Aloperine targets lysosomes to inhibit late autophagy and induces cell death through apoptosis and paraptosis in glioblastoma.

Glioblastoma (GBM) is an aggressive intracranial tumour, and current chemotherapy regimens have limited efficacy. Aloperine (ALO), a natural alkaline compound, has shown potential as an antitumor agent. However, the effect of ALO against GBM remains unclear. This study aimed to investigate the function of ALO in treating GBM. U87, A172, and GL261 cell lines were used for in vitro experiments, and GL261 was also used to establish in vivo models. The results showed that ALO inhibited the proliferation of GBM cells by cell cycle arrest and apoptosis. Furthermore, autophagy was found to play a critical role, suggested by observation of autophagosomes under the transmission electron microscopy. It was discovered for the first time that ALO targeted lysosomes directly in glioma cells, tested by fluo-rescence-labelled ALO and organelle-localizing probes. In addition, ALO inhibited late autophagy and induced paraptosis in GBM, verified by classical gene expression changes in qPCR and western blotting. Also, ALO inhibited tumour growth and acted synergistically with temozolomide in intracranial glioma mice models in vivo. Our findings suggest that ALO targets lysosomes to inhibit late autophagy in GBM, inducing cell cycle arrest, paraptosis, and apoptosis. ALO may therefore be a promising therapeutic agent for the treatment of GBM.

Benign gallbladder disease is a risk factor for colorectal cancer, but cholecystectomy is not: A propensity score matching analysis.

Background: Previous studies reported controversial results on the relationship between cholecystectomy (CHE) and colorectal cancer (CRC). We hypothesized that gallbladder disease (GBD), instead of cholecystectomy, increased the risk of CRC. We aimed to investigate the incidence of benign gallbladder disease (BGBD) and CHE in CRC patients and local adults undergoing annual health examination by analyzing large data from a tertiary hospital in southwest China. Methods: A propensity score matching (PSM) analyzed, retrospective study from January 1, 2013, to August 31, 2020, including 7,471 pathologically confirmed CRC patients and 860,160 local annual health examination adults in the First Affiliated Hospital of Chongqing Medical University, was conducted. The prevalence of BGBD and the CHE rate were analyzed before and after a 1:1 PSM. Results: Of the 7,471 CRC patients, 7,160 were eligible for the case group. In addition, 860,160 local health examination adults were included for comparison. The incidence of BGBD was higher in the CRC patients than in the local adults (19.2% vs. 11.3%, P < 0.001), but no significant difference in CHE rate existed between the case group and the control group (5.0% vs. 4.8%, P = 0.340). In the subgroup analysis, patients with BGBD had a higher risk of colon cancer than rectal cancer (20.4% vs. 18.2%, P = 0.024) and more significantly in the right colon (P = 0.037). A weakly positive correlation between CHE and right colon cancer was observed before PSM but no longer existed after PSM (P = 0.168). Conclusions: Benign gallbladder disease was positively correlated with colorectal cancer, especially right colon cancer. Cholecystectomy did not increase the risk of colorectal cancer.

Role of CYP4F2 as a novel biomarker regulating malignant phenotypes of liver cancer cells via the Nrf2 signaling axis.

Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancer worldwide. The present study attempted to identify a prognostic biomarker for HCC. RNA sequencing data from the GSE63863 dataset were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified based on a protein-protein interaction (PPI) network, and prognostic evaluation was subsequently conducted. Following lentiviral transfection, the migratory, proliferative and apoptotic abilities of cells were evaluated using wound healing, Cell Counting Kit-8, Transwell migration and apoptosis assays. A total of 192 DEGs were identified from 11 pairs of HCC and matched non-tumor samples. The PPI network revealed the top three modules, and eight genes were identified from these modules. The expression levels of cytochrome P450 family 4 subfamily F member 2 (CYP4F2) were downregulated in 50 HCC samples from The Cancer Genome Atlas and in the HCC Hep3B cell line. Low CYP4F2 expression was associated with a lower overall survival time. Functional studies revealed that CYP4F2 overexpression inhibited HCC cell proliferation and migration, and induced apoptosis. Furthermore, CYP4F2 overexpression repressed the expression of genes in the nuclear factor, erythroid 2 like 2 (Nrf2) signaling pathway, including Nrf2, heme oxygenase-1 and ferritin heavy chain 1, while increasing NAD(P)H quinone dehydrogenase 1 expression, suggesting that CYP4F2 overexpression reversed the antioxidant response of liver cancer cells. Overall, the present findings indicated that CYP4F2 may be a potential prognostic biomarker for predicting tumorigenesis and long-term survival rates in patients with HCC.

Peritoneal metastasis after emergency hepatectomy and delayed hepatectomy for spontaneous rupture of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Delayed hepatectomy is the preferred approach for spontaneous rupture of resectable hepatocellular carcinoma (HCC). However, delayed surgery for ruptured HCC may increase the risk of peritoneal metastasis. METHODS: A retrospective analysis was conducted on the pooled data obtained from 44 HCC patients with spontaneously ruptured hemorrhage, These patients were divided into emergency group and delayed group. Perioperative events, overall survival (OS) and disease-free survival (DFS) rates, and the incidence of recurrent and metastatic disease were compared between these two groups. RESULTS: Median survival time was 17.0 months in the emergency group vs. 28.0 months in the delayed group. In the emergency group, the 6-month, 1-year and 3-year OS rates were 58.8%, 57.6% and 11.5%. In the delayed hepatectomy group, the 6-month, 1-year and 3-year OS rates of were 84.3%, 77.5% and 37.8%. The incidence of peritoneal metastasis was higher in delayed group than in the emergency group, but the difference was not statistically significant (40.7% vs. 35.3%, P > 0.05). CONCLUSION: Delayed hepatectomy warrants better short-term prognosis, compared with emergency hepatectomy, for HCC patients with spontaneously ruptured hemorrhage. Delayed hepatectomy does not increase the possibility of postoperative peritoneal metastasis.

Relative Factors Analysis of Imatinib Trough Concentration in Chinese Patients with Gastrointestinal Stromal Tumor.

AIMS: Imatinib plasma trough levels (IM Cmin) have been reported to have a considerable clinical impact in patients with gastrointestinal stromal tumors (GISTs). We therefore have investigated the factors affecting IM plasma concentration in Chinese GIST patients. METHODS: IM Cmin in 190 patients with GIST who were taking IM were measured. RESULTS: In patients treated with IM 300 mg/day (n = 16), 400 mg/day (n = 168), and > 400 mg/day (500: n = 1, 600: n = 5), IM Cmin was 1,564.54 ± 596.15, 1,521.26 ± 610.33, and 2,540.31 ± 1,298.14 ng/mL, respectively. Of the 168 patients treated with IM 400 mg/day, IM Cmin was significantly lower in males (1,353.94 ± 492.89 ng/mL) than in females (1,680.79 ± 669.03 ng/mL, p < 0.01), and in patients with gastrectomy (1,439.60 ± 587.66 ng/mL) than those without gastrectomy (1,649.88 ± 620.12 ng/mL) (p = 0.033). High IM Cmin was correlated with low body weight (p = 0.004) and low body surface area (p < 0.001). CONCLUSION: IM Cmin at steady state was significantly associated with body weight and body surface area. Monitoring of IM Cmin might be particularly important for the optimal treatment with IM of male patients and those who have undergone gastrectomy.

[Short-term use of rapamycin combined with Tregs prolongs mouse cardiac graft survival but attenuates recipient's anti-tumor immunity].

Objective: To study the effect of short-term use of rapamycin( Rap) combined with regulatory T cells( Tregs)on the long-time survival of allogeneic mouse cardiac transplant,and its impact on the anti-tumor immunity of recipient. Methods: Mouse Tregs were purified from recipients' spleen by magnetic activated cell sorting( MACS),and expanded by CD3 / CD28 monoclonal antibody immunomagnetic beads and 2000 U / m L recombinant mouse IL-2( rm IL-2) ex vivo. The purity was tested by fluorescence-activated cell sorting( FACS). Allogeneic mouse cardiac transplanted models were established( H-2~bto H-2~d),and the mice were divided into three groups: control group( transplant only),Rap group,and Rap combined with Tregs group. In the Rap group,the mice were treated with Rap [1 mg /( kg·d),ip] for 14 consecutive days,and the mice in the Rap plus Tregs group received the same treatment,and 1 × 107 Tregs were adoptively transferred through the tail vein on the day of transplantion. Meanwhile,the syngeneic transplanted group was set up( H-2~dto H-2~d). Allograft survival was monitored daily and the graft was harvested on the indicated day and histologically evaluated. In the experiment of recipient's anti-tumor immunity,the similar three groups of allogeneic cardiac transplanted models were established( H-2~bto H-2~d),and B16-F10 cells( recipient derived) were transferred through the tail vein, another three groups of allogeneic cardiac transplanted mice( H-2~dto H-2~b) were also transferred with B16-F10 cells( donor derived). Two weeks later,the tumor nodules of the lung were compared. Results: The median survival time( MST) of the graft was 7 days in the control group,15 days in the Rap group,and 93 days in the Rap combined with Tregs group. Histologic analysis of long-time survival grafts showed lymphocyte infiltration and chronic vasculopathy. For donor-derived tumor,there was no tumor nodule in the control group,and tumor nodules significantly increased to 15 ± 8 in the Rap group and 14 ± 7 in the Rap combined with Tregs group,with no significant difference between the later two groups; for recipient-derived tumor,the tumor nodules in the Rap combined with Tregs group were 146 ± 12,which were significantly elevated compared with the control group( 70 ± 12) and the Rap group( 28 ± 9). Conclusion: Short-term use of low-dose Rap combined with Tregs can significantly prolong the survival of transplanted mouse heart,but cannot inhibit tumorigenesis of the recipient.

Systemic and intratumoral balances between monocytes/macrophages and lymphocytes predict prognosis in hepatocellular carcinoma patients after surgery.

The peripheral neutrophil-monocyte/lymphocyte ratio (NMLR) and intratumoral CD16/CD8 ratio (iMLR) may have prognostic value in hepatocellular carcinoma (HCC) patients after curative resection. In this study, the circulating NMLR was examined 387 HCC patients who underwent curative resection between 2006 and 2009. Intratumoral levels of CD4, CD8, CD16 and CD68 and the CD16/CD8 ratio were determined immunohistologically. The prognostic values of clinicopathological parameters, including NMLR and iMLR, were evaluated. NMLR was predictive of overall survival (OS) and recurrence-free survival (RFS) when patients in the training cohort (n = 256) were separated into high (> 1.2) and low (≤ 1.2) NMLR subgroups. NMLR was also an independent predictor of low alpha-fetoprotein (AFP) expression and early recurrence. High NMLR was associated with increases in clinicopathological variables, including alanine aminotransferase (ALT), tumor number, tumor size and BCLC stage. In addition, iMLR strongly predicted risk of recurrence and patient survival, and was positively correlated with NMLR. These findings were confirmed in an independent validation patient cohort (n = 131). Peripheral NMLR and iMLR may thus be useful prognostic markers, and anti-inflammatory treatment may be beneficial in HCC patients after curative hepatectomy.

Preoperative neutrophil-to-lymphocyte ratio predicts recurrence of patients with single-nodule small hepatocellular carcinoma following curative resection: a retrospective report.

BACKGROUND: Preoperative neutrophil-to-lymphocyte ratio (NLR) has been identified as a predictor for the recurrence of hepatocellular carcinoma (HCC), but the cut-off of NLR is inconsistent in various studies. Thus, we detected the prognostic value of preoperative NLR in the single-nodule small HCC (SHCC) patients using X-tile for cutpoint. METHODS: Between January 2007 and December 2010, a total of 222 single-nodule SHCC patients underwent curative resection and were examined for the prognostic roles of preoperative NLR by X-tile. RESULTS: In this study, all patients were divided into the low-NLR subgroup (NLR ≤ 2.1) and the high-NLR subgroup (NLR > 2.1) by X-tile. Preoperative NLR showed predictive value for time to recurrence (TTR) and overall survival (OS). Moreover, NLR was associated with total bilirubin, white blood cell counts, and HBsAg, respectively (P = 0.012, <0.001, and 0.011, respectively). Especially, NLR could discriminate the outcome of patients in the subgroup with alpha-fetoprotein (AFP) levels of ≤400 ng/mL. Importantly, postoperative transcatheter arterial chemoembolization (TACE) had close relationship with OS (P = 0.001) and TTR (P ≤ 0.001). CONCLUSIONS: Therefore, this study indicates that preoperative NLR, divided by X-tile for the cutpoint, is a simple prognostic marker for the patients with single-nodule SHCC after curative resection.

Conditional survival of pancreatic ductal adenocarcinoma in surgical and nonsurgical patients: a retrospective analysis report from a single institution in China.

BACKGROUND: Conditional survival (CS) could offer reliable prognostic information for patients who survived beyond a specified time since diagnosis when the impact of late effects have the greatest influence on prognosis. We aim to investigate CS for pancreatic ductal adenocarcinoma (PDAC) patients with surgery and nonsurgery. METHODS: Chinese PDAC patients between January 2002 and September 2012 were reviewed for analyses. CS rates were calculated for survivors after surgery and nonsurgery at different time points. RESULTS: Several clinicopathologic features were associated with overall survival (OS) in each subgroup including curative resection, palliative surgery, and nonsurgery. Both univariate and multivariate analyses showed that chemotherapy was a critical predictor for OS regardless of treatment status. CS rates were higher in the curative resected patients than other cases at the same time points. Importantly, stratification of 1-year CS by carcinoembryonic antigen (CEA), (carbohydrate antigen) CA19-9, and tumor stage showed lower CEA, CA19-9, and tumor stage associated with favorable 1-year CS over time (P = 0.016, 0.009 and 0.003). CONCLUSIONS: Dynamic CS estimates could be an accurate assessment for the prognosis of PDAC patients, allowing patients and clinicians to project subsequent survival based on time change.

Transcriptome sequencing and comparative analysis reveal long-term flowing mechanisms in Hevea brasiliensis latex.

BACKGROUND: The rubber tree, Hevea brasiliensis, is a major commercial source of natural rubber. Increasing the rubber yield of rubber trees is a very serious problem since the demands for high quality rubber materials are great. Establishment of a tapping system is based on an estimate of tapping intensity from the rubber tree. Latex flowing time is one of the most critical factors that determine the rubber yield. Long-term flow is a type of phenomenon of the rubber tree latex with longer flowing time than normal latex flow, and is always caused by intensive tapping. Thus, transcriptome and expression profiling data for long-term flowing latex (LFL) are needed as an important resource to identify genes and to better understand the biological mechanisms of latex flow in rubber trees. RESULTS: The transcripts were sequenced using the Illumina sequencing platform. After cleaning, quality checks and sequencing, 98,697 transcripts and 38,584 unigenes were assembled with the mean size of 1437.31bp and 923.86bp, respectively. In BLAST searches of our database against public databases, 65.17% (25,147) of the unigenes were annotated with gene descriptions, conserved protein domains, or gene ontology terms. Functional categorization further revealed 853 individual unigenes related to long-term flow. According to KEGG classification, the clusters for "cysteine and methionine metabolism", "energy", "oxidative phosphorylation", "terpenoid backbone biosynthesis", "plant hormone signal transduction" and "copper, potassium transporter" were significantly enriched metabolic pathways. CONCLUSIONS: We conducted high-resolution transcriptome profiling related to LFL in H. brasiliensis. The research facilitates further studies on gene discovery and on the molecular mechanisms related to the estimation of tapping intensity and prolonging latex flowing time. We concluded that it was necessary to improve energy supplies for intensive tapping and the copper ion content of rubber tree latex could be considered as a standard to estimate tapping intensity.

Outcomes of simple saline-coupled bipolar electrocautery for hepatic resection.

AIM: To evaluate the application of bipolar coagulation (BIP) in hepatectomy by comparing the efficacy of BIP alone, cavitron ultrasonic surgical aspirator (CUSA) + BIP and conventional clamp crushing (CLAMP). METHODS: Based on our database of patient records, a total of 380 consecutive patients who underwent hepatectomy at our hospital were retrospectively studied for the efficacy of BIP alone, CUSA + BIP and CLAMP. Of all the patients, 75 received saline-coupled BIP (Group A), 53 received CUSA + BIP (Group B), and 252 received CLAMP (Group C). The pre-, mid-, and postoperative clinical manifestations were compared, and the effects of those maneuvers were evaluated. RESULTS: There was no obvious difference among the preoperative indexes between the different groups. The operative time was longer in Groups A and B than in Group C (P < 0.001 for both). The amount of bleeding and the rate of transfusion during the operation were significantly higher in Group C than in Groups A and B (P < 0.001 for all). The incidence of postoperative complications in Group C (46.43%) was higher than that in Groups A (30.67%, P = 0.015) and B (28.30%, P = 0.016). The patients' liver function recovery and postoperative hospital stay were not significantly different. BIP could decrease intraoperative hemorrhage and postoperative complications compared to CLAMP. CONCLUSION: Simple saline-coupled BIP should be considered a safe and reliable technique for liver resection to decrease intraoperative hemorrhage and postoperative complications.

[Infusion of ex vivo expanded homologous CD4⁺;CD25⁺; regulatory T cells promotes the susceptibility to tumor in mice].

OBJECTIVE: To study the effects of adoptive transfer of ex vivo expanded homologous CD4⁺;CD25⁺; regulatory T cells (Tregs) on antitumor immunity in mice and explore the potential risk of this therapeutic method. METHODS: Marine CD4⁺;CD25⁺; Tregs were separated from spleens by magnetic activated cell sorting (MACS) and expanded by anti-CD3/CD28-coated microbeads and 1 000 U/mL interleukin 2 (IL-2) in vitro. The purity of fresh and expanded Tregs was determined by FACS. The cells were collected after two rounds of expansion (7 days each), and suppressive activity of expanded Tregs was tested by the mixed lymphocyte reaction (MLR) in vitro. Thereafter, the BALB/c mice were intravenously injected with 1 × 107 expanded Tregs and 24 hours later, they were inoculated intravenously with 1 × 106; B16;F10; tumor cells. The mice injected with tumor cells only were set as the control group. Fourteen days later, the percentage of CD4⁺;CD25⁺;Foxp3⁺; Tregs in peripheral blood was analyzed by flow cytometry and the numbers of pulmonary metastases were counted. Results The purity of expanded Tregs decreased from (96.3 ± 2.88)% to (87.73 ± 2.35)% compared with fresh Tregs, but there was no significant difference in the suppressive activity between fresh Tregs and expanded Tregs (P>0.05). The number of tumor nodules in lung of BALB/c mice was significantly elevated from 14 ± 5 to 73 ± 9 after injected 1 × 107; expanded Tregs compared with the control group (P=0.007), and the same with the mice that were inoculated with 2 × 106; B16;F10; cells alone (P=0.230). What's more, the number of pulmonary metastases was significantly raised from 70 ± 15 to over 300 (P<0.01) in 5 × 105; B16;F10; inoculated C57BL/6 mice if they were injected previously with 8 × 106; expanded Tregs. The percentage of Foxp3⁺; Tregs in peripheral blood significantly increased in the experimental group as compared with normal mice and control group (P<0.05). Conclusion Adoptive transfer of ex vivo expanded Tregs can induce the immune tolerance and inhibit the antitumor immunity at the same time. There was a potential risk in the clinical application of Tregs.

The effect of fibroblast activation on vascularization in transplanted pancreatic islets.

BACKGROUND: Insufficient revascularization of transplanted pancreatic islets is an important reason why the long-term effects of pancreatic islet transplantation on type I diabetes patients have been so limited. The goal of this study was to investigate the role of fibroblasts (FBs) activated by tumor cell supernatants on the vascularization of transplanted pancreatic islets. MATERIALS AND METHODS: Pancreatic islets and activated or inactivated FBs were used for subrenal capsule transplantation. Mouse melanoma cell supernatants were used to activate FBs; the tests of the purity of the pancreatic islet cells of the donor, survival rate, and function of insulin secretion were performed to ensure high-quality transplants. Mice receiving the allogeneic transplantation were given tacrolimus and sirolimus to prevent rejection. The diabetic model was induced by streptozotocin. RESULTS: Conditioned medium made of tumor cell supernatants was found to stimulate the expression of α-smooth muscle actin and vascular endothelial growth factor A to an extent notably greater than that of pancreatic islet transplantation alone or pancreatic islet transplantation combined with inactivated FBs. FBs from the recipient were associated with capillary density in the transplanted pancreatic islet most closely to that observed in isogenically transplanted pancreatic islets and the original pancreatic islet. In this way, activated FBs derived from the recipient combined with pancreatic transplantation were able to treat diabetes, and long-term survival was achieved. CONCLUSIONS: The current research sheds new light on the revascularization of transplanted pancreatic islets: activated FBs derived from the recipients, when transplanted alongside pancreatic tissue, can promote revascularization inside the transplanted pancreatic islet.

[Multivariate analysis of the efficacy of laparoscopic splenectomy in the treatment of immune thrombocytopenic purpura].

OBJECTIVE: To identify factors that can effectively predict the efficacy of laparoscopic splenectomy (LS) in the treatment of immune thrombocytopenic purpura (ITP). METHODS: From January 2007 to September 2012, 78 patients with ITP underwent laparoscopic splenectomy were retrospectively analyzed. According to the postoperative platelet (PLT) count and haemorrhagic manifestations, they were divided into effective group and ineffective group. Nine influencing factors were univariate analyzed and multivariate analyzed. RESULTS: In effective group (65 cases) and ineffective group (13 cases), average PLT count of 1 day before surgery was 47×10(9)/L vs. 21×10(9)/L, average operative time was (166 ± 46) minutes vs. (139 ± 29) minutes. Univariate analysis result: PLT count of 1 day before surgery (Z = -2.776, P = 0.005) and operative time (t = 2.723, P = 0.011) was statistically significant in 2 groups, the rest factors did not significantly influence the result. Multivariate analysis revealed that only PLT count of 1 day before surgery was statistically significant (OR = 0.964, 95%CI: 0.932-0.997, P = 0.031) in 2 groups, but operative time (P = 0.051) was not statistically significant. CONCLUSIONS: PLT count of 1 day before surgery is a predict factor in LS for ITP. Because of the limited sample number, further multi-center prospective study with large sample is warrant.

Impact of simultaneous splenectomy and orthotopic liver transplantation in patients with end-stage liver diseases and splenic hyperfunction.

BACKGROUND: Whether splenectomy can be performed simultaneously during liver transplantation in patients with end-stage liver diseases complicated by hypersplenism remains controversial. This study aimed to compare the impact of simultaneous splenectomy on high- and low-risk liver transplant patients with end-stage liver diseases and severe hypersplenism. METHODS: Forty-two patients with end-stage liver diseases complicated by severe hypersplenism who had undergone orthotopic liver transplantation were enrolled in this study. Splenectomy was performed in 19 of the patients. The 42 patients were grouped according to the risk of liver diseases and operations they received. Patients were considered to be at high-risk if they had at least one of the following conditions: preoperative prothrombin time >5 seconds, portal vein thrombosis, and severe perisplenitis. High-risk patients who had undergone splenectomy were classified into group A, whereas high-risk patients who had not undergone splenectomy were classified into group B. Low-risk patients who had undergone splenectomy were classified into group C, and low-risk patients who had spleen preservation were classified into group D. Operative time, intraoperative blood loss, postoperative bleeding, pulmonary infection, perioperative mortality, and postoperative platelet recovery were analyzed. RESULTS: Operative time and intraoperative blood loss were greater in group A than in groups B-D (P<0.01), but there was no significant difference between groups C and D (P>0.05). In group A, 3 patients had postoperative bleeding, 5 had pulmonary infection, and 2 had perioperative mortality, which was higher than any other group, but postoperative bleeding, pulmonary infection, and perioperative mortality were similar to those in groups C and D. In patients undergoing simultaneous splenectomy, platelet counts recovered within 6 months after surgery. Thrombocytopenia was sustained in 3 of the 23 patients who did not undergo simultaneous splenectomy. CONCLUSION: Splenectomy should be avoided during orthotopic liver transplantation in high-risk patients, but this procedure does not increase the operative risk in low-risk patients and may be a valuable method to ensure good postoperative platelet recovery.

The augmenter of liver regeneration protects the kidneys after orthotopic liver transplantation possibly by upregulating HIF-1α and O2-sensitive K+ channels.

PURPOSE: The augmenter of liver regeneration (ALR) might promote better renal function after orthotopic liver transplantation (OLT). Using a rat allogeneic OLT model, we investigated if ALR can mediate renal protection and its potential mechanisms. METHODS: Orthotopic liver transplant recipients were assigned to a cyclosporine A (CsA)-treated group (CsA group) and an ALR+CsA group (ALR group). Transplanted liver, kidneys, and serum were harvested on post-transplantation days 1, 3, and 7 for histological examination, and hepatic function and renal function analysis. We also measured the expression of hypoxiainducible factor-1 (HIF-1α) and O(2)-sensitive K(+) cannels (KV1.5 and KV2.1), and free Ca(2+) in the smooth muscle cells (SMCs) of intrarenal arterioles in the kidneys. RESULTS: All transplanted livers suffered mild acute rejection after OLT. Recipient kidney damage was more severe in the CsA group, characterized by increased serum creatinine, tubular epithelial apoptosis and necrosis, and the formation of casts. In the ALR group, HIF-1α, KV1.5, and KV2.1 were upregulated, accompanied by lower Ca(2+) concentration, in the SMCs shortly after OLT. CONCLUSION: Augmenter of liver regeneration might increase the expression of HIF-1α and K(+) channels and decrease intracellular free Ca(2+), thereby inhibiting arterial contraction and promoting kidney perfusion immediately after OLT.