TfR1 mediated iron metabolism dysfunction as a potential therapeutic target for osteoarthritis.

OBJECTIVE: Transferrin receptor-1 (TfR1) plays important roles in controlling cellular iron levels, but its role in OA pathology is unknown. Herein we aim to investigate the role of TfR1 in OA progression and its underlying mechanisms. METHODS: TfR1 expression in cartilage during OA development were examined both in vivo and in vitro. Then IL-1ß was used to induce chondrocytes degeneration in vitro and TfR1 siRNA was used for observing the effect of TfR1 in modulating iron homeostasis, mitochondrial function and degrading enzymes expression. Also the inhibitor of TfR1 was exploited to analyze the protective effect of TfR1 inhibition in vivo. RESULTS: TfR1 is elevated in OA cartilage and contributes to OA inflammation condition. Excess iron not only results in oxidative stress damage and sensitizes chondrocytes to ferroptosis, but also triggers c-GAS/STING-mediated inflammation by promoting mitochondrial destruction and the release of mtDNA. Silencing TfR1 using TfR1 siRNA not only reduced iron content in chondrocytes and inhibited oxidative stress, but also facilitated the mitophagy process and suppressed mtDNA/cGAS/STING-mediated inflammation. Importantly, we also found that Ferstatin II, a novel and selective TfR1 inhibitor, could substantially suppress TfR1 activity both in vivo and in vitro and ameliorated cartilage degeneration. CONCLUSION: Our work demonstrates that TfR1 mediated iron influx plays important roles in chondrocytes degeneration and OA pathogenesis, suggesting that maintaining iron homeostasis through the targeting of TfR1 may represent a novel therapeutic strategy for the treatment of OA.

Call properties of the large yellow croaker (Larimichthys crocea) during reproduction with insight into directivity.

The investigation of the large yellow croaker (Larimichthys crocea) deserves more attention due to its high commercial value as an important aquaculture fish species. This study was initiated by deploying a passive acoustic monitoring device to record the calls from the L. crocea during the spawning process in an aquaculture facility. The subsequent analysis suggested the croakers produced at least two types of calls with considerable energy distributed up to 1000 Hz. The acoustic data and the computed tomography scanning of an adult croaker were used to develop a numerical model to address the directivity of the calls at frequencies up to 1000 Hz. The radiation patterns at all frequencies were assigned with respective weights and then combined to estimate an overall acoustic radiation pattern for both types of the calls. The backward transmission was greater for both types of calls by 1.85 dB on average. The reduction of size by 20% in the swim bladder resulted in a stronger sidelobe in the frontal direction, indicating its influence on call directivity. These results provided information on the directivity of the croaker calls and understanding of fish acoustics.

Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2.

Extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling has been shown to be involved in brain injury after subarachnoid hemorrhage (SAH). A first-in-human phase I study reported that ravoxertinib hydrochloride (RAH), a novel Erk1/2 inhibitor, has an acceptable safety profile and pharmacodynamic effects. Here, we showed that the level of Erk1/2 phosphorylation (p-Erk1/2) was significantly increased in the cerebrospinal fluid (CSF) of aneurysmal subarachnoid hemorrhage (aSAH) patients who developed poor outcomes. In a rat SAH model that was produced by the intracranial endovascular perforation method, western blot observed that the level of p-Erk1/2 was also increased in the CSF and basal cortex, showing a similar trend with aSAH patients. Immunofluorescence and western blot indicated that RAH treatment (i.c.v injection, 30 min post-SAH) attenuates the SAH-induced increase of p-Erk1/2 at 24 h in rats. RAH treatment can improve experimental SAH-induced long-term sensorimotor and spatial learning deficits that are evaluated by the Morris water maze, rotarod test, foot-fault test, and forelimb placing test. Moreover, RAH treatment attenuates neurobehavioral deficits, the blood-brain barrier damage, and cerebral edema at 72 h after SAH in rats. Furthermore, RAH treatment decreases the SAH-elevated apoptosis-related factor active caspase-3 and the necroptosis-related factor RIPK1 expression at 72 h in rats. Immunofluorescence analysis showed that RAH attenuated neuronal apoptosis but not neuronal necroptosis in the basal cortex at 72 h after SAH in rats. Altogether, our results suggest that RAH improves long-term neurologic deficits through early inhibition of Erk1/2 in experimental SAH.

The Multiple Influences of Natural Farming Environment on the Cultured Population Behavior of Kuruma Prawn, Penaeus japonicus.

Recent years have witnessed a tremendous development in shrimp farming around the world, which, however, has raised a variety of issues, possibly due to a lack of knowledge of shrimp behavior in farms. This study focused on the relationship between shrimp behavior and the various factors of natural farming environment through situ surveys, as distinguished from the majority of laboratory studies on shrimp behavior. In the survey, the behaviors of kuruma prawn (Penaeus japonicus) were investigated in the groups of swimming in the water, crawling on the sand, resting on the sand, and hiding in the sand, followed by the quantification of the sex ratio, water quality, density, and light intensity. The results showed the average proportions of resting, hiding, crawling, and swimming activities of 69.87%, 20.85%, 8.24%, and 1.04%, respectively, of P. japonicus. The behavior of hiding, resting, and crawling is significantly affected by the sex ratio of the shrimp (p < 0.05). The proportions of hiding behavior exhibited a negative connection with density and a positive connection with light intensity, while the proportions of resting behavior showed the opposite according to both Pearson correlation analysis and multiple linear regression analysis. The light intensity was the only factor that significantly influenced the swimming behavior, in which the probability of the swimming behavior was reduced from 48% to 5% when light intensity varied from 0 to 10 lx, as determined by the generalized linear model. It could be speculated that P. japonicus prefers a tranquil environment. Female shrimp might exhibit less aggression and more adventure compared to male shrimp. The findings suggested light intensity, followed by density, as the most crucial element influencing the behavior of P. japonicus in the culture environment. These findings will contribute to the comprehension of the behavior of P. japonicus and provide a novel perspective for the formulation of its culture management strategy.

Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes.

Iron overload is a common phenomenon in the elderly population. Many clinical studies have indicated an association between iron overload and the incidence and pathological progression of intervertebral disc degeneration (IVDD). However, the role and underlying mechanism by which iron participates in the progression of IVDD has not yet been reported. In the present study, we aimed to elucidate the connection between iron overload and IVDD, and explore the underlying mechanisms of disease. Firstly, a clinical epidemiology study was conducted and revealed that iron overload is an independent risk factor for human IVDD. To elucidate the role of iron overload in IVDD, an iron overload mouse model was established, and we observed that iron overload promoted IVDD and cartilage endplate degeneration in a dose dependent manner. Endplate chondrocytes were further isolated and treated with FAC to mimic iron overload in vitro. Excess iron significantly promoted mineralization of endplate chondrocytes in addition to their degeneration via oxidative stress. Moreover, a high dose of excess iron promoted chondrocytes ferroptosis. An iron chelator (DFO), an antioxidant (NAC) and a ferroptosis inhibitor (Fer-1) demonstrated effective inhibition of endplate chondrocyte degeneration induced by iron overload, and our in vivo studies further demonstrated that DFO, NAC and Fer-1 could rescue high dose iron-induced IVDD and cartilage endplate calcification. In conclusion, our results indicate that iron overload is strongly associated with the onset and development of IVDD via oxidative stress and ferroptosis. Inhibiting oxidative stress or ferroptosis could therefore be promising therapeutic strategies for IVDD induced by iron overload.