MSC-derived exosomal miR-140-3p improves cognitive dysfunction in sepsis-associated encephalopathy by HMGB1 and S-lactoylglutathione metabolism.

MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1. MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1ß, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE.

[Retracted] Glycyrrhizin protects mice against renal ischemia­reperfusion injury through inhibition of apoptosis and inflammation by downregulating p38 mitogen­activated protein kinase signaling.

[This retracts the article DOI: 10.3892/etm.2014.1570.].

Anoikis-related signature in liver hepatocellular carcinoma defines the YBX1/SPP1 axis by machine learning strategies and valid experiments.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) remains a malignant malignancy with a low cure rate. Anoikis is a newly recognized cancer hallmark. However, an Anoikis-related model has not been clarified in LIHC. METHODS: The Anoikis-related score in the present study was created using Survival Random Forest and least absolute shrinkage and selection operator (LASSO) machine learning algorithms. Anoikis-related scores with respect to mutation analysis, immunological analysis, function annotation, and medication prediction were all thoroughly investigated. RESULTS: The Anoikis-related score accurately predicted the patients' immunological activity, altered genes, and medication sensitivity. SPP1 immunological analysis, function annotation, medication prediction, and immunotherapy prediction were systematically investigated. SPP1 may effectively predict the outcomes of immunotherapy. SPP1 was revealed to be a mediator of LIHC cell proliferation and migration. A putative axis in LIHC was YBX1/SPP1. CONCLUSIONS: Clinical care and the treatment plan for patients with LIHC were anticipated to benefit significantly from the established Anoikis-related score.

Single-Cell RNA Transcriptomics Reveals the State of Hepatic Lymphatic Endothelial Cells in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is an acutely decompensated cirrhosis syndrome with high short-term mortality. Very little is known about the relationship between the lymphatic system and ACLF. We explored the role of hepatic lymphatic vessels (LVs) and lymphatic endothelial cells (LyECs) in ACLF using human liver samples with the help of single-cell RNA-sequencing (scRNA-seq) technology. Here, ACLF exhibited more severe liver injury and inflammation than cirrhosis, as indicated by significant increases in plasma levels of alanine/aspartate aminotransferases and total bilirubin. Compared with cirrhosis cases, the number of intrahepatic LVs was decreased significantly in ACLF patients. ScRNA-seq revealed that many monocyte/macrophages infiltrated into the liver of ACLF cases. Meanwhile, scRNA-seq revealed a group of apoptotic and dysfunctional LyECs, which were the result of secreted phosphoprotein 1 (SPP1) released from infiltrating monocyte/macrophages. In vitro, SPP1 increased the proportion of dead LyECs significantly and impaired the ability of tube formation of LyECs in a dose- and time-dependent manner. In conclusion, ACLF is associated with less LV and LyEC dysfunction, at least in part mediated by SPP1 released from infiltrating monocyte/macrophages. Hepatic LVs and LyECs can be a novel therapeutic strategy for ACLF.

The Potential Role of Schistosome-Associated Factors as Therapeutic Modulators of the Immune System.

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.

Gypenoside attenuates renal ischemia/reperfusion injury in mice by inhibition of ERK signaling.

Gynostemma pentaphyllum is a traditional Chinese medicine reported to possess a wide range of health benefits. As the major component of G. pentaphyllum, gypenoside (GP) displays various anti-inflammatory and anti-oxidant properties. However, it is unclear whether GP can protect against ischemia/reperfusion (I/R)-induced renal injury, and the underlying molecular mechanisms associated with this process remain unknown. In the present study, a renal I/R injury model in C57BL/6 mice was established. It was observed that, following I/R, serum concentrations of creatinine (Cr) and blood urea nitrogen (BUN) were significantly increased (P<0.01), indicating renal injury. Pretreatment with GP (50 mg/kg) significantly inhibited I/R-induced upregulation of serum Cr and BUN (P<0.01). Furthermore, renal malondialdehyde levels were significantly reduced in the I/R+GP group, compared with the I/R group (P<0.01), whereas renal tissue superoxide dismutase activity was significantly higher in the I/R+GP group compared with the I/R group (P<0.01). Further investigation demonstrated that pretreatment with GP produced inhibitory effects on the I/R-induced production of pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and interferon-γ (P<0.01). In addition, heme oxygenase 1 (HO-1) expression levels were significantly increased in the I/R group compared with the control (P<0.01), indicating the presence of oxidative damage. However, the I/R-induced upregulation of HO-1 was significantly attenuated by pretreatment with GP (P<0.01), which also suppressed I/R-induced apoptosis by inhibiting pro-apoptotic Bax and upregulating anti-apoptotic Bcl-2 in renal cells (P<0.01). Finally, the activity of ERK signaling was significantly increased in the I/R+GP group compared with the I/R group (P<0.05), which may be associated with the protective effect of GP against I/R-induced renal cell apoptosis. To conclude, the present results suggest that GP produces a protective effect against I/R-induced renal injury as a result of its anti-inflammatory and anti-apoptotic properties.

MicroRNA­144 suppresses tumorigenesis of hepatocellular carcinoma by targeting AKT3.

Aberrant expression of microRNAs (miRNAs) has been shown to be associated with the progression and metastasis of cancer. Dysregulation of miR­144 has been observed in numerous types of cancer; however, the exact role of miR­144 in hepatocellular carcinoma (HCC) remains unclear. The present study observed that miR­144 was downregulated in HCC tissues and cell lines. Forced overexpression of miR­144 suppressed proliferation, migration and invasion of HCC cells. AKT3 was identified as a direct target of miR­144 in HCC, and this was confirmed by a luciferase activity assay and western blot analysis. Overexpression of AKT3 in miR­144 transfected HCC cells effectively reversed the tumor suppressive effects of miR­144. Furthermore, AKT3 expression levels were inversely correlated with miR­144 expression levels in HCC tissues. In conclusion, the results of the present study suggest that miR­144 may act as a tumor suppressor in HCC by targeting AKT3, and miR­144 may be a potential therapeutic candidate for HCC.

Outcome of kidney transplantation between controlled cardiac death and brain death donors: a meta-analysis.

BACKGROUND: Our goal was to evaluate the outcomes of kidney transplants from controlled cardiac death donors compared with brain death donors by conducting a meta-analysis of cohort studies. METHODS: The PubMed database and EMBASE were searched from January 1980 to July 2013 to identify studies that met pre-stated inclusion criteria. Reference lists of retrieved articles were also reviewed. Two authors independently extracted information on the designs of the studies, the characteristics of the study participants, and outcome assessments. RESULTS: Nine cohort studies involving 84 398 participants were included in this meta-analysis; 3 014 received kidneys from controlled cardiac death donors and 80 684 from brain death donors. Warm ischemia time was significantly longer for the controlled cardiac death donor group. The incidence of delayed graft function was 2.74 times (P < 0.001) greater in the controlled cardiac death donor group. The results are in favor of the brain death donor group on short-term patient and graft survival while this difference became nonsignificant at mid-term and long term. Sensitivity analysis yielded similar results. No evidence of publication bias was observed. CONCLUSION: This meta-analysis of retrospective cohort studies suggests that the outcome after controlled cardiac death donors is comparable with that obtained using kidneys from brain death donors.

miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7.

Accumulating evidence shows that microRNAs (miRNAs) are involved in the development and progression of multiple tumors, including hepatocellular carcinoma (HCC). Recent studies have found that miR-24 acts as an oncogene in several tumors; however, the function of miR-24 in HCC remains unclear. In this study, we found that miR-24 was increased in HCC tissues and cell lines. Inhibition of miR-24 by inhibitor significantly suppressed HCC cells proliferation, migration, and invasion. Furthermore, the sex-determining region Y (SRY)-box 7 (SOX7), a putative tumor suppressor, was found to be a target of miR-24 in HCC cells. Forced expression of SOX7 substantially attenuated the oncogenic effects of miR-24. Those results strongly suggest that miR-24 plays important role in HCC development partially by targeting SOX7.

Glycyrrhizin protects mice against renal ischemia-reperfusion injury through inhibition of apoptosis and inflammation by downregulating p38 mitogen-activated protein kinase signaling.

Ischemia-reperfusion (I/R) often leads to acute kidney injury, chronic renal failure and kidney transplantation failure. Glycyrrhizin is extracted from Glycyrrhiza glabra roots and is the predominant active component, which exhibits anti-inflammatory effects. However, to the best of our knowledge, the effect of glycyrrhizin on I/R-induced renal injury has not been investigated. In the present study, glycyrrhizin was demonstrated to attenuate renal I/R injury in mice via administration of glycyrrhizin, which suppressed the serum levels of creatinine and blood urea nitrogen 6 h following reperfusion; furthermore, the superoxide anions as well as the activity of superoxide dismutase within renal tissues was reduced by glycyrrhizin pretreatment. Moreover, the protein level of cleaved caspase-3, as well as its activity in renal tissue, was suppressed as a result of the glycyrrhizin pretreatment, indicating that glycyrrhizin inhibits I/R-induced renal cell apoptosis. In addition, glycyrrhizin pretreatment appeared to ameliorate I/R-induced renal injury via inhibition of inflammatory cell infiltration, as well as the production of pro-inflammatory cytokines, including tumor necrosis factor-α, interferon-γ, interleukin (IL)-1ß and IL-6. The underlying molecular mechanism was investigated and it was shown that the activity of p38 mitogen-activated protein kinase signaling was downregulated as a result of glycyrrhizin administration. In conclusion, the present study indicated that glycyrrhizin provided significant protection against I/R-induced renal injury in mice by inhibiting inflammatory responses and renal cell apoptosis. Therefore, glycyrrhizin may be used in abdominal surgery and kidney transplantation for the prevention of renal I/R damage.

[Gene polymorphisms of CYP3A5 and MDR-1 in Hans renal transplant recipients in Hunan Province].

OBJECTIVE: To identify the polymorphisms of cytochrome P450 3A5 gene (CYP3A5) and multidrug resistance gene 1 (MDR-1) and their distributions in Hans renal transplant recipients in Hunan province, we analyzed the difference of the gene polymorphisms and distributions between Hunan province and 11 other provinces of China. METHODS: We collected 598 Hans renal transplant recipients who had operation or follow-up examination in 3rd Xiangya Hospital from Hunan province. We examined the gene polymorphisms of CYP3A5 and MDR-1 and compared their distributions with the data from 11 other provinces of China by chi-square test. RESULTS: There were CYP3A5*1/*1 genotype in 58 cases (9.7%), CYP3A5*1/*3 genotype in 251 cases (42.0%), CYP3A5*3/*3 genotype in 289 cases (48.3%); MDR-1 3435CC genotype in 238 cases (39.8%), MDR-1 3435CT genotype in 263 cases (44.0%), MDR-1 3435TT genotype in 97 cases (16.2%). Frequency of CYP3A5*1/*1 and *1/*3 genotypes of Hunan province was higher than the that from the 11 other provinces of China and the frequency of mutator *3 was lower. Frequency of MDR-1 3435CC and 3435CT genotypes of Hunan province was higher and the frequency of mutator T was lower than that from the 11 other provinces of China. CONCLUSIONS: There were significant difference in gene polymorphisms and distributions of CYP3A5 and MDR-1 between Hunan province and the 11 other provinces of China. It may be a guideline for us to use calcineurin inhibitor drugs in the early stage after renal transplantation.

[Delayed graft function after DCD kidney transplantation: risk factors for and impact on transplantation].

OBJECTIVE: To evaluate the risk factors of delayed graft function (DGF) and its impact on renal transplantation from donation after cardiac death (DCD). METHODS: We conducted a retrospective study consisting of 48 subjects who underwent a DCD kidney transplantation from February 2010 to March 2012. We classified the recipients into two groups: an IGF (immediate graft function) group (n=30) and a DGF group (n=18), and analyzed the risk factors of DGF and its impact on transplantation. RESULTS: DGF occurred in 18 of the 48 (37.5%) kidneys from DCD donors, and the occurrence of DGF did not adversely influence the survival of patients (P=0.098) and graft (P=0.447). In the univariate analysis, the preoperative dialysis time of recipients (P<0.001), HLA mismatch site (P<0.001), the cause of brain death (P=0.011), BMI (P<0.001), preoperative serum creatinine of donors (P=0.0001), norepinephrine used in donors (P<0.001), warm ischema time (WIT) (P<0.001), cold ischema time (CIT) (P<0.001) showed significant differences. In the multivariate analysis, cerebral hemorrhage as the cause of brain death (P=0.022, OR=39.652), preoperative serum creatinine of donors≥177 µmol/L (P=0.008, OR=57.148) and the preoperative dialysis time of recipients≥12 months (P=0.060, OR=15.060) were independent risk factors for DGF development. CONCLUSION: The independent risk factors for DGF are the cause of brain death, the terminal creatinine level, and the preoperative dialysis time.

Risk factors for delayed graft function in cardiac death donor renal transplants.

BACKGROUND: Delayed graft function (DGF) is common in kidney transplants from organ donation after cardiac death (DCD) donors. It is associated with various factors. Determination of center-specific risk factors may help to reduce the incidence of DGF and improve the transplantation results. The aim of this study is to define risk factors of DGF after renal transplantation. METHODS: From March 2010 to June 2012, 56 cases of recipients who received DCD kidneys were selected. The subjects were divided into two groups: immediate graft function (IGF) and DGF groups. Transplantation factors of donors and recipients as well as early post-transplant results of recipients were compared between the two groups. RESULTS: On univariate analysis, preoperative dialysis time of recipients (P < 0.001), type of dialysis (P = 0.039), human leucocyte antigen (HLA) mismatch sites (P < 0.001), the cause of brain death (P = 0.027), body mass index (BMI) of donors (P < 0.001), preoperative infection (P = 0.002), preoperative serum creatinine of donors (P < 0.001), norepinephrine used in donors (P < 0.001), cardiopulmonary resuscitation (CPR) of donors (P < 0.001), warm ischemia time (WIT) (P < 0.001) and cold ischemia time (CIT) (P < 0.001) showed significant differences. Recipients who experienced DGF had a longer hospital stay, and higher level of postoperative serum creatinine. CONCLUSION: Multiple risk factors are associated with DGF, which had deleterious effects on the early post-transplant period.

Hepatic veins anatomy and piggy-back liver transplantation.

BACKGROUND: The piggy-back caval anastomosis technique is widely used in orthotopic liver transplantation although it carries an increased risk of complications, including outflow obstruction and Budd-Chiari syndrome. The aim of this study is to clarify the anatomy and variations of hepatic veins (HVs) draining into the inferior vena cava (IVC), and to classify the surgical techniques of piggy-back liver transplantation (PBLT) based on the anatomy of HVs which can reduce the occurrence of complications. METHODS: PBLT was performed in 248 consecutive cases at our hospital from January 2004 to August 2011. The anatomy of recipients' HVs was determined when removing the native diseased livers. Both anatomy of HVs and short HVs draining into the IVC were recorded. These data were collected and analyzed. RESULTS: We classified anatomic variations of HVs in the 248 livers into five types according to the way of drainage into the IVC: type I (trunk type of left and middle HVs), 142 (57.3%) patients; type II (trunk type of right and middle HVs), 54 (21.8%); type III (trunk type of left, middle and right HVs), 14 (5.6%); type IV (non-trunk type of left, middle and right HVs), of which, type IVa, 16 (6.5%), in the same horizontal plane; type IVb, 18 (7.3%), in different horizontal planes; and type V (segment type), 4 (1.6%). The patients whose HVs anatomy belonged to types I, II and III underwent classical piggy-back liver transplantation. Type IVa patients had classical PBLT via HV venoplasty prior to piggy-back anastomosis, while type IVb patients and type V patients could only have modified PBLT. CONCLUSION: This study demonstrates that HVs can be classified according to the anatomy of their drainage into the IVC and we can use this classification to choose the best operative approach to PBLT.

[Clinical analysis of 48 cases of kidney transplantation from cardiac death donors].

OBJECTIVE: To evaluate the recovery of patients with end-stage renal disease (ESRD) receiving kidney transplant from cardiac death donors, and to assess graft survival in China from this type of donor. METHODS: A total of 48 cases of patients with ESRD have received the kidneys from cardiac death donors in our hospital between February 2010 and March 2012. We retrospectively analyzed data on the preoperative and postoperative serum creatinine concentrations, on the survival of recipients and allografts with a view to investigating prognoses after this type of kidney transplant. RESULTS: Primary non-function (PNF) did not occur in any of the 48 recipients. Delayed graft function (DGF) occurred in 18 of 48 (37.5%) of kidneys from cardiac death donors, but the occurrence of DGF did not adversely influence patient's survival (P=0.098) or graft survival (P=0.447). Seven of 48 (14.6%) recipients lost their graft. Over a median follow-up period of 8 months (range 0.5-23 months), 39 of 41(95.1%) recipients' graft function had fully recovered. The actuarial graft and patient's survival rates at 1, 3, 6 and 12 months after transplantation were 95.7%, 93.0%, 90.0%, 87.5%, and 100%, 94.9%, 90%, 87.5%, respectively. CONCLUSION: As the legislation of donation after brain death (DBD) has not been ratified in China, the use of kidneys from cardiac death donors might be an effective way to increase the number of kidneys available for transplantation here. Our experience indicates good short- and mid-term outcomes with transplants from cardiac death donors.

[Piggy-back liver transplantation in treating acute liver failure patients: a report of 15 cases].

OBJECTIVE: To study the clinical significance of piggy-back liver transplantation in treating acute liver failure (ALF). METHODS: Fifteen ALF patients (13 caused by HBV and 2 with acute Wilson disease) had piggy-back liver transplantations (PBLT) in our hospital from Sept 1999 to Feb 2006. The outcomes of these patients were retrospectively analyzed. RESULTS: One year survival rate of the 15 patients was 87% (13/15). Excellent outcome was achieved in the 2 acute Wilson disease cases: their corneal Kayser-Fleischer rings disappeared and serum ceruloplasmin levels returned to normal. Among the 15 cases, one died of severe pulmonary infection and another died of multiple organ system failure on the 6th and 11th postoperative days. HBsAg positivity was observed in 13 cases before liver transplantation. Eleven patients survived and later received anti-HBV treatment recommended by the American Association for the Study of Liver Diseases. Their HBsAg became negative. CONCLUSION: Liver transplantation is an effective therapy for ALF and can improve survival rate significantly.