Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated. Objectives: To identify whether excessive mechanical stress can cause ferroptosis. To explore the role of mechanical overloading in chondrocyte ferroptosis. Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and ferroptosis phenotype was tested. Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium. Conclusions: Our findings show that mechanical overloading induces ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment

A Drive to Driven Model of Mapping Intraspecific Interaction Networks.

Community ecology theory suggests that an individual\u27s phenotype is determined by the phenotypes of its coexisting members to the extent at which this process can shape community evolution. Here, we develop a mapping theory to identify interaction quantitative trait loci (QTL) governing inter-individual dependence. We mathematically formulate the decision-making strategy of interacting individuals. We integrate these mathematical descriptors into a statistical procedure, enabling the joint characterization of how QTL drive the strengths of ecological interactions and how the genetic architecture of QTL is driven by ecological networks. In three fish full-sib mapping experiments, we identify a set of genome-wide QTL that control a range of societal behaviors, including mutualism, altruism, aggression, and antagonism, and find that these intraspecific interactions increase the genetic variation of body mass by about 50%. We showcase how the interaction QTL can be used as editors to reconstruct and engineer new social networks for ecological communities

Effect of Feed Supplementation with <i>Bacillus coagulans</i> on <i>Nrf</i> Gene Family Expression in Common Carp (<i>Cyprinus carpio</i>) under Long-Term Exposure to Cd²⁺

Nuclear factor-E2-related factor (Nrf) belongs to the Cap ‘n’ collar basic leucine zipper (CNC-bZIP) family, which plays an important role in the resistance to oxidative stress in the body. In this study, 12 Nrf genes were identified in the common carp genome database. Comparative genomic analysis showed that the Nrf genes of common carp had significant amplification, confirming that the common carp had experienced four genome-wide replication events. Phylogenetic analysis showed that all common carp Nrf clustered with scleractinian fish Nrf, indicating that they were highly conserved during evolution. In addition, tissue distribution results showed that most Nrf genes had a broad tissue distribution but exhibited tissue-specific expression patterns, demonstrating functional differences after WGD events. At 30 and 60 days of Cd2+ stress, most of the Nrf genes showed an increase in expression compared with the control group, indicating that they played a key role in the organism’s response to oxidative stress. To find a suitable concentration of Bacillus coagulans to activate the Nrf genes, we added three different concentrations (2.0 × 107 CFU/g, 2.0 × 108 CFU/g, and 2.0 × 109 CFU/g) of B. coagulans into the feed and defined them as L1, L2, and L3 groups, respectively. We investigated the effect of different concentrations of B. coagulans in the feed on the expression level of Nrf genes in the intestine of common carp under Cd2+ stress at 30 and 60 days. The results showed that, compared with the control/stress group, the expression of different Nrf genes was improved to varying degrees at three concentrations, and the effect of the L2 group (2.0 × 108 CFU/g) was the best. This suggests that the L2 group is the optimum concentration for activating Nrf gene expression when subjected to heavy metal Cd2+ stress and may act as an activation switch with a prominent role in the body’s resistance to oxidative stress and immune response

Effect of Feed Supplementation with Bacillus coagulans on Nrf Gene Family Expression in Common Carp (Cyprinus carpio) under Long-Term Exposure to Cd2+

Nuclear factor-E2-related factor (Nrf) belongs to the Cap &lsquo;n&rsquo; collar basic leucine zipper (CNC-bZIP) family, which plays an important role in the resistance to oxidative stress in the body. In this study, 12 Nrf genes were identified in the common carp genome database. Comparative genomic analysis showed that the Nrf genes of common carp had significant amplification, confirming that the common carp had experienced four genome-wide replication events. Phylogenetic analysis showed that all common carp Nrf clustered with scleractinian fish Nrf, indicating that they were highly conserved during evolution. In addition, tissue distribution results showed that most Nrf genes had a broad tissue distribution but exhibited tissue-specific expression patterns, demonstrating functional differences after WGD events. At 30 and 60 days of Cd2+ stress, most of the Nrf genes showed an increase in expression compared with the control group, indicating that they played a key role in the organism&rsquo;s response to oxidative stress. To find a suitable concentration of Bacillus coagulans to activate the Nrf genes, we added three different concentrations (2.0 &times; 107 CFU/g, 2.0 &times; 108 CFU/g, and 2.0 &times; 109 CFU/g) of B. coagulans into the feed and defined them as L1, L2, and L3 groups, respectively. We investigated the effect of different concentrations of B. coagulans in the feed on the expression level of Nrf genes in the intestine of common carp under Cd2+ stress at 30 and 60 days. The results showed that, compared with the control/stress group, the expression of different Nrf genes was improved to varying degrees at three concentrations, and the effect of the L2 group (2.0 &times; 108 CFU/g) was the best. This suggests that the L2 group is the optimum concentration for activating Nrf gene expression when subjected to heavy metal Cd2+ stress and may act as an activation switch with a prominent role in the body&rsquo;s resistance to oxidative stress and immune response

Intestinal microbiota signatures of common carp (Cyprinus carpio) after the infection of Aeromonas hydrophila

Common carp is an important freshwater farmed fish species worldwide. Intensive rearing in aquaculture causes increasing susceptibility to various pathogens. One of the most frequently encountered pathogens is Aeromonas hydrophila, which has caused huge economic losses to the common carp industry. Extensive studies have been reported on the genetic mechanism underlying common carp against A. hydrophila at the molecular level, however, the influence of intestinal microbiota on host resistance to pathogen is less studied. In the present study, we analyzed the composition and biodiversity of intestinal microbiota in common carp following A. hydrophila infection by utilizing 16S rDNA sequencing. Collectively, the intestinal microbiota in common carp is diverse, but dominated by four phyla, Proteobacteria, Bacteroidetes, Fusobacteria and Firmicutes. The diversity and richness of microbiota was obviously decreased after infection of A. hydrophila. The composition and relative abundance of gut microbiota was significantly altered upon pathogenic invasion. The relative abundance of genera Cetobacterium and Vibrio were significantly increased in the infected groups. Further investigating the divergence of microbes between the resistant fish and susceptible fish showed that the relative abundance of Lactococcus, Akkermansia and Vibrio in resistant fish were significantly higher than that in both the susceptible fish and the control fish, indicating their potential correlation with the host resistance against pathogens. Our study could not only elucidate the dynamic changes in the common carp intestinal microbiota that occur in response to A. hydrophila, but also help us understand the underlying mechanism of intestinal microbial community in resisting pathogens and might suggest strategies for disease control in aquaculture

Genome Wide Identification, Phylogeny, and Expression of <i>Aquaporin</i> Genes in Common Carp (Cyprinus carpio)

<div><p>Background</p><p>Aquaporins (Aqps) are integral membrane proteins that facilitate the transport of water and small solutes across cell membranes. Among vertebrate species, Aqps are highly conserved in both gene structure and amino acid sequence. These proteins are vital for maintaining water homeostasis in living organisms, especially for aquatic animals such as teleost fish. Studies on teleost Aqps are mainly limited to several model species with diploid genomes. Common carp, which has a tetraploidized genome, is one of the most common aquaculture species being adapted to a wide range of aquatic environments. The complete common carp genome has recently been released, providing us the possibility for gene evolution of <i>aqp</i> gene family after whole genome duplication.</p><p>Results</p><p>In this study, we identified a total of 37 <i>aqp</i> genes from common carp genome. Phylogenetic analysis revealed that most of <i>aqp</i>s are highly conserved. Comparative analysis was performed across five typical vertebrate genomes. We found that almost all of the <i>aqp</i> genes in common carp were duplicated in the evolution of the gene family. We postulated that the expansion of the <i>aqp</i> gene family in common carp was the result of an additional whole genome duplication event and that the <i>aqp</i> gene family in other teleosts has been lost in their evolution history with the reason that the functions of genes are redundant and conservation. Expression patterns were assessed in various tissues, including brain, heart, spleen, liver, intestine, gill, muscle, and skin, which demonstrated the comprehensive expression profiles of <i>aqp</i> genes in the tetraploidized genome. Significant gene expression divergences have been observed, revealing substantial expression divergences or functional divergences in those duplicated <i>aqp</i> genes post the latest WGD event.</p><p>Conclusions</p><p>To some extent, the gene families are also considered as a unique source for evolutionary studies. Moreover, the whole set of common carp <i>aqp</i> gene family provides an essential genomic resource for future biochemical, toxicological, physiological, and evolutionary studies in common carp.</p></div

<i>aqp</i> gene family in the genomes of the five vertebrates.

<p><i>aqp</i> gene family in the genomes of the five vertebrates.</p