Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis.

BACKGROUND: Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI. METHODS: In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated. RESULTS: The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues. CONCLUSIONS: Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.

Effects of mating-type ratio imbalance on the degeneration of Cordyceps militaris subculture and preventative measures.

The rapid degeneration of Cordyceps militaris strains during subculture represents a bottleneck problem that affects production stability. This study explored the mechanism underlying this degeneration in three production and three wild-type strains of Cordyceps militaris, isolating single-conidium strains from each. The effects of subculturing on fructification in both original and single mating-type strains were compared. Changes in the ratio of the two mating types were analyzed in both original and degenerated strains. Based on these findings, the two mating strains were paired in different ratios to determine their effects on fruiting. The resulting five strains were heterokaryotic strains with both MAT1-1 and MAT1-2 mating-type genes. Strain jb-2 was a single mating type (MAT1-1) mutant strain that produced stable fruiting bodies but failed to produce ascospores. It was found that the loss of or imbalance in mating types was the main reason for the rapid degeneration of fruiting traits during subculture and that this occurred randomly in the MAT1-1 and MAT1-2 types. The strains differed significantly in their stability during subculture. Fruiting was stable in the single mating-type Jb-2 strain, and the eleventh-generation fruited normally. There were differences in yield between the production and wild strains after inoculation with spawn containing different proportions of mating types. The production strain was more stable when inoculated with strains with mating-type ratios of 1:9 to 9:1 without affecting the yield. However, the yield of the wild-type strain xf-1 was positively correlated with the proportion of the MAT1-2 type, while the other two strains showed no correlations. Subculturing single mating-type mycelia separately and mixing them before production effectively mitigated degeneration during subculture. For Cordyceps militaris breeding, selecting strains containing both mating types, which are insensitive to the proportion of mating-type genes, enhanced stability in subculture and reduced the risk of mating-type loss. Direct breeding of specific single-mating type strains to induce fruiting is thus an effective breeding strategy.

Effect of addition of γ-poly glutamic acid on bacterial nanocellulose production under agitated culture conditions.

BACKGROUND: Bacterial nanocellulose (BNC), a natural polymer material, gained significant popularity among researchers and industry. It has great potential in areas, such as textile manufacturing, fiber-based paper, and packaging products, food industry, biomedical materials, and advanced functional bionanocomposites. The main current fermentation methods for BNC involved static culture, as the agitated culture methods had lower raw material conversion rates and resulted in non-uniform product formation. Currently, studies have shown that the production of BNC can be enhanced by incorporating specific additives into the culture medium. These additives included organic acids or polysaccharides. γ-Polyglutamic acid (γ-PGA), known for its high polymerization, excellent biodegradability, and environmental friendliness, has found extensive application in various industries including daily chemicals, medicine, food, and agriculture. RESULTS: In this particular study, 0.15 g/L of γ-PGA was incorporated as a medium additive to cultivate BNC under agitated culture conditions of 120 rpm and 30 â„ƒ. The BNC production increased remarkably by 209% in the medium with 0.15 g/L γ-PGA and initial pH of 5.0 compared to that in the standard medium, and BNC production increased by 7.3% in the medium with 0.06 g/L γ-PGA. The addition of γ-PGA as a medium additive resulted in significant improvements in BNC production. Similarly, at initial pH levels of 4.0 and 6.0, the BNC production also increased by 39.3% and 102.3%, respectively. To assess the characteristics of the BNC products, scanning electron microscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis were used. The average diameter of BNC fibers, which was prepared from the medium adding 0.15 g/L γ-PGA, was twice thicker than that of BNC fibers prepared from the control culture medium. That might be because that polyglutamic acid relieved the BNC synthesis from the shear stress from the agitation. CONCLUSIONS: This experiment held great significance as it explored the use of a novel medium additive, γ-PGA, to improve the production and the glucose conversion rate in BNC fermentation. And the BNC fibers became thicker, with better thermal stability, higher crystallinity, and higher degree of polymerization (DPv). These findings lay a solid foundation for future large-scale fermentation production of BNC using bioreactors.

An antioxidant hydrogel dressing with wound pH indication function prepared based on silanized bacterial nanocellulose crosslinked with beet red pigment extract.

Maintaining wound moisture and monitoring of infection are crucial aspects of chronic wound treatment. The development of a pH-sensitive functional hydrogel dressing is an effective approach to monitor, protect, and facilitate wound healing. In this study, beet red pigment extract (BRPE) served as a native and efficient pH indicator by being grafted into silane-modified bacterial nanocellulose (BNC) to prepare a pH-sensitive wound hydrogel dressing (S-g-BNC/BRPE). FTIR confirmed the successful grafting of BRPE into the BNC matrix. The S-g-BNC/BRPE showed superior mechanical properties (0.25 MPa), swelling rate (1251 % on average), and hydrophilic properties (contact angle 21.83°). The composite exhibited a notable color change as the pH changed between 4.0 and 9.0. It appeared purple-red when the pH ranged from 4.0 to 6.0, and appeared light pink at pH 7.0 and 7.4, and appeared ginger-yellow at pH 8.0 and 9.0. Subsequently, the antioxidant activity and cytotoxicity of the composite was evaluated, its DPPH·, ABTS+, ·OH scavenging rates were 32.33 %, 19.31 %, and 30.06 %, respectively, and the cytotoxicity test clearly demonstrated the safety of the dressing. The antioxidant hydrogel dressing, fabricated with a cost-effective and easy method, not only showed excellent biocompatibility and dressing performance but could also indicated the wound state based on pH changes.

Transcriptome and metabolome profiling unveils the mechanisms of naphthalene acetic acid in promoting cordycepin synthesis in Cordyceps militaris.

Cordycepin, an important active substance in Cordyceps militaris, possesses antiviral and other beneficial activities. In addition, it has been reported to effectively promote the comprehensive treatment of COVID-19 and thus has become a research hotspot. The addition of naphthalene acetic acid (NAA) is known to significantly improve the yield of cordycepin; however, its related molecular mechanism remains unclear. We conducted a preliminary study on C. militaris with different concentrations of NAA. We found that treatment with different concentrations of NAA inhibited the growth of C. militaris, and an increase in its concentration significantly improved the cordycepin content. In addition, we conducted a transcriptome and metabolomics association analysis on C. militaris treated with NAA to understand the relevant metabolic pathway of cordycepin synthesis under NAA treatment and elucidate the relevant regulatory network of cordycepin synthesis. Weighted gene co-expression network analysis (WGCNA), transcriptome, and metabolome association analysis revealed that genes and metabolites encoding cordycepin synthesis in the purine metabolic pathway varied significantly with the concentration of NAA. Finally, we proposed a metabolic pathway by analyzing the relationship between gene-gene and gene-metabolite regulatory networks, including the interaction of cordycepin synthesis key genes; key metabolites; purine metabolism; TCA cycle; pentose phosphate pathway; alanine, aspartate, and glutamate metabolism; and histidine metabolism. In addition, we found the ABC transporter pathway to be significantly enriched. The ABC transporters are known to transport numerous amino acids, such as L-glutamate, and participate in the amino acid metabolism that affects the synthesis of cordycepin. Altogether, multiple channels work together to double the cordycepin yield, thereby providing an important reference for the molecular network relationship between the transcription and metabolism of cordycepin synthesis.

COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.

COX7A1, a subunit of cytochrome c oxidase, holds an important position in the super-assembly which integrates into multi-unit heteromeric complexes peripherally in the mitochondrial electron transport chain (ETC). Recently, some studies indicated the significant potential of COX7A1 in cancer metabolism and therapy. However, the underlying metabolic process and therapy mechanism remain unclear. In this study, COX7A1-overexpressed cell line was established via lentivirus transduction. The relationship between COX7A1 and ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, was further analyzed in different human non-small-cell lung carcinoma (NSCLC) cells respectively. Our results showed that COX7A1 increased the sensitivity of NSCLC cells to the ferroptosis induced by cysteine deprivation via enhancing the tricarboxylic acid (TCA) cycle and the activity of complex IV in mitochondrial ETC. Meanwhile, COX7A1 suppressed mitochondrial dynamics as well as mitochondrial biogenesis and mitophagy through blocking autophagic flux. The autophagy activator, rapamycin, relieved the autophagic blockage and further strengthened the sensitivity to cysteine deprivation-induced ferroptosis of NSCLC cells in vitro and in vivo. Taken together, our data indicate the close association of COX7A1 with cysteine deprivation-induced ferroptosis, and provide a novel insight into the therapy mode against human NSCLC.

Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment.

Ferroptosis is a novel type of programmed cell death, which is different from apoptosis and autophagic cell death. Recently, ferroptosis has been indicated to contribute to the in vitro neurotoxicity induced by isoflurane, which is one of the most common anesthetics in clinic. However, the in vivo position of ferroptosis in isoflurane-induced neurotoxicity as well as learning and memory impairment remains unclear. In this study, we mainly explored the relationship between ferroptosis and isoflurane-induced learning and memory, as well as the therapeutic methods in mouse model. Our results indicated that isoflurane induced the ferroptosis in a dose-dependent and time-dependent manner in hippocampus, the organ related with learning and memory ability. In addition, the activity of cytochrome c oxidase/Complex IV in mitochondrial electron transport chain (ETC) was increased by isoflurane, which might further contributed to cysteine deprivation-induced ferroptosis caused by isoflurane exposure. More importantly, isoflurane-induced ferroptosis could be rescued by both ferroptosis inhibitor (ferrostatin-1) and mitochondria activator (dimethyl fumarate), which also showed effective therapeutic action against isoflurane-induced learning and memory impairment. Taken together, our data indicate the close association among ferroptosis, mitochondria and isoflurane, and provide a novel insight into the therapy mode against isoflurane-induced learning and memory impairment.

NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway.

Transcription factor nuclear factor-erythroid 2-like 2 (NRF2) mainly regulates cellular antioxidant response, redox homeostasis and metabolic balance. Our previous study illustrated the translational significance of NRF2-mediated transcriptional repression, and the transcription of FOCAD gene might be negatively regulated by NRF2. However, the detailed mechanism and the related significance remain unclear. In this study, we mainly explored the effect of NRF2-FOCAD signaling pathway on ferroptosis regulation in human non-small-cell lung carcinoma (NSCLC) model. Our results confirmed the negative regulation relationship between NRF2 and FOCAD, which was dependent on NRF2-Replication Protein A1 (RPA1)-Antioxidant Response Elements (ARE) complex. In addition, FOCAD promoted the activity of focal adhesion kinase (FAK), which further enhanced the sensitivity of NSCLC cells to cysteine deprivation-induced ferroptosis via promoting the tricarboxylic acid (TCA) cycle and the activity of Complex I in mitochondrial electron transport chain (ETC). However, FOCAD didn't affect GPX4 inhibition-induced ferroptosis. Moreover, the treatment with the combination of NRF2 inhibitor (brusatol) and erastin showed better therapeutic action against NSCLC in vitro and in vivo than single treatment, and the improved therapeutic function partially depended on the activation of FOCAD-FAK signal. Taken together, our study indicates the close association of NRF2-FOCAD-FAK signaling pathway with cysteine deprivation-induced ferroptosis, and elucidates a novel insight into the ferroptosis-based therapeutic approach for the patients with NSCLC.

Long-chain fatty acyl-coenzyme A suppresses hepatitis C virus infection by targeting virion-bound lipoproteins.

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and end-stage liver diseases. Mature HCV virions are bound by host-derived lipoproteins. Lack of an HCV vaccine warrants a major role of antiviral treatment in the global elimination of hepatitis C. Although direct-acting antivirals (DAAs) are replacing the interferon-based treatment and have dramatically improved the cure rate, the presence of viral variants resistant to DAAs, HCV genotype/subtype-specific efficacy, and high cost of DAAs argue novel and affordable regimens. In this study, we identified the antiviral effects of long-chain fatty acyl-coenzyme A (LCFA-CoA) against the infections of HCV genotypes 1-6 through targeting mature HCV-bound lipoproteins, suggesting novel mechanism(s) of antiviral different from those used by host-targeting agents or DAAs. We found that the antiviral activity of LCFA-CoA relied on the long-chain saturated fatty acid and the CoA group, and was enhanced when combined with pegylated-interferon or DAAs. Importantly, we demonstrated that LCFA-CoA efficiently inhibited the infection of HCV variants carrying DAA-resistant mutations. The mechanistic study revealed that LCFA-CoA specifically abolished the attachment and binding steps and also inhibited the cell-to-cell viral transmission. LCFA-CoA targeted mature HCV-bound lipoproteins, but not apolipoproteins B or E. In addition, LCFA-CoA could also inhibit the infection of the dengue virus. Our findings suggest that LCFA-CoA could potentially serve as a supplement HCV therapy, particularly for the DAA-resistant HCV variants. Taken together, LCFA-CoA may be further developed to be a novel class of antivirals with mechanism(s), different from host-targeting agents or DAAs, of targeting the components associated with mature HCV virions.

COX7A1 suppresses the viability of human non-small cell lung cancer cells via regulating autophagy.

COX7A1 is a subunit of cytochrome c oxidase, and plays an important role in the super-assembly that integrates peripherally into multi-unit heteromeric complexes in the mitochondrial respiratory chain. In recent years, some researchers have identified that COX7A1 is implicated in human cancer cell metabolism and therapy. In this study, we mainly explored the effect of COX7A1 on the cell viability of lung cancer cells. COX7A1 overexpression was induced by vector transfection in NCI-H838 cells. Cell proliferation, colony formation and cell apoptosis were evaluated in different groups. In addition, autophagy was analyzed by detecting the expression level of p62 and LC3, as well as the tandem mRFP-GFP-LC3 reporter assay respectively. Our results indicated that the overexpression of COX7A1 suppressed cell proliferation and colony formation ability, and promoted cell apoptosis in human non-small cell lung cancer cells. Besides, the overexpression of COX7A1 blocked autophagic flux and resulted in the accumulation of autophagosome via downregulation of PGC-1α and upregulation of NOX2. Further analysis showed that the effect of COX7A1 overexpression on cell viability was partly dependent of the inhibition of autophagy. Herein, we identified that COX7A1 holds a key position in regulating the development and progression of lung cancer by affecting autophagy. Although the crosstalk among COX7A1, PGC-1α and NOX2 needs further investigation, our study provides a novel insight into the therapeutic action of COX7A1 against human non-small cell lung cancer.

Paracrine action of human placental trophoblast cells attenuates cisplatin-induced acute kidney injury.

AIMS: The action of cell-based therapy against acute kidney injury (AKI) has been demonstrated by different groups for years. However, which kind of cells hold best therapeutic effect remains unclear. In this study, we mainly explored whether human placental trophoblast cells hold the potential to be applied in AKI therapy. MAIN METHODS: To study the renoprotective effect, the trophoblast cells were isolated from human placenta and characterized by flow cytometry first. The AKI model was induced using cisplatin in NOD-SCID mice. The therapeutic effect of human placental trophoblast cells on renal function, apoptosis and inflammation were analyzed respectively. KEY FINDINGS: The administration of trophoblast cells isolated from human placenta improved the pathological changes of kidney tissues and renal dysfunction induced by cisplatin. In addition, the placental trophoblast cell-based treatment also showed anti-apoptotic effect and decreased the level of apoptotic genes (Bax and Caspase 3) expression in damaged kidney tissues obviously. All of the inflammatory components (MCP-1, IL-10 and RANTES) in kidney tissues were down-regulated with the therapy of placental trophoblast cells. Further analysis indicated that the paracrine effects of human placental trophoblast cells may hold a key position in the AKI therapy process. SIGNIFICANCE: In this study, we mainly developed a novel therapeutic strategy to treat cisplatin-induced AKI with human placental trophoblast cells. Even though the detailed mechanism and the optimizations of this cell-based therapy still need further investigation, the application of placental trophoblast cell holds special potential in the treatment of patients with AKI.

Development of an Infectious Cell Culture System for Hepatitis C Virus Genotype 6a Clinical Isolate Using a Novel Strategy and Its Sensitivity to Direct-Acting Antivirals.

Hepatitis C virus (HCV) is classified into seven major genotypes, and genotype 6 is commonly prevalent in Asia, thus reverse genetic system representing genotype 6 isolates in prevalence is required. Here, we developed an infectious clone for a Chinese HCV 6a isolate (CH6a) using a novel strategy. We determined CH6a consensus sequence from patient serum and assembled a CH6a full-length (CH6aFL) cDNA using overlapped PCR product-derived clones that shared the highest homology with the consensus. CH6aFL was non-infectious in hepatoma Huh7.5 cells. Next, we constructed recombinants containing Core-NS5A or 5'UTR-NS5A from CH6a and the remaining sequences from JFH1 (genotype 2a), and both were engineered with 7 mutations identified previously. However, they replicated inefficiently without virus spread in Huh7.5 cells. Addition of adaptive mutations from CH6a Core-NS2 recombinant, with JFH1 5'UTR and NS3-3'UTR, enhanced the viability of Core-NS5A recombinant and acquired replication-enhancing mutations. Combination of 22 mutations in CH6a recombinant with JFH1 5'UTR and 3'UTR (CH6aORF) enabled virus replication and recovered additional four mutations. Adding these four mutations, we generated two efficient recombinants containing 26 mutations (26m), CH6aORF_26m and CH6aFL_26m (designated "CH6acc"), releasing HCV of 104.3-104.5 focus-forming units (FFU)/ml in Huh7.5.1-VISI-mCherry and Huh7.5 cells. Seven newly identified mutations were important for HCV replication, assembly, and release. The CH6aORF_26m virus was inhibited in a dose- and genotype-dependent manner by direct-acting-antivirals targeting NS3/4A, NS5A, and NS5B. The CH6acc enriches the toolbox of HCV culture systems, and the strategy and mutations applied here will facilitate the culture development of other HCV isolates and related viruses.

Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury.

The therapeutic action of umbilical cord-derived mesenchymal stem cells (UC-MSCs) against acute kidney injury (AKI) has been demonstrated by several groups. However, how to further enhance the renoprotective effect of UC-MSCs and improve the therapy effect, are still unclear. In this study, we mainly investigated whether insulin-like growth factor-1 (IGF-1)-modified UC-MSCs hold an enhanced protective effect on gentamicin-induced AKI in vivo. Our results indicated that the IGF-1 overexpression could enhance the therapeutic action of human UC-MSCs, and the AKI rats treated with IGF-1-overexpressed UC-MSCs (UC-MSCs-IGF-1) showed better recovery of biochemical variables in serum or urine associated with renal function, histological injury and renal apoptosis, compared with AKI rats treated with normal UC-MSCs. RNA microarray analysis indicated that some key genes in the signal pathways associated with anti-oxidation, anti-inflammatory, and cell migratory capacity were up-regulated in UC-MSCs-IGF-1, and the results were further confirmed with qPCR. Furthermore, a series of detection in vitro and in vivo indicated that the UC-MSCs-IGF-1 hold better anti-oxidation, anti-inflammatory, and cell migratory capacity for IGF-1 overexpression. Thus, our study indicated that enhancement of UC-MSCs bioactivities with IGF-1 overexpression could increase the UC-MSCs therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells.

AIMS: Umbilical cord derived mesenchymal stem cells (UC-MSCs) have been demonstrated to hold the potential to be applied in the treatment of kinds of disease. In recent years, some scientists have differentiated the cells into neural progenitor cells (NPCs) successfully, providing a new cell source for neural disease therapy. However, the differentiation methods still need to be improved for the clinical studies in the future. In this study, insulin-like growth factor-1 (IGF-1) was tested to ameliorate UC-MSCs neural differentiation. MAIN METHODS: IGF-1 overexpressing UC-MSCs (UC-MSCs-IGF-1) were established through retroviral infection, and further differentiated into NPCs through neural induction. The proliferation and differentiation ability of UC-MSCs derived NPCs were evaluated respectively and the associated signaling mechanisms were further analyzed with RNA microarray, qPCR and western-blot. KEY FINDINGS: Compared with NPCs from normal UC-MSCs, the NPCs derived from UC-MSCs-IGF-1 hold better proliferation ability and more Pax6-positive cells and Nestin-positive cells. Moreover, the UC-MSCs-IGF-1 derived NPCs could differentiate into astrocyte with higher efficiency during the process of terminal differentiation in vitro. RNA microarray analysis indicated that some key genes associated with neural differentiation and NPCs proliferation were upregulated, which were also confirmed with qPCR and western-blot. Finally, NPCs from UC-MSCs-IGF-1 transfected with IGF-1-siRNA showed a decrease of proliferation ability and astrocyte differentiation. SIGNIFICANCE: This study indicated that IGF-1 could improve neural differentiation of human UC-MSCs and provided a novel strategy to enhance astrocyte differentiation of NPCs from UC-MSCs.

Identification of a Potent and Broad-Spectrum Hepatitis C Virus Fusion Inhibitory Peptide from the E2 Stem Domain.

Hepatitis C virus (HCV) envelope proteins E1 and E2 play an essential role in virus entry. However, the fusion mechanisms of HCV remain largely unclear, hampering the development of efficient fusion inhibitors. Here, we developed two cell-based membrane fusion models that allow for screening a peptide library covering the full-length E1 and E2 amino acid sequences. A peptide from the E2 stem domain, named E27, was found to possess the ability to block E1E2-mediated cell-cell fusion and inhibit cell entry of HCV pseudoparticles and infection of cell culture-derived HCV at nanomolar concentrations. E27 demonstrated broad-spectrum inhibition of the major genotypes 1 to 6. A time-of-addition experiment revealed that E27 predominantly functions in the late steps during HCV entry, without influencing the expression and localization of HCV co-receptors. Moreover, we demonstrated that E27 interfered with hetero-dimerization of ectopically expressed E1E2 in cells, and mutational analysis suggested that E27 might target a conserved region in E1. Taken together, our findings provide a novel candidate as well as a strategy for developing potent and broad-spectrum HCV fusion inhibitors, which may complement the current direct-acting antiviral medications for chronic hepatitis C, and shed light on the mechanism of HCV membrane fusion.

Protective effect of vitamin E against acute kidney injury.

It has been well-known for many years now that vitamin E is an essential nutrient; however, some of the physiological functions of this vitamin are still far from being understood. In recent years, a series of preclinical and clinical studies proposed a protective role of vitamin E on acute kidney injury (AKI), which has a high morbidity rate and mortality rate in clinical investigations. Based on the benefits associated with vitamin E, such as strong antioxidant function, low toxicity, rare side-effects, and low cost, this therapy strategy has garnered an extensive amount of interest in the scientific community for the development of new therapy modes against AKI. In this review, a concise overview of the application of vitamin E in the treatment of AKI is provided as well as a summary of a series of published data regarding the combination therapy modes and detailed therapy mechanisms of vitamin E-based therapy against AKI. At present, there are critical points of this therapy mode that are still in need of further clarification, meaning the current understanding of the role of vitamin E in the treatment of AKI remains incomplete. However, the development of more reliable pharmacological or biotechnical strategies with vitamin E for the eventual treatment of patients with AKI may guide the next chapter of vitamin E research.

Therapeutic action of bone marrow-derived stem cells against acute kidney injury.

Acute kidney injury (AKI) is a frequent clinical disease with a high morbidity rate and mortality rate, while the treatment options for this intractable disease are limited currently. In recent years, bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to hold an effect therapeutic action against AKI by scientists gradually, and the cells are capable to localize to renal compartments and contribute to kidney regeneration though differentiation or paracrine action. Especially, the advantages of BMSCs, such as low toxicity and side effect as well as autologous transplantation, endue the cell with a promising potential in clinical therapy against AKI. In this review, we mainly provide a concise overview of the application of BMSCs in the treatment of AKI, and summarize a series of published data regarding the mechanisms and optimizations of the BMSC-based therapy in renal repair after AKI. Even though some critical points about the BMSC-based therapy model still need clarification, we hope to develop more reliable pharmacological or biotechnical strategies utilizing the stem cell for the eventual treatment of humans with AKI, based on these studies and the understanding of mechanism of renal protection by BMSCs.

Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy.

The therapeutic action of bone marrow-derived mesenchymal stem cells (BMSCs) in acute kidney injury (AKI) has been reported by several groups. However, recent studies indicated that BMSCs homed to kidney tissues at very low levels after transplantation. The lack of specific homing of exogenously infused cells limited the effective implementation of BMSC-based therapies. In this study, we provided evidence that the administration of BMSCs combined with muscone in rats with gentamicin-induced AKI intravenously, was a feasible strategy to drive BMSCs to damaged tissues and improve the BMSC-based therapeutic effect. The effect of muscone on BMSC bioactivity was analyzed in vitro and in vivo. The results indicated that muscone could promote BMSC migration and proliferation. Some secretory capacity of BMSC still could be improved in some degree. The BMSC-based therapeutic action was ameliorated by promoting the recovery of biochemical variables in urine or blood, as well as the inhibition of cell apoptosis and inflammation. In addition, the up-regulation of CXCR4 and CXCR7 expression in BMSCs could be the possible mechanism of muscone amelioration. Thus, our study indicated that enhancement of BMSCs bioactivities with muscone could increase the BMSC therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

Study on therapeutic action of bone marrow derived mesenchymal stem cell combined with vitamin E against acute kidney injury in rats.

AIMS: The study aims to investigate the effect to treat acute kidney injury (AKI) with bone marrow derived mesenchymal stem cells (BMSCs) combined with vitamin E and to develop a new treatment mode for AKI preclinical study. MAIN METHODS: BMSCs were separated from rat bone marrow. Gentamicin was used as a damage factor in the culture of renal tubular epithelial cells (RTECs) in vitro. After co-cultured with BMSCs and vitamin E, cell proliferation of each group was detected with CCK-8. In vivo, BMSCs (3.3×10(6)cells/kg) combined with vitamin E (80mg/kg) were administered in AKI rats induced by gentamicin intravenously. The pathological changes, biochemical parameters and apoptosis genes after treatment were investigated furthermore. KEY FINDINGS: In co-cultured system, proliferating ability of RTECs was improved by BMSCs or vitamin E, especially for the combined group (P<0.05). The treated rats in combined group presented the lowest serum creatinine and the highest urea nitrogen compared to non-treated rats. The improvement in renal pathological changes was followed by less necrosis, degeneration and expansion of renal tubule. Under transmission electron microscope, unclear cell structure and reduction of endoplasmic reticulum in the cytoplasm of RTECs were ameliorated with the treatment. Most apoptosis genes were up-regulated in model group while down-regulated with the therapy. Further analysis showed that the two treatments may act independently with each other. SIGNIFICANCE: Our data demonstrated that both BMSC and vitamin E hold therapeutic action to AKI induced by gentamicin. Especially, the combined treatment is better than BMSC or vitamin E alone.