Epidemiology and Genetic Characterization of Leishmania RNA Virus in Leishmania (Viannia) spp. Isolates from Cutaneous Leishmaniasis Endemic Areas in Panama.

Leishmania (Viannia) spp. can harbor a double-stranded RNA virus known as Leishmania RNA virus 1 (LRV-1), whose presence has been reported in nine countries across the Americas and seven Leishmania species. Here, we studied 100 Leishmania (Viannia) isolates from patients with cutaneous leishmaniasis collected from different endemic areas in Panama from 2016 to 2022. We identified L. (V.) panamensis, L. (V.) guyanensis, L. (V.) braziliensis/guyanensis hybrid, and L. (V.) panamensis sp.1. (genetic variant). LRV-1 was detected by RT-PCR in 9% of L. (Viannia) isolates (eight cases in L. (V.) panamensis, and one in L. (V.) guyanensis). Phylogenetic analysis based on sequencing data classified all LRV-1 isolates within genotype A, suggesting that LRV phylogenetic proximity is closely aligned with geographical distribution or to the phylogenetic proximity of the Leishmania host in the case of the L. (V.) panamensis and L. (V.) guyanensis in Panama.

Serological Screening and Risk Factors Associated with Leishmania infantum Positivity in Newly Diagnosed HIV Patients in Greece.

A serological screening was conducted to detect IgG antibodies against Leishmania infantum (L. infantum) in newly diagnosed human immunodeficiency virus (HIV) patients in Greece. The study also examined potential risk factors and the agreement of commercially available serological methods. IgG antibodies against L. infantum were detected using enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence antibody test (IFAT), and Western blot (WB). Out of 155 samples, 14 (9.0%) tested positive for IgG antibodies against L. infantum using at least two methods. Statistical analysis showed substantial agreement between WB and IFAT methods (Cohen's kappa = 0.75) but moderate overall agreement among the three methods (Fleiss' kappa = 0.42). Additionally, HIV+ intravenous drug users faced 3.55 times (p = 0.025) higher risk of testing positive for L. infantum IgG, positing that anthroponotic transmission between these patients is a plausible hypothesis based on existing literature. Non-invasive and cost-effective techniques are preferred to detect asymptomatic infections, and leishmaniasis screening should be conducted immediately after HIV diagnosis in endemic regions to enable prophylactic treatment for leishmaniasis in addition to antiretroviral therapy. To maximize sensitivity, performing at least two different serological methods for each patient is recommended.

A Second Wind for Inorganic APIs: Leishmanicidal and Antileukemic Activity of Hydrated Bismuth Oxide Nanoparticles.

American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology is gaining importance in the field, since it can provide better efficacy and lower toxicity of the drugs. The present study aimed to synthesize, characterize, and evaluate the in vitro leishmanicidal and antileukemic activity of bismuth nanoparticles (BiNPs). Promastigotes and amastigotes of L. (V.) guyanensis and L. (L.) amazonensis were exposed to BiNPs. The efficacy of the nanoparticles was determined by measurement of the parasite viability and the percentage of infected cells, while the cytotoxicity was characterized by the colorimetry. BiNPs did not induce cytotoxicity in murine peritoneal macrophages and showed better efficacy in inhibiting promastigotes (IC50 < 0.46 nM) and amastigotes of L. (L.) amazonensis. This is the first report on the leishmanicidal activity of Bi-based materials against L. (V.) guayanensis. BiNPs demonstrated significant cytotoxic activity against K562 and HL60 cells at all evaluated concentrations. While the nanoparticles also showed some cytotoxicity towards non-cancerous Vero cells, the effect was much lower compared to that on cancer cells. Treatment with BiNPs also had a significant effect on inhibiting and reducing colony formation in HL60 cells. These results indicate that bismuth nanoparticles have the potential for an inhibitory effect on the clonal expansion of cancer cells.

Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential.

A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2-5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure-activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.

Prevalence of Leishmaniasis among Blood Donors: A Systematic Review and Meta-Analysis.

Our study seeks to provide a comprehensive assessment of leishmaniasis prevalence among blood donors, employing rigorous methodologies to inform public health initiatives and transfusion safety measures. A thorough literature search was conducted using electronic databases (Medline, Scopus, Web of Science, and Google Scholar) to identify the relevant studies reporting the prevalence of leishmaniasis among blood donors, gathering a wide range of studies encompassing different geographic locations and time periods. The pooled prevalence with a 95% confidence interval (CI) was estimated, and quality assessment, outlier analysis, and influential analysis were performed to ensure the robustness and validity of the findings. Our search and subsequent analyses led to the inclusion of thirty-five studies in our review. Using molecular diagnostic methods, the prevalence was estimated at 2.3% (95% CI 1-3.9%), while serological diagnostic methods indicated a higher prevalence rate of 4.5% (95% CI 2.8-6.7%). Notably, we observed significant heterogeneity among the included studies for each analysis. The observed heterogeneity highlights the need for future research to delve into the factors influencing leishmaniasis prevalence, with prospective and retrospective studies addressing the limitations identified in this review.

Epidemiological Characteristics and Spatiotemporal Patterns of Visceral Leishmaniasis in Xinjiang, China, during 2004-2021.

The spread of visceral leishmaniasis (VL), a serious global zoonotic parasitic disease, is mostly under control; however, several cases have been reported in recent decades in Xinjiang, China. This study aimed to analyze the epidemiological status and spatiotemporal clustering characteristics of VL in Xinjiang, China, between 2004 and 2021 to provide a basis for the development and implementation of surveillance and response measures. Data on VL incidence during 2004-2021 were collected from the National Diseases Reporting Information System of China. Global spatial autocorrelation analysis, identification of local indicators of spatial association, and spatial-temporal clustering analysis were conducted to identify the distribution and high-risk areas. A total of 2034 VL cases were reported, with a mean annual incidence of 0.50 per 100,000. There was a general decreasing trend in the incidence of VL during our study period. The majority of the cases were reported from October to February of the following year, and fewer cases were reported from April to July. Spatial autocorrelation analysis revealed that the incidence of VL was spatially clustered within a few counties. Significant differences were observed during the study period (Moran's I = 0.74, Z = 4.900, p < 0.05). The male-to-female ratio was 1.37:1, and most patients were in the age group 0-3 years. Cases were primarily distributed in seven regions and two autonomous prefectures, and Kashgar reported the highest number of cases (1688, 82.98%). Spatial analysis revealed that the aggregation of VL was predominantly observed in southwest Xinjiang. This was in alignment with the high-risk areas identified by spatiotemporal clustering analysis. The H-H clustering region was primarily observed in Gashi, Atushi, Shufu, Injisha, Kashgar, Yepuhu, and Bachu. These findings indicate that integrated control measures must be taken in different endemic areas to strengthen the VL control program in Xinjiang, China.

Spliced-Leader RNA as a Dynamic Marker for Monitoring Viable Leishmania Parasites During and After Treatment.

Accurate detection of viable Leishmania parasites is critical for evaluating visceral leishmaniasis (VL) treatment response at an early timepoint. We compared the decay of kinetoplast DNA (kDNA) and spliced-leader RNA (SL-RNA) in vitro, in vivo, and in a VL patient cohort. An optimized combination of blood preservation and nucleic acid extraction improved efficiency for both targets. SL-RNA degraded more rapidly during treatment than kDNA, and correlated better with microscopic examination. SL-RNA quantitative polymerase chain reaction emerges as a superior method for dynamic monitoring of viable Leishmania parasites. It enables individualized treatment monitoring for improved prognoses and has potential as an early surrogate endpoint in clinical trials.

Non-invasive urine-based ELISA using a recombinant Leishmania protein to diagnose tegumentary leishmaniasis.

The diagnosis of tegumentary leishmaniasis (TL) is hampered by variable sensitivity and/or specificity of the tests. Serological assays are suitable to diagnose visceral leishmaniasis (VL); however, they present low performance for the detection of TL cases. Additionally, blood collection to obtain patient serum represents a challenge, as it is an invasive and uncomfortable procedure, requiring laboratorial infrastructure and trained professionals. In this context, the present study proposed to evaluate patient urine to detect TL, given that this analyte has proven to be effective in ELISA experiments for the detection of VL cases. For this, a Leishmania protein called LiHyV, two specific B-cell epitopes derived from protein amino acid sequence, and a Leishmania antigenic extract (SLA) were used as antigens. A total of 215 paired urine and serum samples were evaluated, and results showed that, when serum was employed as an analyte, rLiHyV, Peptide1, Peptide2, and SLA presented a sensitivity of 85 %, 29 %, 58 %, and 31 %, respectively, and a specificity of 97.5 %, 98 %, 100 %, and 97.5 %, respectively, in the diagnosis of TL. When urine was used, rLiHyV, Peptide1, Peptide2, and SLA presented a sensitivity of 95 %, 74 %, 67 %, and 52 %, respectively, and a specificity of 100 %, 99 %, 98 %, and 86 %, respectively. In conclusion, preliminary data suggest that urine could be considered as an alternative biological sample for the detection of TL cases.

Thiourea-functionalized aminoglutethimide derivatives as anti-leishmanial agents.

Aim: We aim to develop new anti-leishmanial agents against Leishmania major and Leishmania tropica. Materials & methods: A total of 23 thiourea derivatives of (±)-aminoglutethimide were synthesized and evaluated for in vitro activity against promastigotes of L. major and L. tropica. Results & conclusion: The N-benzoyl analogue 7p was found potent (IC50 = 12.7 µM) against L. major and non toxic to normal cells. The docking studies, indicates that these inhibitors may target folate and glycolytic pathways of the parasite. The N-hexyl compound 7v was found strongly active against both species, and lacked cytotoxicity against normal cells, whereas compound 7r, with a 3,5-bis-(tri-fluoro-methyl)phenyl unit, was active against Leishmania, but was cytotoxic in nature. Compound 7v was thus identified as a hit for further studies.

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Mortality due to visceral leishmaniasis in Brazil by municipalities, 2001-2018: a spatial-temporal analysis of estimates from the Global Burden of Disease study.

OBJECTIVES: In the American regions, Brazil accounts for 97% of visceral leishmaniasis (VL) cases, with a case fatality rate of approximately 10%. This study aimed to investigate the VL mortality distribution in Brazil and identify high-priority and high-risk areas for intervention strategies. STUDY DESIGN: This was an ecological study that analysed the spatial-temporal patterns of VL mortality in Brazilian municipalities. METHODS: Age-standardised VL mortality rates from the Global Burden of Disease study from 2001 to 2018 were used. The distribution of mortality in the municipalities was assessed, and subsequently the Local Index of Spatial Autocorrelation (LISA) analysis was conducted to identify contiguous areas with high mortality rates. Scan analysis identified clusters of high spatial-temporal risks. RESULTS: The highest mortality rates and clusters were in municipalities located in the Northeast region and in the states of Tocantins and Roraima (North region), Mato Grosso do Sul (Central-West region), and Minas Gerais (Southeast region). According to LISA, there was an increase in the number of municipalities classified as high priority from the first 3-year period (n = 434) to the last 3-year period (n = 644). The spatio-temporal analysis identified 21 high-risk clusters for VL mortality. CONCLUSION: Areas with a high risk of VL mortality should prioritise preventing transmission, invest in early diagnosis and treatment, and promote the training of healthcare professionals.

Targeting Leishmania Promastigotes and Amastigotes Forms through Amino Acids and Peptides: A Promising Therapeutic Strategy.

Millions of people worldwide are affected by leishmaniasis, caused by the Leishmania parasite. Effective treatment is challenging due to the biological complexity of the parasite, drug toxicity, and increasing resistance to conventional drugs. To combat this disease, the development of specific strategies to target and selectively eliminate the parasite is crucial. This Review highlights the importance of amino acids in the developmental stages of Leishmania as a factor determining whether the infection progresses or is suppressed. It also explores the use of peptides as alternatives in parasite control and the development of novel targeted treatments. While these strategies show promise for more effective and targeted treatment, further studies to address the remaining challenges are imperative.

Green solvent-based extraction of three Fabaceae species: A potential antioxidant, anti-diabetic, and anti-leishmanial agents.

The Fabaceae is renowned for its diverse range of chemical compounds with significant biological activities, making it a valuable subject for pharmacological studies. The chemical composition and biological activities of three Fabaceae species were investigated using methanol separately and in combination with dimethyl sulfoxide (DMSO) and glycerol for extraction. The results revealed the highest phenolic (49.59 ± 0.38 mg gallic acid equivalent/g), flavonoid (29.16 ± 0.39 mg rutin equivalent/g), and alkaloid (14.23 ± 0.54 mg atropine equivalent/g) contents in the Caesalpinia decapetala methanol extracts. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and DNA protection activity were the highest (0.88 ± 0.43 µg/mL IC50 and 2149.26 band intensity) in Albizia julibrissin methanol extracts. The α-amylase activity was highest in all methanol extracts (<15 µg/mL IC50 values), while the α-glucosidase inhibition potential was highest (<1 µg/mL IC50 value) in the methanol-glycerol and methanol-DMSO extracts. Pearson coefficient analysis showed a strong positive correlation between the DPPH and α-amylase assays and phytochemicals. Anti-leishmanial activity was observed in decreasing order: A. julibrissin (74.75 %) > C. decapetala (70.86 %) > Indigofera atropurpurea (65.34 %). Gas chromatography-mass spectrometry revealed 33 volatile compounds and, aamong these (Z)-9-octadecenamide was detected in the highest concentration ranging from 21.85 to 38.61 %. Only the methanol extracts of the examined species could be assessed for in vivo studies for immediate applications.

Differences in the Cellular Immune Response during and after Treatment of Sudanese Patients with Post-kala-azar Dermal Leishmaniasis, and Possible Implications for Outcome.

BACKGROUND: The host cellular immune response associated with two treatments for post-kala-azar dermal leishmaniasis (PKDL) - paromomycin plus miltefosine (Arm 1), and liposomal amphotericin B plus miltefosine (Arm 2) - was examined in Sudanese patients before treatment (D0), at the end of treatment (D42), and during the post-treatment period (D180). METHODS: Whole blood samples were stimulated with soluble Leishmania antigen for 24 h (whole blood assay [WBA]) and the concentrations of Th1/Th2/Th17-associated cytokines, IP-10, PDL-1 and granzyme B were determined. RESULTS: The Arm 1 treatment (98.2% cure rate) induced a Th1/Th2/Th17 response, while the Arm 2 treatment (80% cure rate) induced a Th1/Th2 response. Five Arm 2 patients relapsed and showed lower IFN-γ, TNF and IL-1ß concentrations at D0 than non-relapsers in this Arm. In patients with low-IFN-γ-production at D0, Arm 1 treatment led to a better host immune response and clinical outcome than Arm 2 treatment. CONCLUSIONS: A Th1/Th2/Th17 response was associated with a higher cure rate. Patients with low IFN-γ, TNF and IL-1ß before treatment are more likely to relapse if they undergo Arm 2-type treatment. Determining IFN-γ, TNF and IL-10 levels prior to treatment could help predict patients at higher risk of relapse/recovery from PKDL. TRIAL REGISTRATION: ClinicalTrials.gov NCT03399955, Registered 17 January 2018, https://clinicaltrials.gov/study/ NCT03399955.

The role of Nrf2 signaling in parasitic diseases and its therapeutic potential.

In response to invading parasites, one of the principal arms of innate immunity is oxidative stress, caused by reactive oxygen species (ROS). However, oxidative stresses play dual functions in the disease, whereby free radicals promote pathogen removal, but they can also trigger inflammation, resulting in tissue injuries. A growing body of evidence has strongly supported the notion that nuclear factor erythroid 2-related factor 2 (NRF) signaling is one of the main antioxidant pathways to combat this oxidative burst against parasites. Given the important role of NRF2 in oxidative stress, in this review, we investigate the activation mechanism of the NRF2 antioxidant pathway in different parasitic diseases, such as malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, schistosomiasis, entamoebiasis, and trichinosis.

Incidence of cutaneous Leishmaniasis in humans during the COVID-19 pandemic in Baluchistan Province, Pakistan.

INTRODUCTION: Cutaneous leishmaniasis (CL) is one of the neglected tropical diseases that affects impoverished communities throughout the world. In Pakistan CL is an endemic disease. AIMS AND OBJECTIVES: This study aimed to determine the incidence of CL infection in the Baluchistan province of Pakistan from January 2020 to March 2022 during the COVID-19 pandemic. METHODOLOGY: A total of 1047 clinically suspected cases of CL from Bolan Medical College Hospital, Quetta, were followed up in the study. The data regarding the epidemiological characterstics, pathological information, and treatment of patients was collected. RESULTS: Out of 1047 probable cases of CL, 594 (56.73%) cases were found to be positive for CL. Females had the highest infection rate, with the majority of reported cases being in the 0-9-year age group. Most CL cases were reported in April in the year 2020, with a few cases reported in June. But in the year 2021, the highest number of cases were reported in December. The number of overall cases has gradually increased in the year 2022, most likely because of the reduction in COVID-19 pandemic restrictions. The p value for the positive as compared to suspected cases in the years 2020, 2021, and 2022 was calculated as 0.8925, 0.8763, and 0.8535 respectively. CONCLUSIONS: Further epidemiological studies and health education campaigns are recommended to increase public awareness. It is strongly advised that local, provincial, and national health authorities establish and maintain effective leishmaniasis surveillance systems to promptly identify disease outbreaks and implement timely control measures.

Histopathological findings and diagnosis of cutaneous leishmaniasis, confirmed by PCR, in an endemic region of Brazil.

INTRODUCTION: Diagnosis of cutaneous leishmaniasis (CL) is difficult, and the correct use of histopathological criteria can be useful in clinical practice. The present study evaluates the association between histopathological findings and the results of polymerase chain reaction (PCR) in clinically suspected cases of CL. METHODOLOGY: Skin samples were received in a laboratory from an endemic region of Brazil for over nine years. Associations were analyzed by means of the Chi square test with a 5% level of significance. RESULTS: Of the 222 examined samples, 190 (85.6%) tested positive by PCR. All 25 cases identified by microscopic examination also tested positive by PCR. Except for the more intense inflammatory infiltrate, all other evaluated histological variables (ulceration, epidermal hyperplasia, hyperkeratosis, presence of granuloma, neutrophils, histiocytes, lymphocytes, plasmocytes, and necrosis) were not significantly associated with PCR positivity. CONCLUSIONS: The intensity of the inflammatory infiltrate is a good indicator of the occurrence of CL. Histopathological aspects are useful to increase the predictive values of CL diagnoses, but PCR is still necessary to confirm or exclude the disease.

Prevalence of hepatitis B and C virus infections among visceral leishmaniasis patients: a systematic review and meta-analysis.

Background: Visceral leishmaniasis (VL) patients are at high risk of acquiring hepatitis B virus (HBV) and hepatitis C virus (HCV) infections during multiple injections and the anti-leishmanial treatment possesses a potential hepatotoxic effect. This systematic review and meta-analysis determined the pooled prevalence of HBV and HCV infections in VL patients. Methods: This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), with the assigned number CRD42024516889, and conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed using PubMed, Medline, EMBASE, Google Scholar, Web of Science, and Science Direct databases. Data were extracted using Microsoft Excel and analyzed using STATA version 11.0 software. A random-effects model was used to estimate the pooled effect size of outcome variables across studies with a 95% confidence interval and was displayed in a forest plot. The I 2 statistic was used to check for heterogeneity. The presence of publication bias was determined using a funnel plot and Egger's test with a p value <0.05 evidence of statistically significant bias. Results: Among 216 retrieved records, seven studies were eligible for systematic review and meta-analysis. A total of 937 VL patients were examined, revealing that 105 and 93 were infected with HBV and HCV, respectively. The pooled prevalence of HBV was 16.15% (95% CI: -4.10 to 36.39), with a significant heterogeneity (I 2 = 91.4%, p < 0.001). The combined prevalence of HCV was 13.74% (95% CI: 1.32-26.16, I 2 = 71.6%, p = 0.003). The funnel plot (symmetry), and Egger's test in both HBV (p value = 0.650) and HCV (p value = 0.841) revealed no publication bias. In subgroup analysis, high HBV and HCV prevalence was detected in Sudan; 20.64% (95% CI: -13.60 to 54.88) and India; 18.26% (95% CI: -0.40 to 36.92%), respectively. Conclusion: This study revealed a high prevalence of both HBV and HCV infections in VL patients. In subgroup analysis, the prevalence of HBV and HCV was high in Sudan and India, respectively. Therefore, screening of VL patients for HBV and HCV, vaccination of VL patients in endemic regions, and collaboration between kala-azar and hepatitis elimination programs are required. Systematic review registration: https://www.crd.york.ac.uk/prospero/export_details_pdf.php#page=1.00&gsr=0, identifier: CRD42024516889.

Identification of Lutzomyia longipalpis' using MALDI-TOF peptide/protein profiles.

Sand flies are vectors of great public health importance, since they constitute a group of hematophagous insects responsible for etiological agents transmission of zoonotic diseases such a visceral leishmaniasis. In face of the expansion of these diseases, efficient control strategies are needed which depend on comprehending the sand fly eco-epidemiology. In this regard, MALDI-TOF mass spectrometry has been used for bacteria, fungi and yeast detection studies through peptide/protein profiles. However, little is known about interference of biological factors associated with vector ecology, such as blood meal preferences and even sand fly age on the peptide/protein profiles. Thus, the present study aimed to evaluate the differences in peptide/protein profiles of the sand fly Lutzomyia longipalpis, by means of MALDI-TOF, due to the sand fly's age, sex, blood meal source and Leishmania infantum infection. Sample preparation was made removing both head and last abdomen segments keeping the thorax, its appendices and the rest of the abdomen. Five specimens per pool were used to obtain peptide/protein extract of which 1 µL solution was deposited over 1 µL MALDI matrix dried. Characteristic spectra were analyzed using principal coordinate analysis as well as indicator species analysis to discriminate differences in sand flies's peptide/protein profile by sex, age, blood meal source and L. infantum infection. The results show that the evaluated variables produced distinct peptide/protein profiles, demonstrated by the identification of specific diagnostic ions. It was found that the interference of biological factors should be taken into account when using the MALDI-TOF analysis of sand fly species identification and eco-epidemiological applications in field studies. Based on our results, we believe that it is possible to identify infected specimens and the source of blood meal in a collection of wild sand flies, serving to measure infectivity and understand the dynamics of the vector's transmission chain. Our results may be useful for epidemiological studies that look at the ecology of sand flies and leishmaniasis, as well as for raising awareness of biological characteristics' impact on peptide/protein profiles in sand fly species identification.

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis.

Introduction: Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. Methods: We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. Results: The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. Discussion: The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.

Nicotinamide mitigates visceral leishmaniasis by regulating inflammatory response and enhancing lipid metabolism.

BACKGROUND: Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. METHODS: In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. RESULTS: Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid ß-oxidation by upregulating key enzymes to maintain lipid homeostasis. CONCLUSIONS: Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL.