Passive Enhancement of Retinol Skin Penetration by Jojoba Oil Measured Using the Skin Parallel Artificial Membrane Permeation Assay (Skin-PAMPA): A Pilot Study.

Introduction: Retinol is known to have positive benefits on the skin including enhancements in barrier function, increased epidermal thickness, reductions in fine lines and wrinkles and reductions in hyperpigmentation. Improved methods to enhance the penetration of retinol are desirable. Methods: A study was conducted to examine if addition of natural jojoba (Simmondsia chinensis) oil might help passively enhance the penetration of retinol through the skin's lipid barrier. The model used to examine the passive penetration of the retinol is the skin parallel artificial membrane permeation assay (Skin-PAMPA). In this study, three formulations were examined. The formulations included two control blends: a moisturizing emulsion without retinol and the same product containing 1.0% retinol without jojoba oil. The remaining formulation contained similar concentrations of retinol with 10% jojoba oil. The studies were conducted by applying the products to the Skin-PAMPA models at 37°C/5% CO2 for 16 hours and then extraction of the acceptor reservoir with cyclohexane (ratio 1:5 acceptor fluid to cyclohexane). The resulting acceptor reservoir cyclohexane solutions were analyzed for retinol by High Performance Liquid Chromatography (HPLC). Results: The formulations without retinol showed no indications of retinol penetration by HPLC. The control formulation with 1.0% retinol demonstrated that retinol had permeated the membrane in the 16-hour timeframe with a measured Area Under the Curve (AUC) of 7 units. Analysis of the formulation containing 1.0% retinol and 10% jojoba oil indicated retinol had permeated with a AUC of 285 units, a nearly 40-fold increase in active retinol permeation. Discussion: The ability for jojoba oil to directly act to help skin permeation of a key skin care active like retinol has not been previously demonstrated. This potential for jojoba oil to enhance passive skin penetration of critical skin actives, like retinol, can help to improve the performance of skin care products employing active topical ingredients.

Isosorbide Fatty Acid Diesters Have Synergistic Anti-Inflammatory Effects in Cytokine-Induced Tissue Culture Models of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic disease in which epidermal barrier disruption triggers Th2-mediated eruption of eczematous lesions. Topical emollients are a cornerstone of chronic management. This study evaluated efficacy of two plant-derived oil derivatives, isosorbide di-(linoleate/oleate) (IDL) and isosorbide dicaprylate (IDC), using AD-like tissue culture models. Treatment of reconstituted human epidermis with cytokine cocktail (IL-4 + IL-13 + TNF-α + IL-31) compromised the epidermal barrier, but this was prevented by co-treatment with IDL and IDC. Cytokine stimulation also dysregulated expression of keratinocyte (KC) differentiation genes whereas treatment with IDC or IDL + IDC up-regulated genes associated with early (but not late) KC differentiation. Although neither IDL nor IDC inhibited Th2 cytokine responses, both compounds repressed TNF-α-induced genes and IDL + IDC led to synergistic down-regulation of inflammatory (IL1B, ITGA5) and neurogenic pruritus (TRPA1) mediators. Treatment of cytokine-stimulated skin explants with IDC decreased lactate dehydrogenase (LDH) secretion by more than 50% (more than observed with cyclosporine) and in vitro LDH activity was inhibited by IDL and IDC. These results demonstrate anti-inflammatory mechanisms of isosorbide fatty acid diesters in AD-like skin models. Our findings highlight the multifunctional potential of plant oil derivatives as topical ingredients and support studies of IDL and IDC as therapeutic candidates.

Transbuccal platform for delivery of lipogenic actives to facial skin: Because fat matters.

The ability to control facial skin physiology and appearance through the oral mucosa (transbuccally) is largely unexplored. Here, a hypothesis was tested that transbuccal delivery of fat tissue-supportive actives may trigger beneficial cosmetic responses at the level of the skin. First, the importance of the fat tissue for skin structure and function was established by comparative analysis of human biopsies cultured defatted or in the presence of hypodermis, using macroscopic observation, quantitative polymerase chain reaction, and histochemistry. Then, the ability to improve epidermal function and structure through the application of a lipoactive patch to oral mucosa was demonstrated in a clinical case study by the quantification of several epidermal microRNAs (miRNAs). It was found that removal of the hypodermal fat layer accelerated skin biopsy aging as demonstrated by the deterioration of the physical appearance at the macroscopic and microscopic (hematoxylin and eosin stain) levels and the decrease of expression of genes implicated in the structure and function of the skin, such as AQP3 and LOR. Furthermore, when adipogenic actives were applied to the oral mucosa under a form of bioadhesive film in a clinical case study, an improvement in the expression of miRNA biomarkers of senescence and inflammation was observed in the epidermis. Taken together, these results indicate that the transbuccal delivery of lipogenic compounds to face is a novel method for the improvement of facial skin structure and function.

4-Substituted picolinohydrazonamides as a new class of potential antitubercular agents.

The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4-0.8 µg/mL) was higher than that of reference drugs. Moreover, derivative 15 exhibited lower activity against other tested microorganism such as bacteria gram-positive, gram-negative or fungi. Thus, this compound is characterized by the selectivity of antimicrobial activity. Antiproliferative study conducted against human dermal fibroblasts (HDF) and mouse melanoma cell line (B16-F10) revealed low cytotoxicity of compound 15. Conducted research allowed to identify compound 15 as leading for further research.

GM604 regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The peptide drug GM604 (GM6 or Alirinetide) was developed as a candidate ALS therapy, which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood. METHODS: This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 h). RESULTS: We identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors, whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors. Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes (STAT3, HOXD11, HES7, GLI1). We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR < 0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway. CONCLUSIONS: Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.

Novel 2-(2-phenalkyl)-1H-benzo[d]imidazoles as antitubercular agents. Synthesis, biological evaluation and structure-activity relationship.

A series of novel 2-(2-phenalkyl)-1H-benzo[d]imidazole derivatives and analogues (2a-3l) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with phenethyl, styryl and 3,5-dichlorophenethyl moiety were obtained. Compounds 2g, 2h and 2i bearing methyl groups at the benzimidazole system and phenalkyl substituent at the C-2 position showed high tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 0.8 to 6.2 µg/mL (2.5-25 µM). More importantly, derivatives 2g (5,6-dimethyl-2-phenethyl-1H-benzo[d]imidazole) and 2i (2-(3,5-dichlorophenethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis as compared with eukaryotic cells: non-malignant (neonatal human dermal fibroblasts) and malignant (mouse melanoma B16-F10 cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents. SAR studies resulted in interesting conclusions on structural factors affecting tuberculostatic activity.

Synthesis, structure, and biological activity of novel heterocyclic sulfonyl-carboximidamides.

ABSTRACT: A series of novel heterocyclic sulfonyl-carboximidamides were synthesized in satisfactory yields via condensation of heterocyclic methyl carbimidates with 2-chlorobenzenesulfonamide and 4-chloropyridine-3-sulfonamide. New structures were confirmed by IR and NMR spectra as well as elemental analyses. X-ray crystallography of two derivatives was performed. The single-crystal structures confirmed the presence of a primary amine group in the amidine moiety. All the compounds were screened for their tuberculostatic, antibacterial, and anticancer activities. Preliminary results indicated that target compounds exhibited weak tuberculostatic and antibacterial activities. Seven compounds inhibited the growth of some cancer cell lines, whereas one of the 2-quinoline derivatives displayed favorable activity against all tested cancer cells with GI50 values of 0.92-13 µM.

Angelica sinensis isolate SBD.4: composition, gene expression profiling, mechanism of action and effect on wounds, in rats and humans.

This report characterizes an aqueous isolate (SBD.4) of one of the most broadly used Chinese medicinal herbs, Angelica sinensis, from the perspective of its application in skin and wound care. SBD.4 has been chemically defined and was found to increase the strength of healed wounds in retired breeder (older) rats. Furthermore, the mechanism of action of this Angelica sinensis isolate was tested in the zebrafish angiogenesis model, and in human skin substitutes by DNA microarray, revealing a bioactivity profile consistent with skin repair and regeneration. When combined with several types of wound dressings, SBD.4 increased type I collagen production in human dermal fibroblasts, and when formulated in nanosilver hydrocolloid dressing, it was found effective in chronic ulcer management in humans, demonstrating that botanical high-tech wound dressings can be successfully developed to improve the treatment of chronic lesions in humans.

Effect of SBD.4A--a defined multicomponent preparation of Angelica sinensis--in periodontal regeneration models.

Periodontitis is a major cause of tooth motility and loss, resulting in destruction of the supporting structures of the tooth, including periodontal ligaments and alveolar bone. Periodontal surgery can slow the progression of the disease, but is costly, invasive, limited by contraindications and technique-sensitive. Recently, non-invasive pharmacological treatments using proteinaceous biologicals have become available. Here, for the first time, the bone-regenerative capabilities of a non-proteinaceous biological--SBD.4A--a novel, stable multicomponent growth factor isolated from a medicinal plant Angelica sinensis are reported. SBD.4A was tested in osteoblast proliferation and differentiation systems, as well as in a fibroblast-secreted hyaluronic acid assay. Furthermore, SBD.4A was formulated in a slow release matrix and tested in the rat calvarial defect model. Apart from the previously reported strong stimulation of angiogenesis, fibroblast growth and collagen synthesis--the activities needed for periodontal regeneration--SBD.4A enhanced the deposition of hyaluronic acid and proliferation of osteoblasts in vitro, as well as bone regeneration in the rat calvarial defect model. Together, these results indicate the beneficial effect of SBD.4 on periodontal ligament and bone regeneration making the case for further development of this botanical growth factor.

SBD.4 stimulates regenerative processes in vitro, and wound healing in genetically diabetic mice and in human skin/severe-combined immunodeficiency mouse chimera.

In search of novel angiostimulators, we performed a high-throughput screening of medicinal plants beneficial for blood circulation. From the panel of positive hits, Angelica sinensis was selected for further investigation. Purified down to a low-molecular-weight fraction and characterized by high-performance liquid chromatography-mass spectrometry, the material, named SBD.4A, revealed a particularly strong wound healing activity in the diabetic mouse wound-healing model, and in the human/severe combined immunodeficiency mouse chimera wound-healing model. In both models, SBD.4A compared favorably with the Food and Drug Administration-approved wound-healing drug becaplermin, suggesting that this botanical product could be a valuable treatment for difficult-to-heal wounds. Further high-performance liquid chromatography fractionation of SBD.4A yielded a hydrophilic fraction, which strongly stimulated endothelial cell proliferation, tridimensional endothelial cell network formation, as well as the proliferation of human dermal fibroblasts and type I collagen secretion. Because angiogenesis and fibroblast proliferation are essential for wound healing, we propose that this liquid chromatography-mass spectrometry-defined hydrophilic fraction is at least partially responsible for the wound-healing activity of SBD.4A.

[Long-term result of the surgical treatment of craniopharyngiomas]. / Odlegla ocena wyników leczenia chirurgicznego czaszkogardlaków.

BACKGROUND AND PURPOSE: The aim of the study was to assess the long-term outcome in patients with cranipharyngioma, depending on the extent of tumour removal. MATERIAL AND METHODS: Thirty-six patients (17 females and 19 males), aged between 10 and 57, were treated at the Clinic of Neurosurgery of the Medical University of Warsaw between 1990 and 2004. The most common initial symptoms included: decreased visual acuity in 75% of cases, visual field defect in 69% of cases, headaches in 58% cases and endocrine disorders in 50% of cases. The initial diagnosis was based on two-phase computed tomography (CT) and magnetic resonance imaging (MRI). The most common means of surgical access was by pterional craniotomy, which was used in 27 cases. Due to tumour localisation, other accesses (bifrontal - basal, transventricular and transsphenoidal) were also used. RESULTS: The tumour removal was considered total in 31%, subtotal in 38%, and partial in 31%. In the post-operational period 2 patients died. Control examinations were performed to investigate long-term outcome: two-phase MRI or CT, evaluations of visual acuity and visual field. During the follow-up period, tumour recurrence occurred in 1 patient (9%) following complete tumour removal, in 8 patients (57%) after subtotal removal, and in 6 patients (55%) after partial removal. The range of follow-up was between 2 and 14 years. CONCLUSIONS: On the basis of our own experience we conclude that complete removal of the craniopharyngioma leads to the best outcome in terms of survival time and period free of recurrence. Clinical and radiological observation of the patients who underwent nonradical operation seems to be reasonable. In cases with tumour recurrence, reoperation and subsequent radiotherapy are advisable.

[Expression of glutathione S-transferase isoenzymes in human gliomas]. / Ekspresja izoenzymów transferazy S-glutationowej w glejakach czlowieka.

UNLABELLED: Glutathione S-transferase (GST) is a part of the most important enzymatic systems protecting organisms from toxic, electrophilic compounds. Expression of numerous GST isoenzymes is changed in various pathological conditions, including neoplasia. The aim of present study was to analyze the expression pattern of GST pi, mu (mu4 and mu5) and alpha at the mRNA and protein levels in human primary gliomas. The studies were conducted on tissue samples obtained from surgery. RESULTS: There were no changes in GST pi mRNA expression, determined by RT-PCR, between gliomas and tumor adjacent tissues. However, using Western blotting method, an increase in GST pi protein in tumors was observed, which might be caused by the lower rate in protein degradation. Decrease in the expression of GST mu at mRNA level (mu4), as well as at protein level was shown in gliomas compared to control tissues. mRNA for GST mu5 isoform was demonstrated only in two tumor cases, but not in normal tissues, and for GST alpha, in one sample of control tissue. At the protein level, GST pi expression was increased in gliomas, whereas GST mu was decreased. CONCLUSION: Changes in GST isoenzymes expression can play an important role in the susceptibility of central nervous system to carcinogenesis.