Impact of intravesical instillation of a novel biological response modifier (P-MAPA) on progress of non-muscle invasive bladder cancer treatment in a rat model.

This work describes the effects of immunotherapy with Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride in the treatment of non-muscle invasive bladder cancer in an animal model. NMIBC was induced by treating female Fischer 344 rats with N-methyl-N-nitrosourea. After treatment with MNU, the rats were distributed into four experimental groups: Control (without MNU) group, MNU (cancer) group, MNU-BCG (Bacillus Calmette-Guerin) group, and MNU-P-MAPA group. P-MAPA intravesical treatment was more effective in histopathological recovery from cancer state in relation to BCG treatment. Western blot assays showed an increase in the protein levels of c-Myc, COUP-TFII, and wild-type p53 in P-MAPA-treated rats in relation to BCG-treated rats. In addition, rats treated with P-MAPA intravesical immunotherapy showed the highest BAX protein levels and the lowest proliferation/apoptotic ratio in relation to BCG-treated rats, pointing out a preponderance of apoptosis. P-MAPA intravesical treatment increased the wild-type p53 levels and enhanced c-Myc/COUP-TFII-induced apoptosis mediated by p53. These alterations were fundamental for histopathological recovery from cancer and for suppress abnormal cell proliferation. This action of P-MAPA on apoptotic pathways may represent a new strategy for treating NMIBC.

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.

Patents on Violacein: A Compound with Great Diversity of Biological Activities and Industrial Potential.

BACKGROUND: This review outlines the current impact of violacein-derivative materials in several technological areas through patents. METHODS: A comprehensive examination of patent databases on violacein demonstrated the relevance of this pigment, as well as the pertinent topics related to its technological development in order to obtain adaptable new pharmaceuticals, cosmetics, and new quality fiber materials, together with other applications of violacein in different areas. RESULTS: At present, there is no efficient and economical technique for violacein preparation at the industrial scale. Many attempts have been made, but none have overcome the challenge of being an effective and inexpensive process. However, some potential applications of violacein in fields such as biomedicine make the pigment worthy of continuous investigation. In particular, violacein patents covering biosynthesis for different applications have been reported recently. CONCLUSION: Violacein has been used as a unique pigment in distinct specialty areas, such as in medical and industrial fields. This review of patents provides an update on violacein innovations that are useful for researchers working in the expanding and interesting field of biotechnology with natural pigments.

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.

What is the potential use of platelet-rich-plasma (PRP) in cancer treatment? A mini review.

Platelet-rich-plasma (PRP) is an autologous human platelet concentrate extracted from plasma. PRP has been investigated in order to be used in many fields, with emphasis on the musculoskeletal field applied to sports injuries, as well as on other medical fields such as cardiac surgery, gynecology, pediatric surgery, urology, ophthalmology and plastic surgery. Cancer treatment is another important field where PRP should be investigated; thus, it is important validating PRP preparation protocols to be used in clinical research. Many protocols should be revised since, overall, most studies do not provide necessary information to allow them to be multiplied or replicated. The current review focuses on several topics about cancer, mainly on innovative studies about PRP use as a feasible therapeutic alternative to treat bladder cancer - a field where it could play a key role. Relevant aspects such as platelets' contribution to immune regulation and the supportive role they play in innate and adaptive immune functions are also addressed. Another important topic reviewed in the current study refers to inflammatory process regulation associated with cancer and thrombosis sites, which indicated that tumor-induced platelet activation could be used as an important therapeutic target in the future. New aspects concerning nitric oxide's ability to restrain platelet adhesion and aggregation in order to slow metastasis progress in cancer patients provide an important advantage in cancer treatment. Finally, the current review has pointed out perspectives and the main concerns about, and possibilities of, PRP use in cancer treatment.

Nanostructured platelet-rich plasma: state of art in dental treatments / Plasma-rico em plaquetas nanoestruturado: estado da arte nos tratamentos dentais

Objectives: Reviewing information available about platelet-rich plasma (PRP) applied to dental treatments, introducing the general concept of PRP, as well as analyzing actual data about, and challenges faced by, the dental field. Data & sources: The current study analyzed the most informative publications about PRP application available in this field and gathered the maximum information about it as possible. Conclusions: PRP use, either alone or in association with other biomaterials, can significantly favor different fields such as tissue engineering, since it is an innovative technique that attracts the interest of clinicians and basic scientists. However, it is necessary conducting better designed and controlled experiments to enable successful tissue healing based on PRP use. Clinical significance: The current review can be used by clinicians as source of information about the actual rules and protocols adopted in the herein addressed field, besides providing specific examples of such applications. (AU)

Objetivos: Revisar as informações disponíveis sobre o plasma-rico em plaquetas (PRP) aplicado a tratamentos odontológicos, introduzir o conceito geral de PRP e analisar dados reais sobre os desafios enfrentados pelo campo odontológico. Dados e fontes: O presente estudo analisou as publicações mais informativas sobre a aplicação do PRP disponíveis neste campo e reuniu o máximo de informações possível. Conclusões: O uso do PRP, isoladamente ou em associação com outros biomateriais, pode favorecer significativamente diferentes campos, como a engenharia de tecidos, uma vez que é uma técnica inovadora que atrai o interesse de clínicos e cientistas básicos. No entanto, é necessário realizar experimentos mais bem projetados e controlados para permitir a cura bem-sucedida dos tecidos com base no uso do PRP. Significado clínico: A revisão atual pode ser usada pelos médicos como fonte de informações sobre as regras e protocolos atuais adotados no campo aqui tratado, além de fornecer exemplos específicos de tais aplicações.(AU)

Photothermia and Activated Drug Release of Natural Cell Membrane Coated Plasmonic Gold Nanorods and ß-Lapachone.

Plasmonic gold nanoparticles present extraordinary potential for near-infrared photothermal and triggered-therapeutic release treatments of solid tumors. In this study, we create a multifunctional nanocarrier in which PEG-coated gold nanorods are grouped into natural cell membrane vesicles (CM) from lung cancer (A549) cells and loaded with ß-lapachone (CM-ß-Lap-PEG-AuNRs). ß-Lapachone (ß-Lap) is an anticancer agent activated by the enzyme NADP(H):quinine oxidoreductase (NQO1), commonly found at higher levels in cancer cells. The irradiation with near-infrared (NIR) laser leads to disruption of the vesicles and release of the PEG-AuNRs and ß-Lap. The system presents an enhanced in vitro cytotoxicity against A549 cancer cells, which can be attributed to the specific cytotoxicity of ß-Lap combined with heat generated by laser irradiation of the AuNRs. In agreement, in vivo treatment with CM-ß-Lap-PEG-AuNRs and irradiation shows a histopathological recovery from nonmuscle invasive bladder cancer of most of the animals with only one cycle of application and irradiation. Such multifunctional platform is a promissing candidate for improved activated drug release and phototherapy.

Effects of intravesical therapy with platelet-rich plasma (PRP) and Bacillus Calmette-Guérin (BCG) in non-muscle invasive bladder cancer.

This study describes the effects of a promising therapeutic alternative for non-muscle invasive bladder cancer (NMIBC) based on Bacillus Calmette-Guerin (BCG) intravesical immunotherapy combined with Platelet-rich plasma (PRP) in an animal model. Furthermore, this study describes the possible mechanisms of this therapeutic combination involving Toll-like Receptors (TLRs) 2 and 4 signaling pathways. NMIBC was induced by treating female Fischer 344 rats with N-methyl-N-nitrosourea (MNU). After treatment with MNU, the animals were distributed into four experimental groups: Control (without MNU) group, MNU (cancer) group, MNU + PRP group, MNU + BCG group and MNU + PRP + BCG group. Our results demonstrated that PRP treatment alone or associated with BCG triggered significant cytotoxicity in bladder carcinoma cells (HTB-9). Animals treated with PRP associated to BCG clearly showed better histopathological recovery from the cancer state and decrease of urothelial neoplastic lesions progression in 70% of animals when compared to groups that received the same therapies administered singly. In addition, this therapeutic association led to distinct activation of immune system TLRs 2 and 4-mediated, resulting in increased MyD88, TRIF, IRF3, IFN-γ immunoreactivities. Taken together, the data obtained suggest that interferon signaling pathway activation by PRP treatment in combination with BCG immunotherapy may provide novel therapeutic approaches for non-muscle invasive bladder cancer.

Cellulose nanocrystals as carriers in medicine and their toxicities: A review.

Cellulose nanocrystals (CNCs) are crystalline nanoparticles that present myriad applications. CNCs are produced from a variety of renewable sources, and they can be chemically modified. Although there are promising perspectives for introducing CNCs into pharmaceutical formulations, prior to achieving commercial products the influence of many parameters such as extraction and toxicity of the resulting products must be revealed. Since there is great physicochemical flexibility in the steps of obtaining and conjugating CNCs, there are uncountable and complex outcomes from the interactions of those parameters. We present a discussion that helps to unveil the whole panorama on the use of CNCs as drug delivery systems. The methods of producing CNCs are correlated to the resulting nanotoxicity from the cellular to organism level. This review points to relevant concerns that must be overcome to attain safe use of these nanostructures. We also discuss the patents and commercially available products based on CNCs.

Steroid Hormone Receptors as Potential Mediators of the Clinical Effects of Dutasteride: A Prospective, Randomized, Double-Blind Study.

This study characterizes the clinical and morphofunctional effects of a 5α-reductase inhibitor on steroid hormone receptors in normal human prostate tissue, as potential mediators of the clinical effects of dutasteride. This work was a prospective, double-blind, and randomized study that evaluated 49 men aged between 45 and 70 years, with no alterations in a digital rectal examination and prostate-specific antigen measurements between 2.5 and 4.0 ng/mL. These patients underwent prostate biopsy guided by transretal ultrasound with prostate neoplasia being ruled out, and the patients were divided into two groups, with one group receiving dutasteride ( n = 25) and one group receiving a placebo ( n = 24). The patients were clinically assessed each quarter, and at the end of 12 months they underwent new laboratory tests, prostate rebiopsy, and histopathological, immunohistochemical and clinical analyses. The estrogen receptor-beta (ERß) and androgen receptor immunoreactivities were higher, and the proliferation/apoptotic ratio was significantly lower with predominance of the apoptotic process, followed by a significant reduction in the prostate volume and the total serum prostate-specific antigen levels in the dutasteride group when compared with the placebo group, with a clear supremacy of ERß. There were no significant variations in the serum estrogen and testosterone levels, in the body mass index, or in the ERα immunoreactivities in the dutasteride and placebo groups. The results demonstrated the importance of the ERß pathway in the activation mechanisms of apoptosis, exerting a protective effect in the normal prostate, indicating that this receptor might be an important mediator of the clinical effects of dutasteride.

Silver nanoparticles: A new view on mechanistic aspects on antimicrobial activity.

Silver nanoparticles are well known potent antimicrobial agents. Although significant progresses have been achieved on the elucidation of antimicrobial mechanism of silver nanoparticles, the exact mechanism of action is still not completely known. This overview incorporates a retrospective of previous reviews published and recent original contributions on the progress of research on antimicrobial mechanisms of silver nanoparticles. The main topics discussed include release of silver nanoparticles and silver ions, cell membrane damage, DNA interaction, free radical generation, bacterial resistance and the relationship of resistance to silver ions versus resistance to silver nanoparticles. The focus of the overview is to summarize the current knowledge in the field of antibacterial activity of silver nanoparticles. The possibility that pathogenic microbes may develop resistance to silver nanoparticles is also discussed. FROM THE CLINICAL EDITOR: Antibacterial effect of nanoscopic silver generated a lot of interest both in research projects and in practical applications. However, the exact mechanism is still will have to be elucidated. This overview incorporates a retrospective of previous reviews published from 2007 to 2013 and recent original contributions on the progress of research on antimicrobial mechanisms to summarize our current knowledge in the field of antibacterial activity of silver nanoparticles.

Doxorubicin-Functionalized Silica Nanoparticles Incorporated into a Thermoreversible Hydrogel and Intraperitoneally Administered Result in High Prostate Antitumor Activity and Reduced Cardiotoxicity of Doxorubicin.

Described here is an anticancer material based on colloidal mesoporous silica nanoparticles (MSNs) functionalized with doxorubicin (DOX), and incorporated into Pluronic F127 hydrogels for prolonged release, with a potential therapeutic application for prostate cancer treatment. The MSNs have spherical morphology, size of about 60 nm, surface area of 970 cm2 g-1 and average pore width of 2.0 nm. A high colloidal stability for the MSNs in the physiological medium used for in vivo administration (NaCl 0.9% w/v) could be attained in the presence of PF127 (from 5 to 18 wt %), where depletion repulsion forces prevent MSN agglomeration. By conjugating DOX, MSN and PF127 (18 wt %) in NaCl 0.9%, the hybrid system has a gelation temperature of 21 °C, which allowed its in vivo administration in the liquid form and further in situ gelation, generating a drug depot system inside the animals after peritoneal injection. The systems were tested in rats with chemically induced prostate cancer and, after this treatment, histopathological analyses confirmed (i) a reduction in the frequency of aggressive tumors; (ii) that the antitumor effect was dependent on MSN concentration; and most importantly (iii) the reduction of DOX intrinsic cardiotoxicity, indicating that the MSNs play a cardioprotective effect.

Nanobiotechnology of Carbon Dots: A Review.

In recent years, carbon dots (CDs) have gained increasing attention owing to their unique properties and enormous potential for several biomedical and technological applications. CDs are biocompatible, have a small size with a relatively large surface area, are photostable, and have customizable photoluminescence properties. This review is divided into the following discussions of CDs: general definitions; an overview of recent reviews; methods of green and classical synthesis; applications in bioimaging, involving supercapacitors, nanocarriers and nanomedicine; toxicological evaluations (including cytotoxic, genotoxic and anti-cancer properties of CDs); their conjugation with enzymes, biosensors, and cell labeling. Finally the remaining drawbacks and challenges of CD applications are highlighted. In this context, this article aims to provide critical insight and inspire further developments in the synthesis and application of CDs.

Gestational and lactational exposition to Di-N-butyl-phthalate (DBP) increases inflammation and preneoplastic lesions in prostate of wistar rats after carcinogenic N-methyl-N-nitrosourea (MNU) plus testosterone protocol.

In the present study, it was evaluated the susceptibility of prostatic lesions in male adult rats exposed to Di-N-butyl-phthalate during fetal and lactational periods and submitted to MNU plus testosterone carcinogenesis protocol. Pregnant females were distributed into four experimental groups: CN (negative control); CMNU (MNU control); TDBP100 (100 mg/kg of DBP); TDBP500 (500 mg/kg of DBP). Females from the TDBP groups received DBP, by gavage, from gestation day 15 (GD15) to postnatal day 21 (DPN21), while C animals received the vehicle (corn oil). CMNU, TDBP100, and TDBP500 groups received a single intraperitoneal injection of MNU (50 mg/kg) on the sixth postnatal week. After that, testosterone cypionate was administered subcutaneously two times a week (2 mg/kg) for 24 weeks. The animals were euthanized on PND220. Distal segment fragments of the ventral (VP) and dorsolateral prostate (DLP) were fixed and processed for histopathological analysis. Protein extracts from ventral prostate were obtained, and western blotting was performed to AR, ERα, MAPK (ERK1/2), and pan-AKT. Stereological analysis showed an increase in the epithelial compartment in TDBP100 and TDBP500 compared to CN. In general, there was increase in the incidence of inflammation and metaplasia/dysplasia in the DBP-treated groups, mainly in DLP, compared to CN and CMNU. Proliferation index was significant higher in TDBP500 and PIN (prostatic intraepithelial neoplasia) was more frequent in this group compared to CMNU. Western blot assays showed an increase in the expressions of AR and MAPK (ERK1/2) in the TDBP100 compared to CN, and ERα and AKT expressions were higher in the TDBP500 group compared do CN. These results showed that different doses of DBP during prostate organogenesis in Wistar rats could increase the incidence of premalignant lesions in initiated rats inducing distinct biological responses in the adulthood. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1185-1195, 2016.

Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer.

BACKGROUND: Toll-like receptors (TLRs) are effector molecules expressed on the surface of ovarian cancer (OC) cells, but the functions of the TLR2/TLR4 signaling pathways in these cells remain unclear. Melatonin (mel) acts as an anti-inflammatory factor and has been reported to modulate TLRs in some aggressive tumor cell types. Therefore, we investigated OC and the effect of long-term mel therapy on the signaling pathways mediated by TLR2 and TLR4 via myeloid differentiation factor 88 (MyD88) and toll-like receptor-associated activator of interferon (TRIF) in an ethanol-preferring rat model. METHODS: To induce OC, the left ovary of animals either consuming 10% (v/v) ethanol or not was injected directly under the bursa with a single dose of 100 µg of 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 µL of sesame oil. The right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of mel (200 µg/100 g b.w./day) for 60 days. RESULTS: Although mel therapy was unable to reduce TLR2 levels, it was able to suppress the OC-associated increase in the levels of the following proteins: TLR4, MyD88, nuclear factor kappa B (NFkB p65), inhibitor of NFkB alpha (IkBα), IkB kinase alpha (IKK-α), TNF receptor-associated factor 6 (TRAF6), TRIF, interferon regulatory factor 3 (IRF3), interferon ß (IFN-ß), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. In addition, mel significantly attenuated the expression of IkBα, NFkB p65, TRIF and IRF-3, which are involved in TLR4-mediated signaling in OC during ethanol intake. CONCLUSION: Collectively, our results suggest that mel attenuates the TLR4-induced MyD88- and TRIF-dependent signaling pathways in ethanol-preferring rats with OC.

Graphene oxide: a carrier for pharmaceuticals and a scaffold for cell interactions.

During the last ten years, graphene oxide has been explored in many applications due to its remarkable electroconductivity, thermal properties and mobility of charge carriers, among other properties. As discussed in this review, the literature suggests that a total characterization of graphene oxide must be conducted because oxidation debris (synthesis impurities) present in the graphene oxides could act as a graphene oxide surfactant, stabilizing aqueous dispersions. It is also important to note that the structure models of graphene oxide need to be revisited because of significant implications for its chemical composition and its direct covalent functionalization. Another aspect that is discussed is the need to consider graphene oxide surface chemistry. The hemolysis assay is recommended as a reliable test for the preliminary assessment of graphene oxide toxicity, biocompatibility and cell membrane interaction. More recently, graphene oxide has been extensively explored for drug delivery applications. An important increase in research efforts in this emerging field is clearly represented by the hundreds of related publications per year, including some reviews. Many studies have been performed to explore the graphene oxide properties that enable it to deliver more than one activity simultaneously and to combine multidrug systems with photothermal therapy, indicating that graphene oxide is an attractive tool to overcome hurdles in cancer therapies. Some strategic aspects of the application of these materials in cancer treatment are also discussed. In vitro studies have indicated that graphene oxide can also promote stem cell adhesion, growth and differentiation, and this review discusses the recent and pertinent findings regarding graphene oxide as a valuable nanomaterial for stem cell research in medicine. The protein corona is a key concept in nanomedicine and nanotoxicology because it provides a biomolecular identity for nanomaterials in a biological environment. Understanding protein corona-nanomaterial interactions and their influence on cellular responses is a challenging task at the nanobiointerface. New aspects and developments in this area are discussed.

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.

Protective effect of γ-tocopherol-enriched diet on N-methyl-N-nitrosourea-induced epithelial dysplasia in rat ventral prostate.

Despite recent advances in understanding the biological basis of prostate cancer (PCa), the management of this disease remains a challenge. Chemoprotective agents have been used to protect against or eradicate prostate malignancies. Here, we investigated the protective effect of γ-tocopherol on N-methyl-N-nitrosourea (MNU)-induced epithelial dysplasia in the rat ventral prostate (VP). Thirty-two male Wistar rats were divided into four groups (n = 8): control (CT): healthy control animals fed a standard diet; control+γ-tocopherol (CT+γT): healthy control animals without intervention fed a γ-tocopherol-enriched diet (20 mg/kg); N-methyl-N-nitrosourea (MNU): rats that received a single dose of MNU (30 mg/kg) plus testosterone propionate (100 mg/kg) and were fed a standard diet; and MNU+γ-tocopherol (MNU+γT): rats that received the same treatment of MNU plus testosterone and were fed with a γ-tocopherol-enriched diet (20 mg/kg). After 4 months, the VPs were excised to evaluate morphology, cell proliferation and apoptosis, as well as cyclooxygenase-2 (Cox-2), glutathione-S-transferase-pi (GST-pi) and androgen receptor (AR) protein expression, and matrix metalloproteinase-9 (MMP-9) activity. An increase in the incidence of epithelial dysplasias, such as stratified epithelial hyperplasia and squamous metaplasia, in the MNU group was accompanied by augmented cell proliferation, GST-pi and Cox-2 immunoexpression and pro-MMP-9 activity. Stromal thickening and inflammatory foci were also observed. The administration of a γ-tocopherol-enriched diet significantly attenuated the adverse effects of MNU in the VP. The incidence of epithelial dysplasia decreased, along with the cell proliferation index, GST-pi and Cox-2 immunoexpression. The gelatinolytic activity of pro-MMP-9 returned to the levels observed for the CT group. These results suggest that γ-tocopherol acts as a protective agent against MNU-induced prostatic disorders in the rat ventral prostate.

Chronic ethanol consumption alters all-trans-retinoic acid concentration and expression of their receptors on the prostate: a possible link between alcoholism and prostate damage.

BACKGROUND: Ethanol (EtOH) alters the all-trans-retinoic acid (ATRA) levels in some tissues. Retinol and ATRA are essential for cell proliferation, differentiation, and maintenance of prostate homeostasis. It has been suggested that disturbances in retinol/ATRA concentration as well as in the expression of retinoic acid receptors (RARs) contribute to benign prostate hyperplasia and prostate cancer. This study aimed to evaluate whether EtOH consumption is able to alter retinol and ATRA levels in the plasma and prostate tissue as well as the expression of RARs, cell proliferation, and apoptosis index. METHODS: All animals were divided into 4 groups (n = 10/group). UChA: rats fed 10% (v/v) EtOH ad libitum; UChACo: EtOH-naïve rats without access to EtOH; UChB: rats fed 10% (v/v) EtOH ad libitum; UChBCo: EtOH-naïve rats without access to EtOH. Animals were euthanized by decapitation after 60 days of EtOH consumption for high-performance liquid chromatography and light microscopy analysis. RESULTS: EtOH reduced plasma retinol concentration in both UChA and UChB groups, while the retinol concentration was not significantly different in prostate tissue. Conversely, plasma and prostate ATRA levels increased in UChB group compared with controls, beyond the up-regulation of RARß and -γ in dorsal prostate lobe. Additionally, no alteration was found in cell proliferation and apoptosis index involving dorsal and lateral prostate lobe. CONCLUSIONS: We conclude that EtOH alters the plasma retinol concentrations proportionally to the amount of EtOH consumed. Moreover, high EtOH consumption increases the concentration of ATRA in plasma/prostate tissue and especially induces the RARß and RARγ in the dorsal prostate lobe. EtOH consumption and increased ATRA levels were not associated with cell proliferation and apoptosis in the prostate.

Caffeine reduces cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis.

The aim of this study was to investigate the effects of caffeine (20 mg/L) intake on cadmium (15 mg/L) accumulation in the rat blood, testes, epididymis and prostate as well as cadmium-induced changes to the antioxidant defense system of the epididymis. Caffeine reduced the cadmium concentration in all tissues analyzed. Meanwhile, cadmium reduced catalase activity and increased superoxide dismutase (SOD) activity in the epididymis. Caffeine increased SOD activity, catalase and glutathione tissue expression and sustains the cadmium's effect on catalase and GSP-Px activity. No differences in the expression of metallothionein and lipid peroxidation were observed among the different treatments in the epididymis. In conclusion, low doses of cadmium alter the antioxidant enzymatic profile of the epididymis, but not induced oxidative lipid damage. Caffeine intake reduces overall cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis, thus exerting a protective effect against this metal.