Association between lactate dehydrogenase to albumin ratio and acute kidney injury in patients with sepsis: a retrospective cohort study.

BACKGROUND: Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study. METHODS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2 days and 7 days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively. RESULTS: A total of 4010 participants were included in this study. The median age of the participants was 63.5 years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2 days and 7 days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7 days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1 unit increase in LAR(log2), respectively. CONCLUSION: This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

Mild hypothermia alleviates oxygen-glucose deprivation/reperfusion-induced apoptosis by inhibiting ROS generation, improving mitochondrial dysfunction and regulating DNA damage repair pathway in PC12 cells.

The brain ischemia/reperfusion (I/R) injury has a great impact on human life and property safety. As far as we know, mild hypothermia (MH) is an effective measure to reduce neuronal injury after I/R. However, the precise mechanism is not extremely clear. The purpose of this study was to investigate whether mild therapeutic hypothermia can play a protective role in nerve cells dealing with brain I/R injury and explore its specific mechanism in vitro. A flow cytometer, cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) release assay were performed to detect apoptotic rate of cells, cell viability and cytotoxicity, respectively, reactive oxygen species (ROS) assay kit, JC-1 fluorescent methods, immunofluorescence and western blot were used to explore ROS, mitochondrial transmembrane potential (Δψm), mitochondrial permeability transition pore (MPTP) and protein expression, respectively. The result indicated that the cell activity was decreased, while the cytotoxicity and apoptosis rate were increased after treating with oxygen-glucose deprivation/reperfusion (OGD/R) in PC12 cells. However, MH could antagonize this phenomenon. Interestingly, treating with OGD/R increased the release of ROS and the transfer of Cytochrome C (Cyt-C) from mitochondria to cytoplasm. In addition, it up-regulated the expression of γH2AX, Bax and Clv-caspase3, down-regulated the expression of PCNA, Rad51 and Bcl-2, and inhibited the function of mitochondria in PC12 cells. Excitingly, the opposite trend was observed after MH treatment. Therefore, our results suggest that MH protects PC12 cells against OGD/R-induced injury with the mechanism of inhibiting cell apoptosis by reducing ROS production, improving mitochondrial function, reducing DNA damage, and enhancing DNA repair.

Erratum: Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks: Erratum.

[This corrects the article DOI: 10.7150/jca.36372.].

[Mn(PaPy2Q)(NO)]ClO4, a Near-Infrared Light activated release of Nitric Oxide drug as a nitric oxide donor for therapy of human prostate cancer cells in vitro and in vivo.

This study was the first to investigate the synthesis of near-infrared light-sensitive NO prodrug [Mn(PaPy2Q)(NO)]ClO4, and detection the amount of NO released by the drug in different time and near infrared light (10 mW, 20 mW). It showed that with the increase of light power, the time required for the drug to release NO was shortened, and we selected 20 mW, 10 min as a follow-up study of light power and irradiation time while ensuring the near-infrared light did not affect tumor cells. The cells were irradiated with 20 mW of near-infrared light for 10 min at 6 h after treatment with the drug on PC-3, LNCaP and 22RV1 cells, and NO concentration and cell survival rate were tested at 12 h, 24 h and 48 h. Experiments showed that NO concentration remained stable within 48 h and [Mn(PaPy2Q)(NO)]ClO4 inhibited the proliferation of cells in a concentration and time-dependent manner. Then we also found that [Mn(PaPy2Q)(NO)]ClO4 increased the expression of apoptosis-related proteins (PARP, Bax, Caspase 3/9), inhibited the expression of BCl-2 and increased the activity level of Caspase 3/7, which showed [Mn(PaPy2Q)(NO)]ClO4 promoted prostate cancer cells apoptosis. Next, the results in xenograft mouse model showed that [Mn(PaPy2Q)(NO)]ClO4 also had anti-prostate cancer effects in vivo, and the NO concentration increased in the tumor after near-infrared light irradiation. After [Mn(PaPy2Q)(NO)]ClO4 treatment 6 weeks, tumor volume was significantly reduced, Ki67 and BrdU protein expression was significantly reduced. TUNEL assay results showed that [Mn(PaPy2Q)(NO)]ClO4 could promote the apoptosis of solid tumors in vivo and in a concentration-dependent manner.

Resveratrol inhibits proliferation and promotes apoptosis via the androgen receptor splicing variant 7 and PI3K/AKT signaling pathway in LNCaP prostate cancer cells.

Prostate cancer is a common malignant tumor of the male genitourinary system and its incidence increases with age. Studies have shown that resveratrol (Res) inhibits cancer cell proliferation, migration, invasion and promotes apoptosis. The present study evaluated the effect of Res in two human prostate cancer cell lines (the androgen-dependent LNCaP cell line and the non-androgen-independent LNCaP-B cell line) on proliferation and apoptosis. A proliferation assay was used to demonstrate that Res inhibited proliferation of LNCaP and LNCaP-B cells in the range of 25-100 µM, and the effect was time- and dose-dependent. Using flow cytometry, it was reported that various concentrations of Res induced apoptosis in LNCaP and LNCaP-B cells, and that the apoptotic effect of Res was dose-dependent. A chemiluminescence assay showed that Res inhibited prostate specific antigen levels in LNCaP and LNCaP-B cells. Reverse transcription quantitative-PCR showed that Res inhibited the expression of androgen receptor (AR) in LNCaP and LNCaP-B cells at the mRNA level. Western blot analysis showed that Res suppressed the expression of AR protein as well as protein kinase B (AKT) phosphorylation. To study the effect of Res on the expression of AR splicing variant 7 (ARV7) and the PI3K/AKT signaling pathway in prostate cancer cells, as well as the underlying molecular mechanisms, the recombinant ARV7 expression vector Pcdna3.1-ARV7 was transfected into LNCaP and LNCaP cells and the aforementioned experiments were repeated. It was revealed that Res acted via the ARV7 and the AKT pathways. Taken together, the present results suggested that Res suppresses the proliferation of prostate cancer cells, promotes apoptosis and inhibits the expression of AR mRNA and protein. These effects likely resulted from inhibition of ARV7 and the AKT signaling pathway.

Circ-APBB1IP as a Prognostic Biomarker Promotes Clear Cell Renal Cell Carcinoma Progression Through The ERK1/2 Signaling Pathway.

Circular RNA (circRNA), a member of non-coding RNA, plays an essential regulatory role in many human physiological and pathological processes; however, its role in clear cell renal cell carcinoma (ccRCC) still unclear. This study aims to investigate the effect and mechanisms of circRNA on ccRCC progression. A human circRNA microarray was used to discover differential expression circRNA, and a quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the expression of circRNA. The function and mechanism of circRNA were explored by cell transfection, cell counting kit-8, fluorescein isothiocyanate (FITC) Annexin V apoptosis detection, wound healing, transwell, and western blot. The result indicated that circ-APBB1IP was significantly up-regulated in ccRCC. In vitro, knockdown of circ-APBB1IP by siRNA suppressed the proliferation, migration, and invasion and increased the apoptosis of ccRCC cells. Further study found that knockdown of circ-APBB1IP up-regulated protein expression of cleaved caspase-3, cleaved caspase-7, cleaved caspase-8, cleaved caspase-9, Bax, Bad, Bak, E-cadherin and down-regulated expression of Bcl-2, N-cadherin, MMP-2, MMP-9, p-ERK1/2. Our result indicates that circ-APBB1IP has a vital function in ccRCC tumorigenesis. These findings suggest that circ-APBB1IP represents a novel potential biomarker and therapeutic target of ccRCC.

Metformin in combination with JS-K inhibits growth of renal cell carcinoma cells via reactive oxygen species activation and inducing DNA breaks.

Metformin (MET) is taken as a principal medication for remedying Type 2 diabetes mellitus. Its anti-tumor effect has been reported increasingly, but the precise mechanism of it remains unclear. This study aims to explore the efficacy of MET and MET combined with nitric oxide donor prodrug JS-K on the proliferation, apoptosis, and DNA damage in human renal cell carcinoma (RCC) cells, and investigate the possible molecular mechanism involved. The cell proliferation was tested through methyl-tetrazolium assay and cell apoptosis was ascertained by flow cytometry. The dihydroethidium and JC-1 fluorescent methods were used to detect Reactive oxygen species (ROS) and mitochondrial transmembrane potential (Δψm), respectively. Proteins associated with apoptosis and DNA damage were evaluated by Western blotting. Results showed that MET and JS-K could suppress cell growth, and the inhibition concentration 50 of treatment with MET combined with JS-K (MET + JS-K) showed more toxicity than individual agents on RCC cells. This augmented toxicity was associated with intracellular reactive oxygen species (ROS) level, mitochondrial membrane potential alteration, and induced DNA breaks. The results of Western blotting showed that the expression level of pro-apoptotic proteins, such as Bax, Bak, caspase-3, and caspase-9, was up-regulated, and the anti-apoptotic protein Bcl-2 was down-regulated after treatment using MET alone and MET + JS-K, correspondingly. Moreover, MET + JS-K inhibited the expression of cellular PCNA and Rad51, and immunofluorescence analysis of γH2AX proved that MET + JS-K enhanced DNA damage. In summary, the results of this research indicated that MET and JS-K inhibited RCC cell growth by activating ROS, targeting mitochondria-dependent apoptotic pathways, and inducing DNA breaks.