The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. “Lactagenic” or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege.

Abstract:The work reported herein describes the synthesis and the assessment of the trypanocidal activity of thirteen new 1,2,4-triazole-3-thiones obtained from natural piperine, the main constituent of the dry fruits of Piper nigrum. It is part of a research program aiming to use abundant and easily available natural products as starting materials for the design and synthesis of new molecules potentially useful as antiparasitic drugs. The variously substituted triazole derivatives were synthesized from the natural amide in four steps with the use of microwave irradiation on overall yields ranging from 32% to 51%. The cyclohexyl substituted derivative showed the best trypanocidal profile on proliferative forms of Trypanosoma cruzi (Y strain), with IC 50 s = 18.3 and 8.87 μM against epimastigotes and amastigotes, respectively.

Background: Piperine, an amide extracted from the Piper spices, exhibits strong anti-tumor properties. However, its effect on the epithelial–mesenchymal transition (EMT) process has never been investigated. Herein, we evaluate the toxic effect of piperine on lung adenocarcinoma (A549), breast adenocarcinoma (MDA-MB-231) and hepatocellular carcinoma (HepG2) cell lines, as well as its ability to inhibit EMT-related events induced by TGF-β1 treatment. Methods: The cell viability was investigated by MTT assay. Protein expression was evaluated by Western blot. Gene expression was monitored by real-time PCR. Zymography assay was employed to detect metalloproteinase (MMP) activity in conditioned media. Cell motility was assessed by the wound-healing and phagokinetic gold sol assays. Results: The results revealed that piperine was cytotoxic in concentrations over 100 µM, showing IC50 values for HepG2, MDA-MB-231 and A549 cell lines of 214, 238 and 198 µM, respectively. In order to investigate whether piperine would reverse the TGF-β1 induced-EMT, the A549 cell line was pretreated with sublethal concentrations of the natural amide followed by the addition of TGF-β1. Besides disrupting EMT-related events, piperine also inhibited both ERK 1/2 and SMAD 2 phosphorylation. Conclusions: These results suggest that piperine might be further used in therapeutic strategies for metastatic cancer and EMT-related disorders.

This paper describes the importance and potentiality of natural piperine as precursor of new bioactive molecules. This natural product has the fruits of black pepper (Piper nigrum, Piperaceae) as its main source. We focused herein its potential antiparasitic activity against two important protozoa of the Trypanosomatidae family: Trypanosoma cruzi, the causative agent of Chagas` disease; and Leishmania sp., which involves a complex of protozoan responsible for leishmaniasis. These two diseases are responsible for different forms of severe clinical manifestations which can culminate in the death of affected patients. In addition, some aspects involving the accessibility of this natural product; extraction methods; as well as its biosynthesis are also discussed herein.Keywords: Piperi e; la k pepper; Chagas' disease; leish a iasis; atural produ ts; a tiparasiti drugs. ResumoNeste artigo encontram-se descritas a importância e a potencialidade da amida natural piperina, como precursora de novas moléculas com aplicação na modulação de fenômenos biológicos. A principal fonte de obtenção da piperina são os frutos da pimenta do reino (Piper nigrum, Piperaceae). Foi focalizado neste trabalho o potencial antiparasitário do produto natural, seus análogos e derivados frente a dois protozoários da família dos tripanossomatídeos, o Trypanosoma cruzi, agente etiológico da doença de Chagas; e a Leishmania sp., que envolve um complexo de protozoários responsáveis pelas leishmanioses, que se apresentam em diferentes formas de manifestações clínicas severas, as quais podem culminar na morte dos pacientes infectados. Além disso, também são discutidos aqui aspectos envolvendo a acessibilidade ao produto natural, visto que o Brasil é um grande produtor de pimenta do reino; métodos de extração, bem como a sua biossíntese.Palavras-chave: Piperina; pimenta do reino; doença de Chagas; leishmaniose; produtos naturais; fármacos antiparasitários.

Chagas disease is a neglected tropical disease caused by the hemoflagellated parasite Trypanosoma cruzi (Kinetoplastida). The only available drug to treat chagasic patients in Brazil, the nitroheterocycle benznidazole, is effective solely during the acute phase of the infection. There is accordingly a need to develop new therapeutic tools for the treatment of Chagas disease. This work reports the synthesis, trypanocidal evaluation and human serum albumin (HSA) interactions of a novel series of 1,2,4-triazoles. The new derivatives were synthesized via microwave irradiation in good yields. Most compounds showed toxic effects against T. cruzi with low toxicity to host cells. Three S-alkylated-triazoles showed the best activity profile against amastigotes, with half maximal inhibitory concentration (IC 50) values of 3.95 ± 1.41, 4.15 ± 0.92 and 3.61 ± 0.65 μmol L-1 , respectively. The interaction between HSA and 3-[(1E,3E)-4-(1,3-benzodioxol-5-yl)buta-1,3-dien-1-yl]-5-(butylthio)-4-cyclohexyl-4,5-dihydro-1H-1,2,4-triazole was investigated using multiple spectroscopic techniques and molecular docking, revealing that serum albumin is a potential endogenous carrier to this compound in the human bloodstream.