Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis.

Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.

The VDAC1 oligomerization regulated by ATP5B leads to the NLRP3 inflammasome activation in the liver cells under PFOS exposure.

As a persistent organic pollutant, perfluorooctane sulfonate (PFOS) has a serious detrimental impact on human health. It has been suggested that PFOS is associated with liver inflammation. However, the underlying mechanisms are still unclear. Here, PFOS was found to elevate the oligomerization tendency of voltage-dependent anion channel 1 (VDAC1) in the mice liver and human normal liver cells L-02. Inhibition of VDAC1 oligomerization alleviated PFOS-induced nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome activation. Cytoplasmic membrane VDAC1 translocated to mitochondria was also observed in response to PFOS. Therefore, the oligomerization of VDAC1 occurred mainly in the mitochondria. VDAC1 was found to interact with the ATP synthase beta subunit (ATP5B) under PFOS treatment. Knockdown of ATP5B or immobilization of ATP5B to the cytoplasmic membrane alleviated the increased VDAC1 oligomerization and NLRP3 inflammasome activation. Therefore, our results suggested that PFOS induced NLRP3 inflammasome activation through VDAC1 oligomerization, a process dependent on ATP5B to transfer VDAC1 from the plasma membrane to the mitochondria. The findings offer novel perspectives on the activation of the NLRP3 inflammasome, the regulatory mode on VDAC1 oligomerization, and the mechanism of PFOS toxicity.

Substrate-directed divergent annulations of sulfur ylides: synthesis of functionalized bispirocyclopentane and bispirocyclopropane derivatives.

Herein, an efficient, substrate-directed divergent [2 + 3]/[2 + 1] annulation of tetra-substituted oxa-dienes and allylic sulfur ylides has been successfully developed. Under precise annulation regulation, a series of functionalized bispirocyclopentane and bispirocyclopropane derivatives were synthesized in a highly stereoselective and economical manner (up to 95% yield, >20 : 1 dr or >20 : 1 E/Z). This protocol offers the advantages of mild conditions, high chemo-, regio- and diastereoselectivity and broad substrate compatibility. In addition, the synthetic practicality of this protocol was evaluated through a scale-up preparation and a series of three-component reactions utilizing in situ generated sulfur ylides.

Effects of Ankle Orthoses, Taping, and Insoles on Postural Stability of Individuals with Chronic Ankle Instability: A Systematic Review.

Chronic ankle instability (CAI) is a prevalent condition characterized by recurring instances of the ankle giving way and persistent symptoms, including pain and diminished function. Foot and ankle external supports are commonly used in clinical practice and research for treating CAI. This systematic review aimed to assess the effects of foot and ankle external supports on the postural stability of individuals with CAI to guide clinical practice and inform future research. A comprehensive search was conducted in PubMed, Web of Science, Scopus, and Google Scholar databases from 1 January 2012 to 1 November 2022. Eighteen studies involving individuals with CAI were chosen in this systematic review. The quality of the included studies and risk of bias were assessed using Cochrane Collaboration's tool for randomized controlled trials, the Newcastle-Ottawa Scale for case-control studies, and the DELPHl-list for crossover trial studies. The external supports included in this review were ankle orthoses (elastic, semi-rigid, and active orthoses), taping (kinesiotaping and fibular reposition taping), and insoles (textured and supportive insoles). The outcome measures included static and dynamic postural stability tests, such as the single-leg stance test, star excursion balance test, Y-balance test, single-leg landing test, lateral jump test, walking test, and running test. The results showed that elastic orthoses, Kinesiotaping, and textured insoles demonstrated potential benefits in improving postural stability in individuals with CAI. Elastic orthoses decreased ankle joint motion variability, kinesiotaping facilitated cutaneous receptors and proprioceptive feedback, while textured insoles increased tactile stimulation and foot position awareness. However, the effects of semi-rigid orthoses, fibular reposition taping, and arch support insoles were inconsistent across studies. Future research should explore the long-term effects of these external supports, analyze the effects of different characteristics and combinations of supports, and employ standardized outcome measures and testing protocols for assessing postural stability.

Effects of textured insoles and elastic braces on dynamic stability in patients with functional ankle instability.

BACKGROUND: Functional ankle instability (FAI) is a common condition that affects individuals who have experienced previous ankle sprains. Textured insoles and elastic ankle braces have been previously used as interventions to improve stability in FAI patients. However, the optimal combination of these interventions has not been fully explored. The objective of this study was to investigate the effects of different types of textured insoles and elastic ankle braces on the dynamic stability of individuals diagnosed with FAI. METHODS: The study involved 18 FAI patients who performed single-leg landing tasks with and without wearing an eight-band elastic ankle brace while wearing textured insoles with protrusion heights of 0 mm, 1 mm, and 2 mm. The dynamic posture stability index (DPSI) and its components in the anterior-posterior (APSI), mediolateral (MLSI) and vertical (VSI) directions were calculated from the ground reaction force collected from the Kistler force plate during the first three seconds of the landing tasks. RESULTS: A significant interaction was found between textured insole type and ankle brace for DPSI (P = 0.026), APSI (P = 0.001), and VSI (P = 0.021). However, no significant interaction was observed for MLSI (P = 0.555). With elastic ankle braces, textured insoles with 1-mm protrusions significantly enhanced anterior-posterior, mediolateral, vertical, and overall stability compared to textured insoles with no and 2 mm protrusions (P < 0.05). Without elastic ankle braces, textured insoles with 1-mm protrusions significantly improved the anterior-posterior (P = 0.012) and overall stability (P = 0.014) of FAI patients compared to smooth insoles. CONCLUSIONS: The combination of textured insoles with 1-mm protrusion heights and an elastic ankle brace could enhance the dynamic stability of individuals with FAI, potentially mitigating the risk of ankle sprains.