A new NIR emission mitochondrial targetable fluorescent probe and its application in detecting viscosity changes in mouse liver and kidney injury

Hepatorenal syndrome (HRS) is a complication of cirrhosis with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the Toll-like receptor 4 (TLR4) signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response, and fibrosis were examined in mice after 2 wk of BDL. Compared with those of other groups, mice in the BDL + UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients with HRS.NEW & NOTEWORTHY Our study established BDL, UUO, and BDL + UUO models, providing a novel idea for analyzing liver and kidney diseases. It is highlighted that the kidney injury accelerated the aggravation of HRS via inflammatory response, which could be protected by inhibiting the TLR4 signaling pathway. We believed that targeting TLR4 was a promising therapeutic strategy for protecting both liver and kidney functions in patients with HRS.

Sphingosine kinase 1 protects against renal ischemia–reperfusion injury in mice by sphingosine-1-phosphate1 receptor activation

The BH3-Only Protein Bid Does Not Mediate Death-Receptor-Induced Liver Injury in Obstructive Cholestasis

Effect of a newly synthesized leukotriene antagonist, (E)-2,2-diethyl-3′-2-2-(4-isopropyl) thiazolyl ethenyl succinanilic acid (MCI-826), on immunological liver injury and nephritis in mice

Diabetes characterized by hyperglycemia is a chronic metabolic disease with increasing prevalence worldwide, and over time it leads to damage to various organs including the liver. As the liver is the major organ for glucose metabolism, patients with diabetes are prone to liver injuries or damages; and without timely and effective treatment, diabetic liver injury may further deteriorate into serious or life-threatening complications including liver cancer or liver failure. Hence, the accurate detection of diabetic liver injury is of great significance for diabetic patients in terms of improving quality of life. Herein, a fluorescent probe (TTX-P) has been developed for in situ detection and imaging of diabetic liver injury in the near-infrared second-window (NIR-II) region. In routine clinical practice, alkaline phosphatase (ALP) is one of the most commonly assayed enzymes, and thus serving as an important diagnostic biomarker for liver dysfunction or injury. The probe TTX-P responds in situ to the overexpressed ALP in liver and thus giving out strong NIR-II fluorescence as the reporting signals for detection and imaging. The NIR-II probe TTX-P consists of the NIR-II chromophore TTX-OH as the fluorophore and phosphate group as the responsive unit. Without the presence of ALP, the probe TTX-P displays weak fluorescence because the electron-withdrawing phosphate group weakens the electron-pushing capability of the electron-donor side of the NIR-II fluorophore. While in the presence of ALP, the phosphate group is cleaved by the enzyme and consequently the fluorophore emits evident NIR-II fluorescence. The probe TTX-P has been applied in imaging liver injury in diabetic mice. The approach provides a utilitarian means for visualizing detection of diabetic liver injury in mice with NIR-II fluorescence imaging.

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease and has a high mortality rate. Currently, no effective treatments are available to reduce the progression of kidney damage associated with diabetes. To explore the influence and predictive value of the atherogenic index of plasma (AIP) on early chronic kidney disease and liver injury in patients with type 2 diabetes mellitus (T2DM). Medical records of 1057 hospitalized adult patients with T2DM between January 2021 and December 2022 were collected. The predictive value of AIP, renal function, and liver injury in patients with T2DM were analyzed using Pearson's correlation, multiple logistic regression, and receiver operating characteristic (ROC) curve analyses. AIP was a sensitive indicator of early liver and kidney injury in patients with T2DM. Patients in the DKD group showed increased AIP that positively correlated with serum creatinine, uric acid, and β2-microglobulin levels. Increased AIP negatively correlated with estimated glomerular filtration rate (eGFR). AIP significantly correlated with alanine aminotransferase and aspartate aminotransferase levels and glutamyl transpeptidase-to-platelet ratio (GPR). An eGFR of 60-100 mL/min/1.73 m2 significantly increased the risk of DKD as the AIP increased. At lower GPR levels, the risk of DKD significantly increased with increasing AIP. However, no significant difference was found between the 2 groups when the GPR was >0.1407. The ROC curve analysis showed that AIP could predict early liver injury. AIP is directly involved in early liver and kidney injury in T2DM and may be a sensitive indicator for early detection.

Insulin resistance enhances binge ethanol-induced liver injury through promoting oxidative stress and up-regulation CYP2E1

Background: Stress hyperglycemia is common in trauma patients. Increasing injury severity and hemorrhage trigger hepatic gluconeogenesis, glycogenolysis, peripheral and hepatic insulin resistance. Consequently, we expect glucose levels to rise with injury severity in liver, kidney and spleen injuries. In contrast, we hypothesized that in the most severe form of blunt liver injury, stress hyperglycemia may be absent despite critical injury and hemorrhage. Methods: All patients with documented liver, kidney or spleen injuries, treated at a university hospital between 2000 and 2020 were charted. Demographic, laboratory, radiological, surgical and other data were analyzed. Results: A total of 772 patients were included. In liver (n = 456), spleen (n = 375) and kidney (n = 152) trauma, an increase in injury severity past moderate to severe (according to the American Association for the Surgery of Trauma, AAST III-IV) was associated with a concomitant rise in blood glucose levels independent of the affected organ. While stress-induced hyperglycemia was even more pronounced in the most severe forms (AAST V) of spleen (median 10.7 mmol/L, p < 0.0001) and kidney injuries (median 10.6 mmol/L, p = 0.004), it was absent in AAST V liver injuries, where median blood glucose level even fell (5.6 mmol/L, p < 0.0001). Conclusions: Absence of stress hyperglycemia on hospital admission could be a sign of most severe liver injury (AAST V). Blood glucose should be considered an additional diagnostic criterion for grading liver injury.

Nomenclature for kidney function and disease: Executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference

Aim: We aimed to show whether liver and renal function tests impairment have an effect on cardiovascular major adverse events (MACE) in patients with chronic heart failure (CHF). MateriaL and Method: 514 Patients with Ejection Fraction (EF) 40% were screened retrospectively. Biochemical and hemogram parameters of the patients at the first admission were recorded. GFRs were calculated with the MDRD formula. Patients were classified into four groups based on whether they had just a kidney injury, only a liver damage, both a kidney and liver injury, or neither a kidney and liver injury. Exitus, stroke, and hospitalization were taken as major cardiovascular adverse events, and whether they had a major cardiovascular adverse event within one year was recorded. Results: There was no difference between the groups in terms of exitus. When the groups were compared, a difference was found between the groups in terms of stroke, hospitalization, and MACE rates (p=0.001; p= 0.017; p=0.004, respectively). Stroke rate (13.8%) in the only kidney injury group; hospitalization (24%) and MACE (38%) in the liver + kidney injury group were found. As a result of binary logistic regression analysis, it was found that creatinine and EF predicted hospitalization for CHF, stroke, and MACE. Conclusion: In heart failure patients, the rate of stroke was higher in the group with only kidney injury, and the rates of hospitalization and MACE were higher in the group with both liver and kidney injury. It was found that creatinine and EF predicted hospitalization, stroke, and MACE from CHF.

Thymic NF-κB-inducing kinase regulates CD4+ T cell-elicited liver injury and fibrosis in mice

To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis. Animal study. Laboratory investigation. Sixty C57BL/6 male mice. Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro. In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver. Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.

MITOCHONDRIA ISOLATED FROM MESENCHYMAL STROMAL CELLS REDUCE LUNGAND DISTAL ORGAN INJURY IN EXPERIMENTAL SEPSIS

Are nitric oxide synthases new players in the pathophysiology of fulminant hepatic failure?

BackgroundAlcohol consumption and obesity are known synergistic risk factors of steatohepatitis. Combination of high fat diet (HFD) and acute alcohol synergistically induced acute liver inflammation via enhanced hepatic neutrophil infiltration. CRAMP (Cathelicidin‐related antimicrobial peptide), the murine ortholog of LL‐37, which is the only known member of human cathelicidin antimicrobial peptide family, possess both anti‐ and pro‐inflammatory activity. Our previous studies showed that CRMAP deficiency exacerbated binge‐on‐chronic alcohol‐induced liver injury. Here we aimed to investigate the role of CRAMP in alcohol‐induced liver injury in HFD fed mice, and to explore the underlying mechanism.MethodsCRAMP KO mice (Camp−/−) and wild type (WT) mice were fed control diet (CD) or HFD for 10 weeks, a bolus of alcohol was gavaged 9 hours before sample harvesting.ResultsTen‐week HFD + acute alcohol markedly induced liver steatosis and injury in WT mice, reflected by significantly increased liver macrosteatosis and serum levels of AST and ALT. Immunofluorescent assay showed a significantly stronger staining of Ly6G in the livers of mice treated with HFD + acute alcohol compared to CD feeding + acute alcohol, indicating an increased neutrophil infiltration. Interestingly, HFD+acute alcohol treatment significantly increased hepatic protein levels of CRAMP, which co‐localized with Ly6G‐positive neutrophils. In addition, hepatic mRNA expression of chemokines, Mcp‐1 and Cxcl‐2, was markedly increased. Depletion of Camp gene (Camp−/−) markedly reduced HFD + acute alcohol‐induced liver steatosis, injury and neutrophil infiltration, along with reduced expression of Mcp‐1. Importantly, feeding Camp−/− mice with HFD + acute alcohol significantly reduced the mRNA expression level of Cxcr‐2, a known CRAMP receptor. In vitro study showed that synthetic CRAMP peptide increased neutrophil migration, which was dependent on Cxcr‐2 expression upon treatment by fatty acid and ethanol. In addition, significantly decreased mRNA levels of hepatic Tgf‐β and Col‐1a1 were found in Camp−/− mice compared to WT mice, suggesting that CRAMP may play a role in hepatic stellate cells activation.ConclusionsHFD + acute alcohol treatment synergistically induces liver injury through systemic upregulation of chemoattractant CRAMP and subsequent enhancement of hepatic neutrophil infiltration. CRAMP deficiency protects against acute alcohol‐induced steatohepatitis in the HFD primed mice.Support or Funding InformationSupported by grants from NIHSchematic hypothesis of CRAMP‐mediated neutrophils infiltration in HFD and alcohol‐induced liver injury in miceFigure 1