The male reproductive toxicity after 5-Fluorouracil exposure: DNA damage, oxidative stress, and mitochondrial dysfunction in vitro and in vivo.

5-Fluorouracil (5-FU), a chemotherapeutic drug used to treat a variety of cancers, can enter the environment through different routes, causing serious public health and environmental concerns. It has been reported that 5-FU exposure adversely affects male reproductive function, and its effects on this system cannot be avoided. In this study, using western blotting and quantitative polymerase chain reaction studies, we found that 5-FU promoted testicular injury by inducing oxidative stress, which was accompanied by the inhibition of nuclear factor erythroid 2-related factor 2/antioxidant response element signaling. Accumulation of reactive oxygen species (ROS) aggravated 5-FU-mediated mitochondrial dysfunction and apoptosis in murine cell lines and testes, indicating oxidative stress and mitochondrial-dependent apoptotic signaling play crucial roles in the damage of spermatogenic cells caused. N-Acetyl-L-cysteine, an antioxidant that scavenges intracellular ROS, protected spermatogenic cells from 5-FU-induced oxidative damage and mitochondrial dysfunction, revealing the important role of ROS in testicular dysfunction caused by 5-FU. We found that 5-FU exposure induces testicular cell apoptosis through ROS-mediated mitochondria pathway in mice. In summary, our findings revealed the reproductive toxicological effect of 5-FU on mice and its mechanism, provided basic data reference for adverse ecological and human health outcomes associated with 5-FU contamination or poisoning.

Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling.

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

The utility of presepsin in diagnosis and risk stratification for the emergency patients with sepsis.

OBJECTIVES: To evaluate the value of presepsin in diagnosis and risk stratification of septic patients in emergency department, and investigate the utility in differentiation of gram-positive and gram-negative bacterial infection. METHODS: We enrolled 72 patients with sepsis and 23 nonbacterial patients with systemic inflammatory response syndrome (SIRS) who were admitted to the emergency department of Tianjin Medical University General Hospital. Meanwhile, 20 healthy volunteers were included. Plasma presepsin, serum PCT, C-reactive protein (CRP), lactate and white blood cells (WBC) were measured, and APACHE II score were calculated upon admission. The receiver-operating-characteristic curve (ROC) was computed and the area under the ROC curve was for evaluating the value to diagnose sepsis. Then the patients were grouped according to the result of culture and severity of sepsis. RESULTS: The levels of presepsin, PCT, CRP and WBC were apparently higher in sepsis patients than in nonbacterial SIRS group (P<0.05). The levels of presepsin and the APACHEII score were demonstrated the significant difference among sepsis, severe sepsis and septic shock patients (P<0.05). The area under the ROC curve of presepsin, PCT, CRP and WBC were 0.954, 0.874, 0.859 and 0.723 respectively. The cutoff of presepsin for discrimination of sepsis and nonbacterial infectious SIRS was determined to be 407pg/ml, of which the clinical sensitivity and specificity were 98.6% and 82.6%, respectively. Moreover, presepsin was significantly different between gram-positive and gram-negative bacterial infection (P<0.05). CONCLUSION: Presepsin was a promising biomarker for initially diagnosis and risk stratification of sepsis, and a potential marker to distinguish gram-positive and gram-negative bacterial infection.