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Purpose Care bundles are recommended in patients at high risk for acute kidney injury (AKI), although they have not been proven to improve outcomes. We sought to establish the efficacy of an implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines to prevent cardiac surgery-associated AKI in high risk patients defined by renal biomarkers. Methods In this single-center trial, we examined the effect of a “KDIGO bundle” consisting of optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and preventing hyperglycemia in high risk patients defined as urinary [TIMP-2]·[IGFBP7] > 0.3 undergoing cardiac surgery. The primary endpoint was the rate of AKI defined by KDIGO criteria within the first 72 h after surgery. Secondary endpoints included AKI severity, need for dialysis, length of stay, and major adverse kidney events (MAKE) at days 30, 60, and 90. Results AKI was significantly reduced with the intervention compared to controls [55.1 vs. 71.7%; ARR 16.6% (95 CI 5.5–27.9%); p   =  0.004]. The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points ( p  < 0.05), less hyperglycemia ( p  < 0.001) and use of ACEi/ARBs ( p  < 0.001) compared to controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls. There were no significant effects on other secondary outcomes. Conclusion An implementation of the KDIGO guidelines compared with standard care reduced the frequency and severity of AKI after cardiac surgery in high risk patients. Adequately powered multicenter trials are warranted to examine mortality and long-term renal outcomes.

Acute kidney injury (AKI) is a common complication in critically ill patients in the intensive settings with increased risks of short- and long-term complications and mortality. AKI is also associated with an increased length of stay in intensive care units (ICU) and worse kidney function recovery at hospital discharge. The management of AKI is one of the major challenges for nephrologists and intensivists overall for its early diagnosis. The current KDIGO criteria used to define AKI include the serum creatinine and urinary output that are neither sensitive nor specific markers of kidney function, since they can be altered only after hours from the kidney injury. In order to allow an early AKI detection, in the last years, several studies focused on the identification of new biomarkers. Among all these markers, urinary insulin-like growth factor-binding protein (IGFBP-7) and tissue inhibitor of metalloproteinase (TIMP-2) have been proven as the best-performing and have been proposed as a predictive tool for the AKI detection in the critical settings in order to perform an early diagnosis. Patients undergoing major surgery, cardiac surgery, those with hemodynamic instability or those with sepsis are believed to be the top priority patient populations for the biomarker test. In this view, the urinary [TIMP-2] x [IGFBP-7] becomes an important tool for the early detection of patients at high risk for AKI and its integration with the local ICU experience has to provide a multidisciplinary management of AKI with the institution of a rapid response team in order to assess patients and customize AKI management.

Severe burn injuries lead to acute kidney injury (AKI) development, increasing the mortality risk up to 28–100%. In addition, there is an increase in hospitalization days and complications appearance. Various factors are responsible for acute or late AKI debut, like hypovolemia, important inflammatory response, excessive load of denatured proteins, sepsis, and severe organic dysfunction. The main measure to improve the prognosis of these patients is rapidly recognizing this condition and reversing the underlying events. For this reason, different renal biomarkers have been studied over the years for early identification of burn-induced AKI, like neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-2 (TIMP-2), interleukin-18 (IL-18), and insulin-like growth factor-binding protein 7 (IGFBP7). The fundamental purpose of these studies is to find a way to recognize and prevent acute renal injury progression early in order to decrease the risk of mortality and chronic kidney disease (CKD) onset.

Praeruptorin A (PA) is a pyranocumarin present in the dried root of Peucedanumpraeruptorum Dunn that has anticancer effects against several types of cells. However, the effect of PA on human cervical cancer cells is unknown. Our results indicate that PA significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of HeLa and SiHa cells, induced cell cycle arrest at G0/G1 phase, upregulated Rb, p16, p21 and p27 proteins and downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins. PA also significantly reduced expression of matrix metalloproteinase-2 (MMP-2) and increased expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). In addition, PA suppressed ERK1/2 activation and increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregulation of TIMP-2. PA treatment inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation, MMP-2 expression, cellular migration, and invasion of HeLa cells. Our findings are the first to demonstrate the activity of PA against cervical cancer cells, and suggest this agent has promise as a therapeutic agent in treatment of human cervical cancer.

Background Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are markers of tubular stress and urinary [TIMP-2]*[IGFBP7] is an established biomarker for risk assessment of acute kidney injury. There are no studies of expression profiles or localization of these markers in human renal tissue with confirmed renal disease. Methods We analysed 37 kidney biopsies of patients with renal disease and 10 non-diseased control biopsies for TIMP-2 and IGFBP7 expression using immunohistochemistry. Changes in glomerular morphology were evaluated by a semi-quantitative glomerulosclerosis score (GSI) and tubular interstitial changes were graded by the tubular injury score (TSI) using periodic acid–Schiff-stained paraffin sections. Interstitial fibrosis and tubular atrophy (IF/TA) were graded according to the Banff classification. Urinary [TIMP-2]*[IGFBP7] was collected at the time of biopsy. Results TIMP-2 and IGFBP7 had significantly greater expression in kidney biopsies from patients with renal disease compared with control tissue, especially in the tubular compartment. Here, IGFBP7 was detected in proximal and distal tubules while TIMP-2 was predominantly localized in the collecting ducts. Renal injury significantly correlated with staining intensity for TIMP-2 and IGFBP7: GSI weakly correlated with glomerular TIMP-2 (r = 0.36) and IGFBP7 (r = 0.35) and TSI correlated with tubular TIMP-2 (r = 0.41) and IGFBP7 (r = 0.43). Urinary [TIMP-2]*[IGFBP7] correlated weakly with the histopathological damage score but not with glomerular and tubular expression. Conclusion Our findings underline the role of TIMP-2/IGFBP7 as an unspecific marker of renal injury that is already in use for early detection of acute kidney injury. Lay Summary The article is about protein markers, which are already used as early urinary markers to detect acute kidney injury. We showed that these proteins are detectable to a greater extent in tissue of human kidney biopsies with renal disease compared with healthy controls. The markers correlate in their intensity with the extent of renal damage. Graphical Abstract Graphical Abstract

Previous observations indicating a lower incidence of various types of cancer in beekeepers suggest that greater exposure to stings reduces the risk of cancer development. However, it is not known which of the active compounds of the bee venom (BV) may be responsible for the observed properties. The aim of this study is to evaluate the anti-glioblastoma effect of the main BV fractions. In addition, the effect of BV fractions on the activity of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) was assessed. Commercially available BV was divided into three fractions containing one of the main BV components: apamin (fraction #1), phospholipase A2 (fraction #2), or melittin (fraction #3). The viability of glioblastoma lines (LN18 and LN229) compared to a physiological line (human MO3.13) was assessed using the MTT. MMP-2 and MMP-9 activity was assessed using gelatin zymography. Tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) levels in cell culture media were measured with the ELISA method. The fraction containing apamin did not show cytotoxic activity up to a concentration of 100 µg/mL. The fraction containing phospholipase A2 partially reduced the cells’ viability at a concentration of 100 µg/mL. The greatest activity was demonstrated by the melittin-containing fraction which completely reduced the viability of glioma cells from a concentration of 2.5 μg/mL and inhibited the activity of the assessed metalloproteinases in a dose-dependent manner. After 72 h of incubation, the highest concentrations of TIMP-1 and TIMP-2 (approximately 150 ng/mL and 100 ng/mL, respectively) were observed in the LN229 line. In all tested lines, fraction #3, crude BV, and melittin reduced the secretion of both inhibitors into the medium in a dose-dependent manner. The melittin-containing fraction possessed anti-glioma properties in vitro, suggesting that melittin may be the main anticancer compound of BV.

Background Post-operative acute kidney injury (AKI) is associated with increased morbidity and mortality with evidence suggesting that early identification using biomarkers of AKI may impact prognosis. Most studies in surgical patients has focussed on cardiac, vascular and transplant surgery cohorts. Evidence on the utility of biomarkers in major abdominal surgery is sparse. Methods This was a prospective observational single centre diagnostic study conducted on 488 patients undergoing major abdominal surgery. Urine was collected four hours post-surgery. The biomarkers for AKI NGAL, KIM-1, DKK-3 and IGFBP-7*TIMP-2 were measured and diagnostic performance assessed utilising Receiver Operating Characteristic (ROC) curve analysis to predict the development of post operative AKI using serum creatinine and urine output criteria. Results 242 participants developed AKI by urine output criteria (49.5%) and 43 by serum creatinine criteria (8.8%). The area under the receiver operating characteristic curve values for stage 1 AKI as determined by serum creatinine criteria for NGAL was 0.741 (95%CI 0.699–0.770, p  < 0.001) and 0.871 (95%CI 0.838-0.899, p  < 0.001) for stage 2. AUC values for IGFBP-7*TIMP-2 for stage 1 were 0.655 (95% CI 0.611–0.697, p0.003) and stage 2 0.803 (95%CI 0.764–0.837 p0.002). The AUC for KIM-1 was statistically significant for stage 1 (0.68, 95%CI 0.637–0.722) but not for stage 2. No AUC values for DKK-3 were statistically significant. Biomarkers performed poorly for prediction of AKI by urine output criteria. Conclusions In this large prospective study of a clinical cohort of 488 patients undergoing major abdominal surgery AKI rates are dependent on the criteria used with 49.5% of patients developed AKI by urine output criteria, compared to only 8.8% by serum creatinine. NGAL and IGFBP-7*TIMP-2 showed reasonable diagnostic performance when diagnosing AKI by serum creatinine criteria, with NGAL returning the highest AUC values.

Corneal neovascularization (CoNV) disrupts the natural avascularity of the cornea, leading to loss of transparency and visual impairment. Among matrix metalloproteinases (MMP), MMP-14, a membrane-bound MMP, plays a central role in CoNV through matrix remodeling, activation of pro-MMP-2, modulation of growth factors-induced signaling, and regulation of vascular endothelial cell behavior. Under pathogenic conditions, MMP-14 promotes angiogenesis by degrading stromal collagen, enhancing vascular endothelial growth factor (VEGF) signaling, and stimulating vascular endothelial cell migration. However, MMP-14 can also exert anti-angiogenic effects by generating endostatin-like fragments such as neostatin-14. MMP-14 also participates in corneal wound healing and lymphangiogenesis, making it a promising therapeutic target for CoNV. Standard therapies for CoNV, such as corticosteroids, immunosuppressants, and anti-VEGF agents, remain partially effective. Novel strategies targeting MMP-14, including small-molecule inhibitors, selective use of TIMP-2, and recombinant antibodies, are being explored. A deeper understanding of how membrane-bound MMP-14 is regulated and functions in different contexts may allow better modulation of angiogenesis, ultimately preserving corneal clarity and visual function after injury or inflammation.

The main reason for the failure of chemotherapy therapies based on 5‐Fluorouracil (5‐Fu) is the development of resistance to 5‐Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP‐2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5‐Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK‐8 assay was conducted to evaluate the IC50 of 5‐Fu and cell proliferation. ELISA and RT‐qPCR were performed to detect TIMP‐2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP‐2 was significantly increased in CRC drug‐resistant cell lines. In addition, the expression of TIMP‐2 in the serum of patients with CRC resistance to 5‐Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP‐2 regulated the resistance of CRC cells to 5‐Futhrough the JAK–STAT signalling pathway. Moreover, anti‐TIMP‐2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5‐Fu. It is exactly TIMP‐2 that mediates the resistance of CRC to 5‐Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP‐2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5‐Fu resistance in CRC.

The lack of early renal function recovery among geriatric patients with acute kidney injury (AKI) in the intensive care unit (ICU) is a commonly observed and acknowledged poor prognostic factor, especially for older adults. However, no reliable prognostic biomarker is available for identifying individuals at risk of renal non-recovery or mortality in older adults. In this prospective observational cohort study, we enrolled critically ill older adults (aged ≥ 60 years) with AKI from the ICU and followed their disease progression. The primary endpoint was renal non-recovery within seven days of follow-up, while the secondary endpoint was the determinants of 30-day mortality after AKI. We assessed the predictive accuracy using receiver operating characteristic curves and performed between-group comparisons using the log-rank test. Among 209 older adults, 117 (56.0%) experienced renal recovery. Multiple regression analysis revealed that urine levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) multiplied by insulin-like growth factor-binding protein 7 (IGFBP7) ([TIMP-2]*[IGFBP7]), AKI stages 2-3, and the Acute Physiology and Chronic Health Evaluation (APACHE II) score were independently associated with renal non-recovery. The regression model incorporating [TIMP-2]*[IGFBP7] demonstrated a fair predictive value (AUC 0.774,  < 0.001), with the optimal threshold set at 0.81 (ng/mL) /1000. When [TIMP-2]*[IGFBP7] was combined with AKI severity and the APACHE score, the AUC increased to 0.851. In conclusion, urine [TIMP-2]*[IGFBP7] is a reliable biomarker associated with renal non-recovery in critically ill older adults, and its predictive efficacy can be further enhanced when combined with AKI severity and the APACHE score.