Synthesis and Characterization of a Biopolymer Pectin/Ethanolic Extract from Olive Mill Wastewater: In Vitro Safety and Efficacy Tests on Skin Wound Healing.

Wound-healing delay is one of the major problems of type 2 diabetes, representing also a clinical emergency in non-healing chronic wounds. Natural antioxidants show interesting wound-healing properties, including those extracted from waste derived from olive oil production. Olive mill wastewater is one of the main by-products of the olive oil-making process, and it is rich in high-value secondary metabolites, mainly hydroxytyrosol. We proposed an eco-friendly extraction method, employing both ultrasound-assisted and Soxhlet techniques and ethanol as a solvent, to recover valuable molecules from Roggianella cv (Olea europea L.) olive mill wastewater, which was further entrapped in a pectin polymer via an enzymatic reaction using porcine pancreatic lipase. Pectin, in combination with other substances, promoted and accelerated wound healing and demonstrated good potential to produce a biomedical conjugate for wound treatment. The antioxidant activity of the extracts and conjugate were evaluated against lipophilic (IC50 equal to 0.152 mg mL-1) and hydrophilic (IC50 equal to 0.0371 mg mL-1) radical species as well as the in vitro cytotoxicity via NRU, h-CLAT, and a wound-healing scratch assay and assessment. The pectin conjugate did not exert hemolytic effects on the peripheral blood, demonstrating interesting wound-healing properties due to its ability to stimulate cell proliferation in a dose-dependent manner.

Chrysin: A polyedric flavone as a tool to explore new phytotherapeutic applications and drug design.

In the field of pharmaceutical research, a branch that has become more and more interesting is phytochemistry. Among phytochemicals, flavonoids have been studied a lot over the past 30 years. This review summarizes the chemical characteristics, metabolism, applications, and toxicity of a particular flavonoid, chrysin, recorded in the last 10 years and supported by solid biological assays. Furthermore, this review highlights some derivatives of chrysin investigated to obtain more bioavailable molecules that maintain or improve chrysin's bioactivities, enclosing a chrysin patent section, as well.

Case report: Goiter and overt hypothyroidism in an iodine-deficient toddler on soy milk and hypoallergenic diet.

Soy-based infant formulas (SFs) are often consumed by cow's milk allergic children. However, some concerns have risen since soy intake may adversely affect thyroid function in iodine-deficient or subclinical hypothyroid individuals. We report the first Italian case of SF induced goiter and hypothyroidism registered in our country since National Iodine program has been instituted. Finally, we review cases previously reported in literature. A 22-month-old toddler with a previous diagnosis of cow's milk protein allergy came to clinical attention for important goiter and overt hypothyroidism. Detailed dietary anamnesis revealed that he was on a restrictive dietary regimen based on soymilk since 12 months of age. A temporary levothyroxine substitution was instituted to avoid hypothyroidism complications. Adequate iodine supplementation and diet diversification completely reversed SF-induced hypothyroidism and goiter, confirming the diagnostic suspicion of soymilk-induced thyroid dysfunction in a iodine-deficient toddler. This case report demonstrates the importance of careful dietary habits investigation and adequate micronutrients supplementation in children on a restrictive diet due to multiple food allergies in order to prevent nutritional deficits.

Nanotechnologies: An Innovative Tool to Release Natural Extracts with Antimicrobial Properties.

Site-Specific release of active molecules with antimicrobial activity spurred the interest in the development of innovative polymeric nanocarriers. In the preparation of polymeric devices, nanotechnologies usually overcome the inconvenience frequently related to other synthetic strategies. High performing nanocarriers were synthesized using a wide range of starting polymer structures, with tailored features and great chemical versatility. Over the last decade, many antimicrobial substances originating from plants, herbs, and agro-food waste by-products were deeply investigated, significantly catching the interest of the scientific community. In this review, the most innovative strategies to synthesize nanodevices able to release antimicrobial natural extracts were discussed. In this regard, the properties and structure of the starting polymers, either synthetic or natural, as well as the antimicrobial activity of the biomolecules were deeply investigated, outlining the right combination able to inhibit pathogens in specific biological compartments.

In vitro anti-proliferative and anti-bacterial properties of new C7 benzoate derivatives of pinocembrin.

In the present work, the in vitro anti-proliferative and anti-bacterial activities of three semi-synthetic benzoate pinocembrin derivatives, isolated from the aerial parts of Glycyrrhiza glabra L., were investigated. As occurs in most natural compounds, the bioavailability of pinocembrin is very poor, therefore it should be improved by chemical strategies aimed to prolong its shelf life and, consequently, its activity. On this basis, three benzoate derivatives of pinocembrin (a1-a3) were synthesised and assayed in order to ascertain their biological value. Among them, compound a1 showed the highest anti-proliferative activity on a wide panel of cancer cell lines, as well as low toxic effects on non-malignant breast cells. The calculated IC50 values in HeLa and SKBR3 cells were 8.5 and 12.7 µM, respectively. Briefly, a1 treatment increased ROS levels, induced mitochondrial membrane damage leading to necrotic death of HeLa cells. Moreover, a1 displayed a promising anti-bacterial activity.

Exploration of piperazine-derived thioureas as antibacterial and anti-inflammatory agents. In vitro evaluation against clinical isolates of colistin-resistant Acinetobacter baumannii.

A. baumannii is one of the most important multidrug-resistant microorganisms in hospital units. It is resistant to many classes of antibiotics and the development of new therapeutic strategies is necessary. The aim of this study was to evaluate the antibacterial activity of a set of piperazine-derived thioureas against 13 clinical strains of colistin-resistant A. baumannii. Six derivatives were identified to inhibit bacterial growth of 46% of the A. baumannii strains at low micromolar concentrations (Minimum Inhibitory Concentration from 1.56 to 6.25 µM). A common structural feature in most active compounds was the presence of a 3,5-bis-trifluoromethyl phenyl ring at the thiourea function. In addition, the ability of the compounds to inhibit production of nitric oxide (NO) was examined in RAW 264.7 murine macrophages, highlighting the potential of piperazine-derived thioureas as promising scaffolds for the design of new combined anti-bacterial/anti-inflammatory agents.

A Walk in Nature: Sesquiterpene Lactones as Multi-Target Agents Involved in Inflammatory Pathways.

Inflammatory states are among the most common and most treated medical conditions. Inflammation comes along with swelling, pain and uneasiness in using the affected area. Inflammation is not always a simple symptom; more often is part of a defensive response of the body to an external threat or is a sign that the damaged tissue has not healed yet and needs to rest. The management of the pain associated with an inflammatory state could be a tricky task. In fact, most remedies simply quench the pain, leaving the inflammatory state unaltered. This review focuses on sesquiterpene lactones, a class of natural compounds, that represents a future promise in the treatment of inflammation. Sesquiterpene lactones are efficient inhibitors of multiple targets of the inflammatory process. Their natural sources are often ancient remedies with relevant traditional uses in folk medicines. This work also aims to elucidate how these compounds may represent the starting material for the development of new anti-inflammatory drugs.

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from Artemisia californica has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family. Leucodin, α-santonin and sclareolide (three SLs) were chosen to undergo chemical modifications. This pool of molecules underwent molecular modeling experiments using an in-house program, WATGEN, predicting the water network and its contribution to the overall affinity of the enzyme-ligand complex. The anti-inflammatory activity and the ability of compounds to modulate COX-2 expression have been evaluated in LPS-stimulated RAW 264.7 cells and in RIF-1 cells treated according to the Photodynamic Therapy (PDT) protocols using Photoprin (PH) as photosensitizer. Furthermore, commercially available assay kits were used to evaluate the concentration of PGE-2 and the direct inhibition of COX-2. All the tested molecules fit well in the enzyme binding pocket, but to get a substantial inhibition of the expression and activity of the enzyme as well as a reduction in the PGE2 concentration, high concentrations of the compounds are needed. The only exceptions being leucodin itself and FP6, one of the α-santonin derivatives, presenting a CF3 functional group. We believe that this class of compounds has some interesting potential in the treatment of pain and inflammation. Although, the activity seems to be due to a mechanism related to the expression of the COX enzymes rather than on a direct inhibition.

Evaluation of the In Vitro Wound-Healing Activity of Calabrian Honeys.

The healing of skin wounds and particularly chronic wounds, such as diabetic foot ulcers, is still a clinical emergency. Despite the many therapeutic tools that are available so far, none seems to be really effective and safe. In this context, we highlighted the renewed wound healing activity of honey, a viscous aromatic and sweet food, by way of in vitro wound-healing assays, using the HaCaT cell line. Specifically, we investigated five monofloral or multifloral honeys from different Calabrian provinces using them as such or extracted (by Amberlite® or n-hexane and ethyl acetate). The chemical composition of honeys was ascertained by ¹H NMR spectroscopy and by the gas chromatography/mass spectrometry (GC/MS) method for volatile organic compounds (VOCs). Amongst the five tested honeys, BL1 and BL5 honeys showed the most promising healing properties. Pinocembrin, which was revealed in BL1 (multifloral) and BL5 (orange) honey samples, is a flavanol that is already known to possess interesting biological activities, including healing. This study aims to investigate how a traditional food such as honey, which is appreciated for its nutritional value and used in folk medicine, can be enhanced as an effective modern remedial to promote a multifaceted and safe healing activity for all skin wounds.

Advances in the Tyrosinase Inhibitors from Plant Source.

Tyrosinase is a multifunctional copper-containing oxidase which catalyses the oxidation of tyrosine to produce melanin. The alteration in melanin biosynthesis occurs in many diseases. The pigment has a protecting role against skin photo-carcinogenesis, but anomalous melanin pigmentation is an aesthetic problem in human beings. Moreover, the formation of neuromelanin in human brain could contribute to the neurodegeneration associated with Parkinson's disease. Finally, tyrosinase is also responsible for undesired browning in fruits and vegetables. These topics encouraged the search for new inhibitors of this enzyme for pharmaceutical, cosmetic and foods industries. This review is to report recent trends in the discovery of tyrosinase inhibitors from plant sources, to provide a rationale for the continued study of natural tyrosinase inhibitors, and to recognise the potential therapeutic rewards associated with the identification of these agents.

Quercetin and its Natural Sources in Wound Healing Management.

Giving a glance to the report of Wound Care Market by Product updated in 2017, we can see that wound care market is expected to reach USD 22.01 billion by 2022 from USD 18.35 billion at a CAGR of 3.7%. Numerous factors are driving the growth of this market, including the increasing prevalence of chronic wounds and acute wounds, increasing aged population, rising R&D activities and advancement in the field of wound care research. Advanced wound management products are accounted for the largest market share in 2017. These evidences mean that the wound care research represents a Clinical Emergency other than an interesting Marketing tool. Drug therapies so far fight efficaciously with the opportunistic pathologies derived from chronic wounds, although an unsolved challenge is still finding a useful remedy to correct the impaired wound healing process and overcome the chronic wound state, to avoid bacterial rising and severe pain. Traditional medicinal plants have been widely used in the management of wounds and different plant extracts have been evaluated for their wound healing properties through both in vitro and in vivo studies. Their phytochemical components in particular quercetin, contribute to their remedial properties in wound repair. Quercetin has important biological activities related to the improvement of the wound healing process. The present review discusses and focuses on the latest findings of the wound healing properties of quercetin, alone or as a part of plant extract, and its role as a new frontier in wound repair.

From Vegetable Waste to New Agents for Potential Health Applications: Antioxidant Properties and Effects of Extracts, Fractions and Pinocembrin from Glycyrrhiza glabra L. Aerial Parts on Viability of Five Human Cancer Cell Lines.

Glycyrrhiza glabra cultivation and harvesting produces substantial quantities of aerial parts as waste. With the aim to prospect an innovative valorization of these byproducts, the aerial parts were harvested in May and October and analyzed for their chemical profile, antioxidant properties, and effects on viability of five cancer cell lines. Pinocembrin was the main constituent. A significant protection of lipid peroxidation was observed with the May total extract (IC50 of 4.2 ± 0.4 µg/mL at 30 min of incubation). The effects on viability of HeLa, MCF-7, MDA-MB-231, Caco-2, and PC3 human cancer cells were investigated. All samples shown a remarkable activity with IC50 values below 25 µg/mL. Samples from plants harvested in May exhibited greater activity than those harvested in October. MCF-7 and HeLa were the most sensitive cells with IC50 in the range 2.73-3.01 and 3.28-5.53 µg/mL, respectively. G. glabra aerial parts represent a good source of valuable products.

From the hive: Honey, a novel weapon against cancer.

Nowadays there is a folk medicine branch called apitherapy that aims to treat diseases with bee products, including honey. Honey has long been known for its medicinal and health promoting properties. It encloses numerous types of phytochemicals with high phenolic and flavonoid content, which contribute to its antioxidant and anti-inflammatory activities. Varieties and variants of polyphenols in honey showed antiproliferative property against several types of cancer. This review focuses on the latest discoveries about the key role of honey in different stages of carcinogenesis, initiation, proliferation and progression, both in vitro and in vivo, as well as on its adjuvant effect in cancer therapy. Although a possible application of honey and its active compounds as drugs against cancer is still far away from clinical practice, scientific results highlight that they could be used as immune booster for patients undergoing chemotherapy. They showed protective effects against the common exasperating and disabling side effects, mostly mucositis.

Anti-inflammatory and Antioxidant Agents from Salvia Genus (Lamiaceae): An Assessment of the Current State of Knowledge.

BACKGROUND: Salvia species are known for their biological properties in many countries and might potentially provide novel therapeutic agents. This review provides an overview of the available literature on the anti-inflammatory and antioxidant effects of Salvia species. METHODS: Using bibliographic databases, particularly PubMed, this review aims to add new information to the list of Salvia species, including S. ceratophylla, S. chloroleuca, S. fruticosa, S. lachostachys, S. lavandulifolia, S. miltiorrhiza, S. mirzayanii, S. officinalis, S. plebeia, S. verbenaca, and S. virgata, and their main constituents as promising antiinflammatory and antioxidant agents, highlighting their mode of action. RESULTS: Salvia species are sources of health-promoting phytochemicals that comprise polyphenols, flavonoids, terpenes and several other constituents. Many studies have indicated that plants from the Salvia genus reduce the oxidative stress and may be able to prevent and/or to treat inflammatory diseases. These potential beneficial effects have been attributed to the presence of compounds that show antioxidant properties and that demonstrated to inhibit the molecular targets of pro-inflammatory mediators in inflammatory responses. CONCLUSION: Salvia species and their secondary metabolites may be potential agents to improve the quality of life in patients with inflammatory diseases.

Quercetin and derivatives: useful tools in inflammation and pain management.

Inflammation represents a very frequent condition in humans; it is often underestimated, making the problem an increasingly alarming phenomenon. For these reasons, conventional therapies are losing their effectiveness, leaving room for innovative therapies. In this field, natural products showed their efficacy in various diseases; and flavonoids, in particular quercetin, is known for its broad range of activities. In this review, we have highlighted its efficacy in various models of inflammation, focusing also on the activity of its semisynthetic derivatives, and those naturally present in plant extracts. Finally, the analgesic property of quercetin, intrinsically linked to its anti-inflammatory action, has been also evaluated, to investigate about an innovative approach to this interesting natural compound, such as analgesic remedial.

Synthesis and biological evaluation of novel hydrazide based cytotoxic agents.

Recently, we designed and synthesized a series of pyrroloquinoxaline compounds with hydrazine moiety linking a nitrogen-containing polycyclic group to a heteroaroyl system. Several derivatives, with attractive drug-like properties, were identified as promising cytotoxic agents, showing excellent potency in a panel of cancer cell lines. In the current study, we synthesized a further 19 new analogues to optimize their physicochemical properties and assess a coherent mechanism of action. Several chemical modifications were made to the reference compounds by varying the fused-ring system and/or the heteroacyl moiety. To evaluate their in vitro activity, we tested these compounds in six human cancer cell lines derived from different origins. Among them, two compounds ( 9 and 12 ) showed similar potency as the reference compounds with IC(50) values in the sub-micromolar range in all cell lines tested. Furthermore, compound 12 showed excellent in vivo efficacy in our preliminary human ovarian cancer mouse xenograft studies. Flow cytometric studies indicated that both derivatives interrupted cell cycle progression in colorectal cancer HCT116 cell lines and ovarian cancer SKOV-3 cells. Further mechanistic studies revealed that 9 and 12 were able to induce reactive oxygen species in SKOV-3 cells with apparently different kinetic patterns. Considering their cytotoxicity profiles in a variety of in vitro and in vivo cancer models, these hydrazide based compounds seem to have considerable potentials as novel chemotherapeutics.