Helium Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction in Mice via Suppressing Toll-Like Receptor 4-Nuclear Factor κB-Tumor Necrosis Factor-Alpha/ Interleukin-18 Signaling.

The nonanesthetic noble gas helium (He) can protect many organs against ischemia and reperfusion injury, such as liver and heart. However, the role of He on cardiac dysfunction during sepsis is not clear. In this study, we established a lipopolysaccharide (LPS)-induced cardiac dysfunction mouse model to examine the influence of He on the impaired cardiac function, and further investigated the possible innate immune mechanisms that may be involved. LPS induced left ventricular dysfunction and cavity enlargement, as indicated by decreased percent ejection fraction, percent fractional shortening, left ventricular anterior wall thickness in systole, and left ventricular posterior wall thickness in systole, while increased left ventricular end-systolic diameter and left ventricular end-systolic volume. He improved the impaired left ventricular function and cavity enlargement in a dose-dependent manner, and it was beneficial at 1.0 mL/100 g. Mechanistically, He inhibited toll-like receptor 4 (TLR4) expression, reduced the phosphorylation of nuclear factor κB (NF-κB), and subsequently alleviated tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) expression in heart. Therefore, He protects against LPS-induced cardiac dysfunction in mice partially via inhibiting myocardial TLR4-NF-κB-TNF-α/IL-18 signaling.

MeDEStrand: an improved method to infer genome-wide absolute methylation levels from DNA enrichment data.

BACKGROUND: DNA methylation of CpG dinucleotides is an essential epigenetic modification that plays a key role in transcription. Widely used DNA enrichment-based methods offer high coverage for measuring methylated CpG dinucleotides, with the lowest cost per CpG covered genome-wide. However, these methods measure the DNA enrichment of methyl-CpG binding, and thus do not provide information on absolute methylation levels. Further, the enrichment is influenced by various confounding factors in addition to methylation status, for example, CpG density. Computational models that can accurately derive absolute methylation levels from DNA enrichment data are needed. RESULTS: We developed "MeDEStrand," a method that uses a sigmoid function to estimate and correct the CpG bias from enrichment results to infer absolute DNA methylation levels. Unlike previous methods, which estimate CpG bias based on reads mapped at the same genomic loci, MeDEStrand processes the reads for the positive and negative DNA strands separately. We compared the performance of MeDEStrand to that of three other state-of-the-art methods "MEDIPS," "BayMeth," and "QSEA" on four independent datasets generated using immortalized cell lines (GM12878 and K562) and human primary cells (foreskin fibroblasts and mammary epithelial cells). Based on the comparison of the inferred absolute methylation levels from MeDIP-seq data and the corresponding reduced-representation bisulfite sequencing data from each method, MeDEStrand showed the best performance at high resolution of 25, 50, and 100 base pairs. CONCLUSIONS: The MeDEStrand tool can be used to infer whole-genome absolute DNA methylation levels at the same cost of enrichment-based methods with adequate accuracy and resolution. R package MeDEStrand and its tutorial is freely available for download at https://github.com/jxu1234/MeDEStrand.git .

Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside.

Hydrogen (H2) is colorless, odorless, and the lightest of gas molecules. Studies in the past ten years have indicated that H2 is extremely important in regulating the homeostasis of the cardiovascular system and metabolic activity. Delivery of H2 by various strategies improves cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia- or heart transplantation-induced heart injury, obesity and diabetes in animal models or in clinical trials. The purpose of this review is to summarize the physical and chemical properties of H2, and then, the functions of H2 with an emphasis on the therapeutic potential and molecular mechanisms involved in the diseases above. We hope this review will provide the future outlook of H2-based therapies for cardiometabolic disease.

Inhibitory Effects of Hydrogen on Proliferation and Migration of Vascular Smooth Muscle Cells via Down-Regulation of Mitogen/Activated Protein Kinase and Ezrin-Radixin-Moesin Signaling Pathways.

Molecular hydrogen (H2) has recently attracted considerable attention for the prevention of oxidative stress-related vascular diseases. The purpose of this study is to evaluate the effects of hydrogen on proliferation and migration of vascular smooth muscle cells (VSMCs) stimulated by angiotensin II (Ang II) in vitro, and on vascular hypertrophy induced by abdominal aortic coarctation (AAC) in vivo. Hydrogen-rich medium (0.6~0.9 ppm) was added 30 min before 10⁻7 M Ang II administration, then the proliferation and migration index were determined 24 h after Ang II stimulation. Hydrogen gas (99.999%) was given by intraperitoneal injection at the dose of 1 ml/100 g/day consecutively for one week before AAC and lasted for 6 weeks in vivo. Hydrogen inhibited proliferation and migration of VSMCs with Ang II stimulation in vitro, and improved the vascular hypertrophy induced by AAC in vivo. Treatment with hydrogen reduced Ang II- or AAC-induced oxidative stress, which was reflected by diminishing the induction of reactive oxygen species (ROS) in Ang II-stimulated VSMCs, inhibiting the levels of 3-nitrotyrosine (3-NT) in vascular and serum malondialdehyde (MDA). Hydrogen treatment also blocked Ang II-induced phosphorylation of the extracellular signal-regulated kinase1/2 (ERK1/2), p38 MAPK, c-Jun NH2-terminal kinase (JNK) and the ezrin/radixin/moesin (ERM) in vitro. Taken together, our studies indicate that hydrogen prevents AAC-induced vascular hypertrophy in vivo, and inhibits Ang II-induced proliferation and migration of VSMCs in vitro possibly by targeting ROS-dependent ERK1/2, p38 MAPK, JNK and ERM signaling. It provides the molecular basis of hydrogen on inhibiting the abnormal proliferation and migration of VSMCs and improving vascular remodeling diseases.

A deep learning-based quantitative prediction model for the processing potentials of soybeans as soymilk raw materials.

Current technologies as correlation analysis, regression analysis and classification model, exhibited various limitations in the evaluation of soybean possessing potentials, including single, vague evaluation and failure of quantitative prediction, and thereby hindering more efficient and profitable soymilk industry. To solve this problem, 54 soybean cultivars and their corresponding soymilks were subjected to chemical, textural, and sensory analyses to obtain the soybean physicochemical nature (PN) and the soymilk profit and quality attribute (PQA) datasets. A deep-learning based model was established to quantitatively predict PQA data using PN data. Through 45 rounds of training with the stochastic gradient descent optimization, 9 remaining pairs of PN and PQA data were used for model validation. Results suggested that the overall prediction performance of the model showed significant improvements through iterative training, and the trained model eventually reached satisfying predictions (|relative error| ≤ 20%, standard deviation of relative error ≤ 40%) on 78% key soymilk PQAs. Future model training using big data may facilitate better prediction on soymilk odor qualities.

The attenuating effect of fermented soymilk on DSS-induced colitis in mice by suppressing immune response and modulating gut microbiota.

Fermented soymilk (FSM) as a new plant-based yoghurt has attracted attention for its nutritional and health benefits. The aim of this research is to explore the effect of consuming FSM before and during inflammatory bowel disease (IBD) on intestinal immune response, and to assess whether fermentation and sucrose can improve the anti-inflammatory activity of soymilk (SM) and FSM, and finally clarify their effect on the gut microbiota and levels of short-chain fatty acids (SCFAs). Consuming FSM in advance can effectively alleviate weight loss and bloody stools in mice with colitis and is associated with a 27% colon length repair rate. It can also prevent spleen and liver enlargement, inhibit immune response and oxidative stress, and increase the expression of the tight junction protein occludin gene (60%). Meanwhile, intaking FSM during IBD reduced weight loss, prevented liver damage, and repaired colon injury. In addition, fermentation enhance the inhibitory effects of FSM on colitis, whereas adding 3% sucrose to FSM had no effect on its intervention in colitis. Analysis of the composition of the gut microbiota in mice showed that the intake of FSM reduced the relative abundance of the pathogenic bacteria Parasutterella, Turicibater, and Bacteroide by 75%, 62%, and 50%, respectively, and increased the relative abundance of the beneficial bacteria Akkermansiaceae, Lachnospiraceae, Alloprevotella, and Dubosella by 28%, 50%, 80%, and 63%, respectively. It further restored the levels of SCFAs in the mouse intestine. The results provide a scientific basis for FSM as a natural anti-inflammatory food that can improve inflammatory intestinal microbiota imbalance and promote gut health.

Effects of oregano essential oil Pickering emulsion and ZnO nanoparticles on the properties and antibacterial activity of konjac glucomannan/carboxymethyl chitosan nanocomposite films.

Green and environmentally friendly natural bio-based food packaging films are increasingly favored by consumers. This study incorporated carboxylated-cellulose nanocrystal stabilized oregano essential oil (OEO) Pickering emulsion and ZnO nanoparticles (ZNPs) into konjac glucomannan (KGM)/carboxymethyl chitosan (CMCS) complexes to develop active food packaging films. The effects of OEO Pickering emulsion and ZNPs on the physical, structural, and antimicrobial activities of the nanocomposite films were evaluated. The OEO Pickering emulsion had a droplet size of 48.43 ± 3.56 µm and showed excellent dispersion and stability. Fourier transform infrared and X-ray diffraction analyses suggested that the interactions between the Pickering emulsion, ZNPs and KGM/CMCS matrix were mainly through hydrogen bonding. SEM observations confirmed that the Pickering emulsion and ZNPs were well incorporated into the KGM/CMCS matrix, forming tiny pores within the nanocomposite films. The incorporation of the OEO Pickering emulsion and/or ZNPs obviously increased the light and water vapor barrier ability, thermal stability, mechanical strength and antimicrobial properties of the KGM/CMCS nanocomposite film. Notably, KGM/CMCS/ZNPs/OEO Pickering emulsion films exhibited the highest barrier, and mechanical and antimicrobial activities due to the synergistic effect between the OEO Pickering emulsion and ZNPs. These results suggest that KGM/CMCS/ZNPs/OEO Pickering emulsion films can be utilized as novel active food packaging materials to extend the shelf life of packaged foods.

Erratum: Mitoquinone alleviates osteoarthritis progress by activating the NRF2-Parkin axis.

[This corrects the article DOI: 10.1016/j.isci.2023.107647.].

Enhanced stabilization of multifunctional phenolic acids-grafted chitin nanofibers for Pickering emulsions.

The objective of this study was to develop novel functional stabilizers for Pickering emulsions using phenolic acids-grafted chitin nanofibers (phenolic acids-g-ChNF), which were fabricated by grafting ferulic acid (FA), sinapic acid (SA) and caffeic acid (CA) onto ChNF via free radical-mediated method. The Fourier transform infrared spectrum and Proton nuclear magnetic resonance showed that graft copolymerization occurred between the amino groups of ChNF and the carbonyl of the phenolic acids. Further, it was revealed that CA-g-ChNF and SA-g-ChNF possessed stronger antioxidant and antibacterial properties than the original ChNF and FA-g-ChNF. Additionally, we applied phenolic acids-g-ChNF to develop Pickering emulsions and found that SA-g-ChNF- and CA-g-ChNF-stabilized emulsions displayed reduced droplet sizes compared to FA, the main reason for which was that SA and CA had a rather close bonding relationship with ChNF. Taken together, SA-g-ChNF and CA-g-ChNF as novel multi-functional particles can be employed for facilitating the stability of Pickering emulsions.

Genomic Insights into the Role of TOP Gene Family in Soft-Tissue Sarcomas: Implications for Prognosis and Therapy.

This study focuses on the role of topoisomerases (TOPs) in sarcomas (SARCs), highlighting TOPs' influence on sarcoma prognosis through mRNA expression, genetic mutations, immune infiltration, and DNA methylation analysis using transcriptase sequencing and other techniques. The findings indicate that TOP gene mutations correlate with increased inflammation, immune cell infiltration, DNA repair abnormalities, and mitochondrial fusion genes alterations, all of which negatively affect sarcoma prognosis. Abnormal TOP expression may independently affect sarcoma patients' survival. Cutting-edge genomic tools such as Oncomine, gene expression profiling interactive analysis (GEPIA), and cBio Cancer Genomics Portal (cBioPortal) are utilized to explore the TOP gene family (TOP1/1MT/2A/2B/3A/3B) in soft-tissue sarcomas (STSs). This in-depth analysis reveals a notable upregulation of TOP mRNA in STS patients arcoss various SARC subtypes, French Federation Nationale des Centres de Lutte Contre le Cancer classification (FNCLCC) grades, and specific molecular profiles correlating with poorer clinical outcomes. Furthermore, this investigation identifies distinct patterns of immune cell infiltration, genetic mutations, and somatic copy number variations linked to TOP genes that inversely affect patient survival rates. These findings underscore the diagnostic and therapeutic relevance of the TOP gene suite in STSs.

Effect of konjac glucomannan-based preservation pads on quality changes in refrigerated large yellow croaker (Pseudosciaena crocea).

The purpose of this study was to evaluate the preservation effects of konjac glucomannan (KGM)/oregano essential oil (OEO) Pickering emulsion-based pads (K/OPE pads) on large yellow croaker (Pseudosciaena crocea) fillets stored at 4 °C. The K/OPE pads were fabricated using a freeze-drying technique. The homogeneous distribution of the OEO Pickering emulsions in the KGM matrix was observed using scanning electron microscopy. Fourier transform infrared spectroscopy confirmed that the OEO emulsions were encapsulated in the KGM and there was hydrogen bonding interaction between them. Compared with the KGM pads, the K/OPE pad groups demonstrated enhanced antioxidant and antimicrobial properties. When the content of OPE was increased from 20 % to 40 %, the antioxidant performance of the K/OPE pads increased from 48.09 % ± 0.03 % to 86.65 % ± 0.02 % and the inhibition range of Escherichia coli and Staphylococcus aureus increased to 13.84 ± 0.81 and 16.87 ± 1.53 mm, respectively. At the same time, K/OPE pads were more effective in inhibiting the formation of total volatile alkaline nitrogen and the production of thiobarbituric acid-reactive substances, thereby helping in reducing water loss and maintaining the muscle tissue structure of fish fillets for a longer storage time. Consequently, these K/OPE40 pads extended the shelf life of the fish fillets by an additional 4 days and delayed spoilage during refrigerated storage. The findings suggest that the K/OPE pads can effectively safeguard the quality of refrigerated large yellow croaker fillets, presenting their potential as an active packaging material in the fish preservation industry.

Deferoxamine alleviates chondrocyte senescence and osteoarthritis progression by maintaining iron homeostasis.

BACKGROUND: Osteoarthritis (OA) is a prevalent age-related disease characterized by the gradual deterioration of cartilage. The involvement of chondrocyte senescence is crucial in the pathogenesis of OA. Desferoxamine (DFO) is an iron chelator with therapeutic potential in various diseases. However, the relationship of chondrocyte senescence and iron homeostasis is largely unknown. METHODS: Chondrocyte senescence was induced using tert-butyl hydroperoxide (TBHP), and the impact of DFO on chondrocyte senescence and iron metabolism was assessed through techniques such as western blotting, qRT-PCR, and ß-Galactosidase staining. To assess the impact of DFO on chondrocyte senescence and the progression of osteoarthritis (OA), the surgical destabilization of the medial meniscus model was established. RESULTS: In chondrocytes, TBHP administration resulted in elevated expression of P16, P21, and P53, as well as alterations in SA-ß-gal staining. Nevertheless, DFO effectively mitigated chondrocyte senescence induced by TBHP, and reversed the decrease in collagen II expression and increase in MMP13 expression caused by TBHP. Mechanismly, TBHP induced NCOA4 expression and iron release in chondrocytes. Excessive iron could induce chondrocyte senescence, whereas, DFO could inhibit NCOA4 expression and restore ferritin level, and chelate excessive iron. Importantly, intra-articular injection of DFO enhanced collagen II expression and reduced expression of P16, P21, and MMP13 of cartilage in OA mice, and delayed cartilage degeneration. CONCLUSIONS: Overall, this study provides evidence that DFO has the potential to alleviate chondrocyte senescence induced by TBHP and slow down the progression of osteoarthritis (OA) by effectively chelating excessive iron. These findings suggest that iron chelation could be a promising therapeutic strategy for treating OA.

DMT1-mediated iron overload accelerates cartilage degeneration in Hemophilic Arthropathy through the mtDNA-cGAS-STING axis.

INTRODUCTION: Excess iron contributes to Hemophilic Arthropathy (HA) development. Divalent metal transporter 1 (DMT1) delivers iron into the cytoplasm, thus regulating iron homeostasis. OBJECTIVES: We aimed to investigate whether DMT1-mediated iron homeostasis is involved in bleeding-induced cartilage degeneration and the molecular mechanisms underlying iron overload-induced chondrocyte damage. METHODS: This study established an in vivo HA model by puncturing knee joints of coagulation factor VIII gene knockout mice with a needle, and mimicked iron overload conditions in vitro by treatment of Ferric ammonium citrate (FAC). RESULTS: We demonstrated that blood exposure caused iron overload and cartilage degeneration, as well as elevated expression of DMT1. Furthermore, DMT1 silencing alleviated blood-induced iron overload and cartilage degeneration. In hemophilic mice, articular cartilage degeneration was also suppressed by intro-articularly injection of DMT1 adeno-associated virus 9 (AAV9). Mechanistically, RNA-sequencing analysis indicated the association between iron overload and cGAS-STING pathway. Further, iron overload triggered mtDNA-cGAS-STING pathway activation, which could be effectively mitigated by DMT1 silencing. Additionally, we discovered that RU.521, a potent Cyclic GMP-AMP Synthase (cGAS) inhibitor, successfully suppressed the downward cascades of cGAS-STING, thereby protecting against chondrocyte damage. CONCLUSION: Taken together, DMT1-mediated iron overload promotes chondrocyte damage and murine HA development, and targeted DMT1 may provide therapeutic and preventive approaches in HA.

Inhibition of SAT1 alleviates chondrocyte inflammation and ferroptosis by repressing ALOX15 expression and activating the Nrf2 pathway.

Aims: Osteoarthritis (OA) is the most common chronic pathema of human joints. The pathogenesis is complex, involving physiological and mechanical factors. In previous studies, we found that ferroptosis is intimately related to OA, while the role of Sat1 in chondrocyte ferroptosis and OA, as well as the underlying mechanism, remains unclear. Methods: In this study, interleukin-1ß (IL-1ß) was used to simulate inflammation and Erastin was used to simulate ferroptosis in vitro. We used small interfering RNA (siRNA) to knock down the spermidine/spermine N1-acetyltransferase 1 (Sat1) and arachidonate 15-lipoxygenase (Alox15), and examined damage-associated events including inflammation, ferroptosis, and oxidative stress of chondrocytes. In addition, a destabilization of the medial meniscus (DMM) mouse model of OA induced by surgery was established to investigate the role of Sat1 inhibition in OA progression. Results: The results showed that inhibition of Sat1 expression can reduce inflammation, ferroptosis changes, reactive oxygen species (ROS) level, and lipid-ROS accumulation induced by IL-1ß and Erastin. Knockdown of Sat1 promotes nuclear factor-E2-related factor 2 (Nrf2) signalling. Additionally, knockdown Alox15 can alleviate the inflammation-related protein expression induced by IL-1ß and ferroptosis-related protein expression induced by Erastin. Furthermore, knockdown Nrf2 can reverse these protein expression alterations. Finally, intra-articular injection of diminazene aceturate (DA), an inhibitor of Sat1, enhanced type II collagen (collagen II) and increased Sat1 and Alox15 expression. Conclusion: Our results demonstrate that inhibition of Sat1 could alleviate chondrocyte ferroptosis and inflammation by downregulating Alox15 activating the Nrf2 system, and delaying the progression of OA. These findings suggest that Sat1 provides a new approach for studying and treating OA.

P21 resists ferroptosis in osteoarthritic chondrocytes by regulating GPX4 protein stability.

Ferroptosis is involved in the pathogenesis of osteoarthritis (OA) while suppression of chondrocyte ferroptosis has a beneficial effect on OA. However, the molecular mechanism of ferroptosis in OA remains to be elucidated. P21, an indicator of aging, has been reported to inhibit ferroptosis, but the relationship between P21 and ferroptosis in OA remains unclear. Here, we aimed to investigate the expression and function of P21 in OA chondrocytes, and the involvement of P21 in the regulation of ferroptosis in chondrocytes. First, we demonstrated that high P21 expression was observed in the cartilage from OA patients and destabilized medial meniscus (DMM) mice, and in osteoarthritic chondrocytes induced by IL-1ß, FAC and erastin. P21 knockdown exacerbated the reduction of Col2a1 and promoted the upregulation of MMP13 in osteoarthritic chondrocytes. Meanwhile, P21 knockdown exacerbated cartilage degradation in DMM-induced OA mouse models and decreased GPX4 expression in vivo. Furthermore, P21 knockdown sensitized chondrocytes to ferroptosis induced by erastin, which was closely associated with the accumulation of lipid peroxides. In mechanism, we demonstrated that P21 regulated the stability of GPX4 protein, and the regulation was independent of NRF2. Meanwhile, we found that P21 significantly affected the recruitment of GPX4 to linear ubiquitin chain assembly complex (LUBAC) and regulated the level of M1-linked ubiquitination of GPX4. Overall, our results suggest that P21 plays an essential anti-ferroptosis role in OA by regulating the stability of GPX4.

Succession and Diversity of Microbial Flora during the Fermentation of Douchi and Their Effects on the Formation of Characteristic Aroma.

This study aims to understand the development and succession of the microbial community during the production of traditional Aspergillus-type Douchi as well as their effects on the formation and variation of characteristic aroma compounds. High-throughput sequencing technology, solid-phase microextraction, gas chromatography-mass spectrometry, and Spearman correlation analysis were conducted to study the changes in the microbial community and characteristic flavor during the fermentation process. Aspergillus spp. was dominant in the early stage of fermentation, whereas Staphylococcus spp., Bacillus spp., and Millerozyma spp. became dominant later. At the early stage, the main flavor compounds were characteristic soy-derived alcohols and aldehydes, mainly 1-hexanol, 1-octen-3-ol, and nonanal. In the later stage, phenol, 2-methoxy-, and 3-octanone were formed. Correlation analysis showed that six bacterial genera and nine fungal genera were significantly correlated with the main volatile components, with higher correlation coefficients, occurring on fungi rather than bacteria. Alcohols and aldehydes were highly correlated with the relative abundance of bacteria, while that of yeast species such as Millerozyma spp., Kodamaea spp., and Candida spp. was positively correlated with decanal, 3-octanol, 2-methoxy-phenol, 4-ethyl-phenol, 3-octanone, and phenol. The novelty of this work lies in the molds that were dominant in the pre-fermentation stage, whereas the yeasts increased rapidly in the post-fermentation stage. This change was also an important reason for the formation of the special flavor of Douchi. Correlation analysis of fungi and flavor substances was more relevant than that of bacteria. As a foundation of our future focus, this work will potentially lead to improved quality of Douchi and shortening the production cycle by enriching the abundance of key microbes.

Mechanism of the glucono-δ-lactone induced soymilk gelation: Enthalpy and entropy transformation in the cross-linking of protein molecules.

This study aimed to explore new techniques to regulate the quality of soy products. The glucono-δ-lactone (GDL) induced soymilk gelation process and the gel network structure characteristic were compared as a matter of temperature, and the role of reaction kinetics was discussed. Results showed that there were similarities in the development of G' curves under different temperatures, whereas the gel network structures and the energy requirements of cross-linking reactions were different. In the high-temperature region (70 °C-95 °C), the exposure and binding of reactive groups were promoted. The activation enthalpy (ΔH*) required by protein aggregates decreased and the effect of entropy reduction (-TΔS*) was enhanced, which led to shorten the preaggregation time (tg) and increase the gelation rate (k), resulting in the formation of rough, porous gel network with high stiffness. By contrast, in the low-temperature region (40 °C-70 °C), high enthalpy contributions and low entropy changes were required, then a fine, soft, and tender gel network formed. Besides, a funnel-shaped model of the enthalpy-entropy energy transformation mechanism of soymilk gelation was proposed. The results of this study revealed that adjusting the enthalpy-entropy energy requirements of the protein cross-linking reaction could be utilized to the regulation of the network structure and quality of soymilk gels, which could enrich the reaction kinetics theory and provide innovative ideas for food quality control technology from the perspective of energy requirement and energy input.

Micro-structure and tensile properties of microfluidic spinning konjac glucomannan and sodium alginate composite bio-fibers regulated by shear and elongational flow: experiment and multi-scale simulation.

Microfluidic spinning has been widely used to produce bio-fibers with excellent tensile performances by regulating the conformation of biological macromolecules. However, the effect of channel shapes on fiber tensile performances is unclear. In this study, bio-fibers were prepared using konjac glucomannan and sodium alginate by five channels. The micro-morphology and tensile performance of fibers were characterized and measured. Then, the dynamical behaviours of macromolecule clusters in flow fields were simulated by multi-scale numerical methods. The results show that the elongational flow with increasing extension rates produced fibers with a tensile strength of 32.34 MPa and a tensile strain of 18.72 %, which were 1.37 and 1.55 times that for a shear flow, respectively. The difference in tensile performances was attributed to the micro-morphology regulated by flow fields. The continuously increasing extension rate of flow was more effective than the shear rate or the maximum extension rate for the stretching of macromolecule clusters. We conclude that the channel shapes significantly influence flow fields, dynamical behaviours of molecule clusters, the morphology of fibers, and tensile performances. This study provides a novel numerical method and understanding of microfluidic spinning, which will promote the optimization and applications of bio-fibers.

JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy.

Interruption of iron homeostasis is correlated with cell ferroptosis and degenerative diseases. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been reported as a vital mechanism to control cellular iron levels, but its impact on osteoarthritis (OA) pathology and the underline mechanism are unknown. Herein we aimed to investigate the role and regulatory mechanism of NCOA4 in chondrocyte ferroptosis and OA pathogenesis. We demonstrated that NCOA4 was highly expressed in cartilage of patients with OA, aged mice, post-traumatic OA mice, and inflammatory chondrocytes. Importantly, Ncoa4 knockdown inhibited IL-1ß-induced chondrocyte ferroptosis and extracellular matrix degradation. Contrarily, overexpression of NCOA4 promoted chondrocyte ferroptosis and the delivery of Ncoa4 adeno-associated virus 9 into knee joint of mice aggravated post-traumatic OA. Mechanistic study revealed that NCOA4 was upregulated in a JNK-JUN signaling-dependent manner in which JUN could directly bind to the promoter of Ncoa4 and initial the transcription of Ncoa4. NCOA4 could interact with ferritin and increase autophagic degradation of ferritin and iron levels, which caused chondrocyte ferroptosis and extracellular matrix degradation. In addition, inhibition of JNK-JUN-NCOA4 axis by SP600125, a specific inhibitor of JNK, attenuated development of post-traumatic OA. This work highlights the role of JNK-JUN-NCOA4 axis and ferritinophagy in chondrocyte ferroptosis and OA pathogenesis, suggesting this axis as a potential target for OA treatment.

Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis.

Osteoarthritis (OA) is a multifactorial and increasingly prevalent degenerative disease that affects the whole joint. The pathogenesis of OA is poorly understood and there is a lack of therapeutic interventions to reverse the pathological process of this disease. Accumulating studies have shown that the overproduction of reactive oxygen species (ROS) and ROS-induced lipid peroxidation are involved in the pathogenesis of OA. 4-Hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) have received considerable attention for their role in cartilage degeneration and subchondral bone remodeling during OA development. Ferroptosis is a form of cell death characterized by a lack of control of membrane lipid peroxidation and recent studies have suggested that chondrocyte ferroptosis contributes to OA progression. In this review, we aim to discuss lipid peroxidation-derived 4-HNE and MDA in the progression of OA. In addition, the therapeutic potential for OA by controlling the accumulation of lipid peroxidation and inhibiting chondrocyte ferroptosis are discussed.