Dual roles of BK Polyomavirus in promoting urothelial carcinoma progression via regulating CLDN1.

Uncontrolled productive infection of BK polyomaviruses (BKV) in immunocompromised patients was reported to result in serious diseases, especially renourinary malignancies. However, the mechanism of BKV as a role of human carcinogen is still unknown. In this study, we showed that there is a significant association between BKV infection and metastasis of urothelial carcinoma (UCA). BKV-infected tumor tissues exhibit invasive histologic phenomena with vascular invasion and myometrial invasion. Then we identified that BKV promotes UCA invasion in a mode of dual regulation of tumor cells (TCs) invasion and endothelial cells (ECs) adhesion by encoding miRNAs. In cancer cells, BKV-B1-miR-5p promotes cell motility and invasiveness by directly targeting CLDN1. Moreover, exosomal-BKV-B1-miR-3p derived from BK-infected BC cells would be transferred to ECs and increase its adhesion to tumor cells by switching on the CLDN1 enhancer, which subsequently destroyed endothelial monolayers and increased permeability. In a human urothelial cancer metastasis mouse model, BK-inoculated cells exhibited higher incidence of vascular leakage and liver colonization. However, the vascular leakage and liver metastasis could be reduced when knocking down miRNAs in BK-inoculated cells. Our research delineates the bifunctional impact of BKV-encoded microRNAs on the expression of CLDN1 within both TCs and ECs, which orchestrates the establishment of a pre-metastatic niche in UCA.

Polarization- and Gate-Tunable Optoelectronic Reverse in 2D Semimetal/Semiconductor Photovoltaic Heterostructure.

Polarimetric photodetector can acquire higher resolution and more surface information of imaging targets in complex environments due to the identification of light polarization. To date, the existing technologies yet sustain the poor polarization sensitivity (<10), far from market application requirement. Here, the photovoltaic detectors with polarization- and gate-tunable optoelectronic reverse phenomenon are developed based on semimetal 1T'-MoTe2 and ambipolar WSe2 . The device exhibits gate-tunable reverse in rectifying and photovoltaic characters due to the directional inversion of energy band, yielding a wide range of current rectification ratio from 10-2 to 103 and a clear object imaging with 100 × 100 pixels. Acting as a polarimetric photodetector, the polarization ratio (PR) value can reach a steady state value of ≈30, which is compelling among the state-of-the-art 2D-based polarized detectors. The sign reversal of polarization-sensitive photocurrent by varying the light polarization angles is also observed, that can enable the PR value with a potential to cover possible numbers (1→+∞/-∞→-1). This work develops a photovoltaic detector with polarization- and gate-tunable optoelectronic reverse phenomenon, making a significant progress in polarimetric imaging and multifunction integration applications.

Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study.

OBJECTIVE: The demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2. METHODS: Forty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of ≥14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus. RESULTS: A 95% upper confidence bound was -0.05% for the peak concentration (Cmax), -0.02% for the AUC from 0 to the last time point (AUC0-t), and - 0.02% for the AUC from 0 to infinity (AUC0-∞). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%-101.95%) for Cmax, 93.80% (88.52%-99.39%) for AUC0-t, and 94.34% (89.20%-99.77%) for AUC0-∞. Meanwhile, the ratio of within-subject standard deviation of test/reference (σWT/WR) with 90% CI was 0.66 (0.50-0.86) for Cmax, 0.73 (0.55-0.96) for AUC0-t, and 0.75 (0.57-0.98) for AUC0-∞. These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2-5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products. CONCLUSION: Generic tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.

Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells.

Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.

Stir-bar sorptive extraction based on hydroxyl-functionalized zirconium-metal-organic framework for the detection of three quinolones in actual samples.

A novel analytical method based on stir-bar sorptive extraction was proposed for the determination of three trace quinolones in fish and shrimp samples. UiO-66-(OH)2 , a hydroxyl-functionalized zirconium metal-organic framework, has been coated on frosted glass rods by an in situ growth method. The product, UiO-66-(OH)2 modified frosted glass rods, has been characterized and key parameters have been optimized in combination with ultra-high-performance liquid chromatography. The detection limits of enoxacin, norfloxacin, and ciprofloxacin were 0.48-0.8 ng ml-1 , and the detection concentrations were in the range of 10-300 ng ml-1 , showing a good linear relationship. This method was used for the determination of three quinolones in aquatic organisms, and the recoveries in spiked fish and shrimp muscle tissue samples were 74.8%-105.4% and 82.5%-115.8%, respectively. The relative standard deviations were less than 6.9%. The established method combined stir-bar sorptive extraction based on UiO-66-(OH)2 modified frosted glass rods with ultra-high-performance liquid chromatography, has good application prospects for the detection of quinolone residues in fish and shrimp muscle samples.

Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment.

Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N6-methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5-knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5-knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI-Alkbh5fl/flKspCre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target.

Follow-Up Factors Contribute to Immunosuppressant Adherence in Kidney Transplant Recipients.

Purpose: Follow-up and immunosuppressive medication (ISM) adherence are both important for kidney transplant recipients postoperatively and whether follow-up factors affect the ISM adherence remains unclear. The aim of this study was to examine the relationship between follow-up factors and ISM adherence, and the factors associated with ISM adherence. Patients and Methods: An internet-based cross-sectional survey was conducted in a single kidney transplant center in China. The participants completed the internet-based questionnaire and the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS©) from January 12 to January 26, 2021. Results: Finally, 288 (66.7%) participants responded to this survey. The percentage of full adherence to immunosuppressant was 51.7% (149/288), with 33.3% of the participants reporting a problem in timing dimension. We found that follow-up with a fixed doctor was significantly positive to good adherence (OR=2.124, 95% CI=1.111-4.062, P=0.023) after analyzing the survey data. Time since kidney transplantation and number of non-immunosuppressants were both associated with immunosuppressant adherence. No significant difference was found regarding the effect of the follow-up adherence on ISM adherence. Conclusion: Our study demonstrated an insufficient prevalence of adherence to immunosuppressant in Chinese renal transplant recipients and revealed that follow-up with a fixed doctor may be a way to improve the patients' ISM adherence. This anonymous internet-based survey provides valuable insight into the actual adherence rate, factors associated with non-adherence, and situations that may improve medication-taking.

Basiliximab for the therapy of acute T cell-mediated rejection in kidney transplant recipient with BK virus infection: A case report.

A 66-year-old Chinese man underwent a deceased donor kidney transplantation. Induction-immunosuppressive protocol consisted of basiliximab (BAS) and methyl prednisolone (MP), followed by maintenance immunosuppression with cyclosporin (CsA), mycophenolate mofetil (MMF), and prednisone (PED). The patient's post-transplantation course was almost uneventful, and the graft was functioning well [serum creatinine (Scr) 2.15 mg/dL]. The MMF and CsA doses were decreased 1-month post-operative as the BK virus activation was serologically positive. His Scr was elevated to 2.45 mg/dL 45 days after the transplant. A graft biopsy showed BKV nephropathy (BKVN) and acute T cell-mediated rejection (TCMR) Banff grade IIA (I2, t2, ptc2, v1, c4d1, g0, and SV40 positive). The conventional anti-rejection therapy could deteriorate his BKVN, therefore, we administered BAS to eliminate activated graft-infiltrating T cells and combined with low-dose steroid. He responded well to the therapy after two doses of BAS were given, and the kidney graft status has been stable (recent Scr 2.1 mg/dL).

COVID-19 vaccination hesitancy and associated factors among solid organ transplant recipients in China.

The mortality rate from COVID-19 appears to be higher in solid organ transplant (SOT) recipients when compared with other populations. Vaccination is a key strategy to prevent the COVID-19 pandemic. However, it is unclear how readily SOT recipients will get vaccinated against COVID-19. We conducted an internet-based survey to investigate the vaccination willingness among Chinese SOT recipients and further explore possible influencing factors. Eight hundred and thirteen respondents participated in the survey. Overall, 46 (5.7%) recipients were vaccinated against COVID-19, while 767 (94.3%) were not. Among those not vaccinated, 175 (22.8%) intended to be vaccinated, while 592 (77.2%) were categorized as vaccine-hesitant. The most common reason for vaccination hesitancy is fear of preexisting comorbidities, followed by fear of side effects and doctors' negative advice. Factors associated with vaccination willingness were as follows: with liver transplantation, the main source of information on COVID-19 vaccines was from medical doctors, scientists, and scientific journals, with at least college-level education, positive intention toward influenza vaccination during the current season, perceived importance of vaccination for SOT recipients, and having been vaccinated against influenza during the last season. Our survey indicated the necessity for SOT recipients to receive more comprehensive and accessible health education about vaccination and emphasized the critical role of transplantation physicians in promoting vaccine acceptance among SOT recipients. We hope that our survey results will help governments to better target communication in the ongoing COVID-19 vaccination campaign.

Association between preoperative lipid profiles and new-onset diabetes after transplantation in Chinese kidney transplant recipients: A retrospective cohort study.

BACKGROUND: This study investigated the association between the preoperative lipid profiles and new-onset diabetes after transplantation (NODAT) in Chinese kidney transplant recipients (KTRs). METHODS: In this study, of 1140 KTRs registered between January 1993 and March 2018 in Zhongshan Hospital, Fudan University, 449 were enrolled. Clinical data, obtained through a chart review of the patient records in the medical record system, were evaluated, and NODAT was diagnosed based on the American Diabetes Association guidelines. Multivariate Cox regression analysis was conducted to determine whether the preoperative lipid profiles in KTRs were independently associated with NODAT incidence. The preoperative lipid profiles were analyzed as continuous variables and grouped into tertiles. Smooth curve fitting was used to confirm the linear associations. RESULTS: During a median follow-up of 28.03 (interquartile range 12.00-84.23) months, 104 of the 449 (23.16%) participants developed NODAT. The multivariate model analysis, adjusted for all potential covariates, showed that increased values of the following parameters were associated with NODAT (hazard ratio, 95% confidence interval): preoperative total cholesterol (TC; 1.25, 1.09-1.58, p = 0.0495), low-density lipoprotein cholesterol (LDL-C; 1.33, 1.02-1.75, p = 0.0352), non-high-density lipoprotein cholesterol (non-HDL-C; 1.41, 1.09-1.82, p = 0.0084), TC/HDL-C (1.28, 1.06-1.54, p = 0.0109), and non-HDL-C/HDL-C (1.26, 1.05-1.52, p = 0.0138). However, the association between the preoperative triglyceride, HDL-C, or TG/HDL-C and NODAT was not significant. CONCLUSIONS: Preoperative TC, LDL-C, non-HDL-C, TC/HDL-C, and non-HDL-C/HDL-C were independent risk factors for NODAT.

Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells.

Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells (MSCs). However, the biological function of chaperone-mediated autophagy (CMA) in MSCs remains elusive. Here, we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2 (LAMP-2A) in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation, and as expected, LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation. This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10 (CXCL10), which recruits inflammatory cells, especially T cells, to MSCs, and inducible nitric oxide synthase (iNOS), which leads to the subsequent inhibition of T cell proliferation via nitric oxide (NO). Mechanistically, CMA inhibition dramatically promoted IFN-γ plus TNF-α-induced activation of NF-κB and STAT1, leading to the enhanced expression of CXCL10 and iNOS in MSCs. Furthermore, we found that IFN-γ plus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs. More interestingly, CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury. Taken together, our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines and highlighted a previously unknown function of CMA.

Self-Assembly of Single-Polymer-Tethered Nanoparticle Amphiphiles upon Varying Tail Length.

We systematically investigated the roles of tail length on the self-assembly of shape amphiphiles composed of a hydrophobic polymer chain (tail) and a hydrophilic nanoparticle in selective solvent using Brownian dynamics simulations. The shape amphiphiles exhibited a variety of self-assembled aggregate morphologies which can be tuned by changing tail length (n) in combination with amphiphile concentration (φ) and system temperature (T*). Specifically, at high φ with T*=1.4, the morphology varied following the sequence "spheres → cylinders → vesicles" upon increasing n, agreeing well with experimental observations. At low φ with T*=1.4 or at high φ with T*=1.2, the morphology sequence becomes "spheres or spheres and cylinders mixture → cylinders → vesicles → spheres" upon increasing n, which has not been found experimentally. Two morphological phase diagrams depending on n and φ were constructed for T*=1.4 and 1.2, respectively. The rich phase behaviors on varying tail length could provide the feasible routes to fabricate target aggregate morphologies in various applications, especially for the vesicles with tunable thickness of membranes that are crucial in drug and gene delivery.

Histone Methylation Inhibitor DZNep Ameliorated the Renal Ischemia-Reperfusion Injury via Inhibiting TIM-1 Mediated T Cell Activation.

Renal ischemia-reperfusion injury (IRI) after renal transplantation often leads to the loss of kidney graft function. However, there is still a lack of efficient regimens to prevent or alleviate renal IRI. Our study focused on the renoprotective effect of 3-Deazaneplanocin A (DZNep), which is a histone methylation inhibitor. We found that DZNep significantly alleviated renal IRI by suppressing nuclear factor kappa-B (NF-κB), thus inhibiting the expression of inflammatory factors in renal tubular epithelial cells in vivo or in vitro. After treatment with DZNep, T cell activation was impaired in the spleen and kidney, which correlated with the downregulated expression of T-cell immunoglobulin mucin (TIM)-1 on T cells and TIM-4 in macrophages. In addition, pretreatment with DZNep was not sufficient to protect the kidney, while administration of DZNep from before to after surgery significantly ameliorated IRI. Our findings suggest that DZNep can be a novel strategy for preventing renal IRI following kidney transplantation.

Diagnosis and Treatment of Early Transplant Renal Artery Stenosis: Experience From a Center in Eastern China.

Few studies have focused on the clinical characteristics of transplant renal artery stenosis (TRAS) with early onset. Sixteen cases diagnosed with TRAS in our center from January 2014 to August 2018 were retrospectively analyzed. Sixteen transplant patients without TRAS were selected as controls. The median diagnostic time for TRAS was 47.5 days after transplantation. No significant difference was observed between the TRAS group and the control group. The serum creatinine level (Scr), estimated glomerular filtration rate, systolic/diastolic blood pressure, graft artery peak systolic velocity (PSV), and resistive index of intersegmental artery (RI-ISA) between the 2 groups were (5.55 ± 3.49) and (1.89 ± 0.85) mg/dL; (17.83 ± 14.94) and (49.39 ± 19.96) mL/min; (143.50 ± 9.49)/(86.14 ± 7.38) and (130.38 ± 18.86)/(82.81 ± 12.52) mm Hg; (3.39 ± 1.57) and (1.31 ± 0.51) m/s; and (0.51 ± 0.10) and (0.67 ± 0.13), respectively. All showed statistical significance except the diastolic blood pressure. The Scr, estimated glomerular filtration rate, systolic/diastolic blood pressure, graft artery PSV, and RI-ISA in the TRAS group prior and after treatment were (5.55 ± 3.49) and (3.20 ± 1.50) mg/dL; (17.83 ± 14.94) and (25.60 ± 13.29) mL/min; (143.50 ± 9.49)/(86.14 ± 7.38) and (128.07 ± 16.16)/(75.71 ± 7.56) mm Hg; (3.39 ± 1.57) and (2.00 ± 1.04) m/s; and (0.51 ± 0.10) and (0.61 ± 0.10); all showed statistical significance. Receiver operating characteristic analysis showed an area under curve of 0.8616 for PSV and 0.8535 for RI-ISA in diagnosing TRAS. Patients with TRAS in our center showed a unique characteristic of early onset. The most prominent clinical symptom of TRAS is increasing Scr level instead of refractory hypertension. Screening of color Doppler flow imaging with a graft artery PSV >2.5 m/s and RI-ISA <0.5 could yield a preliminary diagnosis of TRAS. Percutaneous transluminal angioplasty/stenting could effectively improve allograft function as well as color Doppler flow imaging indexes.

Corrigendum to "Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications".

[This corrects the article DOI: 10.1155/2017/8746303.].

Effects of preoperative hepatitis B virus infection, hepatitis C virus infection, and coinfection on the development of new-onset diabetes after kidney transplantation.

BACKGROUND: The effects of preoperative hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and HBV plus HCV coinfection on the development of new-onset diabetes after transplantation (NODAT) remain unexplored in kidney transplant recipients (KTRs). This study examined the association between preoperative viral status (i.e., HBV, HCV, and HBC + HCV infection) and incident NODAT in a large population of Chinese KTRs. METHODS: This population-based retrospective cohort study enrolled 557 subjects who underwent kidney transplantation between 1993 and 2014 at Zhongshan Hospital. Pre-, peri-, and postoperative data were extracted and analyzed. Viral status was defined by serological results for hepatitis B surface antigen and anti-HCV antibody. The cumulative incidence of NODAT was compared across four groups of KTRs with different viral status. Multivariate Cox regression models were used to estimate the effects of HBV, HCV, and HBC + HCV infection on incident NODAT after adjusting for important confounders. RESULTS: Patients seropositive for HCV (both HCV monoinfection and HBC + HCV coinfection) had a significantly higher cumulative incidence of NODAT than KTRs who were not infected with HCV (P < 0.05 for both). However, only HCV infection alone was found to be a risk factor for NODAT, increasing the NODAT risk 3.03-fold (95% confidence interval 1.77-5.18; P < 0.001). There was no independent correlation between HBV infection (alone or combined with HCV) and incident NODAT in KTRs. CONCLUSIONS: Preoperative HCV infection significantly increased the risk of NODAT in Chinese KTRs, whereas HBV infection and HBC + HCV coinfection were not correlated with NODAT development.

Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling.

Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy-proved rejection, which confirmed the involvement of complement in IRI. Using FB-, C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1ß, IL-9, and IL-12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI.

GC/MS-based urine metabolomics analysis of renal allograft recipients with acute rejection.

BACKGROUND: Acute renal allograft rejection is a common complication after renal transplantation that often leads to chronic rejection and ultimate graft loss. While renal allograft biopsy remains the gold standard for diagnosis of acute rejection, the possibility of biopsy-associated complications cannot be overlooked. The development of noninvasive methods for accurate detection of acute renal allograft rejection is thus of significant clinical importance. METHODS: Gas chromatography-mass spectrometry (GC/MS) was employed for analysis of urine metabolites in 15 renal allograft recipients with acute rejection and 15 stable renal transplant recipients. Partial least squares (PLS) regression and leave-one-out analyses were performed to ascertain whether the metabolites identified could be exploited to distinguish acute rejection from stable groups as well as their sensitivity and specificity. RESULTS: Overall, 14 metabolites were significantly altered in the acute rejection group (11 and 3 metabolites displayed higher and lower levels, respectively) relative to the stable transplant group. Data from PLS and leave-one-out analyses revealed that the differential metabolites identified not only distinguished acute rejection from stable transplant recipients but also showed high sensitivity and specificity for diagnosis of renal allograft recipients with acute rejection. CONCLUSION: Urine metabolites identified with GC/MS can effectively distinguish acute rejection from stable transplant recipients, supporting the potential utility of metabolome analysis in non-invasive diagnosis of acute rejection.

Sites of gastrointestinal lesion induced by mycophenolate mofetil: a comparison with enteric-coated mycophenolate sodium in rats.

BACKGROUND: Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear. METHODS: In this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg·d), mofetil (30 mg/kg·d), EC-MPS (72 mg/Kg·d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research. RESULTS: The results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption. CONCLUSIONS: Our data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property.

Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications.

Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.