T6SS nuclease effectors in Pseudomonas syringae act as potent antimicrobials in interbacterial competition.

Type VI secretion system (T6SS) is a potent weapon employed by various Pseudomonas species to compete with neighboring microorganisms for limited nutrients and ecological niches. However, the involvement of T6SS effectors in interbacterial competition within the phytopathogen Pseudomonas syringae remains unknown. In this study, we examined two T6SS clusters in a wild-type P. syringae MB03 and verified the involvement of one cluster, namely, T6SS-1, in interbacterial competition. Additionally, our results showed that two T6SS DNase effectors, specifically Tde1 and Tde4, effectively outcompeted antagonistic bacteria, with Tde4 playing a prominent role. Furthermore, we found several cognate immunity proteins, including Tde1ia, Tde1ib, and Tde4i, which are located in the downstream loci of their corresponding effector protein genes and worked synergistically to protect MB03 cells from self-intoxication. Moreover, expression of either Tde1 or C-terminus of Tde4 in Escherichia coli cells induced DNA degradation and changes in cell morphology. Thus, our results provide new insights into the role of the T6SS effectors of P. syringae in the interbacterial competition in the natural environment. IMPORTANCE: The phytopathogen Pseudomonas syringae employs an active type VI secretion system (T6SS) to outcompete other microorganisms in the natural environment, particularly during the epiphytic growth in the phyllosphere. By examining two T6SS clusters in P. syringae MB03, T6SS-1 is found to be effective in killing Escherichia coli cells. We highlight the excellent antibacterial effect of two T6SS DNase effectors, namely, Tde1 and Tde4. Both of them function as nuclease effectors, leading to DNA degradation and cell filamentation in prey cells, ultimately resulting in cell death. Our findings deepen our understanding of the T6SS effector repertoires used in P. syringae and will facilitate the development of effective antibacterial strategies.

Efficient remediation of di-(2-ethylhexyl) phthalate and plant-growth promotion with the application of a phosphate-solubilizing compound microbial agent.

The ecotoxic endocrine-disrupting chemical di-(2-ethylhexyl) phthalate (DEHP) is ubiquitous in agricultural soil, posing a serious threat to human health. Here, we report efficient soil-borne DEHP degradation and plant growth promotion by a microbial organic fertilizer GK-PPB prepared by combining a recycled garden waste-kitchen waste compost product with ternary compound microbial agent PPB-MA, composed of Penicillium oxalic MB08F, Pseudomonas simiae MB751, and Bacillus tequilensis MB05B. The combination of MB08F and MB751 provided synergistic phosphorus solubilization, and MB05B enhanced the DEHP degradation capacity of MB08F via bioemulsification. Under optimal conditions (25.70 °C and pH 7.62), PPB-MA achieved a 96.81 % degradation percentage for 1000 mg L-1 DEHP within 5 days. The degradation curve followed first-order kinetics with a half-life of 18.24 to 24.76 h. A complete mineralization pathway was constructed after identifying the degradation intermediates of 2H-labeled DEHP. Evaluation in Caenorhabditis elegans N2 showed that PPB-MA eliminated the ecological toxicity of DEHP. A pakchoi (Brassica chinensis L.) pot experiment demonstrated that GK-PPB promoted phosphorus solubilization and plant growth, reduced soil DEHP residue, and decreased DEHP accumulation in pakchoi, suggesting its potential practical utility in environmentally responsible and safe cultivation of vegetables.

Copper oxide nanoparticles suppress retinal angiogenesis via inducing endothelial cell cuproptosis.

Background: Copper oxide nanoparticles (CuO NPs) exhibit antitumor activity; however, their potential as an antiangiogenesis agent is unknown. Materials & methods: The antiangiogenesis properties of CuO NPs were evaluated in vitro and in vivo and the underlying mechanism was examined using RNA sequencing and metabolomic analyses. Results: CuO NPs inhibited endothelial cell function in vitro. They also mitigated retinal vasculature development and alleviated pathological retinal angiogenesis in vivo. RNA sequencing and metabolomic analyses revealed that CuO NPs disrupt the tricarboxylic acid cycle and induce cuproptosis, which was further supported by evaluating cuproptosis-related metabolites and proteins. Conclusion: CuO NPs may be an effective antiangiogenic agent for the treatment of retinal angiogenesis.

Complete oxidative degradation of diclofenac via coupling free radicals and oxygenases of a micro/nanostructured biogenic Mn oxide composite from engineered Pseudomonas sp. MB04R-2.

Oxidative degradation can effectively degrade aromatic emerging contaminants (ECs). However, the degradability of lone inorganic/biogenic oxides or oxidases is typically limited when treating polycyclic ECs. Herein, we report a dual-dynamic oxidative system comprising engineered Pseudomonas and biogenic Mn oxides (BMO), which completely degrades diclofenac (DCF), a representative halogen-containing polycyclic EC. Correspondingly, recombinant Pseudomonas sp. MB04R-2 was constructed via gene deletion and chromosomal insertion of a heterologous multicopper oxidase cotA, allowing for enhanced Mn(II)-oxidizing activity and rapid formation of the BMO aggregate complex. Additionally, we characterized it as a micro/nanostructured ramsdellite (MnO2) composite using multiple-phase composition and fine structure analyses. Furthermore, using real-time quantitative polymerase chain reaction, gene knockout, and expression complementation of oxygenase genes, we demonstrated the central and associative roles of intracellular oxygenases and cytogenic/BMO-derived free radicals (FRs) in degrading DCF and determined the effects of FR excitation and quenching on the DCF degradation efficiency. Finally, after identifying the degraded intermediates of 2H-labeled DCF, we constructed the DCF metabolic pathway. In addition, we evaluated the degradation and detoxification effects of the BMO composite on DCF-containing urban lake water and on biotoxicity in zebrafish embryos. Based on our findings, we proposed a mechanism for oxidative degradation of DCF by associative oxygenases and FRs.

Dynamic composting actuated by a Caldibacillus thermoamylovorans isolate enables biodecomposability and reusability of Cinnamomum camphora garden wastes.

The ecotoxic substances in Cinnamomum camphora garden wastes (CGW) often restrain microbe-driven composting process. Here, a dynamic CGW-Kitchen waste composting system actuated by a wild-type Caldibacillus thermoamylovorans isolate (MB12B) with distinctive CGW-decomposable and lignocellulose-degradative activities was reported. An initial inoculation of MB12B optimized for temperature promotion with reduced emission of CH4 and NH3 by 61.9% and 37.6%, respectively, increased germination index and humus content by 18.0% and 44.1%, respectively, and reduced moisture and electrical conductivity, and all were further reinforced by reinoculation of MB12B during the cooling stage of composting. High-throughput sequencing showed varied bacterial community structure and abundance following MB12B inoculation, with temperature-relative Caldibacillus, Bacillus, and Ureibacillus, and humus-forming Sphingobacterium emerging to dominate abundance, which strongly contrasted with Lactobacillus (acidogens related to CH4 emission). Finally, the ryegrass pot experiments showed significant growth-promoting effectiveness of the composted product that successfully demonstrated the decomposability and reuse of CGW.

Improving therapeutic synergy score predictions with adverse effects using multi-task heterogeneous network learning.

Drug combinations could trigger pharmacological therapeutic effects (TEs) and adverse effects (AEs). Many computational methods have been developed to predict TEs, e.g. the therapeutic synergy scores of anti-cancer drug combinations, or AEs from drug-drug interactions. However, most of the methods treated the AEs and TEs predictions as two separate tasks, ignoring the potential mechanistic commonalities shared between them. Based on previous clinical observations, we hypothesized that by learning the shared mechanistic commonalities between AEs and TEs, we could learn the underlying MoAs (mechanisms of actions) and ultimately improve the accuracy of TE predictions. To test our hypothesis, we formulated the TE prediction problem as a multi-task heterogeneous network learning problem that performed TE and AE learning tasks simultaneously. To solve this problem, we proposed Muthene (multi-task heterogeneous network embedding) and evaluated it on our collected drug-drug interaction dataset with both TEs and AEs indications. Our experimental results showed that, by including the AE prediction as an auxiliary task, Muthene generated more accurate TE predictions than standard single-task learning methods, which supports our hypothesis. Using a drug pair Vincristine-Dasatinib as a case study, we demonstrated that our method not only provides a novel way of TE predictions but also helps us gain a deeper understanding of the MoAs of drug combinations.

Complete Degradation and Detoxification of Ciprofloxacin by a Micro-/Nanostructured Biogenic Mn Oxide Composite from a Highly Active Mn2+-Oxidizing Pseudomonas Strain.

Ciprofloxacin (CIP), as a representative broad-spectrum antibiotic, poses a major threat to human health and the ecological environment as a result of its abuse and emissions. In this study, a highly active Mn2+-oxidizing bacterium, Pseudomonas sp. CCTCC M2014168, was induced to form micro-/nanostructured biogenic Mn oxide (BMO) aggregates through continuous culturing with 1 mmoL-1 Mn2+. Following the characterization of Mn4+ oxides and the micro-/nanostructures by scanning electron microscopy, high-resolution transmission electron microscopy and X-ray diffraction assays, the BMO composites were subjected to CIP degradation and detoxification in laboratory trials. High-performance liquid chromatograph (HPLC) analysis identified that the BMO composites were capable of completely degrading CIP, and HPLC with a mass spectrometer (LC/MS) assays identified three intermediates in the degradation pathway. The reaction temperature, pH and initial ciprofloxacin concentration substantially affected the degradation efficiency of CIP to a certain extent, and the metal ions Mg2+, Cu2+, Ni2+ and Co2+ exerted significant inhibitory effects on CIP degradation. A toxicity test of the degradation products showed that CIP was completely detoxified by degradation. Moreover, the prepared BMO composite exhibited a high capacity for repeated degradation and good performance in continuous degradation cycles, as well as a high capacity to degrade CIP in real natural water.

Biocontrol of the root-knot nematode Meloidogyne incognita by a nematicidal bacterium Pseudomonas simiae MB751 with cyclic dipeptide.

BACKGROUND: Root-knot nematodes (RKNs) are harmful plant-parasitic nematodes that cause serious damage to plant hosts. In the long-term practice of RKN management, bacterial nematicides have attracted increasing attention as an effective biocontrol means. Here we determined the active substances against Meloidogyne incognita from a nematicidal bacterium, developed a biocontrol agent (BCA) based on optimized culture processes. The effects of the BCA on RKN control and plant growth-promotion were evaluated in tomato pot trials. RESULTS: Pseudomonas simiae strain MB751 exhibiting significant nematicidal activity against M. incognita second-stage juveniles (J2) with approximately 80% mortality (with culture supernatant, 96% volume percentage) was isolated from a vineyard. A set of purification and identification experiments was performed to determine the main nematicidal component in MB751. A cyclic dipeptide Cyclo(L-Pro-L-Leu) was identified with a lethal concentration necessary to kill 50% of the population (LC50 ) of 65.3 µg mL-1 against M. incognita J2. Following optimization trials on culture medium/fermentation conditions, such as the single factor test, Plackett-Burman test, steepest ascent, and response surface methodology experiments, the MB751 fermentation broth was then prepared as a BCA via a cold-air drying process. The BCA and was evaluated in tomato pot experiments for effectiveness in suppressing M. incognita. Significant effects on M. incognita suppression and plant-growth promotion as well as induced systemic resistance to M. incognita of tomato, were observed. CONCLUSION: The cyclic dipeptide-producing bacterium P. simiae MB751 exhibited high nematicidal activity and performance. Further development of this BCA should be pursued for the management of M. incognita in agriculture. © 2021 Society of Chemical Industry.

Design, synthesis, herbicidal activity and CoMFA of aryl-formyl piperidinone HPPD inhibitors.

Isoxazole, nicotinic acid and benzoic acid are important components in many natural products and useful synthons to build macrostructures having valuable biological activities. In continuation of our effort to discover 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors and search for active fragments from natural products, a series of substituted aryl-formyl piperidinone derivatives with natural product fragments was rationally designed, synthesized and tested for their herbicidal activity. Compound I-9 was considered the most effective candidate with an IC50 value of 0.260 µM. The molecular docking results showed that the triketone group of compound I-9 forms a bidentate complex with a metal ion, and the benzene ring interacted with Phe424 and Phe381 via π-π stacking, which was similar to the mechanisms of mesotrione. The present work indicates that compound I-9 may serve as a potential lead compound for further development of green HPPD inhibitors.

Identification of key residues determining the binding specificity of human 4-hydroxyphenylpyruvate dioxygenase.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is the second enzyme of the tyrosine catabolic pathway. Its physiological function is to catalyze the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, which displays different physiological effects in mammals and plants. Insights on the selective inhibition of human HPPD (hHPPD) by triketone inhibitors were furnished by the integrated application of molecular simulation and biological testing. The binding free energy of hHPPD and inhibitors was obtained through molecular dynamics (MD) simulations, and the result was in agreement with the inhibition experiment in vitro. The binding free energy contribution demonstrated that the formation of hHPPD-inhibitor complexes was mainly driven by van der Waals energy. Ser226, Asn241, Gln265, Phe336, Phe359 and Phe364 made great contributions to binding affinities of all the systems. Among the residues involved in the interaction between nitisinone (NTBC) and hHPPD, Tyr221 and Leu224, whose mutation into Ala caused significant decrease of NTBC binding ability, were two key residues in determining the selective binding affinity of inhibitor and hHPPD. This work provides valuable theoretical basis for rational design of highly selective inhibitors targeting hHPPD.

Based on the Virtual Screening of Multiple Pharmacophores, Docking and Molecular Dynamics Simulation Approaches toward the Discovery of Novel HPPD Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an iron-dependent non-heme oxygenase involved in the catabolic pathway of tyrosine, which is an important enzyme in the transformation of 4-hydroxyphenylpyruvic acid to homogentisic acid, and thus being considered as herbicide target. Within this study, a set of multiple structure-based pharmacophore models for HPPD inhibitors were developed. The ZINC and natural product database were virtually screened, and 29 compounds were obtained. The binding mode of HPPD and its inhibitors obtained through molecular docking study showed that the residues of Phe424, Phe381, His308, His226, Gln307 and Glu394 were crucial for activity. Molecular-mechanics-generalized born surface area (MM/GBSA) results showed that the coulomb force, lipophilic and van der Waals (vdW) interactions made major contributions to the binding affinity. These efforts will greatly contribute to design novel and effective HPPD inhibitory herbicides.

Combined 3D-quantitative structure-activity relationships and topomer technology-based molecular design of human 4-hydroxyphenylpyruvate dioxygenase inhibitors.

Aim: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as an important target against tyrosinemia type I. This paper aimed to explore the structure-activity relationship of HPPD inhibitors with pyrazole scaffolds and to design novel HPPD inhibitors. Methodology & results: The best 3D-quantitative structure-activity relationships model was established by two different strategies based on 40 pyrazole scaffold-based analogs. Screening of molecular fragments by topomer technology, combined with molecular docking, 14 structures were identified for potential human HPPD inhibitory activity. Molecular dynamics results demonstrated that all the compounds obtained bound to the enzyme and possessed a satisfactory binding free energy. Conclusion: The quantitative structure-activity relationship of HPPD inhibitors of pyrazole scaffolds was clarified and 14 original structures with potential human HPPD inhibitory activity were obtained.

Design, Synthesis, and Biological Activity of Novel Diazabicyclo Derivatives as Safeners.

Herbicide safeners selectively protect crops from herbicide damage without reducing the herbicidal efficiency on target weed species. The title compounds were designed by the intermediate derivatization approach and fragment splicing to exploit novel potential safeners. A total of 31 novel diazabicyclo derivatives were synthesized by the microwave-assistant method using isoxazole-4-carbonyl chloride and diazabicyclo derivatives. All synthetic compounds were confirmed by infrared, 1H and 13C nuclear magnetic resonance, and high-resolution mass spectrometry. The bioassay results demonstrated that most of the title compounds could reduce the nicosulfuron phytotoxicity on maize. The glutathione S-transferase (GST) activity in vivo was assayed, and compound 4(S15) revealed an inspiring safener activity comparable to commercialized safeners isoxadifen-ethyl and BAS-145138. The molecular docking model exhibited that the competition at the active sites of target enzymes between compound 4(S15) and nicosulfuron was investigated with respect to herbicide detoxification. The current work not only provided a powerful supplement to the intermediate derivatization approach and fragment splicing in design pesticide bioactive molecules but also assisted safener development and optimization.

Tirofiban hydrochloride sodium chloride injection combined with cardiovascular intervention in the treatment of Acute Myocardial Infarction.

OBJECTIVE: To investigate the therapeutic effect of tirofiban hydrochloride sodium chloride injection combined with cardiovascular intervention on acute myocardial infarction. METHODS: Eighty-four patients with acute myocardial infarction who were treated in our hospital from April 2017 to May 2018 were divided into a control group and a treatment group using random number table method; there were 42 patients in each group. Both groups were given conventional treatment and were treated with aspirin and clopidogrel before and after operation. Moreover, the control group was treated with cardiovascular interventional therapy, while the treatment group was treated with tirofiban hydrochloride on the basis of cardiovascular interventional therapy. The patients were followed up to observe and compare the treatment condition and adverse reactions of the two groups. RESULTS: After percutaneous coronary intervention, the normal rate of myocardial perfusion in the treatment group was 92.86%, which was higher than 69.05% in the control group (P<0.05). After PCI, there were significant differences of thrombolysis in myocardial infarction (TIMI) flow Grade- 2 and 3 between the two groups (P<0.05). The improvement of platelet activation function in the treatment group was better than that in the control group (P<0.05). The incidence of adverse cardiac events in the treatment group was significantly lower than that in the control group (P<0.05). CONCLUSION: Tirofiban hydrochloride sodium chloride injection combined with cardiovascular intervention has a significant clinical effect in the treatment of acute myocardial infarction. It can effectively improve the blood perfusion and reduce the incidence of adverse cardiac events, suggesting a good effect on the prognosis of patients and high application value.

Discovery of N-Aroyl Diketone/Triketone Derivatives as Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibiting-Based Herbicides.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an important target site for discovering new bleaching herbicides. To explore novel HPPD inhibitors with excellent herbicidal activity, a series of novel N-aroyl diketone/triketone derivatives were rationally designed by splicing active groups and bioisosterism. Bioassays revealed that most of these derivatives displayed preferable herbicidal activity against Echinochloa crus-galli (EC) at 0.045 mmol/m2 and Abutilon juncea (AJ) at 0.090 mmol/m2. In particular, compound I-f was more potent compared to the commercialized compound mesotrione. Molecular docking indicated that the corresponding active molecules of target compounds and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD.

Safeners Improve Maize Tolerance under Herbicide Toxicity Stress by Increasing the Activity of Enzymes in Vivo.

Tribenuron-methyl (TM), as one of the sulfonylurea (SU) herbicides, has been widely and effectively applied for many kinds of plants. SUs inhibit plant growth by restraining the biosynthetic pathway of branched-chain amino acids (BCAAs) catalyzed by acetolactate synthase (ALS). Safeners are agrochemicals that protect crops from herbicide injuries. To improve the crop tolerance under TM toxicity stress, this paper evaluated the protective effect of N-tosyloxazolidine-3-carboxamide. It turned out that most of the tested compounds showed significant protection against TM via enhancing the glutathione (GSH) content and glutathione S-transferase (GST) activity. Among all of the tested compounds, compound 16 exhibited more excellent protection than the contrast safener R-28725 and other target compounds. A positive correlation between the growth level, endogenous GSH content, and GST activity was observed in this research. The GST kinetic parameter Vmax of the maize was increased by 29.6% after treatment with compound 16, while Km was decreased by 51.9% compared to the untreated control. The molecular docking model indicated that compound 16 could compete with TM in the active site of ALS, which could interpret the protective effects of safeners. The present work demonstrated that N-tosyloxazolidine-3-carboxamide derivatives could be considered as potential candidates for developing new safeners in the future.

Quantitative Structure Activity Relationship Studies and Molecular Dynamics Simulations of 2-(Aryloxyacetyl)cyclohexane-1,3-Diones Derivatives as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a significant enzyme in the biosynthesis of plastoquinone and tocopherol. Moreover, it is also a potential target to develop new herbicide. The technology of computer-aided drug design (CADD) is a useful tool in the efficient discovery of new HPPD inhibitors. Forty-three compounds with known activities were used to generate comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models based on common framework and molecular docking. The structural contribution to the activity was determined, which provided further information for the design of novel inhibitors. Molecular docking was used to explain the changes in activity caused by the binding mode between ligand and protein. The molecular dynamics (MD) results indicated that the electrostatic energy was the major driving force for ligand-protein interaction and the Phe403 made the greatest contribution to the binding. The present work has provided useful information for the rational design of novel HPPD inhibitors with improved activity.

Aspirin in combination with clopidogrel in the treatment of acute myocardial infarction patients undergoing percutaneous coronary intervention.

OBJECTIVE: To investigate the clinical effect of aspirin combined with clopidogrel on acute myocardial infarction after percutaneous coronary intervention (PCI). METHODS: One hundred thirty two patients with acute myocardial infarction who were admitted to the hospital between December 2016 and December 2017 were divided into a control group and an observation group according to random number table, 66 each group. Both groups were given emergency PCI and symptomatic treatment. The control group was given aspirin on the basis of conventional treatment before and after operation, while the observation group was given clopidogrel treatment on the basis of the treatment the same as the control group. The treatment lasted for 4 months. The clinical efficacy of the two groups was analyzed, and the cardiac function indicator, coagulation indicator and occurrence of adverse reactions were compared before and after treatment. RESULTS: There was no thrombosis at the infarct site in coronary angiography after treatment in both groups. The efficacy in the observation group and control group were 89.4% and 81.8%, respectively; there was no significant difference between the two groups. The incidence of re-thrombosis in the two groups was 1.5% and 12.1% respectively, which was significantly lower in the observation group than in the control group (P<0.05). The cardiac function indicator of both groups improved after treatment, especially the observation group (P<0.05). There was no significant difference in prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin activity (PA) and platelet aggregation rate (PAR) in the two groups before treatment (P>0.05). There was also no significant difference in PT and PA before and after treatment (P>0.05). The APTT and PAR were significantly different after treatment (P<0.05), and the PAR of the observation group was significantly higher than that of the control group (P<0.05). The incidence of adverse reactions in the observation group was 7.58%, which was not significantly different with that of the control group (12.12%) (P<0.05). CONCLUSION: Aspirin combined with clopidogrel can effectively reduce the occurrence of re-thrombosis after PCI and improve the recovery of cardiac function after acute operation, moreover the safety is high. It has important clinical application values.

Ginsenoside Rg1 protects cardiomyocytes from hypoxia-induced injury through the PI3K/AKT/mTOR pathway.

AIM: Myocardial ischemia (MI) is a leading cause of morbidity and mortality which makes the prevention and control of MI tremendously important. We aimed to explore the functional roles of ginsenoside (Gin) Rg1 in cardiomyocytes under hypoxia and to clarify underlying mechanisms. MAIN METHODS: Hypoxia-induced H9c2 cell injury was evaluated by alterations of cell viability, apoptosis and autophagy. Then, effects of Gin Rg1 on hypoxia-induced cell injury were measured. The activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathways as well as expression of hypoxia-inducible factor 1α (HIF-1α) was determined with or without addition of PI3K or mTOR inhibitor. Finally, the effects of Gin Rg1 on rat ischemia/reperfusion (I/R) injury and underlying mechanism were studied. KEY FINDINGS: First of all, hypoxia was identified to induce a decrease in cell viability and to increase cell apoptosis and autophagy. Then, these hypoxia-induced alterations were ameliorated by Gin Rg1, which had no effect on cell viability under normoxia. Subsequently, the phosphorylated levels of key kinases in the PI3K/AKT/mTOR pathways as well as expression of HIF-1α were all elevated by Gin Rg1. Activation of the PI3K/AKT/mTOR pathways and HIF-1α expression were inhibited by PI3K inhibitor, and activation of mTOR pathway and HIF-1α expression were inhibited by mTOR inhibitor. More in vivo experiments proved that Gin Rg1 ameliorated rat I/R injury through activating the PI3K/AKT/mTOR pathways. SIGNIFICANCE: Gin Rg1 protected cardiomyocytes from hypoxia-induced cell injury by upregulating HIF-1α through activation of the PI3K/AKT/mTOR pathways.

Prognostic significance of PD-L1 expression in patients with gastric cancer in East Asia: a meta-analysis.

The overexpression of programmed cell death-ligand 1(PD-L1) has been observed in gastric cancer (GC). However, whether the expression of PD-L1 in tumor cells or blood serum is associated with the prognosis of patients with GC remains unclear. Therefore, we performed a meta-analysis to evaluate the prognostic significance of PD-L1 expression in GC. Electronic databases were searched systematically. Studies that met the inclusion criteria were included in the meta-analysis. Data concerning the hazard ratio (HR) for overall survival and disease-free survival with a 95% confidence interval (CI) according to the expression status of PD-L1 evaluated by immunohistochemistry or enzyme-linked immunosorbent assay were extracted. The data were analyzed using a random effects model. Subgroup analyses were proposed. Our results showed that eight studies with 950 patients met the inclusion criteria and were included in the meta-analysis. The pooled HR for overall survival indicated that patients with PD-L1-positive expression had significantly shorter survival time compared with the PD-L1-negative group (HR 1.60, 95% CI 1.09-2.36, P=0.012). The pooled HR for disease-free survival demonstrated that the difference between the two groups was not statistically significant (HR 1.02, 95% CI 0.32-3.20, P=0.98). In conclusion, our results indicate that the evaluation of PD-L1 overexpression in GC tissue or blood serum may be useful in the future as a novel prognostic factor.