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.

Quercetin Caused Redox Homeostasis Imbalance and Activated the Kynurenine Pathway (Running Title: Quercetin Caused Oxidative Stress).

The search for new and better antimicrobial therapy is a continuous effort. Quercetin is a polyphenol with promising antimicrobial properties. However, the understanding of its antimicrobial mechanism is limited. In this study, we investigated the biochemical mechanistic action of quercetin as an antibacterial compound. Isolates of Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus were initially exposed to quercetin for antibacterial evaluation. Subsequently, S. aureus (Gram-positive) and E. coli (Gram-negative) cells were exposed to quercetin with or without ascorbic acid, and cells were harvested for selected biochemical assays. These assays included redox homeostasis (lipid peroxidation, total thiol, total antioxidant capacity), nitric oxide, and kynurenine concentration as well as DNA fragmentation. The results revealed that quercetin caused lipid peroxidation in the bacterial isolates. Lipid peroxidation may indicate ensuing oxidative stress resulting from quercetin treatment. Furthermore, tryptophan degradation to kynurenine was activated by quercetin in S. aureus but not in E. coli, suggesting that local L-tryptophan concentration might become limiting for bacterial growth. These findings, considered together, may indicate that quercetin restricts bacterial growth by promoting oxidative cellular stress, as well as by reducing the local L-tryptophan availability by activating the kynurenine pathway, thus contributing to our understanding of the molecular mechanism of the antimicrobial action of quercetin.

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.

Correlating possible predisposing demographics and systemic conditions with the aortic root.

Background: The aortic root is an aggregate of various components that connects the left ventricle to the aorta. The most predominant pathologies have been associated with the dilation of the aortic root leading to aneurysms. Aim: This study is designed to measure the role of systemic morbidities such as hypertension, diabetes, and body mass index (BMI) on the dimension of the aortic root. Materials and Methods: Participants were volunteers of African descent who were recruited during and after an organized health fair by the medical students' body from All Saints University, School of Medicine. 169 participants consisting of 62 males and 107 females with ages ranging from 9 to 84 years agreed to volunteer by signing the consent after which a questionnaire was administered and a preliminary clinical procedure was used to check for blood pressure (BP), blood glucose (BG), and BMI. The measurement of the aortic root was carried out by an experienced single investigator who was not aware of the purpose of measurements, using a DUS-5000 ultrasound machine (Miami, Florida, USA) at a low-frequency micro-convex transducer preset to "adult cardiac" with a default frequency of 4 MHz. Results: Among the participants, 35.03%, 47.80%, and 29.11% had normal BP, BG, and BMI readings, respectively. The Chi-squared analysis identified a significant correlation between the diameter of the aortic annulus (AA) and BMI. Diastolic BP is also correlated with the diameter of the AA. Sinus of Valsalva (SV) showed an unusual correlation with BG as opposed to BP and BMI. Conclusion: The disparity in how a systemic factor individually correlates with the AA and the SV is not clear. The study targets to provide educational concept in this regard.

RésuméContexte: La racine aortique est un agrégat de divers composants qui relie le ventricule gauche à l'aorte. Les pathologies les plus prédominantes ont été associées à la dilatation de la racine aortique conduisant à des anévrismes. But: Cette étude est conçue pour mesurer le rôle des morbidités systémiques telles que l'hypertension, le diabète et l'indice de masse corporelle (IMC) sur la dimension de la racine aortique. Matériel et méthodes: Les participants étaient des volontaires d'origine africaine qui ont été recrutés pendant et après une foire organisée de la santé par le corps des étudiants en médecine de l'école de médecine All Saints University. 169 participants, soit 62 hommes et 107 femmes âgés de 9 à 84 ans, ont accepté de faire du bénévolat en signant le consentement après l'administration du questionnaire et en utilisant une procédure clinique préliminaire pour vérifier la tension artérielle, la glycémie (glycémie), et BMI. La mesure de la racine aortique a été effectuée par un chercheur expérimenté qui ne connaissait pas le but des mesures, en utilisant une échographe DUS-5000 (Miami, Floride, USA) à un transducteur micro-convexe basse fréquence préréglé à "adultcardiac" avec une fréquence par défaut de 4 MHz. Résultats: Parmi les participants, 35,03%, 47,80% et 29,11% avaient respectivement des valeurs normales de BP, de BG et de BMI. L'analyse du khi carré a mis en évidence une corrélation significative entre le diamètre de l'anneau aortique (AA) et l'IMC. La pression artérielle diastolique est également corrélée avec le diamètre de l'AA.Sinus de Valsalva (SV) a montré une corrélation inhabituelle avec BG par opposition à BP et BMI. CONCLUSION: La disparité dans la façon dont un facteur systémique est individuellement corrélé avec l'AA et le SV n'est pas clair. L'étude vise à fournir un concept éducatif à cet égard.

Sleep Paralysis, a Medical Condition with a Diverse Cultural Interpretation.

Sleep paralysis (SP) is a state associated with the inability to move that occurs when an individual is about sleeping or just waking. It could occur in healthy individuals as isolated SP. It has also been linked with other underlying psychiatry, familial, and sleep disorders. Statistics show that 8% of the general population suffers from SP. Although this value has been described inaccurately, there is no standard definition or etiology to diagnose SP. There are several speculations describing SP in the current literature. These descriptions can be viewed as either cultural-based or medical-based. The disparity among cultural or ethnic groups and medical professionals in identifying SP has led to the various approaches to managing the condition. This review aims to medically describe SP and how it is interpreted and managed among various cultural groups.

Current Trends in Biomaterial Utilization for Cardiopulmonary System Regeneration.

The cardiopulmonary system is made up of the heart and the lungs, with the core function of one complementing the other. The unimpeded and optimal cycling of blood between these two systems is pivotal to the overall function of the entire human body. Although the function of the cardiopulmonary system appears uncomplicated, the tissues that make up this system are undoubtedly complex. Hence, damage to this system is undesirable as its capacity to self-regenerate is quite limited. The surge in the incidence and prevalence of cardiopulmonary diseases has reached a critical state for a top-notch response as it currently tops the mortality table. Several therapies currently being utilized can only sustain chronically ailing patients for a short period while they are awaiting a possible transplant, which is also not devoid of complications. Regenerative therapeutic techniques now appear to be a potential approach to solve this conundrum posed by these poorly self-regenerating tissues. Stem cell therapy alone appears not to be sufficient to provide the desired tissue regeneration and hence the drive for biomaterials that can support its transplantation and translation, providing not only physical support to seeded cells but also chemical and physiological cues to the cells to facilitate tissue regeneration. The cardiac and pulmonary systems, although literarily seen as just being functionally and spatially cooperative, as shown by their diverse and dissimilar adult cellular and tissue composition has been proven to share some common embryological codevelopment. However, necessitating their consideration for separate review is the immense adult architectural difference in these systems. This review also looks at details on new biological and synthetic biomaterials, tissue engineering, nanotechnology, and organ decellularization for cardiopulmonary regenerative therapies.

Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis; Extensive Review of Reports of Drug-Induced Etiologies, and Possible Therapeutic Modalities.

Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis are adverse hypersensitivity reactions that affect the skin and mucous membranes. They are characterised by erythematous macules and hemorrhagic erosions of the mucous membranes. Epidermal detachments of varying degrees of severity also occur in these conditions. Various aetiologies are associated with these conditions, with adverse drug reaction being the most common. Though the worldwide incidence of these conditions is recorded as low, diverse types of medication are being observed to lead to these conditions. This review compiles information on the details of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis, the pathophysiology, therapeutic management, and largely considers the drug-induced etiologies associated with these conditions.

Correlation of some predisposing intrinsic conditions with the morphological integrity of the Achilles tendon.

BACKGROUND: Most studies have focused on ill-tendons with a little insight on how intrinsic factors correlate with the Achilles tendon (AT) morphology. AIM: This study aims at establishing how blood pressure (BP), blood glucose (BG), and body mass index (BMI) correlate with the morphology of the AT with emphasis on width changes. MATERIALS AND METHODS: Participants were volunteers who were recruited during and after an organized health fair by the Medical Students' body of All Saints University, School of Medicine, Commonwealth of Dominica. A total of 336 people, consisting of 135 males and 201 females volunteered for the study. The most dominant age group was between 60 and 65 years. A self-administered questionnaire was used to acquire necessary information, and a preliminary clinical procedure was used to check for BP, BG, and BMI. Ultrasound examination was done in B-mode using a linear array high-frequency probe with a mediolateral approach at the AT. RESULTS: Among the participants, 42.68%, 69.75%, and 30.38% had normal BP, BG, and BMI readings, respectively. BP, BG, and BMI statistically supported the hypothesis. Individuals with extreme BP, BG, and BMI had their AT width wider when compared with individuals with normal systemic readings. Sonographic examination revealed most participants with normal tendon morphology while some identifiable changes were observed among others. CONCLUSION: This study suggests that BP, BG, and BMI could affect the morphological integrity of the AT. It indicates that asymptomatic high blood sugar and BP could weaken the AT, leading to pain which may appear unrelated to the physician and patient.

Contexte: La plupart des études se sont concentrées sur les tendons avec un aperçu sur la façon de faire correspondre le tendon d'Achille (AT) morphologie. But: Cette étude vise à établir la pression artérielle (BP), la glycémie (BG), et l'indice de masse corporelle (IMC) en corrélation avec la morphologie de l'AT en mettant l'accent sur les changements de largeur. Matériel et Méthodes: Les participants étaient des volontaires qui ont été recrutés pendant et après une foire organisée de la santé par Corps des étudiants en médecine de l'Université All Saints de l'École de médecine du Commonwealth de la Dominique. Un total de 336 personnes, composé de 135 hommes et 201 femmes se sont portées volontaires pour l'étude. Le groupe d'âge le plus dominant était entre 60 et 65 ans. Un questionnaire auto-administré était utilisé pour acquérir les informations nécessaires, et une procédure clinique préliminaire a été utilisée pour vérifier BP, BG et BMI. Examen échographique a été effectuée en mode B en utilisant une sonde à haute fréquence à réseau linéaire avec une approche médiolatérale à l'AT. Résultats: Parmi les participants, 42,68%, 69,75% et 30,38% avaient des valeurs normales de pression artérielle, de glycémie et d'IMC, respectivement. BP, BG et BMI ont statistiquement soutenu l'hypothèse. Les personnes atteintes de TA, de BG et d'IMC extrêmes avaient une largeur AT supérieure par rapport aux personnes ayant des lectures systémiques normales. L'examen échographique a révélé la plupart des participants ayant une morphologie tendineuse normale, tandis que certains changements identifiables ont été observés chez autres. Conclusion: Cette étude suggère que BP, BG et BMI pourraient affecter l'intégrité morphologique de l'AT. Il indique que asymptomatique l'hyperglycémie et la TA pourraient affaiblir l'AT, entraînant une douleur qui peut sembler sans rapport avec le médecin et le patient. Mots-clés: tendon d'Achille, glycémie, tension artérielle, indice de masse corporelle, chaussures à talons hauts, activités sportives, échographie.

Correlation of some predisposing intrinsic conditions with the morphological integrity of the Achilles tendon

Background: Most studies have focused on ill-tendons with a little insight on how intrinsic factors correlate with the Achilles tendon (AT) morphology. Aim: This study aims at establishing how blood pressure (BP), blood glucose (BG), and body mass index (BMI) correlate with the morphology of the AT with emphasis on width changes. Materials and Methods: Participants were volunteers who were recruited during and after an organized health fair by the Medical Students' body of All Saints University, School of Medicine, Commonwealth of Dominica. A total of 336 people, consisting of 135 males and 201 females volunteered for the study. The most dominant age group was between 60 and 65 years. A self-administered questionnaire was used to acquire necessary information, and a preliminary clinical procedure was used to check for BP, BG, and BMI. Ultrasound examination was done in B-mode using a linear array high-frequency probe with a mediolateral approach at the AT. Results: Among the participants, 42.68%, 69.75%, and 30.38% had normal BP, BG, and BMI readings, respectively. BP, BG, and BMI statistically supported the hypothesis.Individuals with extreme BP, BG, and BMI had their AT width wider when compared with individuals with normal systemic readings. Sonographic examination revealed most participants with normal tendon morphology while some identifiable changes were observed among others. Conclusion: This study suggests that BP, BG, and BMI could affect the morphological integrity of the AT. It indicates that asymptomatic high blood sugar and BP could weaken the AT, leading to pain which may appear unrelated to the physician and patient

The Palm-Heart Diameter: A Prospective Simple Screening Tool for Identifying Heart Enlargement.

BACKGROUND: Several speculations have linked the size of the fist to be equal to the size of the heart. However, the substantial scientific report still lacks to support this theory. AIM: This study aims to provide the validity of the fist-heart assumption by correlating the palm and heart diameters while benchmarking it as a reference tool for determining the normal heart size. MATERIALS AND METHOD: Volunteers from the public were recruited during a health fair organised by the school. A self-administered questionnaire for necessary information was distributed after the volunteers signed the consent forms. The palm of both hands was measured in duplicates using a flexible ruler. Ultrasound examination was used in measuring the diameter of the heart with the landmark being from the anterior fibrous pericardium to the lowest part of the posterior fibrous pericardium. The level of significance was kept at P < 0.05. RESULTS: A total of 275 people, consisting of 123 males and 152 females participated in the study. The age range was from 15 to 80 years with a mean age of 28.16 ± 16.18. The measurement showed that the size of both palms correlated with the heart diameter, p < 0.05. Other factors such as age and height showed a substantial level of correlation. However, this correlation ceased with older participants. Palm size did not correlate among participants with previously diagnosed prehypertension. However, participants with previously diagnosed hypertension with good medication compliance maintained the correlation. CONCLUSION: This study establishes the correlation between the palm and heart diameters. Since the heart tissue and the upper limb share a similar embryonic origin, being the mesoderm, this study prospects the fact that heart enlargement could be preliminarily identified by measuring the size of the hand.