Neuropilin-1 regulates renin synthesis in juxtaglomerular cells.

Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.

Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy.

Accumulating evidence highlights mitochondrial dysfunction as a crucial factor in the pathogenesis of acute kidney injury (AKI); thus, novel therapeutic strategies maintaining mitochondrial homeostasis are highly anticipated. Recent studies have shown that cobaltosic oxide has peroxidase-like catalytic activities, although its role and mechanism remain elusive in AKI. In the present study, we synthesized and identified cobaltosic oxide-polyethylene glycol-triphenylphosphine (COPT) nanoparticles by conjugating cobaltosic oxide with polyethylene glycol and triphenylphosphine, to improve its biocompatibility and mitochondria-targeting property. We found that COPT preferentially accumulated in the kidney proximal tubule cells, and significantly alleviated ischemic AKI in mouse models and gentamicin induced-AKI in the zebrafish model. COPT also inhibited the transition from AKI to chronic kidney disease (CKD), with few side effects. Further studies demonstrated that COPT localized in the mitochondria, and ameliorated hypoxia-reoxygenation-mediated mitochondrial damage through enhancing mitophagy in vitro and in vivo. Mechanistically, COPT dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 attenuated COPT-induced mitophagic flux and mitochondrial protection. Thus, our findings suggest that COPT nanoparticles ameliorate AKI and its progression to CKD through inducing BNIP3-mediated mitophagy, indicating that COPT may serve as a promising mitochondria-targeting therapeutic agent against AKI.

Arteriolar hyalinosis and renal outcomes in patients with immunoglobulin A nephropathy.

BACKGROUND: The relationship between arteriolar hyalinosis and renal progression in immunoglobulin A nephropathy (IgAN) is not fully understood. We aimed to investigate the clinicopathological features and outcomes of IgAN with or without arteriolar hyalinosis. METHODS: A total of 762 diagnosed with IgAN patients were retrospectively analyzed. We classified IgAN patients into two groups with or without arteriolar hyalinosis. Then, the clinicopathological characteristics of the two groups were compared. We used Kaplan-Meier survival analysis to compare the composite kidney outcome of the two groups and applied multivariate Cox regression analyses to test the association between arteriolar hyalinosis and composite kidney outcome. RESULTS: Overall, 412 (54.1%) patients had arteriolar hyalinosis, including 173 patients diagnosed with hypertension. IgAN patients with arteriolar hyalinosis were older and had higher proteinuria, urea, uric acid, and blood pressure, while lower eGFR than those without arteriolar hyalinosis. Subgroup analysis showed similar results in IgAN patients with hypertension. Kaplan-Meier survival analysis showed that IgAN patients with arteriolar hyalinosis had worse composite kidney outcome than those without arteriolar hyalinosis. In addition, subgroup analysis revealed that patients with hypertension have worse composite kidney outcome than those without hypertension. Multivariate Cox regression analyses confirm that arteriolar hyalinosis (HR 2.57; 95% CI 1.41-4.69; p = 0.002) is an independent risk factor for renal prognosis in IgAN patients. CONCLUSIONS: Our study demonstrated that arteriolar hyalinosis is a common vascular lesion in IgAN patients. Arteriolar hyalinosis connects closely with hypertension, and arteriolar hyalinosis is an independent risk factor for renal prognosis in patients with IgAN.

CXCL8 is a prognostic biomarker and correlated with TNBC brain metastasis and immune infiltration.

Patients with TNBC are associated with an increased risk of developing brain metastasis and shortest median survival post-brain metastasis-diagnosis. However, the regulatory mechanism of TNBC brain metastasis has not been addressed. Here, by a series of integrated analyses of differential gene expression profile from brain metastases and primary triple negative breast cancer, we identified 15 differentially expressed genes in both TNBC brain metastasis tissue samples and TNBC brain metastasis cell line. After analyzing the prognostic value of those 15 differentially expressed genes, we found that CXCL8 was the only gene associated with multiple prognostic indicators in both all-breast cancer and TNBC populations. Functional and pathway enrichment analyses demonstrated that CXCL8 was associated with humoral immune response and immune cell infiltration. CXCL8 expression had a positive correlation with three immune-related scores (ImmuneScore, ESTIMATEScore and StromalScore), and multiple types of immune cell infiltration, including macrophages, neutrophils and Th1 cells. Besides, we also verified the prometastatic effect of CXCL8, by treating MDA-MB-231 and Hs578t cells with different concentrations of recombinant human CXCL8. Taken together, our results suggest that CXCL8 can be used as a prognostic biomarker and is associated with TNBC brain metastasis and immune infiltration. Our findings provide a new perspective on TNBC brain metastasis and illustrate great potential to develop new CXCL8-targeted therapy for clinical TNBC patients.

Antiplatelet therapy for the prevention of atherosclerosis in chronic kidney disease (ALTAS-CKD) patients: study protocol for a randomized clinical trial.

BACKGROUND: Cardiovascular disease (CVD) is the most common complication and the leading cause of death in patients with chronic kidney disease (CKD). Accelerated atherosclerosis is a pathophysiological process that is vital to the occurrence of cardiovascular complications associated with CKD. Abnormal platelet activation is not only the leading cause of atherosclerosis but also plays a critical role in the occurrence of thrombotic events. Currently, antiplatelet drugs are commonly used as a secondary prevention strategy for high blood pressure, obesity, diabetes, and ischemic heart disease and can reduce the risk of CVD in the susceptible population. However, the benefits and evidence of using antiplatelet agents in patients with CKD remain controversial. This study aimed to determine whether antiplatelet therapy can safely prevent atherosclerosis in patients with CKD in the primary care setting. METHODS/DESIGN: The ALTAS-CKD study is a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 554 adult patients with stage 3-5 non-dialysis-dependent CKD recruited from 10 territory medical centers in China. A secured web-based computer randomization system will be used to administer aspirin 100 mg once daily or a matching inactive placebo for 36 months. The primary endpoint will be the occurrence of atherosclerosis, as measured by carotid ultrasonography. The secondary endpoints will be combined cardiovascular events, all-cause mortality, and 50% decrease in the estimated glomerular filtration rate. TRIAL REGISTRATION {2A}: Current controlled trials number: ChiCTR1900021393 . Registered on 18 February 2019.

Potential Role of the Renal Arterial Resistance Index in the Differential Diagnosis of Diabetic Kidney Disease.

Aims: To investigate the potential role of renal arterial resistance index (RI) in the differential diagnosis between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) and establish a better-quantified differential diagnostic model. Materials and Methods: We consecutively reviewed 469 type 2 diabetes patients who underwent renal biopsy in our center. According to the renal biopsy results, eligible patients were classified into the DKD group and the NDKD group. The diagnostic significance of RI was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to search for independent risk factors associated with DKD. Then a novel diagnostic model was established using multivariate logistic regression analysis. Results: A total of 332 DKD and 137 NDKD patients were enrolled for analysis. RI was significantly higher in the DKD group compared with those in the NDKD group (0.70 vs. 0.63, p< 0.001). The optimum cutoff value of RI for predicting DKD was 0.66 with sensitivity (69.2%) and specificity (80.9%). Diabetic retinopathy, diabetes duration ≥ 60 months, HbA1c ≥ 7.0(%), RI ≥ 0.66, and body mass index showed statistical significance in the multivariate logistic regression analysis. Then, we constructed a new diagnostic model based on these results. And the validation tests indicated that the new model had good sensitivity (81.5%) and specificity (78.6%). Conclusions: RI has a potential role in discriminating DKD from NDKD. The RI-based predicting model can be helpful for differential diagnosis of DKD and NDKD.

Curcumin derivative C212 inhibits Hsp90 and eliminates both growing and quiescent leukemia cells in deep dormancy.

BACKGROUND: Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality. Leukemia relapse is due to residual quiescent leukemia cells that escape conventional therapies and later reemerge. Eliminating not only growing but quiescent leukemia cells is critical to effectively treating leukemia and preventing its recurrence. Such dual targeting therapeutic agents, however, are lacking in the clinic. To start tackling this problem, encouraged by the promising anticancer effects of a set of curcumin derivatives in our earlier studies, we examined in this work the effects of a 4-arylmethyl curcumin derivative (C212) in eliminating both growing and quiescent leukemia cells. METHODS: We analyzed the effects of C212 on the growth and viability of growing and quiescent leukemia cells using MTS, apoptosis, cell cycle and cell tracking assays. The effects of C212 on the quiescence depth of leukemia cells were measured using EdU incorporation assay upon growth stimulation. The mechanisms of C212-induced apoptosis and deep dormancy, particularly associated with its inhibition of Hsp90 activity, were studied using molecular docking, protein aggregation assay, and Western blot of client proteins. RESULTS: C212, on the one hand, inhibits growing leukemia cells at a higher efficacy than curcumin by inducing apoptosis and G2/M accumulation; it, on the other hand, eliminates quiescent leukemia cells that are resistant to conventional treatments. Furthermore, C212 drives leukemia cells into and kills them at deep quiescence. Lastly, we show that C212 induces apoptosis and drives cells into deep dormancy at least partially by binding to and inhibiting Hsp90, leading to client protein degradation and protein aggregation. CONCLUSION: C212 effectively eliminates both growing and quiescent leukemia cells by inhibiting Hsp90. The property of C212 to kill quiescent leukemia cells in deep dormancy avoids the risk associated with awaking therapy-resistant subpopulation of quiescent leukemia cells during treatments, which may lead to the development of novel therapies against leukemia relapse. Video abstract.

An expansion study of genotype-driven weekly irinotecan and capecitabine in combination with neoadjuvant radiotherapy for locally advanced rectal cancer with UGT1A1 *1*1 genotype.

BACKGROUND: In our previous dose-escalation study, we uncovered the maximum tolerated dose (MTD) of weekly irinotecan was escalated to 80 mg/m2 and 65 mg/m2 for UDP glucuronosyltransferase family 1 member A1 (UGT1A1) *1*1 and *1*28 rectal cancer patients in neoadjuvant chemoradiotherapy (nCRT). This is an expansion study for *1*1 patients. METHODS: Patients with clinical stage T3-4, N0-2 rectal cancer eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. A total of 52 patients with the *1*1 genotype were enrolled. Whole-pelvic intensity-modulated radiation therapy was given in 50 Gy/25 fractions. Concurrently, irinotecan of 80 mg/m2 and capecitabine of 625 mg/m2 twice daily from Monday to Friday were administered weekly. Primary endpoint was toxicities; secondary endpoints included pathological complete response (pCR), tumour-regression grading, treatment compliance, overall survival, local recurrence and disease-free survival. RESULTS: All patients completed capecitabine-based radiotherapy as scheduled, and 42 (81%) patients completed more than three cycles of weekly irinotecan. Overall, grade 3/4 toxicities were observed in 20 cases, including 11 leucopenia, 10 neutropenia and 12 diarrhoea. Forty-three patients (83%) underwent a radical surgery, and 12 were evaluated as pCR. Another four patients accepted a watch-and-wait strategy because of clinical complete response (CCR). CONCLUSIONS: Our data demonstrated manageable toxicities and an encouraging CCR rate for UGT1A1 *1*1 genotype in an enhanced neoadjuvant therapy. A phase III trial is ongoing to evaluate the value of irinotecan in neoadjuvant therapy (CinClare) [ClinicalTrials.gov identifier: NCT02605265].

Alloreactive cytotoxic T lymphocyte immunotherapy treatment of a patient with metastatic prostate cancer: A case report.

RATIONALE: Cytotoxic T lymphocyte (CTL) immunotherapy is an autologous cellular immune therapy that has been approved for treating patients with malignant tumors. However, there is still limited information regarding the impact of CTL on metastatic prostate cancer (PC) patients with bone metastatic lesions. PATIENT CONCERNS: An 82-year-old male patient complained of interrupted urination, urination pain, and significant dysuria on November 24, 2014. Transurethral resection of the prostate (TURP) and postoperative pathological examination showed prostatic adenocarcinoma, and a SPECT/CT scan demonstrated multiple bone metastases. In addition, prostate specific antigen (PSA) and free PSA (FPSA) levels were 54.54 µg/mL and 2.63 µg/mL, respectively, at the beginning of treatment. DIAGNOSES: The man was diagnosed with prostatic adenocarcinoma and multiple bone metastases. INTERVENTIONS: The patient received 30 cycles of alloreactive CTL (ACTL) immunotherapy regularly. OUTCOMES: Over the course of the 2-year treatment, the PC patient exhibited diminished bone metastasis accompanied by a marked reduction of serum PSA and FPSA from 54.54 and 2.63 µg/ml to 0.003 and <0.006 µg/ml, respectively. LESSONS: Our clinical observations demonstrate that CTL immunotherapy is a viable treatment option for PC patients, particularly those with bone metastatic lesions and high serum levels of PSA and FPSA.

Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer.

PURPOSE: We aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1∗28 genotype in patients with locally advanced rectal cancer. PATIENTS AND METHODS: Patients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy were screened for the UGT1A1∗28 genotype. Twenty-six patients with either the ∗1∗1 or ∗1∗28 genotype were eligible for dose escalation of irinotecan, and patients with a ∗28∗28 genotype were excluded. The starting dose of weekly irinotecan was 50 mg/m2 for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m2. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions). RESULTS: The dose of weekly irinotecan was escalated to 95 mg/m2 in patients with the ∗1∗1 genotype and to 80 mg/m2 in those with the ∗1∗28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 ∗1∗1 patients at 95 mg/m2 and 2/3 ∗1∗28 patients at 80 mg/m2. No DLT cases were observed among the three ∗1∗1 patients at 80 mg/m2, and one DLT case was observed among the six patients with ∗1∗28 at 65 mg/m2. Hence, 80 mg/m2 and 65 mg/m2 were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. CONCLUSION: A higher dose of weekly irinotecan in combination with capecitabine-based CRT is feasible under the guidance of the UGT1A1∗28 genotype. Further clinical trials at these dose levels are warranted.

Sex, Race, and Age Disparities in the Improvement of Survival for Gastrointestinal Cancer over Time.

There have been notable improvements in survival over the past 2 decades for gastrointestinal (GI) cancer. However, the degree of improvement by age, race, and sex remains unclear. We analyzed data from 9 population-based cancer registries included in the SEER program of the National Cancer Institute (SEER 9) in 1990 to 2009 (n = 288,337). The degree of survival improvement over time by age, race, and sex was longitudinally measured. From 1990 to 2009, improvements in survival were greater for younger age groups. For patients aged 20 to 49 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.74 (95% CI, 0.66-0.83), 0.49 (95% CI, 0.37-0.64), 0.69 (95% CI, 0.65-0.76), 0.62 (95% CI, 0.54-0.69), and 0.56 (95% CI, 0.42-0.76), for cancer of the stomach, small intestine, colon, rectum and anus, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. Compared with African Americans, whites experienced greater improvement in small intestinal and anal cancer survival. Female anal cancer and regional anal cancer patients experienced no improvement. Our data suggest that different improvement in survival in age, sex and race exists.

Comparison of the efficacy and safety of S-1-based and capecitabine-based regimens in gastrointestinal cancer: a meta-analysis.

PURPOSE: Oral fluoropyrimidine (S-1, capecitabine) has been considered as an important part of various regimens. We aimed to evaluate the efficacy and safety of S-1-based therapy versus capecitabine -based therapy in gastrointestinal cancers. METHODS: Eligible studies were identified from Pubmed, EMBASE. Additionally, abstracts presented at American Society of Clinical Oncology (ASCO) conferences held between 2000 and 2013 were searched to identify relevant clinical trials. The outcome included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and advent events. RESULTS: A total of 6 studies (4 RCTs and 2 retrospective analysis studies) containing 790 participants were included in this meta-analysis, including 401 patients in the S-1-based group and 389 patients in the capecitabine-based group. Results of our meta-analysis indicated that S-1-based and capecitabine-based regimens showed very similar efficacy in terms of PFS (HR 0.92, 95% CI 0.78-1.09, P = 0.360), OS (HR 1.01, 95% CI 0.84-1.21, P = 0.949), ORR (HR 1.04, 95% CI 0.87-1.25, P = 0.683) and DCR (HR 1.02, 95% CI 0.94-1.10, P = 0.639). There was also no significant difference in toxicity between regimens other than mild more hand-foot syndrome in capecitabine-based regimens. CONCLUSION: Both the S-1-based and capecitabine-based regimens are equally active and well tolerated, and have the potential of backbone chemotherapy regimen in further studies of gastrointestinal cancers.

[CpG methyltransferase induced down-regulation of claudin-7, -8 and its effects on proliferation and apoptosis of human colorectal cancer HT-29 cells].

OBJECTIVE: To explore the regulatory effect of CpG methyltransferase (M.SssI) on expression of claudin-7 and claudin-8, promoting apoptosis and inhibiting proliferation of human colorectal cancer HT-29 cells. METHODS: HT-29 cells were treated with M.SssI (50 U/ml) for 24 hours. The methylation status of claudin-7 and claudin-8 gene promoters was assayed by bisulfite sequencing PCR (BSP). Real-time PCR with SYBR green I technique was used to detect the relative expression of claudin-7 and -8 mRNA, and claudin-7 and claudin-8 proteins were tested by cell immunofluorescence and Western blotting, while the effect on cell apoptosis was assessed by Hoechst 33342 fluorescence and flow cytometry. Inhibition of cell proliferation was measured by MTT assay. RESULTS: The amounts of methylated claudin-7 and claudin-8 gene CpGs were 25, 10 in the M.SssI group, 9 and 5 in the PBS group, 0 and 3 in the 5-azacytidine group, respectively. Compared with the PBS group, Claudin-7 and -8 were significantly reduced by M.SssI (P < 0.05), but increased by 5-azacytidine (P < 0.05) at both mRNA and protein levels. Hoechst 33342 staining revealed that HT-29 cells treated with PBS and 5-azacytidine were not significantly different, showing even blue fluorescence, round shape and same cell volume. But the M.SssI group presented more apoptotic cells with intensive white fluorescence intensity. Cytometry indicated that early apoptotic index of the M.SssI group was increased by 84.7%, compared with that of the PBS group (P = 0.002). Measurement of MTT optical density demonstrated that cell growth of the M.SssI group was significantly lower than that of the PBS group (P = 0.002), with an inhibition rate of 32.1%, whereas the proliferation of 5-azacytidine group was similar to that of the PBS group (P = 0.084). CONCLUSIONS: Our findings suggest that M.SssI can down-regulate claudin-7, -8 mRNA and proteins in the human colon cancer HT-29 cells by up-regulating methylation status of claudin-7 and -8 gene promoters, and finally induce apoptosis and inhibit proliferation of the tumor cells.

Cronkhite-Canada syndrome associated with rib fractures: a case report.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare multiple gastrointestinal polyposis. Up till now, many complications of CCS have been reported in the literature, but rib fracture is not included. CASE PRESENTATION: We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg. On admission, physical examination revealed alopecia of the scalp, hyperpigmentation of the hands and soles, and dystrophy of the fingernails. Laboratory data revealed hypocalcaemia and hypoproteinemia. Esophagogastroduodenoscopy, video capsule endoscopy and colonoscopy revealed various sizes of generalized gastrointestinal polyps. Histological examination of the biopsy specimens obtained from the stomach and the colon showed adenomatous polyp and inflammatory polyp respectively. Thus, a diagnosis of CCS was made. After treatment with corticosteroids for 24 days and nutritional support for two months, his clinical condition improved. Two months later, he was admitted to our hospital for the second time with frequent diarrhea and weight loss. The chest radiography revealed fractures of the left sixth and seventh ribs. Examinations, including emission computed tomography, bone densitometry test, and other serum parameters, were performed, but could not identify the definite etiology of the rib fractures. One month later, the patient suffered from aggravating multiple rib fractures due to the ineffective treatment, persistent hypocalcaemia and malnutrition. CONCLUSIONS: This is the first case of a CCS patient with multiple rib fractures. Although the association between CCS and multiple rib fractures in this case remains uncertain, we presume that persistent hypocalcaemia and malnutrition contribute to this situation, or at least aggravate this rare complication. Besides, since prolonged corticosteroid therapy will result in an increased risk of osteoporotic fracture, CCS patients who accept corticosteroid therapy could be potential victims of rib fracture.

CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis.

AIM: To investigate the effects of the chemokine stromal cell-derived factor-1 (CXCL12) receptor (CXCR4) antagonist AMD3100 on colonic inflammation and epithelial barrier in dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Experimental colitis was induced by administration of 5% DSS for 7 d, and assays performed on intestinal segments from the ileocecal valve to the anus. Colonic morphology was examined by hematoxylin and eosin staining. Colonic cytokines were determined by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity (indicator of inflammatory infiltration) was observed spectrophotometrically. Gut permeability was assessed by mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran 4000 (FD4) in everted gut sacs. The apoptosis of colonic epithelium was assessed by Hoechst-33342 staining. To further elucidate the role of CXCR4 in colonic inflammation, we also investigated the effect of AMD3100 on migration and cytokine production of isolated peripheral blood mononuclear cells (PBMCs). RESULTS: DSS-induced colitis was characterized by morphologic changes, as well as increased colonic cytokines, inflammatory infiltration, epithelial apoptosis, and intestinal permeability in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced; colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) levels, as well as MPO activity were significantly decreased. Increased intestinal permeability in DSS-treated mice was significantly reduced by AMD3100. The number of apoptotic cells in colitis mice was markedly increased after DSS administration, and decreased when treated with the CXCR4 antagonist AMD3100. In pre-activated PBMCs, CXCL12 stimulation significantly increased the migration of PBMCs, and was inhibited by AMD3100. Moderately increased TNF-alpha, IL-6, and IFN-gamma from CXCL12-treated PBMCs were also reduced by AMD3100. CONCLUSION: The CXCR4 antagonist AMD3100 exerts therapeutic effects on experimental colitis by inhibiting colonic inflammation and enhancing epithelial barrier integrity.