L-Citrulline Ameliorates Iron Metabolism and Mitochondrial Quality Control via Activating AMPK Pathway in Intestine and Improves Microbiota in Mice with Iron Overload.

SCOPE: Oxidative stress caused by iron overload tends to result in intestinal mucosal barrier dysfunction and intestinal microbiota imbalance. As a neutral and nonprotein amino acid, L-Citrulline (L-cit) has been implicated in antioxidant and mitochondrial amelioration properties. This study investigates whether L-cit can alleviate iron overload-induced intestinal injury and explores the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are intraperitoneally injected with iron dextran, then gavaged with different dose of L-cit for 2 weeks. L-cit treatment significantly alleviates intestine pathological injury, oxidative stress, ATP level, and mitochondrial respiratory chain complex activities, accompanied by ameliorating mitochondrial quality control. L-cit-mediated protection is associated with the upregulation of Glutathione Peroxidase 4 (GPX4) expression, inhibition Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis, and improvement of gut microbiota. To investigate the underlying molecular mechanisms, Intestinal Porcine Epithelial Cell line-J2 (IPEC-J2) cells are treated with L-cit or AMP-activated Protein Kinase (AMPK) inhibitor. AMPK signaling has been activated by L-cit. Notably, Compound C abolishes L-cit's protection on intestinal barrier, mitochondrial function, and antioxidative capacity in IPEC-J2 cells. CONCLUSION: L-cit may restrain ferritinophagy and ferroptosis to regulate iron metabolism, and induce AMPK pathway activation, which contributes to exert antioxidation, ameliorate iron metabolism and mitochondrial quality control, and improve intestinal microbiota. L-cit is a promising therapeutic strategy for iron overload-induced intestinal injury.

Innate immune escape and adaptive immune evasion of African swine fever virus: A review.

African swine fever virus (ASFV) causes hemorrhagic fever in domestic and wild pigs. The continued spread of the virus in Africa, Europe and Asia threatens the global pig industry. The lack of an effective vaccine limits disease control. ASFV has evolved a variety of encoded immune escape proteins and can evade host adaptive immunity, inducing cellular inflammation, autophagy, or apoptosis in host cells. Frequent persistent infections hinder the development of a viral vaccine and impose technical barriers. Currently, knowledge of the virulence-related genes, main pathogenic genes and immunoregulatory mechanism of ASFV is not comprehensive. We explain that ASFV invades the host to regulate its inflammatory response, interferon production, antigen presentation and cellular immunity. Furthermore, we propose potential ideas for ASFV vaccine target design, such as knocking out high-virulence genes in ASFV and performing data mining to identify the main genes that induce antiviral responses. To support a rational strategy for vaccine development, a better understanding of how ASFV interacts with the host and regulates the host's response to infection is needed. We review the current knowledge about ASFV targeting of host innate and adaptive immunity and the mechanisms by which the affected immune pathways are suppressed.

CXCR3 Inhibition Blocks the NF-κB Signaling Pathway by Elevating Autophagy to Ameliorate Lipopolysaccharide-Induced Intestinal Dysfunction in Mice.

Autophagy is a cellular catabolic process in the evolutionarily conservative turnover of intracellular substances in eukaryotes, which is involved in both immune homeostasis and injury repairment. CXCR3 is an interferon-induced chemokine receptor that participates in immune regulation and inflammatory responses. However, CXCR3 regulating intestine injury via autophagy along with the precise underlying mechanism have yet to be elucidated. In the current study, we employed an LPS-induced inflammatory mouse model and confirmed that CXCR3 knockout significantly attenuates intestinal mucosal structural damage and increases tight junction protein expression. CXCR3 knockout alleviated the LPS-induced increase in the expression of inflammatory factors including TNF-α, IL-6, p-65, and JNK-1 and enhanced autophagy by elevating LC3II, ATG12, and PINK1/Parkin expression. Mechanistically, the function of CXCR3 regarding autophagy and immunity was investigated in IPEC-J2 cells. CXCR3 inhibition by AMG487 enhanced autophagy and reduced the inflammatory response, as well as blocked the NF-κB signaling pathway and elevated the expression of the tight junction protein marker Claudin-1. Correspondingly, these effects were abolished by autophagy inhibition with the selective blocker, 3-MA. Moreover, the immunofluorescence assay results further demonstrated that CXCR3 inhibition-mediated autophagy blocked p65 nuclear translocation, and the majority of Claudin-1 was located at the tight junctions. In conclusion, CXCR3 inhibition reversed LPS-induced intestinal barrier damage and alleviated the NF-κB signaling pathway via enhancing autophagy. These data provided a theoretical basis for elucidating the immunoregulatory mechanism by targeting CXCR3 to prevent intestinal dysfunction.

L-Citrulline Supplementation Restrains Ferritinophagy-Mediated Ferroptosis to Alleviate Iron Overload-Induced Thymus Oxidative Damage and Immune Dysfunction.

L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+ T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells' viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.

Recent advances in cell homeostasis by African swine fever virus-host interactions.

African swine fever (ASF) is an acute hemorrhagic disease caused by the infection of domestic swine and wild boar by the African swine fever virus (ASFV), with a mortality rate close to 90-100%. ASFV has been spreading in the world and poses a severe economic threat to the swine industry. There is no high effective vaccine commercially available or drug for this disease. However, attenuated ASFV isolates may infect pigs by chronic infection, and the infected pigs will not be lethal, which may indicate that pigs can produce protective immunity to resistant ASFV. Immunity acquisition and virus clearances are the central pillars to maintain the host normal cell activities and animal survival dependent on virus-host interactions, which has offered insights into the biology of ASFV. This review is organized around general themes including native immunity, endoplasmic reticulum stress, cell apoptosis, ubiquitination, autophagy regarding the intricate relationship between ASFV protein-host. Elucidating the multifunctional role of ASFV proteins in virus-host interactions can provide more new insights on the initial virus sensing, clearance, and cell homeostasis, and contribute to understanding viral pathogenesis and developing novel antiviral therapeutics.

[Comparative study on the performance of deformable mirror of NIR based human eye aberration correction system].

The structure features and spatial characteristics of the two kinds of micro-machined membrane deformable mirrors, OKO 37-element and BMC 140-element, which work in the NIR based human eye aberration correction system, are compared and analyzed. At same time, the principal component analysis was carried out for the influence function of the mirror, the voltage control model was established and the optimal control mode of deformable mirror can be determined by adjusting the control parameter d. Finally, the simulation experiments for fitting aberration of unit Zernike mode and human eye aberration of Thibos model were carried out. The experiment results show that the capability for fitting the each Zernike mode of BMC 140-element mirror is twice more than the OKO 37-element mirror at least. When correcting the Thibos model human eye aberration whose average RMS error is 0.638 lambda (lambda=0.785 microm), the residual RMS error of BMC mirror is 0.063 lambda which achieves the diffraction limit (lambda/14) of the optical system, but the correction capability of OKO mirror is far less than BMC mirror due to the large cross-linked value between actuators, small density distribution of actuators and some other influencing factors, and the residual wave-front RMS error is 0.168 lambda. The methodology can also be used for other types of deformable mirror performance evaluation.