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Fluoropyrimidines are commonly used in the treatment of colorectal cancer. They are, however, associated with adverse events (AEs), of which gastrointestinal, myelosuppression and palmar-plantar erythrodysesthesia are the most common. Clinical guidelines are used for fluoropyrimidine dosing based on dihydropyrimidine dehydrogenase (DPYD) genetic polymorphism and have been shown to reduce these AEs in patients of European ancestry. This study aimed to evaluate, for the first time, the clinical applicability of these guidelines in a cohort of cancer patients on fluoropyrimidine standard of care treatment in Zimbabwe. DNA was extracted from whole blood and used for DPYD genotyping. Adverse events were monitored for six months using the Common Terminology Criteria for AEs (CTCAE) v.5.0. None of the 150 genotyped patients was a carrier of any of the pathogenic variants (DPYD*2A, DPYD*13, rs67376798, or rs75017182). However, severe AEs were high (36%) compared to those reported in the literature from other populations. There was a statistically significant association between BSA (p = 0.0074) and BMI (p = 0.0001) with severe global AEs. This study has shown the absence of the currently known actionable DPYD variants in the Zimbabwean cancer patient cohort. Therefore, the current pathogenic variants in the guidelines might not be feasible for all populations hence the call for modification of the current DPYD guidelines to include minority populations for the benefit of all diverse patients.

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.

Silver nanoparticles are increasingly being used in a wide variety of ways that may lead to frequency of exposure for humans and the environment. Thus, it is necessary to understand the biological effect(s) of these nanoparticles. Previously, we showed that AgNPs activated the kynurenine pathway in rat brain independently of oxidative stress in rats. This present study is aimed at evaluating the effect of AgNPs on some selected cytokines, redox parameters, and on the kynurenine level in rats. Male Wistar rats (130-150 g) were divided into 4 groups. Rats were grouped into control, AgNPs only (50 mg/kg bw), coadministration of AgNPs (50 mg/kg bw), and dexamethasone (100 mg/kg bw) and dexamethasone only (100 mg/kg bw). Results indicated that AgNPs did not significantly elevate MDA levels in rat plasma and brain relative to the control group. AgNPs caused a significant alteration in the level of rat brain and plasma total protein concentration. Meanwhile, AgNPs led to an elevation in the level of reduced glutathione (GSH) in rat plasma but decreased plasma kynurenine level significantly. Furthermore, IFN-γ level was reduced following AgNPs administration, IL-1β decreased across the treatment groups, while NF-κB was reduced in the dexamethasone only and AgNPs+dexamethasone groups when compared with the control. AgNPs led to increased IL-4 levels, while IL-10 levels decreased across the treatment groups. Taken together, our data showed a differential immunomodulatory potential of AgNPs in rats.