Mining parasites for their potential as novel therapeutic agents against cancer.

Despite recent advances in the management and therapeutic of cancer, the treatment of the disease is limited by its high cost and severe side effects. In this scenario, there is an unmet need to identify novel treatment alternatives for this dreaded disease. Recently there is growing evidence that parasites may cause anticancer effects because of a negative correlation between parasitic infections and tumour growth despite some parasites that are known to exhibit pro-carcinogenic effects. It has been observed that parasites exert an anticancer effect either by activating the host's immune response or by secreting certain molecules that exhibit anticancer potential. The activation of the immune response by these parasitic organisms results in the inhibition of some of the hallmarks of cancer such as tumour proliferation, angiogenesis, and metastasis. This review summarizes the current advances as well as the mechanisms underlying the possible implications of this diverse group of organisms as anticancer agents.

Anti-inflammatory and immunomodulatory effects of mesenchymal stem cell therapy on parasitic drug resistance.

INTRODUCTION: The emergence of antiparasitic drug resistance poses a concerning threat to animals and humans. Mesenchymal Stem Cells (MSCs) have been widely used to treat infections in humans, pets, and livestock. Although this is an emerging field of study, the current review outlines possible mechanisms and examines potential synergism in combination therapies and the possible harmful effects of such an approach. AREAS COVERED: The present study delved into the latest pre-clinical research on utilizing MSCs to treat parasitic infections. As per investigations, the introduction of MSCs to patients grappling with parasitic diseases like schistosomiasis, malaria, cystic echinococcosis, toxoplasmosis, leishmaniasis, and trypanosomiasis has shown a reduction in parasite prevalence. This intervention also alters the levels of both pro- and anti-inflammatory cytokines. Furthermore, the combined administration of MSCs and antiparasitic drugs has demonstrated enhanced efficacy in combating parasites and modulating the immune response. EXPERT OPINION: Mesenchymal stem cells are a potential solution for addressing parasitic drug resistance. This is mainly because of their remarkable immunomodulatory abilities, which can potentially help combat parasites' resistance to drugs.

Melatonin: A look at protozoal and helminths.

Melatonin is a pleiotropic neurohormone found in different animal, plant, and microorganism species. It is a product resulting from tryptophan metabolism in the pineal gland and is widely known for its ability to synchronize the circadian rhythm to antitumor functions in different types of cancers. The molecular mechanisms responsible for its immunomodulatory, antioxidant and cytoprotective effects involve binding to high-affinity G protein-coupled receptors and interactions with intracellular targets that modulate signal transduction pathways. In vitro and in vivo studies have reported the therapeutic potential of melatonin in different infectious and parasitic diseases. In this review, the protective and pathophysiological roles of melatonin in fighting protozoan and helminth infections and the possible mechanisms involved against these stressors will be discussed.

Evaluating the risk of infections under interleukin 23 and interleukin 17 inhibitors relative to tumour necrosis factor inhibitors - A population-based study.

BACKGROUND: The risk of infections among patients with psoriasis undergoing interleukin (IL)-23 inhibitors (IL-23i) and IL-17 inhibitors (IL-17i) is yet to be exhaustively determined. OBJECTIVE: To assess the risk of infectious complications in patients with psoriasis managed by IL-23i and IL-17i with tumour necrosis factor inhibitors (TNFi) as a comparator. METHODS: A global cohort study comprised two distinct analyses comparing patients with psoriasis under different therapeutic modalities; (i) new users of IL-23i (n = 5272) versus TNFi (n = 5272) and (ii) new users of IL-17i (n = 15,160) versus TNFi (n = 15,160). Study groups were compared regarding the risk of 26 different infections. Propensity score matching was conducted to optimize between-group comparability. RESULTS: Patients under IL-23i had a lower risk of otitis media (HR, 0.66; 95% CI, 0.44-0.97), encephalitis (HR, 0.18; 95% CI, 0.04-0.78), herpes zoster (HZ; HR, 0.58; 95% CI, 0.41-0.82), hepatitis B virus (HBV) reactivation (HR, 0.24; 95% CI, 0.12-0.47), cytomegalovirus (HR, 0.25; 95% CI, 0.07-0.86), influenza (HR, 0.52; 95% CI, 0.38-0.71) and parasitic diseases (HR, 0.78; 95% CI, 0.64-0.95). IL-17i was associated with a decreased risk of pneumonia (HR, 0.76; 95% CI, 0.68-0.85), septicaemia (HR, 0.84; 95% CI, 0.72-0.97), upper respiratory tract infection (HR, 0.84; 95% CI, 0.77-0.92), HZ (HR, 0.79; 95% CI, 0.67-0.92), HBV (HR, 0.59; 95% CI, 0.46-0.76) and hepatitis C virus (HR, 0.71; 95% CI, 0.57-0.88) reactivation, cytomegalovirus (HR, 0.58; 95% CI, 0.36-0.93), Epstein-Barr virus (HR, 0.38; 95% CI, 0.19-0.75), influenza (HR, 0.70; 95% CI, 0.61-0.81) and parasitic diseases (HR, 0.80; 95% CI, 0.72-0.88). CONCLUSION: Compared with TNFi, IL-23i and IL-17i are associated with decreased risk of several infectious diseases. These agents might be preferred in patients with susceptibility to infections.

Cysteine Proteases as Validated Targets for the Treatment of Neglected and Poverty-Related Parasitic Diseases.

Neglected tropical diseases (NTDs) include 20 diverse infections mainly prevalent in tropical areas that mostly affect disadvantaged communities and women and children [...].

Employing "Red Flags" to Fight the Most Neglected Diseases: Nitroaromatic as Still Suitable Tools to Treat Human and Veterinary Parasitosis.

Nitroaromatic compounds have been used for treating parasitic diseases since the 1960s. Pharmacological alternatives to treat them are under observation. However, for the most neglected diseases, such as those caused by worms and less known protozoans, nitro compounds are still among the drugs of choice, despite their well-known collateral effects. In this review, we describe the chemistry and the uses of the still most employed nitroaromatic compounds for treating parasitosis caused by worms or lesser-known protozoans. We also describe their application as veterinary drugs. The most accepted mechanism of action seems to be the same, leading to collateral effects. For this reason, a special session was dedicated to discussing toxicity, carcinogenicity, and mutagenesis, as well as the most acceptable aspects of the known structure-activity/toxicity relationships involving nitroaromatic compounds. It employed the SciFindern search tool from the American Chemical Society in the search for the most relevant bibliography within the field, exploring keyword expressions such as "NITRO COMPOUNDS" and "BIOLOGICAL ACTIVITY" (within Abstracts or Keywords) and concepts related to parasites, pharmacology and toxicology. The results were classified according to the chemical classes of nitro compounds, being the most relevant studies regarding journal impact and interest of the described results chosen to be discussed. From the found literature, it is easy to notice that nitro compounds, especially the nitroaromatic ones, are still widely used in antiparasitic therapy, despite their toxicity. They also are the best starting point in the search for new active compounds.

[Anticancer effect of parasites and its underlying mechanisms: a review].

Both parasitic diseases and cancers are disorders that seriously threaten human health. A strong correlation has been recently found between parasitic infections and cancers, and multiple species of parasites and their derived products have shown effective to suppress cancer development, progression and metastasis. Therefore, deciphering the interaction among parasites, cancers and hosts not only provides new insights into the development of cancer therapy, but also provides the basis for screening of parasites-derived active anticancer molecules. This review summarizes the latest advances in the anticancer activity of parasites and underlying mechanisms.

[Other Central Nervous System Infections(Including Fungal Infection, Tuberculosis, and Parasitic Infection)].

This review describes cryptococcal meningoencephalitis, tuberculous meningitis, neurosyphilis, and toxoplasma encephalitis. Central nervous system infections are neurological emergencies associated with mortality or other outcomes. Therefore, early diagnosis and treatment are critical. Fungal or gondii infections are rare and affect compromised hosts who are HIV positive, have diabetes, or take immunosuppressive or anticancer drugs. Cryptococcal antigens in the serum and cerebrospinal fluid are useful for the diagnosis of cryptococcal meningoencephalitis. RPR and TPHA tests are useful for the diagnosis of neurosyphilis. Cryptococcal meningoencephalitis and tuberculous meningitis often develop into hydrocephalus, making VP shunt necessary. Antifungal drugs for cryptococcal meningitis are limited by the blood-brain barrier, making a full recovery difficult; in such situations, intraventricular antifungal treatment is required.

Comorbidities involving parasitic diseases: A look at the benefits and complications.

Parasitic infections acquired by the population cause substantial morbidity worldwide, with individuals from developing countries being most affected. Some parasites remain in the host for long periods, settling in different organs, manipulating the flow of nutrients and metabolites, and influencing the immune response, favoring their adaptation. The host attempts to counteract the metabolic and immunological alterations and the possible damage caused by infection. These metabolic and immunological changes experienced by the host can influence the progression of other existing morbidities or those that will be acquired in the future. Cancer and metabolic diseases are also frequent causes of morbidity in the world population. The large numbers of individuals affected by cancer and metabolic diseases and the high prevalence of morbidity caused by parasitic diseases favor the development of comorbidity involving these pathologies. This review provides an overview of major advances in research on cancer and metabolic diseases associated with parasitic infections. Information about hosts and parasites such as alterations of the immune response, metabolism and adaptation mechanisms of the parasites, and parasitic molecules with therapeutic potential is provided, as well as the beneficial results or complications related to the comorbidities discussed herein. We emphasize the need to conduct additional studies addressing comorbidities associated with parasitic infections to improve the understanding of the impact of this association on the progression of morbidities, as well as the possibility of the therapeutic use of and therapeutic approaches involving parasites.

Ruthenium Metallotherapeutics: Novel Approaches to Combatting Parasitic Infections.

Human parasitic infections cause a combined global mortality rate of over one million people per annum and represent some of the most challenging diseases for medical intervention. Current chemotherapeutic strategies often require prolonged treatment, coupled with subsequent drug-induced cytotoxic morbidity to the host, while resistance generation is also a major concern. Metals have been used extensively throughout the history of medicine, with more recent applications as anticancer and antimicrobial agents. Ruthenium metallotherapeutic antiparasitic agents are highly effective at targeting a range of key parasites, including the causative agents of malaria, trypanosomiasis, leishmaniasis, amoebiasis, toxoplasmosis and other orphan diseases, while demonstrating lower cytotoxicity profiles than current treatment strategies. Generally, such compounds also demonstrate activity against multiple cellular target sites within parasites, including inhibition of enzyme function, cell membrane perturbation, and alterations to metabolic pathways, therefore reducing the opportunity for resistance generation. This review provides a comprehensive and subjective analysis of the rapidly developing area of ruthenium metal- based antiparasitic chemotherapeutics, in the context of rational drug design and potential clinical approaches to combatting human parasitic infections.

Genus Zanthoxylum as Sources of Drugs for Treatment of Tropical Parasitic Diseases.

The tropical parasitic infections account for more than 2 billion infections and cause substantial morbidity and mortality, and account for several million deaths every year. Majorly parasitic infections in humans and animals are caused by protozoa and helminths. Chronic infections in the host can cause retardation, impairment of cognitive skills, development in young children and weaken the immune system. The burden is felt to a greater extent in developing countries due to poverty, inaccessibility to medicines and resistance observed to drugs. Thus, human health continues to be severely harmed by parasitic infections. Medicinal plants have received much attention as alternative sources of drugs. Zanthoxylum genus has been used ethnobotanically as an antiparasitic agent and the phytoconstituents in Zanthoxylum, show a wide variety of chemical substances with proven pharmacological actions such as alkaloids (isoquinolines and quinolines responsible for antitumor activity, antimalarial, antioxidant and antimicrobial actions), lignans, coumarins (antibacterial, antitumour, vasodilatory and anticoagulant activities), alkamide (strong insecticidal properties, anthelminthic, antitussive and analgesic anti antimalarial property). Therefore, this article is an attempt to review the existing literature that emphasizes on potential of genus Zanthoxylum as a source of lead compounds for the treatment of parasitic diseases.

The clinical characteristics and outcomes of patients with fever of unknown origin caused by parasitic infection.

ABSTRACT: There are over 200 causes of fever of unknown origin (FUO), and although parasitic infection is an increasingly uncommon cause, a definitive diagnosis remains important to ensure rapid treatment and to prevent adverse sequelae through delay. Here, we studied the clinical features and outcomes of patients admitted with FUO and diagnosed with parasitic infection to improve our understanding of the features of parasitic FUO.Medical records of patients admitted to Peking Union Medical College Hospital between 2013 and 2019 with FUO and diagnosed with parasitic infection were reviewed. The clinical features and outcomes of patients for whom follow-up data were available were summarized.Six patients were admitted with FUO and diagnosed with parasitic infections (6/1013; 0.59%). Patients were more commonly middle-aged men and had a relatively long disease course. Most suffered from hyperpyrexia and other non-specific symptoms. Routine examinations were non-specific, and some patients had positive tumor markers, antinuclear antibodies, or positron emission tomography/computed tomography results. Diagnoses were confirmed by bone marrow smears, serum antibody testing, or feces examination. All 6 cases received anthelmintic treatments and recovered well.Parasitic infections must be screened for and actively excluded in FUO patients so that targeted therapy can be rapidly administered to ensure optimal outcomes.

The host mTOR pathway and parasitic diseases pathogenesis.

The mechanistic (or mammalian) target of rapamycin (mTOR) is considered as a critical regulatory enzyme involved in essential signaling pathways affecting cell growth, cell proliferation, protein translation, regulation of cellular metabolism, and cytoskeletal structure. Also, mTOR signaling has crucial roles in cell homeostasis via processes such as autophagy. Autophagy prevents many pathogen infections and is involved on immunosurveillance and pathogenesis. Immune responses and autophagy are therefore key host responses and both are linked by complex mTOR regulatory mechanisms. In recent years, the mTOR pathway has been highlighted in different diseases such as diabetes, cancer, and infectious and parasitic diseases including leishmaniasis, toxoplasmosis, and malaria. The current review underlines the implications of mTOR signals and intricate networks on pathogen infections and the modulation of this master regulator by parasites. Parasitic infections are able to induce dynamic metabolic reprogramming leading to mTOR alterations in spite of many other ways impacting this regulatory network. Accordingly, the identification of parasite effects and interactions over such a complex modulation might reveal novel information regarding the biology of the abovementioned parasites and might allow the development of therapeutic strategies against parasitic diseases. In this sense, the effects of inhibiting the mTOR pathways are also considered in this context in the light of their potential for the prevention and treatment of parasitic diseases.

Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment of Cancer, Immune Disorders, and Viral/Parasitic Infections.

The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP3 are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies. The type III phosphatidylinositol 4-kinase beta isoform (PI4KB), which are evolutionarily similar to the class I PI3Ks, have been found to be essential host factors mediating the replication of numerous devastating pathogenic viruses. Finally, targeting the parasite variant of PI4KB has been established as one of the most promising strategies for the development of anti-malarial and anti-cryptosporidium strategies. Therefore, the development of targeted isoform selective inhibitors for these enzymes are of paramount importance. The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors.

Vorinostat as potential antiparasitic drug.

OBJECTIVE: Vorinostat is a drug used to treat cutaneous T cell lymphoma whose action mechanism is based on Histone Deacetylase inhibition. Histone Deacetylases are a family of enzymes that remove acetyl groups from histone and non-histone proteins that control many crucial processes, such as gene regulation, cell cycle progression, differentiation, and apoptosis. Histone Deacetylase homologues are also expressed in parasites of the genus Plasmodium, Leishmania, Cryptosporidium, Schistosoma, Entamoeba, and others. In this way, antiparasitic properties of Vorinostat have been explored. The aim of this review is to report the current state knowledge of Vorinostat as antiparasitic drug against Plasmodium, Leishmania, Cryptosporidium, Schistosoma and Entamoeba in order to support future investigation in this field. MATERIALS AND METHODS: The authors revised the recent and relevant literature concerning the topic and discussed advances and limitations of studies on Vorinostat as potential drug to treat human parasitic diseases. RESULTS: Vorinostat has been efficient in vitro and, in some cases, in vivo, against parasites that cause parasitic diseases, such as malaria, leishmaniasis, cryptosporidiosis, amoebiasis, and schistosomiasis. CONCLUSIONS: In vitro and in vivo models have demonstrated the antiparasitic activity of Vorinostat, however, the challenge is to assay its activity in animal models and to evaluate if Vorinostat is safe for humans as new alternative to treat human parasitic infections.

The Phylum Bryozoa: From Biology to Biomedical Potential.

Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.

Kaposi's sarcoma-associated herpesvirus seropositivity is associated with parasite infections in Ugandan fishing communities on Lake Victoria islands.

We investigated the impact of helminths and malaria infection on Kaposi's sarcoma associated herpesvirus (KSHV) seropositivity, using samples and data collected from a cluster-randomised trial of intensive versus standard anthelminthic treatment. The trial was carried out in 2012 to 2016 among fishing communities on Lake Victoria islands in Uganda. Plasma samples from 2881 participants from two household surveys, the baseline (1310 participants) and the final (1571 participants) surveys were tested for KSHV IgG antibody responses to K8.1 and ORF73 recombinant proteins using ELISA. The baseline survey was carried out before the trial intervention while the final survey was carried out after three years of the trial intervention. Additionally, a subset sample of 372 participants from the final survey was tested for IgE, IgG and IgG4 antibody concentrations to S. mansoni adults worm antigen (SWA) and S. mansoni egg antigen (SEA) using ELISA. Infection by helminths (S. mansoni, N. americanus, T. trichiura and S. stercoralis) was diagnosed using real-time PCR, urine circulating cathodic antigen (CCA) and stool microscopy (Kato-Katz method) while malaria infection was diagnosed using microscopy. We analysed the relationship between helminth and malaria infections and KSHV seropositivity using regression modelling, allowing for survey design. At baseline, 56% of the participants were male while 48% of the participants were male in the final survey. The most prevalent helminth infection was S. mansoni (at baseline 52% and 34% in the final survey by microscopy, 86% by CCA and 50% by PCR in the final survey). KSHV seropositivity was 66% (baseline) and 56% (final survey) among those 1-12 years and >80% in those 13+ years in both surveys; malaria parasitaemia prevalence was 7% (baseline) and 4% (final survey). At baseline, individuals infected with S. mansoni (detected by microscopy) were more likely to be KSHV seropositive (aOR = 1.86 (1.16, 2.99) p = 0.012) and had higher anti-K8.1 antibody levels (acoefficient = 0.03 (0.01, 0.06) p = 0.02). In the final survey, S. mansoni (by microscopy, adjusted Odds Ratio (aOR = 1.43 (1.04-1.95), p = 0.028) and malaria parasitaemia (aOR = 3.49 (1.08-11.28), p = 0.038) were positively associated with KSHV seropositivity. Additionally, KSHV seropositive participants had higher S. mansoni-specific IgE and IgG antibody concentrations in plasma. Furthermore, HIV infected individuals on cART were less likely to be KSHV seropositive compared to HIV negative individuals (aOR = 0.46 (0.30, 0.71) p = 0.002). Schistosoma species skew the immune response towards Th2 and regulatory responses, which could impact on KSHV reactivation if co-infected with both organisms.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Development and application of anthelminthic drugs in China.

China was once a country plagued by parasitic diseases. At the beginning of the founding of the People's Republic of China, nearly 80% of the population suffered from parasitic diseases because of poverty and poor sanitary conditions. After nearly 70 years of development, China has made remarkable achievements in the prevention and control of parasitic diseases, and the prevalence of parasitic diseases has been greatly reduced. In addition to organizational leadership from the government and various preventive measures, drug treatment and drug research & development are important and irreplaceable links in prevention and control work. Since the 1950s, China has begun to introduce, produce and imitate antiparasitic drugs from abroad, such as santonin, benzimidazole, and praziquantel. Chinese scientists have also contributed to the optimization of production techniques, improvements in drug formulation, the application in the clinic and the mechanisms of actions of generic drugs. At the same time, China has independently developed tribendimidine (TrBD, a broad spectrum anthelminthic), and its anthelminthic spectrum has been comprehensively studied. It is active against almost 20 parasites, is especially superior to benzimidazoles against Necator americanus, and surpasses the effectiveness of praziquantel against Clonorchis sinensis. In the treatment of tapeworm disease, the traditional Chinese medicines pumpkin seeds and betel nuts have good curative effects for taeniasis. Chinese scientists have explored the action modes and clinical administration methods of pumpkin seeds and betel nuts, which is still the main clinical regimen for the disease. This paper reviews the history and progress of the study of anthelmintics in intestinal helminth infections since the founding of the People's Republic of China and aiming to support clinicians and drug researchers in China and other countries.

Parasitosis ocular por Acanthamoeba / Acanthamoeba parasitic eye infection

RESUMEN El parasitismo es uno de los fenómenos más sorprendentes de los observados en los animales. El número de organismos conocidos de vida parasitaria es muy elevado. Existe una gran cantidad de especies cuya supervivencia está relacionada con la de otras y dependen, en distinta medida, de ellas. Esta dependencia no implica que los animales parásitos sean organismos degenerados o deficientes; al contrario, a la vida parasitaria se ha llegado tras largo tiempo de evolución, en el que los parásitos han ido superando barreras y adaptándose a vivir en, o sobre sus hospedadores. Las queratitis por Acanthamoeba son infrecuentes; pero se describe un aumento a nivel mundial relacionado con el uso creciente de lentes de contacto. El diagnóstico precoz y el tratamiento adecuado deben realizarse para evitar la pérdida de la visión. Se realizó una búsqueda de artículos publicados, con el objetivo de conocer sobre la Acanthamoeba como parásito y su afectación ocular. Se utilizó la plataforma Infomed, específicamente la Biblioteca Virtual de Salud(AU)

ABSTRACT Parasitism is one of the most surprising phenomena among those occurring in animals. The number of known parasitic organisms is very high. There is a large number of species whose survival is related to that of others and depend on them to a greater or lesser degree. Such dependence does not imply that parasitic animals are either degenerate or deficient. On the contrary, parasitic life has been the result of a long process of evolution along which parasites have gradually overcome hurdles and have adapted to live in or on their hosts. Acanthamoeba keratitis is a rare disease, but a worldwide increase has been reported due to the growing use of contact lenses. Early diagnosis and appropriate treatment are required to prevent sight loss. A search was conducted for published papers with the purpose of learning about Acanthamoeba as a parasite and the related eye conditions. Use was made of the platform Infomed, specifically the Virtual Health Library(AU)