Validation of the kidney donor profile index (KDPI) for deceased donor kidney transplants in China.

BACKGROUND: The kidney donor profile index (KDPI) evaluates kidney donor's age, height, weight, ethnicity, cause of death, high blood pressure, diabetes, exposure to hepatitis C and estimated glomerular filtration (eGFR). Kidneys with lower KDPI scores are expected to function longer that those with higher KPDI values. The applicability of KDPI score in Chinese kidney transplant donation has not yet been validated. This study evaluated the prognostic value of KDPI score in Chinese kidney transplant patients. METHODS: A retrospective analysis was conducted on 184 deceased donors and 353 corresponding kidney transplant patients at the Organ Transplantation Department of Renmin Hospital of Wuhan University between 2018 and 2021. The donors and recipients were stratified into four groups based on their KDPI score: KDPI 85-100, KDPI 60-84, KDPI 21-59, and KDPI 0-20. RESULTS: As expected, the KDPI 85-100 group was associated with a poor short-term renal function (both postoperative creatinine and eGFR with P > 0.05), a higher incidence of delayed graft function (DGF; 25.5% for KDPI 85-100 group vs. 10.2% for KDPI 60-84 group vs. 5.4% for KDPI 21-59 group vs. 0 for KDPI 0-20 group, all P > 0.05). Furthermore, the same groups showed worse 3-year patient survival rate: 86.3% for KDPI 85-100 group vs. 97.01% for KDPI 60-84 group vs. 97.83% for KDPI 21-59 group vs. 100% for KDPI 0-20 group, all P > 0.05); and renal survival rate: 82.6% for KDPI 85-100 group vs. 92.99% KDPI 60-84 group vs.97.83% for KDPI 21-59 group vs. 100% for KDPI 0-20 group, all P > 0.05). Our analysis showed that the KDPI score had a good predictive value for the survival of kidney transplants and patients in our center (area under the curve: 0.728 and 0.76, P > 0.05). CONCLUSION: We recommend that the KDPI scoring system can be employed as an effective tool to predict kidney transplantation outcomes in deceased donation in China.

Hepatocellular SETDB1 Regulates Hepatic Ischemia-Reperfusion Injury through Targeting Lysine Methylation of ASK1 Signal.

Background: Hepatic ischemia-reperfusion injury (HIRI) stands as an unavoidable complication arising from liver surgery, profoundly intertwined with its prognosis. The role of lysine methyltransferase SET domain bifurcated 1 (SETDB1) in HIRI remains elusive, despite its confirmation as a potential therapeutic target for diverse diseases. Here, we investigated the mechanism by which SETDB1 regulated HIRI. Methods: RNA sequencing data were used to identify the expression and potential targets of SETDB1 through bioinformatics analysis. To elucidate the impact of SETDB1 on HIRI, both an in vivo model of HIRI in mice and an in vitro model of hepatocyte hypoxia/reoxygenation were established. Biochemical and histological analyses were used to investigate the influence of SETDB1 on liver damage mediated by HIRI. Chromatin immunoprecipitation and coimmunoprecipitation were implemented to explore the in-depth mechanism of SETDB1 regulating HIRI. Results: We confirmed that hepatocellular SETDB1 was up-regulated during HIRI and had a close correlation with HIRI-related inflammation and apoptosis. Moreover, inhibition of SETDB1 could mitigate HIRI-induced liver damage, inflammation, and apoptosis. Through our comprehensive mechanistic investigation, we revealed that SETDB1 interacts with apoptosis-signal-regulating kinase 1 (ASK1) and facilitates the methylation of its lysine residues. Inhibition of SETDB1 resulted in reduced phosphorylation of ASK1, leading to a marked suppression of downstream c-Jun N-terminal kinase (JNK)/p38 signaling pathway activation. The therapeutic effect on inflammation and apoptosis achieved through SETDB1 inhibition was nullified by the restoration of JNK/p38 signaling activation through ASK1 overexpression. Conclusions: The findings from our study indicate that SETDB1 mediates lysine methylation of ASK1 and modulates the activation of the ASK1-JNK/p38 pathway, thus involved in HIRI-induced inflammation and apoptosis. These results suggest that SETDB1 holds promise as a potential therapeutic target for mitigating HIRI.

Co-Exposure of Polycyclic Aromatic Hydrocarbons and Phthalates with Blood Cell-Based Inflammation in Early Pregnant Women.

Cumulative evidence has demonstrated that exposure to polycyclic aromatic hydrocarbons (PAHs) or phthalates (PAEs) contributes to a variety of adverse health effects. However, the association of PAHs and PAEs co-exposure with blood cell-based inflammatory indicators during early pregnancy is still unclear. We aimed to investigate the single and mixed associations of exposure to PAHs and PAEs with blood cell-based inflammatory indicators among early pregnant women. A total of 318 early pregnant women were included in this study. General linear regressions were used to estimate the relationships of individual OH-PAHs and mPAEs with blood cell-based inflammatory indicators. The key pollutants were selected by an adapted least absolute shrinkage and selection operator (LASSO) penalized regression model and wasemployed to build the Bayesian kernel machine regression (BKMR) and quantile g-computation (Q-g) models, which can assess the joint association of OH-PAHs and mPAEs with blood cell-based inflammatory indicators. General linear regression indicated that each 1% increase in MOP was associated with a 4.92% (95% CI: 2.12%, 7.68%), 3.25% (95% CI: 0.50%, 6.18%), 5.87% (95% CI: 2.22%, 9.64%), and 6.50% (95% CI: 3.46%, 9.64%) increase in WBC, lymphocytes, neutrophils, and monocytes, respectively. BKMR and Q-g analysis showed that the mixture of OH-PAHs and mPAEs was linked with increased levels of white blood cells (WBC), neutrophils, monocytes, and lymphocytes, and MOP was identified as the dominant contributor. OH-PAHs and mPAEs co-exposure in early pregnancy was associated with elevated blood cell-based inflammatory indicators reactions. More attention should be paid to the inflammation induced by environmental pollution for perinatal women, especially early pregnant women.

Single and Joint Associations of Polycyclic Aromatic Hydrocarbon Exposure with Liver Function during Early Pregnancy.

The individual and combined associations of polycyclic aromatic hydrocarbons (PAHs) metabolites on liver function during pregnancy are still lacking. We aimed to explore the connection between urinary PAH metabolites and liver function in early pregnant women in southwest China based on the Zunyi birth cohort. Ten urinary PAH metabolites and five liver function parameters during early pregnancy were measured. The associations of single PAHs with parameters of liver function were assessed using multiple linear regression. A Bayesian kernel machine regression (BKMR) model was used to evaluate the joint associations of the PAH mixture with outcomes. We found that each 1% increment of urinary 2-hydroxyphenanthrene (2-OH-PHE) was associated with 3.36% (95% CI: 0.40%, 6.40%) higher alanine aminotransferase (ALT) and 2.22% (95% CI: 0.80%, 3.67%) higher aspartate aminotransferase (AST). Each 1% increment in 1-hydroxy-phenanthrene (1-OH-PHE) was significantly associated with 7.04% (95% CI: 1.61%, 12.75%) increased total bile acid (TBA). Additionally, there was a significant positive linear trend between 2-OH-PHE and AST and 1-OH-PHE and TBA. BKMR also showed a significant positive association of PAH mixture with AST. Our results indicate that PAH metabolites were associated with increased parameters of liver function among early pregnant women. Early pregnant women should pay more attention to the adverse relationships between PAHs and liver function parameters to prevent environment-related adverse perinatal outcomes.

The utilization of nanopore targeted sequencing proves to be advantageous in the identification of infections present in deceased donors.

Background: Nanopore Target Sequencing (NTS) represents a novel iteration of gene sequencing technology; however, its potential utility in the detection of infection in deceased donors has yet to be documented. The present study endeavors to assess the applicability of NTS in this domain. Methods: This retrospective study comprised a cohort of 71 patients who were under intensive care at Renmin Hospital of Wuhan University between June 2020 and January 2022. The specimens were subjected to microbiological tests utilizing NTS, culture, and other techniques, and subsequently, the diagnostic accuracy of NTS was compared with conventional methods. Results: Blood NTS exhibited a better agreement rate of 52.11% and a greater positive rate of pathogen detection than blood culture (50.70% vs. 5.63%, p < 0.001). In NTS of deceased donors, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii were the most frequently found bacteria, and Candida was the most frequently found fungus. Blood NTS had a considerably better sensitivity for detecting clinical bloodstream infection than blood culture (62.50%: 7.14%, p < 0.001). These findings were supported by comparisons between blood NTS and conventional microbial detection methods (such as blood culture, glucan testing, galactomannan testing, T cell spot testing for tuberculosis infection, smear, etc.). Conclusion: The pathogen detection technology NTS has a high sensitivity and positive rate. It can more accurately and earlier detect infection in deceased donors, which could be very important for raising the donation conversion rate.

A comprehensive survival and prognosis analysis of GPR55 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype, accounting for about 90% of all primary liver cancers. The liver is rich in a large number of immune cells, thus forming a special immune microenvironment, which plays a key role in the occurrence and development of hepatocellular carcinoma. Nowadays, tumor immunotherapy has become one of the most promising cancer treatment methods. Immune checkpoint inhibitors (ICIs) combined with VEGF inhibitors are listed as first-line treatment options for advanced HCC. Therefore, the search for a potential biomarker to predict the response to immunotherapy in HCC patients is urgently needed. The G protein-coupled receptor 55 (GPR55), a lysophosphatidylinositol (LPI) receptor, has recently emerged as a potential new target for anti-tumor therapy. Previous studies have found that GPR55 is highly expressed in breast cancer, pancreatic cancer, skin cancer and cholangiocarcinoma, and is involved in tumor proliferation and migration. However, the role and mechanism of GPR55 in HCC has not been elucidated. Therefore, this article discusses the clinical significance of GPR55 in HCC and its correlation with the immune response of HCC patients, so as to provide theoretical basis for improving the prognosis of HCC.

Ubiquitin-specific protease 29 attenuates hepatic ischemia-reperfusion injury by mediating TGF-ß-activated kinase 1 deubiquitination.

Background and aims: In the course of clinical practice, hepatic ischemia/reperfusion (I/R) injury is a prevalent pathophysiological event and is caused by a combination of complex factors that involve multiple signaling pathways such as MAPK and NF-κB. USP29 is a deubiquitinating enzyme important during the development of tumors, neurological diseases, and viral immunity. However, it is unknown how USP29 contributes to hepatic I/R injury. Methods and results: We systematically investigated the role of the USP29/TAK1-JNK/p38 signaling pathway in hepatic I/R injury. We first found reduced USP29 expression in both mouse hepatic I/R injury and the primary hepatocyte hypoxia-reoxygenation (H/R) models. We established USP29 full knockout mice (USP29-KO) and hepatocyte-specific USP29 transgenic mice (USP29-HTG), and we found that USP29 knockout significantly exacerbates the inflammatory infiltration and injury processes during hepatic I/R injury, whereas USP29 overexpression alleviates liver injury by decreasing the inflammatory response and inhibiting apoptosis. Mechanistically, RNA sequencing results showed the effects of USP29 on the MAPK pathway, and further studies revealed that USP29 interacts with TAK1 and inhibits its k63-linked polyubiquitination, thereby preventing the activation of TAK1 and its downstream signaling pathways. Consistently, 5z-7-Oxozeaneol, an inhibitor of TAK1, blocked the detrimental effects of USP29 knockout on H/R-induced hepatocyte injury, further confirming that USP29 plays a regulatory role in hepatic I/R injury by targeting TAK1. Conclusion: Our findings imply that USP29 is a therapeutic target with promise for the management of hepatic I/R injury via TAK1-JNK/p38 pathway-dependent processes.

MAPK Signaling Pathways in Hepatic Ischemia/Reperfusion Injury.

The mitogen-activated protein kinase signaling pathway can be activated by a variety of growth factors, cytokines, and hormones, and mediates numerous intracellular signals related to cellular activities, including cell proliferation, motility, and differentiation. It has been widely studied in the occurrence and development of inflammation and tumor. Hepatic ischemia-reperfusion injury (HIRI) is a common pathophysiological phenomenon that occurs in surgical procedures such as lobectomy and liver transplantation, which is characterized by severe inflammatory reaction after ischemia and reperfusion. In this review, we mainly discuss the role of p38, ERK1/2, JNK in MAPK family and TAK1 and ASK1 in MAPKKK family in HIRI, and try to find an effective treatment for HIRI.

A case report of two Chinese monozygotic twins with NPHP1 gene-associated nephronophthisis undergoing kidney transplantation from a related living-donor.

BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most common hereditary disease leading to end-stage renal disease in children and adolescents. The NPHP1 gene was the first NPHP gene to be discovered. Pathogenic variation of the NPHP1 gene can cause juvenile renal wasting disease type 1. CASE PRESENTATION: Here, we report the first case of living related kidney transplantation of monozygotic twins with NPHP1 nephronophthisis in China; one of these cases involved cross-blood type kidney transplantation. Our experience shows that patients with NPHP1 nephronophthisis have almost no risk recurrent kidney disease following living related kidney transplantation and genetic testing. The two twins recovered well without any complications. CONCLUSIONS: This is the first report of living related kidney transplantation of monozygotic twins with heterozygous deletion of the NPHP1 gene in a Chinese family with NPHP. In addition, genetic testing provides an efficient means of evaluating the safety of living related kidney transplantation in patients with NPHP1 nephronophthisis.

Meta-analysis of echinocandins combined with trimethoprim-sulfamethoxazole for treatment of Pneumocystis pneumonia.

Echinocandins form a new drug class for the treatment of Pneumocystis pneumonia (PCP), but their efficacies have not been confirmed. The objective of this study was to review the all-cause mortality and efficacy of echinocandins combined with trimethoprim/sulfamethoxazole (TMP/SMZ) for the treatment of PCP. A meta-analysis of retrospective case-control studies of echinocandins combined with TMP/SMZ or TMP/SMZ alone for treating adult PCP was performed. Pubmed, Web of Sciences, Cochrane Register of Controlled Trials, and Embase databases were searched from inception to October 20, 2021. The quality of the included studies was assessed using the Newcastle-Ottawa scale (NOS). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a fixed effects model in the meta-analysis to derive pooled estimates of effect size. Five-hundred forty articles were identified and screened, and five studies were included meta-analysis. Echinocandins combined with TMP/SMZ led to a reduction in all-cause mortality of pneumocystis pneumonia (OR = 0.47; 95%CI 0.32-0.71; P = 0.0003), and the total positive response rate of echinocandins combined with TMP/SMZ was higher than that of TMP/SMZ (OR = 2.16; 95%CI 1.46-3.19; P = 0.0001). This meta-analysis based on retrospective case-control studies was first to show that echinocandins combined with TMP/SMZ for the treatment of pneumocystis pneumonia can lead to a reduction in mortality and improvement in treatment response rates. It is suggested that echinocandins may be a good drug for treating PCP.

Single-center retrospective analysis of Pneumocystis jirovecii pneumonia in patients after deceased donor renal transplantation.

OBJECTIVE: To investigate the clinical features, early diagnosis, and treatment methods of Pneumocystis jirovecii pneumonia (PJP) after renal transplantation (RT). METHODS: We retrospectively analyzed the clinical data of 80 patients with confirmed PJP who underwent RT between 2018 and 2021 in our hospital. RESULTS: In the present study, the incidence of PJP was 6.2% (80/1300). A 50% of cases (40 out of 80 patients) had developed a PJP infection during the first 6 months after RT and 81.3% (65 out of 80 patients) within 12 months. The median onset time of PJP was 6.5 months after RT. The most common symptom was fever (73.8%), followed by progressive dyspnea (51.3%) and dry cough (31.3%). In the initial phase of PJP, the most frequent CT finding was the presence of diffuse ground-grass shadows. In all, 27.5%, 37.5%, and 35% patients were diagnosed by induced sputum metagenomic next-generation sequencing (mNGS), peripheral blood mNGS, and characteristic clinical diagnostic features, respectively. The median 1,3-ß-D-glucan level was 500 pg/mL, while the median C-reactive protein level was 63.4 mg/L. In most patients (83.8%), the procalcitonin levels were negative. The mean serum creatinine level was 171.9 ± 87.4 µmol/L. Of the 80 patients, 37 (46.2%) had coexisting cytomegalovirus (CMV) infection. All patients were treated with trimethoprim-sulfamethoxazole and third generation cephalosporin to prevent bacterial infection. The methylprednisolone dose (40-120 mg/d) varied according to illness. CONCLUSION: PJP usually occurs within 1 year after RT, typically within 6 months. Fever, dry cough, and progressive dyspnea are the most common clinical symptoms. PJP should be highly suspected if the patient has clinical symptoms and diffuse, patchy, ground-glass opacities on CT in both lungs after RT within 1 year. Peripheral blood or induced sputum mNGS is helpful for early diagnosis of PJP. Trimethoprim-sulfamethoxazole is still the first choice for the treatment of PJP. Combined use of caspofungin can reduce the dose and adverse reactions of trimethoprim-sulfamethoxazole in theory.

Clinical Manifestations and Outcomes of Renal Transplantation Patients With Pneumocystis jirovecii Pneumonia and Cytomegalovirus Co-infection.

Background: Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection are common opportunistic infections among renal transplantation (RT) recipients, and both can increase the risk of graft loss and patient mortality after RT. However, few studies had evaluated PJP and CMV co-infection, especially among RT patients. Therefore, this study was performed to evaluate the impact of CMV co-infection with PJP among RT recipients. Methods: We retrospectively analyzed the clinical data of patients with confirmed diagnosis of PJP between 2015 and 2021 in our hospital. We divided patients into PJP and PJP+CMV groups according to their CMV infection status, and the clinical severity and outcomes of the two groups were evaluated. Results: A total of 80 patients after RT were diagnosed with PJP. Of these, 37 (46.2%) patients had co-existing CMV viremia. There were no statistically significant intergroup differences in age, sex, diabetes, onset time of PJP after RT and postoperative immunosuppressant. Compared to serum creatinine (Cr) at admission, the serum Cr at discharge in both the PJP and PJP+CMV groups were decreased. The PJP+CMV group had a higher C-reactive protein level, higher procalcitonin level, and lower albumin level than the PJP group. The PJP+CMV group showed a higher PSI score than the PJP group. Moreover, the initial absorption time of the lesion was longer in the PJP+CMV group. However, the duration of hospitalization showed no significant differences between the two groups. The mortality rate was 9.4-times higher in the PJP+CMV group than in the PJP group. The rate of admittance to the intensive care unit was 3.2-times higher in the PJP+CMV group than in the PJP group. Conclusion: CMV co-infection may result in more serious inflammatory response. RT patients with PJP+CMV infection had more severe clinical symptoms, slower recovery from pneumonia, and higher mortality than those with PJP alone. Therefore, when RT patients present with severe PJP, the possibility of CMV co-infection should be considered. Short-term withdrawal of immunosuppressants in case of severe infection is safe for the renal function of RT patients.

Clinical characteristics of tuberculous infection following renal transplantation.

OBJECTIVE: This study investigated the clinical characteristics of patients with tuberculosis (TB) following renal transplantation (RT) in order to identify markers or signs that can facilitate early diagnosis. METHODS: A retrospective analysis was performed on 12 cases of Mycobacterium tuberculosis infection treated at our hospital between 2005 and 2020. RESULTS: The incidence of TB after RT at our hospital was 0.9%, and the median postoperative onset time was 22 months. The average age of patients included in our analysis was 44.2 ± 9.4 years; 11 of the 12 patients were male, and most patients had (low) fever as the first or only manifestation. Five patients had respiratory symptoms; 5 had typical computed tomography (CT) presentation; and 2 had a confirmed history of TB. Two sputum smears from 12 patients were positive by acid fast staining, and M. tuberculosis was detected in peripheral blood samples by metagenomic next-generation sequencing (NGS). One patient had a positive result in the purified protein derivative (PPD) test, 7 were positive with the interferon gamma release assay (IGRA), 8/12 patients were confirmed to have TB infection by NGS and 1 was confirmed positive by lung biopsy. CONCLUSION: Because of the use of immunosuppressive agents, most patients with TB following RT have atypical clinical symptoms and CT findings, and may have a high probability of a false negative result with the traditional PPD test and a low probability of M. tuberculosis detection, making early diagnosis difficult. Therefore, in RT recipients with prolonged fever of unknown origin and unusual clinical manifestations, especially those who are unresponsive to antibiotic treatment, a diagnosis of TB should be considered. The interferon gamma release assay and NGS are relatively new detection methods with high sensitivity and specificity; these along with regular, repeated testing by various approaches can aid the early diagnosis of TB.

Summary report of seven cases of COVID-19 infection in renal transplant recipients.

The coronavirus disease 2019 (COVID-19) has swept the world, posing a serious threat to people's lives and health. Several cases of COVID-19 infection in renal transplant recipients (RTRs) have been reported, but the treatment and prognosis have not been fully elucidated. We followed-up with RTRs infected with SARS-CoV2 in our center and classified them as five clinical types-asymptomatic, mild, moderate, severe, and critical. The immunosuppressive agents were not adjusted in asymptomatic carriers and mild patients, the former was mainly treated by isolation, and the latter was treated by low-dose intravenous immunoglobulin (IVIG) to enhance immunity. For moderate or severe patients, the immunosuppressive agents were largely reduced or even interrupted, low-dose IVIG was adopted, and low-dose methylprednisolone (MP) was used to inhibit inflammation and rejection. Immunosuppressants were discontinued early in critical patients; IVIG, high-dose MP, and antibiotics were used. Meanwhile, all patients received at least one antiviral drugs. After aggressive treatment, three patients developed acute kidney injury, and two showed reversal, while the remaining one lost the allograft kidney; one patient died, while other patients were discharged. For different clinical types of RTRs infected with COVID-19, personalized therapies were essential, Meanwhile, patients with COVID-19 infection may have different outcomes due to their different clinical manifestations.

A patient with end-stage renal disease who recovered from coronavirus disease 2019 then received a kidney transplant.

Since its emergence in December 2019 many end-stage renal disease (ESRD) patients have been infected with coronavirus disease 2019 (COVID-19). Herein, we describe the case of an ESRD patient who received a kidney transplant after recovering from COVID-19. We described the clinical course of COVID-19 and kidney transplant management, including the patient's symptoms, laboratory results, computed tomography, and antibody profiles. He recovered well, without complications. Chest computed tomography, PCR, and IgG results indicated no recurrence of COVID-19 during the subsequent two weeks. Therefore, kidney transplantation is feasible in an ESRD patient who has recovered from COVID-19, under a normal immunosuppressive regimen.

Bioavailable testosterone is associated with symptoms of depression in adult men.

OBJECTIVE: This study aimed to determine the relationship between serum testosterone levels and depressive symptoms in an adult male population. METHODS: We conducted a cross-sectional study of 1166 male participants from Zunyi, Guizhou, China. Each participant completed a questionnaire, a brief clinical exam, and had a fasting blood sample taken. We measured serum testosterone, sex hormone-binding globulin, and luteinizing hormone levels. Multiple linear regression was used to evaluate the effect of demographic factors on the relationship between the depressive symptom score and serum sex hormone levels. RESULTS: Mean testosterone, sex hormone-binding globulin, and luteinizing hormone levels were significantly higher in the depressive symptom group than in the non-depressed group. The mean calculated free serum testosterone level and free testosterone index (FTI) were significantly lower in the depressive symptom group than in the non-depressed group. Additionally, the mean FTI was significantly negatively correlated with the Beck Depression Inventory scale score in the multiple linear regression model (95% confidence interval: -3.274 to -0.406). CONCLUSIONS: Decreased bioactive testosterone levels might be a contributing factor of depression in adult men. The FTI could be the most sensitive biomarker reflecting the level of bioavailable testosterone in patients with depression.

DUSP12 protects against hepatic ischemia-reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo.

Hepatic ischemia-reperfusion (I/R) injury is an important risk factor resulting in liver failure during liver surgery. However, there is still lack of effective therapeutic methods to treat hepatic I/R injury. DUSP12 is a member of the dual specific phosphatase (DUSP) family. Some DUSPs have been identified as being involved in the regulation of hepatic I/R injury. However, the role of DUSP12 during hepatic I/R injury is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in a hepatic I/R injury mouse model in vivo and in hypoxia/reoxygenation (H/R) model in vitro. Using hepatocyte-specific DUSP12 knockout mice and DUSP12 transgenic mice, we demonstrated that DUSP12 apparently relieved I/R-induced liver injury. Moreover, DUSP12 inhibited hepatic inflammatory responses and alleviated apoptosis both in vitro and in vivo. Furthermore, we demonstrated that JNK and p38 activity, but not ERK1/2, was increased in the DUSP12-deficient mice and decreased in the DUSP12 transgenic mice under I/R condition. ASK1 was required for DUSP12 function in hepatic I/R injury and inhibition of ASK1 prevented inflammation and apoptosis in DUSP12-deficient hepatocytes and mice. In conclusion, DUSP12 protects against hepatic I/R injury and related inflammation and apoptosis. This regulatory role of DUSP12 is primarily through ASK1-JNK/p38 signaling pathway. Taken together, DUSP12 could be a potential therapeutic target for hepatic I/R injury.

Elevated whole blood arsenic level is associated with type 2 diabetes in coal-burning areas in Guizhou.

The potential association between coal-burning arsenic exposure and type 2 diabetes (T2D) was examined through a case control study, conducted in coal-burning arsenic poisoning areas in the Guizhou Province. This study included patients diagnosed with type 2 diabetes. Control subjects without type 2 diabetes were recruited randomly after gender and age 1:1 matching. All subjects completed questionnaire surveys and underwent physical examination and whole blood arsenic level testing. The whole blood arsenic level was associated with a significant increase in the risk of type 2 diabetes (75th versus 25th, adjusted OR = 1.76, 95% CI: 1.03-3.01). However, a nonlinear relationship was observed between the blood arsenic level and type 2 diabetes. The risk of type 2 diabetes increased with blood arsenic levels above 3.69 µg/L (Log As ≥0.57). The subgroup analysis revealed that blood arsenic levels were associated with significantly increased risk of type 2 diabetes in people who ever smoked (P < .05), particularly those who smoked ≥15 years (adjusted OR = 3.15, 95% CI: 1.9-7.28). Therefore, prolonged arsenic exposure, even at a low level, is associated with a higher prevalence of type 2 diabetes in a nonlinear pattern. Blood arsenic levels less than 3.69 µg/L may be considered safe with respect to the risk of T2D. However, smoking, particularly smoking ≥15 years, may be associated with the development of diabetes in patients with arsenic exposure.

Ubiquitin-specific protease-44 inhibits the proliferation and migration of cells via inhibition of JNK pathway in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer. Ubiquitin-specific protease (USP)44 has been reported to be involved in various cancers. We investigated the function, role and molecular mechanism of USP44 in ccRCC. METHODS: Data obtained from the Cancer Genome Atlas Data Portal and Gene Expression Omnibus database were analyzed to uncover the clinical relevance of USP44 expression and tumor development. USP44 function in the proliferation and migration of tumor cells was assessed by cellular and molecular analyses using ccRCC lines (786-O cells and Caki-1 cells). RESULTS: USP44 showed low expression in ccRCC cancer tissues compared with that in normal tissue. USP44 expression was negatively correlated with tumor stage, tumor grade, and patient survival. USP44 overexpression inhibited the proliferation and migration of 786-O cells and Caki-1 cells significantly. USP44 overexpression also prohibited cell proliferation by upregulating expression of P21, downregulating cyclin-D1 expression, and inhibiting cell migration by downregulating expression of matrix metalloproteinase (MMP)2 and MMP9. USP44 knockdown enhanced the proliferation and migration of 786-O cells and Caki-1 cells. USP44 function in inhibiting the proliferation and migration of 786-O cells and Caki-1 cells was associated with phosphorylation of Jun N-terminal kinase (JNK). CONCLUSION: USP44 may be a marker in predicting ccRCC progression. Inhibition by USP44 of the proliferation and migration of 786-O cells and Caki-1 cells is dependent upon the JNK pathway.

Leukocyte immunoglobulin-like receptor B4 deficiency exacerbates acute lung injury via NF-κB signaling in bone marrow-derived macrophages.

Acute lung injury (ALI) is an acute inflammatory disease. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing inhibitory receptor that is implicated in various pathological processes. However, the function of LILRB4 in ALI remains largely unknown. The aim of the present study was to explore the role of LILRB4 in ALI. LILRB4 knockout mice (LILRB4 KO) were used to construct a model of ALI. Bone marrow cell transplantation was used to identify the cell source of the LILRB4 deficiency-aggravated inflammatory response in ALI. The effect on ALI was analyzed by pathological and molecular analyses. Our results indicated that LILRB4 KO exacerbated ALI triggered by LPS. Additionally, LILRB4 deficiency can enhance lung inflammation. According to the results of our bone marrow transplant model, LILRB4 regulates the occurrence and development of ALI by bone marrow-derived macrophages (BMDMs) rather than by stromal cells in the lung. The observed inflammation was mainly due to BMDM-induced NF-κB signaling. In conclusion, our study demonstrates that LILRB4 deficiency plays a detrimental role in ALI-associated BMDM activation by prompting the NF-κB signal pathway.