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Depletion of Igfbp7 alleviates zebrafish NAFLD progression through inhibiting hepatic ferroptosis.

The global increased expression of Insulin-like growth factor binding protein 7 (IGFBP7) has been detected in non-alcoholic fatty liver disease (NAFLD) patients, however, its roles in NAFLD and the mechanism remain largely unclear. The goal of this study is to investigate the effect and mechanism of Igfbp7 using a zebrafish NAFLD model. The igfbp7-/- null zebrafish mutant and the Igfbp7 liver overexpressed (LOE) transgenic zebrafish based on Gal4/UAS system were generated by CRISPR/Cas9 and Tol2 transgenic technique, respectively. The zebrafish NAFLD models in wildtypes, igfbp7-/- mutants and Igfbp7 LOE fishes have been established by high-fat diet feeding. The Igfbp7 dynamic expression and its effects on NAFLD progression have been detected and analyzed in both human NAFLD patients and zebrafish models. And the potential mechanism has been investigated through transcriptome analysis and subsequent detection and verification. High Igfbp7 levels in NASH and fibrosis stages have been detected in liver tissues of both human NAFLD patients and zebrafish models. Depletion of Igfbp7 significantly alleviated liver steatosis, inflammation, and fibrosis, whereas liver specific Igfbp7 overexpression dramatically exacerbated liver fibrosis in zebrafish NAFLD model. The hepatic iron deposition, lipid peroxidation products, and ferroptosis-related index were also significantly reduced at the NASH stage in the absence of Igfbp7. Igfbp7 promotes NAFLD progression through regulating ferroptosis, and Ncoa4-mediated ferritinophagy may be the pathway of Igfbp7-regulated ferroptosis. Igfbp7 is confirmed as an important regulator in NAFLD progression. Depleting Igfbp7 effectively alleviates zebrafish NAFLD progression by inhibiting hepatic ferroptosis, suggesting a novel potential target for NAFLD treatment.

Mitochondrial transplantation strategies in multifaceted induction of cancer cell death.

Otto Warburg hypothesized that some cancer cells reprogram their metabolism, favoring glucose metabolism by anaerobic glycolysis (Warburg effect) instead of oxidative phosphorylation, mainly because the mitochondria of these cells were damaged or dysfunctional. It should be noted that mitochondrial apoptosis is decreased because of the dysfunctional mitochondria. Strategies like mitochondrial transplantation therapy, where functional mitochondria are transplanted to cancer cells, could increase cell death, such as apoptosis, because the intrinsic apoptosis mechanisms would be reactivated. In addition, mitochondrial transplantation is associated with the redox state, which could promote synergy with common anticancer treatments such as ionizing radiation, chemotherapy, or radiotherapy, increasing cell death due to the presence or decrease of oxidative stress. On the other hand, mitochondrial transfer, a natural process for sharing mitochondrial between cells, induces an increase in chemoresistance and invasiveness in cancer cells that receive mitochondria from cells of the tumor microenvironment (TME), which indicates an antitumor therapeutic target. This review focuses on understanding mitochondrial transplantation as a therapeutic outcome induced by a procedure in aspects including oxidative stress, metabolism shifting, mitochondrial function, auto-/mitophagy, invasiveness, and chemoresistance. It also explores how these mechanisms, such as apoptosis, necroptosis, and parthanatos, impact cell death pathways. Finally, it discusses the chemoresistance and invasiveness in cancer cells associated with mitochondria transfer, indicating an antitumor therapeutic target.

TLR2 deficiency is beneficial at the late phase in MPTP-induced Parkinson' disease mice.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. The etiology of PD is still elusive but neuroinflammation is proved to be an important contributor. Toll-like receptor 2 (TLR2) involves in the release of several inflammatory cytokines. Whether TLR2 serves as a mediator contributing to the damage of DA system in PD remain unclear. Tlr2 knockout (Tlr2-/-) and wild-type (WT) mice were treated with a subacute regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At 3, 7 and 14days after MPTP injection, the behavioral performance, including the Pole test, the Rotarod test, the Rearing test and the Wire hang test was evaluated. Moreover, the PD-like phenotypes, including dopaminergic degeneration, the activation of glial cells and the α-Syn expression were systematically analyzed in the nigrostriatal pathway. Finally, the composition of gut microbiota in the MPTP-treated groups were assessed. TLR2 deficiency had no obvious impact on the dopaminergic injury at 3 and 7days following MPTP administration. On the contrary, at 14days post injection, TLR2 deficiency not only significantly attenuated motor deficits in the Pole test and the Rotarod test, and the nigrostriatal dopaminergic degeneration, but also mitigated α-Syn abnormality, astrocyte activation and neuroinflammation through the suppressed TLR2/MyD88/TRAF6/NF-κB signaling pathways. Additionally, the alteration of gut microbiota was also detected in the mutant mice. These findings highlight the neuroprotective effect of TLR2-pathways at the late phase in the MPTP-induced PD mouse model.

Moderate mechanical strain and exercise reduce inflammation and excessive autophagy in osteoarthritis by downregulating mitofusin 2.

The major pathological mechanisms of osteoarthritis (OA) progression include inflammation, autophagy, and apoptosis, etc. Moderate mechanical strain and exercise effectively improve chondrocyte degeneration by reducing these adverse factors. Mitofusin 2 (MFN2) is a crucial regulatory factor associated with inflammation, autophagy and apoptosis, and its expression is regulated by exercise. This study aims to elucidate the effects of moderate mechanical strain and exercise on MFN2 expression and its influence on OA progression. Destabilization of the medial meniscus (DMM) surgery was performed on rats to induce an OA rat model. Subsequently, adeno-associated virus (overexpression/knockdown) intra-articular injection or moderate treadmill exercise was administered to evaluate the effects of these treatments on MFN2 expression and OA progression. Overexpressed plasmids and siRNA vectors were used to regulate MFN2 expression in chondrocytes. An inflammatory degeneration cell model was generated by IL-1β stimulation. Moderate mechanical strain was applied to MFN2-overexpressing cells to explore their interactions. MFN2 overexpression aggravated inflammation by activating the NF-κB and P38 pathways and induced excessive autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby causing chondrocyte apoptosis and metabolic disorder. Moderate mechanical strain partially reversed these adverse effects. In the DMM rat model, MFN2 overexpression in articular cartilage exacerbated OA progression, whereas MFN2 knockdown and treadmill exercise alleviated cartilage degeneration, inflammation, and mechanical pain. MFN2 is a critical factor mediating the association between inflammation and excessive autophagy in OA progression. Moderate mechanical strain and treadmill exercise may improve OA through downregulating MFN2 expression. This study may provide a theoretical basis for exercise therapy in OA treatment.

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