Genus schistosoma is a very well-preserved parasite among millions of years. Over many decades, is responsible for the morbidity and mortality of hundreds of million humans. Effective medication (Praziquantel) for acute treatment is commercially available, and prophylaxis by vaccination is promising. Where endemic Schistosomiasis is still prevalent, causing significant morbidity and mortality have far-reaching complications in many human organ systems, including irreversible pulmonary hypertension, genitourinary, central nervous system conditions, and also neoplasia. Natural products have been the source of multiple medicines for thousands of years. The discovery of pure compounds as active ingredients in plants was first described at the beginning of the 19th century. Natural products have come from variable source materials including terrestrial microorganisms, terrestrial plants, marine organisms, and terrestrial invertebrates and vertebrates. The use of drugs extracted from bacteria, fungi, plants, and marine organisms has a long common and tradition in medicine. Among these, medicinal plants include variable active principles that have been exploited against schistosomiasis syndrome, and in recent decades, natural products have attracted worldwide interest.
Schistosomiasis affects an estimated 240 million people are affected in 78 countries, (Butrous, 2019). Schistosomiasis pathogenicity can cause acute and chronic clinical syndromes (Coltart and Whitty, 2015; Bonnefond et al., 2019). It was approved that schistosomiasis can cause changes in hematological parameters, the elevation of oxidative stress represented in lipid peroxide with diminishing in antioxidant’s factors (Sorgho et al., 2017; Jatsa et al., 2018; El-khadragy et al., 2019). At the molecular level, scientists found that Schistosoma is a harmful genotoxic agent (Madbouly et al., 2007; Abdel-Wahhab et al., 2017, Abdalkareem and Yin, 2019).
Investigators recorded that praziquantel (PZQ) efficacy, the drug of choice, had been reduced as anti-schistosomal (Crellen et al., 2016; Woldegerima et al., 2019). Schistosomiasis still searches for antiparasitic drugs from the natural origin for the development of new medications (Simões et al., 2015; Selem et al., 2018; Acheampong et al., 2020).
Allicin (AL) is the main active ingredient of
Curcumin (CU), the active ingredient of
Schistosomiasis
Schistosomiasis is a parasitic disease that is historically known as bilharzia resulted from the trematode of the genus Schistosoma. Estimates place the affected all over the world population for all forms of schistosomiasis at 230 million, with about 700 million at risk (Tan, 2007). The schistosome life cycle includes two hosts: snails and mammals. Asexual reproduction happens in freshwater snails;
In acute schistosomiasis, most people do not develop symptoms. Although symptoms usually resolve after a few weeks, mortality rates can be as high as 25% during this acute stage. A maculopapular rash appears at the site of infection (penetration of schistosomula) (Nour, 2010).
In the chronic stage, symptoms can observe months or years later. They vary based on the species that has infected the host. In general, the eggs induce a marked immune response and form granulomas.
Using the drug in the treatment
Scientists still searching for antiparasitic drugs from natural origin, mainly from plants, which are the main source of biologically active ingredients for the development of new medications (Magalhães et al., 2009; Silva et al., 2009). Traditional medicinal plants were utilized by some authors for the treatment of schistosomiasis (Soliman, 2012; Sheir et al., 2015; Wangchuk et al., 2016; Al-Kazzaz, 2018).
Using the natural product in the treatment
Most of the old studies have focused on studying the effect of the plant itself as an extract on different helminths (Sparg et al., 2000; Molgaard et al., 2001) but the more modern studies especially those in the last 10 years focusing on the effective ingredients (Metwally et al., 2018) were applied. The great development in biochemical and analytical methods over the past 10 years allowed the separation of plant phytochemicals and consequently analysis of their chemical nature.
3.1
Since ancient times, garlic has been utilized all over the world, as a food and also as a treatment. In ancient civilizations, including Egyptian, Phoenicians, Greek, Indian, Roman, Babylonian, Viking, and Chinese, garlic was used as a medication for different disorders including heart conditions, arthritis, pulmonary diseases, respiratory infections, skin disease, symptoms of aging, diarrhea, headache, different bites, worms, wounds, ulcers, and multiple tumors (Rivlin, 2001).
Garlic (
AL cannot be found in raw garlic, but it is quickly produced by the action of CS-lyase (allinase) on alliin. Allinase is energized by crushing or cutting the garlic cloves (Caporaso et al., 1983; Block, 1985). AL has been reported to have antitumor, antioxidant anti-inflammatory, and antischistosomal effect (Gruhlke et al
Curcumin is a phytochemical present in the Indian spice turmeric,
Curcumin is a highly yellow pigment from rhizomatous plant turmeric (
In vitro
In the last decade, there was a general trend toward testing the efficacy of the different drugs
Parasitological studies
The main aim of any drug against schistosomiasis is to achieve high mortality rates in different developmental stages.
Mohamed et al. (2005) found that
The highest 100% mortality rates were recorded in animals treated orally with 160 mg/kg/day of
In the dorsal side of the adult male worms, there were tubercles with numerous spines randomly distributed throughout the body and the area between the oral and ventral suckers did not have any tubercles, spines, or sensory papillae (Lima et al., 2011; Abdel-Zaher et al., 2016). The female tegument is smooth without tubercles or spines, the mid-dorsal surface of females showing fine circular ridges interspaced with regular clefts and carrying conspicuous sensory bulbs (Abdel-Zaher et al., 2016).
Tegument of parasitic Platyhelminthes is the main protective sheath that improves the defense and also important in the uptake of nutrients, osmoregulation, and excretion. Hence, the importance of topographical studies can clarify aspects of drug-induced damage (Wendt
Ultrastructure changes using an electron scanning microscope contributed to the understanding of the mechanism of treatment of each therapy (Santiago et al., 2014; Abdel-Zaher et al., 2016; Hassan et al., 2016).
Previous studies classified the types of eggs in the oogram pattern according to the maturation stages and/or count the total number of eggs to reflect the level of schistosomiasis progress (Metwalley, 2015; Shams El-Din, 2016; Abououf et al., 2018).
Selem et al. (2018) reported that PZQ caused a significant reduction in the average egg load of 1964.8 ± 909.7 in comparison with infected untreated group 8507.4 ± 915.2. The egg load average was enhanced in the group that received a mixture of PZQ and
The liver tissue sections of the control untreated mice showed the polyhedral hepatocytes with a centrally positioned nucleus and granular cytoplasm. The hepatocytes coordinated in strands alternating with the blood sinusoid pa network around the central vein. There were negligible amounts of collagen fibers around some hepatic blood vessels (Ali et al., 2015b).
Egg deposition in the central veins and/or blood sinusoids induces the formation of granuloma. The host's defense mechanism cannot perfectly just eliminate the parasite but the body diminishes the damage by surrounding the parasite with a capsule of inflammatory cells (Rashed et al., 1997). The host immune cells' response to
Liver fibrosis is a major complement of granulomatous schistosomiasis
Schistosomiasis showed deformations in the histological tissues rather than the liver such as intestine, kidney, spleen, and lungs (Soliman and El-Shenawy, 2003; Mostafa et al., 2011; Scheer et al., 2014; Dkhil et al., 2016).
6.
Schistosomiasis causing enlargement of the liver as a result of egg deposition in the hepatic tissue, while in the case of the spleen the enlargement occurs due to passive pressure of blood flow and reticuloendothelial hyperplasia (Hamed, 2011; Wilson et al., 2011).
The reduction in kidney weight in mice infected with
Schistosomiasis caused changes in different parameters (Da Silva et al., 2005; Sorgho et al., 2017). A marked increase in monocytes, lymphocytes, and neutrophils as well as mild eosinophilia were recorded in schistosomiasis (Da Silva et al., 2005; Mohammed et al., 2006).
Infected mice treated with a mixture of aqueous garlic extract (AGE) and garlic oil extract (GOE) showed a significant increase in Hb average in both infected and non-infected groups (Sadrefozalayi et al., 2018). Mahmoud and ELbessoumy (2014) reported that anemia leucopenia, neutropenia, and eosinophilia were observed in infected groups untreated with enhancement in the groups received diet mixed with
Many underestimated plants or it is products were used as ant parasitic drugs and at the same time responsible for the enhancement of lipid profile, oxidative stress, and other biochemical parameters (El-Shenawy et al., 2006; Mahmoud and Elbessoumy, 2014; Oyinloye, et al., 2015).
The estimation of serum total cholesterol (TC) is one of the essential tools in the diagnosis and classification of lipemia. High blood cholesterol is one of the major risk factors for heart disorders (Burtis and Ashwood, 1999). The concentration of serum high-density lipoprotein-cholesterol (HDL-c) diminished significantly in infected untreated mice (Doenhoff et al., 2002). The factors mediated serum cholesterol-lowering effect were produced from
Garlic extract as a treatment of schistosomiasis mansoni did not induce any marked effect on the cholesterol level compared to the infected untreated animals, while the combination of garlic extract and
The rise in serum triglycerides (TG) is relatively non-specific. A liver disorder resulting from hepatitis, extrahepatic biliary obstruction, or cirrhosis, diabetes mellitus is associated with the increase in TG levels (Burtis and Ashwood, 1999). Serum TG levels increased in infected
Row garlic, oil, and powder extracts have recorded multiple activities such as reduction of TC and TG of blood levels during the rich fat meal intake in human research (Bayan et al., 2014). Mice infected with
Alanine aminotransferase (ALT) catalyzes the transport of the amino group of L-alanine and α-ketoglutarate to produce L-glutamate. The highest levels were found mainly in the liver and the kidneys, and smaller quantities in the heart and skeletal muscles (Kim
In general, the use of phytosome curcumin reduced significantly the activities of ALT and AST (Tung et al., 2017). Curcumin extract induced a significant reduction in ALT activity in mice infected with
Uric acid is one of the end products of purine metabolism (Johnson
The injury produced by
Reactive oxygen species (ROS) are formed by living organisms as a result of cellular metabolism in normal conditions. At low to moderate concentrations, they function in different cell processes, while at higher concentrations, they produce multiple modifications to cell components, such as lipids, proteins, and DNA (Halliwell and Gutteridge, 1999; Valko
ROS can be classified into two groups of compounds known as; radicals and non-radicals. The common free radicals are oxygen radical (O∙∙2), hydroxyl (OH∙), peroxyl radical (ROO∙), nitric oxide (NO∙), and nitrogen dioxide (NO∙2), while the common nonradicals are hydrogen peroxide (H2O2), hypochlorous acid (HOCl), etc (Kohen and Nyska, 2002).
The odd number of the electron(s) of free radicals makes them unstable, with a short life span, and greatly reactive. Because of their high reactivity, they can attract electrons from other stable compounds to obtain stability (Phaniendra et al., 2015). Thus, the molecules that lose their electrons become unstable and free radical themselves, beginning a chain reaction cycle that finally destroying the living cells.
The process of lipid peroxidation (LPO) composing of three steps: initiation, propagation, and termination (Yin et al., 2011). LPO with unsaturated lipids produces a wide variety of oxidation products. The principal primary products of LPO are lipid hydroperoxides (LOOH). A secondary product during LPO includes; malondialdehyde (MDA), propanol, hexanal, and 4-hydroxynonenal (4-HNE) (Esterbauer et al., 1991).
The levels of MDA were significantly increased in mice infected with
There are two types of antioxidants known as the enzymatic and non-enzymatic antioxidants alter the free radical different reactions. Body defense itself against ROS by using enzymatic antioxidant mechanisms. The antioxidant enzymes diminish the levels of lipid hydroperoxide and H2O2, thus, they are essential in preventing LPO and maintaining the structure and function of cell membranes. (Koruk et al., 2004).
Glutathione (GSH) can be considered as the most abundant molecule between the endogenous non-enzymatic antioxidants. GSH is a reduced peptide composing of three-amino acids (glutamine, cysteine, and glycine). This tripeptide can be found intracellularly in either an oxidized (GSSG) or reduced (GSH) form (Townsend et al., 2003).
Glutathione reductase (GRx) is an important antioxidant enzyme, which plays a main role in GSH metabolism, reducing glutathione disulfide (GSSG) to the sulfhydryl form, GSH, by the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) dependent reaction. The function of the enzyme is to keep the cellular concentration of reduced GSH higher than its oxidized form, GSSG (Ribeiro et al., 2012). GSH is significantly more beneficial than GSSG under healthy physiological states (Ballatori et al., 2009).
Glutathione-S-transferase (GST) are a group of enzymes or binding proteins found in multiple species and tissues. These enzymes are identified to catalyze the conjugation of GSH with numerous electrophilic molecules which are the first step in mercapturic acid formation before elimination. They also work as binding proteins for a variety of carcinogens that do not serve as substrates (Habig et al., 1974).
Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) are antioxidant enzymes that do not only play an essential but needful role in the antioxidant defense ability of the different biological systems against the free radical offensive. H2O2, when accumulated, is toxic to body different cells (Ighodaro and Akinloye, 2018). The superoxide radical (O2.-) or singlet oxygen radical (1O2−) generated in tissues through metabolism process or reactions in cells are catalytically transformed into H2O2 and molecular oxygen (O2) by (SOD). H2O2, when accumulated, is toxic to body different cells (Ighodaro and Akinloye, 2018). SODs can be mainly classified into four types: iron SOD (Fe-SOD), manganese SOD (Mn-SOD), copper/zinc SOD (Cu/Zn-SOD), and nickel SOD (Ni-SOD) (Abreu and Cabelli, 2010).
In the presence of Fe2+, H2O2 is converted to deleterious ∗OH through a Fenton reaction. This process can be prevented by CAT which breaks down H2O2 into water and molecular oxygen. However, CAT is absent in the mitochondria, hence the reduction of H2O2 to water and lipid peroxides to their corresponding alcohols is carried out by GPx (Ighodaro and Akinloye, 2018)
There were improvements in the antioxidants (CAT, SOD, and GPx) activities in mice orally treated with garlic by 14.2%, 69.23%, and 56.91%, respectively. The percentage of CAT only increased in the group received a mixture of PZQ and garlic to be 17.47%, while that of SOD and GPx were 50.41 and 48.21, respectively (Mantawy et al., 2012). Infected mice treated with 125 mg kg-1 of AGE or 125 mg/kg of GOE or a mixture of AGE (62.5 mg/kg) and GOE (62.5 mg/kg) showed a significant increase in the level of GSH as compared with infected-untreated animals (Sadrefozalayi et al
The molecular applications were more recently also used in the evaluation of the therapies' efficacy (de Oliveira et al
More studies give more interest to the role of parasitic reactive electrophilic compounds, e.g., estrogen-as-like metabolites, on the overture of squamous cell carcinoma (SCC) (Correia da Costa et al., 2014; Vale et al., 2017). Maybe, these metabolites can react with host DNA leading to the formation of DNA-adducts and liberation of ROS, inducing a cascade of events that finally leads to the development of SCC. Some evidence mentions that antioxidants can prevent DNA damage (Pinlaor et al., 2009).
DNA fragmentation caused during apoptosis can be categorized into three types; 1) inter-nucleosomal DNA breakage, 2) cleavage into large 50-300 kb lengths and 3) single-strand cleavage process (Bortner et al., 1995). DNA fragmentation and also cellular nuclear condensation can be described as features of the late apoptosis process (Wadskog
Garlic ingredients including AL have been reported to have antimutagenic effects as mentioned previously by some authors (Siddique and Afzal, 2005; Belloir et al
CU diminished oxidative and nitrative DNA damage by suppression of oxidant‐generating genes and enhancement of antioxidant genes, resulting in inhibition of oxidative and nitrative stress in hamsters infected with
Inflammation-induced by
Schistosomes are identified can disrupt the genetic constitution of their hosts, or, at least, act as apromutagen (Habib et al., 2006; Madbouly et al., 2007). The genotoxic effect of schistosomes and the DNA alkylation high damage observed in the schistosome-infected liver DNA are hypothesized to be caused by free radical produced during the inflammatory response triggered by schistosomal eggs (Madbouly et al., 2007). The high DNA fragmentation level quantified in hepatic tissues of infected
Garlic exerted has not caused major changes in the genome of schistosomes isolated from infected mice after seven weeks of treatment. However, schistosomal mansoni infection caused genetic alterations in the DNA of mice liver, and garlic was able to ameliorate such deformations to a great extent (Riad et al., 2013). DNA fragmentation detection by gel electrophoresis showed that CU (
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