P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy.

Sepsis is defined as a dysregulated host response to infection resulting in life-threatening organ dysfunction. Sepsis-associated encephalopathy (SAE) is the main manifestation of sepsis. Inflammation, peroxidation stress injury, and apoptosis are the main factors involved in the pathogenesis of SAE. A growing body of evidence has proved that P2X7 receptor (P2X7R), a cationic channel receptor that is widely distributed in the body, plays a major role in the occurrence and development of inflammatory injury. Therefore, this review mainly describes the activation of P2X7R in sepsis, which leads to the recruitment of inflammatory cells to the cerebral vasculature, the destruction of the blood-brain barrier, the activation of microglial cells in the brain, the apoptosis of brain cells, and other damage processes. This review also illustrates the potential therapeutic value of P2X7R inhibition in SAE.

Prognostic factors for surgical site infection in patients with spinal metastases and following surgical treatment.

There were few articles reviewed prognostic factors of surgical site infection (SSI) in patients with spinal metastases following surgery. The purpose of the present study was to systematically: (1) investigate the incidence rates of SSI following spinal metastases surgery; (2) identify the factors which were independently associated with postoperative wound infection. One hundred sixty-seven consecutive adult patients with spinal metastases and underwent surgical treatment were retrospectively enrolled from January 2011 to February 2022. Demographic data, disease and operation-related indicators were extracted and analyzed. Univariate and multivariate logistic analysis model were performed respectively to determine independent risk factors of SSI. 17 cases infection were collected in this study. The overall incidence of SSI after surgery of spinal metastases patients was 10.2%. Univariate regression analysis showed that age (P = .028), preoperative ALB level (P = .024), operation time (P = .041), intraoperative blood loss (P = .030), Karnofsky Performance Status score (P = .000), body mass index (P = .013), American Society of Anesthesiologists > 2 (P = .010), Tobacco consumption (P = .035), and number of spinal levels involved in surgical procedure (P = .007) were associated with wound infection. Finally, the multivariate logistic model demonstrated that body mass index (P = .043; OR = 1.038), preoperative ALB level (P = .018; OR = 1.124), and number of spinal levels (P = .003; OR = 1.753) were associated with SSI occurrence. Surgery on multiple vertebral levels for spinal metastases significantly increases the risk of SSI and weight management, nutritional support and palliative surgery have the positive significance in reducing wound complications. Orthopedist should focus on identifying such high-risk patients and decrease the incidence of wound infection by formulating comprehensive and multi-disciplinary care strategy.

Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction.

BACKGROUND: Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. METHODS: By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. RESULTS: Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. CONCLUSIONS: Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

Connecting the Dots: The Cerebral Lymphatic System as a Bridge Between the Central Nervous System and Peripheral System in Health and Disease.

As a recently discovered waste removal system in the brain, cerebral lymphatic system is thought to play an important role in regulating the homeostasis of the central nervous system. Currently, more and more attention is being focused on the cerebral lymphatic system. Further understanding of the structural and functional characteristics of cerebral lymphatic system is essential to better understand the pathogenesis of diseases and to explore therapeutic approaches. In this review, we summarize the structural components and functional characteristics of cerebral lymphatic system. More importantly, it is closely associated with peripheral system diseases in the gastrointestinal tract, liver, and kidney. However, there is still a gap in the study of the cerebral lymphatic system. However, we believe that it is a critical mediator of the interactions between the central nervous system and the peripheral system.

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases.

Dichloroacetate (DCA) is an investigational drug used to treat lactic acidosis and malignant tumours. It works by inhibiting pyruvate dehydrogenase kinase and increasing the rate of glucose oxidation. Some studies have documented the neuroprotective benefits of DCA. By reviewing these studies, this paper shows that DCA has multiple pharmacological activities, including regulating metabolism, ameliorating oxidative stress, attenuating neuroinflammation, inhibiting apoptosis, decreasing autophagy, protecting the blood‒brain barrier, improving the function of endothelial progenitor cells, improving mitochondrial dynamics, and decreasing amyloid ß-protein. In addition, DCA inhibits the enzyme that metabolizes it, which leads to peripheral neurotoxicity due to drug accumulation that may be solved by individualized drug delivery and nanovesicle delivery. In summary, in this review, we analyse the mechanisms of neuroprotection by DCA in different diseases and discuss the causes of and solutions to its adverse effects.

α-Cyano-3-aminocinnamic acid: A novel reactive matrix for qualitative and quantitative analysis of plant N-glycans by MALDI-MS.

N-glycans have a diversity of crucial biological roles in organisms. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has become an indispensable analytical instrument for biomolecules. However, due to the inherent low abundance, high structural heterogeneity, and poor ionization efficiency of N-glycans, as well as the extremely inhomogeneous co-crystal property using traditional matrices, the qualitation and quantitation of N-glycans by MALDI-MS remains challenging. In the present study, α-cyano-3-aminocinnamic acid (3-CACA) was reasonably designed and synthesized as a novel reactive matrix for N-glycan analysis. Combining with traditional matrix α-cyano-4-hydroxycinnamic acid (CHCA) as an acidic catalyst, a combinational matrix 3-CACA/CHCA was obtained with homogeneous co-crystallization and high derivatization efficiency, achieving the sensitive qualitation with the limits of detection low to femtomole and reproducible quantitation with good linearity (R2 > 0.998). As a result, the established method was successfully applied to the on-target derivatization and high-throughput quantification of N-glycans in eight varieties of the peach complex system, indicating that N-glycan has the potential to become a new biomarker for food allergy, and elucidating the prospective correlation between N-glycan epitopes and allergic reactions.

Aerobic Exercise Ameliorates Liver Injury in Db/Db Mice by Attenuating Oxidative Stress, Apoptosis and Inflammation Through the Nrf2 and JAK2/STAT3 Signalling Pathways.

Objective: Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury. Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry. Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice. Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response.

A New Predictive Nomogram for the Risk of Delayed Incision Healing After Open Posterior Lumbar Surgery: A Retrospective Study.

STUDY DESIGN: This was a primary research study. OBJECTIVE: A risk nomogram was established and externally validated by exploring the related risk factors for delayed incision healing in patients undergoing open posterior lumbar surgery. SUMMARY OF BACKGROUND DATA: The use of a nomogram model to predict prognosis in patients with delayed incision healing is an evolving field given the complex presentation of patients with this condition. PATIENTS AND METHODS: This study reviewed 954 patients with data collected from January 2017 to December 2021 who were randomized into a training set and a validation set (7:3). We built a prediction model based on a training set of 616 patients. The "least absolute shrinkage and selection operator" regression model was applied to screen out the optimal prediction features, and binary logistic regression was used to develop a prediction model. The discrimination, calibration, and clinical applicability of the prediction model were assessed by using the area under the curve, C -index, calibration curve, and decision curve analysis. RESULTS: Postoperative delayed incision healing occurred in 214 (24.4%) patients. The least absolute shrinkage and selection operator regression model showed that smoking, white blood cell count, infection, diabetes, and obesity were involved in delayed incision healing ( P ≠ 0). A binary logistic regression model confirmed that smoking [odds ratio (OR) = 3.854, 95% CI: 1.578~9.674, P = 0.003], infection (OR = 119.524, 95% CI: 59.430~263.921, P < 0.001), diabetes (OR = 3.935, 95% CI: 1.628~9.703, P = 0.003), and obesity (OR = 9.906, 95% CI: 4.435~23.266, P < 0.001) were predictors of delayed incision healing, and a nomogram model was established. The area under the curve was 0.917 (95% CI: 0.876-0.959). The calibration curve showed good consistency. Decision curve analysis showed that when the risk threshold of delayed incision healing was >5%, the use of this nomogram was more clinically valuable. CONCLUSIONS: Smoking, infection, diabetes, and obesity are risk factors for delayed incision healing. The nomogram model could be used to predict the risk of delayed incision healing and could provide a reference for early clinical intervention.

Quantitative N-Glycomic and N-Glycoproteomic Profiling of Peach [Prunus persica (L.) Batsch] during Fruit Ripening.

Being part of the human diet, peach is an important fruit consumed worldwide. In the present study, a systematic first insight into the N-glycosylation of peach fruit during ripening was provided. First, N-glycome by reactive matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry indicated that 6 of 24 N-glycans of peach were differentially expressed. Second, a comparative N-glycoproteome was characterized via 18O-tagged N-glycosylation site labeling followed by nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS/MS). Totally 1464 N-glycosites on 881 N-glycoproteins were identified, among which 291 N-glycosites on 237 N-glycoproteins were expressed differentially with a fold change value of 1.5 or 0.67. The enrichment analysis of GO and KEGG revealed that four pathways including other glycan degradation, phenylpropanoid biosynthesis, amino sugar and nucleotide sugar metabolism, and protein processing in endoplasmic reticulum were mainly enriched, in which several important N-glycoproteins with dynamic change during fruit ripening were further screened out. Our findings on a large scale for N-glycosylation analysis of peach fruit during ripening may provide new molecular insights for comprehending N-glycoprotein functions, which should be of great interest to both glycobiologists and analytical chemists.

2-Hydrazinoterephthalic Acid as a Novel Negative-Ion Matrix-Assisted Laser Desorption/Ionization Matrix for Qualitative and Quantitative Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Analysis of N-Glycans in Peach Allergy Research.

Glycans recently attracted considerable attention as the proposal of cross-reactive carbohydrate determinants for food allergy. Matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) is powerful in analyzing biomolecules, while its applications in glycans are still challenging. Herein, a novel reactive matrix-assisted laser desorption/ionization (MALDI) matrix, 2-hydrazinoterephthalic acid, was rationally designed and synthesized. It provides uniform co-crystallization with glycans and only produces deprotonated ions with high intensities in the negative-ion mode. In combination with sinapic acid, a rapid and high-throughput method was established for on-target analysis of glycans with a superior limit of detection at the femtomole level and a good linearity (R2 > 0.999). Furthermore, the established method was successfully applied to quantify N-glycans in different cultivars and tissues of peach [Prunus persica (L.) Batsch]. Our work suggests the potential role of N-glycans as biomarkers for food-borne allergy and lays a methodological foundation for the elucidation of the possible relationship between carbohydrate epitopes and food allergy.

Fascia iliaca compartment block can reduce the incidence of early post-operative cognitive impairment in elderly patients with high-risk hip replacement.

Objective: In this study, we aimed to observe the effects of ultrasound-guided fascia iliaca compartment block (FICB) combined with hypobaric spinal anesthesia on post-operative pain and cognitive function in elderly patients with high-risk hip replacement. Methods: A total of 84 elderly patients-aged 65-85 years, with American Society of Anesthesiologists physical status III-IV, and scheduled for hip arthroplasty between September 2021 and May 2022-were selected. One or more organs with moderate to severe impairment were included in all patients. The patients were randomly divided into a hypobaric spinal anesthesia group (group C, control group) and an ultrasound-guided FICB combined with hypobaric spinal anesthesia group (group E, experimental group). Group C was given 3.5 mL of 0.32% ropivacaine hypobaric spinal anesthesia, and group E received ultrasound-guided FICB combined with 3.5 mL of 0.32% ropivacaine hypobaric spinal anesthesia. The patients were compared using the visual analog scale (VAS) for pain, Harris hip function score, and simple Mini-Mental State Examination (MMSE) scale. Blood ß-amyloid (Aß) and neuronal microtubule-associated protein (tau) levels were measured. We compared intraoperative conditions and post-operative complications between the two groups to assess the effects of FICB combined with hypobaric spinal anesthesia on post-operative pain and cognitive function in elderly patients with high-risk hip replacement. Results: At 1 and 3 days after the operation, patients in group C had significantly higher VAS and lower MMES scores than those in group E. The differences were statistically significant at 1 (P < 0.01) and 3 (P < 0.05) days after the operation. At 1 day after operation, the Harris score of patients in group C was significantly lower than that of patients in group E (P < 0.05). The Aß and tau levels of patients in group C were significantly higher than those of patients in group E at 1 day after the operation (P < 0.01). The Aß levels of patients in group C were significantly higher than those of patients in group E at 3 days after the operation (P < 0.05). The intraoperative conditions and post-operative complication rates did not differ significantly between the two groups. At 1 day before and 5 days after the operation, there was no difference in any of the indicators. Conclusion: By lowering pain and managing Aß and tau protein concentrations, FICB can successfully lower the incidence of early post-operative cognitive impairment in elderly patients with high-risk hip replacement. Clinical trial registration: www.chictr.org.cn, identifier: ChiCTR2100051162.

Opioid-reduced anesthesia based on esketamine in gynecological day surgery: a randomized double-blind controlled study.

BACKGROUND: Opioid-reduced anesthesia may accelerate postoperative rehabilitation by reducing opioid-related side effects. The objective was to investigate the feasibility of opioid-reduced general anesthesia based on esketamine and to observe postoperative nausea and vomiting (PONV), postoperative pain, hemodynamics and other adverse reactions in gynecological day surgery compared with the traditional opioid-based anesthesia program. METHOD: This study was conducted as a prospective parallel-group randomized controlled trial. A total of 141 adult women undergoing gynecological day surgery were included. Patients were randomly assigned to receive traditional opioid-based anesthesia (Group C) with alfentanil, or opioid-reduced anesthesia (a moderate-opioid group (Group MO) and low-opioid group (Group LO) with esketamine and alfentanil). For anesthesia induction, the three groups received 20, 20, 10 µg/kg alfentanil respectively and Group LO received an additional 0.2 mg/kg esketamine. For maintenance of anesthesia, the patients in Group C received 40 µg/kg/h alfentanil, and those in Group MO and Group LO received 0.5 mg/kg/h esketamine. RESULTS: Patients in the three groups had comparable clinical and surgical data. A total of 33.3% of patients in Group C, 18.4% of patients in Group MO and 43.2% of patients in Group LO met the primary endpoint (p = 0.033), and the incidence of nausea within 24 hours after surgery in Group MO was lower than in Group LO (p < 0.05). The extubation time, median length of stay in the hospital after surgery and visual analog scale (VAS) of postoperative pain were equivalent in the three groups. The frequencies of adverse hemodynamic events in the MO 1(0, 2) and LO 0(0, 1) groups were significantly decreased (p < 0.05). Compared with Group C, the median length of stay in the postanesthesia care unit (PACU) in Group LO was increased, 60.0 (36.25, 88.75) vs. 42.5 (25, 73.75) minutes (p < 0.05). CONCLUSIONS: Opioid-reduced anesthesia based on esketamine is feasible and provides effective analgesia for patients. Esketamine provided a positive analgesic effect and the opioid-reduced groups showed more stable hemodynamics. However, less or no use of opioids did not result in a more comfortable prognosis. TRIAL REGISTRATION: This study was registered at Chictr.org.cn (NO. ChiCTR2100053153 ); November 13, 2021.

DNA Methyltransferase Inhibitor 5-AZA-DC Regulates TGFß1-Mediated Alteration of Neuroglial Cell Functions after Oxidative Stress.

5-AZA-DC is an efficient methylation inhibitor that inhibits methylation of target DNA. In this study, we explored the effects of 5-AZA-DC on the regulation of TGFß1 on target genes in neuroglial cell, as well as neuroglial cell functions under oxidative stress. The oxidative stress was constructed by editing CRISPR/Cas9 for knock out Ang-1 and ApoE4 genes. Cells were subjected to TGFß1OE (or shTGFß1) transfection and/or 5-AZA-DC intervention. Results showed that under oxidative stress, both TGFß1OE and shTGFß1 transfection raised DNMT1, but reduced TGFß1, PTEN, and TSC2 expressions in neuroglial cells. TGFß1 directly bind to the promoter of PTEN gene. 5-AZA-DC intervention lowered DNMT1 and raised TGFß1 expression, as well as promoted the binding between TGFß1 and promoter of PTEN. TGFß1OE caused a significant increase in the DNA demethylation level of PTEN promoter, while 5-AZA-DC intervention reduced the DNA demethylation level of PTEN promoter. Under oxidative stress, TGFß1OE (or shTGFß1) transfection inhibited neuroglial cell proliferation, migration, and invasion, promoted cell apoptosis. 5-AZA-DC intervention alleviated TGFß1OE (or shTGFß1) transfection caused neuroglial cell proliferation, migration, and invasion inhibition, as well as cell apoptosis. To conclude, these results suggest that 5-AZA-DC can be used as a potential drug for epigenetic therapy on oxidative stress damage in neuroglial cells. The findings of this research provide theoretical basis and research ideas for methylation drug intervention and TGFß1 gene as a possible precise target of glial oxidative stress diagnosis and treatment.

Arthrobacter cavernae sp. nov., a novel actinobacterium isolated from sediment of karst cave.

A novel, Gram-stain-positive, aerobic, non-endospore-forming, non-motile and rod-shaped bacterium designated PO-11T was isolated from sediment of karst cave collected in Libo county, Guizhou Province, PR China. The isolate grew optimally on R2A agar at 25 °C, pH 8.0 and with 0.5 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that PO-11T belonged to the genus Arthrobacter and was most closely related to Arthrobacter methylotrophus TGAT (98.3 % sequence similarity), Arthrobacter alkaliphilus LC6T (97.7 %) and Arthrobacter ramosus CCM1646T (97.1 %). Genome sequencing revealed a genome size of 4 073 119 bp and the genomic DNA G+C content was 66.16 mol%. Its DNA-DNA relatedness values with A. methylotrophus TGAT, A. alkaliphilus LC6T and A. ramosus CCM1646T were 23.0, 22.9 and 23.2 %, respectively. The main fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The major respiratory quinone was MK-9(H2). The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, glycolipid, phosphatidylethanolamine, phosphatidylinositol and unidentified lipids. Thus, based on phylogenetic and phenotypic and chemotaxonomic data, strain PO-11T represents a novel species of the genus Arthrobacter, for which the name Arthrobacter cavernae sp. nov. is proposed. The type strain is strain PO-11T (=CCTCC AB 2021070T=LMG 32459T).

Two Myricetin-Derived Flavonols from Morella rubra Leaves as Potent α-Glucosidase Inhibitors and Structure-Activity Relationship Study by Computational Chemistry.

Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia, and oxidative stress is an important cause and therapeutic target of DM. Phytochemicals such as flavonols are important natural antioxidants that can be used for prevention and treatment of DM. In the present study, six flavonols were precisely prepared and structurally elucidated from Morella rubra leaves, which were screened based on antioxidant assays and α-glucosidase inhibitory activities of different plant tissues. Myricetin-3-O-(2″-O-galloyl)-α-L-rhamnoside (2) and myricetin-3-O-(4″-O-galloyl)-α-L-rhamnoside (3) showed excellent α-glucosidase inhibitory effects with IC50 values of 1.32 and 1.77 µM, respectively, which were hundredfold higher than those of positive control acarbose. Molecular docking simulation illustrated that the presence of galloyl group altered the binding orientation of flavonols, where it occupied the opening of the cavity pocket of α-glucosidase along with Pi-anion interaction with Glu304 and Pi-Pi stacked with His279. Pi-conjugations generated between galloyl moiety and key residues at the active site of α-glucosidase reinforced the flavonol-enzyme binding, which might explain the greatly increased activity of compounds 2 and 3. In addition, 26 flavonols were evaluated for systematic analysis of structure-activity relationship (SAR) between flavonols and α-glucosidase inhibitory activity. By using their pIC50 (-log IC50) values, three-dimensional quantitative SAR (3D-QSAR) models were developed via comparative molecular field analysis (CoMFA) and comparative similarity index analysis (CoMSIA), both of which were validated to possess high accuracy and predictive power as indicated by the reasonable cross-validated coefficient (q 2) and non-cross-validated coefficient (r 2) values. Through analyzing 3D contour maps of both CoMFA and CoMSIA models, QSAR results were in agreement with in vitro experimental data. Therefore, such results showed that the galloyl group in compounds 2 and 3 is crucial for interacting with key residues of α-glucosidase and the established 3D-QSAR models could provide valuable information for the prediction of flavonols with great antidiabetic potential.

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice.

Gut Flora Mediates the Rapid Tolerance of Electroacupuncture on Ischemic Stroke by Activating Melatonin Receptor through Regulating Indole-3-Propionic Acid.

Electroacupuncture (EA) is commonly used to treat cerebrovascular diseases. This study aimed to clarify the mechanisms of action of treatments of cerebral ischemic stroke from the perspective of gut microecology. We used a mouse model and cell cultures to investigate the effects of EA on the intestinal microflora in mice models of middle cerebral artery occlusion (MCAO) and the mechanisms underlying the antioxidant activities of metabolites. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota. Metabolomic analysis was performed to characterize the metabolic profile differences between the mice in the EA + MCAO and MCAO groups. Gavaging with feces relieved brain damage in mice that received EA (EA mice) more than in mice that did not (non-EA [NEA] mice). The gut microbial composition and metabolic profiles of the EA and NEA mice were different. In particular, the microbiota from the mice in the EA or EA-FMT groups generated more indole-3-propionic acid (IPA) than the microbiota from the mice in the MCAO or NEA-FMT groups. We confirmed that IPA binds to specific melatonin receptors (MTRs) in target cells and exerts antioxidant effects by adding MTR inhibitors or knocking out the MTR1 gene in vivo and in the oxygen and glucose deprivation/reperfusion models of N2a cell experiments. EA can prevent ischemic stroke by improving the composition of intestinal microbiota in MCAO mice. Moreover, this study reveals a new mechanism of intestinal flora regulation of stroke that differs from inflammation/immunity, namely gut microbiota regulates stroke by affecting IPA levels.

Pd nanoparticles decorated thiol-functionalized MOF as an efficient matrix for differentiation and quantitation of oligosaccharide isomers by laser desorption/ionization mass spectrometry.

Oligosaccharides play a key role in many biological functions, and the accurate identification of oligosaccharide structures is an important prerequisite for a comprehensive understanding of the biological functions of oligosaccharides. MALDI-TOF/TOF tandem mass spectrometry has been considered as a potential technique for the structural characterization of oligosaccharides. In this work, palladium nanoparticles decorated thiol-functionalized metal organic framework nanocomposite (UiO-66-(SH)2@Pd NPs) was fabricated as an efficient matrix to assist laser desorption/ionization mass spectrometry (LDI-MS) for oligosaccharides analysis. The ionization efficiency of oligosaccharides was significantly improved owning to the synergistic effect of MOF and Pd nanoparticles, which is favorable for further oligosaccharide structure identification. By combining LDI-LIFT-TOF/TOF, 24 oligosaccharide isomers including disaccharides, trisaccharides and tetrasaccharides, were effectively distinguished. In addition, the relative quantification curves for isomeric oligosaccharides were established with good linear correlations. The method was successfully applied to the identification and quantification of sucrose and maltose in three batches of Asian ginseng and American ginseng respectively, showing potentiality of MOF materials and metal nanomaterials assisted structural analysis of oligosaccharide isomers.

6-Glycosylaminoquinoline-assisted LDI MS for detection and imaging of small molecules with enhanced detection selectivity and sensitivity.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a powerful tool in the analysis and imaging of small molecules. However, MALDI MS analysis is easily subjected to poor signal reproducibility and selectivity, especially for complex samples. In this study, a matrix glycosylation strategy was proposed to synthesize glycosylated matrices with excellent performances by enhancing the interaction of the matrix with small molecules. A series of glycosylated matrices including 3-glycosylaminoquinoline (3-GAQ), 6-glycosylaminoquinoline (6-GAQ), and 1-amino-5-glycosylaminoquinoline (GDAN) were synthesized by connecting glucose with the existing amine matrices. Compared with their parent matrices and the existing matrix (1,5-diaminonaphathelene, 1,5-DAN), the glycosylated matrices exhibited remarkably-improved sensitivity, higher signal reproducibility (RSD < 9%) in detecting metabolites, demonstrating the effectiveness of the glycosylation strategy. Among them, 6-GAQ exhibited the best performance. Using 6-GAQ, the detection limit of citric acid reached the low fmol range, and the calibration curve of citric acid had ideal linearity (R2 > 0.99), proving that 6-GAQ was capable of accurate quantitative analysis of metabolites. Furthermore, 6-GAQ was used for the imaging of metabolites in the mouse kidney section, showing higher sensitivity and lower background noise than the commonly-used matrices, 9-aminoquinoline (9-AA), and 1,5-DAN. More importantly, 6-GAQ can selectively detect the hydrophilic metabolites, especially the hydrophilic lipids in the mouse kidney. Overall, 6-GAQ is an ideal matrix potentially applied in the imaging and quantitative analysis of hydrophilic small molecules in complex samples.

Unravelling the consecutive glycosylation and methylation of flavonols in peach in response to UV-B irradiation.

Flavonol glycosides are bioactive compounds important for plant defence and human nutrition. Glycosylation and methylation play an important role in enriching the diversity of flavonols in response to the environment. Peach flowers and fruit are rich in flavonol diglycosides such as isorhamnetin 3-O-rutinoside (I3Rut), kaempferol 3-O-rutinoside and quercetin 3-O-rutinoside, and flavonol monoglycosides such as I 3-O-glucoside and Q 3-O-galactoside. UV-B irradiation of fruit significantly induced accumulation of all these flavonol glycosides. Candidate biosynthetic genes induced by UV-B were identified by genome homology searches and the in vitro catalytic activities of purified recombinant proteins determined. PpUGT78T3 and PpUGT78A2 were identified as flavonol 3-O-glucosyltransferase and 3-O-galactosyltransferase, respectively. PpUGT91AK6 was identified as flavonol 1,6-rhamnosyl trasferase catalysing the formation of flavonol rutinosides and PpFOMT1 was identified as a flavonol O-methyltransferase that methylated Q at the 3'-OH-OH to form isorhamnetin derivatives. Transient expression in Nicotiana benthamiana confirmed the specificity of PpUGT78T3 as a flavonol 3-O-glucosyltransferase, PpUGT78A2 as a 3-O-galactosyltransferase, PpUGT91AK6 as a 1,6-rhamnosyltrasferase and PpFOMT1 as an O-methyltransferase. This study provides new insights into the mechanisms of glycosylation and methylation of flavonols, especially the formation of flavonol diglycosides such as I3Rut, and will also be useful for future potential metabolic engineering of complex flavonols.