First Principles Investigation of C, Cl2 and CO Co-Adsorption on ZrSiO4 Surfaces for Carbochlorination Reaction.

The study of the adsorption behavior of C, CO and Cl2 on the surface of ZrSiO4 is of great significance for the formulation of the technological parameters in the carbochlorination reaction process. Based on first principles, the adsorption structure, adsorption energy, Barder charge, differential charge density, partial density of states and energy barrier were calculated to research the adsorption and reaction mechanism of C and Cl2 on ZrSiO4 surfaces. The results indicated that when C, CO and Cl2 co-adsorbed on the surface of ZrSiO4, they interacted with surface atoms and the charge transfer occurred. The Cl2 molecules dissociated and formed Zr-Cl bonds, while C atoms formed C1=O1 bonds with O atoms. Compared with CO, the co-adsorption energy and reaction energy barrier of C and Cl2 are lower, and the higher the C content, the lower the adsorption energy and energy barrier, which is beneficial for promoting charge transfer and the dissociation of Cl2. The 110-2C-2Cl2 has the lowest adsorption energy and the highest reaction activity, with adsorption energy and energy barriers of -13.45 eV and 0.02 eV. The electrons released by C are 2.30 e, while the electrons accepted by Cl2 are 2.37 e.

FTO attenuates LPS-induced acute kidney injury by inhibiting autophagy via regulating SNHG14/miR-373-3p/ATG7 axis.

N6-methyladenosine (m6A) is a master driver of RNA function and implicates in the pathogenesis of renal injury. LncRNA SNHG14 is highly expressed in sepsis patients with acute kidney injury (AKI) and aggravates kidney cell dysfunction. This study aimed to explore whether demethylase FTO affect m6A methylation of SNHG14 in AKI injury and its underlying mechanism. The expression level of FTO was obviously downregulated in sepsis-associated AKI patients compared with normal controls. Mechanistically, FTO overexpression impeded SNHG14 expression by decreasing the stability of SNHG14 in an m6A-dependent manner in LPS-induced HK-2 cells. Additionally, FTO overexpression inhibited cell autophagy and apoptosis while promoting cell viability of LPS-induced HK-2 cells. Moreover, overexpression of FTO inhibited SNHG14 expression and autophagy in LPS-induced AKI mice. Functionally, SNHG14 acts as a competing endogenous RNA (ceRNA) via directly sponging miR-373-3p in LPS induced HK-2 cells. Additionally, miR-373-3p directly targets ATG7. Inhibition of SNHG14 suppresses NF-κB signaling pathway and production of inflammatory cytokines (TNF-α, IL-6, and IL-1ß) via miR-373-3p/ATG7 in LPS-induced HK-2 cells. Furthermore, the SNHG14/miR-373-3p/ATG7 interaction network contributes to the regulatory effect of FTO on LPS-induced HK-2 cell viability, apoptosis and autophagy. These results suggested demethylase FTO suppressed the m6A modification of lncRNA SNHG14 and inhibits autophagy in LPS-induced AKI via regulating miR-373-3p/ATG7, which provided an important novel perspective for understanding sepsis-associated AKI and is conducive for developing new therapeutic targets and strategies.

Bakuchiol regulates TLR4/MyD88/NF-κB and Keap1/Nrf2/HO-1 pathways to protect against LPS-induced acute lung injury in vitro and in vivo.

Bakuchiol (Bak) possesses a protective effect in acute lung injury (ALI). Nonetheless, the molecular processes that regulate the protective activity of Bak in ALI remain elusive. Lipopolysaccharide (LPS)-treated rats and RLE-6TN cells were used as the ALI models in vivo and in vitro to investigate the function and mechanism of Bak. Rats were divided into four groups: control, LPS, LPS + Bak (30 mg/kg), and LPS + Bak (60 mg/kg). RLE-6TN cells were assigned into four groups: control, LPS, LPS + Bak (10 µM), and LPS + Bak (20 µM). Myeloperoxidase (MPO) and 4-hydroxy-2-nonenal (4-HNE) levels were detected by immunohistochemistry (IHC). The levels of TNF-α, IL-6, and IL-1ß were quantified by ELISA. Apoptosis was analyzed by TdT-mediated dUTP nick-end labeling (TUNEL) staining and flow cytometry. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were assayed to evaluate oxidative stress. In LPS-induced rats, Bak attenuated pathological injury, lung wet/dry weight ratio, MPO expression, and protein concentration and cell number in bronchial alveolar lavage fluid (BALF). Bak decreased the secretion of TNF-α, IL-6, and IL-1ß in BALF. Bak reduced MDA content and 4-HNE expression, and increased SOD and GSH-Px activities in lung tissues. Bak also repressed pulmonary apoptosis by decreasing Bax expression and enhancing Bcl-2 expression. In LPS-treated RLE-6TN cells, Bak downregulated the mRNA levels of TNF-α, IL-6, and IL-1ß and inhibited the protein expression of iNOS and COX2. Bak decreased MDA level and ROS production and increased SOD and GSH-Px activities. Bak also suppressed cell apoptosis, reduced Bax expression, and increased Bcl-2 expression. Moreover, Bak decreased the expression of TLR4, MyD88, p-IκBα, and p-p65. Additionally, Bak inhibited Keap1 expression and increased Nrf2 and HO-1 levels. Bak protects against LPS-induced inflammation, oxidative stress, and apoptosis in ALI by regulating TLR4/MyD88/NF-κB and Keap1/Nrf2/HO-1 pathways.

Effect of antimicrobial de-escalation strategy on 14-day mortality among intensive care unit patients: a retrospective propensity score-matched cohort study with inverse probability-of-treatment weighting.

PURPOSE: This study aimed to investigate the prevalence of antimicrobial de-escalation (ADE) strategy and assess its effect on 14-day mortality among intensive care unit patients. METHODS: A single-center retrospective cohort study was conducted on patients admitted to the intensive care unit (ICU) with infectious diseases between January 2018 and December 2020. Patients were stratified into three groups based on the initial treatment regimen within 5 days of antimicrobial administration: ADE, No Change, and Other Change. Confounders between groups were screened using one-way ANOVA and Chi-square analysis. Univariate and multivariate analyses were performed to identify risk factors for 14-day mortality. Potential confounders were balanced using propensity score inverse probability of treatment weighting (IPTW), followed by multivariate logistic regression analysis to evaluate the effect of ADE strategy on 14-day mortality. RESULTS: A total of 473 patients met the inclusion criteria, with 53 (11.2%) in the ADE group, 173 (36.6%) in the No Change group, and 247 (52.2%) in the Other Change group. The 14-day mortality rates in the three groups were 9.4%, 11.6%, and 21.9%, respectively. After IPTW, the adjusted odds ratio for 14-day mortality comparing No Change with ADE was 1.557 (95% CI 1.078-2.247, P = 0.0181) while comparing Other Change with ADE was 1.282(95% CI 0.884-1.873, P = 0.1874). CONCLUSION: The prevalence of ADE strategy was low among intensive care unit patients. The ADE strategy demonstrated a protective effect or no adverse effect on 14-day mortality compared to the No Change or Other Change strategies, respectively. These findings provide evidence supporting the implementation of the ADE strategy in ICU patients.

Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury?

Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.

New insights into lipid metabolism and prostate cancer (Review).

Prostate cancer (PCa) is the most common malignant tumor of the male urological system and poses a severe threat to the survival of middle­aged and elderly males worldwide. The development and progression of PCa are affected by a variety of biological processes, including proliferation, apoptosis, migration, invasion and the maintenance of membrane homeostasis of PCa cells. The present review summarizes recent research advances in lipid (fatty acid, cholesterol and phospholipid) metabolic pathways in PCa. In the first section, the metabolism of fatty acids is highlighted, from formation to catabolism and associated proteins. Subsequently, the role of cholesterol in the pathogenesis and evolution of PCa is described in detail. Finally, the different types of phospholipids and their association with PCa progression is also discussed. In addition to the impact of key proteins of lipid metabolism on PCa growth, metastasis and drug resistance, the present review also summarizes the clinical value of fatty acids, cholesterol and phospholipids, as diagnostic and prognostic indicators and therapeutic targets in PCa.

[Retracted] MicroRNA­153 is a prognostic marker and inhibits cell migration and invasion by targeting SNAI1 in human pancreatic ductal adenocarcinoma.

Subsequently to the publication of the above article, a concerned reader drew to the Editors' attention that the cell invasion and migration assay data shown in Fig. 3B and D were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that these contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 34: 595­602, 2015; DOI: 10.3892/or.2015.4051].

Large scale controlled Fab exchange GMP process to prepare bispecific antibodies.

Objective: Bispecific antibodies (BsAbs) have demonstrated significant therapeutic impacts for the treatment of a broad spectrum of diseases that include oncology, auto-immune, and infectious diseases. However, the large-scale production of clinical batches of bispecific antibodies still has many challenges that include having low yield, poor stability, and laborious downstream purification processes. To address such challenges, we describe the optimization of the controlled Fab arm exchange (cFAE) process for the efficient generation of BsAbs. Methods: The process optimization of a large-scale good manufacturing practice (GMP) cFAE strategy to prepare BsAbs was based on screening the parameters of temperature, reduction, oxidation, and buffer exchange. We include critical quality standards for the reducing agent cysteamine hydrochloride. Results: This large-scale production protocol enabled the generation of bispecific antibodies with >90% exchange yield and at >95% purity. The subsequent downstream processing could use typical mAb procedures. Furthermore, we demonstrated that the bispecific generation protocol can be scaled up to ∼60 L reaction scale using parental monoclonal antibodies that were expressed in a 200 L bioreactor. Conclusion: We presented a robust development strategy for the cFAE process that can be used for a larger scale GMP BsAb production.

Emerging Proteins in CRPC: Functional Roles and Clinical Implications.

Prostate cancer (PCa) is the most common cancer in men in the western world, but the lack of specific and sensitive markers often leads to overtreatment of prostate cancer which eventually develops into castration-resistant prostate cancer (CRPC). Novel protein markers for diagnosis and management of CRPC will be promising. In this review, we systematically summarize and discuss the expression pattern of emerging proteins in tissue, cell lines, and serum when castration-sensitive prostate cancer (CSPC) progresses to CRPC; focus on the proteins involved in CRPC growth, invasion, metastasis, metabolism, and immune microenvironment; summarize the current understanding of the regulatory mechanisms of emerging proteins in CSPC progressed to CRPC at the molecular level; and finally summarize the clinical applications of emerging proteins as diagnostic marker, prognostic marker, predictive marker, and therapeutic marker.

SLC1A5 Prefers to Play as an Accomplice Rather Than an Opponent in Pancreatic Adenocarcinoma.

Background: SLC1A5, a ferroptosis regulator gene, plays a dual role in cancer regulation. However, the roles of SLC1A5 in pancreatic adenocarcinoma (PAAD) remain elusive. Methods: SLC1A5's expression and somatic mutation information were determined by TCGA, GEO, Oncomine, and cBioPortal databases. Its prognostic value was assessed in TCGA cohort and was validated in three independent cohorts. The effects of SLC1A5 on the tumor immune microenvironment were analyzed by the CIBERSORT algorithm, ssGSEA method, and TISIDB and TIMER databases. The "oncoPredict" R package, TIDE algorithm, ImmuCellAI online tool, and GSE35141 and GSE59357 datasets were used to ascertain its therapeutic correlations. GSEA and Western blot were applied to reveal the effects of SLC1A5 on the mTORC1 signaling pathway and ferroptosis process. The biofunctions of SLC1A5 were assessed by MTT, wound-healing, Transwell, and xenograft assays. Results: SLC1A5 was significantly upregulated in the PAAD samples but was not commonly accompanied with somatic mutation (2.3%). Overexpression of SLC1A5 led to a poor prognosis and was identified as an independent prognostic factor. Moreover, high SLC1A5 expression suppressed the antitumor immune process by changing the infiltrating levels of immune cells. As for therapeutic correlations, SLC1A5 was related to the efficacy of dasatinib, sunitinib, sorafenib, and imatinib but may not predict that of radiotherapy, chemotherapeutic drugs, and immune checkpoints inhibitors (ICIs). Notably, the overexpression of SLC1A5 could activate the mTORC1 signaling pathway and may increase the cellular sensitivity to ferroptosis. Finally, the overexpression of SLC1A5 markedly promoted proliferation, migration, and invasion of pancreatic cancer cells. At the in vivo level, SLC1A5 deletion inhibited tumor growth in a mice xenograft model. Conclusions: SLC1A5 prefers to play as an accomplice rather than an opponent in PAAD. Our findings provide novel insights into PAAD treatment.

Tanshinone IIA improves sepsis-induced acute lung injury through the ROCK2/NF-κB axis.

BACKGROUND: This research sought to explore the effects of Tanshinone IIA (TIIA) and its potential mechanism in sepsis-induced acute lung injury. METHODS: Cecal ligation and puncture (CLP) was performed to construct a sepsis model in vivo. RLE-6TN cells were treated with lipopolysaccharide (LPS) to establish a sepsis model for in vitro experiments. The histopathological changes of the lung tissues were scored using HE staining, IHC, and dry and wet method. Apoptosis in the lung tissues was detected by TUNEL assay. Meanwhile, ELISA was used to determine the levels of the pro-inflammatory factors. Cell proliferation and apoptosis were evaluated using CCK-8, EdU assays and flow cytometry, respectively. RT-qPCR analysis was carried out to measure the expression of Rho associated coiled-coil containing protein kinase 2 (ROCK2). RESULTS: TIIA dramatically alleviated the pathological injuries of the lung, and relieved apoptosis, neutrophil infiltration, lung edema and inflammation response. Highly expressed ROCK2 was observed in septic rats in vivo and LPS-induced RLE-6TN cells in vitro. We found that ROCK2 knockdown promoted cell proliferation, and inhibited cell apoptosis and inflammation in LPS-treated RLE-6TN cells. Moreover, TIIA improved LPS-caused injury in RLE-6TN cells through downregulating ROCK2 expression. Mechanistically, TIIA repressed LPS-caused activation of the NF-κB pathway by regulating ROCK2 in RLE-6TN cells. Additionally, TIIA assuaged CLP-induced lung injury in the rats via downregulating ROCK2 to inactivate the NF-κB pathway in vivo. CONCLUSION: Our data demonstrated that TIIA improved sepsis-induced lung injury by downregulating ROCK2 and further inactivating the NF-κB signaling pathway in vivo and in vitro.

Pyroptosis-Related Risk Signature Exhibits Distinct Prognostic, Immune, and Therapeutic Landscapes in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a common abdominal cancer. The existing therapeutic approaches often fail to achieve satisfactory results. Pyroptosis, an inflammatory form of programmed cell death, provides new ideas for anticancer treatment. However, the roles of pyroptosis-related (PR) genes (PRGs) in HCC remain elusive. Methods: Differentially expressed genes (DEGs) (n = 22) were screened out using TCGA and GTEx databases. A novel PR risk signature was constructed through Lasso regression analysis. Its prognostic value was evaluated through a series of survival analyses and was tested in ICGC and GSE14520 cohorts. CIBERSORT, ssGSEA, and ESTIMATE methods were employed to determine the effects of the PR risk score on the tumor immune microenvironment (TIM). The TIDE scoring system, IMvigor210 cohort, GSE109211 dataset, and GSDC database were applied to explore the associations of the PR risk score with therapeutic effects. The biofunctions of WNK1 in hepatocellular cancer (HC) cells were confirmed through qPCR, colony formation, and Transwell assays. Results: Overall, 22 of 45 PRGs (48.9%) were abnormally expressed in HCC samples. Then, a PR risk signature consisting of eight PRGs was constructed. A high PR risk score led to an unfavorable prognosis. The PR risk score was identified as an independent prognostic factor of HCC and could increase the decision-making benefit of the traditional TNM model. In addition, we established a nomogram containing the clinical stage and PR risk score to predict the survival rates of HCC patients. The prognostic value of the PR model was successfully validated in ICGC and GSE14520 cohorts. Moreover, high PR risk conferred the decreased infiltration level of CD8+ T cells and weakened the activities of "cytolytic activity" pathways. As for therapeutic correlation, a high PR risk score seemed to imply a poor efficacy of PD-1/L1 inhibitors and sorafenib. Finally, the overexpression of WNK1 could promote the proliferation, migration, and invasion of HC cells. Conclusions: The PR risk score was closely related to the prognosis, antitumor immune process, therapeutic outcomes, and malignant progression of HCC. WNK1, the core regulator of pyroptosis, possesses pro-oncogenic abilities, showing promise as a novel treatment target.