Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

BACKGROUND: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. METHODS: For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. RESULTS: The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. CONCLUSIONS: In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases

Trypanosomatid-caused conditions: State of the art of therapeutics and potential applications of lipid-based nanocarriers

Trypanosomatid-caused conditions (African trypanosomiasis, Chagas disease, and leishmaniasis) are neglected tropical infectious diseases that mainly affect socioeconomically vulnerable populations. The available therapeutics display substantial limitations, among them limited efficacy, safety issues, drug resistance, and, in some cases, inconvenient routes of administration, which made the scenarios with insufficient health infrastructure settings inconvenient. Pharmaceutical nanocarriers may provide solutions to some of these obstacles, improving the efficacy–safety balance and tolerability to therapeutic interventions. Here, we overview the state of the art of therapeutics for trypanosomatid-caused diseases (including approved drugs and drugs undergoing clinical trials) and the literature on nanolipid pharmaceutical carriers encapsulating approved and non-approved drugs for these diseases. Numerous studies have focused on the obtention and preclinical assessment of lipid nanocarriers, particularly those addressing the two currently most challenging trypanosomatid-caused diseases, Chagas disease, and leishmaniasis. In general, in vitro and in vivo studies suggest that delivering the drugs using such type of nanocarriers could improve the efficacy–safety balance, diminishing cytotoxicity and organ toxicity, especially in leishmaniasis. This constitutes a very relevant outcome, as it opens the possibility to extended treatment regimens and improved compliance. Despite these advances, last-generation nanosystems, such as targeted nanocarriers and hybrid systems, have still not been extensively explored in the field of trypanosomatid-caused conditions and represent promising opportunities for future developments. The potential use of nanotechnology in extended, well-tolerated drug regimens is particularly interesting in the light of recent descriptions of quiescent/dormant stages of Leishmania and Trypanosoma cruzi, which have been linked to therapeutic failure.Fil: Muraca, Giuliana Sabrina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Ministerio de Salud. Administración Nacional de Medicamentos, Alimentos y Tecnología Médica; ArgentinaFil: Rivero Berti, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Sbaraglini, Maria Laura. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Fávaro, Wagner J.. Universidade Estadual Do Campinas. Instituto de Biologia. Departamento de Biologia Estructural y Funcional.; BrasilFil: Durán, Nelson. Universidade Estadual Do Campinas. Instituto de Biologia. Departamento de Biologia Estructural y Funcional.; Brasil. Universidad Federal do Abc; BrasilFil: Castro, Guillermo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Characterization Of Chemically Induced Ovarian Carcinomas In An Ethanol-preferring Rat Model: Influence Of Long-term Melatonin Treatment.

Ovarian cancer is the fourth most common cause of cancer deaths among women, and chronic alcoholism may exert co-carcinogenic effects. Because melatonin (mel) has oncostatic properties, we aimed to investigate and characterize the chemical induction of ovarian tumors in a model of ethanol-preferring rats and to verify the influence of mel treatment on the overall features of these tumors. After rats were selected to receive ethanol (EtOH), they were surgically injected with 100 µg of 7,12-dimethyl-benz[a]anthracene (DMBA) plus sesame oil directly under the left ovarian bursa. At 260 days old, half of the animals received i.p. injections of 200 µg mel/100 g b.w. for 60 days. Four experimental groups were established: Group C, rats bearing ovarian carcinomas (OC); Group C+EtOH, rats voluntarily consuming 10% (v/v) EtOH and bearing OC; Group C+M, rats bearing OC and receiving mel; and Group C+EtOH+M, rats with OC consuming EtOH and receiving mel. Estrous cycle and nutritional parameters were evaluated, and anatomopathological analyses of the ovarian tumors were conducted. The incidence of ovarian tumors was higher in EtOH drinking animals 120 days post-DMBA administration, and mel efficiently reduced the prevalence of some aggressive tumors. Although mel promoted high EtOH consumption, it was effective in synchronizing the estrous cycle and reducing ovarian tumor mass by 20%. While rats in the C group displayed cysts containing serous fluid, C+EtOH rats showed solid tumor masses. After mel treatment, the ovaries of these rats presented as soft and mobile tissues. EtOH consumption increased the incidence of serous papillary carcinomas and sarcomas but not clear cell carcinomas. In contrast, mel reduced the incidence of sarcomas, endometrioid carcinomas and cystic teratomas. Combination of DMBA with EtOH intake potentiated the incidence of OC with malignant histologic subtypes. We concluded that mel reduces ovarian masses and the incidence of adenocarcinomas in ethanol-deprived rats.8e8167

Multi-target drug with potential applications: violacein in the spotlight

The aim of the current review is to address updated research on a natural pigment called violacein, with emphasis on its production, biological activity and applications. New information about violacein’s action mechanisms as antitumor agent and about its synergistic action in drug delivery systems has brought new alternatives for anticancer therapy. Thus, violacein is introduced as reliable drug capable of overcoming at least three cancer hallmarks, namely: proliferative signaling, cell death resistance and metastasis. In addition, antimicrobial effects on several microorganisms affecting humans and other animals turn violacein into an attractive drug to combat resistant pathogens. Emphasis is given to effects of violacein combined with different agents, such as antibiotics, anticancer agents and nanoparticles. Although violacein is well-known for many decades, it remains an attractive compound. Thus, research groups have been making continuous effort to help improving its production in recent years, which can surely enable its pharmaceutical and chemical application as multi-task compound, even in the cosmetics and food industries.Fil: Durán, Nelson. Universidade Estadual de Campinas; BrasilFil: Nakazato, Gerson. Universidade Estadual de Londrina; BrasilFil: Durán, Marcela. Universidade Estadual de Campinas; BrasilFil: Rivero Berti, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Castro, Guillermo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Stanisic, Danijela. Universidade Estadual de Campinas; BrasilFil: Brocchi, Marcelo. Universidade Estadual de Campinas; BrasilFil: Fávaro, Wagner J.. Universidade Estadual de Campinas; BrasilFil: Ferreira Halder, Carmen V.. Universidade Estadual de Campinas; BrasilFil: Justo, Giselle Z.. Universidade Federal de Sao Paulo.; BrasilFil: Tasic, Ljubica. Universidade Estadual de Campinas; Brasi

Interlab study on nanotoxicology of representative graphene oxide

The graphene sample GO: Single-layer graphene oxide, purity 99%, thickness 0.7-1.2 nm (AFM); similar to 300-800nm X&Y dimensions is the standard size 50 mu g/mL) were observed. Genotoxic study using the Comet assay showed slight DNA damage in lymphocytes at all concentrations tested, while more significant effects was observed in CHO cells. Econanotoxicity was carried out by lethality assays in the nematode Caenorhabditis elegans, d in the freshwater coelenterate Hydra, Daphania amd in Shrimp with no signs of toxicity at concentrations varying from 0.1-100 mu g/mL of GO. However, death and disintegration of Hydra was observed after exposition to 100 mu g/mL for 72 h. In in vivo studies, no changes in biochemical parameters of Fischer 344 rats were observed after the i. p. administration of GO. Some black agglomerates were found in the intraperitoneal cavity of rats injected with GO. However, in Fisher 344 rats-bearing prostate tumors, treatment with GO (up to 100 mu g/mL) negatively affected the hepatic parameters, whilst in the renal ones, an improvement was observed. Studies are in progress to understand the mechanisms involved in the uptake of GO by RES. GO appears as a potential non-toxic in vitro and in vivo assays at the concentrations used in this interlab experiments.The graphene sample GO:Single-layer graphene oxide, purity 99%, thickness 0.7-1.2 nm (AFM); ~300-800nm X&Y dimensions is the standard size <450 nm & 1-20 μm lateral dimensions. Cheap Tubes Inc., Bratleboro, USA was selected for our study. Exhaustive chara617CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOsem informaçãosem informação4th International Conference on Safe Production and Use of NanomaterialsSupport from the Brazilian Network of Nanotoxicology (CIGENANOTOX) (MCTI/CNPq), INOMAT (MCTI/CNPq), NanoBioss (MCTI) and FAPESP are acknowledged

Nanopharmaceuticals and Their Applications in Bladder Cancer Therapy: a Mini Review

<div><p>The primary treatment for high-grade non-muscle invasive bladder cancer (NMIBC) is based on surgery by transurethral resection of bladder tumor (TURBT), followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) to prevent recurrence and to reduce the tumor progression. However, BCG therapy shows several undesirable effects. The current treatment on NMIBC is doxorubicin (DOX), but with high toxicity. Our nanotechnology strategy was done through scaffolds for the NMIBC treatment: graphene oxide (GO) and a nanostructured lipid carrier (NLC). A GO hybrid for administration of DOX and small interfering RNA (siRNA) was developed. This hybrids administered in vivo against NMIBC in rats gave absence of lesions. NLC was prepared by using a mixture of two lipids stabilized by a surfactant and DOX by high homogenization pressure technique. In this case showed a 20% of the animals exhibited benign lesions (papillary hyperplasia), however, in the presence of siRNA reached 40% of rats with benignant lesions. These two scaffolds are potential new drugs for DOX for bladder cancer treatment without any cardiotoxicity problems.</p></div

The Action of Platelet-Rich Plasma (PRP) in Cardiovascular Disease Treatment

Atherosclerosis, or coronary artery disease, is an inflammatory disorder capable of affecting large arteries. It is also the main cause of cardiovascular disease and stroke, and its main causative factors lie on lipid accumulation in, and inflammation of, large arteries. The aim of the current study is to investigate the need of conducting better therapeutic assessments in more clinically relevant animal models of ischemic stroke, as well as the action of platelet rich plasma in modulating inflammatory processes in cardiac injury cases

Violacein, A Microbial Antiviral Product: Does Play Key Role as Active Agent Against SARS-CoV-2?

Violacein, a microbial product was characterized after continuous attempts to feature it, based on degradation and synthesis procedures, at the University of Liverpool (England), from 1958 to 1960 and only at 2001 was chemically synthesized. It is a quite known antimicrobial and antiviral natural product. New attempts to solve the infection caused by, or find the proper therapy for, COVID19, must adopt multidisciplinary approach. The aim of the current study is to address the targets, possible strategies and perspectives of new technologies and therapies on COVID19. It also hypothesizes the potential of using the therapeutic drug called violacein as multifunctional agent to treat patients at different COVID19 contamination stages. Our experience and knowledge about violacein has led us to extrapolate the potential use of this pigment.  Violacein multiple biological activities as also knowledge on its toxicity and antiviral activity enabled suggesting that it could be the new important agent used to treat COVID19.  Violacein is highly likely to act as protease inhibitor, at ACE2 receptor level and as immunotherapeutic drug against Covid19. In term of chemotherapy, it will be discussed the actual antiviral used against COVID19, such as, thalidomide, ivermectin and melatonin, among others

NANOTOXICOLOGIA DE NANOPARTÍCULAS DE PRATA: TOXICIDADE EM ANIMAIS E HUMANOS

Silver nanoparticles (AgNPs) have important antimicrobial activity. These nanoparticles are present in several commercial products, leading to human and environmental exposure. This review presents a critical view of the toxic effects of Ag NPs on in vitro and in vivo biological models. It is noteworthy that the toxicity of AgNPs is dependent on several parameters, such as the preparation mode of the colloidal suspension of the nanoparticles, their state of aggregation, the chemical nature of the nanoparticles, surface size, morphology, dose, cell type, nature of the living organism, among others. In general, low concentrations of AgNPs do not present significant toxicity in in vitro and in vivo assays, however with the increase of the concentration of AgNPs there is a significant increase of nanoparticle toxicity and its accumulation in diverse tissues/organs. It should be emphasized that in living organisms, exposure routes should be taken into account, such as ingestion and inhalation. At high concentrations, inhalation or ingestion of AgNPs can cause adverse effects and even lead to human death. In this context, the importance of further studies of the toxicity of AgNPs in several in vitro and in vivo models is emphasized