Design, synthesis and evaluation of benzothiazole derivatives as multifunctional agents.

Oxidative stress is the product or aetiology of various multifactorial diseases; on the other hand, the development of multifunctional compounds is a recognized strategy for the control of complex diseases. To this end, a series of benzothiazole derivatives was synthesized and evaluated for their multifunctional effectiveness as antioxidant, sunscreen (filter), antifungal and antiproliferative agents. Compounds were easily synthesized via condensation reaction between 2-aminothiophenols and different benzaldehydes.

A New Approach to UV Protection by Direct Surface Functionalization of TiO with the Antioxidant Polyphenol Dihydroxyphenyl Benzimidazole Carboxylic Acid.

Skin cancer is the most common malignant cancer with an incidence of 1 million cases/year. It is well known that exposure to UV radiation from sunlight leads the most frequent risk factors for several skin disorders including skin cancer. Sunscreen filters represent a valid protection against dangerous effects derived from UV radiation, and they can be divided in organic and inorganic UV filters.

Synthesis and Characterization of New Multifunctional Self-Boosted Filters for UV Protection: ZnO Complex with Dihydroxyphenyl Benzimidazole Carboxylic Acid.

The incidence of skin cancer is increasing both because of climate change and the increase in pollution than people's incorrect habits of sun exposure. In these regards, sunscreen and photoprotection are essential tools in consenting the benefits induced by safe solar light exposition and skin cancer prevention. In this work, a new class of sunscreen filter was synthesized by chemical combination of a physical filter (ZnO) and Oxisol (dihydroxyphenyl benzimidazole carboxylic acid), an antioxidant molecule with booster effect.

Moringa oleifera Leaf Extracts as Multifunctional Ingredients for "Natural and Organic" Sunscreens and Photoprotective Preparations.

has gained increasing popularity as a food supplement but not in the pharmaceutical and cosmetic area. The aim of this study was the preparation, characterization, and evaluation of extracts from the leaves of as a herbal sun care phytocomplex. Three different extracts of leaves, from Senegal, have been prepared and chemically characterized in the phenolic fraction by HPLC-DAD and Folin-Ciocalteu test.

A Multitarget Approach toward the Development of 8-Substituted Purines for Photoprotection and Prevention of UV-Related Damage.

Ultraviolet (UV) light is the most abundant and significant modifiable risk factor for skin cancer and many other skin diseases such as early photo-aging. Across the solar radiation spectrum, UV light is the main cause behind skin problems. In the search for novel photoprotective compounds, a new series of 8-substituted purines were synthesized from commercially available 6-hydroxy-4,5-diaminopyrimidine hemisulfate or 4,5-diaminopyrimidine.

Design, synthesis and biological evaluation of novel hydroxy-phenyl-1H-benzimidazoles as radical scavengers and UV-protective agents.

An ever-increasing incidence of skin neoplastic diseases is registered. Therefore, it is important to protect the skin from the UV radiation that reaches the epidermis and dermis but also to block ROS generated by them. Our attention was attracted in developing new compounds provided with both UV filtering and antioxidant capacities.

Factors affecting SPF in vitro measurement and correlation with in vivo results.

Objective: The in vitro evaluation of SPF is still a problem due to the lack of repeatability and correlation between the in vitro and in vivo data, and many authors are currently working to develop an internationally harmonized method. Very recently, the use of several "adjuvant" ingredients such as boosters, antioxidants, immunomodulators, solvents and film-forming ingredients have further complicated the pattern for product developers that should frequently run in vivo test. The aim of this study was to understand whether a simple and cheap in vitro method could be optimized in order to provide both statistically repeatable and predictive SPF measurement.

Herbal extracts, lichens and biomolecules as natural photo-protection alternatives to synthetic UV filters. A systematic review.

Besides the unquestionable positive effects of solar exposure for human health, UV rays have been widely investigated for toxicology aspects related to excessive UVB and UVA doses, which involve sunburns, skin aging, DNA skin damage and tumorigenesis. At present, synthetic and mineral sunscreens are used to protect against these damages but several natural molecules can provide UV protection, including also synergic effect or enhanced photo stability. Although a large number of herbal extracts and plant origin molecules can deserve potential applications, most of the study reported utilizes different method and different strategies of investigation, making thus difficult to understand the real versus claimed potential.

Particulate adducts based on sodium risedronate and titanium dioxide for the bioavailability enhancement of oral administered bisphosphonates.

Adducts based on a bisphosphonate drug (sodium risedronate) and titanium dioxide (TiO(2)) particles have been developed and characterized in order to improve the bioavailability of orally administrated bisphosphonates. Nanocrystalline and colloidal TiO(2), both characterized by powder X-ray diffraction, were used to obtain the adducts 1 and 2, respectively. Adducts 1 and 2 appeared constituted by nanoparticles of about 50nm and 90nm grouped in clusters of about 0.

Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade.

Purpose: CTL-associated antigen 4 (CTLA4)-blocking monoclonal antibodies induce long-term regression of metastatic melanoma in some patients, but the exact mechanism is unknown. In this study, biopsies of selected accessible tumor lesions from patients treated with tremelimumab were examined to further elucidate the mechanism of its antitumor activity.

Experimental Design: Fifteen tumor biopsies from 7 patients who had been treated with tremelimumab (CP-675,206) were collected.

Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.

We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally.

A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides.

Alpha-fetoprotein (AFP) is a self protein expressed by fetal liver at high levels, but is transcriptionally repressed at birth. AFP is up-regulated in hepatocellular carcinomas, and patients with active disease could have plasma levels as high as 1 mg/mL. We previously identified four immunodominant HLA-A*0201-restricted peptides [hAFP(137-145) (PLFQVPEPV), hAFP(158-166) (FMNKFIYEI), hAFP(325-334) (GLSPNLNRFL), and hAFP(542-550) (GVALQTMKQ)] derived from human AFP that could stimulate specific T cell responses in healthy donor peripheral blood lymphocytes in vitro.

Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade).

Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more sensitive to immune effector cells. We established a murine model to test whether the proteasome inhibitor bortezomib could sensitize established B16 melanoma tumors to dendritic cell (DC)-activated immune effector cells. Day 3-established s.

Broad antitumor protection by dendritic cells administered to CD8alpha knock out mice.

Dendritic cell (DC) administration to CD8alpha knock-out (CD8alphaKO) mice results in a strong antigen-non-specific protection to a B16 murine melanoma tumor challenge. This response is mediated by lytic NK cells and cytokine-producing CD4 cells. We aimed to determine the signals that guide tumor targeting of this response.

Natural killer cells play a critical role in the immune response following immunization with melanoma-antigen-engineered dendritic cells.

Tumor antigen gene-modified dendritic cells (DC) generates robust antigen-specific protective antitumor responses. Though the role of CD4 positive and CD8 positive cells in the immunological response to gene-modified DC has been well-characterized, the role of NK cells in this response has been somewhat less clear. Owing to the significant contribution of innate immunity in other model systems, we postulated that NK cells would hold a critical position in the generation of an immune response following immunization with tumor antigen-engineered DC.

Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy.

MART-1(27-35)-peptide-pulsed immature dendritic cells (DCs) resulted in immunologic and clinical activity in a prior phase 1 trial. A phase 2 cohort expansion was initiated to further characterize the phenotype and cytokine milieu of the DC vaccines and their immunologic activity in vitro and to further examine a possible link between clinical activity and determinant spreading. In an open-label phase 2 trial, 10(7) autologous ex vivo generated DCs pulsed with the HLA-A*0201 immunodominant peptide MART-1(27-35) were administered to 10 subjects with stage II-IV melanoma.

Human dendritic cell maturation by adenovirus transduction enhances tumor antigen-specific T-cell responses.

Dendritic cells (DCs) have been shown to require a degree of maturation to stimulate antigen-specific, type 1 cytotoxic T lymphocytes in numerous murine models. Limited data in humans suggest that immature DCs (DC) can induce tolerance, yet a variety of nonmatured DC used clinically have induced antigen-specific type 1 T cells in vivo to various tumor-associated antigens. Use of adenovirus to engineer DCs is an efficient method for delivery of entire genes to DC, but the data on the biologic effects of viral transduction are contradictory.

Enhanced tumor responses to dendritic cells in the absence of CD8-positive cells.

Wild-type mice immunized with MART-1 melanoma Ag-engineered dendritic cells (DC) generate strong Ag-specific immunity that has an absolute requirement for both CD8(+) and CD4(+) T cells. DC administration to CD8 alpha knockout mice displayed unexpectedly enhanced levels of protection to tumor challenge despite this deficiency in CD8(+) T cells and the inability to mount MHC class I-restricted immune responses. This model has the following features: 1) antitumor protection is Ag independent; 2) had an absolute requirement for CD4(+) and NK1.

T-cell responses to HLA-A*0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer.

Purpose: An existing immunological paradigm is that high concentrations of soluble protein contribute to the maintenance of peripheral tolerance/ignorance to self protein. We tested this hypothesis in a clinical immunotherapy trial using class I-restricted peptide epitopes derived from alpha-fetoprotein (AFP). AFP is a self protein expressed by fetal liver at high levels, but transcriptionally repressed at birth.

Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma.

Purpose: The purpose of this study was to determine the toxicity and immunological effects of three different doses and two routes of administration of autologous dendritic cells (DCs) pulsed with the MART-1(27-35) immunodominant epitope.

Experimental Design: Eighteen HLA-A*0201-positive subjects with stage III-IV melanoma received three biweekly i.v.

Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene-modified dendritic cell vaccines.

Genetic immunotherapy with tumor antigen gene-modified dendritic cells (DC) generates robust immunity, although antitumor protection is not complete in all models. Previous experience in a model in which C57BL/6 mice immunized with DC transduced with adenoviral vectors expressing MART-1 demonstrated a 20-40% complete protection to a tumor challenge with B16 melanoma cells. Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in naïve mice.

CD40 cross-linking bypasses the absolute requirement for CD4 T cells during immunization with melanoma antigen gene-modified dendritic cells.

Genetic immunization of mice with dendritic cells (DCs) engineered to express a melanoma antigen generates antigen-specific, MHC-restricted, CD4-dependent protective immune responses. We wanted to determine the role of CD4 cells and CD40 ligation of MART-1 gene-modified DC in an animal model of immunotherapy for murine melanoma. CD4 knock-out (CD4KO) or antibody-depleted mice were immunized with DC adenovirally transduced with the MART-1 gene (AdVMART1/DC) with or without CD40 cross-linking.

alpha-Fetoprotein-specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination.

alpha-Fetoprotein (AFP) is a potential target for immunotherapy in hepatocellular carcinoma; both the murine and human T-cell repertoires can recognize AFP-derived epitopes in the context of the MHC. Protective immunity can be generated with AFP-engineered dendritic cell-based vaccines. We now report a DNA-based immunization strategy using a prime-boost approach: coadministration of plasmid DNA encoding murine AFP and murine granulocyte-macrophage colony-stimulating factor followed by boosting with an AFP-expressing nonreplicating adenoviral vector.

Fine specificity analysis of an HLA-A2.1-restricted immunodominant T cell epitope derived from human alpha-fetoprotein.

Human alpha-fetoprotein (AFP) is a potentially important target for the immunotherapy of hepatocellular carcinoma (HCC). AFP(542-550) (GVALQTMKQ) is one of several HLA-A2.1-restricted immunodominant AFP peptides that consistently generate AFP-specific T cell responses in human T cell cultures and in HLA-A2.

T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein.

alpha fetoprotein (AFP)-derived peptide epitopes can be recognized by human T cells in the context of MHC class I. We determined the identity of AFP-derived peptides, presented in the context of HLA-A*0201, that could be recognized by the human (h) T cell repertoire. We screened 74 peptides and identified 3 new AFP epitopes, hAFP(137-145), hAFP(158-166), and hAFP(325-334), in addition to the previously reported hAFP(542-550.