Essential oil of oregano (Origanum vulgare L.) reduces infection and proliferation of Toxoplasma gondii in BeWo cells with induction of autophagy and death of tachyzoites through a mechanism similar to necrosis.

Toxoplasmosis poses a global health threat, ranging from asymptomatic cases to severe, potentially fatal manifestations, especially in immunocompromised individuals and congenital transmission. Prior research suggests that oregano essential oil (OEO) exhibits diverse biological effects, including antiparasitic activity against Toxoplasma gondii. Given concerns about current treatments, exploring new compounds is important. This study was to assess the toxicity of OEO on BeWo cells and T. gondii tachyzoites, as well as to evaluate its effectiveness in in vitro infection models and determine its direct action on free tachyzoites. OEO toxicity on BeWo cells and T. gondii tachyzoites was assessed by MTT and trypan blue methods, determining cytotoxic concentration (CC50), inhibitory concentration (IC50), and selectivity index (SI). Infection and proliferation indices were analyzed. Direct assessments of the parasite included reactive oxygen species (ROS) levels, mitochondrial membrane potential, necrosis, and apoptosis, as well as electron microscopy. Oregano oil exhibited low cytotoxicity on BeWo cells (CC50: 114.8 µg/mL ± 0.01) and reduced parasite viability (IC50 12.5 ± 0.06 µg/mL), demonstrating 9.18 times greater selectivity for parasites than BeWo cells. OEO treatment significantly decreased intracellular proliferation in infected cells by 84% after 24 h with 50 µg/mL. Mechanistic investigations revealed increased ROS levels, mitochondrial depolarization, and lipid droplet formation, linked to autophagy induction and plasma membrane permeabilization. These alterations, observed through electron microscopy, suggested a necrotic process confirmed by propidium iodide labeling. OEO treatment demonstrated anti-T. gondii action through cellular and metabolic change while maintaining low toxicity to trophoblastic cells.

Vitamin D3 and Salinomycin synergy in MCF-7 cells cause cell death via endoplasmic reticulum stress in monolayer and 3D cell culture.

1α, 25, dihydroxyvitamin D3 (1,25D), the active form of vitamin D3, has antitumor properties in several cancer cell lines in vitro. Salinomycin (Sal) has anticancer activity against cancer cell lines. This study aims to examine the cytotoxic and antiproliferative effect of Sal associated with 1,25D on MCF-7 breast carcinoma cell line cultured in monolayer (2D) and three-dimensional models (mammospheres). We also aim to evaluate the molecular mechanism of Sal and 1,25D-mediated effects. We report that Sal and 1,25D act synergistically in MCF-7 mammospheres and monolayer causing G1 cell cycle arrest, reduction of mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) overproduction with a long-lasting cytotoxic response represented by clonogenic and mammosphere assay. We observed the induction of cell death by apoptosis with upregulation in mRNA levels of apoptosis-related genes (CASP7, CASP9, and BBC3). Extensive cytoplasmic vacuolization, a morphological characteristic found in paraptosis, was also seen and could be triggered by endoplasmic reticulum stress (ER) as we found transcriptional upregulation of genes related to ER stress (ATF6, GADD153, GADD45G, EIF2AK3, and HSPA5). Overall, Sal and 1,25D act synergistically, inhibiting cell proliferation by activating simultaneously multiple death pathways and may be a novel and promising luminal A breast cancer therapy strategy.

Biogenic silver nanoparticles (AgNp-Bio) restore testosterone levels and increase TNF-α and IL-6 in Leydig cells infected with Toxoplasma gondii.

Toxoplasma gondii, a protozoan parasite, is responsible for toxoplasmosis. The available therapy for patients with toxoplasmosis involves a combination of pyrimethamine and sulfadiazine, which have several adverse effects, including bone marrow suppression, megaloblastic anemia, leukopenia, and granulocytopenia. The development of therapeutic alternatives is essential for the management of toxoplasmosis, emphasizing the recent advances in nanomedicine. This study aimed to evaluate the in vitro effects of biogenic silver nanoparticles (AgNp-Bio) on tachyzoite forms and Leydig cells infected with T. gondii. We observed that the AgNp-Bio reduced the viability of the tachyzoites and did not exhibit cytotoxicity against Leydig cells at low concentrations. Additionally, treatment with AgNp-Bio reduced the rate of infection and proliferation of the parasite, and lowered the testosterone levels in the infected cells. It increased the levels of IL-6 and TNF-α and reduced the levels of IL- 10. Among the morphological and ultrastructural changes, AgNp-Bio induced a reduction in the number of intracellular tachyzoites and caused changes in the tachyzoites with accumulation of autophagic vacuoles and a decrease in the number of tachyzoites inside the parasitophorous vacuoles. Collectively, our data demonstrate that the AgNp-Bio affect T. gondii tachyzoites by activating microbicidal and inflammatory mechanisms and could be a potential alternative treatment for toxoplasmosis.

Strongyloides-specific IgA, IgG and IgG immune complex profile in patients with pulmonary tuberculosis.

AIMS: To describe an anti-Strongyloides IgA, IgG and IgG immune complex antibody response profile in patients with pulmonary tuberculosis. METHODS AND RESULTS: Saliva and serum samples were collected from 100 individuals: group I, 50 apparently healthy individuals; and group II, 50 pulmonary tuberculosis patients. The IgA, IgG and IgG immune complex detection were carried out via an ELISA immunoenzymatic test. Optical density medians in saliva samples of IgA antibody (median of 7.21) and IgG-IC (median of 4.95) were significantly higher in tuberculosis group compared to control individuals (median IgA of 3.93 and IgG-IC of 2.38). CONCLUSION: This study presents antibody data to the field of pulmonary tuberculosis and strongyloidiasis coinfection, including saliva samples, and especially IgG immune complex detection.

Moringa oleifera extract promotes apoptosis-like death in Toxoplasma gondii tachyzoites in vitro.

Toxoplasma gondii is the causative agent of toxoplasmosis, and an important problem of public health. The current treatment for toxoplasmosis is the combination of pyrimethamine and sulphadiazine, which do not act in the chronic phase of toxoplasmosis and have several side-effects. This study evaluated the anti-T. gondii activity and potential mechanism of Moringa oleifera seeds' aqueous extract in vitro. The concentration of M. oleifera extract in HeLa cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assays. The presence of T. gondii was assessed by quantitative polymerase chain reaction and toluidine blue staining. Pyrimethamine and sulphadiazine were used as drug controls. Modifications in T. gondii morphology and ultrastructure were observed by electron microscopy. In vitro, the M. oleifera extract had no toxic effect on HeLa cells at concentrations below 50 µg mL−1. Moringa oleifera extract inhibits T. gondii invasion and intracellular proliferation with similar results for sulphadiazine + pyrimethamine, and also shows cellular nitric oxide production at a concentration of 30 µg mL−1. Electron microscopy analyses indicated structural and ultrastructural modifications in tachyzoites after treatment. We also observed an increase in reactive oxygen species production and a loss of mitochondrial membrane integrity. Nile Red staining assays demonstrated a lipid accumulation. Annexin V­fluorescein isothiocyanate and propidium iodide staining demonstrated that the main action of M. oleifera extract in T. gondii tachyzoites was compatible with late apoptosis. In conclusion, M. oleifera extract has anti-T. gondii activity in vitro and might be a promising substance for the development of a new anti-T. gondii drug.

Biogenic silver nanoparticles reduce adherence, infection, and proliferation of toxoplasma gondii RH strain in HeLa cells without inflammatory mediators induction.

The highlights of biogenic silver nanoparticles (AgNp-Bio) include low toxicity - depending on size and concentration - and efficient antiparasitic activity. Therefore, the objective of this study was to assess the action of the AgNp-Bio on HeLa cells in an infection with strain of RH Toxoplasma gondii. Firstly, we performed a cellular viability test and characterized the AgNp-Bio to proceed with the infection of HeLa cells with T. gondii to be treated using AgNp-Bio or conventional drugs. Subsequently, we determined the level of standard cytokines Th1/Th2 as well as the content of nitric oxide (NO) and reactive oxygen species (ROS). Results indicated a mean size of 69 nm in diameter for the AgNp-Bio and obtained a dose-dependent toxicity. In addition, the concentrations of 3 and 6 µM promoted a significant decrease in adherence, infection, and intracellular proliferation. We also found lower IL-8 and production of inflammatory mediators. Thus, the nanoparticles reduced the adherence, infection, and proliferation of ROS and NO, in addition to immunomodulating the IL-8. Therefore, our data proved relevant to introduce a promising therapeutic alternative to toxoplasmosis.

Interferon-gamma in mobilized stem cells: A possible prognostic marker in early post-transplant management in multiple myeloma.

INTRODUCTION: A complex network of cytokines in the bone marrow microenvironment has been implicated as an important factor in the pathogenesis of multiple myeloma (MM). Different cytokines have been studied in MM, both in peripheral blood and/or bone marrow, but there are few data correlating cytokines in leukapheresis product with post-transplant response depth to treatment. MATERIALS AND METHODS: In a retrospective cross-sectional study, levels of tumor necrosis factor alpha (TNF-α), transforming growth factor beta-1 (TGF-ß1) and interferon gamma (IFN-γ) in peripheral hematopoietic stem cells/leukapheresis product (PHSC) of patients with MM eligible for transplantation were evaluated. Association of these cytokines with certain factors such as mobilized CD34 + cells/kg, staging, response to treatment and outcome were analyzed. RESULTS: The median baseline IFN-γ level was 826.4 pg/mL. IFN-γ levels in the leukapheresis product were significantly lower in patients who achieved complete response (CR) three months post-transplant when compared to patients with very good partial response (VGPR) (674.75 ±â€¯80.32 pg/mL versus 939.6 ±â€¯106.8 pg/mL, p = 0.02), respectively. Patients who lost depth of response at the third-month post-transplant had a median level of IFN-γ 1133, being considered "high-expressors" of IFN-γ, while those reaching improved response were called "low-expressors" (median level IFN-γ 485 pg/mL). Overall and progression-free survival did not have a statistically significant correlation with TNF-α, TGF-ß1 or IFN-γ, as well as TNF-α and TGF-ß1 levels in post-transplant response assessment. CONCLUSION: IFN-γ in PHSC seems to be an important biomarker of loss of response in MM, suggesting a role in early post-transplant therapeutic management.

Concanavalin-A displays leishmanicidal activity by inducing ROS production in human peripheral blood mononuclear cells.

The context of the article: Leishmania amazonensis has a wide geographical distribution throughout South American countries and can cause self-healing to severe cases as mucocutaneous or visceral forms. Leishmaniasis presents a balance of inflammatory and anti-inflammatory cytokines which is responsible for promoting the activation of phagocytes, essential to control the infection and lead to tissue repair/resolution of the disease, respectively. Results and discussion: Our model revealed that the treatment with Con-A was capable to stimulate human PBMC cells by increasing the phagocytic capacity and promoting parasite elimination. The pretreatment with Con-A promoted inflammatory (IFN-γ, TNF-α, IL-2 and IL-6) and anti-inflammatory (IL-4 and IL-10) cytokines production, increased the reactive oxygen species (ROS) sinthesys as well as the expression and presence of iNOS enzyme, but not nitric oxide production. Conclusion: Based on the data obtained, it was possible to infer that Con-A induces the ROS production, responsible for eliminating parasites in addition to regulatory cytokines synthesis which are important for disease resolution.

Brazilian propolis promotes immunomodulation on human cells from American Tegumentar Leishmaniasis patients and healthy donors infected with L. braziliensis.

American Tegumentar Leishmaniasis (ATL) is an infectious disease caused by Leishmania parasites with ineffective treatment. The properties of propolis have been studied in different experimental studies, however, few works have investigated the effects of propolis on human-derived peripheral blood mononuclear cells (PBMC) in leishmaniasis models. Thus, we investigate the immunomodulatory effects of propolis treatment on PBMC from ATL patients and on PBMC from healthy donors infected with Leishmania braziliensis. Our data demonstrate that propolis pretreatment shows immunomodulatory effects on both healthy donors and ATL patients adherent cells, increasing IL-4 and IL-17 and decreasing IL-10, in either the presence or absence of the L. braziliensis infection, demonstrating that propolis contributes with the decrease of the inflammation and could also contribute with parasite control.

Activity of rosuvastatin in tachyzoites of Toxoplasma gondii (RH strain) in HeLa cells.

Due to the toxicity of conventional medication in toxoplasmosis, some drugs are being studied for treating this infection, such as statins, especially rosuvastatin compound, which is efficient in inhibiting the initial isoprenoid biosynthesis processes in humans and the parasite. The goal of this study was to assess the activity of rosuvastatin in HeLa cells infected with the RH strain of T. gondii. In the experiment, HeLa cells (1 × 105) were infected with tachyzoites of T. gondii (5 × 105). After the experimental infection, we assessed the number of infected cells and the amount of intracellular tachyzoites. In addition, culture supernatants were collected to determine the amount of cytokines by cytometric bead array. We observed that there was no cytotoxicity in the concentrations tested in this cell line. The effect of rosuvastatin showed a significant reduction in both the number of infected cells and the proliferation index of the intracellular parasite, when compared with the conventional treatment combining sulfadiazine and pyrimethamine for toxoplasmosis. There were also reduced levels of cytokines IL-6 and IL-17. Therefore, it was concluded that rosuvastatin exhibited antiproliferative activity. The data presented are significant to promote further studies and the search for alternative treatment for toxoplasmosis.

Nanomedicine advances in toxoplasmosis: diagnostic, treatment, and vaccine applications.

Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii that affects about one third of the world's population. The diagnosis of this disease is carried out by parasite isolation and host antibodies detection. However, the diagnosis presents problems in regard to test sensitivity and specificity. Currently, the most effective T. gondii treatment is a combination of pyrimethamine and sulfadiazine, although both drugs are toxic to the host. In addition to the problems that compromise the effective diagnosis and treatment of toxoplasmosis, there are no reports or indications of any vaccine capable of fully protecting against this infection. Nanomaterials, smaller than 1000 nm, are currently being investigated as an alternative tool in the management of T. gondii infection. This article reviews how recent nanotechnology advances indicate the utility of nanomaterials in toxoplasmosis diagnosis, treatment, and vaccine development.

Isolation of dengue virus serotype 4 genotype II from a patient with high viral load and a mixed Th1/Th17 inflammatory cytokine profile in South Brazil.

BACKGROUND: We report the isolation and characterization of dengue virus (DENV) serotype 4 from a resident of Santa Fé, state of Paraná, South Brazil, in March 2013. This patient presented with hemorrhagic manifestations, high viral load and, interestingly, a mixed Th1/Th17 cytokine profile. CASE PRESENTATION: The patient presented with classical dengue symptoms, such as fever, rash, myalgia, arthralgia, and hemorrhagic manifestations including petechiae, gum bleeding and a positive tourniquet test result. A serum sample obtained 1 day after the initial appearance of clinical symptoms was positive for NS1 viral antigen, but this sample was negative for both IgM and IgG against DENV. Dengue virus infection was confirmed by isolation of the virus from C6/36 cells, and dengue virus serotyping was performed via one-step RT-PCR. The infection was confirmed to be caused by a serotype 4 dengue virus. Additionally, based on multiple alignment and phylogeny analyses of its complete genome sequence, the viral strain was classified as genotype II (termed LRV13/422). Moreover, a mixed Th1/Th17 cytokine profile was detected in the patient's serum, and this result demonstrated significant inflammation. Biological characterization of the virus via in vitro assays comparing LRV13/422 with a laboratory-adapted reference strain of dengue virus serotype 4 (TVP/360) showed that LRV13/422 infects both vertebrate and invertebrate cell lines more efficiently than TVP/360. However, LRV13/422 was unable to inhibit type I interferon responses, as suggested by the results obtained for other dengue virus strains. Furthermore, LRV13/422 is the first completely sequenced serotype 4 dengue virus isolated in South Brazil. CONCLUSION: The high viral load and mixed Th1/Th17 cytokine profile observed in the patient's serum could have implications for the development of the hemorrhagic signs observed, and these potential relationships can now be further studied using suitable animal models and/or in vitro systems.

Antileishmanial Activity and Inducible Nitric Oxide Synthase Activation by RuNO Complex.

Parasites of the genus Leishmania are capable of inhibiting effector functions of macrophages. These parasites have developed the adaptive ability to escape host defenses; for example, they inactivate the NF-κB complex and suppress iNOS expression in infected macrophages, which are responsible for the production of the major antileishmanial substance nitric oxide (NO), favoring then its replication and successful infection. Metal complexes with NO have been studied as potential compounds for the treatment of certain tropical diseases, such as ruthenium compounds, known to be exogenous NO donors. In the present work, the compound cis-[Ru(bpy)2SO3(NO)]PF6, or RuNO, showed leishmanicidal activity directly and indirectly on promastigote forms of Leishmania (Leishmania) amazonensis. In addition, treatment with RuNO increased NO production by reversing the depletion of NO caused by Leishmania. We also found increased expression of Akt, iNOS, and NF-κB in infected and treated macrophages. These results demonstrated that RuNO was able to kill the parasite by NO release and modulate the transcriptional capacity of the cell.

Cytokines as Mediators of Pain-Related Process in Breast Cancer.

Pain is a clinical sign of inflammation found in a wide variety of chronic pathologies, including cancer. The occurrence of pain in patients carrying breast tumors is reported and is associated with aspects concerning disease spreading, treatment, and surgical intervention. The persistence of pain in patients submitted to breast surgery is estimated in a range from 21% to 55% and may affect patients before and after surgery. Beyond the physical compression exerted by the metastatic mass expansion and tissue injury found in breast cancer, inflammatory components that are significantly produced by the host-tumor interaction can significantly contribute to the generation of pain. In this context, cytokines have been studied aiming to establish a cause-effect relationship in cancer pain-related syndromes, especially the proinflammatory ones. Few reports have investigated the relationship between pain and cytokines in women carrying advanced breast cancer. In this scenario, the present review analyzes the main cytokines produced in breast cancer and discusses the evidences from literature regarding its role in specific clinical features related with this pathology.

Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL-1ß/cNOS/NO Pathway.

Leishmania amazonensis (L. amazonensis) infection can cause severe local and diffuse injuries in humans, a condition clinically known as American cutaneous leishmaniasis (ACL). Currently, the therapeutic approach for ACL is based on Glucantime, which shows high toxicity and poor effectiveness. Therefore, ACL remains a neglected disease with limited options for treatment. Herein, the in vitro antiprotozoal effect and mechanisms of the diterpene kaurenoic acid [ent-kaur-16-en-19-oic acid] (KA) against L. amazonensis were investigated. KA exhibited a direct antileishmanial effect on L. amazonensis promastigotes. Importantly, KA also reduced the intracellular number of amastigote forms and percentage of infected peritoneal macrophages of BALB/c mice. Mechanistically, KA treatment reestablished the production of nitric oxide (NO) in a constitutive NO synthase- (cNOS-) dependent manner, subverting the NO-depleting escape mechanism of L. amazonensis. Furthermore, KA induced increased production of IL-1ß and expression of the inflammasome-activating component NLRP12. These findings demonstrate the leishmanicidal capability of KA against L. amazonensis in macrophage culture by triggering a NLRP12/IL-1ß/cNOS/NO mechanism.

Trilobolide-6-O-isobutyrate from Sphagneticola trilobata acts by inducing oxidative stress, metabolic changes and apoptosis-like processes by caspase 3/7 activation of human lung cancer cell lines.

BACKGROUND: Lung cancer, a chronic and heterogeneous disease, is the leading cause of cancer-related death on a global scale. Presently, despite a variety of available treatments, their effectiveness is limited, often resulting in considerable toxicity and adverse effects. Additionally, the development of chemoresistance in cancer cells poses a challenge. Trilobolide-6-O-isobutyrate (TBB), a natural sesquiterpene lactone extracted from Sphagneticola trilobata, has exhibited antitumor effects. Its pharmacological properties in NSCLC lung cancer, however, have not been explored. PURPOSE: This study evaluated the impact of TBB on the A549 and NCI-H460 tumor cell lines in vitro, examining its antiproliferative properties and initial mechanisms of cell death. METHODS: TBB, obtained at 98 % purity from S. trilobata leaves, was characterized using chromatographic techniques. Subsequently, its impact on inhibiting tumor cell proliferation in vitro, TBB-induced cytotoxicity in LLC-MK2, THP-1, AMJ2-C11 cells, as well as its effects on sheep erythrocytes, and the underlying mechanisms of cell death, were assessed. RESULTS: In silico predictions have shown promising drug-likeness potential for TBB, indicating high oral bioavailability and intestinal absorption. Treatment of A549 and NCI-H460 human tumor cells with TBB demonstrated a direct impact, inducing significant morphological and structural alterations. TBB also reduced migratory capacity without causing toxicity at lower concentrations to LLC-MK2, THP-1 and AMJ2-C11 cell lines. This antiproliferative effect correlated with elevated oxidative stress, characterized by increased levels of ROS, superoxide anion radicals and NO, accompanied by a decrease in antioxidant markers: SOD and GSH. TBB-stress-induced led to changes in cell metabolism, fostering the accumulation of lipid droplets and autophagic vacuoles. Stress also resulted in compromised mitochondrial integrity, a crucial aspect of cellular function. Additionally, TBB prompted apoptosis-like cell death through activation of caspase 3/7 stressors. CONCLUSION: These findings underscore the potential of TBB as a promising candidate for future studies and suggest its viability as an additional component in the development of novel anticancer drugs prototypes.

Leishmania amazonensis infection regulates oxidate stress in hyperglycemia and diabetes impairing macrophage's function and immune response.

Leishmaniasis is a group of infectious diseases caused by protozoa of the Leishmania genus and its immunopathogenesis results from an unbalanced immune response during the infection. Diabetes is a chronic disease resulting from dysfunction of the body's production of insulin or the ability to use it properly, leading to hyperglycemia causing tissue damage and impairing the immune system. AIMS: The objective of this work was to evaluate the effects of hyperglycemia and diabetes during Leishmania amazonensis infection and how these conditions alter the immune response to the parasite. METHODS: An in vitro hyperglycemic stimulus model using THP-1-derived macrophages and an in vivo experimental diabetes with streptozotocin (STZ) in C57BL/6 mice was employed to investigate the impact of diabetes and hyperglicemia in Leishmania amazonensis infection. RESULTS: We observed that hyperglycemia impair the leishmanicidal capacity of macrophages derived from THP-1 cells and reverse the resistance profile that C57BL/6 mice have against infection by L. amazonensis, inducing more exacerbated lesions compared to non-diabetic animals. In addition, the hyperglycemic stimulus favored the increase of markers related to the phenotype of M2 macrophages. The induction of experimental diabetes in C57BL/6 mice resulted in a failure in the production of nitric oxide (NO) in the face of infection and macrophages from diabetic animals failed to process and present Leishmania antigens, being unable to activate and induce proliferation of antigen-specific lymphocytes. CONCLUSION: Together, these data demonstrate that diabetes and hyperglycemia can impair the cellular immune response, mainly of macrophages, against infection by parasites of the genus Leishmania.

Antioxidant Compounds and Health Benefits of Citrus Fruits.

Recent evidence emanating from epidemiological prospective studies shows that increased intakes of antioxidant-rich fruits, vegetables, and legumes are associated with a lower risk of developing chronic oxidative stress-related diseases like cardiovascular diseases and cancer, as well as with a lower risk of cardiovascular, cancer, and all-cause mortality rates [...].

Viremia and Inflammatory Cytokines in Dengue: Interleukin-2 as a Biomarker of Infection, and Interferon-α and -γ as Markers of Primary versus Secondary Infection.

The pathogenesis of Dengue virus (DENV) infection is complex and involves viral replication that may trigger an inflammatory response leading to severe disease. Here, we investigated the correlation between viremia and cytokine levels in the serum of DENV-infected patients. Between 2013 and 2014, 138 patients with a diagnosis of acute-phase DENV infection and 22 patients with a non-dengue acute febrile illness (AFI) were enrolled. Through a focus-forming assay (FFU), we determined the viremia levels in DENV-infected patients and observed a peak in the first two days after the onset of symptoms. A higher level of viremia was observed in primary versus secondary DENV-infected patients. Furthermore, no correlation was observed between viremia and inflammatory cytokine levels in DENV-infected patients. Receiver operating characteristic (ROC) curve analysis revealed that IL-2 has the potential to act as a marker to distinguish dengue from other febrile illnesses and is positively correlated with Th1 cytokines. IFN-α and IFN-γ appear to be potential markers of primary versus secondary infection in DENV-infected patients, respectively. The results also indicate that viremia levels are not the main driving force behind inflammation in dengue and that cytokines could be used as infection biomarkers and for differentiation between primary versus secondary infection.

Melatonin modulates the Warburg effect and alters the morphology of hepatocellular carcinoma cell line resulting in reduced viability and migratory potential.

AIMS: Hepatocellular Carcinoma (HCC) is a primary neoplasm derived from hepatocytes with low responsiveness and recurrent chemoresistance. Melatonin is an alternative agent that may be helpful in treating HCC. We aimed to study in HuH 7.5 cells whether melatonin treatment exerts antitumor effects and, if so, what cellular responses are induced and involved. MAIN METHODS: We evaluated the effects of melatonin on cell cytotoxicity and proliferation, colony formation, morphological and immunohistochemical aspects, and on glucose consumption and lactate release. KEY FINDINGS: Melatonin reduced cell motility and caused lamellar breakdown, membrane damage, and reduction in microvillus. Immunofluorescence analysis revealed that melatonin reduced TGF and N-cadherin expression, which was further associated with inhibition of epithelial-mesenchymal transition process. In relation to the Warburg-type metabolism, melatonin reduced glucose uptake and lactate production by modulating intracellular lactate dehydrogenase activity. SIGNIFICANCE: Our results indicate that melatonin can act upon pyruvate/lactate metabolism, preventing the Warburg effect, which may reflect in the cell architecture. We demonstrated the direct cytotoxic and antiproliferative effect of melatonin on the HuH 7.5 cell line, and suggest that melatonin is a promising candidate to be further tested as an adjuvant to antitumor drugs for HCC treatment.