Pachymic acid protects hepatic cells against oxygen-glucose deprivation/reperfusion injury by activating sirtuin 1 to inhibit HMGB1 acetylation and inflammatory signaling.

Ischemia-reperfusion injury is an important cause of liver injury occurring during liver transplantation. It is usually caused by inflammatory response and oxidative stress-induced oxidative damage. Pachymic acid (PA) has various biological activities such as anti-inflammatory, antioxidant and anti-cancer. However, the action mechanism of PA in hepatic ischemia-reperfusion injury is currently unknown. In this study, liver cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate a hepatic ischemia-reperfusion injury model. The binding relationship between PA and sirtuin 1 (SIRT1) was analyzed by molecular docking. Cell viability was detected by Cell Counting Kit-8. Expression levels of SIRT1 and high mobility group box 1 (HMGB1) were detected by western blot. Subsequent levels of inflammatory factors were detected by related kits and western blot. Meanwhile, related kits were used to examine levels of oxidative stress markers including reactive oxygen species, malondialdehyde, superoxide dismutase and cytotoxicity-associated lactate dehydrogenase. Finally, cell apoptosis was detected by flow cytometry and western blot. The results showed that PA significantly ameliorated OGD/R-induced decrease in SIRT1 expression, increase in HMGB1 acetylation and HMGB1 translocation. Moreover, the elevated levels of inflammatory factors, oxidative stress indexes and cell apoptosis upon exposure to OGD/R were reversed by PA treatment. Moreover, the addition of SIRT1 agonist and inhibitor further demonstrated that PA exerted the aforementioned effects in OGD/R-exposed cells by targeting SIRT1. Thus, the present study revealed the mechanism by which PA ameliorated OGD/R-induced hepatic injury via SIRT1. These results might provide a clearer theoretical basis for the targeted treatment of OGD/R-induced hepatic injury with PA.

Donor-Derived Transmission of Scedosporiosis in Kidney Transplant Recipients from a Systemic lupus erythematosus donor.

Donor-derived infection (DDI) associated with Scedosporium spp is extremely rare, and results in a very poor prognosis. The present study reports a probable DDI due to Scedosporium boydii (S. boydii) from a donor with neuropsychiatric systemic lupus erythematosus. Two recipients developed Scedosporiosis after kidney transplantation from the same donor. Recipient 1 died of central nervous system infection due to S. boydii based on the clinical presentations, and the positive metagenomic next-generation sequencing (mNGS) and culture results for the cerebrospinal fluid. The other recipient with urinary tract obstruction due to S. boydii, which was identified through the positive culture and mNGS results of the removed stents, was successfully treated by stent replacement and voriconazole administration. Undiagnosed disseminated donor infection and the transmission of S. boydii should be given attention, particularly when the donor and recipients have primary immunodeficiency disease. The screening of donors and recipients for S. boydii using mNGS may be helpful in guiding antifungal prophylaxis and treatment recipients, due to its higher sensitivity and shorter diagnostic time relative to other traditional techniques.

Efficacy of Interferon-Based Therapy for COVID-19: A Systematic Review and Meta-Analysis.

Background: The aim of this study was to determine the efficacy of interferon (IFN)-based therapy for coronavirus disease 2019 (COVID-19) based on relevant qualified studies. We searched for pertinent studies using keywords via PubMed, Cochrane and Embase databases. Studies from other pertinent sources and that were published before September 2021 were also reviewed. Methods: For each study, we assessed and synthesized the outcomes by relative risk (RR) or weighted mean difference (WMD) combined with a 95% confidence interval (CI). A total of 8 studies involving 2442 patients with COVID-19 were evaluated in this meta-analysis. Results: The IFN group had a significant decrease in ICU admissions (RR: 0.705; 95% CI, 0.515-0.964) and death (RR: 0.416; 95% CI, 0.217-0.797), and increased duration of ICU stay (WMD: 0.996; 95% CI, 0.834-1.158) compared with the control group in the randomized clinical trial (RCT) subgroup analysis. In non-RCT subgroup analysis, the IFN group showed a significant increase in discharge rate (RR: 1.052; 95% CI, 1.004-1.101) compared with the control group. Conclusion: IFN therapy appears to have better efficacy than non-IFN therapy as sedatives in patients with COVID-19 in terms of decreasing ICU admissions and death and increasing discharge. However, more high-quality RCTs are needed to confirm these findings.

Hypothermic oxygenated perfusion combined with TJ-M2010-5 alleviates hepatic ischemia-reperfusion injury in donation after circulatory death.

Ischemia-reperfusion injury (IRI) is an inevitable pathological process during donation after circulatory death (DCD) liver transplantation, which contributes to serious damage to the graft. Oxidative stress, inflammation and apoptosis are all fatal causes of IRI of the liver. Hypothermic oxygenated perfusion (HOPE), as an emerging dynamic preservation technology, has a more significant effect on reducing DCD liver IRI than static cold storage (CS) mainly by regulating oxidative stress and inflammation. To further enhance the effect of HOPE and reveal its underlying mechanisms, investigators have recently combined HOPE with various methods. Excessive activation of the TLR/MyD88 signaling pathway can lead to severe immune inflammatory response. TJ-M2010-5 (TJ-5), a novel thiazaol-aminoramification MyD88 inhibitor, plays an essential role in the treatment of various diseases or pathological injuries in mice, such as hepatocellular carcinoma, acute liver injury and myocardial IRI. However, little is known about the role of TJ-5 in HOPE alleviating DCD liver IRI. Herein, we sought to investigate the role of HOPE combined with TJ-5 in reducing DCD liver IRI. We found that HOPE combined with TJ-5 significantly reduced oxidative stress, lessened inflammation, and decreased apoptosis during DCD liver IRI. Furthermore, HOPE combined with TJ-5 exerted their effects by inhibiting the TLR/MyD88 signaling pathway. Overall, these results demonstrated that HOPE combined with TJ-5 has a significant effect on alleviating DCD liver IRI. Therefore, the combined application of HOPE and TJ-5 may be an available and valid treatment option for DCD liver IRI.

Association between the overexpression of PBOV1 and the prognosis of patients with hepatocellular carcinoma.

Prostate and breast cancer overexpressed 1 (PBOV1) is a known human protein-coding gene with an uncharacterized function; it has been demonstrated to be overexpressed in a variety of human cancer types. The overexpression of PBOV1 has been indicated as significantly associated with the poor prognosis of these types of cancer. However, the function of PBOV1 in hepatocellular carcinoma (HCC) has not yet been elucidated. The present study was designed to evaluate the expression and prognostic significance of PBOV1 in HCC. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were conducted to measure the expression of PBOV1 in HCC cell lines and tissues. The associations between PBOV1 expression and clinicopathological features were statistically analyzed. The association between PBOV1 expression and the prognosis of HCC patients was analyzed by the Kaplan-Meier method. The mRNA and protein expression levels of PBOV1 were significantly increased in the HCC cell lines and HCC tissues (all P<0.05) compared with normal cell lines and tissues. In addition, PBOV1 expression was significantly associated with maximal tumor size (P=0.032), tumor metastasis (P=0.035) and tumor stage (P=0.017). The Kaplan-Meier survival curves indicated that overall survival was significantly poorer in patients with HCC with PBOV1 overexpression (P<0.05) compared with patients with low expression levels. The multivariate analysis indicated that high PBOV1 expression was an independent predictor of poor overall survival. To the best of our knowledge, the data of the present study describes the expression pattern of PBOV1 in HCC for the first time, and also suggests that PBOV1 may serve as a valuable prognostic biomarker for HCC.

Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.

The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.

NF-κB downregulates Cbl-b through binding and suppressing Cbl-b promoter in T cell activation.

T cell activation causes the translocation of NF-κB dimers from the cytoplasm into the nucleus where NF-κB regulates inflammatory and immune response genes. Cbl-b is a negative regulator of T cell activation. However, the correlation between NF-κB activity and Cbl-b expression remains unclear. We showed that IκBαΔN-Tg T cells exhibited less NF-κB activity but higher levels of Cbl-b when compared with wild-type T cells. Furthermore, ursolic acid suppressed NF-κB activation and inhibited the downregulation of Cbl-b in wild-type T cells. NF-κBp65 specifically bound to an 11-bp NF-κB consensus sequence (gcaggaagtcc) in the Cbl-b promoter. Binding of NF-κB to this sequence suppressed Cbl-b transcription, thereby resulting in the negative regulation of Cbl-b expression. In addition, Cbl-b knockout led to the loss of cardiac allograft tolerance in IκBαΔN-Tg mice. These results indicated that NF-κB downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-κB signaling in T cell activation.

miR-202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post-transcriptionally.

MicroRNAs have emerged as important regulators of carcinogenesis. In the current study, we observed that microRNA-202 (miR-202) is downregulated in hepatocellular carcinoma (HCC) cells and tissues, indicating a significant correlation between miR-202 expression and HCC progression. Overexpression of miR-202 in HCC cells suppressed cell proliferation and tumorigenicity, while downregulation of miR-202 enhanced the cells' proliferative capacity. Furthermore, we identified low-density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-202. miR-202 suppresses the expression of LRP6 by binding to the 3'-untranslated region (UTR) of its mRNA. Finally, we found that silencing the expression of LRP6 is the essential biological function of miR-202 during HCC cell proliferation. Collectively, our findings reveal that miR-202 is a potential tumor suppressive miRNA that participates in carcinogenesis of human HCC by suppressing LRP6 expression.

Powerful protection against renal ischemia reperfusion injury by T cell-specific NF-κB inhibition.

BACKGROUND: NF-κB plays a key role in ischemia reperfusion injury (IRI). Systemic inhibition of NF-κB by various methods has been proven to ameliorate IRI. However, NF-κB is also responsible for tissue protection against IRI. Systemic NF-κB inhibition may not be the optimal way for preventing IRI because of its complex roles. T cells are essential in mediating IRI. NF-κB is an important molecule during T cell activation. It is not clear the effect of T cell-specific NF-κB inhibition on IRI. We aimed to study the effect of T cell-specific NF-κB inhibition on renal IRI in IκBαΔN-Tg mice. We also compared the different effects between T cell-specific and systemic NF-κB inhibition on IRI. METHODS: Renal IRI was induced by left renal pedicle clamping for 60 or 80 min in wild-type, ursolic acid-treated or IκBαΔN-Tg mice. Renal function, histologic examination and overall survival after lethal IRI was evaluated in each group. RESULTS: Serum creatinine, BUN, and pathologic damage were all reduced in IκBαDN-Tg mice and ursolic acid-treated mice than those in the control group. All the above indexes were improved better in IκBαDN-Tg mice than those in ursolic acid-treated mice. The survival rate of IκBαDN-Tg mice was higher than that of ursolic acid-treated mice after lethal kidney ischemia reperfusion injury. Immunohistochemistry showed a significant reduced CD4+ T cells and neutrophil infiltration in IκBαDN-Tg mice. CONCLUSION: T cell-specific NF-κB inhibition provides powerful protective effect against renal IRI.