Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model.

JOURNAL/nrgr/04.03/01300535-202503000-00030/figure1/v/2024-06-17T092413Z/r/image-tiff Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

4-Nitrophenol at environmentally relevant concentrations mediates reproductive toxicity in Caenorhabditis elegans via metabolic disorders-induced estrogen signaling pathway.

4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.

Bamboo-like MnO2⋠Co3O4: High-performance catalysts for the oxidative removal of toluene.

The manganese-cobalt mixed oxide nanorods were fabricated using a hydrothermal method with different metal precursors (KMnO4 and MnSO4·H2O for MnOx and Co(NO3)2⋅6H2O and CoCl2⋅6H2O for Co3O4). Bamboo-like MnO2⋅Co3O4 (B-MnO2⋅Co3O4 (S)) was derived from repeated hydrothermal treatments with Co3O4@MnO2 and MnSO4⋅H2O, whereas Co3O4@MnO2 nanorods were derived from hydrothermal treatment with Co3O4 nanorods and KMnO4. The study shows that manganese oxide was tetragonal, while the cobalt oxide was found to be cubic in the crystalline arrangement. Mn surface ions were present in multiple oxidation states (e.g., Mn4+ and Mn3+) and surface oxygen deficiencies. The content of adsorbed oxygen species and reducibility at low temperature declined in the sequence of B-MnO2⋅Co3O4 (S) > Co3O4@MnO2 > MnO2 > Co3O4, matching the changing trend in activity. Among all the samples, B-MnO2⋅Co3O4 (S) showed the preeminent catalytic performance for the oxidation of toluene (T10% = 187°C, T50% = 276°C, and T90% = 339°C). In addition, the B-MnO2⋅Co3O4 (S) sample also exhibited good H2O-, CO2-, and SO2-resistant performance. The good catalytic performance of B-MnO2⋅Co3O4 (S) is due to the high concentration of adsorbed oxygen species and good reducibility at low temperature. Toluene oxidation over B-MnO2⋅Co3O4 (S) proceeds through the adsorption of O2 and toluene to form O*, OH*, and H2C(C6H5)* species, which then react to produce benzyl alcohol, benzoic acid, and benzaldehyde, ultimately converting to CO2 and H2O. The findings suggest that B-MnO2⋅Co3O4 (S) has promising potential for use as an effective catalyst in practical applications.

Identification of organic constituents on atmospheric particulate matter in the East Asian background air of free troposphere by GC×GC-TOFMS.

The presence of organic compounds on the particulate matter (PM) or aerosols can arise from the condensation of gaseous organic compounds on the existing aerosols, or from organic precursors to form secondary organic aerosols (SOA) through photochemistry. The objective of this study is to characterize organic constituents on aerosols relevant to their emission sources and the key compounds revealing the evolution of aerosols with the use of a novel analytical technique. A time-of-flight mass spectrometry (TOFMS) coupled with comprehensive two-dimensional gas chromatography (GC×GC) was developed using a flow type of modulator instead of a thermal type as a prelude to field applications without the need for cryogen. The methodology of GC×GC-TOFMS is discussed in this study in detail. Since the coarse PM (PM10-2.5) may exhibit with a relatively high OC content compared to PM2.5, the GC×GC results have been obtained by analyzing PM10 samples collected in parallel with OC/EC analysis of PM2.5 samples at the Lulin Atmospheric Background Station (LABS, 23.47°N, 120.87°E, 2,862 m ASL) as the high-mountain background site in East Asia. We found that the organic analytes were in a majority in the range of 12 - 30 carbon numbers falling in the category of semi-volatile organic compounds (SVOCs) with 43 compounds of alcohol, aldehyde, ketone, and ester varieties if excluding alkanes. Intriguingly, trace amounts of plasticizers and phosphorus flame retardants such as phthalates (PAEs) and triphenyl phosphate (TPP) were also found, likely originating from regions involved in open burning of household solid waste in Southeast Asia or e-waste recycling in southern China and along the long-range transport route. Compounds such as these are unique to the specific sources, demonstrating the wide spread of these hazardous compounds in the environment.

ARNTL2 facilitates bladder cancer progression through potentiating ENO1-mediated glycolysis in a SLC31A1-independent and -dependent manner.

BACKGROUND: Basic helix-loop-helix ARNT like 2 (ARNTL2) is a transcription factor that controls the circadian rhythm. Amounts of studies have demonstrated the carcinogenic function of ARNTL2 in human malignant tumors albeit the underlying mechanisms remain poorly understood. We aimed to study the significance of ARNTL2 in bladder cancer (BLCA). METHODS: Immunohistochemical staining, immunoblotting and the database from TCGA were used to analyze the clinical relevance of ARNTL2, enolase 1 (ENO1) and solute carrier family 31 member 1 (SLC31A1) in BLCA. The function of ARNTL2 was explored by cell proliferation assay, apoptosis, colony formation and xenografted tumorigenesis. The molecular mechanisms of ARNTL2-driving BLCA development were investigated by RT-qPCR, immunoblotting and luciferase assays. Glycolysis was checked by measuring glucose consumption and lactate production. ENO1 activity was assessed by using indicated assay kit. RESULTS: Overexpression of ARNTL2 facilitates the proliferation and tumorigenesis of BLCA cells through suppression of apoptosis and enhancement of glycolysis. Up-regulation of SLC31A1, ENO1, and enhancement of SLC31A1-mediated ENO1 activity were critical for ARNTL2-triggered glycolysis and malignant growth in BLCA cells. ARNTL2 was positively correlated with SLC31A1 and ENO1 in BLCA patients. High expression of ARNTL2, SLC31A1 or ENO1 predicted the poor prognosis of BLCA patients. Depletion of SLC31A1 and inhibition of glycolysis completely blunted the growth ability of BLCA cells. CONCLUSION: In summary, ARNTL2 facilitates the progression of BLCA via activating ENO1-mediated glycolysis in a SLC31A1-independent and -dependent manner. Inhibiting SLC31A1 and glycolysis may be an aspirational approach for the treatment of BLCA patients with overexpression of ARNTL2.

Binding characterization of odorant-binding protein BhorOBP29 in Batocera horsfieldi (Hope) with host-plant volatiles.

Odorant binding proteins (OBPs) are involved in odorant discrimination and act as the first filter in the peripheral olfactory system. Previous studies have shown that BhorOBP29 is potentially involved in olfactory perception in an important wood-boring pest Batocera horsfieldi (Hope) (Coleoptera: Cerambycidae), however, its function remains unclear. Here, we investigated the ligand-binding profiles of recombinant BhorOBP29 with 22 compounds from its host plant using fluorescence competitive binding assays and fluorescence quenching assays. The results showed that BhorOBP29 could bind to five ligands relying mainly on hydrophobic interactions. Molecular docking analysis indicated that residues Ile48, Leu51, Met52, Trp57, Asn105, and Val119 were extensively involved in the interactions between BhorOBP29 and the five ligands. Furthermore, the site-directed mutagenesis analysis revealed that Leu51 and Met52 residues were indispensable for BhorOBP29-ligands binding. Finally, electroantennogram (EAG) assays confirmed that hexanal, (-)-limonene, and 2-methylbutyraldehyde elicited a concentration-dependent EAG response with a maximum at the concentration of 1/10 v/v. These findings suggest that BhorOBP29 may play a significant role in the perception of host plant volatiles by B. horsfieldi. This study may help to discover novel behavioral regulation and environmentally friendly strategies for controlling B. horsfieldi in the future.

[Magnetic stimulation combined with moxibustion improves mild to moderate overactive bladder and sexual function in women].

OBJECTIVE: To investigate the clinical effect of magnetic stimulation combined with moxibustion on mild to moderate overactive bladder (OAB) and sexual function in women. METHODS: We enrolled 80 female patients with mild to moderate OAB in this study and equally randomized them into a control and an experimental group, the former treated by magnetic stimulation and the latter by magnetic stimulation combined with moxibustion, both for 8 weeks. We obtained from the patients their OAB syndrome scores (OABSS), 72-hour urination diary (72-h UD) scores, International Consultation on Incontinence Questionnaire － Overactive Bladder (ICIQ-OAB) scores and female sexual function indexes (FSFI), and compared them between the two groups before and after intervention. RESULTS: A total of 77 patients completed the study, 37 in the control and 40 in the experimental group. There were no statistically significant differences in the baseline data between the two groups (P > 0.05). Compared with the baseline, the experimental group showed significant improvement after treatment in the OABSS (7.54±1.12 vs 4.46±0.96), 72-h urine volume (ï¼»126.40±46.04ï¼½ vs ï¼»216.63±38.26ï¼½ ml), urination frequency (15.55±3.21 vs 8.03±1.40), ICIQ-OAB score (10.25±1.15 vs 6.32±1.07) and FSFI (20.00±12.40 vs 33.30±21.00) (all P < 0.05), even more significantly than in the control group (OABSS: 4.46±0.96 vs 5.59±0.90; 72-h urine volume: ï¼»216.63±38.26ï¼½ vs ï¼»173.41±15.55ï¼½ ml; urination frequency: 8.03±1.40 vs 9.90±1.49; ICIQ-OAB score: 6.32±1.07 vs 7.89±0.77; FSFI: 33.30±21.00 vs 30.40±10.40) (all P < 0.01). CONCLUSION: Magnetic stimulation combined with moxibustion can improve the symptoms of mild to moderate overactive bladder and improve sexual function in females.

Folic acid for the primary prevention of stroke: a systematic review and meta-analysis.

Objectives: Results from studies were inconsistent with regard to the effect of folic acid on the primary prevention of stroke. The aim of this study was to analyze the association between folic acid and the primary prevention of stroke using the data from observational studies and randomized controlled trials (RCTs). Methods: Eligible publications published until June 2024 were searched in the database of PubMed, Web of Science and Embase. This study included all observational studies and RCTs of folic acid with first stroke as the reporting endpoints. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled in the random-effects model to assess the effect of folic acid on the primary prevention of stroke. Results: Results from 12 observational publications with 16 research, including 312,320 participants, were combined to explore the association between dietary folic acid intake and the primary prevention of stroke. The results showed that high dietary folic acid intake was associated with a 17% reduction in stroke incidence (RR:0.83; 95% CI: 0.73-0.94), and the effect of dietary folic acid was greater in areas without grain fortification (RR:0.80; 95% CI: 0.67-0.95). The pooled results from 12 RCTs, totaling 75,042 participants, indicated that folic acid supplementation was not associated with the stroke primary prevention (RR:0.92; 95% CI: 0.80-1.05), but folic acid supplementation was effective in areas without grain fortification (RR:0.78; 95% CI: 0.68-0.89). Conclusion: Our meta-analysis demonstrated that dietary folic acid is effective in stroke primary prevention, and folic acid supplementation is effective in stroke primary prevention only in areas without grain fortification. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprospero, identifier CRD42024516991.

Short-chain fatty acids reverses gut microbiota dysbiosis-promoted progression of glioblastoma by up-regulating M1 polarization in the tumor microenvironment.

Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the "gut-brain" axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients.

Developing a modified textbook outcome for elderly patients with gastric cancer: a multi-center study.

OBJECTIVE: Textbook outcome (TO) is widely recognized as a comprehensive prognostic indication for patients with gastric cancer (GC). This study aims to develop a modified TO (mTO) for elderly patients with GC. METHODS: Data from the elderly patients (aged ≥ 65 years) in two Chinese tertiary referral hospitals were analyzed. 1389 patients from Fujian Medical University Union Hospital were assigned as the training cohort and 185 patients from Affiliated Hospital of Putian University as the validation cohort. Nomogram was developed by the independent prognostic factors of Overall Survival (OS) based on Cox regression. RESULTS: In the training cohort, laparoscopic surgery was significantly correlated with higher TO rate (P < 0.05). Cox regression analysis revealed that surgical approach was also an independent factor of OS (P < 0.001), distinct from the traditional TO. In light of these findings, TO parameters were enhanced by the inclusion of surgical approach, rendering a modified TO (mTO). Further analysis showed that mTO, tumor size, pTNM staging, and adjuvant chemotherapy were independent prognostic factors associated with OS (all P < 0.05). Additionally, the nomogram incorporating these four indicators accurately predicted 1-, 3-, and 5-year OS in the training cohort, with AUC values of 0.793, 0.814, and 0.807, respectively, and exhibited outstanding predictive performance within the validation cohort. CONCLUSION: mTO holds a robust association with the prognosis of elderly patients with GC, meriting intensified attention in efforts aimed at enhancing surgical quality. Furthermore, the predictive model incorporating mTO demonstrates excellent predictive performance for elderly patients with GC.

Signal mining and gender differences analysis of adverse events in NMIBC treatment with gemcitabine and BCG bladder instillation based on the FAERS database.

OBJECTIVE: To explore safety differences and perform a gender-based analysis of adverse events related to gemcitabine and Bacillus Calmette-Guérin (BCG) vaccine using the U.S. FDA Adverse Event Reporting System (FAERS) database. METHODS: Using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods, adverse events associated with gemcitabine and BCG were mined from FAERS database reports spanning from Q1 2004 to Q3 2023. RESULTS: The study extracted 37,855 reports with gemcitabine and 5,455 reports with BCG as the primary suspected drugs. Adverse events were more prevalent in males (male-to-female ratio: gemcitabine 1.10, BCG 4.25). Differences in high-frequency adverse events among the top 20 signals were detected for both drugs. Both drugs affected similar organ systems, including potential pulmonary, ocular, and renal toxicity, with gemcitabine showing a broader range of adverse events. Gender analysis revealed fewer adverse reactions to gemcitabine in females, while males had fewer adverse reactions to BCG. CONCLUSION: Differences in high-frequency adverse events between gemcitabine and BCG, including some not listed on drug labels, were observed. Both drugs affect similar organ systems, with gemcitabine showing a broader range of adverse events. Gender differences in adverse events were notable.

Photolysis of dinotefuran and nitenpyram in water and ice phase: Influence mechanism of temperature over photolysis.

Neonicotinoids are widely used pesticides around the world, but the photolysis of neonicotinoids in cold agricultural region are still in blank. This paper aimed to study the influence of cold temperature over photolysis of neonicotinoids. To this end, the photolysis rates and photoproducts of dinotefuran and nitenpyram in water, ice and freeze-thawing condition were determined. Coupled with quantum chemistry calculation, the influence mechanisms of temperature and medium were investigated. The results showed the photolysis rates of neonicotinoids in water condition slightly declined with the lowered temperature due to the photolysis reactions were endothermic reactions. However, the photolysis rates increased by 89.8 %, 59.2 %, 49.4 % and 9.5 % for dinotefuran and nitenpyram in ice and thawing condition, respectively. This phenomenon was posed by the concentration-enhancing effect and change of photo-chemical properties of neonicotinoids in ice condition, which included lowered bond cleavage energy, lowered first excited singlet state energy and expanded light absorption range. The photolysis pathways of the two neonicotinoids did not change in different medium, but the concentration of carboxyl products was relatively higher than that of water condition due to the more amounts of reactive oxygen species in ice medium, which might increase the secondary pollution risk after ice-off in spring due to the higher ecotoxicity to nontarget organism of these photoproducts. The influence of cold temperature and medium change should be considered for the environmental fate and risk assessment of neonicotinoids in cold agricultural region.

Characteristics of psychrophilic bacterial communities and associated metabolism pathways in different environments by a metagenomic analysis.

Psychrophilic bacteria, the dominant spoilage organisms in raw milk, secrete heat-stable extracellular proteases and lipases that lead to the decomposition of milk and dairy products. In this study, we investigated psychrophilic bacteria in 165 raw milk samples collected across four seasons and six regions in China using shotgun metagenomic sequencing and traditional culture methods. The isolated psychrophilic bacteria were classified into 40 genera and 185 species. Pseudomonas was the most prevalent, accounting for 51.13 % of the genera, while Lactococcus and Chryseobacterium were also notably abundant (> 6.0 %). Metagenomic sequencing revealed that Pseudomonas (47.9 %), Stenotrophomonas (9.75 %), Sphingomonas (6.73 %), Latilactobacillus (6.38 %) and Lactococcus (5.16 %) were the dominant genera in the raw milk samples. The diversity of psychrophilic bacteria in raw milk was strongly influenced by seasonal variations, with the sampling region being a less significant factor. KEGG annotation indicated that carbohydrate and amino acid metabolism were the primary metabolic pathways in these bacteria. Metagenomic sequencing not only accurately identifies species but also provides functional insights into psychrophilic bacteria in raw milk, aiding in understanding their activities, promoting their control on farms, and ultimately improving raw milk quality.

Unexpected antagonism of deoxynivalenol and enniatins in intestinal toxicity through the Ras/PI3K/AKT signaling pathway.

Deoxynivalenol (DON) is a kind of widespread traditional Fusarium mycotoxins in the environment, and its intestinal toxicity has received considerable attention. Recently, the emerging Fusarium mycotoxin enniatins (ENNs) have also been shown to frequently coexist with DON in animal feed and food with large consumption. However, the mechanism of intestinal damage caused by the two mycotoxins co-exposure remains unclear. In this study, Caco-2 cell line was used to investigate the combined toxicity and potential mechanisms of four representative ENNs (ENA, ENA1, ENB, and ENB1) and DON. The results showed that almost all mixed groups showed antagonistic effects, particularly ENB at 1/4 IC50 (CI = 6.488). Co-incubation of ENNs mitigated the levels of signaling molecule levels disrupted by DON, including reactive oxygen species (ROS), calcium mobilization (Ca2+), adenosine triphosphate (ATP). The differentially expressed genes (DEGs) between the mixed and ENB groups were significantly enriched in the Ras/PI3K/Akt signaling pathway, including 28 up-regulated genes and 40 down-regulated genes. Quantitative real-time PCR further confirmed the lower expression of apoptotic gene in the mixed group, thereby reducing the cytotoxic effects caused by DON exposure. This study emphasizes that co-exposure of ENNs and DON reduces cytotoxicity by regulating the Ras/PI3K/Akt signaling pathway. Our results provide the first comprehensive evidence about the antagonistic toxicity of ENNs and DON on Caco-2 cells, and new insights into mechanisms investigated by transcriptomics.

BRAFV600E/ p-ERK/ p-DRP1(Ser616) Promotes Tumor Progression and Reprogramming of Glucose Metabolism in Papillary Thyroid Cancer.

BACKGROUND: Papillary thyroid cancer (PTC) with the BRAFV600E mutation is associated with a poorer prognosis. BRAF inhibitors may demonstrate limited efficacy due to emerging drug resistance. The Warburg effect may have cancer therapeutic implications. It is not known if the BRAFV600E mutation is associated with altered glucose metabolism in PTC. METHODS: This study examined the effect of the BRAFV600E and DRP1 on various cellular processes in PTC cells, including: cell proliferation, migration, invasion, mitochondrial fission, glucose metabolism, reactive oxygen species (ROS) generation and apoptosis. We used RT-qPCR to assess the expression of key glycolytic enzymes in thyroid cancer tissues. Additionally, the regulatory interaction between BRAFV600E and DRP1 was investigated through Western Blot and immunohistochemical staining. We further evaluated the impact of DRP1 in PTC and inhibitory effects of Dabrafenib and 2-DG in vitro and in vivo. RESULTS: We found that the BRAFV600E mutation significantly augments aerobic glycolysis while suppressing oxidative phosphorylation in PTC. We identified the BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway as a critical mediator in PTC progression. The BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway enhances cell proliferation by upregulating HK2 expression and thereby increasing aerobic glycolysis. Secondly, it inhibits apoptosis by promoting mitochondrial fission and reducing ROS levels. Moreover, we demonstrated that the combination therapy of 2-DG and Dabrafenib markedly impedes the progression of BRAFV600E-positive PTC. CONCLUSION: The BRAFV600E/p-ERK/p-DRP1(Ser616) signaling pathway plays a pivotal role in glucose metabolism reprogramming, contributing to the aggressiveness and progression of BRAFV600E-positive PTC. Our findings suggest that a combined therapeutic approach using 2-DG and Dabrafenib has potential to improve the outcome of PTC patients with BRAFV600E.

The delivery of PD-L1 siRNA by neutrophil-targeted lipid nanoparticles effectively ameliorates sepsis.

BACKGROUND: Sepsis, a complex and life-threatening disease, poses a significant global burden affecting over 48 million individuals. Recently, it has been reported that programmed death-ligand 1 (PD-L1) expressed on neutrophils is involved in both inflammatory organ dysfunction and immunoparalysis in sepsis. However, there is a dearth of strategies to specifically target PD-L1 in neutrophils in vivo. METHODS: We successfully developed two lipid nanoparticles (LNPs) specifically targeting neutrophils by delivering PD-L1 siRNA via neutrophil-specific antibodies and polypeptides. In vivo and in vitro experiments were performed to detect lipid nanoparticles into neutrophils. A mouse cecal ligation and puncture (CLP) model was used to detect neutrophil migration, neutrophil extracellular traps (NETs) level, and organ damage. RESULT: The PD-L1 siRNA-loaded LNPs that target neutrophils suppressed inflammation, reduced the release of NETs, and inhibited T-lymphocyte apoptosis. This approach could help maintain homeostasis of both the immune and inflammatory responses during sepsis. Furthermore, the PD-L1 siRNA-loaded LNPs targeting neutrophils have the potential to ameliorate the multi-organ damage and lethality resulting from CLP. CONCLUSIONS: Taken together, our data identify a previously unknown drug delivery strategy targeting neutrophils, which represents a novel, safe, and effective approach to sepsis therapy.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between migraine and five psychiatric disorders.

Background: The question of whether a correlation exists between migraine and five psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), anorexia nervosa (AN), bipolar disorder (BIP), and schizophrenia (SCZ), remains a matter of controversy. Hence, this research aims to investigate whether there is a possible association between migraine and five psychiatric disorders. Methods: We performed a bidirectional 2-sample Mendelian randomization (MR) analysis to assess the causality between migraine and five psychiatric disorders. Genetic associations of PTSD, MDD, AN, BIP, and SCZ were obtained from the Psychiatric Genomics Consortium (PGC) database and genetic associations of migraine with aura and migraine without aura were obtained from the FinnGen dataset. We used the inverse-variance weighted (IVW), weighted median, weighted mode, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and MR Egger regression methods to evaluate the association of genetically predicted exposure with the risk of outcome. Results: MR demonstrated that MDD was associated with a high risk of migraine without aura (OR = 1.930578, 95% confidence interview (CI): 1.224510, 3.043550, p < 0.05), but BIP was related to a low risk of migraine without aura (OR = 0.758650, 95%CI: 0.639601, 0.899858, p < 0.05). According to the results of reverse MR, migraine with aura was associated with a high risk of BIP (OR = 1.019100, 95%CI: 1.002538, 1.035935, p < 0.05), and migraine without aura was associated with an increased risk of AN (OR = 1.055634, 95%CI: 1.023859, 1.088394, p < 0.05). Conclusion: Our results provide evidence of the potential causal association between migraine and some psychiatric disorders. It may contribute to the prevention of migraine and some psychiatric disorders.

[Research progress in biosynthesis of arbutin].

Arbutin, a glycosylated compound of hydroquinone, exists in two forms of ß-arbutin and α-arbutin based on the configuration of the glycosidic bond. As a safe and stable whitening agent, arbutin is widely used in cosmetics, and it has antioxidant, antimicrobial, anti-inflammatory, and anti-tumor activities. The production of arbutin by plant extraction faces challenges such as long plant growth periods, complex extraction processes, and low yields. The chemical synthesis of arbutin suffers from harsh reaction conditions, poor stereo-selectivity, and low yields. In recent years, biosynthesis emerges as the most popular method to produce arbutin because of the simple and mild reaction conditions, low costs, and environmental friendliness. This review summarizes the research progress in four biosynthetic strategies for arbutin, including plant conversion, enzyme catalysis, whole-cell catalysis, and microbial fermentation. The advantages and limitations of these biosynthetic strategies are discussed, and future research directions are proposed.

[Construction of microbial cell factories for synthesizing value-added chemicals with xylose].

Lignocellulose is the most abundant renewable resource on earth. Constructing microbial cell factories for synthesizing value-added chemicals with lignocellulose is the key to realize green biomanufacturing. Xylose is the second most fermentable sugar in lignocellulose after glucose. Building microbial cell factories that can efficiently metabolize xylose is of great significance to achieve full utilization of lignocellulose. However, the lower metabolism efficiency of xylose than that of glucose in most microorganisms limits the application of xylose. In recent years, the deepening understanding of microbial metabolic mechanisms and the continuous advancement of synthetic biology have greatly improved the efficiency of microbial metabolism of xylose and expanded the spectrum of xylose-derived products. This article introduces several xylose metabolic pathways that exist in the nature and the derived products, summarizes the strategies for constructing recombinant strains that can co-utilize xylose and glucose, and reviews the research progress in the application of lignocellulose hydrolysates in the synthesis of target products. Finally, this article discusses the current technical bottlenecks and prospects the future development directions in this field.

Delta magnetic resonance imaging radiomics features­based nomogram predicts long­term efficacy after induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: To establish and validate a delta-radiomics-based model for predicting progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) following induction chemotherapy (IC). METHODS AND MATERIALS: A total of 250 LA-NPC patients (training cohort: n = 145; validation cohort: n = 105) were enrolled. Radiomic features were extracted from MRI scans taken before and after IC, and changes in these features were calculated. Following feature selection, a delta-radiomics signature was constructed using LASSO-Cox regression analysis. A prognostic nomogram incorporating independent clinical indicators and the delta-radiomics signature was developed and assessed for calibration and discrimination. Risk stratification by the nomogram was evaluated using Kaplan-Meier methods. RESULTS: The delta-radiomics signature, consisting of 12 features, was independently associated with prognosis. The nomogram, integrating the delta-radiomics signature and clinical factors demonstrated excellent calibration and discrimination. The model achieved a Harrell's concordance index (C-index) of 0.848 in the training cohort and 0.820 in the validation cohort. Risk stratification identified two groups with significantly different PFS rates. The three-year PFS for high-risk patients who received concurrent chemoradiotherapy (CCRT) or radiotherapy plus adjuvant chemotherapy (RT+AC) after IC was significantly higher than for those who received RT alone, reaching statistical significance. In contrast, for low-risk patients, the three-year PFS after IC was slightly higher for those who received CCRT or RT+AC compared to those who received RT alone; however, this difference did not reach statistical significance. CONCLUSIONS: Our delta MRI-based radiomics model could be useful for predicting PFS and may guide subsequent treatment decisions after IC in LA-NPC.