Plants of the Phytolaccaceae family with antimicrobial activity: A systematic review.

Phytolaccaceae is a plant family of the order Caryophyllales, which includes species used in traditional medicine to treat diseases. The purpose of this study was to investigate Phytolaccaceae family plants with potential antimicrobial action, through a systematic review. The study was conducted following the criteria of PRISMA protocol. The search was performed in the electronic databases PubMed, Web of Science, Scopus, and LILACS, in March 2021. The search strategy used free descriptors and terms, limiting articles to the English language, regardless of publication year. The risk of bias and the quality of publications were based on the CONSORT checklist, modified for in vitro studies and SYRCLE's RoB tool for in vivo study. Five independent judges performed quality assessments of publications and risk of bias analysis. Ninety-five publications were retrieved from the databases and, after screening and eligibility criteria, 22 articles remained, from 1998 to 2019. In the selected studies, the plants were obtained from eight countries. In vivo and in vitro studies of extracts from the Phytolaccaceae family plants, evaluating antibacterial (8 publications), antifungal (8), anti-Trypanosoma (2), anti-Leishmania (2), antiviral (1), and antiamoebic (1) activities, are included. The plant species identified belong to genera Petiveria, Phytolacca, Gallesia, Trichostigma, and Seguieria. The risk of bias in the 22 publications both in vitro and in vitro was suboptimal. The evidence obtained showed that the Phytolaccaceae family, a source of plants with antimicrobial action, can serve as a basis for the creation of new herbal medicines, expanding the possibility of treatment for infectious diseases and stimulating their preservation and biodiversity. However, more high-quality studies are needed to establish the clinical efficacy of the plant.

A standardized intraperitoneal Glucantime™ for experimental treatment of cutaneous leishmaniasis caused by Leishmania amazonensis in BALB/c mice.

Glucantime™ is the pentavalent antimony (Sb+5) recommended as the first choice for treating cutaneous leishmaniasis (CL). It has been used as treatment control in animal studies to investigate new anti-Leishmania compounds. However, these studies have a range of Glucantime™ doses, different treatment times and routes of administration, and differing results. Our goal was to standardize intraperitoneal Glucantime™ treatment for CL in BALB/c mice infected with L. amazonensis. BALB/c mice were divided into six groups, with eight animals per group. The animals were infected with L. amazonensis and intraperitoneally treated with different doses of Sb+5 (20, 100 and 200 mg/kg/day) for 30 consecutive days. Healthy animals were used as negative infection and treatment control. Infected and untreated animals were used as positive infection control. Animals infected and treated with Ampho B were used as treatment control. Biochemical and histological analysis was performed to assess renal and liver toxicity. The parasite load in the popliteal lymph node, spleen and liver was determined by limiting dilution. Histological and collagen fiber analyses were performed on the lesions. Animals treated with Sb+5 100 and 200 mg/kg/day showed a decreased paw measurements, associated with a reduction in the parasite load, with a clinical cure rate of 50% and 37.5%, respectively. These groups of animals also showed tissue regeneration and reduced inflammation. Animals treated with 100 mg/kg/day had collagen fiber parameters similar to those of the negative infection control. There were no biochemical signs of renal or liver toxicity in any of the groups. We found that Sb+5 100 mg/kg/day was the lowest dose that showed effectiveness in treating CL in mice, and it may be a good model of treatment control in studies evaluating new treatments for CL in BALB/c mice.

The anti-Leishmania potential of bioactive compounds derived from naphthoquinones and their possible applications. A systematic review of animal studies.

Leishmaniasis affects millions of people worldwide, and available treatments have severe limitations. Natural and derivative products are significant sources of innovative therapeutic agents. Naphthoquinones are natural or synthetic chemical compounds with broad biological activity. This systematic review aimed to evaluate the potential anti-Leishmania activity of bioactive compounds derived from naphthoquinones in animal models. Conducted in accordance with PRISMA guidelines, two blocks of MeSH terms were assembled: group I, Leishmania OR Leishmaniasis; group II, Atovaquone OR Lapachol OR Beta lapachone OR Naphthoquinones. The search was performed on PubMed, Web of Science, SCOPUS, EMBASE, and Lilacs databases. Twenty-four articles were retrieved and submitted for quality assessment using the SYRCLE critical appraisal tool. The in vivo anti-Leishmania potential of naphthoquinones was evaluated in visceral and cutaneous leishmaniasis using several measurement parameters. Analyzed compounds varied in structure, association with reference drugs, and encapsulation using a drug delivery system. The study design, including treatment protocol, differed between studies. The findings of the studies in this systematic review indicate the anti-Leishmania potential of naphthoquinones in vivo, with different treatment regimens directed against different Leishmania species. The employed drug delivery systems improve the results concerning selectivity, distribution, and required therapeutic dose. The immunomodulatory action was shown to be beneficial to the host, favoring an adequate immune response against infection by Leishmania parasites since it favored Th1 responses. All studies presented a moderate to high risk of bias. These findings suggest that more studies are needed to assess the overall effectiveness and safety of these treatments.

Genetic variations in the human immune system influence susceptibility to tegumentary leishmaniasis: a systematic review and meta-analysis.

OBJECTIVES: The outcomes of tegumentary leishmaniasis (TL) rely on a complex interaction between the host immune system and the parasite. This study assessed the influence of polymorphisms in immune-related genes on TL. METHODS: Web of Science, Scopus, PubMed, and Embase databases were searched systemically. The meta-analysis used a retrospective model in examining alleles, heterozygotes, and homozygotes. A quality assessment and an analysis of cumulative evidence were performed. RESULTS: A total of 29 genes (encoding for cytokines, chemokines, and other immune receptors) and 84 polymorphisms were analyzed. The IL-1ß_rs16944 (OR = 1.341, p = 0.003), TNF-α_rs1800629 (OR = 3.804, p = 0.004), MIF_rs755622 (OR = 3.357, p = 0.001), and INF- γ_rs243056 (OR = 1.670, p = 0.028) polymorphisms were speculated as risk factor for TL. They decrease the expression of the corresponding genes crucial for TL control. The quality assessment score was approximately 50%, suggesting the need for a clear method and polymorphism characterization for further comparison. The relevant risk of bias and other considerations resulted in low and moderate cumulative evidence confidence. CONCLUSIONS: IL-1ß_rs16944, TNF-α_rs1800629, MIF_rs755622, and INF-γ_rs2430561 polymorphisms were speculated as risk factor for TL, corroborating that IL-1ß, TNF-α, INF-γ, and MIF are involved in the TL pathogenesis.

Leukocyte Behavior in Mesenteric Microcirculation upon Experimental By Leishmania Spp. in BALB/c Mice.

BACKGROUND: We aimed to determine the cellular recruitment (leukocyte rolling and adhesion) by which the Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis, and L. (Leishmania) major species in the mesenteric microcirculation of BALB/c mice. METHODS: Five experimental groups were considered: group 1 (L. braziliensis); group 2 (L. amazonensis); group 3 (L. major); group 4 (control group with PBS); group 5 (negative control group), analyzed 3, 6, 12, and 24 h after parasite inoculation. RESULTS: Infections by the different Leishmania species caused an increase in the number of rolling leukocytes: L. braziliensis a peak at 6 h; L. amazonensis and L. major a peak at 3 h. The Leishmania infections induced leukocyte adhesion: L. major and L. amazonensis showed an increase after 3 and 6 h, respectively. CONCLUSION: The kinetics of cellular recruitment in Leishmania infections, leading to infection susceptibility or resistance, indicates that distinct mechanisms regulate the initial response to Leishmania infection and determine its course.

Screening of six medicinal plant species for antileishmanial activity.

This study is aimed to investigate the in vitro anti-leishmanial activity of ethanolic, aqueous or dichloromethane extracts of leaves, flowers, fruits or roots, of six medicinal plant species, namely, Nectandra megapotamica, Brunfelsia uniflora, Myrcianthes pungens, Anona muricata, Hymenaea stigonocarpa and Piper corcovandesis. After isolation and analysis of chemical components by ultra-high performance liquid chromatography-high-resolution tandem mass spectrometry (UHPLC-HRMS/MS), the extracts were also tested for toxicity in J774.A1 macrophages and human erythrocytes. Phenolic acids, flavonoids, acetogenins, alkaloids and lignans were identified in these extracts. Grow inhibition of promastigotes forms of Leishmania amazonensis and Leishmania braziliensis and the cytotoxicity in J774.A1 macrophages were estimated by the XTT method. The most promising results for L. amazonensis and L. braziliensis were shown by the ethanolic extract of the fruits of Hymenaea stigonocarpa and dichloromethane extract of the roots of Piper corcovadensis, with IC 50 of 160 and 150 µg mL-1, resp. Ethanolic extracts of A. muricata (leaf), B. uniflora (flower and leaf), M. pungens (fruit and leaf), N. megapotamica (leaf), and aqueous extract of H. stigonocarpa (fruit) showed IC 50 > 170 µg mL-1 for L. amazonensis and > 200 µg mL-1 for L. braziliensis. The extracts exhibited low cytotoxicity towards J774.A1 macrophages with CC 50 > 1000 µg mL-1 and hemolytic activity from 0 to 46.1 %.

Campomanesia xanthocarpa (Mart.) O. Berg essential oil induces antileishmanial activity and remodeling of the cytoplasm organelles.

Leishmaniasis is a neglected disease that affects millions of people worldwide. This study aimed to analyze antileishmanial activity of Campomanesia xanthocarpa leaf essential oil (EO) on promastigote and amastigote forms of Leishmania amazonensis, cytotoxicity in murine macrophages and sheep erythrocytes. The essential oil (EO) was analyzed by gas chromatography/mass spectrophotometry. The main and most abundant compounds were sesquiterpene hydrocarbons (71.22%) such as trans-caryophyllene (7.87%), bicyclogermacrene (11.28%), and δ-cadinene (8.34%). The IC50 for promastigote and amastigote forms of L. amazonensis was 70 µg mL-1 and 6 µg mL-1, respectively. C. xanthocarpa EO was not cytotoxic for murine macrophages (CC50 1860 µg mL-1) and sheep erythrocytes (1.5%), presenting high selectivity index for protozoan (310). C. xanthocarpa EO induced effects on the morphology and ultrastructure of this parasite. The high activity for intracellular amastigote forms, low toxicity to murine macrophages, and erythrocytes, suggest that C. xanthocarpa EO is promising for the treatment of leishmaniasis.

Filter paper performance in PCR for cutaneous leishmaniasis diagnosis

Abstract INTRODUCTION: The objective of this study was to evaluate the performance of filter paper (FP) for lesion scraping collection in a polymerase chain reaction (PCR) for cutaneous leishmaniasis (CL) diagnosis. METHODS: Lesion scrapings from 48 patients were collected and analyzed for PCR. RESULTS: PCR with FP detected up to three Leishmania braziliensis promastigotes. Considering the direct search by microscopy or PCR of samples collected in STE buffer as standards, the sensitivity of PCR with FP was 100%. CONCLUSIONS: FP can be useful for CL diagnosis in remote regions, allowing high sensitivity in the detection of the parasite by PCR.

Filter paper performance in PCR for cutaneous leishmaniasis diagnosis.

INTRODUCTION: The objective of this study was to evaluate the performance of filter paper (FP) for lesion scraping collection in a polymerase chain reaction (PCR) for cutaneous leishmaniasis (CL) diagnosis. METHODS: Lesion scrapings from 48 patients were collected and analyzed for PCR. RESULTS: PCR with FP detected up to three Leishmania braziliensis promastigotes. Considering the direct search by microscopy or PCR of samples collected in STE buffer as standards, the sensitivity of PCR with FP was 100%. CONCLUSIONS: FP can be useful for CL diagnosis in remote regions, allowing high sensitivity in the detection of the parasite by PCR.

Effect of essential oils on Leishmania amazonensis: a systematic review.

This systematic review investigated the evidence for the therapeutic potential of essential oils (EOs) against Leishmania amazonensis. We searched available scientific publications from 2005 to 2019 in the PubMed and Web of Science electronic databases, according to PRISMA statement. The search strategy utilized descriptors and free terms. The EOs effect of 35 species of plants identified in this systematic review study, 45.7% had half of the maximal inhibitory concentration (IC50) 10 < IC50 ⩽ 50 µg mL-1 and 14.3% had a 10 < IC50µg mL-1 for promastigote forms of L. amazonensis. EOs from Cymbopogon citratus species had the lowest IC50 (1.7 µg mL-1). Among the plant species analyzed for activity against intracellular amastigote forms of L. amazonensis, 39.4% had an IC50 10 < IC50 ⩽ 50 µg mL-1, and 33.3% had an IC50 10 < IC50µg mL-1. Aloysia gratissima EO showed the lowest IC50 (0.16 µg mL-1) for intracellular amastigotes. EOs of Chenopodium ambrosioides, Copaifera martii and Carapa guianensis, administered by the oral route, were effective in reducing parasitic load and lesion volume in L. amazonensis-infected BALB/c mice. EOs of Bixa orellana and C. ambrosioides were effective when administered intraperitoneally. Most of the studies analyzed in vitro and in vivo for the risk of bias showed moderate methodological quality. These results indicate a stimulus for the development of new phytotherapy drugs for leishmaniasis treatment.

PCR primers designed for new world Leishmania: A systematic review.

Studies of the primers that were designed to detect New World Leishmania were systematically reviewed to report the characteristics of each target, detection limit, specificity of the primers designed and diagnostic sensibility. The papers identified in the databases PubMed and Web of Science involved 50 studies. Minicircle is the most applied target in molecular research for diagnosis, due to its high sensitivity in detecting Leishmania in different clinical samples, a characteristic that can be partially attributed to the higher number of copies of the minicircle per cell. The other molecular targets shown in this review were less sensitive to diagnostic use because of the lower number of copies of the target gene per cell, but more specific for identification of the subgenus and/or species. The choice of the best target is an important step towards the result of the research. The target allows the design of primers that are specific to the genus, subgenus or a particular species and also imparts sensitivity to the method for diagnosis. The findings of this systematic review provide the advantages and disadvantages of the main molecular targets and primers designed for New World Leishmania, offering information so that the researcher can choose the PCR system best suited to their research need. This is a timely and extremely thorough review of the primers designed for New World Leishmania.

Potential of Pluronics® P-123 and F-127 as nanocarriers of anti-Leishmania chemotherapy.

Leishmaniasis is a neglected disease and drugs approved for its treatment often lead to abandonment, failure of therapy and even death. Photodynamic therapy (PDT) has been shown to be a promising, non-invasive and selective for a target region without requiring high-cost technology. Usually, it is employed a photosensitizing agent (PS) incorporated into nanoparticles (NP). Pluronics® P-123 and F-127 micelles are very interesting aqueous NP promoting efficient and selective delivery and less adverse effects. This study aimed to detect the activity of Pluronics® P-123 and F-127 themselves since there is a scarcity of data on these NP activities without drugs incorporation. This study evaluated, in vitro, the activity of Pluronics® against promastigotes and amastigotes of Leishmania amazonensis and also their cytotoxicities. Additionally, the determination of the mitochondria membrane potential in promastigotes, internalization of these Pluronics® in the parasite membrane and macrophages and its stability in the culture medium was evaluated. Results showed that Pluronics® did not cause significant damage to human red cells and promastigotes. The P-123 and F-127 inhibited the survival rate of L. amazonensis amastigotes, and also presented loss of mitochondrial membrane potential on promastigotes. The Pluronics® showed low cytotoxic activity on J774A.1 macrophages, while only P-123 showed moderate cytotoxicity for BALB/c macrophages. The stability of P-123 and F-127 in culture medium was maintained for ten days. In conclusion, the NP studied can be used for incorporating potent leishmanicidal chemotherapy, due to their selectivity towards macrophages, being a promising system for the treatment of cutaneous leishmaniasis.

6,7-Dehydroroyleanone diterpene derived from Tetradenia riparia essential oil modulates IL-4/IL-12 release by macrophages that are infected with Leishmania amazonensis.

The treatment of cutaneous leishmaniasis in associated with several adverse effects and therapeutic failure, resulting in patients' abandonment of treatment. Research on new drugs with leishmanicidal potential from medicinal plants is essential. The anti-Leishmania activity of Tetradenia riparia essential oil (TrEO) and its derivatives, such as the diterpene 6,7-dehydroroyleanone (TrROY), and the immunomodulatory effects of TrEO have been reported. However, few studies have investigated the effects of TrROY. The present study evaluated the modulation of cytokine production by murine macrophages that were infected with Leishmania amazonensis (6 parasites/macrophage) and treated with TrROY (0.1, 1, and 100 µg/ml). Cytokine levels were measured by flow cytometry. The results were analyzed using Student's t test at a 95% confidence interval. Microscopic counting was performed to evaluate the inhibitory effects of TrROY on intracellular infection. TrROY modulated the production of cytokines that are essential for the immune defense response to Leishmania, with a decrease in interleukin-4 (IL-4) levels and an increase in IL-12 levels. A TrROY concentration of 0.1 µg/ml was chosen for the subsequent experiments. This dose was chosen because it modulated IL-4/IL-12 release by murine macrophages that were infected with Leishmania and because it presented no cytotoxic effects. TrROY (0.1 µg/ml) induced a 31% reduction of the rate of infection in murine macrophages compared with untreated cells. TrROY may be a promising leishmanicidal agent. Further in vitro and in vivo studies should be conducted to evaluate the anti-Leishmania and immunomodulatory activity of TrROY.

Alterations induced in the ileum of mice upon inoculation with different species of Leishmania: a preliminary study.

INTRODUCTION: Leishmania species cause skin, mucosal, and disseminated lesions. We studied the effects of three Leishmania species on ileal morphology in mice. METHODS: BALB/c mice were intraperitoneally inoculated with Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, and Leishmania (Leishmania) major (4 animals/group). After 72h, the ilea were collected and histologically processed. RESULTS: Following inoculation, the goblet cell and intraepithelial lymphocyte populations increased, while Paneth cell number and crypt width decreased. In addition, enterocyte size, villi height, and mucosa, submucosa, and muscular tunic thickness increased. CONCLUSIONS: Leishmania modified the quantity of cells in and morphology of mice ilea.

Alterations induced in the ileum of mice upon inoculation with different species of Leishmania: a preliminary study

Abstract INTRODUCTION: Leishmania species cause skin, mucosal, and disseminated lesions. We studied the effects of three Leishmania species on ileal morphology in mice. METHODS: BALB/c mice were intraperitoneally inoculated with Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, and Leishmania (Leishmania) major (4 animals/group). After 72h, the ilea were collected and histologically processed. RESULTS: Following inoculation, the goblet cell and intraepithelial lymphocyte populations increased, while Paneth cell number and crypt width decreased. In addition, enterocyte size, villi height, and mucosa, submucosa, and muscular tunic thickness increased. CONCLUSIONS: Leishmania modified the quantity of cells in and morphology of mice ilea.

Therapeutic Effects of Medicinal Plants on Cutaneous Wound Healing in Humans: A Systematic Review.

The pharmaceutical industry has made great strides in providing drugs that are able to stimulate the healing process, but only 1-3% of all drugs that are listed in Western pharmacopoeias are intended for use on the skin or cutaneous wounds. Of these, at least one-third are obtained from plants. We sought to review the therapeutic effects of medicinal plants on human skin lesions. For this systematic review, we searched the PubMed, Scopus, and Web of Science databases to identify clinical trials that were published from 1997 to 2017. We reviewed studies that described the use of medicinal plants for the treatment of skin lesions in humans. Ten studies were selected, eight of which were published from 2007 to 2016, with a total of 503 patients. Among the plant species that were used for the treatment of human skin lesions, 12 belonged to 11 families and were included in the analysis. All of the plant species that were studied presented high therapeutic potential for the treatment of cutaneous lesions.

The role of metalloproteases in Leishmania species infection in the New World: a systematic review.

This is a systematic review on the role of metalloproteases in the pathogenicity of the American tegumentary leishmaniasis (ATL) caused by New World Leishmania species. The review followed the PRISMA method, searching for articles in PubMed, EMBASE, LILACS and ISI Web of Science, by employing the following terms: 'leishmaniasis', 'cutaneous leishmaniasis', 'mucocutaneous leishmaniasis', 'diffuse cutaneous leishmaniasis', 'Leishmania' and 'metalloproteases'. GP63 of New World Leishmania species is a parasite metalloproteases involved in the degradation and cleavage of many biological molecules as kappa-B nuclear factor, fibronectin, tyrosine phosphatases. GP63 is capable of inhibiting the activity of the complement system and reduces the host's immune functions, allowing the survival of the parasite and its dissemination. High serological/tissue levels of host matrix metalloproteases (MMP)-9 have been associated with tissue damage during the infection, while high transcriptional levels of MMP-2 related with a satisfactory response to treatment. Host MMPs serological and tissue levels have been investigated using Western Blot, zymography, and Real Time polymerase chain reaction. GP63 detection characterizes species and virulence in promastigotes isolated from lesions samples using techniques mentioned previously. The monitoring of host MMPs levels and GP63 in Leishmania isolated from host samples could be used on the laboratory routine to predict the prognostic and treatment efficacy of ATL.

American tegumentary leishmaniasis: diagnostic and treatment challenges in a clinical case.

This clinical case presents a patient with a raised and ulcerative lesion with erythematous edges in the mouth, on the lower lip that was unsuccessfully treated as herpes labialis. Clinical data and laboratory tests (Montenegro skin test, indirect immunofluorescence, direct parasite search and polymerase chain reaction) led to the diagnosis of American tegumentary leishmaniasis caused by Leishmania (Viannia) sp. Treatment with pentavalent antimonial (Glucantime®) for 120 days was not effective and administration of amphotericin B for 30 days resulted in wound healing. Glucantime® treatment protocol was longer than the recommended by the Brazilian Ministry of Health in the handbook of mucosal leishmaniasis. This suggests that amphotericin B should have been administered earlier, preventing the psychological and social problems faced by the patient. This study reports a rare clinical case of primary mucosal leishmaniasis on the lip that had a delayed diagnosis, highlighting the precariousness in the management of disease and showing that, despite the importance of leishmaniasis in Brazil, it is still neglected by health professionals.

Contribution of photodynamic therapy in wound healing: A systematic review.

OBJECTIVE: We researched articles that used photodynamic therapy (PDT) for skin wound healing in humans. METHODS: The systematic review was conducted through scientific articles that investigated the action of PDT on wound healing in humans, published from July 2005 to March 2017, in the data bases PubMed and LILACS. RESULTS: The main types of wound described in selected articles in this review were chronic ulcer and non-melanoma skin cancer. For accomplishing the PDT, second generation of photosensitizing agents with laser or light emitting diode were used. The studies demonstrated that PDT contribute in several ways to the wound healing process: leading to cellular death; reducing or increasing inflammation; stimulating fibroblasts proliferation and, consequently, of collagen and elastin; raising transforming growth factor beta and metalloproteinases. Based on this, PDT provided good results in wound healing process, acting in several steps and accelerating tissue repair. CONCLUSIONS: PDT improved healing in many wound models in humans, revealing itself as a promising therapeutic modality for stimulating wound healing and remodelling.