Propranolol can correct prolonged QT intervals in patients with cirrhosis.

Background: Prolonged QT intervals are extremely common in patients with cirrhosis and affect their treatment outcomes. Propranolol is often used to prevent gastroesophageal variceal hemorrhage in patients with cirrhosis; however, it is uncertain whether propranolol exerts a corrective effect on QT interval prolongation in patients with cirrhosis. Aim: The study aimed to investigate the therapeutic effects of propranolol on patients with cirrhosis and prolonged QT intervals. Methods: A retrospective cohort study approach was adopted. Patients with cirrhosis complicated by moderate-to-severe gastroesophageal varices, who were hospitalized at the Affiliated Hospital of Guangdong Medical University between 1 December 2020 and 31 November 2022, were included in the study. The patients were divided into the propranolol and control groups based on whether they had received propranolol. Upon admission, the patients underwent tests on liver and kidney functions, electrolytes, and coagulation function, as well as abdominal ultrasonography and electrocardiography. In addition to conventional treatment, the patients were followed up after the use or non-use of propranolol for treatment and subsequently underwent reexamination of the aforementioned tests. Results: The propranolol group (26 patients) had an average baseline corrected QT (QTc) interval of 450.23 ± 37.18 ms, of which 14 patients (53.8%) exhibited QTc interval prolongation. Follow-up was continued for a median duration of 7.00 days after the administration of propranolol and conventional treatment. Electrocardiographic reexamination revealed a decrease in the QTc interval to 431.04 ± 34.64 ms (p = 0.014), and the number of patients with QTc interval prolongation decreased to five (19.2%; p < 0.001). After treatment with propranolol and multimodal therapy, QTc interval normalization occurred in nine patients with QTc interval prolongation, leading to a normalization rate of 64.3% (9/14). The control group (n = 58) had an average baseline QTc interval of 453.74 ± 30.03 ms, of which 33 patients (56.9%) exhibited QTc interval prolongation. After follow-up for a median duration of 7.50 days, the QTc interval was 451.79 ± 34.56 ms (p = 0.482), and the number of patients with QTc interval prolongation decreased to 30 (51.7%; p = 0.457). The QTc interval normalization rate of patients in the control group with QTc interval prolongation was merely 10.0% (3/33), which was significantly lower than that in the propranolol group (p < 0.001). Conclusion: In patients with cirrhosis complicated by QT interval prolongation, the short-term use of propranolol aids in correction of a long QT interval and provides positive therapeutic value for cirrhotic cardiomyopathy.

Whole-body water mass and kidney function: a Mendelian randomization study.

Background: The morbidity and mortality of chronic kidney disease (CKD) are increasing worldwide, making it a serious public health problem. Although a potential correlation between body water content and CKD progression has been suggested, the presence of a causal association remains uncertain. This study aimed to determine the causal effect of body water content on kidney function. Methods: Genome-wide association study summary data sourced from UK Biobank were used to evaluate single-nucleotide polymorphisms (SNPs) associated with whole-body water mass (BWM). The summary statistics pertaining to kidney function were extracted from the CKDGen consortium. The primary kidney function outcome measures included estimated glomerular filtration rate (eGFR), albuminuria, CKD stages 3-5, and rapid progression to CKD (CKDi25). Two-sample Mendelian randomization (MR) analysis estimated a potential causal relationship between the BWM and kidney function. The inverse variance weighted MR method was used as the primary analysis, accompanied by several sensitive MR analyses. Results: The increase of BWM exhibited a correlation with a reduction in eGFR (ß = -0.02; P = 6.95 × 10-16). Excluding 13 SNPs responsible for pleiotropy (P = 0.05), the increase of BWM was also associated with the decrease of the ratio of urinary albumin to creatinine (ß = -0.16; P = 5.91 × 10-36). For each standard deviation increase in BWM, the risk of CKD stages 3-5 increases by 32% (OR, 1.32; 95% CI, 1.19-1.47; P = 1.43 × 10-7), and the risk of CKDi25 increases by 22% (OR, 1.22; 95% CI, 1.07-1.38; P = 0.002). Conclusion: The increase of BWM is associated with impaired kidney function. Proactively managing body water content is of great significance in preventing the progression of CKD.

Prediction of immunotherapy response in idiopathic membranous nephropathy using deep learning-pathological and clinical factors.

Background: Owing to individual heterogeneity, patients with idiopathic membranous nephropathy (IMN) exhibit varying sensitivities to immunotherapy. This study aimed to establish and validate a model incorporating pathological and clinical features using deep learning training to evaluate the response of patients with IMN to immunosuppressive therapy. Methods: The 291 patients were randomly categorized into training (n = 219) and validation (n = 72) cohorts. Patch-level convolutional neural network training in a weakly supervised manner was utilized to analyze whole-slide histopathological features. We developed a machine-learning model to assess the predictive value of pathological signatures compared to clinical factors. The performance levels of the models were evaluated using the area under the receiver operating characteristic curve (AUC) on the training and validation tests, and the prediction accuracies of the models for immunotherapy response were compared. Results: Multivariate analysis indicated that diabetes and smoking were independent risk factors affecting the response to immunotherapy in IMN patients. The model integrating pathologic features had a favorable predictive value for determining the response to immunotherapy in IMN patients, with AUCs of 0.85 and 0.77 when employed in the training and test cohorts, respectively. However, when incorporating clinical features into the model, the predictive efficacy diminishes, as evidenced by lower AUC values of 0.75 and 0.62 on the training and testing cohorts, respectively. Conclusions: The model incorporating pathological signatures demonstrated a superior predictive ability for determining the response to immunosuppressive therapy in IMN patients compared to the integration of clinical factors.

Correlation between soluble klotho and chronic kidney disease-mineral and bone disorder in chronic kidney disease: a meta-analysis.

We conducted a systematic search across medical databases, including PubMed, Web of Science, EMBASE, and Cochrane Library, up to March 2023. A total of 1944 subjects or individuals from 17 studies were included in our final analysis. The correlation coefficient (r) between sKlotho and calcium was [0.14, (0.02, 0.26)], and a moderate heterogeneity was observed (I2 = 66%, P < 0.05). The correlation coefficient (r) between Klotho and serum phosphate was [- 0.21, (- 0.37, - 0.04)], with apparent heterogeneity (I2 = 84%, P < 0.05). The correlation coefficient (r) between sKlotho and parathyroid hormone and vascular calcification was [- 0.23,(- 0.29, - 0.17); - 0.15, (- 0.23, - 0.08)], with no significant heterogeneity among the studies. (I2 = 40%, P < 0.05; I2 = 30%, P < 0.05). A significant correlation exists between low sKlotho levels and an increased risk of CKD-MBD in patients with CKD. According to the findings, sKlotho may play a role in alleviating CKD-MBD by lowering phosphorus and parathyroid hormone levels, regulating calcium levels, and suppressing vascular calcification. As analysis showed that sKlotho has an important impact on the pathogenesis and progression of CKD-MBD in CKD patients. Nonetheless, further comprehensive and high-quality studies are needed to validate our conclusions.

Advances in energy metabolism in renal fibrosis.

Renal fibrosis is a common pathway toward chronic kidney disease (CKD) and is the main pathological predecessor for end-stage renal disease; thus, preventing progressive CKD and renal fibrosis is essential to reducing their consequential morbidity and mortality. Emerging evidence has connected renal fibrosis to metabolic reprogramming; abnormalities in energy metabolism pathways, such as glycolysis, the tricarboxylic acid cycle, and lipid metabolism, are known to cause diseases of diverse etiologies. Cytokine interventions in affected metabolic pathways may significantly reduce the degree of fibrosis, highlighting therapeutic targets for drug development for renal fibrosis. Here, we discuss the relationship between glycolysis, lipid metabolism, mitochondrial and peroxisome dysfunction, and renal fibrosis in detail and propose that targeted therapies for specific metabolic pathways are expected to represent the next generation of treatments for renal fibrosis.

Changes of macrophage and CD4+ T cell in inflammatory response in type 1 diabetic mice.

Immune cells play an important role in the development of inflammation in type 1 diabetes mellitus, so we want to explore the changes of CD4+ T cells and macrophages in vivo, which can provide an experimental basis for immunotherapy based on CD4+ T cells and macrophages. The intraperitoneal injection of streptozocin was used to induce a type 1 diabetes mellitus mouse model; the blood glucose, body weight, and the expression of inflammatory factors in the kidney were measured. Immunohistochemistry was applied to determine and analyze the infiltration of CD4+ T cells and macrophages in the spleen, pancreas, and kidney. The subtypes of macrophages in the kidney and CD4+ T cells in the spleen were analyzed by flow cytometry. Our study suggests that CD4+ T cells and macrophages increase, while the inflammatory immune response system is activated in the development of T1DM. CD4+ T cells positively correlated with macrophages in the pancreas and kidney of T1DM. CD4+ T cells turn to pro-inflammatory subtypes in the spleen of T1DM, while macrophages turn to pro-inflammatory subtypes in the kidney of T1DM. Therefore, regulation of CD4+ T cells and macrophages may be a potential target for T1DM and kidney complications.

Roxadustat: Not just for anemia.

Roxadustat is a recently approved hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated favorable safety and efficacy in the treatment of renal anemia. Recent studies found it also has potential for the treatment of other hypoxia-related diseases. Although clinical studies have not yet found significant adverse or off-target effects of roxadustat, clinicians must be vigilant about these possible effects. Hypoxia-inducible factor regulates the expression of many genes and physiological processes in response to a decreased level of oxygen, but its role in the pathogenesis of different diseases is complex and controversial. In addition to increasing the expression of hypoxia-inducible factor, roxadustat also has some effects that may be HIF-independent, indicating some potential off-target effects. This article reviews the pharmacological characteristics of roxadustat, its current status in the treatment of renal anemia, and its possible effects on other pathological mechanisms.

Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis.

Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases.

Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-ß: transforming growth factor-ß; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response.

Magnesium in renal fibrosis.

PURPOSE: Renal fibrosis (RF) is the main pathological feature of chronic kidney disease (CKD). The main focus of research on treatment for CKD is to develop strategies that delay or prevent RF from progressing to end-stage renal disease (ESRD). Inflammation and oxidative stress occur during all stages of CKD. The magnesium cation (Mg2+) can reduce inflammation and oxidative stress, regulate apoptosis, and improve RF, and magnesium-based therapies are promising new treatments that can prevent RF. We reviewed the current evidence on the effects of magnesium in RF and examined the possible mechanism of magnesium in delaying RF. METHODS: We searched PubMed, Web of Science, and EMBASE for articles on magnesium and fibrosis, with a focus on magnesium and RF. RESULTS: Inflammation, oxidative stress, and apoptosis are related to the occurrence of CKD. Previous research showed that Mg2+ inhibits the differentiation of inflammatory cells, down-regulates the production of inflammatory cytokines, reduces inflammation, and reduces the production of reactive oxygen species (ROS) and oxidative stress. In addition, Mg2+ also regulates apoptosis and protects renal tubular function. Magnesium may also regulate TRPM6/7, promote the secretion of klotho protein and improve renal fibrosis. Therefore, Mg2+ can protect the kidney from damage and slow down the progression of RF through many molecular and cellular effects. Some of the anti-fibrotic effects of Mg2+ may be related to its antagonism of intracellular Ca2+. CONCLUSION: Magnesium may prevent the progression of renal fibrosis and delay CKD by reducing renal inflammation and oxidative stress, and by regulating fibrosis-related signaling pathways and cytokines.

Metabolic Reprogramming and Renal Fibrosis.

There are several causes of chronic kidney disease, but all of these patients have renal fibrosis. Although many studies have examined the pathogenesis of renal fibrosis, there are still no effective treatments. A healthy and balanced metabolism is necessary for normal cell growth, proliferation, and function, but metabolic abnormalities can lead to pathological changes. Normal energy metabolism is particularly important for maintaining the structure and function of the kidneys because they consume large amounts of energy. We describe the metabolic reprogramming that occurs during renal fibrosis, which includes changes in fatty acid metabolism and glucose metabolism, and the relationship of these changes with renal fibrosis. We also describe the potential role of novel drugs that disrupt this metabolic reprogramming and the development of fibrosis, and current and future challenges in the treatment of fibrosis.

Recent research progress on the role of ulinastatin in chronic kidney disease.

With the continuous improvement in living standards, lifestyle changes and ageing of the population, the prevalence of chronic kidney disease (CKD) has increased significantly, and its prevention and treatment have become important public health issues worldwide. Renal fibrosis is the main pathological basis of CKD progression to end-stage renal disease. Preventing the progression of renal fibrosis has always been the focus of clinical and scientific research. Ulinastatin is a serine protease inhibitor that is found in human blood and urine and inhibits the inflammatory response, regulates immunity and improves the microcirculation. It is widely used in patients with sepsis and septic shock in clinical practice. Recent studies have shown that ulinastatin can also play an important anti-fibrotic and organ protective role and can provide a new therapeutic hope for CKD patients. This review mainly introduced the research progress of UTI in inflammation, oxidative stress, apoptosis, acute kidney injury and renal fibrosis. By investigating the role of ulinastatin in CKD, we can determine the possible mechanisms for its renal protection and improvement of renal fibrosis, so as to provide new ideas for the treatment of CKD.

Advances in understanding the role of adiponectin in renal fibrosis.

Renal fibrosis is characterized by the proliferation of renal intrinsic cells, activation of renal interstitial fibroblasts and deposition of extracellular matrix (ECM), processes that lead to the progressive loss of renal function. Renal fibrosis is characterized by the proliferation of renal intrinsic cells, activation of renal interstitial fibroblasts, and septal fibrosis is recognized as a marker for the progression of chronic kidney disease, a condition that is associated with high morbidity and mortality and is a significant public health burden. Despite extensive studies, there are no effective treatments for renal fibrosis. Adiponectin (APN) is a protein mainly produced by adipocytes that has anti-inflammatory and anti-atherosclerotic effects, improves insulin resistance and provides other salutary effects. Recent studies found that APN can inhibit ECM deposition by inhibiting inflammation and oxidative stress, and by regulating the TGF-ß, AMPK, MCP-1 and other signalling pathways. Many recent studies have examined the roles of these pathways in the pathogenesis of renal fibrosis. In this article, we review the pathogenic mechanism of APN in renal fibrosis and provide a theoretical basis for delaying and blocking renal fibrosis by alteration of APN activity.

Andrographolide sensitizes human renal carcinoma cells to TRAIL­induced apoptosis through upregulation of death receptor 4.

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL­mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose­dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL­mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro­apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro­treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.

Effects of Statins on Lipid Profile of Kidney Transplant Recipients: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To assess the benefits of statins on lipid profile in kidney transplant recipients via a meta-analysis. METHODS: We systematically identified peer-reviewed clinical trials, review articles, and treatment guidelines from PubMed, Embase, the Cochrane Library, Wanfang, Chinese National Knowledge Infrastructure (CNKI), SinoMed (CBM), and Chongqing VIP databases from inception to April 2019. In the analysis, only randomized controlled clinical trials performed in human were included. RESULTS: Eight articles were included in the analysis, involving 335 kidney transplant recipients who received statins and 350 kidney transplant patients as the control group. Results revealed that statins improved the lipid profile of kidney transplant recipients. Specifically, statin therapy significantly reduced total cholesterol and low-density lipoprotein cholesterol. However, it had no effects on high-density lipoprotein cholesterol and triglyceride levels. CONCLUSIONS: The present study provides valuable knowledge on the potential benefits of statins in kidney transplant recipients. This meta-analysis shows that statin therapy modifies the lipid profile in this patient population.

Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis.

Renal fibrosis is the most common pathological manifestation of chronic kidney disease (CKD), and with numerous influencing factors, its pathogenesis is complex. Epithelial-mesenchymal transition (EMT) is known to promote the progression of renal fibrosis via alterations in the secreted proteome. Moreover, blocking or even reversing EMT can effectively reduce the degree of fibrosis. As such, targeting the key molecules responsible for promoting EMT may be an effective strategy for inhibiting renal fibrosis. Research in recent years has demonstrated that hypoxia-inducible factor 1α (HIF-1α) acts to promote renal fibrosis through regulation of EMT. However, the relationship between HIF-1α and EMT remains incompletely understood. In the present review, the underlying mechanism of the interaction between HIF-1α and EMT is explored to provide novel insight into the pathogenesis of renal fibrosis and new ideas for early targeted intervention.

Advances in Understanding the Effects of Erythropoietin on Renal Fibrosis.

Renal fibrosis is the common manifestation of the pathogenesis of end-stage renal disease that results from different types of renal insult, and is a hallmark of chronic kidney disease (CKD). The main pathologic characteristics of renal fibrosis are renal interstitial fibroblast hyperplasia and the aberrant and excessive deposition of extracellular matrix, pathologies that lead to the destruction of normal renal tubules and interstitial structures. However, the biological significance of fibrosis during the progression of CKD is not clear, and there are no approved clinical treatments for delaying or reversing renal fibrosis. Studies of the mechanism of renal fibrosis and of potential measures of prevention and treatment have focused on erythropoietin (EPO), a hormone best known as a regulator of red blood cell production. These recent studies have found that EPO may also provide efficient protection against renal fibrosis. Future therapeutic approaches using EPO offer new hope for patients with CKD. The aim of the present review is to briefly discuss the role of EPO in renal fibrosis, to identify its possible mechanisms in preventing renal fibrosis, and to provide novel ideas for the use of EPO in future treatments of renal fibrosis.

Ulinastatin enhances autophagy against radiation-induced lung injury in mice.

BACKGROUND: To investigate the enhancement of autophagy by ulinastatin for protecting against radiation-induced lung injury (RILI) in mice. METHODS: Forty C57BL/6 mice were equally divided into (I) control (C), (II) irradiation (R), (III) ulinastatin (U), (IV) 3-methyladenine (3-MA) (M), and (V) ulinastatin plus 3-MA (U+M) groups. Three mice in each group were infected with adeno-associated virus (AAV) carrying green fluorescent protein (GFP)-1A/1B-light chain 3 (GFP-LC3) in the lung for the marker of autophagy. All mice in R, U, M and U+M groups were given chest irradiation (1 Gy/min, 12 min), following injection with normal saline in C and U groups, ulinastatin (500,000 IU/kg·d, i.p., 7 d) in U group, 3-MA (10 mg/kg·d, i.p., 7 d) in M group, and ulinastatin plus 3-MA in U+M group. The effects of ulinastatin on lung injury and autophagy were evaluated by electron microscope (EM), immunohistochemistry, mRNA expression levels of collagen alpha-1 (COL1A1), collagen alpha-2 (COL1A2), α-smooth muscle actin (α-SMA) and transforming growth factor ß1 (TGF-ß1), and protein levels of LC3, α-SMA, COL1A2, TGF-ß1, matrix metalloproteinase-2 (MMP-2) and MMP-9. RESULTS: EM observation revealed that the radiation caused the injury of type I and II alveolar epithelial cells, which was improved by ulinastatin treatment associated with increased the numbers of autophagosomes. GFP-LC3 signals was significantly enhanced by ulinastatin detected by immune histochemical tests. At transcriptional and/or translational levels, ulinastatin significantly enhanced the expression levels of TGF-ß1 and LC3 but reduced COL1A1, COL1A2, α-SMA, MMP-2 and MMP-9 after radiation-induced RILI. CONCLUSIONS: Ulinastatin reduces RILI by enhancing autophagy, which might be a potential therapeutic drug in the protection against RILI.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

Andrographolide Enhances TRAIL-Induced Apoptosis via p53-Mediated Death Receptors Up-Regulation and Suppression of the NF-кB Pathway in Bladder Cancer Cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective chemotherapeutic agent that specifically impairs cancer cells while sparing normal cells; however, some cancer cells develop resistance to TRAIL. Here, we identified Andrographolide, a diterpenoid lactone derived from a traditional herbal medicine Andrographis paniculata, as an ideal sensitizer for TRAIL to overcome bladder cancer. Our results showed that combination treatment of Andro and TRAIL retarded growth, attenuated proliferation, decreased colony formation, inhibited migration and promoted caspases-mediated apoptosis in T24 cells. Additionally, the sensitization by Andro is achieved through up-regulation of death receptors (DR4 and DR5) of TRAIL in a p53-dependent manner. Crucially, Andro is also capable of inactivating NF-κB signaling pathway via transcriptional down-regulation p65/RelA, which is further contributed to enhancement of TRAIL-mediated cytotoxicity. These results indicated that non-toxic doses of Andrographolide sensitized bladder cancer cells to TRAIL-mediated apoptosis, suggesting it as an effective therapeutic agent for TRAIL resistant human bladder cancers.