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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.

Blood-dwelling schistosomes and cancer severely impact human health, welfare, and survival, essentially because of their ability to evade host immune cells and humoral effectors. The host immune defenses interact with the surface membrane of the worm and tumor cell. Schistosomes use their sphingomyelin (SM)-rich outer lipid bilayer to form with the surrounding water molecules a tight hydrogen bond barrier in which they open, at will, pores that allow entry of nutrients but not lethal complement components and antibodies. In parasite-free humans, impaired expression of one or more cellular genes linked to lipid metabolism may allow the accumulation of SM at the plasma membrane. Drastic changes in surface membrane fluidity, permeability and integrity deprive the cell from its defense mechanisms and promote chaos in the signals it receives and emits, notably those controlling proliferation and locomotion. The hydrolysis of SM at the surface membrane of schistosomes and cancer cells to phosphocholine and the pro-apoptotic ceramide is feasible via the activation of membrane-associated neutral sphingomyelinase (nSMase). Arachidonic acid (ARA), a critical nutrient for all organisms and cells, is a powerful nSMase activator. Accordingly, ARA is the safest molecule for preventing schistosome and tumor cell development and growth. If readily accessible for human use in terms of availability and cost effectiveness, ARA could be considered a schistosomicide and tumoricide in the future. Highlights • Increased sphingomyelin content at the surface of schistosomes and preneoplastic cells is a key player in immune evasion. • SM hydrolysis is feasible via the activation of surface membrane-associated neutral sphingomyelinase via arachidonic acid. • Surface membrane SM hydrolysis elicits proapoptotic ceramide accumulation, and eventual schistosome and tumor cell death. • ARA does not kill all schistosome eggs in vivo, but readily eliminates larval stages in the intermediate and final hosts. • ARA elicits cancer cell apoptosis, but is readily converted to inflammatory metabolites after chemo- and radiotherapy. • ARA could safely be used in the future for cancer prophylaxis, and treatment immediately upon clinical detection.

The dramatic rise in cancer incidence, alongside treatment deficiencies, has elevated cancer to the second-leading cause of death globally. The increasing morbidity and mortality of this disease can be traced back to a number of causes, including treatment-related side effects, drug resistance, inadequate curative treatment and tumor relapse. Recently, anti-cancer bioactive peptides (ACPs) have emerged as a potential therapeutic choice within the pharmaceutical arsenal due to their high penetration, specificity and fewer side effects. In this contribution, we present a general overview of the literature concerning the conformational structures, modes of action and membrane interaction mechanisms of ACPs, as well as provide recent examples of their successful employment as targeting ligands in cancer treatment. The use of ACPs as a diagnostic tool is summarized, and their advantages in these applications are highlighted. This review expounds on the main approaches for peptide synthesis along with their reconstruction and modification needed to enhance their therapeutic effect. Computational approaches that could predict therapeutic efficacy and suggest ACP candidates for experimental studies are discussed. Future research prospects in this rapidly expanding area are also offered.

Cell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and β2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.

Multiple antigen peptide (MAP) construct of peptide with high homology to Schistosoma mansoni cathepsin B1, MAP-1, and to cathepsins of the L family, MAP-2, consistently induced significant (P < 0.05) reduction in challenge S. mansoni worm burden. It was, however, necessary to modify the vaccine formula to counteract the MAP impact on the parasite egg counts and vitality, and discover the mechanisms underlying the vaccine protective potential. Outbred mice were immunized with MAP-2 in combination with alum and/or MAP-1. Challenge infection was performed three weeks (wks) after the second injection. Blood and liver pieces were obtained on an individual mouse basis, 23 days post-infection (PI), a time of S. mansoni development and feeding in the liver before mating. Serum samples were examined for the levels of circulating antibodies and cytokines. Liver homogenates were used for assessment of liver cytokines, uric acid, arachidonic acid (ARA), and reactive oxygen species (ROS) content. Parasitological parameters were evaluated 7 wks PI. Immunization of outbred mice with MAP-2 in combination with alum and/or MAP-1 elicited highly significant (P < 0.005) reduction of around 60% in challenge S. mansoni worm burden and no increase in worm eggs' loads or vitality, compared to unimmunized or alum pre-treated control mice. Host memory responses to the immunogens are expected to be expressed in the liver stage when worm feeding and cysteine peptidases release start to be active. Serum antibody and cytokine levels were not significantly different between control and vaccinated mouse groups. Highly significant (P < 0.05 - <0.0001) increase in liver interleukin-1, ARA, and ROS content was recorded in MAP-immunized compared to control mice. The findings provided an explanation for the gut cysteine peptidases vaccine-mediated reduction in challenge worm burden and increase in egg counts.

Blood flukes of the genus Schistosoma are covered by a protective heptalaminated, double lipid bilayer surface membrane. Large amounts of sphingomyelin (SM) in the outer leaflet form with surrounding water molecules a tight hydrogen bond barrier, which allows entry of nutrients and prevents access of host immune effectors. Excessive hydrolysis of SM to phosphoryl choline and ceramide via activation of the parasite tegument-associated neutral sphingomyelinase (nSMase) with the polyunsaturated fatty acid, arachidonic acid (ARA) leads to parasite death, via allowing exposure of apical membrane antigens to antibody-dependent cell-mediated cytotoxicity (ADCC), and accumulation of the pro-apoptotic ceramide. Surface membrane nSMase represents, thus, a worm Achilles heel, and ARA a valid schistosomicide. Several experiments conducted in vitro using larval, juvenile, and adult Schistosoma mansoni and Schistosoma haematobium documented ARA schistosomicidal potential. Arachidonic acid schistosomicidal action was shown to be safe and efficacious in mice and hamsters infected with S. mansoni and S. haematobium , respectively, and in children with light S. mansoni infection. A combination of praziquantel and ARA led to outstanding cure rates in children with heavy S. mansoni infection. Additionally, ample evidence was obtained for the powerful ARA ovocidal potential in vivo and in vitro against S. mansoni and S. haematobium liver and intestine eggs. Studies documented ARA as an endogenous schistosomicide in the final mammalian and intermediate snail hosts, and in mice and hamsters, immunized with the cysteine peptidase-based vaccine. These findings together support our advocating the nutrient ARA as the safe and efficacious schistosomicide of the future.

The study of the interactions between biomolecules and nanostructures is quite fascinating. Herein, the adsorption propensity of beryllium oxide (Be 12 O 12 ) nanocarrier toward nucleobases (NBs) was investigated. In terms of DFT calculations, the adsorption tendency of Be 12 O 12 toward NBs, including cytosine (NB-C), guanine (NB-G), adenine (NB-A), thymine (NB-T), and uracil (NB-U), was unveiled through various configurations. Geometrical, electronic, and energetic features for Be 12 O 12 , NBs, and their associated complexes were thoroughly evaluated at M06-2X/6-311+G** level of theory. The potent adsorption process within NBs∙∙∙Be 12 O 12 complexes was noticed through favorable interaction ( E int ) and adsorption ( E ads ) energies with values up to –53.04 and –38.30 kcal/mol, respectively. Generally, a significant adsorption process was observed for all studied complexes, and the favorability followed the order: NB-C∙∙∙ > NB-G∙∙∙ > NB-A∙∙∙ > NB-T∙∙∙ > NB-U∙∙∙Be 12 O 12 complexes. Out of all studied complexes, the most potent adsorption was found for NB-C∙∙∙Be 12 O 12 complex within configuration A ( E int = –53.04 kcal/mol). In terms of energy decomposition, SAPT analysis revealed electrostatic ( E elst ) forces to be dominant within the studied adsorption process with values up to –99.88 kcal/mol. Analyzing QTAIM and NCI, attractive intermolecular interactions within the studied complexes were affirmed. From negative values of thermodynamic parameters, the nature of the considered adsorption process was revealed to be spontaneous and exothermic. Regarding density of state, IR, and Raman analyses, the occurrence of the adsorption process within NBs∙∙∙Be 12 O 12 complexes was confirmed. Noticeable short recovery time values were observed for all studied complexes, confirming the occurrence of the desorption process. The findings provided fundamental insights into the potential application of Be 12 O 12 nanocarrier in drug and gene delivery processes.

Schistosomiasis, a severe disease caused by parasites of the genus Schistosoma, is prevalent in 74 countries, affecting more than 250 million people, particularly children. We have previously shown that the Schistosoma mansoni gut-derived cysteine peptidase, cathepsin B1 (SmCB1), administered without adjuvant, elicits protection (>60%) against challenge infection of S. mansoni or S. haematobium in outbred, CD-1 mice. Here we compare the immunogenicity and protective potential of another gut-derived cysteine peptidase, S. mansoni cathepsin L3 (SmCL3), alone, and in combination with SmCB1. We also examined whether protective responses could be boosted by including a third non-peptidase schistosome secreted molecule, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH), with the two peptidases. While adjuvant-free SmCB1 and SmCL3 induced type 2 polarized responses in CD-1 outbred mice those elicited by SmCL3 were far weaker than those induced by SmCB1. Nevertheless, both cysteine peptidases evoked highly significant (P < 0.005) reduction in challenge worm burden (54-65%) as well as worm egg counts and viability. A combination of SmCL3 and SmCB1 did not induce significantly stronger immune responses or higher protection than that achieved using each peptidase alone. However, when the two peptidases were combined with SG3PDH the levels of protection against challenge S. mansoni infection reached 70-76% and were accompanied by highly significant (P < 0.005) decreases in worm egg counts and viability. Similarly, high levels of protection were achieved in hamsters immunized with the cysteine peptidase/SG3PDH-based vaccine. Gut-derived cysteine peptidases are highly protective against schistosome challenge infection when administered subcutaneously without adjuvant to outbred CD-1 mice and hamsters, and can also act to enhance the efficacy of other schistosome antigens, such as SG3PDH. This cysteine peptidase-based vaccine should now be advanced to experiments in non-human primates and, if shown promise, progressed to Phase 1 safety trials in humans.

Schistosomiasis is caused by several worm species of the genus Schistosoma and afflicts up to 600 million people in 74 tropical and sub-tropical countries in the developing world. Present disease control depends on treatment with the only available drug praziquantel. No vaccine exists despite the intense search for molecular candidates and adjuvant formulations over the last three decades. Cysteine peptidases such as papain and Der p 1 are well known environmental allergens that sensitize the immune system driving potent Th2-responses. Recently, we showed that the administration of active papain to mice induced significant protection (P<0.02, 50%) against an experimental challenge infection with Schistosoma mansoni. Since schistosomes express and secrete papain-like cysteine peptidases we reasoned that these could be employed as vaccines with inbuilt adjuvanticity to protect against these parasites. Here we demonstrate that sub-cutaneous injection of functionally active S. mansoni cathepsin B1 (SmCB1), or a cathepsin L from a related parasite Fasciola hepatica (FhCL1), elicits highly significant (P<0.0001) protection (up to 73%) against an experimental challenge worm infection. Protection and reduction in worm egg burden were further increased (up to 83%) when the cysteine peptidases were combined with other S. mansoni vaccine candidates, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH) and peroxiredoxin (PRX-MAP), without the need to add chemical adjuvants. These studies demonstrate the capacity of helminth cysteine peptidases to behave simultaneously as immunogens and adjuvants, and offer an innovative approach towards developing schistosomiasis vaccines.

The potentiality of monoamine oxidase (MAO) enzymes to break monoamine neurotransmitters makes them efficacious druggable targets. Molecules having MAO‐A inhibition characteristics are utilized as antidepressants while molecules with MAO‐B inhibition prospective are utilized to treat Parkinson's and Alzheimer's diseases. Herein, we have shown how the selective inhibition of both isozymes can be attained by varying the substitution of electron‐withdrawing and donating groups on the phenyl rings of tetrahydropyridines, i. e., ethyl 1,2,6‐triaryl‐4‐(arylamino)‐1,2,5,6‐tetrahydropyridine‐3‐carboxylate (4 a–4 o). The structures of these piperidines (4 a–4 o) were unambiguously established by different spectro‐analytical techniques, including 1H‐ and 13C‐NMR. Among the synthesized compounds, compounds 4 l and 4 n were identified as the most promising inhibitors of MAO‐A and MAO‐B, with IC50 values of 0.40±0.05 and 1.01±0.03 μM, respectively, compared with positive controls, namely clorgyline and l‐deprenyl, with IC50 values of 0.0045±0.0003 and 0.0196±0.001 μM, respectively. The binding interactions of the most potent derivatives within the binding pocket of the MAO‐A and MAO‐B enzymes were predicted by molecular docking studies. Binding mode analysis revealed the capacity of compounds 4 l and 4 n to exhibit a hydrogen bond with PHE177 of MAO‐A and GLN206 of MAO‐B, respectively. This work investigates the selective inhibition of MAO enzymes by varying the substitution of electron‐withdrawing and donating groups on the phenyl rings of tetrahydropyridines (4 a–4 o). Compounds 4 l and 4 n exhibit promising IC50 values of 0.40±0.05 and 1.01±0.03 μM against MAO‐A and MAO‐B, respectively. Molecular docking studies demonstrate the binding modes of 4l  and 4 n with MAO enzymes.