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.

Low expression of hypoxia-inducible factor-1α and differential expression of immune mediators during experimental infection with Leishmania (Viannia) spp.

Leishmania (Viannia) species are the major agents of cutaneous leishmaniasis (CL) in the Americas. Ulcerative stigmatizing skin lesions generally characterize CL. The microenvironment during Leishmania infection is rich in inflammatory cells and molecules, which contrasts with low oxygen levels. The hypoxia-inducible factor (HIF)-1α activates several genes in response to hypoxia and inflammatory reactions, but its role in the CL course is poorly understood. We investigated the expression pattern of the genes HIF-1α, arginase, inducible NO synthase (iNOS), interferon (IFN)-γ, interleukin (IL)-12, and IL-10 in skin lesions and lymph nodes of golden hamsters infected with L. braziliensis, L. lainsoni, and L. naiffi. The animals were infected and followed for 105 days, with paw volume measurements and photos taken weekly. Euthanasia was performed at 0, 15, 56, and 105 days post-infection. The parasite load of paw and lymph node tissues were measured through absolute quantification at real-time PCR (qPCR), and reverse transcription qPCR (RT-qPCR) was applied to demonstrate the relative mRNA expression of the target genes. Among groups, animals infected with L. braziliensis had the highest parasite load in paws and lymph nodes. HIF-1α mRNA was down-regulated during chronic Leishmania (Viannia) infection but demonstrated less inhibition in hamsters infected with L. lainsoni and L. naiffi. Arginase was the most detectable gene in animals infected by L. braziliensis; IFN-γ and IL-10 genes were the most detectable in L. lainsoni and L. naiffi-infected animals. HIF-1α gene transcription seemed to be down-modulated byL. (Viannia)infection and was less inhibited by L. lainsoni and L. naiffi when compared toL. braziliensis. Animals with L. lainsoni and L. naiffi showed better control of the disease. Further studies are necessary to evaluate the mechanism influencing HIF-1α expression and its role on CL protection; such research could elucidate potential use of HIF-1α as a therapeutic target.

In vitro activity of cinnamaldehyde on Leishmania (Leishmania) amazonensis.

Tegumentary leishmaniasis is an endemic disease that urgently needs new and effective treatments. L. amazonensis is one of the main species involved in the transmission of this infectious and non-contagious disease. The currently available treatments for leishmaniasis have high toxicity and vary in efficacy. Natural compounds have been used as alternative therapies for various other diseases, often presenting excellent results with little or no adverse reaction. Cinnamaldehyde is the primary compound of essential oil from cinnamon bark; it is used in the cosmetic, pharmaceutical, and food industries for its antimicrobial and anti-inflammatory effects, as shown in the literature. As far as we know, no studies have evaluated cinnamaldehyde activity against L. amazonensis. In this context, we investigated the anti-Leishmania potential of cinnamaldehyde against promastigote and amastigote forms of L. amazonensis; cytotoxicity in erythrocytes, HaCat cells, and macrophages J774A.1; and its ability to stimulate nitric oxide. Cinnamaldehyde showed anti-Leishmania activity, with an average IC50 of approximately 212 µM against promastigote forms of L. amazonensis (three study periods: 24, 48, and 72 h) and an IC50 of 398.06 ± 42.10 µM against amastigote forms of L. amazonensis. Considerable toxicities to human erythrocytes and HaCat cells were not recorded from treatments with 4000 µM and 1000 µM of cinnamaldehyde, respectively. However, we recorded cytotoxicity with J774A.1 macrophages (0.48-1000 µM), which resulted in a low therapeutic selectivity index. The compound did not alter the production of nitric oxide in the cells evaluated. Overall, we observed that cinnamaldehyde showed anti-Leishmania activity and moderate toxicity. We encourage further research into the use of cinnamaldehyde to treat cutaneous leishmaniasis.

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.

Successful combined therapy with Glucantime™ and pentoxifylline for the nasal mucosal lesion recently developed in a leishmaniasis patient having untreated cutaneous lesion for seven decades.

Leishmaniasis is a worldwide problem and has been neglected in a wide range of fields, from diagnosis to treatment. This report describes a case of mucosal leishmaniasis, which may developped after seven decades of an inadequately treated cutaneous lesion. A female patient, 79 years old, from the non-endemic area for leishmaniasis in northern Paraná, presenting mucosal lesion in the nose and throat, reported an "angry ulcer" treated inappropriately as a child when she lived in an endemic region of the state of São Paulo. Indirect immunofluorescence and direct parasite screening were positive. Polymerase chain reaction detected a parasite belonging to the subgenus Leishmania (Viannia) sp. Due to patients limitations, such as low weight and advanced age, the therapeutic model adopted was the combined small doses of Glucantime™ to pentoxifylline, which ensured treatment success.

Three decades of clinical trials on immunotherapy for human leishmaniases: a systematic review and meta-analysis.

Aim: Current treatments for leishmaniases are not satisfactory, thus alternatives are needed. We searched for clinical trials with immunotherapeutic approaches for patients with leishmaniasis. Materials & methods: Out of 205 articles, 24 clinical trials were selected, and eight submitted to meta-analysis. Results: A reduction in healing time was observed in patients with tegumentary leishmaniasis treated with pentavalent antimony plus granulocyte-macrophage colony-stimulating factor, and therapeutic vaccines. Overall meta-analysis indicated that immunotherapy associated with the standard chemotherapy generated a significantly reduced risk of treatment failure than the pentavalent antimony alone (p = 0.03). Conclusion: Our review confirmed the efficacy of immunotherapies for the treatment of cutaneous and visceral leishmaniasis and highlighted the importance of clinical trials using immunotherapies for leishmaniases.

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.