Short-chain fatty acids in diseases.

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.

Lactobacillus plantarum alleviates irradiation-induced intestinal injury by activation of FXR-FGF15 signaling in intestinal epithelia.

Abdominal irradiation (IR) may destroy the intestinal mucosal barrier, leading to severe intestinal infection and multiple organ dysfunction syndromes. The role of intestinal microbiota in the development of IR-induced intestinal injury remains largely unknown. Herein, we reported that abdominal IR altered the composition of the microbiota and reduced the abundance and diversity of the gut microbiome. Alterations of bacteria, in particular reduction of Lactobacillus, played a critical role in IR-induced intestinal injury. Fecal microbiota transplant (FMT) from normal mice or administration of Lactobacillus plantarum to intestinal microbiota-eliminated mice substantially reduced IR-induced intestinal damage and prevented mice from IR-induced death. We further characterized that L. plantarum activated the farnesoid X receptor (FXR) - fibroblast growth factor 15 (FGF15) signaling in intestinal epithelial cells and hence promoted DNA-damage repair. Application of GW4064, an activator of FXR, to microbiota eliminated mice markedly mitigated IR-induced intestinal damage, reduced intestinal epithelial cell death and promoted the survival of IR mice. In contrast, suppression of FXR with Gly-ß-MCA, a bile acid and an intestine-selective and high-affinity FXR inhibitor, abrogated L. Plantarum-mediated protection on the ileum of IR mice. Taken together, our findings not only provide new insights into the role of intestinal flora in radiation-induced intestinal injury but also shed new light on the application of probiotics for the protection of radiation-damaged individuals.

Upregulation of programmed death ligand 1 by liver kinase B1 and its implication in programmed death 1 blockade therapy in non-small cell lung cancer.

AIMS: Liver kinase B1 (LKB1) deficiency is associated with reduced expression of programmed death ligand 1 (PD-L1) and inferior clinical outcomes of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC). This study aimed to investigate the mechanism by which LKB1 regulates PD-L1 expression and its role in programmed death 1 (PD-1) blockade therapy in NSCLC. MAIN METHODS: The impact of LKB1 on PD-L1 was assessed by western blot, qRT-PCR and immunohistochemistry in NSCLC. Activators/inhibitors of AMPK and NRF2 were applied to explore the mechanisms underlying the regulation of PD-L1 by LKB1. Efficiency of combined application of metformin and PD-1 blockade was evaluated in immunocompetent C57BL/6 mice. KEY FINDINGS: A remarkable positive correlation between LKB1 and PD-L1 expression was demonstrated in NSCLC tissues. Knockdown of LKB1 decreased PD-L1 in TC-1 cells, whereas overexpression of LKB1 increased PD-L1 in A549 cells. We further characterized that AMPK mediated the upregulation of PD-L1 by LKB1. Inhibition of AMPK or NRF2 markedly reduced PD-L1 in LKB1-intact NSCLC cells. In contrast, activation of AMPK or NRF2 reversed PD-L1 expression in LKB1-deficient NSCLC cells. Combined administration of metformin and anti-PD-1 antibody efficiently inhibited the growth of LKB1-intact tumors, whereas no obvious suppression was observed in LKB1-deficient tumors. SIGNIFICANCE: These findings demonstrated that LKB1 upregulates PD-L1 expression in NSCLC by activating the AMPK and KEAP1/NRF2 signaling. Activation of LKB1-AMPK with metformin improves the therapeutic effect of PD-1 blockade in NSCLC with wild-type LKB1.

Enhanced O-linked Glcnacylation in Crohn's disease promotes intestinal inflammation.

BACKGROUND: Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked ß-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD. METHODS: O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82-infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study. FINDINGS: O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKß and NF-κB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKß (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKß and NF-κB and inhibited AIEC LF82-induced activation of NF-κB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-κB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice. INTERPRETATION: Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-κB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease. FUNDING: National Natural Science Foundation of China (Nos. 81573087 and 81772924) and International Cooperation Foundation of Jilin Province (20190701006GH).

Delayed graft function is correlated with graft loss in recipients of expanded-criteria rather than standard-criteria donor kidneys: a retrospective, multicenter, observation cohort study.

BACKGROUND: Although the use of expanded-criteria donors (ECDs) alleviates the problem of organ shortage, it significantly increases the incidence of delayed graft function (DGF). DGF is a common complication after kidney transplantation; however, the effect of DGF on graft loss is uncertain based on the published literature. Hence, the aim of this study was to determine the relationship between DGF and allograft survival. METHODS: We conducted a retrospective, multicenter, observation cohort study. A total of 284 deceased donors and 541 recipients between February 2012 and March 2017 were included. We used logistic regression analysis to verify the association between clinical parameters and DGF, and Cox proportional hazards models were applied to quantify the hazard ratios of DGF for kidney graft loss. RESULTS: Among the 284 deceased donors, 65 (22.8%) donors were ECD. Of the 541 recipients, 107 (19.8%) recipients developed DGF, and this rate was higher with ECD kidneys than with standard-criteria donor (SCD) kidneys (29.2% vs. 17.1%; P = 0.003). The 5-year graft survival rate was not significantly different between SCD kidney recipients with and without DGF (95.8% vs. 95.4%; P = 0.580). However, there was a significant difference between ECD kidney recipients with and without DGF (71.4% vs. 97.6%; P = 0.001), and the adjusted hazard ratio (HR) for graft loss for recipients with DGF was 1.885 (95% confidence interval [CI] = 1.305-7.630; P = 0.024). Results showed that induction therapy with anti-thymocyte globulin was protective against DGF (odds ratio = 0.359; 95% CI = 0.197-0.652; P = 0.001) with all donor kidneys and a protective factor for graft survival (HR = 0.308; 95% CI = 0.130-0.728; P = 0.007) with ECD kidneys. CONCLUSION: DGF is an independent risk factor for graft survival in recipients with ECD kidneys, but not SCD kidneys.

Biomarkers for immune checkpoint therapy targeting programmed death 1 and programmed death ligand 1.

Rapidly increasing usages of immune checkpoint therapy for cancer treatment, particularly monoclonal antibodies that target programmed cell death-1 (PD-1) and its ligand PD-L1, have been achieved due to startling durable therapeutic efficacy with limited toxicity. The therapeutics significantly prolonged the overall survival and progression free survival of patients across multiple cancer types. However, the objective response rate of patients receiving this kind of treatment is substantially low. Therefore, it is of great importance to exploit reliable biomarkers that can robustly predict the therapeutic effects. Several biomarkers have been characterized for the selection of patients, which is mainly based on immunological and genetic criteria. Herein, we focus on the current progress regarding the biomarkers for anti-PD-1/PD-L1 therapy.

Cell Cycle Arrest as a Therapeutic Target of Acute Kidney Injury.

The current lack of complete understanding of the pathogenesis of acute kidney injury (AKI) is a significant barrier to its early diagnosis and treatment. Cell cycle arrest plays an important role in the protection of renal tubular epithelial cells and maladaptive repair following AKI. G1 phase cell arrest serves as a protective mechanism following AKI, avoiding replication of damaged DNA. Insulinlike growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) are closely associated with G1 cell cycle arrest during the very early phase of cellular damage and can serve as an ideal biomarker to predict AKI. However, sustained cell cycle arrest after severe AKI may result in cell senescence and maladaptive repair, with typical characteristics of the development of cell cycle arrest in the gap 2 (G2) or mitotic (M) phase. Markers of cell cycle arrest signal and spread the "alarm" from the site of injury to adjacent cells in an autocrine or paracrine manner, giving rise to abnormal amplification and release of profibrogenic factors, activation of pericytes/perivascular fibroblasts, and eventually fibrosis. Therefore, cell cycle regulation has become a potentially new target for the prevention and treatment of AKI. In this review, we summarize the characteristics of the cell cycle following AKI and the markers of cell cycle arrest that enable the early detection of AKI. We also discuss how to prevent the progression of chronic kidney disease (CKD) by regulating cell cycle arrest.

Diagnosis and treatment of carcinosarcoma of the renal pelvis: A case report.

Carcinosarcoma is a rare type of renal pelvis malignancy, the diagnosis of which requires the presence of malignant epithelial and mesenchymal components. The prognosis of this disease is extremely poor due to its rapid progression and widespread metastases. The present study describes a case of carcinosarcoma involving the right renal pelvis in a 73-year-old female who presented with intermittent hematuria and right-flank pain that had persisted for one month. Computed tomography revealed a 2.4×2.5 cm mass in the right renal pelvis, which was diagnosed as a right renal pelvic tumor. Laparoscopic radical resection of the right kidney and ureter was performed. Following surgery, immunohistochemical analysis showed positive reactions for epithelial and mesenchymal markers. Based on these findings, the patient was diagnosed with carcinosarcoma. Thus, immunohistochemical analysis is a critical method for the accurate diagnosis of carcinosarcoma.

The effect of erectile dysfunction on quality of life in male kidney transplant recipients.

UNLABELLED: Objective : To assess how erectile dysfunction (ED) affects the quality of life in male kidney transplant recipients. METHODS: We randomly selected 150 cases of married male kidney transplant recipients. Using the International Index of Erectile Function (IIEF-5) Questionnaire, we divided our research subjects into ED group (n=63) and non-ED group (n = 87). The Short-Form health survey (SF-36) was used to evaluate the quality of life of the recipients. Hamilton Anxiety Rating Scale was used to compare the mental health status of the two groups. RESULTS: No significant differences (P > 0.05) were observed between the ED and non-ED groups in physical functioning (PF), role-physical (RP), or bodily pain (BP). However, the ED group exhibited a lower score (P < 0.05) than the non-ED group in general health (GH), vitality, social functioning (SF), role emotional (RE) and mental health (MH). There were 13 cases in the ED group with anxiety disorders (20.6%), which was clearly more than in the non-ED group (3.4%, P < 0.05). CONCLUSION: Erectile dysfunction is an important factor in the quality of life of male kidney transplant recipients.

Macrophages and T lymphocytes are the predominant cells in intimal arteritis of resected renal allografts undergoing acute rejection.

BACKGROUND: In acute renal allograft rejection, T-cell-mediated processes have been generally regarded as dominant. Although there is recent evidence that macrophages play important roles in acute vascular rejection, less is known about the exact proportion of immunocytes in the intimal arteritis of renal allografts with unfavorable outcomes. METHODS: By immunohistochemical staining using nine primary antibodies, we classified the proportions of infiltrating immunocytes in intimal arteritis and glomerulitis in five allografts resected because of acute irreversible graft failure. RESULTS: All five allografts had features of antibody-mediated rejection based on criteria established by the Banff classification. In intimal arteritis, CD3+ T-lymphocytes accounted for 30.6±13.3% of the immunocytes and macrophages for 40.4±9.2%. 45.4% of the T-cells were CD8+ cytotoxic T-cells. Neutrophils were also present but accounted for a relatively low proportion of the cells (8.8±8.6%). B-cells and plasma cells all accounted for <5% of the immunocytes. NK cells were readily detected (4.2±4.2%). When we compared types of arteritis, the CD15+ neutrophils accounted for as many as 27.8±15.1% of immunocytes in V3 vasculitis and only 1.0±1.4% in V2 vasculitis. CD3+ T-lymphocytes accounted for 25.8±7.3% of immunocytes in V3 vasculitis and 41.5±7.9% in V2 vasculitis. In glomerulitis, the immunocytes were mainly macrophages (53.1±9.1%) and neutrophils (34.6±9.9%). CONCLUSION: Macrophages and T-lymphocytes accounted for the highest percentage of immunocytes in the intimal arteritis of irreversible renal failure associated with antibody-mediated rejection. 45.4% of the T-cells were CD8+ cytotoxic T-cells. Neutrophils and NK cells were also present in these lesions. The proportion of neutrophils in V3 vasculitis was much higher than in V2 vasculitis. These observations suggest that besides macrophages and T-lymphocytes, neutrophils may also play a role in the more severe arterial lesion. To our knowledge this is the first report of this observation. Macrophages and neutrophils were the main inflammatory cells in the glomerulitis of acute rejection.

Presence of donor-and-recipient-derived DNA microchimerism in the cell-free blood samples of renal transplantation recipients associates with the acceptance of transplanted kidneys.

AIM: To examine whether the existence of the donor-and recipient-derived DNA chimerism in recipient's plasma can be a predictive marker for the status of transplanted organ. METHODS: One hundred and twenty-six female patients who had been transplanted with male kidneys were enrolled in the present study. In these female recipients, the SRY(1), DYZ(1)(1st) and DYZ(1)(2nd) genes on the Y chromosome from the plasma were prospectively examined using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: SRY, DYZ(1)(1st) and DYZ(1)(2nd) sequences were detected in the cell-free blood (plasma) of 97 (77%) of 126 female patients with male kidney. The average time that the transplanted kidneys functioned was 8.7 years and 5.4 years among microchimerism-positive and microchimerism-negative recipients, respectively. The frequency of the patients who had acute rejection after renal transplantation was approximately 10% and 28% in microchimerism-positive and microchimerism-negative recipients, respectively. Serum creatinine levels in microchimerism-positive patients were significantly lower than those in microchimerism-negative patients. CONCLUSION: These results suggest that plasma DNA microchimerism present in certain patients following renal transplantation and measurement of plasma DNA microchimerism using quantitative RT-PCR might be a useful predictor for the acceptance of transplanted kidneys.

[Effects of donor-specific bone marrow cell infusion on chimerism and acute rejection in kidney transplantation].

OBJECTIVE: To evaluate the effect of donor-specific bone marrow cell infusion on the production of chimerism and acute rejection in kidney transplantation. METHODS: Sixty-one patients, 48 males and 13 females, aged 38.4 (23 - 45), underwent transplantation of cadaveric kidneys, 24 of which underwent kidney transplantation combined with donor-specific bone marrow cell infusion and 37 of which underwent pure transplantation of kidney. During the kidney transplantation combined with donor-specific bone marrow cell infusion the donor bone marrow cells (DBMC) were isolated from the thoracic vertebrae and iliac bones of the donors-cadavers and infused into the recipients of the kidneys of the same donors. After operation the peripheral blood was collected from the 61 recipients every 2 - 3 months for at least 1 year to undergo PCR to detect the presence of chimerism, and the rates of chimerism and acute rejection were compared between these 2 groups. RESULTS: During the follow-up the presence rate of chimerism was 87.5% (21/24) in the marrow recipients, significantly higher than that in the control group (40.5%, 15/37, P < 0.001). The prevalence of acute rejection in the chimerism positive patients was 19.4% (7/16), significantly lower than that in the chimerism negative patients (44%, 11/25, P < 0.05). CONCLUSION: Donor-specific bone marrow cell infusion in cadaver kidney transplantation induces the production of chimerism, and increases the immune tolerance to the donor organs, thus finally decreasing the incidence of acute rejection. Chimerism is correlated with immune tolerance.