A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Ethnography, ethnobiology and natural history: narratives on hunting and ecology of mammals among quilombolas from Southeast Brazil.

BACKGROUND: As a leading practice of Homo sapiens' environmental experience for hundreds of millennia, hunting continues to evoke key research inquiries in the fields of archaeology, human ecology, and conservation biology. Broadly speaking, hunting has been mainly a subject of qualitative-symbolic and quantitative-materialistic schemata of analyze, among anthropologists and biologists, respectively. However, the phenomenological dimension of the hunting experience, in the course of individuals` everyday life, received little academic attention until this century. This study analyzes the daily praxis of hunting among quilombolas (descendants from runaway African slaves) in Southeast Brazil, making use of an ethnographic approach of phenomenological orientation, which dialogue with central ethnobiological issues. The authors also report the local ecological knowledge about mammals hunted in the area, and its relationship to the scientific literature on this subject. METHODS: Between 2016 and 2019, the authors made use of participant observation and informal interviews among eight key local participants, in three quilombola communities in the Ribeira Valley (São Paulo, Brazil). Fragments of authors' field notes and parts of interviewers' speeches make up the core results obtained. RESULTS: Articulating local knowledge to scientific literature, this study yielded a hybrid and comprehensive narrative about natural history of the mammals in the area. The authors also accessed elementary aspects of research participants' experience in hunting, such as strategies, tactics, motivations, and feelings. They reveal a set of human behavior dispositions that seems to emerge only in the context of the action, modulating the praxis of hunting on the course of individuals' everyday life. CONCLUSION: Ethnography, ethnobiology, and natural sciences backgrounds were systematically articulated in this research. This made possible to get a contextualized and multifaceted understanding of hunting praxis in the Ribeira Valley, an important socioenvironmental context of Atlantic Forest in Brazil. The role of an ethnographic approach applied to ethnoecological and biological conservation issues is especially considered here.