Multi-scale analysis of nutrient and environmental dynamics in Hongfeng Lake Southwest China.

Traditional linear correlation analysis may not fully capture the true relationship between these variables. Therefore, multi-scale running correlation analysis, such as time-dependent intrinsic correlation (TDIC) and continuous wavelet transform based on Hilbert-Huang transform (HHT), provides valuable insights into local correlations and the evolving relationship between nutrients and environmental factors over time. In this study, we investigated seven environmental factors and four water quality nutrient indicators in deep lakes on the Yungui Plateau in southwestern China. The results revealed that there may be strong correlations between environmental factors and nutrient levels during certain periods, while opposite trends may emerge at other times. These variations in correlation could be attributed to uncertain physical processes, spatial heterogeneity, or the impact of different climatic factors on local hydrological processes. Wavelet analysis indicated that changes in environmental factors lag behind those in nutrient levels, particularly on a cycle of about 12 months. This suggests that changes in environmental factors align with natural patterns after the water body has been polluted. These conclusions underscore the complexity and dynamic nature of the relationship between environmental factors and nutrient levels in water bodies, highlighting the importance of employing advanced analysis techniques to capture this complexity.

Neurofeedback technique for treating male schizophrenia patients with impulsive behavior: a randomized controlled study.

Background: Schizophrenia is one of the most severe mental disorders, frequently associated with aggression and violence, particularly in male patients. The underlying mechanisms of violent behavior in these patients remain unclear, limiting effective treatment options and highlighting the need for further research into interventions for impulsive behaviors. This study aims to evaluate the clinical efficacy of neurofeedback treatment in hospitalized male schizophrenia patients exhibiting impulsive behaviors. Methods: The study was designed as a single-center, randomized, single-blind, sham-controlled parallel trial. Eighty patients were randomly assigned to either a study group or a control group. The control group received risperidone and sham neurofeedback, while the study group received risperidone and active neurofeedback therapy. Both groups underwent training five times per week, with each session lasting 20 minutes, over a six-week period. Clinical symptoms were assessed at baseline, three weeks and six weeks using the Positive and Negative Syndrome Scale (PANSS), the Modified Overt Aggression Scale (MOAS), and the Rating Scale for Extrapyramidal Side Effects (RSESE). Statistical analyses were conducted to compare the therapeutic effects between the two groups at the study's conclusion. Results: Initial comparisons showed no significant differences in baseline data, except for the number of prior hospitalizations (P<0.018). By the end of the study, the study group demonstrate significant improvements in MOAS and PANSS scores (including the Excited, Positive, Cognitive, and Depressive/Anxiety Components), with no significant changes in RSESE scores. Discussion: Both time and group interactions were significant across most outcomes, underscoring the efficacy of neurofeedback in reducing the severity of impulsive behaviors and associated schizophrenia symptoms. Clinical trial registration: chictr.org.cn, identifier ChiCTR2200063407.

Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE.

Severe steatosis in donor livers is contraindicated for transplantation due to the high risk of ischemia-reperfusion injury (IRI). Although Ho-1 gene-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) can mitigate IRI, the role of gut microbiota and metabolites in this protection remains unclear. This study aimed to explore how gut microbiota and metabolites contribute to HO-1/BMMSCs-mediated protection against IRI in severe steatotic livers. Using rat models and cellular models (IAR20 and THLE-2 cells) of steatotic liver IRI, this study revealed that ischemia-reperfusion led to significant liver and intestinal damage, heightened immune responses, impaired liver function, and altered gut microbiota and metabolite profiles in rats with severe steatosis, which were partially reversed by HO-1/BMMSCs transplantation. Integrated microbiome and metabolome analyses identified gut microbial metabolite oleanolic acid as a potential protective agent against IRI. Experimental validation showed that oleanolic acid administration alone alleviated IRI and inhibited ferroptosis in both rat and cellular models. Network pharmacology and molecular docking implicated KEAP1/NRF2 pathway as a potential target of oleanolic acid. Indeed, OA experimentally upregulated NRF2 activity, which underlies its inhibition of ferroptosis and protection against IRI. The gut microbial metabolite OA protects against IRI in severe steatotic liver by promoting NRF2 expression and activity, thereby inhibiting ferroptosis.

Ferrostatin-1 improves prognosis and regulates gut microbiota of steatotic liver transplantation recipients in rats.

Aims: To investigate the effects of Ferrostatin-1 (Fer-1) on improving the prognosis of liver transplant recipients with steatotic liver grafts and regulating gut microbiota in rats. Methods: We obtained steatotic liver grafts and established a liver transplantation model. Recipients were divided into sham, liver transplantation and Fer-1 treatment groups, which were assessed 1 and 7 days after surgery (n = 6). Results & conclusion: Fer-1 promotes recovery of the histological structure and function of steatotic liver grafts and the intestinal tract, and improves inflammatory responses of recipients following liver transplantation. Fer-1 reduces gut microbiota pathogenicity, and lowers iron absorption and improves fat metabolism of recipients, thereby protecting steatotic liver grafts.

Exosomes derived from bone marrow mesenchymal stem cells alleviate biliary ischemia reperfusion injury in fatty liver transplantation by inhibiting ferroptosis.

Fatty liver grafts are susceptible to ischemia reperfusion injury (IRI), increasing the risk of biliary complications after liver transplantation (LT). Ferroptosis, a newly recognized programmed cell death, is expected to be a novel therapeutic target for IRI. We investigated whether exosomes derived from heme oxygenase 1-modified bone marrow mesenchymal stem cells (HExos) relieve ferroptosis and protect biliary tracts from IRI in a rat fatty liver transplantation model. Rats were fed with a methionine choline deficient (MCD) diet for 2 weeks to induce severe hepatic steatosis. Steatotic grafts were implanted and HExos were administered after liver transplantation. A series of functional assays and pathological analysis were performed to assess ferroptosis and biliary IRI. The HExos attenuated IRI following liver transplantation, as demonstrated by less ferroptosis, improved liver function, less Kupffer and T cell activation, and less long-term biliary fibrosis. MicroRNA (miR)-204-5p delivered by HExos negatively regulated ferroptosis by targeting a key pro-ferroptosis enzyme, ACSL4. Ferroptosis contributes to biliary IRI in fatty liver transplantation. HExos protect steatotic grafts by inhibiting ferroptosis, and may become a promising strategy to prevent biliary IRI and expand the donor pool.

Identification and characterization of colorectal-cancer-associated SNPs on the SMAD7 locus.

PURPOSE: Genome-wide association studies have identified SMAD7 as a colorectal cancer (CRC) susceptibility gene. However, its underlying mechanism has not yet been characterized. This study screened functional SNPs (fSNPs) related to colorectal cancer through Reel-seq and obtained regulatory proteins on functional SNPs. METHODS: The candidate fSNPs on the SMAD7 locus were screened by Reel-seq method. Eight SNPs such as rs8085824 were identified as functional SNPs by luciferase reporter assay and EMSA, SDCP-MS and AIDP-WB revealed that HNRNPK can specifically bind to the rs8085824-C allele. The knockdown of HNRNPK by RNAi proved that HNRNPK could affect cell function by regulating SMAD7. RESULTS: Eight functional SNPs was found on the SMAD7 locus in linkage disequilibrium (LD) with R2 > 0.8, i.e., rs12953717, rs7227023, rs34007497, rs58920878, rs8085824, rs4991143, rs4939826, and rs7227023. We also identified allele-imbalanced binding of HNRNPK to rs8085824, H1-3 to rs12953717, THOC6 to rs7227023, and DDX21 to rs58920878. Further functional analysis revealed that these proteins are the regulatory proteins that modulate the expression of SMAD7 in the human colorectal cancer cell line DLD1. In particular, we discovered that siRNA knockdown of HNRNPK inhibits cell proliferation and cell clonal formation by downregulating SMAD7, as the decreased cell proliferation and cell clonal formation in the siRNA HNRNPK knockdown cells was restored by SMAD7 overexpression. CONCLUSION: Our findings reveal a mechanism which underlies the contribution of the fSNP rs8085824 on the SMD7 locus to CRC susceptibility.

Heme Oxygenase-1-Modified BMMSCs Activate AMPK-Nrf2-FTH1 to Reduce Severe Steatotic Liver Ischemia-Reperfusion Injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is an important cause of graft dysfunction post-liver transplantation, where donor liver with severe steatosis is more sensitive to IRI. Liver IRI involves ferroptosis and can be alleviated by heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs). AIMS: To explore the role and mechanism of HO-1/BMMSCs in severe steatotic liver IRI. METHODS: A severe steatotic liver IRI rat model and a hypoxia/reoxygenation (H/R) of severe steatosis hepatocyte model were established. Liver and hepatocyte damage was evaluated via liver histopathology and cell activity. Ferroptosis was evaluated through ferroptosis indexes. Nuclear factor erythroid 2-related factor 2 (Nrf2) was knocked down in severe steatotic hepatocytes. The role of Nrf2 and AMPK in HO-1/BMMSC inhibition of ferroptosis was examined using the AMP-activated protein kinase (AMPK) pathway inhibitor Compound C. RESULTS: The HO-1/BMMSCs alleviated severe steatotic liver IRI and ferroptosis. HO-1/BMMSCs promoted ferritin heavy chain 1(FTH1), Nrf2, and phosphorylated (p)-AMPK expression in the H/R severe steatotic hepatocytes. Nrf2 knockdown decreased FTH1 expression levels but did not significantly affect p-AMPK expression levels. The protective effect of HO-1/BMMSCs against H/R injury in severe steatotic hepatocytes and the inhibitory effect on ferroptosis were reduced. Compound C decreased p-AMPK, Nrf2, and FTH1 expression levels, weakened the HO-1/BMMSC protective effect against severe steatotic liver IRI and H/R-injured severe steatotic hepatocytes, and reduced the inhibition of ferroptosis. CONCLUSIONS: Ferroptosis was involved in HO-1/BMMSC reduction of severe steatotic liver IRI. HO-1/BMMSCs protected against severe steatotic liver IRI by inhibiting ferroptosis through the AMPK-Nrf2-FTH1 pathway. HO-1/BMMSCs activate AMPK, which activates Nrf2, promotes its nuclear transcription, then promotes the expression of its downstream protein FTH1, thereby inhibiting ferroptosis and attenuating severe steatotic liver IRI in rats. Glu: glutamic acid; Cys: cystine; GSH: glutathione; GPX4: glutathione peroxidase 4; HO-1/BMMSCs: HO-1-modified BMMSCs; Fer-1: ferrostatin-1; DFO: deferoxamine; FTH1: ferritin heavy chain1; p-AMPK: phosphorylated AMP-activated protein kinase; Nrf2: nuclear factor erythroid 2-related factor 2; IRI: ischemia-reperfusion injury; MCD: methionine-choline deficiency.

Small extracellular vesicles from HO-1-modified bone marrow-derived mesenchymal stem cells attenuate ischemia-reperfusion injury after steatotic liver transplantation by suppressing ferroptosis via miR-214-3p.

Donor shortage is a major problem that limits liver transplantation availability. Steatotic donor liver presents a feasible strategy to solve this problem. However, severe ischemia-reperfusion injury (IRI) is an obstacle to the adoption of steatotic transplanted livers. Evidence from our prior studies indicated that bone marrow mesenchymal stem cells modified with heme oxygenase-1 (HMSCs) can attenuate non-steatotic liver IRI. However, the contribution of HMSCs in transplanted steatotic liver IRI is unclear. Here, HMSCs and their derived small extracellular vesicles (HM-sEVs) alleviated IRI in transplanted steatotic livers. After liver transplantation, there was significant enrichment of the differentially expressed genes in the glutathione metabolism and ferroptosis pathways, accompanied by ferroptosis marker upregulation. The HMSCs and HM-sEVs suppressed ferroptosis and attenuated IRI in the transplanted steatotic livers. MicroRNA (miRNA) microarray and validation experiments indicated that miR-214-3p, which was abundant in the HM-sEVs, suppressed ferroptosis by targeting cyclooxygenase 2 (COX2). In contrast, COX2 overexpression reversed this effect. Knockdown of miR-214-3p in the HM-sEVs diminished its ability to suppress ferroptosis and protect liver tissues/cells. The findings suggested that HM-sEVs suppressed ferroptosis to attenuate transplanted steatotic liver IRI via the miR-214-3p-COX2 axis.

Response of nutrient loss to natural erosive rainfall events under typical tillage practices of contour ridge system in the rocky mountain areas of Northern China.

Changes in natural rainfall characterized by heavy precipitation and high rainfall intensity would increase the risks and uncertainty of nutrients losses. Losses of nitrogen (N) and phosphorus (P) with water erosion from agriculture-related activities has become the principal nutrients resulting the eutrophication of water bodies. However, a little attention has been paid to the loss characteristic of N and P responding to natural rainfall in widely used contour ridge systems. To explore the loss mechanism of N and P in contour ridge system, nutrient loss associated with runoff and sediment yield was observed in in situ runoff plots of sweet potato (SP) and peanut (PT) contour ridges under natural rainfall. Rainfall events were divided into light rain, moderate rain, heavy rain, rainstorm, large rainstorm, and extreme rainstorm level, and rainfall characteristics for each rainfall level were recorded. Results showed that rainstorm, accounting for 46.27% of the total precipitation, played a destructive role in inducing runoff, sediment yield, and nutrient loss. The average contribution of rainstorm to sediment yield (52.30%) was higher than that to runoff production (38.06%). Rainstorm respectively generated 43.65-44.05% of N loss and 40.71-52.42% of P loss, although light rain induced the greatest enrichment value for total nitrogen (TN, 2.44-4.08) and PO4-P (5.40). N and P losses were dominated by sediment, and up to 95.70% of the total phosphorus and 66.08% of TN occurred in sediment. Nutrient loss exhibited the highest sensitivity to sediment yield compared to runoff and rainfall variables, and a significant positive linear relationship was observed between nutrient loss and sediment yield. SP contour ridge presented higher nutrient loss than that in PT contour ridge, especially for P loss. Findings gained in this study provide references for the response strategies of nutrient loss control to natural rainfall change in contour ridge system.

Potential ecological risks of heavy metals and Cd accumulation characteristics of Suaeda salsa under different Cd input and water logging conditions in the Yellow River estuary, China.

To improve the remediation of heavy metal pollution by typical wetland vegetation and maintain the health of wetland ecosystems under the water-sediment regulation scheme (WSRS) application, we evaluated the potential ecological risk of heavy metals in surface sediment in the Yellow River estuary affected by the WSRS. The ranges of Cr, Cu, Zn, Cd, and Pb content in surface sediment were 52.44-100.80 mg·kg-1 dry weight (DW), 16.38-21.19 mg·kg-1 DW, 64.77-255.50 mg·kg-1 DW, 0.12-0.24 mg·kg-1 DW, and 5.40-8.63 mg·kg-1 DW, respectively, and potential ecological risk coefficients showed that Cd was associated with moderate potential risk. We further examined effects of Cd in a greenhouse experiment to explore the influence of short-term Cd input and water logging condition changes induced by WSRS on the Cd absorption characteristics of Suaeda salsa (L.) Pall in the Yellow River estuary. The results showed that total biomass decreased but Cd content in tissue of S. salsa increased with increasing Cd input and the accumulation factor reached maximum values at 100 µg·L-1 of Cd, indicating that S. salsa efficiently accumulated Cd. Water logging depth significantly affected S. salsa growth and Cd absorption with deeper water logging being detrimental to growth. The interaction effect of Cd input and water logging depth on Cd content and accumulation factor was significant. These results suggest that WSRS caused short-term heavy metal input and changes in water conditions affect wetland vegetation growth and heavy metal absorption in the downstream estuary.

ISG15 is a potential therapeutic target for osteosarcoma: a comprehensive analysis based on bioinformatics and in vitro experiments.

BACKGROUND: The expression of aberrant interferon-stimulated gene 15 (ISG15) is connected with various human diseases, including cancer. ISG15 is involved in tumor formation and metastasis. However, its role in osteosarcoma is uncertain. METHODS: ISG15 expression in pan-cancer from RNA Sequencing data were obtained from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases. The relationship between ISG15 expression and prognosis was assessed through TCGA clinical survival data. Immunohistochemistry (IHC) images of ISG15 were retrieved using the Human Protein Atlas to analyze the differences in selected normal and tumor tissues. Gene enrichment analysis and signaling pathway analysis were used to assess the potential role of ISG15 in sarcoma, and the correlation between ISG15 expressions and immune cell infiltration levels was estimated by immune infiltration analysis. The expression levels of ISG15 were assessed by qRT-PCR and IHC. Colony formation, wound healing assay and transwell assay were used to detect the effects of ISG15 on the biological behaviors of osteosarcoma cells. The correlation between ISG15 levels and CD8+/CD68+ cells was further examined by double-labeled immunofluorescence. The chemotactic effect of ISG15 on CD8+/CD68+ cells was demonstrated by chemotactic experiments and flow cytometry. RESULTS: ISG15 was highly expressed in most cancers, while high ISG15 expression was significantly correlated with poor overall survival. Gene enrichment analysis in sarcoma suggested that antigen processing and presentation might be involved in the oncogenic mechanism of ISG15. Further immune infiltration analysis showed that high ISG15 expression might reflect the infiltration level of certain immune cells. Additionally, our verification showed that ISG15 was significantly related to the occurrence and metastasis of osteosarcoma, and knockdown of ISG15 significantly altered cell biological behavior, resulting in decreased proliferation, migration and invasion capabilities of osteosarcoma cells. The high expression of ISG15 in osteosarcoma tissue was associated with a high level of CD68+ immune cell infiltration while a low level of CD8+ T cell infiltration. CD68+ immune cells were recruited in vitro by overexpression of ISG15, which on the contrary could weaken the chemotaxis of CD8+ T cells. CONCLUSION: High ISG15 expression is an inherent feature of osteosarcoma and triggers tumorigenesis and metastasis by regulating tumor immunogenicity. ISG15 is expected to be the target of osteosarcoma treatment.

Development of magnetic poly(L-lactic Acid) nanofibrous microspheres for transporting and delivering targeted cells.

To avoid infection and other risks caused by large open-surgery incisions using scaffold transplants, it is very important to study injectable microcarrier-loaded cells for targeted therapy and tissue regeneration. In this study, on the one hand, to simulate the hierarchical structure of the extracellular matrix and carry cells, poly(L-lactic acid) (PLLA) nanofibrous microspheres (large microspheres) were initially fabricated as cell carriers. On the other hand, to precisely deliver cells through a magnetic field and promote stem cell differentiation, drug-loaded mesoporous Fe3O4@SiO2 microspheres (small microspheres) were prepared and coated on the surface PLLA nanofibrous microspheres. The coating conditions were systematically studied and optimized. The results showed that planetary-satellite-like cell carriers were successfully prepared and the carriers were capable of freely translocating under the influence of a magnetic field. It has been demonstrated in vitro experiments that the carriers are biocompatible and are capable of acting as drug carriers. Specifically, they were able to load and release cells in response to magnetic fields. In vivo experiments indicated that the carriers could successfully load and release GFP-labelled cells in nude mice. The study presented in this paper provides a versatile and promising platform for the cell-based therapy in tissue engineering and regenerative medicine.

Influence of Potamogeton crispus harvesting on phosphorus composition of Lake Yimeng.

Harvesting is an important method used to control the overproduction of Potamogeton crispus in lakes. A three-year comparative field study was performed in a eutrophic lake (harvested area) and its connected lake (non-harvested area) to determine the effects of harvesting on the phosphorus (P) composition and environmental factors in the water and sediment. Results revealed that harvesting significantly reduced the dissolved total P and dissolved organic P (DOP) and increased the alkaline phosphatase activity and particulate P (PP) in the water. No significant differences were detected in the water total P (TP), soluble reactive P, chlorophyll-a, pH, and dissolved oxygen between the harvested and non-harvested areas. Sediment TP and organic P (OP) were significantly reduced in the harvested area. Harvesting changed the P composition in the water. In the non-harvested area, P was mainly formed by DOP (40%) in the water body, while in the harvested area, PP was the main water component (47%). Harvesting increased the proportion of inorganic P (IP) in the sediment and decreased the proportion of OP. In the water, the IP to TP ratio in the non-harvested and harvested areas were 58.26% and 63.51%, respectively. Our results showed that harvesting changed the P composition in the water and sediment. In the harvesting of submerged vegetation, our results can serve as a reference for the management of vegetation-rich lakes.

Social support and quality of life among chronically homeless patients with schizophrenia.

This study aimed to describe the sociodemographic characteristics, social support received, and quality of life of chronically homeless patients with schizophrenia in China. A self-prepared sociodemographic questionnaire, the Social Support Rating Scale (SSRS), European Five-dimensional Health Scale (EQ-5D), and Eysenck Personality were administrated to 3,967 chronically homeless and 3,724 non-homeless patients from the Department of Xiangtan Fifth People's Hospital, Hunan, China, between April 2011 and October 2016. Results indicated that the homeless patients were more likely to live outside the city and be ethnic minorities compared with non-homeless patients. Although the married proportion was higher among homeless patients, they had a higher rate of being divorced or widowed. Notably, the homeless patients had higher employment rates before illness, despite significantly lower education (P < 0.001). Chronically homeless patients with schizophrenia showed a lower score in the SSRS (30.29 ± 7.34 vs. 26.16 ± 10.04, p < 0.001); they had significantly lower objective support, subject support, social support, and EQ-Visual Analog Scale, Eysenck Personality Questionnaire-Psychoticism, and Eysenck Personality-Neuroticism scores (p < 0.001). Homeless patients may be worse off, and could be assisted by providing accommodation, family intervention, medical services (such as pain medication), and other comprehensive measures.

miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2.

Hepatic ischemia-reperfusion injury (IRI) is an inevitable result of liver surgery. Steatotic livers are extremely sensitive to IRI and have worse tolerance. Ferroptosis is considered to be one of the main factors of organ IRI. This study is aimed at exploring the role of ferroptosis in the effect of heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) on steatotic liver IRI and its mechanism. An IRI model of a steatotic liver and a hypoxia reoxygenation (HR) model of steatotic hepatocytes (SHPs) were established. Rat BMMSCs were extracted and transfected with the Ho1 gene to establish HO-1/BMMSCs, and their exosomes were extracted by ultracentrifugation. Ireb2 was knocked down to verify its role in ferroptosis and cell injury in SHP-HR. Public database screening combined with quantitative real-time reverse transcription PCR identified microRNAs (miRNAs) targeting Ireb2 in HO-1/BMMSCs exosomes. miR-29a-3p mimic and inhibitor were used for functional verification experiments. Liver function, histopathology, terminal deoxynulceotidyl transferase nick-end-labeling staining, cell viability, mitochondrial membrane potential, and cell death were measured to evaluate liver tissue and hepatocyte injury. Ferroptosis was assessed by detecting the levels of IREB2, Fe2+, malondialdehyde, glutathione, lipid reactive oxygen species, glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2 mRNA, and mitochondrial morphology. The results revealed that HO-1/BMMSCs improved liver tissue and hepatocyte injury and suppressed ferroptosis in vivo and in vitro. The expression of IREB2 was increased in steatotic liver IRI and SHP-HR. Knocking down Ireb2 reduced the level of Fe2+ and inhibited ferroptosis. HO-1/BMMSC exosomes reduced the expression of IREB2 and inhibited ferroptosis and cell damage. Furthermore, we confirmed high levels of miR-29a-3p in HO-1/BMMSCs exosomes. Overexpression of miR-29a-3p downregulated the expression of Ireb2 and inhibited ferroptosis. Downregulation of miR-29a-3p blocked the protective effect of HO-1/BMMSC exosomes on SHP-HR cell injury. In conclusion, ferroptosis plays an important role in HO-1/BMMSC-mediated alleviation of steatotic liver IRI. HO-1/BMMSCs could suppress ferroptosis by targeting Ireb2 via the exosomal transfer of miR-29a-3p.

Intestinal Microbiota Participates in the Protective Effect of HO-1/BMMSCs on Liver Transplantation With Steatotic Liver Grafts in Rats.

The present study aimed to explore whether heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) have a protective effect on liver transplantation with steatotic liver grafts in rats, and to determine the role of the intestinal microbiota in such protection. HO-1/BMMSCs were obtained by transduction of Hmox1 gene [encoding heme oxygenase (HO-1)]-encoding adenoviruses into primary rat BMMSCs. Steatotic livers were obtained by feeding rats a high-fat diet, and a model of liver transplantation with steatotic liver grafts was established. The recipients were treated with BMMSCs, HO-1/BMMSCs, or neither, via the portal vein. Two time points were used: postoperative day 1 (POD 1) and POD 7. The results showed that under the effect of HO-1/BMMSCs, the degree of steatosis in the liver grafts was significantly reduced, and the level of liver enzymes and the levels of pro-inflammatory cytokines in plasma were reduced. The effect of HO-1/BMMSCs was better than that of pure BMMSCs in the prolongation of the rats' postoperative time. In addition, HO-1/BMMSCs promoted the recovery of recipients' intestinal structure and function, especially on POD 7. The intestinal villi returned to normal, the expression of tight junction proteins was restored, and intestinal permeability was reduced on POD 7. The intestinal bacterial of the LT group showed significantly weakened energy metabolism and overgrowth. On POD 1, the abundance of Akkermansiaceae was higher. On POD 7, the abundance of Clostridiaceae increased, the level of lipopolysaccharide increased, the intestinal mucosal barrier function was destroyed, and the levels of several invasive bacteria increased. When treated with HO-1/BMMSCs, the energy metabolism of intestinal bacteria was enhanced, and on POD 1, levels bacteria that protect the intestinal mucosa, such as Desulfovibrionaceae, increased significantly. On POD 7, the changed intestinal microbiota improved lipid metabolism and increased the levels of butyrate-producing bacteria, such as Lachnospiraceae. In conclusion, HO-1/BMMSCs have protective effects on steatotic liver grafts and the intestinal barrier function of the recipients. By improving lipid metabolism and increasing the abundance of butyrate-producing bacteria, the changed intestinal microbiota has a protective effect and prolongs the recipients' survival time.

Relationship between the coprecipitation of phosphorus-on-calcite by submerged macrophytes and the phosphorus cycle in water.

To assess potential phosphorus removal, we utilized Potamogeton crispus to determine the effects of calcium addition on phosphorus removal. Plastic film was used to block material exchange between the overlying water and the sediment, and we compared the experimental results with long-term monitoring results of Yimeng Lake, which contained a dense population of P. crispus. The results revealed that the first 10-40 days constituted a period of rapid P decrease, as P. crispus could effectively remove the phosphorus in the water through coprecipitation of CaCO3-P. The treatment groups indicated that P. crispus released calcium into the overlying water, and after the addition of calcium ions, P. crispus showed increased phosphorus removal efficiency in the water. Total phosphorus (TP) and P/Ca content increased with increasing pH in the treatment groups, and the TP and pH declined as the calcium content increased in the treatment groups. Long-term field observations showed that the calcium-to-phosphorus ratio in the coprecipitates was dependent on the pH during the crystallization process. Thus, water calcium driven by P. crispus plays an important role in the phosphorus cycle of water, due to P. crispus assisted precipitation. This study revealed the effect of P. crispus on the water purification, the migration and transformation of Ca and P in sediment and overlying water under the condition of sediment calcium addition, so as to provide a theoretical basis for the ecological restoration of shallow lakes eutrophication.

miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia-reperfusion injury in steatotic grafts.

BACKGROUND: Steatotic livers tolerate ischemia-reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered the initiating factor of organ IRI. Heme oxygenase oxygen-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, the role of ferroptosis in IRI of steatotic grafts and the effect of HO-1/BMMSCs-derived exosomes (HM-exos) on ferroptosis remain unknown. METHODS: A model of rat liver transplantation (LT) with a severe steatotic donor liver and a model of hypoxia and reoxygenation (H/R) of steatotic hepatocytes were established. Exosomes were obtained by differential centrifugation, and the differentially expressed genes (DEGs) in liver after HM-exo treatment were detected using RNA sequencing. The expression of ferroptosis markers was analyzed. microRNA (miRNA) sequencing was used to analyze the miRNA profiles in HM-exos. RESULTS: We verified the effect of a candidate miRNA on ferroptosis of H/R treated hepatocytes, and observed the effect of exosomes knockout of the candidate miRNA on hepatocytes ferroptosis. In vitro, HM-exo treatment reduced the IRI in steatotic grafts, and enrichment analysis of DEGs suggested that HM-exos were involved in the regulation of the ferroptosis pathway. In vitro, inhibition of ferroptosis by HM-exos reduced hepatocyte injury. HM-exos contained more abundant miR-124-3p, which reduced ferroptosis of H/R-treated cells by inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression of Steap3 reversed the effect of mir-124-3p. In addition, HM-exos from cell knocked out for miR-124-3p showed a weakened inhibitory effect on ferroptosis. Similarly, HM-exo treatment increased the content of miR-124-3p in grafts, while decreasing the level of STEAP3 and reducing the degree of hepatic ferroptosis. CONCLUSION: Ferroptosis is involved in the IRI during LT with a severe steatotic donor liver. miR-124-3p in HM-exos downregulates Steap3 expression to inhibit ferroptosis, thereby attenuating graft IRI, which might be a promising strategy to treat IRI in steatotic grafts.

Bone marrow mesenchymal stem cells modified with heme oxygenase-1 alleviate rejection of donation after circulatory death liver transplantation by inhibiting dendritic cell maturation in rats.

Immature dendritic cells induce immune tolerance and mature dendritic cells induce acute rejection. We infused bone marrow mesenchymal stem cells (BMMSCs) expressing heme oxygenase 1 (HO-1) (HO-1/BMMSCs) into donation after circulatory death (DCD) livers using normothermic machine perfusion (NMP), and then performed transplantation, with the aim of determining the effects of HO 1/BMMSCs on liver DC maturation and graft rejection. A rat model of acute liver transplantation rejection was established from Lewis to BN rats, in which six experimental groups were set up: Sham operation, static cold storage, NMP, BMMSCs + NMP, HO-1/BMMSCs + NMP (HBP), and NMP + FK506 gavage. Flow cytometry was performed to detect the maturation of DCs and the activation of CD4+ T cells in the liver. In vitro, HO-1/BMMSCs were cocultured with liver DCs, and then the phenotype and ability to stimulate lymphocyte proliferation of DCs were measured. MAPK inhibitors were added to observe the effect of MAPK signaling on DC maturation. The resultsindicatedthatHO-1/BMMSCs could stably colonize the transplanted liver. In the HBP group, rejection was reduced, the maturation of DCs was inhibited, and the infiltration and activation of CD4+ T cells were reduced. In vitro, DCs cocultured with HO-1/BMMSCs showed an immature phenotype and inhibited T cell proliferation. HO-1/BMMSCs inhibited the maturation of DCs by blocking the phosphorylation of p38 and ERK1/2. This study suggested that infusion of HO-1/BMMSCs into DCD livers could reduce acute rejection significantly by inhibiting DC maturation. DC maturation regulation by HO-1/BMMSCs involves ERK1/2/MAPK and p38/MAPK signaling.