Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer's Disease.

Neurodegenerative diseases (NDs) like Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease predominantly pose a significant socioeconomic burden. Characterized by progressive neural dysfunction coupled with motor or intellectual impairment, the pathogenesis of ND may result from contributions of certain environmental and molecular factors. One such condition is hypoxia, characterized by reduced organ/tissue exposure to oxygen. Reduced oxygen supply often occurs during the pathogenesis of ND and the aging process. Despite the well-established relationship between these two conditions (i.e., hypoxia and ND), the underlying molecular events or mechanisms connecting hypoxia to ND remain ill-defined. However, the relatedness may stem from the protective or deleterious effects of the transcription factor, hypoxia-inducible factor 1-alpha (HIF-1α). The upregulation of HIF-1α occurs in the pathogenesis of most NDs. The dual function of HIF-1α in acting as a "killer factor" or a "protective factor" depends on the prevailing local cellular condition. The kynurenine pathway is a metabolic pathway involved in the oxidative breakdown of tryptophan. It is essential in neurotransmission and immune function and, like hypoxia, associated with ND. Thus, a good understanding of factors, including hypoxia (i.e., the biochemical implication of HIF-1α) and kynurenine pathway activation in NDs, focusing on Alzheimer's disease could prove beneficial to new therapeutic approaches for this disease, thus the aim of this review.

The anti-parasite action of imidazole derivatives likely involves oxidative stress but not HIF-1α signaling.

BACKGROUND: Therapeutic options for toxoplasmosis are limited. This fact underscores ongoing research efforts to identify and develop better therapy. Previously, we reported the anti-parasitic potential of a new series of derivatives of imidazole. OBJECTIVE: In the current investigation, we attempted the investigation of the possible action mechanism of few promising anti-parasite imidazole derivatives namely C1 (bis-imidazole), C2 (phenyl-substituted 1H-imidazole) and C3 (thiophene-imidazole) METHODS: We evaluated if oxidative stress, hypoxia as well as metabolic reprogramming of host l-tryptophan pathway form part of the parasite growth inhibition by imidazoles. Anti-parasite assay was performed for imidazoles at concentrations ranging from 0 to 10 µM, while pyrimethamine was used as reference drug to validate assay. RESULTS: Imidazole compounds restricted parasite growth dose-dependently. However, in the presence of an antioxidant (Trolox), l-tryptophan and/or CoCl2 (chemical inducer of hypoxia), the growth inhibitory efficacy of imidazoles was appreciably abolished. Further, imidazole treatment led to elevated level of reactive oxygen species, while reducing parasite mitochondrial membrane potential compared with control. In contrast, imidazole had no effect on host HIF-1α level suggesting its exclusion in the anti-parasite action. CONCLUSION: Taken together, imidazole-based compounds might restrict parasite growth by causing oxidative stress. The findings provide new insight on the likely biochemical mechanisms of imidazoles as prospective anti-parasite therapy. Data gives new perspective that not only underscores the anti-parasite prospects of imidazoles, but implicates the host l-tryptophan pathway as a feasible treatment option for T. gondii infections.

Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders.

Reactive species, such as those of oxygen, nitrogen, and sulfur, are considered part of normal cellular metabolism and play significant roles that can impact several signaling processes in ways that lead to either cellular sustenance, protection, or damage. Cellular redox processes involve a balance in the production of reactive species (RS) and their removal because redox imbalance may facilitate oxidative damage. Physiologically, redox homeostasis is essential for the maintenance of many cellular processes. RS may serve as signaling molecules or cause oxidative cellular damage depending on the delicate equilibrium between RS production and their efficient removal through the use of enzymatic or nonenzymatic cellular mechanisms. Moreover, accumulating evidence suggests that redox imbalance plays a significant role in the progression of several neurodegenerative diseases. For example, studies have shown that redox imbalance in the brain mediates neurodegeneration and alters normal cytoprotective responses to stress. Therefore, this review describes redox homeostasis in neurodegenerative diseases with a focus on Alzheimer's and Parkinson's disease. A clearer understanding of the redox-regulated processes in neurodegenerative disorders may afford opportunities for newer therapeutic strategies.

Imidazole derivatives as antiparasitic agents and use of molecular modeling to investigate the structure-activity relationship.

Toxoplasmosis is a common parasitic disease caused by Toxoplasma gondii. Limitations of available treatments motivate the search for better therapies for toxoplasmosis. In this study, we synthesized a series of new imidazole derivatives: bis-imidazoles (compounds 1-8), phenyl-substituted 1H-imidazoles (compounds 9-19), and thiopene-imidazoles (compounds 20-26). All these compounds were assessed for in vitro potential to restrict the growth of T. gondii. To explore the structure-activity relationships, molecular analyses and bioactivity prediction studies were performed using a standard molecular model. The in vitro results, in combination with the predictive model, revealed that the imidazole derivatives have excellent selectivity activity against T. gondii versus the host cells. Of the 26 compounds screened, five imidazole derivatives (compounds 10, 11, 18, 20, and 21) shared a specific structural moiety and exhibited significantly high selectivity (> 1176 to > 27,666) towards the parasite versus the host cells. These imidazole derivatives are potential candidates for further studies. We show evidence that supports the antiparasitic action of the imidazole derivatives. The findings are promising in that they reinforce the prospects of imidazole derivatives as alternative and effective antiparasitic therapy as well as providing evidence for a probable biological mechanism.

In Vitro Screening to Identify Anti-Toxoplasma Compounds and In Silico Modeling for Bioactivities and Toxicity.

Toxoplasmosis, which affects more than a billion people worldwide, is a common parasitic infection caused by the obligate intracellular parasite, Toxoplasmagondii. Current treatment strategies have several limitations, including unwanted side effects and poor efficacy. Therefore, newer therapies are needed for toxoplasmosis. Drug repurposing and screening of a vast array of natural and/or synthetic compounds is a viable option for antiparasitic drug discovery. In this study, we screened 62 compounds comprising natural products (NPs) and FDA-approved (FDA) drugs, to identify the hit compounds that suppress the growth of T. gondii. To determine the parasite inhibitory potential of the compounds, host mammalian cells were infected with a transgenic T. gondii strain, and the viability of the parasite was evaluated by luminescence. Of the 62 compounds, tubericidin, sulfuretin, peruvoside, resveratrol, narasin and diacetoxyscirpenol of the natural product isolates, as well as bortezonib, 10-Hydroxycamtothecin, mebendazole, niflumic acid, clindamycin HCl, mecamylamine, chloroquine, mitomycin C, fenbendazole, daunorubicin, atropine, and cerivastatin of FDA molecules were identified as "hits" with ≥ 40 percent anti-parasite action. Additionally, mitomycin C, radicicol, naringenin, gitoxigenin, menadione, botulin, genistin, homobutein, and gelsemin HCl of the natural product isolates, as well as lomofungin, cyclocytidine, prazosin HCl, cerivastatin, camptothecin, flufenamic acid, atropine, daunorubicin, and fenbendazole of the FDA compounds exhibited cytotoxic activity, reducing the host viability by ≥ 30 percent. Our findings not only support the prospects of drug repurposing, but also indicate that screening a vast array of molecules may provide viable sources of alternative therapies for parasitic infection.

The oral administration of silver nanoparticles activates the kynurenine pathway in rat brain independently of oxidative stress.

In this work, we determined whether oxidative stress contributed to the activation of the kynurenine pathway by AgNPs. Male Wistar rats weighing between 130 and 146 g were randomly assigned into six groups. Animals in the negative control group were orally administered distilled water while, the other treatment groups were respectively given AgNPs (25 and 50 mg/kg bw) alone or in combination with Trolox (100 mg/kg bw). Results showed that treatments with AgNPs significantly raised protein carbonyl level in rat liver, but the co-treatment with Trolox attenuated the elevation. Conversely, AgNPs raised the level of reduced glutathione (GSH) in rat plasma and tissues compared to the negative control. Further, oral exposure to AgNPs (50 mg/kg bw) significantly elevated rat plasma and brain kynurenine levels compared to the negative control. Meantime, the co-treatment with Trolox appreciably restored kynurenine level in rat plasma, but not in the rat brain. Taken together, findings indicate that the oral administration of AgNPs alone at the doses used in this study, might not have caused oxidative stress. However, the co-treatment with Trolox appears to potentiate oxidative stress in rats following exposure to AgNPs. Furthermore, data support that the activation of the kynurenine pathway in the rat brain by AgNPs might be independent of oxidative stress. The findings are new and contribute to deepen our understanding of the cellular interaction by nanoparticles.

Cellular apoptosis of HFF cells by inorganic nanoparticles not susceptible to modulation by Toxoplasma gondii infection in vitro.

The interaction of nanoparticles with living cells is becoming one of the urgent areas of collaborative research in materials science and biology. Previously, we showed that nanoparticles have promising anti-Toxoplasma gondii properties. Meanwhile, Toxoplasma gondii has been shown to avert apoptosis in host cells whereas nanoparticles have been implicated for apoptotic tendency. Therefore, in the present study, we assessed the in vitro apoptotic properties of inorganic nanoparticles in the absence or presence of Toxoplasma infection and/or small molecules used as metabolic modulators. Results showed that inorganic nanoparticles dose-dependently caused cellular apoptosis. However, in the presence of infection by Toxoplasma gondii, nanoparticles-induced cellular apoptosis was not mitigated. Likewise, use of several small molecules (anti-metabolites) as metabolic modulators either mildly or nearly failed to abate cellular apoptosis by nanoparticles. Taken together, our findings do not only confirm the apoptotic potential of inorganic nanoparticles but show evidence that cellular apoptosis by inorganic nanoparticles of gold and silver might not be susceptible to modulation by Toxoplasma gondii infection. The findings are new and contribute to deepen our understanding of the cellular interaction of nanoparticles.

Metal nanoparticles restrict the growth of protozoan parasites.

The Trypanosoma and Toxoplasma spp, are etiological agents of diseases capable of causing significant morbidity, mortality and economic burden, predominantly in developing countries. Currently, there are no effective vaccines for the diseases caused by these parasites; therefore, therapy relies heavily on antiprotozoal drugs. However, the treatment options for these parasitic diseases are limited, thus underscoring the need for new anti-protozoal agents. Here, we investigated the anti-parasite action of nanoparticles. We found that the nanoparticles have strong and selective in vitro activity against T. b. brucei but moderate in vitro activity against T. congolense and T. evansi. An estimation of the in vitro anti-Trypanosoma efficacy showed that the nanoparticles had ≥200-fold selective activity against the parasite versus mammalian cells. Moreover, the nanoparticle alloys moderately suppressed the in vitro growth of T. gondii by ≥60%. In our in vivo study, the nanoparticles appeared to exhibit a trypanostatic effect, but did not totally suppress the rat parasite burden, thereby failing to appreciably extend the survival time of infected animals compared with the untreated control. In conclusion, this is the first study to demonstrate the selective in vitro anti-Trypanosoma action of nanoparticles and thus supports the potential of nanoparticles as alternative anti-parasitic agents.

Anti-inflammatory and bronchodilatory constituents of leaf extracts of Anacardium occidentale L. in animal models.

OBJECTIVE: Anacardium occidentale L. leaf is useful in the treatment of inflammation and asthma, but the bioactive constituents responsible for these activities have not been characterized. Therefore, this study was aimed at identifying the bioactive constituent(s) of A. occidentale ethanolic leaf extract (AOEL) and its solvent-soluble portions, and evaluating their effects on histamine-induced paw edema and bronchoconstriction. METHODS: The bronchodilatory effect was determined by measuring the percentage protection provided by plant extracts in the histamine-induced bronchoconstriction model in guinea pigs. The anti-inflammatory effect of the extracts on histamine-induced paw edema in rats was determined by measuring the increase in paw diameter, after which the percent edema inhibition was calculated. The extracts were analyzed using gas chromatography-mass spectrometry to identify the bioactive constituents. Column chromatography and Fourier transform infrared spectroscopy were used respectively to isolate and characterize the constituents. The bronchodilatory and anti-inflammatory activities of the isolated bioactive constituent were evaluated. RESULTS: Histamine induced bronchoconstriction in the guinea pigs and edema in the rat paw. AOEL, hexane-soluble portion of AOEL, ethyl acetate-soluble portion of AOEL, and chloroform-soluble portion of AOEL significantly increased bronchodilatory and anti-inflammatory activities (P < 0.05). Oleamide (9-octadecenamide) was identified as the most abundant compound in the extracts and was isolated. Oleamide significantly increased bronchodilatory and anti-inflammatory activities by 32.97% and 98.41%, respectively (P < 0.05). CONCLUSION: These results indicate that oleamide is one of the bioactive constituents responsible for the bronchodilatory and anti-inflammatory activity of A. occidentale leaf, and can therefore be employed in the management of bronchoconstriction and inflammation.