylidenechromanone (1) and 3arylideneflavanone (2) on HL-60 and NALM-6 cell lines (two human leukemia cell lines) and a WM-115 melanoma cell line. Both compounds exhibited high cytotoxic activity with higher cytotoxicity exerted by compound 2, for which IC50 values below 10 µM were found for each cell line. For compound 1, the IC50 values were higher than 10 µM for HL-60 and WM-115 cell lines, but IC50 < 10 µM was found for the NALM-6 cell line. Both compounds, at the concentrations close to IC50 (concentration range: 5⁻24 µM/L for compound 1 and 6⁻10 µM/L for compound 2), are not toxic towards red blood cells. The synthesized compounds were characterized using spectroscopic methods ¹H- and 13C-NMR, IR, MS, elemental analysis, and X-ray diffraction. The lipophilicity of both synthesized compounds was determined using an RP-TLC method and the logP values found were compared with the theoretical ones taken from the Molinspiration Cheminformatics (miLogP) software package. The mode of binding of both compounds to human serum albumin was assessed using molecular docking methods.

Melanin and lipofuscin as hallmarks of skin aging.

Discoloration are symptoms of skin aging. They are connected with presence of melanin and lipofuscin, whose excess and abnormal distribution in the skin cause dark spots to appear. Melanin is formed under the influence of tyrosinase during melanogenesis. Its content changes with age, which may be a result of menopause. Lipofuscin is another example of the age pigment. It is composed of proteins, lipids and carbohydrates. It is described as an age pigment because its content increases with age. The formation and accumulation of lipofuscin is inevitable and leads to cell and homeostasis dysfunction because it reduces the proteasome activity.

Quantitative relationships between structure and cytotoxic activity of flavonoid derivatives. An application of Hirshfeld surface derived descriptors.

Quantitative relationships between the structure and cytotoxic activity of series flavonoid derivatives were examined. The first regression-based model, developed for 18 flavanone-2-pyrazoline hybrids, involved two interpretable descriptors: a Mor04v and partial atomic charge. The second model, developed for structurally diverse set of compounds, was based on descriptors derived from Hirshfeld surface analysis. This model suggests that cytotoxic activity of compounds can be successfully predicted based on a fraction of H⋯H contacts and a fraction of interactions involving a halogen atom. For non-halogen derivatives, the data reveal that cytotoxic activity is inversely proportional to the percentage of O⋯H and N⋯H close contacts to Hirshfeld surface, while directly proportional to the percentage of H⋯H interactions. Chlorine (1k) and bromine (1l) derivatives of compounds, containing flavanone fused with N-methyl-2-pyrazoline, exhibited high cytotoxic potential against HL-60 cancer cell line (IC50<10µM). The cytotoxicity of 1k and 1l towards normal cells (HUVEC) was 10 and 25-fold lower, respectively.

Paxillin and its role in the aging process of skin cells.

Morphology of senescent cells is constantly changing at the molecular level, which in turn leads to disruption of their function. It is connected with reduced ability to synthesize extracellular matrix (ECM) and leads to the dysfunction of integrin adhesion molecules and adhesion clusters. In skin, these factors cause a loss of communication between the extracellular matrix and fibroblasts. This contributes to the appearance of signs of aging. The aim of this study is to draw attention to the very important molecule such as paxillin, which is an adaptor protein with mass of 68 kDa. This family of proteins includes Hic-5, PaxB and leupaxin. Paxillin binds to actin-binding proteins such as vinculin, actopaxin, and kinases (e.g. Integrin-linked kinase (ILK)). Moreover, it plays an important role in the integrity of the matrix, because it transduces transmembrane signaling between integrins and growth factors. Paxillin is a scaffold protein, activating the arrangement and organization of the cytoskeleton. Signaling through paxillin affects the long-term changes in gene expression, cell proliferation, and organization of the ECM. Correct functioning of the ECM is important for the wound healing processes and regeneration of tissues or tissue repair. Decrease or lack of paxillin expression results in changes in the structure and integrity of the ECM, which are manifested by aging of cells and organs. Restoration of the cellular matrix connections would be a significant element in the processes related to the anti-aging activities.

New look at the role of progerin in skin aging.

Current literature data indicate that progerin, which is a mutant of lamin A, may be one of several previously known physiological biomarkers of the aging process which begins at the age of 30. Lamins belong to the family of intermediate filaments type V and are an important component of the nuclear envelope (NE). The physiological processes of an alternative splicing of LMNA (lamin A/C) gene and posttranslational processing result in the formation of different variants of this gene. Prelamin A is generated in cytosol and modified by respective enzymes. In the final step, 15-aa peptide is released at the C-terminus, resulting in mature lamin A. Point mutation of cytosine to thymine at position 1824 in exon 11 of LMNA gene causes a truncated form of lamin A, which is defined as progerin. In the course of time, progerin is mainly found in skin fibroblasts and reticular layers of terminally differentiated keratinocytes. Changes take place in the nucleus and they are similar to those observed in patients with Hutchinson-Gilford progeria syndrome and refer mainly to an increase in the amount of reactive oxygen species which reduce the level of antioxidant enzymes, DNA damage and histone modification. There are still pending studies on working out new anti-aging strategies and the skin is the main area of research. Biomimetic peptides (analogues of elafin) are used in cosmetics to reduce the formation of progerin.

Ascorbic Acid Treatments as Effective and Safe Anti-Aging Therapies for Sensitive Skin.

The most common signs of aging skin include a decrease in firmness and density, uneven skin tone, and a tendency to erythema. There is an ever-increasing interest in aesthetic treatments that maintain the skin's favorable appearance. However, such therapies are difficult in the case of sensitive skin, defined as a set of stimuli-triggered symptoms (stinging, erythema, burning, and itching) that would not appear in healthy skin. Sensitive skin is common and affects, to varying degrees, about half of the European population. This study was aimed at evaluating the effects of ascorbic acid-a known antioxidant-applied with sonophoresis and microneedling on the signs of photoaging in reactive and erythematous skin. A significant improvement in skin elasticity was observed after a series of tests. A significant reduction in erythema was observed after both therapies. The greatest reduction was observed on the cheeks after applying vitamin C combined with microneedling. At the same time, the results showed an excellent tolerance of both treatments, which proved them to be safe and effective.

The inhibitory effects of polyphenols on skin UV immunosuppression .

Long-term exposure to UV radiation leads to skin ageing and may initiate carcinogenesis. In both cases immunosuppressive activity of UV radiation plays an important role. The aim of the study is to present polyphenols commonly seen in flora and their properties protecting the skin from the damaging influence of UV rays. Polyphenols are a group of compounds which are present in plants. Their common features are: the ring structure of a molecule, hydroxyl groups in the rings and a conjugated double bond system. Such structure makes polyphenols active antioxidants. They also demonstrate anti-immunosuppressive properties.

Copper(II) complexes with derivatives of pyrazole as potential antioxidant enzyme mimics.

A series of six mononuclear Cu(II) complexes with pyrazole-based ligands: 5-(2-hydroxybenzoyl)-3-methyl-1-(2-pyridinyl)-1H-pyrazol-4-phosphonic acid dimethyl ester (1a), 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1H-pyrazole-4-carboxylic acid methyl ester (1b) and 1-benzothiazol-2-yl-5-(2-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboxylic acid methyl ester (1c) were characterized regarding to electrochemical and antioxidant properties. All complexes exhibit suitable Cu(II)/Cu(I) redox potential (E1/2) to act as antioxidant enzymes mimic. The five of these complexes were found to be trifunctional enzyme mimics possessing SOD, CAT and GPx-like catalytic activities. Moreover, Cu(II) complexes were capable to decrease ROS level in melanoma cells and observed effects were not merely a reflection of cytotoxicity.