The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease.

Pin1 is a member of the peptidyl-prolyl cis/trans isomerase subfamily and is widely expressed in various cell types and tissues. Alterations in Pin1 expression levels play pivotal roles in both physiological processes and multiple pathological conditions, especially in the onset and progression of kidney diseases. Herein, we present an overview of the role of Pin1 in the regulation of fibrosis, oxidative stress, and autophagy. It plays a significant role in various kidney diseases including Renal I/R injury, chronic kidney disease with secondary hyperparathyroidism, diabetic nephropathy, renal fibrosis, and renal cell carcinoma. The representative therapeutic agent Juglone has emerged as a potential treatment for inhibiting Pin1 activity and mitigating kidney disease. Understanding the role of Pin1 in kidney diseases is expected to provide new insights into innovative therapeutic interventions and strategies. Consequently, this review delves into the molecular mechanisms of Pin1 and its relevance in kidney disease, paving the way for novel therapeutic approaches.

Cope with copper: From molecular mechanisms of cuproptosis to copper-related kidney diseases.

Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases.

Inhibition of Drp1-mediated mitochondrial fission improves contrast-induced acute kidney injury by targeting the mROS-TXNIP-NLRP3 inflammasome axis.

Acute kidney injury (AKI) is a critical complication known for their extremely high mortality rate and lack of effective clinical therapy. Disorders in mitochondrial dynamics possess a pivotal role in the occurrence and progression of contrast-induced nephropathy (CIN) by activating NLRP3 inflammasome. The activation of dynamin-related protein-1 (Drp1) can trigger mitochondrial dynamic disorders by regulating excessive mitochondrial fission. However, the precise role of Drp1 during CIN has not been clarified. In vivo experiments revealed that inhibiting Drp1 through Mdivi-1 (one selective inhibitor of Drp1) can significantly decrease the expression of p-Drp1 (Ser616), mitochondrial p-Drp1 (Ser616), mitochondrial Bax, mitochondrial reactive oxygen species (mROS), NLRP3, caspase-1, ASC, TNF-α, IL-1ß, interleukin (IL)-18, IL-6, creatinine (Cr), malondialdehyde (MDA), blood urea nitrogen (BUN), and KIM-1. Moreover, Mdivi-1 reduced kidney pathological injury and downregulated the interaction between NLRP3 and thioredoxin-interacting protein (TXNIP), which was accompanied by decreased interactions between TRX and TXNIP. This resulted in increasing superoxide dismutase (SOD) and CAT activity, TRX expression, up-regulating mitochondrial membrane potential, and augmenting ATP contents and p-Drp1 (Ser616) levels in the cytoplasm. However, it did not bring impact on the expression of p-Drp1 (Ser637) and TXNIP. Activating Drp-1though Acetaldehyde abrogated the effects of Mdivi-1. In addition, the results of in vitro studies employing siRNA-Drp1 and plasmid-Drp1 intervention in HK-2 cells treated with iohexol were consistent with the in vivo experiments. Our findings revealed inhibiting Drp1 phosphorylation at Ser616 could ameliorate iohexol -induced acute kidney injury though alleviating the activation of the TXNIP-NLRP3 inflammasome pathway.

Artificial intelligence for the prediction of acute kidney injury during the perioperative period: systematic review and Meta-analysis of diagnostic test accuracy.

BACKGROUND: Acute kidney injury (AKI) is independently associated with morbidity and mortality in a wide range of surgical settings. Nowadays, with the increasing use of electronic health records (EHR), advances in patient information retrieval, and cost reduction in clinical informatics, artificial intelligence is increasingly being used to improve early recognition and management for perioperative AKI. However, there is no quantitative synthesis of the performance of these methods. We conducted this systematic review and meta-analysis to estimate the sensitivity and specificity of artificial intelligence for the prediction of acute kidney injury during the perioperative period. METHODS: Pubmed, Embase, and Cochrane Library were searched to 2nd October 2021. Studies presenting diagnostic performance of artificial intelligence in the early detection of perioperative acute kidney injury were included. True positives, false positives, true negatives and false negatives were pooled to collate specificity and sensitivity with 95% CIs and results were portrayed in forest plots. The risk of bias of eligible studies was assessed using the PROBAST tool. RESULTS: Nineteen studies involving 304,076 patients were included. Quantitative random-effects meta-analysis using the Rutter and Gatsonis hierarchical summary receiver operating characteristics (HSROC) model revealed pooled sensitivity, specificity, and diagnostic odds ratio of 0.77 (95% CI: 0.73 to 0.81),0.75 (95% CI: 0.71 to 0.80), and 10.7 (95% CI 8.5 to 13.5), respectively. Threshold effect was found to be the only source of heterogeneity, and there was no evidence of publication bias. CONCLUSIONS: Our review demonstrates the promising performance of artificial intelligence for early prediction of perioperative AKI. The limitations of lacking external validation performance and being conducted only at a single center should be overcome. TRIAL REGISTRATION: This study was not registered with PROSPERO.

HMGB1-TLR4-IL-23-IL-17A axis accelerates renal ischemia-reperfusion injury via the recruitment and migration of neutrophils.

Renal ischemia-reperfusion injury (IRI) is an important cause of setting off acute kidney injury. Neutrophil-mediated immunomodulation has a pivotal role in the evolving of IRI. The HMGB1-TLR4-IL-23-IL-17A axis gives rise to neutrophil activation. Therefore, in the study, the role of the HMGB1-TLR4-IL-23-IL-17A axis in IRI was evaluated. Cell viability, inflammation, apoptosis, oxidative stress, survival, renal function and pathology, and the activation of macrophages and neutrophils were measured. Moreover, we evaluated the acetylation, translocation, and secretion of HMGB1 as well as levels of TLR-4, IL-23, IL-17A, and neutrophil chemokines (KC, LIX, and MIP-2). In vivo, anti-HMGB1 antibody decreased the acetylation, translocation, and secretion of HMGB1, reduced the expression of TLR-4, IL-23, IL-17A, KC, LIX, and MIP-2, alleviated the activation of macrophages and neutrophils, improved the survival rate and renal dysfunction, and decreased inflammation, apoptosis, oxidative stress, and pathological injury of the kidney. However, the intervention with recombinant HMGB1(R-HMGB1) significantly abolish the above effect of anti-HMGB1 in IRI. Neutralization IL-23 or IL-17A can alleviated the neutrophils mediated renal dysfunction by suppressing inflammation, apoptosis, and oxidative stress in IRI. In vitro, we confirmed that hypoxic/deoxygenation (H/R) induces the secretion of HMGB1 though acetylation on HK-2 and HMGB1 promotes the secretion of IL-23 in a HMGB1/TLR-4-dependent manner on macrophages. Together, these results implied that the HMGB1-TLR4-IL-23-IL-17A axis regulates inflammation, oxidative stress, apoptosis, and renal injury in IRI by promoting the recruitment and migration of neutrophils.

Clinical characteristics of 31 hemodialysis patients with 2019 novel coronavirus: a retrospective study.

AIM: Novel coronavirus pneumonia (COVID-19) has become pandemic. It brings serious threat to hemodialysis (HD) patients. Therefore, we carried out a study on the clinical characteristics of HD patients with COVID-19. METHODS: We retrospectively analyzed the data of 31 HD patients with COVID-19. The clinical features of patients include epidemiology, clinical symptoms, laboratory and imaging test, treatment and prognosis. RESULTS: 61.3% were severe, and 38.7% were mild. 83.9% had a close contact history with COVID-19 patients. The average age was 62.3 years comprising of 58.1% men and 41.9% women. Ninety percent had chronic diseases except ESRD. Clinical symptoms include cough (85%), fever (43%), and shortness of breath (48.4%), etc. Complications included ARDS (25.8%), AHF (22.6%), and septic shock (16.1%), etc. 64.5% of patients had remission, and 35.5% of patients had no remission with 6.5% deaths. Compared with the baseline before infection, HD patients with COVID-19 had lower lymphocytes, albumin and glucose, and higher D-dimer, albumin, phosphorus, lactate dehydrogenase, and CRP. There was no significant correlation between the neutrophils/lymphocytes ratio and the severity of the disease. CONCLUSIONS: Compared with the reported general population, the HD patients are susceptible to COVID-19 infection, especially older men and those with other underlying diseases. Moreover, HD patients have more severe infection and inflammation with less symptoms and worse outcome. COVID-19 infection can cause dialysis patients lower immunity, stronger inflammation, malnutrition, and internal environment disorder. Neutrophils/lymphocytes ratio does not reflect the severity of the HD patients with COVID-19.

Prevalence and associated factors of depressive symptoms among chronic kidney disease patients in China: Results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE).

OBJECTIVE: Depression is the most common mental disorder in patients with chronic kidney disease (CKD), and previous studies have found that: (a) depression can accelerate the progression of CKD; and (b) depression is an independent risk factor for hospitalization and death among patients with CKD. Therefore, the objective of the current study was to investigate the prevalence of depression in Chinese patients with CKD, and to identify variables associated with depression. METHODS: The study analyzed baseline data from a multicenter prospective cohort study of Chinese patients with chronic kidney disease (the C-STRIDE study). In all, 2995 participants in CKD stages 1 to 4 who completed a survey of depressive symptoms were included in the analyses. Depressive symptoms were assessed by the Zung Self-Rating Depression Scale (ZSDS). A ZSDS ≥50 was used as the cut-off score for the presence of depressive symptoms. Multivariable logistic regression was used to identify variables associated with depression. RESULTS: The mean estimated glomerular filtration rate (eGFR) in the study sample was 51.59±29.49 ml/min/1.73 m2. The prevalence of depressive symptoms was 37.8% and increased significantly with CKD stage. Being female, a higher level of education, a low income, a larger economic impact of disease cost, comorbid cardiovascular disease, anemia, and impaired physical ability were independently associated with depressive symptoms. CONCLUSION: Our study revealed that depressive symptoms were common among patients with CKD in China. Sociodemographic variables and the clinical characteristics of disease severity were strongly associated with depressive symptoms.

Retracted Article: Ligustrazine attenuates renal damage by inhibiting endoplasmic reticulum stress in diabetic nephropathy by inactivating MAPK pathways.

Background: Diabetic nephropathy (DN) is a major cause of chronic kidney disease around the world. Endoplasmic reticulum (ER) stress plays an important role in DN progression. Ligustrazine (Lig) is derived from the Chinese herb Ligusticum wallichii and is reported to exert anti-oxidant, anti-inflammation and anti-fibrosis effects. The aim of our study was to investigate the influence of Lig on the treatment of DN. Methods: Streptozotocin (STZ) was used to induce diabetes in Sprague-Dawley (SD) rats. Then, STZ-induced rats were treated with different concentrations of Lig (50 or 150 mg kg-1 day-1) for 8 weeks of treatment. Urinary albumin concentrations, blood urea nitrogen (BUN), serum creatinine (Scr) and creatinine clearance (Ccr) were determined. The levels of proinflammatory cytokines (IL-8, IL-6, IL-1ß and TNF-α) were estimated by ELISA. TUNEL assay was used for apoptosis index measurement. Western blot was used for the detection of GRP78, CHOP, p-eIF2α, eIF2α, p-p38, p-38, p-ERK1/2 and ERK1/2. Results: Lig treatment significantly reduced urinary albumin excretion, BUN and Scr and increased Ccr in STZ-induced rats. Lig also suppressed the levels of IL-8, IL-6, IL-1ß and TNF-α and inhibited apoptosis dose-dependently. In addition, Lig inhibited GRP78 and CHOP expression and prevented the phosphorylation of eIF2α, p-38 and ERK1/2. Conclusion: Our study indicated that Lig attenuated renal damage by inhibiting ER stress in DN by inactivating MAPK pathways.

Tacrolimus Monotherapy after Intravenous Methylprednisolone in Adults with Minimal Change Nephrotic Syndrome.

Glucocorticoid treatment is the first choice therapy for adults with minimal change nephrotic syndrome; however, this therapy associates with many adverse effects. Tacrolimus may be an alternative to conventional glucocorticoid therapy. To investigate this possibility, we conducted a prospective, randomized, controlled trial (WHO International Clinical Trials Registry Platform: ChiCTR-TRC-11001454) in eight renal units across China. We randomized enrolled patients with adult-onset minimal change nephrotic syndrome (n=119) to receive glucocorticoid therapy or tacrolimus after intravenous methylprednisolone (0.8 mg/kg per day) for 10 days. Patients received a conventional glucocorticoid regimen or tacrolimus monotherapy, starting with 0.05 mg/kg per day (target trough whole-blood level of 4-8 ng/ml) for 16-20 weeks and subsequently tapering over approximately 18 weeks. Remission occurred in 51 of 53 (96.2%; all complete remission) glucocorticoid-treated patients and 55 of 56 (98.3%; 52 complete and three partial remission) tacrolimus-treated patients (P=0.61 for remission; P=0.68 for complete remission). The groups had similar mean time to remission (P=0.55). Relapse occurred in 49.0% and 45.5% of the glucocorticoid- and tacrolimus-treated patients, respectively (P=0.71), with similar time to relapse (P=0.86). Seven (13.7%) glucocorticoid-treated and four (7.3%) tacrolimus-treated patients suffered frequent relapse (P=0.28); five glucocorticoid-treated and two tacrolimus-treated patients became drug dependent (P=0.26). Adverse events occurred more frequently in the glucocorticoid group (128 versus 81 in the tacrolimus group). Seven adverse events in the glucocorticoid group and two adverse events in the tacrolimus group were serious. Consequently, tacrolimus monotherapy after short-term intravenous methylprednisolone is noninferior to conventional glucocorticoid treatment for adult-onset minimal change nephrotic syndrome in this cohort.

The Related Risk Factors Analysis of Snake-Bite Induced Acute Kidney Injury.

BACKGROUND The pathogenic mechanism of snake-bite induced acute kidney injury (AKI) remains unclear. Analyzing the risk factors for snake-bite induced AKI may provide the guidance needed for AKI prevention and early treatment. MATERIAL AND METHODS This retrospective study included 119 snake-bite patients who were hospitalized at the emergency department of Sichuan Provincial People's Hospital from January 2011 to September 2013. The patients were divided into AKI and non-AKI groups according to the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Gender, age, and clinical examination data of the patients were recorded. The Mann-Whitney U test and Fisher exact test were performed to analyze the collected data; preliminary analysis of independent risk factors was performed with multivariate logistic regression. RESULTS Among the snake-bite patients, 98.3% were farmers. The mean age of patients was 46±12 years. Of the 119 patients (13.4%), 16 suffered from AKI. There were statistically significant differences between the AKI and non-AKI groups with respect to age, time interval from snake bite to antivenin therapy, creatine kinase, blood myoglobin, advanced age, regional lymphadenopathy, incision drainage, and hemoglobin. Preliminary analysis with multivariate logistic regression showed that advanced age and increased time interval from snake bite to antivenin therapy might be independent risk factors for snake-bite induced AKI. CONCLUSIONS Age, time interval from snake bite to antivenin therapy, creatine kinase, blood myoglobin, advanced age, regional lymphadenopathy, incision drainage, and hemoglobin were risk factors for snake-bite induced AKI. Advanced age and delayed antivenin therapy might be independent risk factors for snake-bite induced AKI.

Correlation of serum 25-hydroxyvitamin D level with vascular calcification in hemodialysis patients.

OBJECTIVE: The aim of this study was to analyze the correlation of serum 25-hydroxyvitamin D level with vascular calcification in patients treated with hemodialysis. METHODS: As a cross-sectional study, 126 patients receiving maintenance hemodialysis (MHD) in our hospital were enrolled in this study. According to the serum 25-hydroxyvitamin D level, the patients were divided into 25-hydroxyvitamin D deficiency group (30 ηg/ml or less than 30 ηg/ml) and 25-hydroxyvitamin D normal level group (>30 ηg/ml). All of the subjects underwent lateral lumbar, pelvis and hands X-ray examination to score the degree of calcification (Kauppila score). RESULTS: Among the 126 patients treated with MHD, there were 110 patients with 25-hydroxyvitamin D deficiency and 16 patients with normal 25-hydroxyvitamin D level. There was no significant difference found in gender, age, age of dialysis, active vitamin D treatment, blood calcium, blood phosphorus, blood parathyroid hormone (PTH) and other related indicators between the two groups. The incidence of vascular calcification in patients with 25-hydroxyvitamin D deficiency was significantly higher than that in patients with normal 25-hydroxyvitamin D level (P = 0.001). Serum 25-hydroxyvitamin D level had a negative correlation with the calcification score (r = 0.193, P = 0.193). Logistic regression showed that 25-hydroxyvitamin D was not a risk factor for vascular calcification in MHD patients. Serum 25-hydroxyvitamin D level is generally low in patients with MHD. CONCLUSIONS: Patients with 25-hydroxyvitamin D deficiency have a higher incidence of vascular calcification with a markedly negative correlation. Thus, for the patients treated with MHD, vitamin D deficiency should be actively treated.

Oral active vitamin d treatment and mortality in maintenance hemodialysis patients.

AIMS: To analyze the relationship between oral active vitamin D treatment and mortality in maintenance hemodialysis (MHD) patients. METHODS: We examined the association of oral calcitriol treatment with mortality in 156 MHD patients (80 men and 76 women; mean age: 59 ± 15 years). The survival analysis of all-cause and cardiovascular mortality was performed using the Kaplan-Meier survival and Cox proportional-hazards analyses. RESULTS: In all, 108 of the 156 patients received active vitamin D treatment. The intact parathyroid hormone level was obviously lower in the patients who received active vitamin D treatment than in those who did not. Throughout the whole follow-up, overall mortality was 16.7% (26 deaths, 13 in each group). The cardiovascular mortality rates were 14.6% (8/48) in the control group and 4.6% (5/108) in the calcitriol group. The crude analysis of all-cause and cardiovascular mortality using the Kaplan-Meier curve showed a significant reduction in mortality risk for patients who received oral active vitamin D compared with those who did not receive it (p = 0.015 and 0.026, respectively). Cox's regression analysis showed that active vitamin D treatment was associated with a significantly lower risk of all-cause mortality (RR = 0.399, 95% CI 0.185-0.862, p = 0.019) and cardiovascular mortality (RR = 0.295, 95% CI 0.094-0.93, p = 0.037). However, after adjusting for potential confounding variables, oral active vitamin D therapy was no longer clearly associated with a lower risk of either all-cause or cardiovascular mortality. CONCLUSION: Oral active vitamin D treatment was associated with improved survival in MHD patients. However, this survival benefit was smaller than previously reported, and a large cohort study should be performed.

Abdominal aortic calcification is not superior over other vascular calcification in predicting mortality in hemodialysis patients: a retrospective observational study.

BACKGROUND: KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend that a lateral abdominal radiograph should be performed to assess vascular calcification (VC) in dialysis patients. However, abdominal aortic calcification is a prevalent finding, and it remains unclear whether other anatomical areas of VC can predict mortality more accurately. METHODS: A total of 217 maintenance hemodialysis patients were enrolled at the Sichuan Provincial People's Hospital between July 2010 and March 2011. Radiographs of the abdomen, pelvis and hands were evaluated by a radiologist to evaluate the presence of VC. The correlation between different areas of VC and all-cause or cardiovascular mortality was analyzed using univariate and multivariate models. RESULTS: The prevalence of VC was 70.0% (152 patients), and most had abdominal aortic calcification (90.1%). During 26 ± 7 months of follow-up, 37 patients died. The VC score was independently associated with patient mortality. VC observed on abdominal radiographs (abdominal aortic calcification) was associated with all-cause mortality in models adjusted for cardiovascular risk factors (HR, 4.69; 95%CI, 1.60-13.69) and dialysis factors (HR, 3.38; 95%CI, 1.18-9.69). VC in the pelvis or hands was associated with all-cause mortality in the model adjusted for dialysis factors. When three combinations of VC in different radiographs were included in models, the presence of abdominal VC was only significantly associated with all-cause mortality in the integrated model. VC in the abdomen and pelvis was associated with all-cause mortality in the model adjusted for cardiovascular factors and the integrated model, but neither was significantly associated with cardiovascular mortality. VC in all radiographs was significantly associated with a more than 6-fold risk of all-cause mortality and a more than 5-fold risk of cardiovascular mortality compared to patients without VC. CONCLUSIONS: VC in different arteries as shown on radiographs is associated with different levels of risk for mortality. The lateral abdominal radiograph may not be superior to other radiographs for predicting patient outcomes. Further research is needed to elucidate the effects of difference burdens of VC on patient outcomes.

[Expressions of phosphorylated-Smad2 and PTEN in hepatocellular carcinomas and adjacent liver tissues].

OBJECTIVE: To investigate the expressions of phosphorylated Smad2 (P-Smad2) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) in hepatocellular carcinoma (HCC) tissues. METHODS: The expressions of P-Smad2 and PTEN were detected using Envision immunohistochemical technique in 31 cases of HCC tissues, 25 cases of HCC adjacent liver tissues and 13 cases of non-hepatocellular carcinoma tissues. RESULTS: The positive expression and staining intensity of PTEN in the cytoplasm of HCC cells (64.5%, 4.19+/-3.31) was significantly lower than those of the cells of the cancer adjacent tissues and non-cancerous tissues (96.0%, 7.88+/-0.93; 100%, 7.77+/-0.93). The staining intensity of PTEN in the cytoplasm of Edmondson pathologic grade III HCC cells was lower than those of the Edmondson grade I. The expression of PTEN was negatively correlated with intrahepatic vascular cancer thrombi (r=-0.43) and the expression of PTEN in the nuclei or cytoplasm of liver cells was negatively correlated with the liver disease progressions (r=-0.34). The positive rate and expression intensity of phosphorylated Smad2 in nuclei of HCC cells were the same as those in cancer adjacent and non-tumor liver tissues. The expression was mostly in the nucleus and cytoplasm of Edmondson grade I HCC cells, cancer adjacent liver tissue cells and non-tumor liver tissues, but its expression was only in the nuclei of Edmondson grade II and III HCC cells. The phosphorylated Smad2 expression appeared in the nuclei and in the cytoplasm of liver cells and it was positively correlated with the severity of the tumor pathology (r=0.22). Spearman correlation analysis revealed a significant inverse correlation between PTEN and phosphorylated Smad2 in HCC tissues (r=-0.73). CONCLUSIONS: The aberrant expressions of PTEN and phosphorylated Smad2 and their interaction may play an important role in the pathogenesis of hepatocellular carcinoma.

Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues.

AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 +/- 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 +/- 0.93; 100%, 7.77 +/- 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades II-III and above, was also lower than that of grade I and I-II. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson grade I and I-II HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade > or = II, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of grade I and I-II HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade II and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.