Unveiling the emerging role of curcumin to alleviate ochratoxin A-induced muscle toxicity in grass carp (Ctenopharyngodon idella): in vitro and in vivo studies.

BACKGROUND: Ochratoxin A (OTA), a globally abundant and extremely hazardous pollutant, is a significant source of contamination in aquafeeds and is responsible for severe food pollution. The developmental toxicity of OTA and the potential relieving strategy of natural products remain unclear. This study screened the substance curcumin (Cur), which had the best effect in alleviating OTA inhibition of myoblast proliferation, from 96 natural products and investigated its effect and mechanism in reducing OTA myotoxicity in vivo and in vitro. METHODS: A total of 720 healthy juvenile grass carp, with an initial average body weight of 11.06 ± 0.05 g, were randomly assigned into 4 groups: the control group (without OTA and Cur), 1.2 mg/kg OTA group, 400 mg/kg Cur group, and 1.2 mg/kg OTA + 400 mg/kg Cur group. Each treatment consisted of 3 replicates (180 fish) for 60 d. RESULTS: Firstly, we cultured, purified, and identified myoblasts using the tissue block culture method. Through preliminary screening and re-screening of 96 substances, we examined cell proliferation-related indicators such as cell viability and ultimately found that Cur had the best effect. Secondly, Cur could alleviate OTA-inhibited myoblast differentiation and myofibrillar development-related proteins (MyoG and MYHC) in vivo and in vitro and improve the growth performance of grass carp. Then, Cur could also promote the expression of OTA-inhibited protein synthesis-related proteins (S6K1 and TOR), which was related to the activation of the AKT/TOR signaling pathway. Finally, Cur could downregulate the expression of OTA-enhanced protein degradation-related genes (murf1, foxo3a, and ub), which was related to the inhibition of the FoxO3a signaling pathway. CONCLUSIONS: In summary, our data demonstrated the effectiveness of Cur in alleviating OTA myotoxicity in vivo and in vitro. This study confirms the rapidity, feasibility, and effectiveness of establishing a natural product screening method targeting myoblasts to alleviate fungal toxin toxicity.

TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.

Physiological and transcriptomic analyses reveal the cadmium tolerance mechanism of Miscanthus lutarioriparia.

Miscanthus lutarioriparia is a promising energy crop that is used for abandoned mine soil phytoremediation because of its high biomass yield and strong tolerance to heavy metals. However, the biological mechanism of heavy metal resistance is limited, especially for applications in the soil restoration of mining areas. Here, through the investigation of soil cadmium(Cd) in different mining areas and soil potted under Cd stress, the adsorption capacity of Miscanthus lutarioriparia was analyzed. The physiological and transcriptional effects of Cd stress on M. lutarioriparia leaves and roots under hydroponic conditions were analyzed. The results showed that M. lutarioriparia could reduce the Cd content in mining soil by 29.82%. Moreover, different Cd varieties have different Cd adsorption capacities in soils with higher Cd concentration. The highest cadmium concentrations in the aboveground and belowground parts of the plants were 185.65 mg/kg and 186.8 mg/kg, respectively. The total chlorophyll content, superoxide dismutase and catalase activities all showed a trend of increasing first and then decreasing. In total, 24,372 differentially expressed genes were obtained, including 7735 unique to leaves, 7725 unique to roots, and 8912 unique to leaves and roots, which showed differences in gene expression between leaves and roots. These genes were predominantly involved in plant hormone signal transduction, glutathione metabolism, flavonoid biosynthesis, ABC transporters, photosynthesis and the metal ion transport pathway. In addition, the number of upregulated genes was greater than the number of downregulated genes at different stress intervals, which indicated that M. lutarioriparia adapted to Cd stress mainly through positive regulation. These results lay a solid foundation for breeding excellent Cd resistant M. lutarioriparia and other plants. The results also have an important theoretical significance for further understanding the detoxification mechanism of Cd stress and the remediation of heavy metal pollution in mining soil.

Genetic characterization of bovine coronavirus strain isolated in Inner Mongolia of China.

BACKGROUND: Bovine coronavirus (BCoV) is implicated in severe diarrhea in calves and contributes to the bovine respiratory disease complex; it shares a close relationship with human coronavirus. Similar to other coronaviruses, remarkable variability was found in the genome and biology of the BCoV. In 2022, samples of feces were collected from a cattle farm. A virus was isolated from 7-day-old newborn calves. In this study, we present the genetic characteristics of a new BCoV isolate. The complete genomic, spike protein, and nucleocapsid protein gene sequences of the BCoV strain, along with those of other coronaviruses, were obtained from the GenBank database. Genetic analysis was conducted using MEGA7.0 and the Neighbor-Joining (NJ) method. The reference strains' related genes were retrieved from GenBank for comparison and analysis using DNAMAN. RESULTS: The phylogenetic tree and whole genome consistency analysis showed that it belonged to the GIIb subgroup, which is epidemic in Asia and America, and was quite similar to the Chinese strains in the same cluster. Significantly, the S gene was highly consistent with QH1 (MH810151.1) isolated from yak. This suggests that the strain may have originated from interspecies transmission involving mutations of wild strains. The N gene was conserved and showed high sequence identity with the epidemic strains in China and the USA. CONCLUSIONS: Genetic characterization suggests that the isolated strain could be a new mutant from a wild-type lineage, which is in the same cluster as most Chinese epidemic strains but on a new branch.

Exploring the dietary strategies of phenylalanine: Improving muscle nutraceutical quality as well as muscle glycogen and protein deposition in adult grass carp (Ctenopharyngodon idella).

Muscle is the main edible part of bony fish. The purpose of this study was to investigate the influences of phenylalanine (Phe) on muscle quality, amino acid composition, fatty acid composition, glucose metabolism, and protein deposition in adult grass carp. The diets at 2.30, 4.63, 7.51, 10.97, 13.53, and 17.07 g/kg Phe levels were fed for 9 weeks. The results manifested that Phe (10.97-13.53 g/kg) increased the pH of the fillets and decreased muscle cooking loss and lactic acid content; Phe (7.51-17.07 g/kg) improved the composition of the fillets in terms of flavor (free) amino acids, bound amino acids (especially EAA), and fatty acids (especially EPA and DHA); Phe (7.51-13.53 g/kg) increased muscle glycogen content (possibly related to the AMPK signaling pathway) and muscle protein deposition (possibly related to IGF-1/4EBP1/TOR and AKT/FOXOs signaling pathways). In conclusion, a diet with appropriate Phe levels could improve fillet quality.

The role of neurovascular coupling dysfunction in cognitive decline of diabetes patients.

Neurovascular coupling (NVC) is an important mechanism to ensure adequate blood supply to active neurons in the brain. NVC damage can lead to chronic impairment of neuronal function. Diabetes is characterized by high blood sugar and is considered an important risk factor for cognitive impairment. In this review, we provide fMRI evidence of NVC damage in diabetic patients with cognitive decline. Combined with the exploration of the major mechanisms and signaling pathways of NVC, we discuss the effects of chronic hyperglycemia on the cellular structure of NVC signaling, including key receptors, ion channels, and intercellular connections. Studying these diabetes-related changes in cell structure will help us understand the underlying causes behind diabetes-induced NVC damage and early cognitive decline, ultimately helping to identify the most effective drug targets for treatment.

Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer.

BACKGROUND: The incidence and mortality of colorectal cancer (CRC) are among the highest in the world, and its occurrence and development are closely related to tumor neovascularization. When the balance between pigment epithelium-derived factors (PEDF) that inhibit angiogenesis and vascular endothelial growth factors (VEGF) that stimulate angiogenesis is broken, angiogenesis is out of control, resulting in tumor development. Therefore, it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment. AIM: To investigate the expression and significance of PEDF, VEGF, and CD31-stained microvessel density values (CD31-MVD) in normal colorectal mucosa, adenoma, and CRC. METHODS: In this case-control study, we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022. Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy (normal control group), 50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy (adenoma group), and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery (CRC group). An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens, analyze their differences, study the relationship between the two and clinicopathological factors in CRC group, record CD31-MVD in the three groups, and analyze the correlation of PEDF, VEGF, and CD31-MVD in the colorectal adenoma group and the CRC group. The F test or adjusted F test is used to analyze measurement data statistically. Kruskal-Wallis rank sum test was used between groups for ranked data. The chi-square test, adjusted chi-square test, or Fisher's exact test were used to compare the rates between groups. All differences between groups were compared using the Bonferroni method for multiple comparisons. Spearman correlation analysis was used to test the correlation of the data. The test level (α) was 0.05, and a two-sided P< 0.05 was considered statistically significant. RESULTS: The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group, adenoma group, and CRC group (100% vs 78% vs 50%, χ2 = 34.430, P < 0.001; ++~++ vs +~++ vs -~+, H = 94.059, P < 0.001), while VEGF increased gradually (0% vs 68% vs 96%, χ2 = 98.35, P < 0.001; - vs -~+ vs ++~+++, H = 107.734, P < 0.001). In the CRC group, the positive expression rate of PEDF decreased with the increase of differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (χ2 = 20.513, 4.160, 5.128, 6.349, 5.128, P < 0.05); the high expression rate of VEGF was the opposite (χ2 = 10.317, 13.134, 17.643, 21.844, 17.643, P < 0.05). In the colorectal adenoma group, the expression intensity of PEDF correlated negatively with CD31-MVD (r = -0.601, P < 0.001), whereas VEGF was not significantly different (r = 0.258, P = 0.07). In the CRC group, the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF (r = -0.297, P < 0.05; r = -0.548, P < 0.05), while VEGF expression intensity was positively related to CD31-MVD (r = 0.421, P = 0.002). CONCLUSION: It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.

Mucosa color and size may indicate malignant transformation of chicken skin mucosa-positive colorectal neoplastic polyps.

BACKGROUND: Lipid metabolism reprogramming is suspected to exist in pre-cancerous lesions, including colorectal adenoma. Screening colonoscopy frequently reveals chicken skin mucosa (CSM; white or yellow-white speckled mucosa) surrounding colorectal polyps, caused by macrophages engulfing and accumulating the lipids decomposed by colon cells or adjacent tumors. CSM-positive colorectal polyps are associated with various diseases; however, their prognosis varies greatly. Cold snare polypectomy is commonly used to resect lesions up to 10 to 15 mm in diameter without signs of submucosal invasion but is controversial for CSM-positive colorectal polyps. Improved imaging is required to diagnose and treat CSM-positive colorectal polyps. AIM: To highlight the clinical significance of CSM surrounding colorectal polyps and clarify the associated treatment for endoscopists. METHODS: This retrospective cohort study included 177 patients with CSM-positive colorectal polyps diagnosed using endoscopy. All patient-related information was extracted from the Goldisc soft-clinic DICOM system or electronic medical record system. Based on the pathological results, patients were classified as non-neoplastic polyps (five juvenile polyps), neoplastic polyps, non-invasive high-grade neoplasia (NHGN), or submucosal invasive carcinoma (SM stage cancer). We analyzed and compared the clinical features, suspected risk factors for malignant transformation of neoplastic polyps, and early infiltration of submucosal carcinoma. RESULTS: The diameters of NHGN and SM polyps were much smaller than those of neoplastic polyps. Most NHGN polyps had a deeper red mucosal color. On logistic regression analyses, diameter and deeper red mucosal color were independent risk factors for malignant transformation of neoplastic polyps. Type 1 CSM was more common in high-grade intraepithelial neoplasia and SM; type 2 CSM was more common in neoplastic polyps. Logistic regression analyses revealed no significant differences in the malignant transformation of neoplastic polyps or early submucosal invasion of CSM-positive colorectal cancer. Changes in the CSM mucosa surrounding neoplastic polyps and submucosal invasion of colorectal cancer disappeared within 12 months. No tumor recurrence was found during either partial or complete endoscopic resection of the CSM. CONCLUSION: CSM-positive colorectal polyps > 1 cm in diameter or with deeper red mucosa may be related to NHGN. Resection of CSM surrounding colorectal adenomas did not affect tumor recurrence.

Therapeutic effects and mechanisms of isoxanthohumol on DSS-induced colitis: regulating T cell development, restoring gut microbiota, and improving metabolic disorders.

Ulcerative colitis (UC) is a severe hazard to human health. Since pathogenesis of UC is still unclear, current therapy for UC treatment is far from optimal. Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, possesses anti-microbial, anti-oxidant, anti-inflammatory, and anti-angiogenic properties. However, the potential effects of IXN on the alleviation of colitis and the action of the mechanism is rarely studied. Here, we found that administration of IXN (60 mg/kg/day, gavage) significantly attenuated dextran sodium sulfate (DSS)-induced colitis, evidenced by reduced DAI scores and histological improvements, as well as suppressed the pro-inflammatory Th17/Th1 cells but promoted the anti-inflammatory Treg cells. Mechanically, oral IXN regulated T cell development, including inhibiting CD4+ T cell proliferation, promoting apoptosis, and regulating Treg/Th17 balance. Furthermore, IXN relieved colitis by restoring gut microbiota disorder and increasing gut microbiota diversity, which was manifested by maintaining the ratio of Firmicutes/Bacteroidetes balance, promoting abundance of Bacteroidetes and Ruminococcus, and suppressing abundance of proteobacteria. At the same time, the untargeted metabolic analysis of serum samples showed that IXN promoted the upregulation of D-( +)-mannose and L-threonine and regulated pyruvate metabolic pathway. Collectively, our findings revealed that IXN could be applied as a functional food component and served as a therapeutic agent for the treatment of UC.

Wnt5a deficiency in osteocalcin-expressing cells could not alleviate the osteoarthritic phenotype in a mouse model of post-traumatic osteoarthritis.

Objectives: Wnt5a, which regulates the activities of osteoblasts and osteoclasts, is reportedly overexpressed in osteoarthritis (OA) tissues. The purpose of this study was to elucidate its role in the development of OA by deleting Wnt5a in osteocalcin (OCN)-expressing cells. Materials and Methods: Knee OA was induced by anterior cruciate ligament transection (ACLT) in OCN-Cre;Wnt5afl/fl knockout (Wnt5a-cKO) mice and control littermates. Eight weeks after surgery, histological changes, cell apoptosis, and matrix metabolism of cartilage were evaluated by toluidine blue, TUNEL staining, and im-immunohistochemistry analyses, respectively. In addition, the subchondral bone microarchitecture of mice was examined by micro-computed tomography (micro-CT). Results: Histological scores show substantial cartilage degeneration occurred in ACLT knees, coupled with decreased collagen type II expression and enhanced matrix metalloproteinase 13 expression, as well as higher proportions of apoptotic cells. Micro-CT results show that ACLT resulted in decreased bone mineral density, bone volume/trabecular volume, trabecular number, and structure model index of subchondral bones in both Wnt5a-cKO and control littermates; although Wnt5a-cKO mice display lower BMD and BV/TV values, no significant difference was observed between Wnt5a-cKO and control mice for any of these values. Conclusion: Our findings indicate that Wnt5a deficiency in OCN-expressing cells could not prevent an osteoarthritic phenotype in a mouse model of post-traumatic OA.

Biohybrid Flexible Sperm-like Microrobot for Targeted Chemo-Photothermal Therapy.

Magnetic micro/nanorobots are promising platforms for targeted drug delivery, and their construction with soft and flexible features has received extensive attention for practical applications. Despite significant efforts in this field, facile fabrication of magnetic microrobots with flexible structures and versatility in targeted therapy remains a big challenge. Herein, we proposed a novel universal strategy to fabricate a biohybrid flexible sperm-like microrobot (BFSM) based on a Chlorella (Ch.) cell and artificial flagella, which showed great potential for targeted chemo-photothermal therapy for the first time. In this approach, microspherical Ch. cells were utilized to construct the microrobotic heads, which were intracellularly deposited with core-shell Pd@Au, extracellularly magnetized with Fe3O4, and further loaded with anticancer drug. The magnetic heads with excellent photothermal and chemotherapeutic capability were further assembled with flexible polypyrrole nanowires via biotin-streptavidin bonding to construct the BFSMs. Based on the exquisite head-to-tail structures, the BFSMs could be effectively propelled under precessing magnetic fields and move back and forth without a U-turn. Moreover, in vitro chemo-photothermal tests were conducted to verify their performance of targeted drug delivery toward localized HeLa cells. Due to this superior versatility and facile fabrication, the BFSMs demonstrated great potential for targeted anticancer therapy.

Exploring the role of Prx II in mitigating endoplasmic reticulum stress and mitochondrial dysfunction in neurodegeneration.

BACKGROUND: Neurodegenerative diseases are increasingly recognized for their association with oxidative stress, which leads to progressive dysfunction and loss of neurons, manifesting in cognitive and motor impairments. This study aimed to elucidate the neuroprotective role of peroxiredoxin II (Prx II) in counteracting oxidative stress-induced mitochondrial damage, a key pathological feature of neurodegeneration. METHODS: We investigated the impact of Prx II deficiency on endoplasmic reticulum stress and mitochondrial dysfunction using HT22 cell models with knocked down and overexpressed Prx II. We observed alcohol-treated HT22 cells using transmission electron microscopy and monitored changes in the length of mitochondria-associated endoplasmic reticulum membranes and their contact with endoplasmic reticulum mitochondria contact sites (EMCSs). Additionally, RNA sequencing and bioinformatic analysis were conducted to identify the role of Prx II in regulating mitochondrial transport and the formation of EMCSs. RESULTS: Our results indicated that Prx II preserves mitochondrial integrity by facilitating the formation of EMCSs, which are essential for maintaining mitochondrial Ca2+ homeostasis and preventing mitochondria-dependent apoptosis. Further, we identified a novel regulatory axis involving Prx II, the transcription factor ATF3, and miR-181b-5p, which collectively modulate the expression of Armcx3, a protein implicated in mitochondrial transport. Our findings underscore the significance of Prx II in protecting neuronal cells from alcohol-induced oxidative damage and suggest that modulating the Prx II-ATF3-miR-181b-5p pathway may offer a promising therapeutic strategy against neurodegenerative diseases. CONCLUSIONS: This study not only expands our understanding of the cytoprotective mechanisms of Prx II but also offers necessary data for developing targeted interventions to bolster mitochondrial resilience in neurodegenerative conditions.

Association of blood eosinophils with corticosteroid treatment failure stratified by smoking status among inpatients with AECOPD.

BACKGROUND: Recent studies have suggested elevated blood eosinophils are independent predictors of response to corticosteroid therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Smoking status has been shown to affect corticosteroid response. Whether the association between high blood eosinophils and corticosteroid treatment failure is modified by smoking has not been fully investigated so far. OBJECTIVES: This study aimed to assess whether the association between high blood eosinophils and corticosteroid treatment failure is modified by smoking. METHODS: We included 3402 inpatients with AECOPD treated with corticosteroids at Beijing Chao-Yang Hospital from July 2013 to June 2021. Blood eosinophil counts were measured within 24 hours of admission. An eosinophil percentage ≥2% was considered as high eosinophilic. Smokers in this study were defined as current or former smokers. Treatment failure was defined as a worsening of AECOPD that led to adverse clinical outcomes or required further treatment or an extended hospital stay or hospitalisation following the exacerbation. Multivariate-adjusted logistic models were used to estimate the OR and 95% CI associated with treatment failure. RESULTS: There were 958 (28.2%) treatment failure events occurring. Patients with high eosinophils had a lower risk of treatment failure (OR 0.74, 95% CI 0.63 to 0.87) than patients with low eosinophils. Compared with never smoking and low eosinophilic group, the ORs for treatment failure were 0.70 (95% CI 0.52 to 0.96) for never smoking and high eosinophilic group, 0.82 (95% CI 0.64 to 1.05) for smoking and low eosinophilic group and 0.62 (95% CI 0.47 to 0.81) for smoking and high eosinophilic group. Furthermore, there was no significant interaction between eosinophils and smoking status in relation to treatment failure (p for interaction=0.73). Similar results were obtained from multiple secondary outcomes and subgroup analyses. CONCLUSION: Elevated blood eosinophils are associated with a lower rate of corticosteroid treatment failure, regardless of smoking status. Smoking does not modify the association between blood eosinophil level and corticosteroid treatment failure among inpatients with AECOPD.

Declined flesh quality resulting from niacin deficiency is associated with elevated glycolysis and impaired mitochondrial homeostasis in grass carp (Ctenopharyngodon idella).

Energy metabolism exerts profound impacts on flesh quality. Niacin can be transformed into nicotinamide adenine dinucleotide (NAD), which is indispensable to energy metabolism. To investigate whether niacin deficiency could affect energy metabolism and flesh quality, six diets with graded levels of 0.49, 9.30, 21.30, 33.30, 45.30 and 57.30 mg/kg niacin were fed to grass carp (Ctenopharyngodon idella) for 63 days. The results showed that niacin deficiency declined flesh quality by changing amino acid and fatty acid profiles, decreasing shear force, increasing cooking loss and accelerating pH decline. The accelerated pH decline might be associated with enhanced glycolysis as evident by increased hexokinase (HK), pyruvate kinase (PK) and lactic dehydrogenase (LDH) activities, and mitochondrial dysfunction as evident by destroyed mitochondrial morphology, impaired respiratory chain complex I and antioxidant ability. Based on PWG and cooking loss, the niacin requirements for sub-adult grass carp were 31.95 mg/kg and 29.66 mg/kg diet, respectively.

Aflatoxin B1 inhibited the development of primary myoblasts of grass carp (Ctenopharyngodon idella) by degrading extracellular matrix.

According to the International Agency for Research on Cancer (IARC), aflatoxin B1 (AFB1) has been recognized as a major contaminant in food and animal feed and which is a common mycotoxin with high toxicity. Previous research has found that AFB1 inhibited zebrafish muscle development. However, the potential mechanism of AFB1 on fish muscle development is unknown, so it is necessary to conduct further investigation. In the present research, the primary myoblast of grass carp was used as a model, we treated myoblasts with AFB1 for 24 h. Our results found that 5 µM AFB1 significantly inhibited cell proliferation and migration (P < 0.05), and 10 µM AFB1 promoted lactate dehydrogenase (LDH) release (P < 0.05). Reactive oxygen species (ROS), protein carbonyl (PC) and malondialdehyde (MDA) levels were increased in 15, 5 and 10 µM AFB1 (P < 0.05), respectively. Catalase (CAT), glutathione peroxidase (GPx) and total superoxide dismutase (T-SOD) activities were decreased in 10, 10 and 15 µM AFB1 (P < 0.05), respectively. Furthermore, 15 µM AFB1 induced oxidative damage by Nrf2 pathway, also induced apoptosis in primary myoblast of grass carp. Meanwhile, 15 µM AFB1 decreased MyoD gene and protein expression (P < 0.05). Importantly, 15 µM AFB1 decreased the protein expression of collagen Ⅰ and fibronectin (P < 0.05), and increased the protein levels of urokinase plasminogen activator (uPA), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), and p38 mitogen-activated protein kinase (p38MAPK) (P < 0.05). As a result, our findings suggested that AFB1 damaged the cell morphology, induced oxidative damage and apoptosis, degraded ECM components, in turn inhibiting myoblast development by activating the p38MAPK/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase (MMPs)/extracellular matrix (ECM) signaling pathway.

Neutralization of CX3CL1 Attenuates TGF-ß-Induced Fibroblast Differentiation Through NF-κB Activation and Mitochondrial Dysfunction in Airway Fibrosis.

BACKGROUND: Severe asthma, characterized by inflammation and airway remodeling, involves fibroblast differentiation into myofibroblasts expressing α-SMA. This process leads to the production of fibronectin and connective tissue growth factor (CTGF), driven by factors such as transforming growth factor (TGF)-ß. Furthermore, the persistent presence of myofibroblasts is associated with resistance to apoptosis and mitochondrial dysfunction. The chemokine (C-X3-C motif) ligand 1 (CX3CL1) plays a role in tissue fibrosis. However, it is currently unknown whether neutralization of CX3CL1 decreases TGF-ß-induced fibroblast differentiation and mitochondrial dysfunction in normal human lung fibroblasts (NHLFs). METHODS: CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1), CX3CL1 was analyzed by immunofluorescence (IF) or immunohistochemical (IHC) staining of ovalbumin-challenged mice. CX3CL1 release was detected by ELISA. TGF-ß-induced CTGF, fibronectin, and α-SMA expression were evaluated in NHLFs following neutralization of CX3CL1 (TP213) treatment for the indicated times by Western blotting or IF staining. Mitochondrion function was detected by a JC-1 assay and seahorse assay. Cell apoptosis was observed by a terminal uridine nick-end labeling (TUNEL) assay. RESULTS: An increase in CX3CL1 expression was observed in lung tissues from mice with ovalbumin-induced asthma by IF staining. CX3CR1 was increased in the subepithelial layer of the airway by IHC staining. Moreover, CX3CR1 small interfering (si)RNA downregulated TGF-ß-induced CTGF and fibronectin expression in NHLFs. CX3CL1 induced CTGF and fibronectin expression in NHLFs. TGF-ß-induced CX3CL1 secretion from NHLFs. Furthermore, TP213 decreased TGF-ß-induced CTGF, fibronectin, and α-SMA expression in NHLFs. Mitochondrion-related differentially expressed genes (DEGs) were examined after CX3CL1 neutralization in TGF-ß-treated NHLFs. TP213 alleviated TGF-ß-induced mitochondrial dysfunction and apoptosis resistance in NHLFs. CX3CL1 induced p65, IκBα, and IKKα phosphorylation in a time-dependent manner. Furthermore, CX3CL1-induced fibronectin expression and JC-1 monomer were decreased by p65 siRNA. TP213 reduced TGF-ß-induced p65 and α-SMA expression in NHLFs. CONCLUSIONS: These findings suggest that neutralizing CX3CL1 attenuates lung fibroblast activation and mitochondrial dysfunction. Understanding the impacts of CX3CL1 neutralization on fibroblast mitochondrial function could contribute to the development of therapeutic strategies for managing airway remodeling in severe asthma.

Parent-child attachment mediates the association between parental conflict perceptions and suicide intention: a cross-sectional survey among middle school students in China.

Introduction: Adolescent suicide is a prevalent issue globally, with various factors contributing to this phenomenon. This study aimed to investigate these factors and their interrelationships to better understand the causes of adolescent suicide and provide evidence for its prevention. Methods: This study conducted among middle school students in Liaoning Province, China, from April to May 2016, A cross-sectional survey was administered to 1,028 students aged 10-19, using instruments such as the Behavior Questionnaire-Revised (SBQ-R), Children's Perception of Interparental Conflict Scale (CPIC), and revised version of Inventory of Parent Attachment (IPPA-R). Result: Binary logistic regression analysis revealed that adolescents aged 15-19, adolescents with strong perceptions of parental conflict were at high risk of suicide intention. Adolescents living in rural areas, adolescents with high mother-child attachment, adolescents with high father-child attachment were at low risk of suicide intention. Furthermore, parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention. Discussion: The study concludes that adolescents living in urban areas, older adolescents, adolescents with a high level of parental conflict intensity, and those with low levels of parent-child attachment are at high risk of suicide intention. parent-child attachment played a mediating role between two dimensions of parental conflict perception (resolved situations and response effect) and suicide intention. Interventions aimed at reducing family conflicts and improving parent-child relationships are recommended to decrease the incidence of adolescent suicide.

A Porphyrin-Based 3D Metal-Organic Framework Featuring [Cu8Cl6]10+ Cluster Secondary Building Units: Synthesis, Structure Elucidation, Anion Exchange, and Peroxidase-Like Activity.

Herein, we report a rare example of cationic three-dimensional (3D) metal-organic framework (MOF) of [Cu5Cl3(TMPP)]Cl5 ⋅ xSol (denoted as Cu-TMPP; H2TMPP=meso-tetrakis (6-methylpyridin-3-yl) porphyrin; xSol=encapsulated solvates) supported by [Cu8Cl6]10+ cluster secondary building units (SBUs) wherein the eight faces of the Cl--based octahedron are capped by eight Cu2+. Surface-area analysis indicated that Cu-TMPP features a mesoporous structure and its solvate-like Cl- counterions can be exchanged by BF4 -, PF6 -, and NO3 -. The polyvinylpyrrolidone (PVP) coated Cu-TMPP (denoted as Cu-TMPP-PVP) demonstrated good ROS generating ability, producing ⋅OH in the absence of light (peroxidase-like activity) and 1O2 on light irradiation (650 nm; 25 mW cm-2). This work highlights the potential of Cu-TMPP as a functional carrier of anionic guests such as drugs, for the combination therapy of cancer and other diseases.

Hidden diversity and potential ecological function of phosphorus acquisition genes in widespread terrestrial bacteriophages.

Phosphorus (P) limitation of ecosystem processes is widespread in terrestrial habitats. While a few auxiliary metabolic genes (AMGs) in bacteriophages from aquatic habitats are reported to have the potential to enhance P-acquisition ability of their hosts, little is known about the diversity and potential ecological function of P-acquisition genes encoded by terrestrial bacteriophages. Here, we analyze 333 soil metagenomes from five terrestrial habitat types across China and identify 75 viral operational taxonomic units (vOTUs) that encode 105 P-acquisition AMGs. These AMGs span 17 distinct functional genes involved in four primary processes of microbial P-acquisition. Among them, over 60% (11/17) have not been reported previously. We experimentally verify in-vitro enzymatic activities of two pyrophosphatases and one alkaline phosphatase encoded by P-acquisition vOTUs. Thirty-six percent of the 75 P-acquisition vOTUs are detectable in a published global topsoil metagenome dataset. Further analyses reveal that, under certain circumstances, the identified P-acquisition AMGs have a greater influence on soil P availability and are more dominant in soil metatranscriptomes than their corresponding bacterial genes. Overall, our results reinforce the necessity of incorporating viral contributions into biogeochemical P cycling.