Latest Articles
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Healthy individuals demonstrate considerable heterogeneity upon dynamic quantitative sensory testing assessment of endogenous pain modulatory mechanisms. For those who stratify into a 'pro-nociceptive profile' cohort, consisting of inefficient conditioned pain modulation (CPM) and elevated temporal summation of pain (TSP), the optimal approach for balancing the net output of pain modulatory processes towards anti-nociception remains unresolved. In this translational healthy human and rat study, we examined whether descending modulation countered spinal amplification during concurrent application of a CPM and TSP paradigm alongside pupillometry since pontine activity was previously linked to functionality of endogenous pain modulatory mechanisms and pupil dilation. ⋯ In this translational healthy human and rat study, activity in descending inhibitory controls did not counter spinal amplification processes underpinned by wind up. Despite pupil dilation being previously linked to modulatory mechanisms, dilatory responses did not offer a reliable indicator of functionality. For pro-nociceptive individuals exhibiting inefficient conditioned pain modulation and/or high temporal summation of pain, dampening faciliatory mechanisms rather than augmenting top-down inhibitory processes may be a more effective pain-relief strategy.
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Renal hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD), yet its underlying mechanism(s) are poorly understood. Here we study the effect of the SGLT2 inhibitor, canagliflozin on tubulopathy (fibrosis and apoptosis) in Akita/HhipRPTC-transgenic (Tg) mice with overexpression of Hhip in their renal proximal tubular cells (RPTCs) and its relevant mechanisms. The DKD-tubulopathy with pronounced Sglt2 expression was aggravated in the kidney of Akita/HhipRPTC-Tg cf. ⋯ Further, Hhip stimulated β2-microglobulin, which further interacts with EVsHhip, together facilitating RPTC turn-over from cellular senescence to fibrosis and/or apoptosis, ultimately leading to advanced tubulopathy. In contrast, canagliflozin administration offset the action of Hhip in RPTCs, thereby preventing DKD progression. In conclusion, canagliflozin prevented excessive Hhip-mediated tubulopathy, possibly via the inhibition of excessive Hhip carried by extracellular vehicles in DKD.
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Renal ischemia-reperfusion injury (IRI) is a prevalent clinical syndrome, yet its underlying pathogenesis remains largely unknown. Aldehyde dehydrogenase 2 (ALDH2), an enzyme responsible for detoxifying lipid aldehydes, has been suggested to play a protective role against IRI. In our study, we observed that Aldh2 knock-out C57BL/6 mice experienced more severe renal functional impairment following IRI. ⋯ ALDH2 specifically interacts with the N-terminal domain of NCOR1, which is responsible for its interaction with its E3 ligase SIAH2. This interaction inhibits the proteasome degradation of NCOR1, ultimately stabilizing the NCOR1 transcriptional repression complex. In summary, our research uncovers the role of ALDH2 in mitigating renal IRI by inhibiting 20-HETE synthesis through the transcriptional repression of Cyp4a.