The potential role of Listeria monocytogenes in promoting colorectal adenocarcinoma tumorigenic process.

BACKGROUND: Listeria monocytogenes is a foodborne pathogen, which can cause a severe illness, especially in people with a weakened immune system or comorbidities. The interactions between host and pathogens and between pathogens and tumor cells have been debated in recent years. However, it is still unclear how bacteria can interact with tumor cells, and if this interaction can affect tumor progression and therapy. METHODS: In this study, we evaluated the involvement of L. monocytogenes in pre-neoplastic and colorectal cancer cell proliferation and tumorigenic potential. RESULTS: Our findings showed that the interaction between heat-killed L. monocytogenes and pre-neoplastic or colorectal cancer cells led to a proliferative induction; furthermore, by using a three-dimensional cell culture model, the obtained data indicated that L. monocytogenes was able to increase the tumorigenic potential of both pre-neoplastic and colorectal cancer cells. The observed effects were then confirmed as L. monocytogenes-specific, using Listeria innocua as negative control. Lastly, data suggested the Insulin Growth Factor 1 Receptor (IGF1R) cascade as one of the possible mechanisms involved in the effects induced by L. monocytogenes in the human colorectal adenocarcinoma cell line. CONCLUSIONS: These findings, although preliminary, suggest that the presence of pathogenic bacterial cells in the tumor niches may directly induce, increase, and stimulate tumor progression.

A home-based lifestyle intervention program reduces the tumorigenic potential of triple-negative breast cancer cells.

Translational research for the evaluation of physical activity habits and lifestyle modifications based on nutrition and exercise has recently gained attention. In this study, we evaluated the effects of serum samples obtained before and after a 12-week home-based lifestyle intervention based on nutrition and exercise in breast cancer survivors in terms of modulation of the tumorigenic potential of breast cancer cells. The home-based lifestyle intervention proposed in this work consisted of educational counselling on exercise and nutritional behaviors and in 12 weeks of structured home-based exercise. Triple-negative breast cancer cell line MDA-MB-231 was cultured in semi-solid medium (3D culture) with sera collected before (PRE) and after (POST) the lifestyle intervention program. Spheroid formation was evaluated by counting cell colonies after 3 weeks of incubation. Results show a slight but significant reduction of spheroid formation induced by serum collected POST in comparison to those obtained PRE. Moreover, statistical analyses aimed to find physiologic and metabolic parameters associated with 3D cell proliferation revealed the proliferative inducer IGF-1 as the only predictor of cell tumorigenic potential. These results highlight the importance of lifestyle changes for cancer progression control in a tertiary prevention context. Translational research could offer a useful tool to identify metabolic and physiological changes induced by exercise and nutritional behaviors associated with cancer progression and recurrence risk.

Association between metabolic syndrome, insulin resistance, and IGF-1 in breast cancer survivors of DIANA-5 study.

PURPOSE: Circulating insulin-like growth factor-1 (IGF-1) is positively associated with the risk of BC recurrence, and is more frequently dysregulated in older people, especially in those with metabolic syndrome (MetS) and obesity. This study aimed to analyze the association between IGF-1 levels and indices of MetS and insulin resistance in BC survivors. METHODS: Baseline data of 563 BC survivors enrolled in the DIet and ANdrogen-5 (DIANA-5; NCT05019989) study were analyzed. RESULTS: Lower circulating IGF-1 levels in subjects with MetS than in those without MetS were found. After stratification of the patients according to the diagnosis of MetS, we highlighted that the insulin was the main predictor of elevated IGF-1 levels only in subjects without MetS. Moreover, we found an interaction between high-density lipoprotein cholesterol (HDL-C), glycemia, and IGF-1 levels, showing a positive correlation between HDL-C and IGF-1, especially in subjects with higher values of glycemia and without a diagnosis of MetS. CONCLUSIONS: While IGF-1 levels appear to be much more impaired in subjects diagnosed with MetS, in non-MetS subjects, IGF-1 levels may respond better to metabolic parameters and lifestyle changes. Further studies are needed to analyze the role of physical activity and/or dietary intervention in modulating IGF-1 concentrations in BC survivors. IMPLICATIONS FOR CANCER SURVIVORS: These results could have important clinical implications for planning customized strategies aimed at modulating IGF-1 levels in BC survivors. In fact, while the IGF-1 system seems to be much more compromised in subjects with a diagnosis of MetS, in noMetS subjects, IGF-1 levels could better respond to lifestyle changes.

Movement and health beyond care, MoviS: study protocol for a randomized clinical trial on nutrition and exercise educational programs for breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common invasive cancer in women, and exercise can significantly improve the outcomes of BC survivors. MoviS (Movement and Health Beyond Care) is a randomized controlled trial aimed to evaluate the potential health benefits of exercise and proper nutritional habits. This study aims to assess the efficacy of aerobic exercise training in improving quality of life (QoL) and health-related factors in high-risk BC. METHODS: One hundred seventy-two BC survivor women, aged 30-70 years, non-metastatic, stage 0-III, non-physically active, 6-12 months post-surgery, and post chemo- or radiotherapy, will be recruited in this study. Women will be randomly allocated to the intervention arm (lifestyle recommendations and MoviS Training) or control arm (lifestyle recommendations). The MoviS training consists of 12 weeks of aerobic exercise training (2 days/week of supervised and 1 day/week of unsupervised exercise) with a progressive increase in exercise intensity (40-70% of heart rate reserve) and duration (20-60 min). Both arms will receive counseling on healthy lifestyle habits (nutrition and exercise) based on the World Cancer Research Fund International (WCRF) 2018 guidelines. The primary outcome is the improvement of the QoL. The secondary outcomes are improvement of health-related parameters such as Mediterranean diet adherence, physical activity level, flexibility, muscular fitness, fatigue, cardiorespiratory fitness (estimated maximal oxygen uptake), echocardiographic parameters, heart rate variability (average of the standard deviations of all 5 min normal to normal intervals (ASDNN/5 min) and 24 h very low and low frequency), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein). DISCUSSION: This trial aims to evaluate if supervised exercise may improve QoL and health-related factors of BC survivors with a high risk of recurrence. Findings from this project could provide knowledge improvement in the field of exercise oncology through the participation of a multidisciplinary team that will provide a coordinated program of cancer care to improve healthcare quality, improve prognosis, increase survival times and QoL, and reduce the risk of BC recurrence. TRIAL REGISTRATION: ClinicalTrials.gov  NCT04818359 . Retrospectively registered on March 26, 2021.

Physical activity interventions to improve the quality of life of older adults living in residential care facilities: a systematic review.

PURPOSE: Pursuing active aging and maintaining the quality of life (QoL) is essential, particularly in older people living in residential care facilities (RCFs). We evaluated physical activity (PA) as an intervention to improve the QoL in this population, trying to hypothesize future perspectives in this field. METHODS: A systematic search was performed on Pubmed. Only randomized control trials or quasi-experimental control group trials were considered. RESULTS: Results showed that a high-frequency PA can be effective in older people, allowing them to improve their functional mobility, autonomy, anxiety level, balance, and social interactions. Moreover, a moderate-intensity PA showed the most interesting results, improving all the QoL-related aspects considered. CONCLUSION: Results highlight the beneficial effects of multidisciplinary intervention strategies in increasing QoL and QoL-related aspects of RCFs older residents, contemplating PA as the main instrument. However, structured PA is necessary to fully understand which protocol could be the most effective.

Seroprevalence of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection in an Italian cohort in Marche Region, Italy.

BACKGROUND AND AIM: The COVID-19 is an infectious disease caused by the novel coronavirus SARS-CoV-2, declared a public health emergency by the World Health Organization. In this study, we evaluated the seroconversion of SARS-CoV-2 antibodies to find predictors of infection in terms of symptoms, health status, and professions. METHODS: Serological samples of 341 volunteers in a cohort in Marche Region, Italy, were analyzed for the presence of IgM and/or IgG immunoglobulins specific for the SARS-CoV-2. Contextually, an anamnestic questionnaire was administered. The binary logistic regression analysis was used to find the predictors of seroconversion. RESULTS: Forty-nine subjects (14.4 %) were found positive, without significant differences between gender and age groups. The predictors identified inside the variable categories "symptoms," "risk factors" (smoking habit and established pathologies), and "professions" were the loss of taste and smell (OR, 8.563), cardiovascular diseases (OR, 2.912), and policeman profession (OR, 3.875), respectively. CONCLUSIONS: Although the limited number of subjects recruited in this study, our results could give important findings to be considered for planning preventive strategies in the view of the next COVID-19 waves.

Whole-Genome Sequencing Characterization of Virulence Profiles of Listeria monocytogenes Food and Human Isolates and In Vitro Adhesion/Invasion Assessment.

Listeria monocytogenes (Lm) is the causative agent of human listeriosis. Lm strains have different virulence potential. For this reason, we preliminarily characterised via Whole-Genome Sequencing (WGS) some Lm strains for their key genomic features and virulence-associated determinants, assigning the clonal complex (CC). Moreover, the ability of the same strains to adhere to and invade human colon carcinoma cell line Caco-2, evaluating the possible correspondence with their genetic virulence profile, was also assessed. The clinical strains typed belonged to clonal complex (CC)1, CC31, and CC101 and showed a very low invasiveness. The Lm strains isolated from food were assigned to CC1, CC7, CC9, and CC121. All CC1 carried the hypervirulence pathogenicity island LIPI-3 in addition to LIPI-1. Premature stop codons in the inlA gene were found only in Lm of food origin belonging to CC9 and CC121. The presence of LIPI2_inlII was observed in all the CCs except CC1. The CC7 strain, belonging to an epidemic cluster, also carried the internalin genes inlG and inlL and showed the highest level of invasion. In contrast, the human CC31 strain lacked the lapB and vip genes and presented the lowest level of invasiveness. In Lm, the genetic determinants of hypo- or hypervirulence are not necessarily predictive of a cell adhesion and/or invasion ability in vitro. Moreover, since listeriosis results from the interplay between host and virulence features of the pathogen, even hypovirulent clones are able to cause infection in immunocompromised people.

Comparison of real-time PCR assay with a commercial rapid test based on the immunochromatographic principle for the detection of Chlamydia trachomatis in seminal fluid and urine specimens.

Chlamydia trachomatis is the most common sexually transmitted bacterial infection worldwide, with the highest prevalence in sexually active young women. Since most chlamydial infections are asymptomatic, facilitating the transmission of the pathogen in the population, regular screening is recommended for at-risk sexually active individuals. Hence, a sensitive, specific, inexpensive diagnostic test that can be executed efficiently and quickly to yield results would be helpful. In this study, we evaluated the performance (sensitivity and specificity) of the Chlamydia Rapid Test Device, an inexpensive rapid test based on immunochromatographic analysis. We then compared these results to those obtained using real-time PCR, the gold standard for C. trachomatis testing. Seminal fluid and urine specimens of male subjects were tested. The rapid test was applied to 220 seminal fluid samples, showing a sensitivity of 0%. On the other hand, used in 114 urine specimens, the rapid test showed 37.5% and 100% sensitivity and specificity, respectively. Hence, the Chlamydia Rapid Test Device was shown to be insufficiently sensitive to be recommended as a screening test and diagnostic method for the detection of C. trachomatis in symptomatic and asymptomatic subjects. Finally, the present investigation showed an infection prevalence of 5% calculated using seminal fluid, with a mean age of 28 years.

Phenotype Screening of an Azole-bisindole Chemical Library Identifies URB1483 as a New Antileishmanial Agent Devoid of Toxicity on Human Cells.

We report the evaluation of a small library of azole-bisindoles for their antileishmanial potential, in terms of efficacy on Leishmania infantum promastigotes and intracellular amastigotes. Nine compounds showed good activity on L. infantum MHOM/TN/80/IPT1 promastigotes with IC50 values ranging from 4 to 10 µM. These active compounds were also tested on human (THP-1, HEPG2, HaCaT, and human primary fibroblasts) and canine (DH82) cell lines. URB1483 was selected as the best compound, with no quantifiable cytotoxicity in mammalian cells, to test the efficacy on intracellular amastigotes. URB1483 significantly reduced the infection index of both human and canine macrophages with an effect comparable to the clinically used drug pentamidine. URB1483 emerges as a new anti-infective agent with remarkable antileishmanial activity and no cytotoxic effects on human and canine cells.

Physical activity as a tool for health promotion: the evolution of international strategies and interventions.

Physical activity (PA) has a great potential impact in the prevention and control of non-communicable diseases. However, epidemiologic data reporting a high percentage of inactive people, still indicate a scarce perception of PA benefits. Therefore, in the past decades, a number of documents has been produced by international organizations with the aim of changing policies and institutional actions towards the promotion of PA. Several actions have been put in place and an evolution process in international strategies for PA promotion is ongoing. Nevertheless, there is a need to continue updating these policies in light of new knowledge about evidence-based PA health effects. A stimulating discussion about effective PA promotion programs is useful for future planning of interventions. The aim of this work is to report the evolution of international strategies aimed to PA promotion, from early PA recommendations, to the recent WHO Global Action Plan on Physical Activity 2018-2030.

Differentiation of Leishmania (L.) infantum, Leishmania (L.) amazonensis and Leishmania (L.) mexicana Using Sequential qPCR Assays and High-Resolution Melt Analysis.

Leishmania protozoa are the etiological agents of visceral, cutaneous and mucocutaneous leishmaniasis. In specific geographical regions, such as Latin America, several Leishmania species are endemic and simultaneously present; therefore, a diagnostic method for species discrimination is warranted. In this attempt, many qPCR-based assays have been developed. Recently, we have shown that L. (L.) infantum and L. (L.) amazonensis can be distinguished through the comparison of the Cq values from two qPCR assays (qPCR-ML and qPCR-ama), designed to amplify kDNA minicircle subclasses more represented in L. (L.) infantum and L. (L.) amazonensis, respectively. This paper describes the application of this approach to L. (L.) mexicana and introduces a new qPCR-ITS1 assay followed by high-resolution melt (HRM) analysis to differentiate this species from L. (L.) amazonensis. We show that L. (L.) mexicana can be distinguished from L. (L.) infantum using the same approach we had previously validated for L. (L.) amazonensis. Moreover, it was also possible to reliably discriminate L. (L.) mexicana from L. (L.) amazonensis by using qPCR-ITS1 followed by an HRM analysis. Therefore, a diagnostic algorithm based on sequential qPCR assays coupled with HRM analysis was established to identify/differentiate L. (L.) infantum, L. (L.) amazonensis, L. (L.) mexicana and Viannia subgenus. These findings update and extend previous data published by our research group, providing an additional diagnostic tool in endemic areas with co-existing species.

Mediterranean diet adherence and weight status among Sicilian Middle school adolescents.

During the last decades, an important modification of dietary habits has been observed in the Mediterranean countries, especially among young people. The aim of this study was to evaluate adherence to the Mediterranean diet (MedDiet) and its relationship with weight status in a group of Italian middle school adolescents by using the KIDMED test. The evaluation of weight status revealed that 61.5, 26.8, and 11.7% were normal weight, overweight, and obese, respectively. MedDiet adherence was high in 13.3%, average in 27.1%, and low in 59.6% of the students with no differences by gender and age. MedDiet adherence was found significatively higher in normal weight and in played sport adolescents, in comparison to the overweight and obese ones (p < .001) who showed incorrect nutritional habits. This cross-sectional study shows a very low MedDiet adherence among adolescent living in the Mediterranean basin and highlights the role of Mediterranean dietary pattern in the fight against obesity.

Listeriosis Outbreak in South Africa: A Comparative Analysis with Previously Reported Cases Worldwide.

Listeria species are Gram-positive, rod-shaped, facultative anaerobic bacteria, which do not produce endospores. The genus, Listeria, currently comprises 17 characterised species of which only two (L. monocytogenes and L. ivanovii) are known to be pathogenic to humans. Food products and related processing environments are commonly contaminated with pathogenic species. Outbreaks and sporadic cases of human infections resulted in considerable economic loss. South Africa witnessed the world's largest listeriosis outbreak, characterised by a progressive increase in cases of the disease from January 2017 to July 2018. Of the 1060 laboratory-confirmed cases of listeriosis reported by the National Institute of Communicable Diseases (NICD), 216 deaths were recorded. Epidemiological investigations indicated that ready-to-eat processed meat products from a food production facility contaminated with L. monocytogenes was responsible for the outbreak. Multilocus sequence typing (MLST) revealed that a large proportion (91%) of the isolates from patients were sequence type 6 (ST6). Recent studies revealed a recurrent occurrence of small outbreaks of listeriosis with more severe side-effects in humans. This review provides a comparative analysis of a recently reported and most severe outbreak of listeriosis in South Africa, with those previously encountered in other countries worldwide. The review focuses on the transmission of the pathogen, clinical symptoms of the disease and its pathogenicity. The review also focuses on the major outbreaks of listeriosis reported in different parts of the world, sources of contamination, morbidity, and mortality rates as well as cost implications. Based on data generated during the outbreak of the disease in South Africa, listeriosis was added to the South African list of mandatory notifiable medical conditions. Surveillance systems were strengthened in the South African food chain in order to assist in preventing and facilitating early detection of both sporadic cases and outbreaks of infections caused by these pathogens in humans.

Real-time PCR to differentiate among Leishmania (Viannia) subgenus, Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis: Application on Brazilian clinical samples.

Leishmaniasis is a complex disease caused by Leishmania species belonging to subgenera Leishmania and Viannia. In South America, L. (L.) infantum is considered the most important causative agent of visceral leishmaniasis, while L. (L.) amazonensis and Viannia subgenus species are responsible for the different cutaneous or mucocutaneous forms. In our previous work, we developed a diagnostic approach for Leishmania species discrimination based on two qPCRs (qPCR-ML and qPCR-ama) targeting the minicircle kDNA followed by melting analysis. This approach allowed to (i) differentiate the subgenera Leishmania and Viannia, and (ii) distinguish between L. (L.) infantum and L. (L.) amazonensis. The aim of this work was to demonstrate the applicability of the approach previously described, using human and canine clinical samples and strains from a Brazilian region, where L. (L.) infantum, L. (L.) amazonensis and Viannia subgenus species coexist. After validation on New World strains, the diagnostic approach was applied blindly to 36 canine clinical samples (peripheral blood and bone marrow) and 11 human clinical samples (peripheral blood and bone marrow). The sensitivity was 95.6% (95% confidence interval 77.3-100%) and 100% (95% confidence interval 76.9-100%) in the canine bone marrow samples and human (peripheral blood and bone marrow) samples, respectively, compared to conventional PCR assays. Concerning the Leishmania species identification, the conventional and qPCR-based methods showed kappa value of 0.876 (95% confidence interval 0.638-1.000), indicating good agreement. Therefore, this approach proved to be useful in both veterinary and human clinical context in regions co-endemic for L. (L.) infantum, L. (L.) amazonensis, and Viannia subgenus, helping to provide rapid diagnosis and to allow studies of species distribution.

Data on the differentiation among Leishmania (Viannia) spp., Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis in Brazilian clinical samples using real-time PCR.

This article contains the data regarding Leishmania species identification in human and canine clinical samples from a Brazilian region endemic for Leishmania (Viannia) spp., Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis, using a previously developed approach involving two qPCR assays (qPCR-ML and qPCR-ama). The data are related to the article "Real-time PCR to differentiate among Leishmania (Viannia) subgenus, Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis: application on Brazilian clinical samples" [1], and include also details of clinical evaluation/diagnosis of human patients and primer sequences used in the qPCR assays. The Leishmania species has been determined in 27 canine samples and 11 human samples, exploiting HRM analysis of qPCR-ML and Cq values of qPCR-ML and qPCR-ama, as reported previously [2]. The qPCR data were in agreement with the species characterization obtained with other methods such as conventional species-specific PCR, ITS1 PCR-RFLP or DNA sequencing. Despite the limited number of clinical samples, these data are encouraging for a potential application in regions where L. (Viannia) spp., L. (L.) infantum and L. (L.) amazonensis are co-endemic.

A dataset on the effect of exercise-conditioned human sera in three-dimensional breast cancer cell culture.

Epidemiological evidence shows that physical activity lowers the risk of developing breast cancer and decreases the risk of disease recurrence [1,2]. The main hypothesis on the positive effects of exercise-oncology has focused on lowering the basal systemic levels of cancer risk factors with exercise training. Recently, the effects of cancer progression control by components released after acute exercise bouts have gained attention [3,4]. However, the evaluation of the antiproliferative potential of a single exercise bout needs technical improvement. Here, we present data of a pilot study showing how to evaluate the anti-cancer potential of single exercise bouts with an in vitro three-dimensional cell growth assay, using a triple-negative breast cancer cell line cultured with exercise-conditioned serum.

Chemopreventive Potential of Apple Pulp Callus Against Colorectal Cancer Cell Proliferation and Tumorigenesis.

This study focused on the evaluation of the chemopreventive potential of tissue in vitro culture of the "Mela Rosa Marchigiana" apple (MRM callus) that allows the amplification of secondary metabolites. The MRM pulp and MRM callus chemopreventive potential was evaluated in terms of antiproliferative activity, inhibition of tumorigenesis in soft agar cultures, cell cycle and western blotting analyses in CaCo2 and LoVo colon cancer cell lines and in JB6 promotion-sensitive (JB6 P+) cells. MRM callus induced a strong concentration-dependent inhibition of colon cancer cell proliferation and suppressed 12-o-tetra-decanoyl-phorbol-13-acetate-induced tumorigenesis of JB6 P+ cells in soft agar cultures. MRM callus inhibited the phosphorylation of JNK, p38, and eIF2alpha. Our data indicate that the MRM callus exerts a good antiproliferative and antitumorigenic potential through the MAP kinase inhibition and could provide natural compounds with chemopreventive properties.

Metformin prevents cell tumorigenesis through autophagy-related cell death.

Autophagy is a cellular mechanism by which cells degrade intracellular components in lysosomes, maintaining cellular homeostasis. It has been hypothesized that autophagy could have a role in cancer prevention through the elimination of damaged proteins and organelles; this could explain epidemiological evidence showing the chemopreventive properties of the autophagy-inducer metformin. In this study, we analyzed the autophagy-related effect of metformin in both cancer initiation and progression in non-tumorigenic cells. We also analyzed the induction of tumorigenesis in autophagy-deficient cells, and its correlation with the ER stress. Our results showed that metformin induced massive cell death in preneoplastic JB6 Cl 41-5a cells treated with tumor promoter (phorbol) and in NIH/3T3 treated with H2O2. Inhibiting autophagy with wortmannin or ATG7 silencing, the effect of metformin decreased, indicating an autophagy-related cytotoxic activity under stress conditions. We also found an induction of tumorigenesis in ATG7-silenced NIH/3T3 cell clone (3T3-619C3 cells), but not in wild-type and in scrambled transfected cells, and an upregulation of unfolded protein response (UPR) markers in 3T3-619C3 cells treated with H2O2. These findings suggest that autophagic cell death could be considered as a new mechanism by which eliminate damaged cells, representing an attractive strategy to eliminate potential tumorigenic cells.

New Insights into the Role of Exercise in Inhibiting mTOR Signaling in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 and is characterized by its aggressive nature, lack of targets for targeted therapies, and early peak of recurrence. Due to these specific characteristics, chemotherapy does not usually yield substantial improvements and new target therapies and alternative strategies are needed. The beneficial responses of TNBC survivors to regular exercise, including a reduction in the rate of tumor growth, are becoming increasingly apparent. Physiological adaptations to exercise occur in skeletal muscle but have an impact on the entire body through systemic control of energy homeostasis and metabolism, which in turn influence the TNBC tumor microenvironment. Gaining insights into the causal mechanisms of the therapeutic cancer control properties of regular exercise is important to improve the prescription and implementation of exercise and training in TNBC survivors. Here, we provide new evidence of the effects of exercise on TNBC prevention, control, and outcomes, based on the inhibition of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB also known as Akt)/mammalian target of rapamycin (mTOR) (PI3K-Akt-mTOR) signaling. These findings have wide-ranging clinical implications for cancer treatment, including recurrence and case management.

Leishmania Infection Induces MicroRNA hsa-miR-346 in Human Cell Line-Derived Macrophages.

Leishmaniasis is an anthropo-zoonotic disease caused by various Leishmania species. The clinical manifestations of the disease vary according to the species and host characteristics. Leishmania infection leads to subversion/modulation of the host's innate immune response and cellular metabolic pathways. In the last years, it has been shown that many host cell gene expression and signaling pathways are targeted by Leishmania to subvert host defenses (e.g., oxidative damage, immune activation, antigen presentation, apoptosis) and allow parasite survival and replication. However, the molecular mechanisms triggered by the parasite are not fully elucidated. The role of miRNA has recently been evaluated in human or murine macrophages infected with Leishmania (Leishmania) major, L. (L.) donovani or L. (L.) amazonensis. However, no literature exists regarding miRNA dysregulation in host cells infected with L. (L.) infantum or L. (Viannia) species. Since we previously showed that L. (L.) infantum infection induced unfolded protein response (UPR) in macrophages, we focused on miR-346, which has been shown to be induced by the UPR-activated transcription factor sXBP1 and has a potential role in the modulation of the immune response. Macrophages differentiated from U937 and/or THP-1 human monocytic cells were infected with four L. (L.) infantum strain/clinical isolates and one L. (V.) sp. clinical isolate. A significant upregulation of miR-346 (p < 0.05) was observed in infections with all the Leishmania species tested. Moreover, RFX1 (a miR-346 predicted target gene) was found to be significantly downregulated (p < 0.05) after 48h infection, and miR-346 was found to have a role in this downregulation. The induction of miR-346 in macrophages infected with L. (L.) infantum and L. (V.) sp., reported here for the first time, could play a role in regulating macrophage functions since several MHC- or interferon-associated genes are among the targets of this miRNA. Hence, miR-346 could be considered an attractive anti-Leishmania drug target.