Advances in Nanoplatforms for Immunotherapy Applications Targeting the Tumor Microenvironment.

Cancer immunotherapy is a treatment method that activates or enhances the autoimmune response of the body to fight tumor growth and metastasis, has fewer toxic side effects and a longer-lasting efficacy than radiotherapy and chemotherapy, and has become an important means for the clinical treatment of cancer. However, clinical results from immunotherapy have shown that most patients lack responsiveness to immunotherapy and cannot benefit from this treatment strategy. The tumor microenvironment (TME) plays a critical role in the response to immunotherapy. The TME typically prevents effective lymphocyte activation, reducing their infiltration, and inhibiting the infiltration of effector T cells. According to the characteristic differences between the TME and normal tissues, various nanoplatforms with TME targeting and regulation properties have been developed for more precise regulation of the TME and have the ability to codeliver a variety of active pharmaceutical ingredients, thereby reducing systemic toxicity and improving the therapeutic effect of antitumor. In addition, the precise structural design of the nanoplatform can integrate specific functional motifs, such as surface-targeted ligands, degradable backbones, and TME stimulus-responsive components, into nanomedicines, thereby reshaping the tumor microenvironment, improving the body's immunosuppressive state, and enhancing the permeability of drugs in tumor tissues, in order to achieve controlled and stimulus-triggered release of load cargo. In this review, the physiological characteristics of the TME and the latest research regarding the application of TME-regulated nanoplatforms in improving antitumor immunotherapy will be described. Furthermore, the existing problems and further applications perspectives of TME-regulated platforms for cancer immunotherapy will also be discussed.

Role of reactive oxygen species in myelodysplastic syndromes.

Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Microbial Dysbiosis Linked to Metabolic Dysfunction-Associated Fatty Liver Disease in Asians: Prevotella copri Promotes Lipopolysaccharide Biosynthesis and Network Instability in the Prevotella Enterotype.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by hepatic fat accumulation by metabolic dysfunction. The rising prevalence of MAFLD, especially among Asians, may be associated with changes in gut microbiota. We investigated gut microbiota characteristics and potential mechanisms leading to MAFLD development according to enterotypes. Case-control studies examining the gut microbiota composition between MAFLD and non-MAFLD participants were searched in public databases until July 2023. Gut microbiota was categorized into two enterotypes by principal component analysis. According to the enterotypes, LEfSe, ALDEx2, XGBoost, and DCiPatho were utilized to identify differential abundances and pathogenic microbes in the gut between the MAFLD and non-MAFLD groups. We analyzed microbial community networks with the SprCC module and predicted microbial functions. In the Prevotella enterotype (ET-P), 98.6% of Asians and 65.1% of Caucasians were associated with MAFLD (p = 0.049). MAFLD incidence was correlated with enterotype, age, obesity, and ethnicity (p < 0.05). Asian MAFLD patients exhibited decreased Firmicutes and Akkermansia muciniphila and increased Bacteroidetes and P. copri. The pathogenicity scores were 0.006 for A. muciniphila and 0.868 for P. copri. The Asian MAFLD group showed decreased stability and complexity in the gut microbiota network. Metagenome function analysis revealed higher fructose metabolism and lipopolysaccharide (LPS) biosynthesis and lower animal proteins and α-linolenic acid metabolism in Asians with MAFLD compared with the non-MAFLD group. LPS biosynthesis was positively correlated with P. copri (p < 0.05). In conclusion, P. copri emerged as a potential microbial biomarker for MAFLD. These findings enhance our understanding of the pathological mechanisms of MAFLD mediated through the gut microbiota, providing insights for future interventions.

Generalization Analysis of Pairwise Learning for Ranking With Deep Neural Networks.

Pairwise learning is widely employed in ranking, similarity and metric learning, area under the ROC curve (AUC) maximization, and many other learning tasks involving sample pairs. Pairwise learning with deep neural networks was considered for ranking, but enough theoretical understanding about this topic is lacking. In this letter, we apply symmetric deep neural networks to pairwise learning for ranking with a hinge loss ϕh and carry out generalization analysis for this algorithm. A key step in our analysis is to characterize a function that minimizes the risk. This motivates us to first find the minimizer of ϕh-risk and then design our two-part deep neural networks with shared weights, which induces the antisymmetric property of the networks. We present convergence rates of the approximation error in terms of function smoothness and a noise condition and give an excess generalization error bound by means of properties of the hypothesis space generated by deep neural networks. Our analysis is based on tools from U-statistics and approximation theory.

Enantioselective Alkynylation of Pyrazole-4,5-diones with Terminal Alkynes Catalyzed by Copper/PyBisulidine.

A copper/PyBisulidine-catalyzed enantioselective alkynylation of electrophilic pyrazole-4,5-dione with terminal alkynes has been developed. Chiral tertiary propargylic alcohols bearing the pyrazolone motif were prepared with yields (up to 99%) and enantioselectivities (up to 99% ee). The prominent feature of this protocol includes its mild reaction conditions and good stereoselectivities. The nonlinear effect study showed that the catalytically active specie was a monomeric catalyst and that the excess copper activated the alkynes through the π-system.

High diastereo- and enantioselective Michael addition of 3-acetoxy-2-oxindoles with nitroalkenes catalyzed by nickel/PyBisulidine.

A Ni/PyBisulidine catalyzed asymmetric Michael addition of 3-acyloxy-2-oxindoles to nitroalkenes has been developed. Various quaternary substituted 3-acyloxy-2-oxindoles were obtained with excellent yields and diastereo- and enantioselectivities in a low-toxic green solvent, ethyl acetate, with a low catalyst loading (1 mol%). The reaction process is air and moisture tolerant. The substrate scope was also extended to α,ß-disubstituted nitroalkenes and 3-hydroxy-2-oxindoles, and good results were obtained.

Interaction of environmental factors with the polygenic risk scores of thinness-related genes in preventing obesity risk in middle-aged adults: The KoGES.

BACKGROUND: Some persons are genetically resistant to obesity, but only a few studies have evaluated thinness genes for preventing obesity. We aimed to investigate the association of polygenic variants with being underweight and their interaction with the lifestyles of middle-aged and elderly persons and identify potential new genetic approaches for managing body weight. METHODS: In total, 58,701 participants aged 40-77 years were recruited from urban hospitals in Korea. Underweight (case) was defined as body mass index (BMI) < 18.5 kg m2 (n = 991) and normal weight (control, n = 21,921) was defined as 18.5 ≤ BMI < 23 kg m2 . A genome-wide association study was run to identify thinness-related single nucleotide polymorphisms (SNPs) after adjustment for compound factors using Gplink. The generalised multifactor dimensionality reduction program was used to identify the genetic variants with SNP-SNP interactions. The polygenic risk score (PRS) was calculated by summing up the number of risk alleles in each SNP and classifying them into low-, medium- and high-PRS. RESULTS: The best model included the ANK2_rs7656666, CAST_rs28042, SLC1A3_rs928431867, CHST12_rs2906173, ALOX5_rs1051713, RGS6_rs17180754, ST8SIA5_rs79491311 and DCC_rs35721894 alleles. The participants with high-PRS had a lower BMI (p < 0.0001) than those with low-PRS and were 3.834 (2.58-5.70) times more likely to be underweight after multivariate adjustment (p < 0.001). The selected SNPs were correlated with each other and highly expressed in brain-related genes. The genes with minor alleles of CAST_rs28042 and CHST12_rs2906173 exhibited a higher expression frequency in brain-related tissues. PRS had significant interactions with protein, sodium, indigestible carbohydrates, calcium intake and exercise (p < 0.05), influencing the underweight state. People with a high-PRS were more underweight than those with low-PRS under high protein, sodium, high calcium, low indigestible carbohydrate intake and low exercise by 3.75, 3.88, 7.05, 3.18 and 3.80 times, respectively (p < 0.0001). CONCLUSIONS: In conclusion, adults having a high-PRS were significantly correlated with being underweight, especially in combination with a particular nutritional status. These results show the potential for thinness genes to be applied to personalised nutrition for preventing obesity through targeted gene therapy.

Isolation and identification of mucin-degrading bacteria originated from human faeces and their potential probiotic efficacy according to host-microbiome enterotype.

AIM: Mucin-degrading bacteria are known to be beneficial for gut health. We aimed to isolate human-derived mucin-degrading bacteria and identify potential probiotic characteristics and their effects on the bacterial community and short-chain fatty acid (SCFA) production according to three different enterotypes of the host. METHODS AND RESULTS: Bacteria with mucin decomposition ability from human faeces were isolated and identified by 16S rRNA sequencing and MALDI-TOF. Heat resistance, acid resistance, antibiotic resistance, and antibacterial activity were analysed in the selected bacteria. Their adhesion capability to the Caco-2 cell was determined by scanning electron microscopy. Their ability to alter the bacterial community and SCFA production of the isolated bacteria was investigated in three enterotypes. The three isolated strains were Bifidobacterium(Bif.) animalis SPM01 (CP001606.1, 99%), Bif. longum SPM02 (NR_043437.1, 99%), and Limosilactobacillus(L.) reuteri SPM03 (CP000705.1, 99%) deposited in Korean Collection for Type Culture (KCTC-18958P). Among them, Bif. animalis exhibited the highest mucin degrading ability. They exhibited strong resistance to acidic conditions, moderate resistance to heat, and the ability to adhere tightly to Caco-2 cells. Three isolated mucin-degrading bacteria incubation increased Lactobacillus in the faecal bacteria from Bacteroides and Prevotella enterotypes. However, only L. reuteri elevated Lactobacillus in the faecal bacteria from the Ruminococcus enterotype. B. longum and B. animalis increased the α-diversity in the Ruminococcus enterotype, while their incubation with other intestinal types decreased the α-diversity. Bifidobacterium animalis and L. reuteri increased the butyric acid level in faecal bacteria from the Prevotella enterotype, and L. reuteri elevated the acetic acid level in those from the Ruminococcus enterotype. However, the overall SCFA changes were minimal. CONCLUSIONS: The isolated mucin-degrading bacteria act as probiotics and modulate gut microbiota and SCFA production differently according to the host's enterotypes. SIGNIFICANCE AND IMPACT OF STUDY: Probiotics need to be personalized according to the enterotypes in clinical application.

Bioactive prenylated coumarins as potential anti-inflammatory and anti-HIV agents from Clausena lenis.

The phytochemical study on the stems of Clausena lenis resulted in the isolation of three new prenylated coumarins, clauselenins A-C (1-3), together with nine known prenylated coumarins (4-12). The chemical structures of new prenylated coumarins (1-3) were elucidated by means of comprehensive spectral analyses and the known compounds (4-12) were determined by means of comparing their experimental spectral data with those described data in the literatures. All isolated prenylated coumarins were assessed for their anti-inflammatory effects together with anti-HIV activities in vitro. Prenylated coumarins 1-12 displayed remarkable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells in vitro with the IC50 values which are comparable to hydrocortisone. Meanwhile, prenylated coumarins 1-12 exhibited considerable anti-HIV-1 reverse transcriptase (RT) activities possessing EC50 values in the range of 0.17-9.08 µM. These findings indicate that the isolation and identification of these prenylated coumarins with pronounced anti-inflammatory effects as well as anti-HIV activities separated from the stems of C. lenis could be of great significance to the development of new anti-inflammatory and anti-HIV agents and their potential applications in the pharmaceutical industry.

The decade long achievements of China's marine ecological civilization construction (2006-2016).

China needs to balance between current population pressures and a vulnerable marine environment, creating a national, political outline or management strategy dubbed an ecological civilization construction. The nation's effort to protect and maintain a sustainable ocean and address the relevant economic, resource and environmental issues relies on Marine Ecological Civilization (MEC) construction. The quantification of MEC progress is essential to track the management performance and guide the subsequent development and implementation. This study evaluates the performance of China's MEC from 2006 to 2016 based on a comprehensive index system. Our findings are as follows: During 2006-2016, the overall MEC performance score increased from 0.3426 to 0.4850 nationwide. Large space-time variations exist among the eleven coastal regions. The Shandong and Guangdong regions showed relatively good performances, whereas the Jiangsu, Guangxi and Shanghai regions had low scores. A decade long change in MEC scores showed that Hebei achieved the largest increase ratio. Marine management was improved by implementing various conservation strategies by China's government. Marine education and human talent introduction deserve more attention in less developed areas such as Hainan and Guangxi, and poor marine environmental quality was an urgent issue of the Yangtze river estuary economic zone. More accessible marine monitoring dataset are needed to track future space-time progress dynamics towards MEC construction. Our results provide a decade long retrospect of China's MEC achievements, and the quantified evaluation for each coastal region can provide valuable insight to policy-makers.

Carbohydrate and sodium intake and physical activity interact with genetic risk scores of four genetic variants mainly related to lipid metabolism to modulate metabolic syndrome risk in Korean middle-aged adults.

Metabolic syndrome (MetS) risk is influenced by genetic and environmental factors. The present study explored genetic risk scores (GRS) of genetic variants that influence the MetS and the effect of interactions between GRS and nutrient intake on MetS risk. The genetic variants that influence MetS risk were selected by genome-wide association study after adjusting for age, sex, area of residence and BMI in 8840 middle-aged adults. GRS were calculated by summing the risk alleles of the selected SNP and divided into low (0-1), medium (2-3) and high (4-7) risk groups, and the relationships between the MetS and GRS were determined by logistic regression after adjusting covariates involved in MetS risk. We also analysed the interaction between GRS and lifestyles. Four genetic variants (APOA5_rs651821, EFCAB4B_rs4766165, ZNF259_rs2160669 and APOBEC1_rs10845640) were selected because they increased MetS risk after adjusting for covariates. Individuals with medium-GRS and high-GRS alleles had a higher MetS risk by 1·48- and 2·23-fold, respectively, compared with those with low-GRS after adjusting for covariates. The increase in MetS risk was mainly related to serum TAG and HDL-cholesterol concentrations. The GRS had an interaction with carbohydrate (CHO) and Na intakes and daily physical activities for MetS risk. In conclusion, Asian middle-aged adults with high-GRS alleles were at increased MetS risk mainly due to dyslipidaemia. High daily physical activity (≥1 h moderate activity per d) reduced the MetS risk but a low-CHO diet (<65 % of total energy intake) increased the risk in carriers with high-GRS alleles. Low Na intake (<1·6 g Na intake/4 MJ) did not decrease its risk.

Effects of the complete replacement of fish oil with linseed oil on growth, fatty acid composition, and protein expression in the Chinese mitten crab (Eriocheir sinensis).

BACKGROUND: The finite marine resources make it difficult for us to obtain enough fish oil (FO) used in aquatic feeds. Another sustainable ingredients should be found to substitute FO. The effects of replacing FO with vegetable oil have been studied in a variety of crustaceans, but most studies have focused on the phenotypic effects. Little is known about the mechanisms of the effects. METHODS: To understand the molecular responses during the replacement of FO in Eriocheir sinensis, we investigated the effects of feeding FO or linseed oil (LO) on growth performance, digestive enzyme activity, fatty acid composition and protein expression in E. sinensis. Twenty-four juvenile crabs were fed diets containing FO or LO for 112 days. Weight, carapace length and width were recorded. Fatty acid composition of the diets and the hepatopancreas and protein expression in the hepatopancreas were analyzed. RESULTS: Growth performance and molting interval were unchanged by diet. Crabs fed FO and LO had same activity of lipase and amylase, but comparing with crabs fed LO, crabs fed FO had higher trypsin activity and lower pepsin activity. Hepatopancreas fatty acid composition changed to reflect the fatty acid composition of the diets. In total, 194 proteins were differentially expressed in the hepatopancreas between the diets. Expression of heat shock proteins was higher in crabs fed LO. Expression of fatty acid synthase, long-chain fatty acid transport protein 4, acyl-CoA delta-9 desaturase, and fatty acid-binding protein 1, was higher in crabs fed FO. CONCLUSIONS: The substitution of FO with LO didn't have any effects on the growth and molting of mitten crab, but could significantly decrease the ability of mitten crab to cope with stress. The high content of HUFAs in the hepatopancreas of mitten crab fed FO is due to the high abundance of the proteins relative to the transport of the HUFAs. These findings provide a reason of the high content of EPA and DHA in crabs fed with FO, and provide new information for the replacement of FO in diets of mitten crab.

Gold-coated polydimethylsiloxane microwells for high-throughput electrochemiluminescence analysis of intracellular glucose at single cells.

In this communication, a gold-coated polydimethylsiloxane (PDMS) chip with cell-sized microwells was prepared through a stamping and spraying process that was applied directly for high-throughput electrochemiluminescence (ECL) analysis of intracellular glucose at single cells. As compared with the previous multiple-step fabrication of photoresist-based microwells on the electrode, the preparation process is simple and offers fresh electrode surface for higher luminescence intensity. More luminescence intensity was recorded from cell-retained microwells than that at the planar region among the microwells that was correlated with the content of intracellular glucose. The successful monitoring of intracellular glucose at single cells using this PDMS chip will provide an alternative strategy for high-throughput single-cell analysis. Graphical abstract ᅟ.

Localized Electrochemiluminescence from Nanoneedle Electrodes for Very-High-Density Electrochemical Sensing.

In this paper, localized electrochemiluminescence (ECL) was visualized from nanoneedle electrodes that achieved very-high-density electrochemical sensing. The localized luminescence at the nanometer-sized tip observed was ascribed to enhanced mass transfer of the luminescence probe at the tip than on the planar surface surrounding the tip, which provided higher luminescence at the tip. The size of the luminescence spots was restricted to 15 µm permitting the electrochemical analysis with a density over 4 × 103 spots/mm2. The positive correlation between the luminescence intensity at the tips and the concentration of hydrogen peroxide supported the quantitative ECL analysis using nanoneedle electrodes. The further modification of glucose oxidase at the electrode surface conceptually demonstrated that the concentration of glucose ranging from 0.5 to 5 mM could be quantified using the luminescence at the tips, which could be further applied for the detection of multiple molecules in the complex biosystem. This successful localized ECL offers a specific strategy for the development of very-high-density electrochemical arrays without the complicated chip design.

Application of primary halogenated hydrocarbons for the synthesis of 3-aryl and 3-alkyl indolizines.

Indolizine is an important heterocyclic compound with several interesting properties that make it suitable for numerous applications in many fields, such as biology, medicine and materials. However, the synthesis of 3-alkyl indolizines from bulky primary halogenated alkanes has not yet been reported. Herein, a transition-metal-free synthetic route to 3-aryl and 3-alkyl indolizines from electron-deficient alkenes, pyridines and primary halogenated hydrocarbons has been reported for the first time using a tandem reaction. The key step of this method is the oxidative dehydrogenative aromatization of a tetrahydroindolizine intermediate with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as the oxidant. The advantages of this protocol are its use of easily available and low-cost starting materials, the transition-metal-free conditions and its ready scalability.

Unexpected Thiols Triggering Photoluminescent Enhancement of Cytidine Stabilized Au Nanoclusters for Sensitive Assays of Glutathione Reductase and Its Inhibitors Screening.

The photoluminescence (PL) of nonthiolate ligand capped Au nanoclusters (NCs) is usually quenched by thiols due to the tight adsorption of thiols to the Au surface and formation of larger non-PL species. However, we here report an unexpected PL enhancement of cytidine stabilized Au (AuCyt) NCs triggered by thiols, such as reduced glutathione (GSH) at sub-µM level, while such phenomena have not been observed for Au NCs capped with similar adenosine/cytidine nucleotides. The mass spectroscopic results indicate that this enhancement may be caused by the formation of smaller, but highly fluorescent, Au species etched by thiols. This enables the sensitive detection of GSH from 20 nM to 3 µM, with an ultralow detection limit of 2.0 nM. Moreover, the glutathione reductase (GR) activity can be determined by the initial rate of GSH production, i.e., the maximum PL increasing rate, with a linear range of 0.34-17.0 U/L (1 U means reduction of 1.0 µmol of oxidized glutathione per min at pH 7.6 at 25 °C) and a limit of detection of 0.34 U/L. This method allows the accurate assays of GR in clinical serum samples as well as the rapid screening of GR inhibitors, indicating its promising biomedical applications.

Electrochemiluminescence imaging for parallel single-cell analysis of active membrane cholesterol.

Luminol electrochemiluminescence (ECL) imaging was developed for the parallel measurement of active membrane cholesterol at single living cells, thus establishing a novel electrochemical detection technique for single cells with high analysis throughput and low detection limit. In our strategy, the luminescence generated from luminol and hydrogen peroxide upon the potential was recorded in one image so that hydrogen peroxide at the surface of multiple cells could be simultaneously analyzed. Compared with the classic microelectrode array for the parallel single-cell analysis, the plat electrode only was needed in our ECL imaging, avoiding the complexity of electrode fabrication. The optimized ECL imaging system showed that hydrogen peroxide as low as 10 µM was visible and the efflux of hydrogen peroxide from cells could be determined. Coupled with the reaction between active membrane cholesterol and cholesterol oxidase to generate hydrogen peroxide, active membrane cholesterol at cells on the electrode was analyzed at single-cell level. The luminescence intensity was correlated with the amount of active membrane cholesterol, validating our system for single-cell cholesterol analysis. The relative high standard deviation on the luminescence suggested high cellular heterogeneities on hydrogen peroxide efflux and active membrane cholesterol, which exhibited the significance of single-cell analysis. This success in ECL imaging for single-cell analysis opens a new field in the parallel measurement of surface molecules at single cells.

Fast serial analysis of active cholesterol at the plasma membrane in single cells.

Previously, our group has utilized the luminol electrochemiluminescence to analyze the active cholesterol at the plasma membrane in single cells by the exposure of one cell to a photomultiplier tube (PMT) through a pinhole. In this paper, fast analysis of active cholesterol at the plasma membrane in single cells was achieved by a multimicroelectrode array without the pinhole. Single cells were directly located on the microelectrodes using cell-sized microwell traps. A cycle of voltage was applied on the microelectrodes sequentially to induce a peak of luminescence from each microelectrode for the serial measurement of active membrane cholesterol. A minimal time of 1.60 s was determined for the analysis of one cell. The simulation and the experimental data exhibited a semisteady-state distribution of hydrogen peroxide on the microelectrode after the reaction of cholesterol oxidase with the membrane cholesterol, which supported the relative accuracy of the serial analysis. An eight-microelectrode array was demonstrated to analyze eight single cells in 22 s serially, including the channel switching time. The results from 64 single cells either activated by low ion strength buffer or the inhibition of intracellular acyl-coA/cholesterol acyltransferase (ACAT) revealed that most of the cells analyzed had the similar active membrane cholesterol, while few cells had more active cholesterol resulting in the cellular heterogeneity. The fast single-cell analysis platform developed will be potentially useful for the analysis of more molecules in single cells using proper oxidases.

The comparison of preoxygenation methods before endotracheal intubation: a network meta-analysis of randomized trials.

Background: Preoxygenation before endotracheal intubation (ETI) maintains asphyxiated oxygenation and reduces the risk of hypoxia-induced adverse events. Previous studies have compared various preoxygenation methods. However, network meta-analyses (NMAs) of the combined comparison of preoxygenation methods is still lacking. Methods: We searched for studies published in PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. Review Manager version 5.3 was used to evaluate the risk of bias. The primary outcome of this meta-analysis was low oxygen saturation (SpO2) during ETI. The secondary outcomes included SpO2 <80%, SpO2 <90%, and apnea time during ETI. NMA was performed using R 4.1.2 software gemtc packages in RStudio. Results: A total of 15 randomized controlled trials were included in this study. Regarding the lowest SpO2, the noninvasive ventilation (NIV) with high-flow nasal cannula (HFNC) group performed better than the other groups. For SpO2 <80%, the NIV group (0.8603467) performed better than the HFNC (0.1373533) and conventional oxygen therapy (COT, 0.0023) groups, according to the surface under the cumulative ranking curve results. For SpO2 <90%, the NIV group (0.60932667) performed better than the HFNC (0.37888667) and COT (0.01178667) groups. With regard to apnea time, the HFNC group was superior to the COT group (mean difference: -50.05; 95% confidence interval: -90.01, -10.09; P = 0.01). Conclusion: Network analysis revealed that NIV for preoxygenation achieved higher SpO2 levels than HFNC and COT and offered a more significant advantage in maintaining patient oxygenation during ETI. Patients experienced a longer apnea time after HFNC preoxygenation. The combination of NIV with HFNC proved to be significantly superior to other methods. Given the scarcity of such studies, further research is needed to evaluate its effectiveness. Systematic review registration: identifier CRD42022346013.

Glucose Fluctuation Inhibits Nrf2 Signaling Pathway in Hippocampal Tissues and Exacerbates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats.

Background: This research investigated whether glucose fluctuation (GF) can exacerbate cognitive impairment in streptozotocin-induced diabetic rats and explored the related mechanism. Methods: After 4 weeks of feeding with diets containing high fats plus sugar, the rat model of diabetes mellitus (DM) was established by intraperitoneal injection of streptozotocin (STZ). Then, GF was triggered by means of alternating satiety and starvation for 24 h. The weight, blood glucose level, and water intake of the rats were recorded. The Morris water maze (MWM) test was carried out to appraise the cognitive function at the end of week 12. Moreover, the morphological structure of hippocampal neurons was viewed through HE and Nissl staining, and transmission electron microscopy (TEM) was performed for ultrastructure observation. The protein expression levels of Nrf2, HO-1, NQO-1, Bax, Bcl-2, and Caspase-3 in the hippocampal tissues of rats were measured via Western blotting, and the mRNA expressions of Nrf2, HO-1, and NQO-1 were examined using qRT-PCR. Finally, Western blotting and immunohistochemistry were conducted to detect BDNF levels. Results: It was manifested that GF not only aggravated the impairment of spatial memory in rats with STZ-induced type 2 DM but also stimulated the loss, shrinkage, and apoptosis of hippocampal neurons. Regarding the expressions in murine hippocampal tissues, GF depressed Nrf2, HO-1, NQO-1, Bcl-2, and BDNF but boosted Caspase-3 and Bax. Conclusions: GF aggravates cognitive impairment by inhibiting the Nrf2 signaling pathway and inducing oxidative stress and apoptosis in the hippocampal tissues.