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Simple Summary The most frequent adverse effect for patients receiving radiotherapy, an effective treatment for skin cancer when surgical removal of the tumor is impossible, is acute radiodermatitis, affecting patients’ physical function and often leading to therapy termination. Creams and other topical formulations used so far for the prevention of acute radiodermatitis are applied at regular intervals but do not ensure a constant and controlled transepidermal absorption. The aqueous extract of Aleppo pine bark, previously preclinically and clinically assessed in the form of gel, was herein loaded on micro/nanofibrous patches and clinically evaluated in comparison with a commercially used reference cream on non-melanoma skin carcinoma patients undergoing radiotherapy. The experimental patch significantly contributed to prophylaxis and successful management of acute radiodermatitis, safely restoring skin and its biophysical parameters to normal levels and reducing patients’ discomfort. Topical application of pine-loaded micro/nanofibrous patches holds great potential for the development of a new generation of anti-inflammatory skin care dressings against radiodermatitis. Abstract Acute radiodermatitis is the most common side effect in non-melanoma skin cancer patients undergoing radiotherapy. Nonetheless, despite the ongoing progress of clinical trials, no effective regimen has been found yet. In this study, a non-woven patch, comprised of electrospun polymeric micro/nanofibers loaded with an aqueous extract of Pinus halepensis bark (PHBE), was fabricated and clinically tested for its efficacy to prevent radiodermatitis. The bioactivity of the PHBE patch was evaluated in comparison with a medical cream indicated for acute radiodermatitis. Twelve volunteer patients were selected and randomly assigned to two groups, applying either the PHBE patch or the reference cream daily. Evaluation of radiation-induced skin reactions was performed during the radiotherapy period and 1 month afterwards according to the Radiation Therapy Oncology Group (RTOG) grading scale, photo-documentation, patient-reported outcomes (Visual Analog Scale, questionnaire), biophysical measurements (hydration, transepidermal water loss, erythema, melanin), and image analysis. In contrast with the reference product, the PHBE patch showed significant anti-inflammatory activity and restored most skin parameters to normal levels 1 month after completion of radiation therapy. No adverse event was reported, indicating that the application of the PHBE patch can be considered as a safe medical device for prophylactic radiodermatitis treatment.

Hybrid composites of synthetic and natural polymers represent materials of choice for bone tissue engineering. Ulvan, a biologically active marine sulfated polysaccharide, is attracting great interest in the development of novel biomedical scaffolds due to recent reports on its osteoinductive properties. Herein, a series of hybrid polycaprolactone scaffolds containing ulvan either alone or in blends with κ-carrageenan and chondroitin sulfate was prepared and characterized. The impact of the preparation methodology and the polysaccharide composition on their morphology, as well as on their mechanical, thermal, water uptake and porosity properties was determined, while their osteoinductive potential was investigated through the evaluation of cell adhesion, viability, and osteogenic differentiation of seeded human adipose-derived mesenchymal stem cells. The results verified the osteoinductive ability of ulvan, showing that its incorporation into the polycaprolactone matrix efficiently promoted cell attachment and viability, thus confirming its potential in the development of biomedical scaffolds for bone tissue regeneration applications.

The ubiquitin-proteasome system (UPS) is a key player in the maintenance of cellular protein homeostasis (proteostasis). Since proteasome function declines upon aging leading to the acceleration of its progression and the manifestation of age-related pathologies, many attempts have been performed towards proteasome activation as a strategy to promote healthspan and longevity. The marine environment hosts a plethora of organisms that produce a vast array of primary and secondary metabolites, the majority of which are unique, exhibiting a wide spectrum of biological activities. The fact that these biologically important compounds are also present in edible marine organisms has sparked the interest for elucidating their potential health-related applications. In this review, we focus on the antioxidant, anti-aging, anti-aggregation and anti-photoaging properties of various marine constituents. We further discuss representatives of marine compounds classes with regard to their potential (direct or indirect) action on UPS components that could serve as UPS modulators and exert beneficial effects on conditions such as oxidative stress, aging and age-related diseases., Graphical abstract Image 1, Highlights • Proteasome has been implicated in oxidative stress, aging and age-related diseases. • Various marine natural products exert strong antioxidant activities. • Various marine natural products possess anti-aging and anti-aggregation properties. • Various marine natural products can serve as potential proteasome modulators. • Various marine natural products represent promising anti-photoaging agents.

Six new (1, 2, 6, 8, 13, and 20) and twenty previously isolated (3&ndash, 5, 7, 9&ndash, 12, 14&ndash, 19, and 21&ndash, 26) steroids featuring thirteen different carbocycle motifs were isolated from the organic extract of the soft coral Sinularia polydactyla collected from the Hurghada reef in the Red Sea. The structures and the relative configurations of the isolated natural products have been determined based on extensive analysis of their NMR and MS data. The cytotoxic, anti-inflammatory, anti-angiogenic, and neuroprotective activity of compounds 3&ndash, 7, 9&ndash, 20, and 22&ndash, 26, as well as their effect on androgen receptor-regulated transcription was evaluated in vitro in human tumor and non-cancerous cells. Steroids 22 and 23 showed significant cytotoxicity in the low micromolar range against the HeLa and MCF7 cancer cell lines, while migration of endothelial cells was inhibited by compounds 11, 12, 22, and 23 at 20 &micro, M. The results of the androgen receptor (AR) reporter assay showed that compound 11 exhibited the strongest inhibition of AR at 10 &micro, M, while it is noteworthy that steroids 10, 16, and 20 displayed increased inhibition of AR with decreasing concentrations. Additionally, compounds 11 and 23 showed neuroprotective activity on neuron-like SH-SY5Y cells.

Bacterial systems have gained wide attention for depolymerization of lignocellulosic biomass, due to their high functional diversity and adaptability. To achieve the full microbial exploitation of lignocellulosic residues and the cost-effective production of bioproducts within a biorefinery, multiple metabolic pathways and enzymes of various specificities are required. In this work, highly diverse aerobic, mesophilic bacteria enriched from Keri Lake, a pristine marsh of increased biomass degradation and natural underground oil leaks, were explored for their metabolic versatility and enzymatic potential towards lignocellulosic substrates. A high number of Pseudomonas species, obtained from enrichment cultures where organosolv lignin served as the sole carbon and energy source, were able to assimilate a range of lignin-associated aromatic compounds. Comparatively more complex bacterial consortia, including members of Actinobacteria, Proteobacteria, Bacilli, Sphingobacteria, and Flavobacteria, were also enriched from cultures with xylan or carboxymethyl cellulose as sole carbon sources. Numerous individual isolates could target diverse structural lignocellulose polysaccharides by expressing hydrolytic activities on crystalline or amorphous cellulose and xylan. Specific isolates showed increased potential for growth in lignin hydrolysates prepared from alkali pretreated agricultural wastes. The results suggest that Keri isolates represent a pool of effective lignocellulose degraders with significant potential for industrial applications in a lignocellulose biorefinery., Microbial bioprospecting; Lignocellulose biodegradation; Lignin metabolism; Cellulases; Xylanases; Ligninases; Lignin related aromatics.

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Ulvan, a bioactive natural sulfated polysaccharide, and gelatin, a collagen-derived biopolymer, have attracted interest for the preparation of biomaterials for different biomedical applications, due to their demonstrated compatibility for cell attachment and proliferation. Both ulvan and gelatin have exhibited osteoinductive potential, either alone or in combination with other materials. In the current work, a series of novel hybrid scaffolds based on crosslinked ulvan and gelatin was designed, prepared and characterized. Their mechanical performance, thermal stability, porosity, water-uptake and in vitro degradation ability were assessed, while their morphology was analyzed through scanning electron microscopy. The prepared hybrid ulvan/gelatin scaffolds were characterized by a highly porous and interconnected structure. Human adipose-derived mesenchymal stem cells (hADMSCs) were seeded in selected ulvan/gelatin hybrid scaffolds and their adhesion, survival, proliferation, and osteogenic differentiation efficiency was evaluated. Overall, it was found that the prepared hybrid sponge-like scaffolds could efficiently support mesenchymal stem cells&rsquo, adhesion and proliferation, suggesting that such scaffolds could have potential uses in bone tissue engineering.

Wound healing is a fundamental response to tissue injury and a number of natural products has been found to accelerate the healing process. Herein, we report the preparation of a series of different polarity (organic and aqueous) extracts of the marine isopod Ceratothoa oestroides and the in vivo evaluation of their wound healing activity after topical administration of ointments incorporating the various extracts on wounds inflicted on SKH-hr1 hairless mice. The most active extract was fractionated for enrichment in the bioactive constituents and the fractions were further evaluated for their wound healing activity, while their chemical profiles were analyzed. Wound healing was evaluated by clinical assessment, photo-documentation, histopathological analysis and measurement of biophysical skin parameters, such as transepidermal water loss (TEWL), hydration, elasticity, and skin thickness. The highest levels of activity were exerted by treatment of the wounds with a fraction rich in eicosapentaenoic acid (EPA), as well as myristic and palmitoleic acids. Topical application of the bioactive fraction on the wounds of mice resulted in complete wound closure with a skin of almost normal architecture without any inflammatory elements.

Conium divaricatum, even though exhibiting morphological differences in comparison to its congener of European origin Conium maculatum, is still considered a disputed taxon often referred to as a synonym of the latter. Herein, essential oils of various plant tissues from several populations of both taxa were comparatively investigated, showing distinct chemical profiles. In the case of C. divaricatum, the essential oils were dominated by hydrocarbon esters, among which the main constituents 4'-oxodecyl hexanoate, 4'-oxododecyl hexanoate and 4'-oxooctyl hexanoate were isolated and identified as undescribed natural products. In contrast, the essential oils of C. maculatum were dominated by hydrocarbon alkanes, alkenes and ketones, as well as the polyacetylene (Z)-falcarinol. Even though determination of the total alkaloids content and toxicity assessment against the crustacean Artemia salina did not reveal significant differences, the distinct chemical profiles and the morphological differences observed for both taxa, strongly support their distinction as separate species.

In the last decades the paradigm of including excipients in the formulations as inert substances, aiding production processes, has changed and they are now approached as multifunctional compounds. This means that several functions apply, spreading from the stabilization and modified release, to providing biocompatible properties and targeting moieties. In the present work, the algal sulfated polysaccharide ulvan, which remains a rather unexploited biomaterial for applications in the design of drug delivery systems, was used as a formulant in hydrophilic matrix systems, containing the chronobiotic hormone melatonin (MLT). The MLT's in vitro modified release profile in gastrointestinal-like fluids was probed. In general, the % release profile of MLT from ulvan-based tablets, was found to be relatively higher than that of the market drug Circadin® at pH 1.2 (2 h), with the exception of the formulations containing HPMC K15M. The release of most of the ulvan-based formulations follow a sigmoidal pattern (Super Case II mechanism, n > 0.89), which denotes that the drug release is controlled by polymer relaxation and/or erosion.

Background/Aims: There is no treatment, without side effects, efficiently preventing or curing skin burns, caused by radiotherapy. A new experimental topical treatment protocol was assessed in mice receiving orthovoltage X-rays at an equivalent dose to that applied to human breast cancer patients in conventional radiotherapy. Methods: SKH-HR2 female hairless mice were irradiated on their dorsum with a total dose of 4,300 cGy during a 1-month period (20 fractions). The treatment group received a combination of 3 topical products, an oil-in-water cream, a gel containing Pinus halepensis bark aqueous extract, and an ointment containing olive oil extract of the marine isopod Ceratothoa oestroides. The positive control group was treated with a conventionally used commercial gel, whereas the negative control group did not receive any topical treatment. Skin alterations were evaluated by macroscopic examinations, measurements of transepidermal water loss (TEWL), melanin content, erythema intensity, hydration, and histopathology assessment. Results: Sixty days after radiation, TEWL and hydration values were abnormal and elements of acute, chronic, and granulomatous inflammation were present in all cases. The severest damage was detected in the deeper dermis. Treatment showed a comparatively beneficial effect on chronic and granulomatous inflammation while positive control was beneficial on acute inflammation. Conclusion: Skin anti-inflammatory treatment was the most effective but must be applied for several months. Further preclinical studies should be conducted, assimilating a human cancer radiation therapeutic schema with the aim of optimizing skin inflammation treatment.

The aim of the present study was the encapsulation of Rosmarinus officinalis essential oil (REO) in β-cyclοdextrin (β-CD) and two chemically modified β-CD matrices and the evaluation of the antibacterial activity of the prepared inclusion complexes against Staphylococcus aureus. The inclusion complexes possessed nanoscale size ranging from 395.7 ± 13.7 to 594.9 ± 18.8 nm, good size dispersion (0.366 ± 0.009 to 0.482 ± 0.043) and satisfactory stability in suspension (ζ-potential, −24.3 ± 4.2 to −31.5 ± 4.9 mV), while the inclusion efficiency ranged from 65% to 78%. The in vitro release profiles of the inclusion complexes revealed an initial burst effect, with the release kinetics being better fitted on the Higuchi model following quasi-Fickian diffusion. The antibacterial activity of the inclusion complexes of REO in β-CD, HP-β-CD and Me-β-CD against S. aureus was evaluated for 3 days and it was observed that both β-CD and HP-β-CD exhibited prolonged activity in comparison to the pure REO.

New systems for the controlled release of 1,7-dioxaspiro[5.5]undecane and (Z)-7-tetradecenal, the sex pheromones of olive fruit fly, Bactrocera oleae, and olive moth, Prays oleae, respectively, were developed utilizing electrospun micro/nanofiber matrices from inexpensive, biodegradable polymers, namely polycaprolactone, cellulose acetate and polyhydroxybutyrate. The incorporation of the pheromones in 5, 10 and 20% w/w in the electrospinning polymer blends allowed for the production of fiber mats with variable loading levels and release rates, ensuring however in all cases the release of pheromones for more than 16 weeks. Laboratory bioassays and field trapping tests showed that the fiber mats obtained from electrospinning of polyhydroxybutyrate solution containing 5% w/w 1,7-dioxaspiro[5.5]undecane and polycaprolactone solution containing 5% w/w (Z)-7-tetradecenal were almost twice as effective in attracting B. oleae and P. oleae males, respectively, in comparison to the positive controls used.

CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure–activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.

Dinoflagellates contain large amounts of omega-3 fatty acids, including the nutritionally important docosahexaenoic acid (DHA). However, their cultivation in suspensions is characterized by low growth rates. Twin-layer porous substrate photobioreactors (TL-PSBRs) have been shown to support growth of different microalgal species, including the robust dinoflagellate Symbiodinium voratum. In the present study, the potential of cultivating marine autotrophic dinoflagellate species in a TL-PSBR for DHA production was explored. Based on initial screening experiments, two Symbiodinium species with high biomass and DHA productivities were selected: the symbiotic Symbiodinium microadriaticum CCAC 2475 B and the free-living Symbiodinium voratum CCAC 3869 B. The effects of three different temperatures (17, 22 and 27 °C) and nitrogen regimes (nitrate, ammonium and nitrogen-free) on biomass growth, total lipid accumulation and fatty acid methyl esters (FAMEs) content, with emphasis on DHA, were evaluated. The two lower temperatures (17 and 22 °C) enhanced growth and total lipid accumulation of S. microadriaticum CCAC 2475 B and S. voratum CCAC 3869 B. Cultivation at 22 °C and nitrogen limitation led to a significant positive effect on DHA productivity. Symbiodinium. microadriaticum CCAC 2475 B reached a DHA productivity of 145.4 mg m−2 day−1 and DHA content in the dry biomass of 2% (w/w) after 4 days of nitrogen depletion. The results of the present study demonstrated that autotrophic dinoflagellates, when cultivated on a TL-PSBR, produce comparable amounts of lipids and fatty acids to other commercially used microalgal species including the valuable DHA.

Red algae of the genus Laurencia are known to biosynthesize and secrete an immense variety of secondary metabolites possessing a spectrum of biological activities against bacteria, invertebrates and mammalian cell lines. Following a rigorous cross-species screening process, herein we report the antifouling potential of 25 secondary metabolites derived from species of the genus Laurencia, as well as the thorough evaluation of the ecotoxicity of selected metabolites against non-target marine arthropods and vertebrate cell lines. A number of these secondary metabolites exhibited potent antifouling activity and performed well in all screening tests. Our results show that perforenol (9) possesses similar antifouling activity with that already described for bromosphaerol, which is used herein as a benchmark.

Thuwalallenes A&ndash, E (1&ndash, 3, 5 and 8) and thuwalenynes A&ndash, C (4, 6, 7), new C15 acetogenins featuring uncommon ring systems, along with cis-maneonene D (9), thyrsiferol (10) and 23-acetyl-thyrsiferol (11) were isolated from the organic extract of a population of the red alga Laurencia sp., collected at Rose Reef off the village of Thuwal in the Red Sea waters of the Kingdom of Saudi Arabia. The structure elucidation of the isolated natural products was based on extensive analysis of their spectroscopic data. Compounds 1&ndash, 6, 8, 10 and 11 were evaluated for their anti-inflammatory activity by quantifying nitric oxide (NO) release in response to TLR4 stimulation in macrophages. Besides compound 4 that did not exhibit any activity, all other tested metabolites inhibited NO production from activated macrophages. Among them, thyrsiferol (10) and 23-acetylthyrsiferol (11) displayed activity with IC50 values in the low nM scale without cytotoxicity.

Skin inflammation is the most common symptom in dermatological diseases. It is usually treated by topically applied products, such as creams, gels and lotions. Skin dressings offer a promising alternative as they are endowed with more controlled administration conditions. In this study, the anti-inflammatory activity of electrospun alginate micro/nanofibrous dressings loaded with the aqueous extract of Pinus halepensis bark (PHBE) was evaluated in vivo in mice. The upper back skin of SKH-1 female hairless mice was exposed to a single dose of ultraviolet radiation (3 MEDs) and the inflamed area was treated daily by the direct application of a nanofibrous patch. The condition of the skin was evaluated primarily on the basis of clinical observation, photo-documentation and histopathological assessment, while measurements of the erythema, hydration, transepidermal water loss (TEWL) and sebum production were also taken into account. The results showed that the topical application of alginate micro/nanofibrous dressings loaded with PHBE on UV-inflamed skin significantly attenuated inflammation damage, reducing the healing period. Increase of the loading dose of PHBE resulted in a proportional reduction of the extent, the density and the depth of skin inflammation. With the steadily increasing interest of the skin dressing industry towards nanofibrous matrices, electrospun nonwovens could serve as ideal candidates for the development of multifunctional anti-inflammatory care systems.

Vagiallene (1), a rearranged C

In this work sixteen hydroxyl ammonium Protic Ionic Liquids derived from a proton transfer reaction between four different substituted amines and four different low molecular weight aliphatic and alicyclic carboxylic acids have been synthesized. The synthesized PILs were structurally characterized by NMR and FT-IR spectroscopy whereas two of their more important physicochemical properties namely viscosity and glass transition temperature (T g ) were evaluated. The effect of alkyl chain length and substitution on the anionic and cationic component of the PILs scaffold has been discussed for the studied properties. It seems that T g values are mainly affected by the carboxylate anion structure whereas viscosity is controlled mainly by the structural features of the cationic part of the PILs. In order to estimate their environmental impact and reinforce their “green” character, biodegradation studies, as well as toxicity evaluation experiments have also been conducted. The synthesized PILs can be confidently labelled as green considering that they are not toxic or present low toxicity to the nauplii of the brine shrimp A. salina whereas they show biodegradability levels between 41–64%, according to the manometric respirometric method which measures the biological oxygen demand (BOD 5 ) by microorganisms in order to degrade PILs via bio-oxidation in five days.

Twenty one sesquiterpenes were isolated from the organic extract of the Caribbean gorgonian Pseudopterogogia rigida. Among them, seven bisabolanes (1, 2, 9–11, 13 and 14), six cadinanes (15–20) and one sesquiterpene featuring a new tricyclic carbon skeleton (21) are new natural products, while two (6 and 7) are reported for the first time from a natural source. The structures of the new compounds were established by detailed analyses of their NMR and MS data. The isolated metabolites were evaluated for their inhibitory activity against CDC25 phosphatases, which represent possible targets related to cancer therapy. Compounds 4 and 18 were the most active with IC50 values of 1.88 and 3.44 μM, respectively, against the CDC25A isoform.

Six new (1, 2, and 4-7) and two previously reported (3 and 8) disulfides, along with 4-butyl-2,6-cycloheptadienone, γ-tocopherol, and δ-tocopherol, were isolated from an organic extract of the brown alga Dictyopteris membranacea, collected at Gerolimenas Bay, Greece. The structure elucidation of the isolated natural products was based on analysis of their spectroscopic data. Compounds 1, 3-6, and 8 were evaluated for their antibacterial and anti-inflammatory activities. None of the compounds displayed antibacterial activity against two resistant strains of Staphylococcus aureus and one strain of Escherichia coli. In contrast, metabolite 5 was able to cause strong inhibition of NO production with an IC50 value of 3.8 μM using an LPS stimulation assay.

Inflammation is part of the organism&rsquo, s response to deleterious stimuli, such as pathogens, damaged cells, or irritants. Macrophages orchestrate the inflammatory response obtaining different activation phenotypes broadly defined as M1 (pro-inflammatory) or M2 (homeostatic) phenotypes, which contribute to pathogen elimination or disease pathogenesis. The type and magnitude of the response of macrophages are shaped by endogenous and exogenous factors and can be affected by nutrients or therapeutic agents. Multiple studies have shown that natural products possess immunomodulatory properties and that marine algae contain products with such action. We have previously shown that disulfides isolated from Dictyopteris membranacea suppress nitric oxide (NO) production from activated macrophages, suggesting potential anti-inflammatory actions. In this study, we investigated the anti-inflammatory mechanism of action of bis(5-methylthio-3-oxo-undecyl) disulfide (1), 5-methylthio-1-(3-oxo-undecyl) disulfanylundecan-3-one (2) and 3-hexyl-4,5-dithiocycloheptanone (3). Our results showed that all three compounds inhibited M1 activation of macrophages by down regulating the production of pro-inflammatory cytokines TNF&alpha, IL-6 and IL-12, suppressed the expression of the NO converting enzyme iNOS, and enhanced expression of the M2 activation markers Arginase1 and MRC1. Moreover, disulfides 1 and 2 suppressed the expression of glucose transporters GLUT1 and GLUT3, suggesting that compounds 1 and 2 may affect cell metabolism. We showed that this was due to AKT/MAPK/ERK signaling pathway modulation and specifically by elevated AKT phosphorylation and MAPK/ERK signal transduction reduction. Hence, disulfides 1&ndash, 3 can be considered as potent candidates for the development of novel anti-inflammatory molecules with homeostatic properties.

Vagiallene (1), a rearranged C15 acetogenin with a molecular formula and a carbon skeleton unprecedented in natural products, was isolated as a trace constituent from the organic extract of the red alga Laurencia obtusa from Lefkada island. The planar structure and the relative configuration of 1 were established on the basis of extensive analysis of its spectroscopic data, while its absolute configuration was determined by comparison of its experimental and quantum-mechanically predicted electronic circular dichroism spectra.

From the organic extracts of five bacterial strains isolated from marine sediments collected in the East Mediterranean Sea, three new (15, 16, 31) and twenty-nine previously reported (1&ndash, 14, 17&ndash, 30, 32) metabolites bearing the 2,5-diketopiperazine skeleton were isolated. The structures of the chlorinated compounds 15, 16, and 31 were elucidated by extensive analysis of their spectroscopic data (NMR, MS, UV, IR). Compounds 15 and 16 were evaluated for their antifungal activity against Candida albicans and Aspergillus niger but were proven inactive. The relevant literature is supplemented with complete NMR assignments and revisions for the 29 previously reported compounds.

Macrophages are central mediators of inflammation, orchestrating the inflammatory response through the production of cytokines and nitric oxide. Macrophages obtain pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, which can be modulated by soluble factors, including natural products. Despite the crucial protective role of inflammation, chronic or deregulated inflammation can lead to pathological states, such as autoimmune diseases, metabolic disorders, cardiovascular diseases, and cancer. In this case, we studied the anti-inflammatory activity of neorogioltriol (1) in depth and identified two structurally related diterpenes, neorogioldiol (2), and O11,15-cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (3), with equally potent activity. We investigated the mechanism of action of metabolites 1–3 and found that all three suppressed macrophage activation and promoted an M2-like anti-inflammatory phenotype by inducing expression of Arginase1, MRC1, IRAK-M, the transcription factor C/EBPβ, and the miRNA miR-146a. In addition, they suppressed iNOS induction and nitric oxide production. Importantly, treatment of mice with 2 or 3 suppressed DSS-induced colitis by reducing tissue damage and pro-inflammatory cytokine production. Thus, all these three diterpenes are promising lead molecules for the development of anti-inflammatory agents targeting macrophage polarization mechanisms.

Covering: 1957 to 2017 Algae constitute a heterogeneous group of eukaryotic photosynthetic organisms, mainly found in the marine environment. Algae produce numerous metabolites that help them cope with the harsh conditions of the marine environment. Because of their structural diversity and uniqueness, these molecules have recently gained a lot of interest for the identification of medicinally useful agents, including those with potential anticancer activities. In the current review, which is not a catalogue-based one, we first highlight the major biological events that lead to various types of cancer, including metastatic ones, to chemoresistance, thus to any types of current anticancer treatment relating to the use of chemotherapeutics. We then review algal metabolites for which scientific literature reports anticancer activity. Lastly, we focus on algal metabolites with promising anticancer activity based on their ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. Thus, we highlight compounds that have, among others, one or more of the following characteristics: selectivity in reducing the proliferation of cancer cells over normal ones, potential for killing cancer cells through non-apoptotic signaling pathways, ability to circumvent MDR-related efflux pumps, and activity in vivo in relevant pre-clinical models.

Mosquitoes are hematophagous insects of major public health concern, serving as vectors of many diseases. Available products for personal protection against mosquitoes lack adequate efficacy and in most cases need to be reapplied or replaced frequently. In recent years, the encapsulation of the active repellents in various matrices has arisen as an alternative method for the development of new-generation repellent systems. The aim of the present study was to explore the potential of functional micro/nanofibrous matrices as systems for the sustained release of the highly volatile insect-repellent citronella oil.Micro/nanofibrous single- and triple-layer systems incorporating citronella oil as the active agent were developed via the electrospinning technique using the low-cost, non-toxic, biodegradable polymers cellulose acetate and polyvinylpyrrolidone. All the micro/nanofiber systems produced exhibited prolonged release of citronella oil and a high repellent activity in laboratory bioassays against the mosquito Aedes albopictus for at least 4 weeks.Considering the high volatility of the embedded repellent, the present study demonstrates the strong potential of the micro/nanofibrous matrices to act as carriers of highly volatile repellents for an effective and sustained protection from mosquitoes. © 2019 Society of Chemical Industry.

Non-invasive biophysical methods were used to study the effect of antioxidant gels, which were prepared from Pinus halepensis bark extracts, vitamin C and water, on the skin of diabetic hairless mice irradiated with UV radiation of 1 and 2 minimal erythemal doses (MEDs). The calculated transepidermal water loss (TEWL) for diabetic mice was found to be fivefold higher on day 11 after irradiation, and in all cases, the TEWL values converged to their initial values on day 21. Both pinus and vitamin C gels inhibited the dehydration of the skin, while water gels did not show similar protection. At low dose of UV-irradiation (1 MED), vitamin C gels showed the best hydration, while by doubling the UV dose, pinus gels induced significant skin-protective effects. Upon irradiation, the mice treatment with pinus gel showed diminished inflammation in comparison with the other gels. Pinus also inhibited the hyperkeratosis of skin. As expected, 2 MEDs caused greater skin damage, such as inflammation, dryness, oxidative stress and rides (aging) compared to the damage induced by 1 MED.

Ulvan, a marine sulfated polysaccharide isolated from green algae, has been recently recognized as a natural biopolymer of biomedical interest. A series of lysozyme/ulvan complexes prepared under various charge ratios at physiological pH were studied. The resulting complexes were examined with light scattering techniques in order to characterize the size, the distribution and the ζ-potential of the nanocarriers, which were found to depend on the charge ratio employed. Increased complexation efficiency of lysozyme was observed for certain charge ratios, while ATR-FTIR data suggested that the protein structure after complexation was retained. Bacterial growth studies showed that lysozyme once complexed with ulvan not only retains its antibacterial activity against the Gram positive strain Staphylococcus aureus, but actually exhibits increased levels of activity. In this model study, the results highlight the potential of ulvan as a promising nanocarrier for positively charged bioactive molecules.

Objective: Aiming at the modified release of melatonin (MLT), electrospun-MLT loaded nanofibers, filled into hard gelatin and DRcapsTM capsules, were used as formulants. Methods: Cellulose acetate, polyvinylpyrrolidinone and hydroxypropylmethylcellusose (HPMC 2910) were used for the preparation of the fiber matrices through electrospinning. The in vitro modified release profile of MLT from the fabricated matrices in gastrointestinal-like fluids was studied. At pH 1.2, the formulations CA1, CA2, PV1, HP1, HP2 and the composite formulations CAPV1-CAPV5 in hard gelatin capsules exhibited fast MLT release. Results: In general, the same trend was observed at pH 6.8, with the exception of CAPV1 and CAPV2. These two composite formulations delivered 52.08% and 75.25% MLT, respectively at a slower pace (6 h) when encapsulated in DRcapsTM capsules. In all other cases, the release of MLT from DRcapsTM capsules filled with the MLT-loaded nanofibers reached 100% at 6h. Conclusion: These findings suggest that the MLT-loaded nanofibrous mats developed in this study exhibit a promising profile for treating sleep dysfunctions.

Extracts from three Salvia sp. (S. fruticosa, S. pomifera, and S. sclarea), native to the island of Crete, were fractionated using ethyl acetate and n-butanol and analyzed using liquid chromatography–diode array–mass spectrometry. The antioxidant potency of each fraction was assessed by the antiradical activity (AAR) and the hydroxyl free radical scavenging activity (SAHFR). The chromatographic analyses revealed a rich profile, composed of mainly of flavones, accompanied by a limited number of phenylpropanoids. The highest antioxidant activity was displayed by the n-butanol fraction of S. fruticosa, which also had the richest polyphenolic composition.

Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene's industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.

This work was performed under the frame of COST Action collaboration (COST Action CM1106). The generous contribution of AIRC (The Italian Association for Cancer Research) IG14536 to G.D. is gratefully acknowledged. A.H. acknowledges support from the János Bolyai fellowship of the Hungarian Academy of Sciences. Background: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and to the development of drug resistance after a first platinum-based regimen. The presence of a specific population of “cancer stem cells” could be responsible of the relapse of the tumor, and of the development of resistance to therapy. For this reason, it would be important to specifically target this subpopulation of tumor cells in order to increase the response to therapy. Method: We screened a chemical compound library assembled during the COST CM1106 action to search for compound classes active in targeting ovarian stem cells. We here report the results of the high-throughput screening assay in two ovarian cancer stem cells and the differentiated cells derived from them. Results and conclusion: Interestingly there were compounds active only on stem cells, only on differentiated cells and compounds active on both cell populations. Even if these data need to be validated in ad hoc dose response cytotoxic experiments, the ongoing analysis of the compound structures will open up to mechanistic drug studies to select compounds able to improve the prognosis of ovarian cancer patients. Postprint

Food, besides providing nutrients to satisfy the metabolic requirements, through various bioactive constituents modulates a number of functions in the body, thus playing detrimental or beneficial roles in a number of diseases. Seaweeds are rich in polysaccharides, proteins, minerals, vitamins, secondary metabolites, and polyunsaturated fatty acids, with low caloric value. Macroalgae, producing a great variety of bioactive compounds that have exhibited a wide spectrum of activities ranging from the treatment of allergies, diabetes, hypertension, oxidative stress, inflammation, thrombosis, obesity, and lipidemia to serious degenerative disorders and cancer, have a high potential as a source of functional ingredients. In this chapter, an overview of the most important bioactive seaweed constituents with their potential use in functional foods is presented.

A chemical investigation of the organic extract of the sea hare Aplysia depilans, collected off Skyros Island, Greece, yielded eight new brominated diterpenes (1-8), featuring the rare dactylomelane skeleton, together with the previously reported luzodiol (9). The structure elucidation and the assignment of the relative configurations of the new natural products were based on extensive NMR spectroscopic and MS spectrometric analyses. Compounds 1-9 were evaluated for their cytotoxic activities against five human tumor cell lines, but were proven inactive.

International audience; Conventional treatment of advanced colorectal cancer is associated with tumor resistance and toxicity towards normal tissues. Therefore, development of effective anticancer therapeutic alternatives is still urgently required. Nowadays, marine secondary metabolites have been extensively investigated due to the fact that they frequently exhibit anti-tumor properties. However, little attention has been given to terpenoids isolated from seaweeds. In this study, we isolated the halogenated monoterpene mertensene from the red alga Pterocladiella capillacea (S.G. Gmelin) Santelices and Hommersand and we highlight its inhibitory effect on the viability of two human colorectal adenocarcinoma cell lines HT29 and LS174. Interestingly, exposure of HT29 cells to different concentrations of mertensene correlated with the activation of MAPK ERK-1/-2, Akt and NF-κB pathways. Moreover, mertensene-induced G2/M cell cycle arrest was associated with a decrease in the phosphorylated forms of the anti-tumor transcription factor p53, retinoblastoma protein (Rb), cdc2 and chkp2. Indeed, a reduction of the cellular level of cyclin-dependent kinases CDK2 and CDK4 was observed in mertensene-treated cells. We also demonstrated that mertensene triggers a caspase-dependent apoptosis in HT29 cancer cells characterized by the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP). Besides, the level of death receptor-associated protein TRADD increased significantly in a concentration-dependent manner. Taken together, these results demonstrate the potential of mertensene as a drug candidate for the treatment of colon cancer.

Pines, usually tall and stout trees and less often shrubs, have evergreen foliage leaves in the shape of needles and contain resin in their bark. The techniques commonly applied for the assessment of the physicochemical properties of pine needle oil include the measurement of specific gravity, the determination of refractive index, and the measurement of optical rotation. There is an ancient belief that there is a relation between the pine needle oil and good health. This belief is based on its strong disinfectant and therapeutic properties. A parasite affected by pine needle oil is the nematode Bursaphelenchus xylophilus, which causes the pine wilt disease. The use of pine needle essential oils against human and agricultural pests and parasites has certain limitations relating to the toxicity of the oils and their inefficiency against a number of pest organisms.

In search of alternative and safer sources of collagen for biomedical applications, the marine demosponges Axinella cannabina and Suberites carnosus, collected from the Aegean and the Ionian Seas, respectively, were comparatively studied for their insoluble collagen, intercellular collagen, and spongin-like collagen content. The isolated collagenous materials were morphologically, physicochemically, and biophysically characterized. Using scanning electron microscopy and transmission electron microscopy the fibrous morphology of the isolated collagens was confirmed, whereas the amino acid analysis, in conjunction with infrared spectroscopy studies, verified the characteristic for the collagen amino acid profile and its secondary structure. Furthermore, the isoelectric point and thermal behavior were determined by titration and differential scanning calorimetry, in combination with circular dichroism spectroscopic studies, respectively.

Introduction The bioactive metabolites derived from weeds have attracted the interest of the food and pharmaceutical industries due to their health benefits. Objective To evaluate the anti-oxidant and acetylcholinesterase activity of Dittrichia viscosa extracts and characterise the polyphenolic metabolites using the LC coupled with diode-array detection (DAD) and positive mode electrospray ionisation (ESI) MS method with a view to evaluating the exploitation potential of this invasive weed. Materials and methods Roots and aerial parts of D. viscosa were extracted with solvents of increasing polarity and their major polyphenolic metabolites were identified by LC − DAD/ESI(+)/MS. The total phenolic content of the extracts was determined using the Folin–Ciocalteu method, while their anti-oxidant activity was evaluated on the basis of their ability to scavenge the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide. Thin-layer chromatography was used to screen for acetylcholinesterase inhibitors. Results Stem extracts gave the highest phenolic content, whereas the roots showed the lowest content. Twenty-five polyphenolic constituents of the extracts were tentatively characterised according to their MS and UV spectroscopic data. Among the extracts studied, roots–ethyl acetate and flowers–diethyl ether revealed the highest activity according to the DPPH and chemiluminescence assays respectively. Conclusion The metabolic profile of D. viscosa was studied and the structures of the major polyphenolic metabolites were tentatively assigned based on their MS and UV–vis spectra. The extracts exhibited high levels of anti-oxidant and acetylcholinesterase inhibitory activity and the inhibitors are probably localised mainly in flowers and roots. Copyright © 2014 John Wiley & Sons, Ltd.

The fresh needles of 46 pine species, including 37 and 17 taxa of the subgenera Pinus and Strobus, respectively, were subjected to hydrodistillation and the essential oils obtained were analyzed by means of GC–FID and GC–MS. The comprehensive analyses of the needle oils, which allowed for the identification of 161 constituents comprising the majority of the volatiles, showed significant, not only quantitative, but also qualitative differences between the samples. Monoterpenes, sesquiterpenes and diterpenes dominated the pine foliage oils, with the presence of the monoterpene hydrocarbons α- and β-pinene and the sesquiterpene hydrocarbon germacrene D characterizing most of the oils. This is the first report on the chemical composition of the essential oils of 21 pine taxa, including 15 taxa of subgenus Pinus and 6 taxa of subgenus Strobus.

Eight new (1-8) structurally diverse diterpenes featuring five different carbocycles were isolated from the organic extracts of the red alga Sphaerococcus coronopifolius collected from the coastline of the Ionian Sea in Greece. The structures of the new natural products, seven of which were halogenated, and the relative configuration of their stereocenters were determined on the basis of comprehensive spectroscopic analyses, including NMR and HRMS data. Compounds 5 and 8 were found to possess in vitro antitumor activity against one murine and five human cancer cell lines with mean IC50 values 15 and 16 μM, respectively., SCOPUS: ar.j, info:eu-repo/semantics/published

Protic Ionic Liquids (PILs) are promising solvents with desirable physicochemical properties for a variety of applications. They are considered as greener alternatives to common organic solvents but in order to efficiently be characterized as green their environmental impact has to be assessed. In the present study, the design, synthesis and an initial potential hazard assessment of 11 naphthenic and benzoic acid based PILs is presented. PILs’ “greenness” is enhanced considering that they are non-toxic according to the aquatic toxicity evaluation and most of them show satisfactorily to extremely high biodegradability level. Moreover, two of their most important physicochemical properties, viscosity and glass transition temperature (Tg), were determined for selected ILs. The effect of the aromatic and alicyclic ring on the anions, the size and the presence of a hydroxyl substituent at anions and cations has been also discussed for the studied environmental and physicochemical properties.

Furosemide, a chloride channel blocker ordinarily used as a high-ceiling or loop diuretic, is practically insoluble in water and dilute acids. Due to its acidic nature, furosemide is mostly absorbed in the stomach and in the upper small intestine. Efforts have focused on the development of sustained release systems of furosemide in order to improve the effectiveness of the drug, which exhibits poor aqueous solubility and poor permeability. Recently, electrospun nanofibrous drug delivery systems have emerged as promising alternative solid-dosage forms due to their advantages of high porosity, high surface to volume ratio, and high drug-loading efficacy. Herein, a number of nanofibrous mats composed of different types of Eudragit&reg, polymers in various concentrations and combinations loaded with furosemide were designed, successfully electrospun, and characterized using SEM, FTIR, DSC, and TGA analyses. The nanofibrous nonwovens were formulated in nanofiber tablets and the release profile of furosemide from them was evaluated at pH 1.2 and 6.8 and compared to that of physical mixture matrix tablets of analogous composition as well as to that of a commercial formulation. It was found that the release of furosemide was compatible with the gastroretentive and slower intestinal release requirements with a well-defined absorption window, while some nanofiber formulations could act as furosemide carriers in emergency situations where a relatively fast onset of its action is required, as in the case of critically ill post-traumatic patients.

Twenty one sesquiterpenes were isolated from the organic extract of the Caribbean gorgonian Pseudopterogogia rigida. Among them, seven bisabolanes (1, 2, 9–11, 13 and 14), six cadinanes (15–20) and one sesquiterpene featuring a new tricyclic carbon skeleton (21) are new natural products, while two (6 and 7) are reported for the first time from a natural source. The structures of the new compounds were established by detailed analyses of their NMR and MS data. The isolated metabolites were evaluated for their inhibitory activity against CDC25 phosphatases, which represent possible targets related to cancer therapy. Compounds 4 and 18 were the most active with IC50 values of 1.88 and 3.44 μM, respectively, against the CDC25A isoform.

Nature, the most prolific source of biological and chemical diversity, has provided mankind with treatments for health problems since ancient times and continues to be the most promising reservoir of bioactive chemicals for the development of modern drugs. In addition to the terrestrial organisms that still remain a promising source of new bioactive metabolites, the marine environment, covering approximately 70% of the Earth's surface and containing a largely unexplored biodiversity, offers an enormous resource for the discovery of novel compounds. According to the MarinLit database, more than 27,000 metabolites from marine macro- and microorganisms have been isolated to date providing material and key structures for the development of new products in the pharmaceutical, food, cosmeceutical, chemical, and agrochemical sectors. Algae, which thrive in the euphotic zone, were among the first marine organisms that were investigated as sources of food, nutritional supplements, soil fertilizers, and bioactive metabolites.Red algae of the genus Laurencia are accepted unanimously as one of the richest sources of new secondary metabolites. Their cosmopolitan distribution, along with the chemical variation influenced to a significant degree by environmental and genetic factors, have resulted in an endless parade of metabolites, often featuring multiple halogenation sites.The present contribution, covering the literature until August 2015, offers a comprehensive view of the chemical wealth and the taxonomic problems currently impeding chemical and biological investigations of the genus Laurencia. Since mollusks feeding on Laurencia are, in many cases, bioaccumulating, and utilize algal metabolites as chemical weaponry against natural enemies, metabolites of postulated dietary origin of sea hares that feed on Laurencia species are also included in the present review. Altogether, 1047 secondary metabolites, often featuring new carbocyclic skeletons, have been included.The chapter addresses: (1) the "Laurencia complex", the botanical description and the growth and population dynamics of the genus, as well as its chemical diversity and ecological relations; (2) the secondary metabolites, which are organized according to their chemical structures and are classified into sesquiterpenes, diterpenes, triterpenes, acetogenins, indoles, aromatic compounds, steroids, and miscellaneous compounds, as well as their sources of isolation which are depicted in tabulated form, and (3) the biological activity organized according to the biological target and the ecological functions of Laurencia metabolites.