Praziquantel and Arachidonic Acid Combination — An Innovative Approach to the Treatment of Schistosomiasis

Schistosomiasis is a debilitating disease caused by trematode worms of the genus Schistosoma. Three members Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum are responsible for the great majority of human infections. Schistosomiasis is widespread in sub-Saharan Africa, several countries of the Middle East, South America, and South-East Asia. Vaccination against the infection would be the most reliable way to combat the infection and decrease or interrupt its transmission, but a commercial vaccine is still unavailable. Praziquantel (PZQ) is the only drug considered for schistosomiasis treatment as it is effective against the major human schistosomes, commercially available, cost-affordable, and elicits limited side-effects. Several reports documented the highly significant PZQ efficacy in treatment of light infections in areas of low S. mansoni and S. haematobium endemicity and PZQ use. Chemotherapy with PZQ alone of patients residing in regions of high schistosome endemicity and afflicted with light, moderate, or heavy infection is not efficacious. Accordingly, we propose implementation of cost-affordable arachidonic acid (ARA), a polyunsaturated omega-6 fatty acid and efficacious in vitro and in vivo schistosomicide, for oral therapy of children with Schistosoma mansoni and Schistosoma haematobium light infection, as adjunct to PZQ for cure of children with moderate and heavy infections, and for counteracting schistosome resistance to PZQ that arises in endemic areas exposed to repeated and intense PZQ mass treatment campaigns

Mechanisms of Arachidonic Acid In Vitro Tumoricidal Impact

To promote the potential of arachidonic acid (ARA) for cancer prevention and management, experiments were implemented to disclose the mechanisms of its tumoricidal action. Hepatocellular, lung, and breast carcinoma and normal hepatocytes cell lines were exposed to 0 or 50 μM ARA for 30 min and then assessed for proliferative capacity, surface membrane-associated sphingomyelin (SM) content, neutral sphingomyelinase (nSMase) activity, beta 2 microglobulin (β2 m) expression, and ceramide (Cer) levels. Reactive oxygen species (ROS) content and caspase 3/7 activity were evaluated. Exposure to ARA for 30 min led to impairment of the tumor cells’ proliferative capacity and revealed that the different cell lines display remarkably similar surface membrane SM content but diverse responses to ARA treatment. Arachidonic acid tumoricidal impact was shown to be associated with nSMase activation, exposure of cell surface membrane β2 m to antibody binding, and hydrolysis of SM to Cer, which accumulated on the cell surface and in the cytosol. The ARA and Cer-mediated inhibition of tumor cell viability appeared to be independent of ROS generation or caspase 3/7 activation. The data were compared and contrasted to findings reported in the literature on ARA tumoricidal mechanisms

Clarification of Arachidonic Acid Metabolic Pathway Intricacies

Surrounding inflammation activates phospholipase A, which cleaves and releases arachidonic acid (ARA) from cell membranes. The four cis double bonds are instrumental in ARA susceptibility to oxidation, resulting in the generation of numerous bioactive metabolites of critical importance for the immune system, namely inflammation in response to pathogens, resolution of inflammation, wound healing, and mood and energy balance. The ARA metabolism steps are replete with intricacies, deterring researchers from identifying targets, which could be useful in modulating the synthesis of ARA metabolites toward exclusive protection of the host from pathogens, endogenous excessive danger signals, pain, inflammation, stress, and anxiety disorders. While ARA metabolic pathways are reasonably defined, it was deemed mandatory to fully clarify the flow and direction of protons, electrons, and oxygen atoms and the intricacies behind formation and breakage of double bonds and cyclic structures. This in-depth novel information will perfect the development of strategies and drugs aimed at counteracting inflammation and promoting healing

Is arachidonic acid an endoschistosomicide?

Schistosoma mansoni and Schistosoma haematobium are intravascular, parasitic flatworms that infect \u3e250 million people in 70 developing countries, yet not all people of the same community and household are afflicted. Regarding laboratory rodents, mice but not rats are susceptible to infection with S. mansoni and hamsters but not mice are entirely permissive to infection with S. haematobium. A recent Brazilian publication has demonstrated that resistance of the water-rat, Nectomys squamipes to S. mansoni infection might be ascribed to stores of arachidonic acid (ARA)-rich lipids in liver. Several reports have previously shown that ARA is a safe and effective schistosomicide in vitro, and in vivo in mice, hamsters and in children. Schistosoma haematobium appeared more sensitive than S. mansoni to ARA in in vitro and in vivo experiments. Accordingly, it was proposed that ARA increased levels might be predominantly responsible for natural attrition of S. mansoni and S. haematobium in resistant experimental rodents. Therefore, the levels of ARA in serum, lung, and liver of rats (resistant) and mice (susceptible) at 1, 2, 3, 4 and 6 weeks after infection with S. mansoni cercariae and between mice (semi-permissive) and hamster (susceptible) at 1, 2, 3, 4, and 12 weeks after infection with S. haematobium cercariae were compared and contrasted. Neutral triglycerides and ARA levels were assessed in serum using commercially available assays and in liver and lung sections by transmission electron microscopy, Oil Red O staining, and specific anti-ARA antibody-based immunohistochemistry assays. Significant (P \u3c.05), consistent, and reproducible correlation was recorded between ARA content in serum, lung, and liver and rodent resistance to schistosome infection, thereby implicating ARA as an endoschistosomicide

Role of T lymphocytes and papain enzymatic activity in the protection induced by the cysteine protease against Schistosoma mansoni in mice

Papain, an experimental model protease, was used to decipher the protective mechanism(s)of the cysteine peptidase-based schistosomiasis vaccine. To examine the role of T lymphocytes, athymic nude (nu/nu)and immunocompetent haired (nu/+)mice were subcutaneously (sc)injected with 50 µg active papain two days before percutaneous exposure to 100 cercariae of Schistosoma mansoni. Highly significant (P \u3c 0.005)reductions in worm burden required competent T lymphocytes, while significant increases (P \u3c 0.05)of \u3e80% in dead parasite ova in the small intestine were independent of T cell activity and likely relied on the innate immune axis. To investigate the role of enzymatic activity, immunocompetent mice were sc injected with 50 µg active or E-64-inactivated papain two days before exposure to cercariae. The reductions in worm burden were highly significant (P \u3c 0.0001), reaching \u3e65% and 40% in active and inactivated papain-treated mice, respectively. Similar highly significant (P \u3c 0.0001)decreases of 85% in the viability of parasite ova in the small intestine occurred in both active and inactivated papain-treated mice. These findings indicated that immune responses elicited by one or more papain structural motifs are necessary and sufficient for induction of considerable parasite and egg attrition. Correlates of protection included IgG1-dominated antibody responses and increases in the levels of uric acid and arachidonic acid in the lung and liver upon parasite migration in these sites. Identification of the shared patterns or motifs in cysteine peptidases and evaluation of their immune protective potential will pave the way to the development of a safe, efficacious, storage-stable, and cost-effective schistosomiasis vaccine

Physiological functions and pathogenic potential of uric acid: A review

Uric acid is synthesized mainly in the liver, intestines and the vascular endothelium as the end product of an exogenous pool of purines, and endogenously from damaged, dying and dead cells, whereby nucleic acids, adenine and guanine, are degraded into uric acid. Mentioning uric acid generates dread because it is the established etiological agent of the severe, acute and chronic inflammatory arthritis, gout and is implicated in the initiation and progress of the metabolic syndrome. Yet, uric acid is the predominant anti-oxidant molecule in plasma and is necessary and sufficient for induction of type 2 immune responses. These properties may explain its protective potential in neurological and infectious diseases, mainly schistosomiasis. The pivotal protective potential of uric acid against blood-borne pathogens and neurological and autoimmune diseases is yet to be established

Arachidonic acid: Physiological roles and potential health benefits – A review

It is time to shift the arachidonic acid (ARA) paradigm from a harm-generating molecule to its status of polyunsaturated fatty acid essential for normal health. ARA is an integral constituent of biological cell membrane, conferring it with fluidity and flexibility, so necessary for the function of all cells, especially in nervous system, skeletal muscle, and immune system. Arachidonic acid is obtained from food or by desaturation and chain elongation of the plant-rich essential fatty acid, linoleic acid. Free ARA modulates the function of ion channels, several receptors and enzymes, via activation as well as inhibition. That explains its fundamental role in the proper function of the brain and muscles and its protective potential against Schistosoma mansoni and S. haematobium infection and tumor initiation, development, and metastasis. Arachidonic acid in cell membranes undergoes reacylation/deacylation cycles, which keep the concentration of free ARA in cells at a very low level and limit ARA availability to oxidation. Metabolites derived from ARA oxidation do not initiate but contribute to inflammation and most importantly lead to the generation of mediators responsible for resolving inflammation and wound healing. Endocannabinoids are oxidation-independent ARA derivatives, critically important for brain reward signaling, motivational processes, emotion, stress responses, pain, and energy balance. Free ARA and metabolites promote and modulate type 2 immune responses, which are critically important in resistance to parasites and allergens insult, directly via action on eosinophils, basophils, and mast cells and indirectly by binding to specific receptors on innate lymphoid cells. In conclusion, the present review advocates the innumerable ARA roles and considerable importance for normal health. Keywords: Arachidonic acid, Ion channels, Schistosomicide, Endotumoricide, Lipoxin A4, Endocannabinoid

Mechanisms of Arachidonic Acid In Vitro Tumoricidal Impact

To promote the potential of arachidonic acid (ARA) for cancer prevention and management, experiments were implemented to disclose the mechanisms of its tumoricidal action. Hepatocellular, lung, and breast carcinoma and normal hepatocytes cell lines were exposed to 0 or 50 μM ARA for 30 min and then assessed for proliferative capacity, surface membrane-associated sphingomyelin (SM) content, neutral sphingomyelinase (nSMase) activity, beta 2 microglobulin (β2 m) expression, and ceramide (Cer) levels. Reactive oxygen species (ROS) content and caspase 3/7 activity were evaluated. Exposure to ARA for 30 min led to impairment of the tumor cells’ proliferative capacity and revealed that the different cell lines display remarkably similar surface membrane SM content but diverse responses to ARA treatment. Arachidonic acid tumoricidal impact was shown to be associated with nSMase activation, exposure of cell surface membrane β2 m to antibody binding, and hydrolysis of SM to Cer, which accumulated on the cell surface and in the cytosol. The ARA and Cer-mediated inhibition of tumor cell viability appeared to be independent of ROS generation or caspase 3/7 activation. The data were compared and contrasted to findings reported in the literature on ARA tumoricidal mechanisms

Why the radiation-attenuated cercarial immunization studies failed to guide the road for an effective schistosomiasis vaccine: A review

AbstractSchistosomiasis is a debilitating parasitic disease caused by platyhelminthes of the genus Schistosoma, notably Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum. Pioneer researchers used radiation-attenuated (RA) schistosome larvae to immunize laboratory rodent and non-human primate hosts. Significant and reproducible reduction in challenge worm burden varying from 30% to 90% was achieved, providing a sound proof that vaccination against this infection is feasible. Extensive histopathological, tissue mincing and incubation, autoradiographic tracking, parasitological, and immunological studies led to defining conditions and settings for achieving optimal protection and delineating the resistance underlying mechanisms. The present review aims to summarize these findings and draw the lessons that should have guided the development of an effective schistosomiasis vaccine