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James V Gruber,1 Nicole Terpak,2 Sebastien Massard,2 Amber Schwartz,3 Krzysztof Bojanowski4 1Research, Vantage Specialties, Fairfield, NJ, USA; 2Research, Vantage Specialties, Warren, NJ, USA; 3Production, Vantage Specialties, Tucson, AZ, USA; 4Research, Sunny Biodiscovery, Santa Paula, CA, USACorrespondence: James V Gruber, Email Vincent.Gruber@Vantagegrp.comIntroduction: 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.Keywords: skin permeation, retinoids, HPLC, lipid barrier, Simmondsia chinensis oil

Abstract Lycium barbarum L. (Solanaceae) glycoconjugates (LbGp) display an interesting array of anti-apoptotic and antioxidant properties, which may be beneficial for human skin. We therefore set out to determine the [...]

Two-dimensional (2D) cell culture is an important tool in the discovery of skin-active agents. Fibroblasts and keratinocytes, more rarely fibroblast-keratinocyte cocultures, are usually used for that purpose, where test compounds are added by mixing with the overlaying growth medium. However, such an approach is suboptimal because it lacks the stratum corneum component. The stratum corneum acts as a selective gatekeeper and opposes the intradermal permeation of many compounds that are bioactive when placed in direct contact with cells. One solution is to use reconstituted epidermis, but this approach is costly and time consuming. Here, a model is proposed, where the simplicity and convenience of the 2D cell culture is combined with the advantage of a hydrophobic barrier reminiscent of the skin horny layer. This model was tested with skin-relevant solvents, as well as with "naked" hydrophilic and encapsulated compounds. Cell viability and collagen stimulation were used as readouts. The results showed that the incorporation of a stratum corneum -substitute barrier on top of a 2D cell culture reduced the cytotoxicity of a common cosmetic solvent, dimethyl isosorbide (DMI), in cell culture and modified the bioactivity of the added actives (magnesium ascorbyl phosphate [MAP] and oligomeric proanthocyanidins [OPCs]/levan biopolymer), which became dependent on their ability to penetrate through a lipidic layer. Taken together, these results indicate a better physiological relevance of this cell culture model in workflows aimed at the discovery and analysis of skin-active compounds than conventional 2D systems., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Geovani Quijas et al.)

To investigate how structural modifications affect tuberculostatic potency, we synthesized seven new piperidinothiosemicrabazone derivatives 8 - 14 , in which three of them had a pyrazine ring replacing the pyridine ring. Derivatives 8 - 9 and 13 - 14 exhibited significant activity against the standard strain (minimum inhibitory concentration (MIC) 2-4 μg/mL) and even greater activity against the resistant M. tuberculosis strain (MIC 0.5-4 μg/mL). Additionally, the effects of compounds 8 - 9 were entirely selective (MIC toward other microorganisms ≥ 1000 μg/mL) and non-toxic (IC50 to HaCaT cells 5.8 to >50 μg/mL). The antimycobacterial activity of pyrazine derivatives 11 - 12 was negligible (MIC 256 to >500 μg/mL), indicating that replacing the aromatic ring was generally not a promising line of research in this case. The zwitterionic structure of compound 11 was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion (ADME) calculations showed that all compounds, except 11 , could be considered for testing as future drugs. An analysis of the structure-activity relationship was carried out, indicating that the higher basicity of the substituent located at the heteroaromatic ring might be of particular importance for the antituberculous activity of the tested groups of compounds.

Bakusylan (bakuchiol salicylate) is a bipartite compound obtained by merging two skin-active entities with complementary bioactivities-bakuchiol and salicylic acid-for the purpose of generating a new class of functional retinoids with enhanced skin benefits. Here, we describe its preparation process and report that pure bakusylan exhibits potential for an improved permeation through the stratum corneum, enhances type IV collagen gene expression in organotypic skin substitutes containing both epidermal and dermal layers, and upregulates this protein in adult human dermal fibroblast cultures. The mechanism of action underlying these effects appears to involve the components of the IP3K/Akt signaling pathway selectively implicated in the maintenance of skin integrity, further underlying the suitability of this ester for skin care applications requiring enhanced cutaneous permeation targeting the dermal-epidermal junction.

In this study, six new 2,6-disubstituted thiosemicarbazone derivatives of pyridine were synthesized (4−9), and their tuberculostatic activity was evaluated. All of them showed two- to eightfold higher activity (minimum inhibitory concentration (MIC) 0.5−4 µg/mL) against the resistant strain compared with the reference drug. Compounds 5 and 7, which contained the most basic substituents—pyrrolidine and piperidine—in their structure, strongly inhibited the growth of the standard strain (MIC 2 µg/mL). Furthermore, the same derivatives exhibited activity comparable to that of the reference drugs against some types of Gram-positive bacteria (MIC 0.49 µg/mL) and showed no cytotoxicity (IC50 > 50 µg/mL) in HaCaT cells. The zwitterionic structure of each compound was determined using X-ray crystallography. Absorption, distribution, metabolism, and excretion analyses showed that all compounds are good drug candidates. Thus, compounds 5 and 7 were identified as leading structures for further research on antituberculosis drugs with extended effects.

The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as cannabidiol modulate this system but also act through eCB-independent mechanisms. This study evaluated the effects of cannabidiol, bakuchiol (BAK), and ethyl (linoleate/oleate) (ELN) in keratinocytes and reconstituted human epidermis. Molecular docking simulations showed that each compound binds the active site of the eCB carrier FABP5. However, BAK and ethyl linoleate bound this site with the highest affinity when combined 1:1 (w/w), and in vitro assays showed that BAK + ELN most effectively inhibited FABP5 and fatty acid amide hydrolase. In TNF-stimulated keratinocytes, BAK + ELN reversed TNF-induced expression shifts and uniquely downregulated type I IFN genes and PTGS2 ( COX2 ). BAK + ELN also repressed expression of genes linked to keratinocyte differentiation but upregulated those associated with proliferation. Finally, BAK + ELN inhibited cortisol secretion in reconstituted human epidermis skin (not observed with cannabidiol). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I IFN). A topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting novel ways to modulate the eCB system for innovative skincare product development., (© 2022 The Authors.)

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.

Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-κB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-κB inhibition, and we confirmed IDMF-mediated NF-κB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition sequences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates, such as DRF and IDMF, have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-κB and IRF1 contributing to mitigation of inflammation and pyroptosis.

Introduction: Peroxisome proliferator-activated receptor (PPAR) agonists are known to modulate the synthesis of dermal lipids and proteins including collagens. Olive (Olea europaea) leaves have been reported to contain PPAR-binding ligands. Collagen IV, a major dermal-epidermal junction (DEJ) protein, degrades with both age and disease. Here, we report the formulation of a novel multi-ligand complex, Linefade, and its effects on collagen IV synthesis., Methods: Linefade prepared from the leaves of Olea europaea contains 2% w/w plant extract solids dissolved in a mixture of glyceryl monoricinoleate and dimethyl isosorbide. In silico docking was performed with PPAR-α (PDB ID: 2P54). Linefade was evaluated for PPAR-α-dependent transcription in a luciferase reporter assay system. Cell viability and collagen IV levels in human dermal fibroblast cultures were measured using the MTT method and ELISA assay, respectively. Transcriptome analysis was conducted on a full-thickness reconstituted human skin (EpiDermFT) model. Ex vivo cell viability and collagen IV immunostaining were performed on human skin explants., Results: In silico docking model of the major constituents (oleanolic acid and glyceryl monoricinoleate) produced a co-binding affinity of -6.7 Kcal/mole. Linefade significantly increased PPAR-α transcriptional activity in CHO cells and collagen IV synthesis in adult human dermal fibroblasts. Transcriptome analysis revealed that 1% Linefade modulated the expression of 280 genes with some related to epidermal differentiation, DEJ, PPAR, Nrf2 and retinoid pathways. An ex vivo human explant study showed that 1% Linefade, delivered via a triglycerides excipient, increased collagen IV levels along the dermal-epidermal junction by 52%., Conclusion: In silico modelling and in vitro and ex vivo analyses confirmed Linefade-mediated activation of PPAR-α and stimulation of collagen IV synthesis., (© 2021 Contrast Product Development, LLC. International Journal of Cosmetic Science published by John Wiley & Sons Ltd on behalf of Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

Tetrahexyldecyl Ascorbate (THDC) is an L-ascorbic acid precursor with improved stability and ability to penetrate the epidermis. The stability and transdermal penetration of THDC, however, may be compromised by the oxidant-rich environment of human skin. In this study, we show that THDC is a poor antioxidant that degrades rapidly when exposed to singlet oxygen. This degradation, however, was prevented by combination with acetyl zingerone (AZ) as a stabilizing antioxidant. As a standalone ingredient, THDC led to unexpected activation of type I interferon signaling, but this pro-inflammatory effect was blunted in the presence of AZ. Moreover, the combination of THDC and AZ increased expression of genes associated with phospholipid homeostasis and keratinocyte differentiation, along with repression of MMP1 and MMP7 expression, inhibition of MMP enzyme activity, and increased production of collagen proteins by dermal fibroblasts. Lastly, whereas THDC alone reduced viability of keratinocytes exposed to oxidative stress, this effect was completely abrogated by the addition of AZ to THDC. These results show that AZ is an effective antioxidant stabilizer of THDC and that combination of these products may improve ascorbic acid delivery. This provides a step towards reaching the full potential of ascorbate as an active ingredient in topical preparations.

Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. However, its potential has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide DMF (IDMF), which was designed to have antipsoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is nonirritating and nonsensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically upregulated in psoriatic skin lesions but not those of other skin diseases. IDMF also downregulated genes induced by IL-17A and TNF in keratinocytes as well as predicted targets of NF-κB and the antidifferentiation noncoding RNA (i.e., ANCR ). IDMF further stimulated the transcription of oxidative stress response genes ( NQO1 , GPX2 , GSR ) with stronger NRF2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing the expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data show that IDMF exhibits antipsoriatic activity that is similar or improved compared with that exhibited by DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule., (© 2021 The Authors.)

The breakdown of the epidermal barrier and consequent loss of skin hydration is a feature of skin aging and eczematous dermatitis. Few treatments, however, resolve these underlying processes to provide full symptomatic relief. In this study, we evaluated isosorbide di-(linoleate/oleate) (IDL), which was generated by esterifying isosorbide with sunflower fatty acids. Topical effects of IDL in skin were compared with those of ethyl linoleate/oleate, which has previously been shown to improve skin barrier function. Both IDL and ethyl linoleate/oleate downregulated inflammatory gene expression, but IDL more effectively upregulated the expression of genes associated with keratinocyte differentiation (e.g., KRT1, GRHL2, SPRR4). Consistent with this, IDL increased the abundance of epidermal barrier proteins (FLG and involucrin) and prevented cytokine-mediated stratum corneum degradation. IDL also downregulated the expression of unhealthy skin signature genes linked to the loss of epidermal homeostasis and uniquely repressed an IFN-inducible coexpression module activated in multiple skin diseases, including psoriasis. In a double-blind, placebo-controlled trial enrolling females with dry skin, 2% IDL lotion applied over 2 weeks significantly improved skin hydration and decreased transepidermal water loss (NCT04253704). These results demonstrate mechanisms by which IDL improves skin hydration and epidermal barrier function, supporting IDL as an effective intervention for the treatment of xerotic pruritic skin., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The opportunity to shape facial appearance through noninvasive muscle relaxation procedures remains largely unfulfilled. Here, a hypothesis was tested whether an intraoral application of a mucoadhesive, biodegradable slow release formulation may trigger beneficial cosmetic outcomes in and around the mouth., Aims: A clinical case study was designed to determine the effect of a transbuccal delivery of a formulation containing a botanical muscle relaxant on the appearance of the smile line. The ingredients of this formulation were then tested for metalloproteinase inhibition, in fibroblast culture model, to further determine their value for intraoral application., Patients/methods: A bioadhesive patch device was engineered and applied under the upper lip of three volunteers. Changes in gingival coverage were interrogated by morphometry. Levels of MMP1 and MMP3 in fibroblast culture-conditioned medium were measured by sandwitch ELISA and cell proliferation by sulforhodamine B method., Results: The cosmetic benefit of the transoral delivery of skeletal muscle relaxing formulation was demonstrated by loosening upper lip skin and improving the gummy smile condition. The ingredients of that formulation also had an inhibitory effect on MMP1 and MMP3 protein level in vitro, and enhanced cell proliferation in the adult fibroblast model., Conclusion: Taken together, these results indicate that the transbuccal delivery platform is an effective approach to improve gingival coverage, while potentially providing beneficial functionality for both skin and the oral cavity., (© 2020 Wiley Periodicals, LLC.)

Dimethyl fumarate (DMF) has emerged as a first-line treatment for the relapsing-remitting multiple sclerosis (RRMS) subtype. It is hypothesized that DMF has anti-inflammatory and antioxidant effects although mechanisms are not fully understood. This study used RNA-seq to profile gene expression responses to DMF in cultured astrocytes. Responses were compared with those of isosorbide di-(methyl fumarate) (IDMF), a newly designed fumarate that may partially replicate DMF activity with fewer adverse effects. Both compounds altered the expression of MS-associated genes, including those near MS susceptibility loci and genes dysregulated in MS patient astrocytes. The shared DMF/IDMF transcriptome response involved altered expression of antioxidant genes (e.g., HMOX1) and genes linked to extracellular matrix integrity (TIMP3, MMP9) and migration of pro-inflammatory cells into CNS (CCL2). IDMF-specific transcriptome responses included down-regulation of mitotic genes associated with a proliferative reactive astrocyte phenotype (ICAM1) and repression of genes encoding NF-kappaB subunits (NFKB2, RELA, RELB) and NF-kappaB targets (NCAPG, CXCL1, OAS3). Overall, these results identify astrocyte-centered mechanisms that may contribute to the established efficacy of DMF as an RRMS treatment. Furthermore, our findings support a rationale for further studies of IDMF as a novel fumarate, which may have unique suppressive effects on astrocyte reactivity and glial scar formation. [200 words]., Competing Interests: Declaration of competing interest IDMF was developed and patented by Sytheon Ltd (Boonton, NJ). RKC is president and CEO of Sytheon with ownership interest. KB is chief executive officer of Sunny BioDiscovery, Inc. (Santa Paula, CA). WRS and KB have received consulting reimbursement from Sytheon., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Terminalia chebula (TC) is a deciduous tree of which extracts have demonstrated efficacy for treatment of photodamage, skin aging, and wound healing. However, molecular and cellular mechanisms underlying these benefits remain unclear., Objective: To profile dermal expression responses to a standardized tannin-enriched TC fruit extract (Synastol ® TC)., Materials and Methods: Microarrays were used to evaluate gene expression in three-dimensional reconstituted human skin cultures., Results: Genome-wide expression responses to TC were the opposite to those observed in cells exposed to oxidative stress, solar-simulated UV radiation, and wounding, with increased expression of genes associated with water homeostasis, skin barrier establishment, blood vessel development, and circadian rhythms. TC also increased expression of extracellular matrix components, such as collagens (COL1A1, COL1A2) and proteoglycans (PRELP, OGN), and in separate assays, we showed that TC inhibits MMP enzymes (MMP-1, MMP-2, MMP-3, MMP-9, MMP-12) and microbial activity (S. aureus, P. acnes). Unexpectedly, mRNA and protein levels of late keratinocyte (KC) differentiation markers (FLG, LOR) were increased by TC, and expression responses in skin cultures broadly resembled those that occur with KC differentiation. Consistent with these results, TC increased expression of transcription factors regulating KC differentiation (FOS, GHRL3, PPARG) and we noted enrichment of AP-1 binding sites in regions upstream of TC-increased genes., Conclusion: These results demonstrate that functionally important TC extract responses occur in the epidermis and are therefore not restricted to the dermal layer. Our findings thus suggest mechanisms by which TC may strengthen full-thickness skin architecture for treatment of skin aging and/or chronic wounds.

[This corrects the article DOI: 10.1186/s40035-018-0135-7.]., (© The Author(s) 2020.)

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., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Zingerone (Z) is a phenolic alkanone derived from natural sources with anti-inflammatory and antioxidant effects. Acetyl zingerone (AZ) is a recently designed molecule that shares structural features with Z but is expected to have improved stability and antioxidant function. This study utilized microarrays to compare the effects of Z and AZ on gene expression in reconstituted human epidermis. Both Z and AZ increased Notch pathway gene expression (NOTCH1 and MAML3) and decreased expression of genes linked to extracellular matrix disassembly (MMP3 and CTSV) and reactive oxygen species metabolism (PMAIP1 and ARG2). Although Z and AZ each inhibited in vitro matrix metallopeptidase (MMP)-1, MMP-3, and MMP-12 activity, inhibition of MMP-3 and MMP-12 was greater with AZ. Moreover, AZ led to more consistent increases in the expression of genes encoding collagens (COL11A2), proteoglycans (VCAN), and extracellular matrix glycoproteins (SPARC). Finally, AZ opposed gene expression patterns associated with fibroblast senescence, keratinocyte differentiation, and IL-17A stimulation. These effects were AZ-specific and not replicated by Z. These results show that AZ improves extracellular matrix integrity with retinoid-like effects on differentiation and inflammation. Our findings provide a rationale for clinical studies to understand the benefits of AZ in the treatment or prevention of skin aging, or potentially, as a treatment for other human skin diseases., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Not applicable.Not applicable.GM604 is an investigational drug product developed by Genervon Biopharmaceuticals, LLC (Pasadena, CA). DK is an executive of Genervon with ownership interest and has been listed as an inventor for patents related to GM604. RMWC is a Genervon associate, has been listed as an inventor for patents related to GM604, and has received consulting reimbursement from Genervon Biopharmaceuticals. MK has been listed as an inventor on patents related to GM604 and has received consulting reimbursement from Genervon Biopharmaceuticals. KB is chief executive officer of Sunny BioDiscovery, Inc. (Santa Paula, CA) and has received consulting reimbursement from Genervon Biopharmaceuticals. WRS has been listed as an inventor for pending patent applications related to GM604 and has received consulting reimbursement from Genervon Biopharmaceuticals.

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: Multi-profile monitoring of various blood serum factors during acute subarachnoid haemorrhage (SAH) is crucial for successful treatment. The aim of the study is to evaluate the serum concentration of different blood factors in the acute period of SAH., Material and Methods: 31 patients with confirmed aneurysmal SAH were enrolled in a prospective study. The concentrations of the following serum compounds were assessed on the day of admission and reassessed after 5 days: lipids profile, cardiac functionality enzymes and markers, electrolytes, osmolality, CRP (C-reactive protein), glucose, creatinine, urine., Results: The mean level of high-density lipoprotein (HDL) changed significantly from 43.9±23.9 mg/dL to 27.5±19,8 mg/dL, p=0,013 (mean dif. 16.5±14,1 mg/dL; 37,3%). Concentration of low-density lipoprotein (LDL) decreased by 28.6% (mean dif. 26.78±61.32; p=0.047). Values of triglicerydes and total cholesterol did not differ significantly between the initial evaluations and these repeated after 5 days. The overall serum ions (Na < sup > + < /sup > , K < sup > + < /sup > , Mg < sup > 2+ < /sup > , Ca < sup > 2+ < /sup > ) concentrations and osmolality did not differ significantly between the initial measurements and after 5 days from SAH. The only mean value that appeared to be substantially increased at initial measurement was NT-proBNP and reached 1928.8±4952 pg/ ml, this value dropped down to 392.87±1147.9 mg/ml after 5 days (mean dif. 1535.96±4808.76 pg/ml; 79,6%; p = 0.247). CRP increased over 2 fold after 5 days up to 29.267±28.614 mg/L (mean dif. 16.06±34.05 pg/L; 121.6%; p=0.028). At 5-day follow up hematocrit dropped to 33.38 ± 3.81% from the initial value of 39.63 ± 2,56% (p=0.02)., Conclusion: This study showed a significant decrease in the serum level of LDL and HDL, while triglycerides were moderately heightened. Routine monitoring of lipid profile and statin administration at the early stage of SAH is recommended.

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 GI 50 values of 0.92-13 μM.

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.

A series of novel 3-cyclohexylpropanoic acid derivatives and 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds (1-8) have been synthesized and evaluated for tuberculostatic activity. Compounds 1a, 1c, 1e and 1f bearing benzimidazole or benzimidazole-like systems showed the most potent tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 1.5 to 12.5μg/mL. More importantly 1a (6-chloro-2-(2-cyclohexylethyl)-4-nitro-1H-benzo[d]imidazole) and 1f (2-(2-cyclohexylethyl)-1H-imidazo[4,5-b]phenazine) appeared selective for M. tuberculosis as compared with eukaryotic cells (human fibroblasts), and other antimicrobial strains. These compounds may thus represent a novel, selective class of antitubercular agents. Additionally compound 1a stimulated type I collagen output by fibroblasts, in vitro., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Type II diabetes is a metabolic disease mediated through multiple molecular pathways. Here, we report anti-diabetic effect of a standardized isolate from a fossil material - a mineraloid leonardite - in in vitro tests and in genetically diabetic mice. The mineraloid isolate stimulated mitochondrial metabolism in human fibroblasts and this stimulation correlated with enhanced expression of genes coding for mitochondrial proteins such as ATP synthases and ribosomal protein precursors, as measured by DNA microarrays. In the diabetic animal model, consumption of the Totala isolate resulted in decreased weight gain, blood glucose, and glycated hemoglobin. To our best knowledge, this is the first description ever of a fossil material having anti-diabetic activity in pre-clinical 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.

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.