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Intervertebral disc degeneration (IVDD) is a chronic age-related degenerative disease accompanied by complex pathophysiological mechanisms. Increasing evidence indicates that NLRP3 inflammasome mediated pyroptosis of nucleus pulposus (NP) cells displays an important role in the pathological progression of IVDD. Milk fat globule-EGF factor-8 (MFG-E8) is an endogenously secreted glycoprotein with beneficial effects of anti-inflammatory, antioxidant, and modulation of NLRP3 inflammasome. However, the effect of MFG-E8 on IVDD remains unclear. In this study, our purpose is to clarify the expression changes of MFG-E8 in the IVDD process and explore the role and mechanism of MFG-E8. We found that MFG-E8’s expression was reduced in degraded nucleus pulposus tissues of humans and rats as well as hydrogen peroxide (H2O2)-treated NP cells. Exogenous supplementation of MFG-E8 could rescue H2O2-induced oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activation and protect NP cells from pyroptosis and extracellular matrix (ECM) degradation. Mechanistically, Nrf2/TXNIP/NLRP3 axis plays a crucial role in MFG-E8-mediated suppression of the above-pathological events. In vivo, we established a rat intervertebral disc acupuncture model and found that MFG-E8 administration effectively alleviated IVDD development by imageological and histomorphological evaluation. Overall, our findings revealed the internal mechanisms underlying MFG-E8 regulation in NP cells and its intrinsic value for IVDD therapy.

IL-1β promotes inflammatory response and extracellular matrix (ECM) degradation through NF-κB signaling pathway; while cardamonin attenuates the inflammatory response and ECM degradation by suppressing NF-κB signaling pathway via Nrf2/HO-1 axis.

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Expressive writing has been shown to improve physical, mental, and social health outcomes for patients struggling with difficult diagnoses. In many online health communities, writing comprises a substantial portion of the user experience, yet little work has explored how writing itself affects user engagement. This paper explores user engagement on CaringBridge, a prominent online community for writing about personal health journeys. We build a survival analysis model, defining a new set of variables that operationalize expressive writing, and comparing these effects to those of social support, which are well-known to benefit user engagement. Furthermore, we use machine learning methods to estimate that approximately one third of community members who self-identify with a cancer condition cease engagement due to literal death. Finally, we provide quantitative evidence that: (1) receiving support, expressive writing, and giving support, in decreasing magnitude of relative impact, are associated with user engagement on CaringBridge, and (2) that considering deceased sites separately in our analysis significantly shifts our interpretations of user behavior.

No abstract

Multiterritory perforator flap survival is commonly applied in surgical tissue reconstructions and covering of large skin defects. However, multiple risk factors such as ischemia, reperfusion injury, and apoptosis after reconstructive surgeries cause necrosis in distal parts with outcomes ranging from poor aesthetic appearance to reconstructive failure. A few studies have reported that sitagliptin (Sit) promotes angiogenesis and inhibits apoptosis. However, little is known about Sit-induced autophagy especially on the flap model. Therefore, our study investigated the effect of Sit and its induced autophagy on the perforator flap survival. Ninety male Sprague-Dawley rats were randomly separated into control, Sit, and Sit+3-methyladenine group. Results revealed that Sit significantly promoted flap survival by enhancing angiogenesis, reducing oxidative stress, and attenuating apoptosis. In addition, flap survival was further improved after co-administration with 3-methyladenine to inhibit autophagy. Overall, our results established that Sit has positive effects in promoting survival of multiterritory perforator flap. Sit-induced autophagy was detrimental for flap survival and its inhibition may further improve flap survival.

Background: Caloric restriction mimetics (CRMs) mimic the favourable effects of caloric restriction (CR) and have been shown to have therapeutic effects in neuroinflammatory disease. However, whether CRMs improve the functional recovery from spinal cord injury (SCI) and the underlying mechanism of action remain unclear. In this study, we used the CRMs 3,4-dimethoxychalcone (3,4-DC) to evaluate the therapeutic value of CRMs for SCI. Methods: HE, Masson and Nissl staining; footprint analysis; and the Basso mouse scale were used to determine the functional recovery from SCI after 3,4-DC treatment. RNA sequencing was used to identify the mechanisms of 3,4-DC in SCI. Western blotting, qPCR and immunofluorescence were used to detect the levels of pyroptosis, necroptosis, autophagy and the AMPK-TRPML1-calcineurin signalling pathway. We employed a dual-luciferase reporter assay in vitro and applied AAV vectors to inhibit TFEB in vivo to explore the mechanism of 3,4-DC. Results: 3,4-DC reduced glial scar area and motor neuron death and improved functional recovery after SCI. RNA-sequencing results indicated that oxidative stress, pyroptosis, necroptosis, and autophagy may be involved in the ability of 3,4-DC to improve functional recovery. Furthermore, 3,4-DC inhibited pyroptosis and necroptosis by enhancing autophagy. We also found that 3,4-DC enhances autophagy by promoting TFEB activity. A decrease in the TFEB level abolished the protective effect of 3,4-DC. In addition, 3,4-DC partially regulated TFEB activity through the AMPK-TRPML1-calcineurin signalling pathway. Conclusions: 3,4-DC promotes functional recovery by upregulating TFEB-mediated autophagy and inhibiting pyroptosis and necroptosis after SCI, which may have potential clinical application value.