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Mesenchymal stem cell-derived extracellular vesicles (MSCs-EVs) possess cardioprotection in acute myocardial infarction. Nevertheless, the therapeutic intervention potential and the molecular mechanism of EVs from NMN (Nicotinamide mononucleotide) preconditioned hUCMSCs (N-EVs) in acute myocardial infarction remains unknown. In the present study, EVs from hUCMSCs (M-EVs) and N-EVs were identified by electron microscopy, immunoblotting and nanoparticle tracking analysis. Compared with M-EVs, N-EVs significantly increased the proliferation, migration, and angiogenesis of HUVECs. Meanwhile, N-EVs markedly reduced apoptosis and cardiac fibrosis and promoted angiogenesis in the peri-infarct region in the MI rats. A high-throughput miRNA sequencing and qPCR methods analysis revealed that miR-210-3p was abundant in N-EVs and the expression of miR-210-3p was obviously upregulated in HUVECs after N-EVs treated. Overexpression of miR-210-3p in HUVECs significantly enhanced the tube formation, migration and proliferative capacities of HUVECs. However, downregulation of miR-210-3p in HUVECs markedly decreased the tube formation, migration and proliferative capacities of HUVECs. Furthermore, bioinformatics analysis and luciferase assays revealed that EphrinA3 (EFNA3) was a direct target of miR-210-3p. Knockdown of miR-210-3p in N-EVs significantly impaired its ability to protect the heart after myocardial infarction. Altogether, these results indicated that N-EVs promoted the infarct healing through improvement of angiogenesis by miR-210-3p via targeting the EFNA3. Graphical Abstract Created with Biorender.com.

Aims To explore the predictive value of ferroptosis-related (FR) biomarkers for diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods This prospective observational study enrolled patients with T2DM at the Second Hospital of Jilin University between December 2021 and March 2022. DKD was measured by the urinary albumin-to-creatinine ratio. Receiver operating characteristic curve (ROC) analysis was performed to assess the predictive value of ferroptosis-related biomarkers for DKD.The risk factors for massive proteinuria were performed by multivariable logistic regression analysis. Results Finally, 118 patients (53.0 ± 12.2 years, 76 males) were enrolled, 52 of them without DKD (had normal proteinuria), while 66 with DKD. (Forty-one had microproteinuria, and 25 had massive proteinuria.) FR biomarkers, including acyl-CoA synthase long chain family member 4 (ACSL4), malondialdehyde (MDA), and reactive oxygen species (ROS), were significantly higher in the massive proteinuria group than in the other groups, while glutathione peroxidase 4 (GPX4) was significantly lower (all P < 0.05). The area under the ROC of the combination of GPX4, ACSL4, MDA, and ROS for predicting DKD was 0.804 (P < 0.001). Additionally, multivariate logistic regression analysis showed that the course of disease and ferritin levels were independent risk factors for massive proteinuria, while high serum iron, transferrin, and GPX4 levels were independent protective factors for massive proteinuria in patients with T2DM (all P < 0.05). Conclusions The GPX4, ACSL4, MDA, and ROS combination might have a good predictive value for DKD. Additionally, the course of disease, ferritin levels, serum iron, transferrin, and GPX4 were independently associated with massive proteinuria.

The effect of Pseudomonas aeruginosa (P. aeruginosa) on the phytoremediation efficiency of ryegrass on soil contaminated with nonylphenol (NP) and cadmium (Cd) was investigated by pot experiments. Pseudomonas aeruginosa application stimulated the adsorption of Cd by ryegrass and facilitated the biodegradation of NP in the soil. Exogenous P. aeruginosa inoculation increased the activities of urease, dehydrogenase, and polyphenol oxidase in the soil of the T4 treatment by 38.5%, 50.0%, and 56.5% compared to that of the T2 treatment, respectively. There was a significant positive correlation between the activities of dehydrogenase and polyphenol oxidase and the NP removal rate (P 0.001). The relative abundances of beneficial microorganisms (such as Sphingomonas, Lysobacter, Streptomyces, Chloroflexia, Deltaproteobacteria, and Alphaproteobacteria) were increased as a result of P. aeruginosa inoculation. These microorganisms play important roles in nutrient cycling, Cd adsorption, and NP degradation. Additionally, P. aeruginosa was not the dominate bacterial species at the end of the experiment. According to this study, P. aeruginosa application improved the phytoremediation efficiency of ryegrass on soil contaminated with NP and Cd, with a minimal risk of alien microbial invasion.

Lubricants have played important roles in friction and wear reduction and increasing efficiency of mechanical systems. To optimize tribological performance, chemical reactions between a lubricant and a substrate must be designed strategically. Tribochemical reactions are chemical reactions enabled or accelerated by mechanical stimuli. Tribochemically activated lubricant additives play important roles in these reactions. In this review, current understanding in mechanisms of chemical reactions under shear has been discussed. Additives such as oil-soluble organics, ionic liquids (ILs), and nanoparticles (NPs) were analyzed in relation to the tribochemical reaction routes with elements in metallic substrates. The results indicated that phosphorus, sulfur, fluorine, and nitrogen are key elements for tribochemical reactions. The resulting tribofilms from zinc dithiophosphates (ZDDP) and molybdenum dithiocarbamate (MoDTC) have been widely reported, yet that from ILs and NPs need to investigate further. This review serves as a reference for researchers to design and optimize new lubricants.

In recent years, the risk from environmental pollution caused by chloramphenicol (CAP) has emerged as a serious concern worldwide, especially for the co-selection of antibiotic resistance microorganisms simultaneously exposed to CAP and salts. In this study, the multistage contact oxidation reactor (MCOR) was employed for the first time to treat the CAP wastewater under the co-existence of CAP (10-80 mg/L) and salinity (0-30 g/L NaCl). The CAP removal efficiency reached 91.7% under the co-existence of 30 mg/L CAP and 10 g/L NaCl in the influent, but it fluctuated around 60% with the increase of CAP concentration and salinity. Trichococcus and Lactococcus were the major contributors to the CAP and salinity shock loads. Furthermore, the elevated CAP and salinity selection pressures inhibited the spread of CAP efflux pump genes, including cmlA, tetC, and floR, and significantly affected the composition and abundance of antibiotic resistance genes (ARGs). As the potential hosts of CAP resistance genes, Acinetobacter, Enterococcus, and unclassified_d_Bacteria developed resistance against high osmotic pressure and antibiotic environment using the efflux pump mechanism. The results also revealed that shifting of potential host bacteria significantly contributed to the change in ARGs. Overall, the co-existence of CAP and salinity promoted the enrichment of core genera Trichococcus and Lactococcus; however, they inhibited the proliferation of ARGs. KEY POINTS: • Trichococcus and Lactococcus were the core bacteria related to CAP biodegradation • Co-existence of CAP and salinity inhibited proliferation of cmlA, tetC, and floR • The microorganism resisted the CAP using the efflux pump mechanism.

Background Recurrence-free survival (RFS) and overall survival (OS) data for adjuvant nivolumab versus placebo (proxy for routine surveillance) in patients with high-risk, resected melanoma are lacking. This post hoc, indirect treatment comparison (ITC) used pooled data from the phase 3 EORTC 18,071 (ipilimumab vs. placebo) and CheckMate 238 (nivolumab vs. ipilimumab) trials to assess RFS and OS with nivolumab versus placebo and the numbers needed to treat (NNT) over 4 years. Methods Patients with resected stage IIIB-C cutaneous melanoma (American Joint Committee on Cancer seventh edition) were included. Inverse probability treatment weighting (IPTW) was used to balance baseline characteristics. RFS NNTs were calculated for nivolumab versus ipilimumab and placebo. OS NNTs were calculated for nivolumab versus placebo. To adjust for different post-recurrence treatments, the difference in post-recurrence survival between the two ipilimumab arms was added to OS of the placebo arm. Results This ITC included 278, 643, and 365 patients treated with nivolumab, ipilimumab, and placebo, respectively. Following IPTW, nivolumab was associated with improved RFS versus placebo (hazard ratio [HR]: 0.49; 95% confidence interval [CI] 0.39–0.61) and ipilimumab (HR: 0.69; 95% CI 0.56–0.85). RFS NNT was 4.2 for nivolumab versus placebo and 8.9 for nivolumab versus ipilimumab. After post-recurrence survival adjustment, weighted 4-year OS rates were 75.8% for nivolumab and 64.1% for placebo; OS NNT for nivolumab versus placebo was 8.5. Conclusions In patients with resected stage IIIB-C cutaneous melanoma in this ITC, nivolumab improved RFS versus placebo and ipilimumab, and OS versus placebo after post-recurrence survival adjustment.

Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis, which is a hallmark of cancer that promotes cancer growth and metastasis. It is of great significance to find new intervention targets and related regulatory mechanisms of VEGFA related angiogenesis for the treatment of tumors. This study focuses on the role of tribbles pseudokinase 3 (TRIB3)/signal transducer and activator of transcription 3 (STAT3)/VEGFA signaling axis in colon cancer angiogenesis.This study investigated the expression level of TRIB3 in colon cancer through database analysis and tissue microarray analysis. The effect of TRIB3 on proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) was further confirmed by CCK8 assay, scratch-wound assay/migration assay and tube formation assay respectively. The regulatory relationship of TRIB3/VEGFA signaling axis was identified by qPCR and Western blotting, which was further confirmed through animal experiments, and the specific regulatory mechanism was explored by immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) with colon cancer cell lines.TRIB3 was increased in colon cancer tissues compared to normal tissues, and elevated TRIB3 expression indicated a poor prognosis in colon cancer patients. Moreover, it was found that silencing TRIB3 could inhibit cancer angiogenesis, whereas overexpressing TRIB3 promoted cancer angiogenesis in vitro and in vivo. Mechanistically, TRIB3 physically interacted with STAT3 and enhanced STAT3-mediated transcriptional activity. Furthermore, the function of TRIB3 in cancer angiogenesis was through cooperating with STAT3 to increase the VEGFA expression.Our study provides insights into cancer angiogenesis and offers a potential therapeutic strategy for TRIB3-overexpressed cancer.

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (Hace1) is a crucial mediator of multiple pathological disorders. However, there are few studies regarding the role of Hace1 in myocardial ischemia/reperfusion injury. Here, we studied the functional role of Hace1 on myocardial ischemia/reperfusion injury using hypoxia/reoxygenation (H/R)-injured cardiac cells in vitro. Reduced levels of Hace1 were observed in H/R-exposed cardiac cells. Hace1-overexpressed cardiac cells were resistant to H/R injuries with reduced apoptosis, lowered oxidative stress, and a suppressed inflammatory response. Subsequent analysis revealed that Hace1 overexpression enhanced the activation of nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and increased the transcriptional activity of Nrf2 in H/R-exposed cardiac cells. The knockout of kelch-like ECH-associated protein 1 (Keap1) diminished the regulatory role of Hace1 on Nrf2 activation. Additionally, inhibiting Nrf2 reversed Hace1-elicited cardioprotective effects in H/R-injured cardiac cells. In short, these data demonstrated that Hace1 overexpression mitigated myocardial H/R injury by enhancing the Nrf2 pathway via Keap1. This work underlines a possible role of Hace1 in myocardial ischemia/reperfusion injury and suggests Hace1 as a candidate target for exploiting cardioprotective therapy.

Manipulation under anesthesia (MUA) is often used for frozen shoulder treatment, but controversy still exists regarding MUA compared with conservative treatment. This research was conducted to compare the outcome between MUA and celecoxib (CLX) in secondary frozen shoulder.Patients with secondary frozen shoulder were randomized into two groups, an MUA plus exercise (EX) group and a CLX plus EX group. Clinical outcomes were documented at baseline and at 1 day, 2, 4, and 12 weeks after intervention, including Constant-Murley Score (CMS) for function, Pain Rating Index (PRI) and Present Pain Intensity (PPI) for pain, passive range of motion (ROM) measurements including external rotation, internal rotation, forward flexion, and abduction. Primary outcome was CMS. Secondary outcomes were PRI, PPI, and passive ROM.Sixty-seven patients out of 68 in the MUA group and 66 out of 68 in the CLX group finished the entire study period. There were no significant differences in basic properties of the two groups before intervention. As the primary outcome, CMS changes in the MUA group improved faster than the CLX group. Secondary outcomes, passive ROM, and pain PPI were faster and significant in the MUA group from 1 day after intervention compared with CLX (P 0.05). At 12 weeks, a statistically significant difference was not observed in the PPI (P 0.05). A statistically significant difference was not observed in the PRI between groups in 1 day (P 0.05). For the primary outcome, from 0 to 12 weeks the mean changes in CMS were 44.00 for MUA plus EX (95% CI 43.07-44.93, P 0.001) and 27.09 for CLX plus EX (26.20-27.98, P 0.001). The significant difference in improvement appeared from 2 weeks.To treat secondary frozen shoulder with MUA, this treatment could achieve better therapeutic effects on improvement of function, pain, and passive ROM than CLX did.The trial was registered at www.chictr.org.cn , identifier ChiCTR2200060269.

Changes in the metabolic profile within the intestine of lenok (Brachymystax lenok) when challenged to acute and lethal heat stress (HS) are studied using no-target HPLC-MS/MS metabonomic analysis. Of 51 differentially expressed metabolites identified in response to HS, 34 occurred in the positive ion mode and 17 in negative ion mode (VIP > 1, P < 0.05). Changes in metabolites (i.e. alpha-D-glucose, stachyose and L-lactate) related to carbohydrate and glycolysis are identified in HS-treated lenok. Fatty acid β-oxidation in HS-treated lenok was inhibited by accumulation of acetyl carnitine, palmitoylcarnitine, carnitine, and erucic acid. Many amino acids (L-tryptophan, D-proline, L-leucine, L-phenylalanine, L-aspartate, L-tyrosine, L-methionine, L-histidine and L-glutamine) decreased to support energy demands in HS-treated lenok. Oxidative damage in HS-treated lenok was indicated by decreased glycerophospholipid metabolites (i.e. glycerophosphocholine, 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine, 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, and 1, 2-dioleoyl-sn-glycero-3-phosphatidylcholine), and increased oxylipin production (12-HETE and 9R, 10S-EpOME). Oxidative stress increased formation of eicosanoids and dicarboxylic acids, overwhelming the mitochondrial β-oxidation pathway, while minor oxidative pathways (omega-oxidation and peroxisomal beta-oxidation) were likely to be activated in HS-treated lenok.