Synthesis and Self-Assembly Behavior of Chlorophyll Derivatives for Ratiometric Photoacoustic Signal Optimization.

Self-assembly provides researchers powerful tools for creating ordered functional structures and complex architectures. Investigation of in vivo self-assembly reveals the assembly/aggregation-induced retention (AIR) effect and enhanced targeting effect, which can be applied to promising biomedical applications by enhancing molecular accumulation in the target region. These unique bioeffects inspire the interest of researchers in construction of self-assembled nanomaterials in biological systems. Although many efforts have been achieved, the in-depth analysis of the relationship between assemblies and functions is rarely reported. Here, we focus on the relationship of chlorophyll-derivative assemblies and their photoacoustic signals and attempt to establish a method for monitoring the aggregation efficiency in vivo based on photoacoustic signals. Three arginine-rich peptide-purpurin molecules were designed and synthesized. The assembled capabilities and assembly processes of these molecules were characterized and monitored by UV, fluorescence, and CD spectra images of gradually changing polarities in mixed solvents, and the morphologies of the assemblies were observed by TEM. Furthermore, the relationship between the aggregation ratios of the molecules and the ratiometric photoacoustic signals was systemically studied. We prospect that the fundamental research in revealing objective laws will be useful for future guidance in optimizing photoacoustic detection windows and assembled molecule design.

Andrographolide inhibits secretagogue-induced pseudo-allergic reaction.

Many kinds of drugs induce pseudo-allergic reactions due to activation of mast cells. We investigated the anti-pseudo-allergic effect of andrographolide (Andro). The effects of Andro on pseudo-allergic reactions were investigated in vivo and in vitro. Andro suppressed compound 48/80 (C48/80) induced pseudo-allergic reactions in mice in a dose-dependent manner. Andro also inhibited C48/80-induced local inflammatory reactions in mice. In vitro studies revealed that Andro reduced C48/80-induced mast cells degranulation. Human phospho-kinase array kit and western blotting showed that Andro could inhibit pseudo-allergic responses via the calcium signaling pathway.

Astrocytic N-Myc Downstream-regulated Gene-2 Is Involved in Nuclear Transcription Factor κB-mediated Inflammation Induced by Global Cerebral Ischemia.

BACKGROUND: Inflammation is a key element in the pathophysiology of cerebral ischemia. This study investigated the role of N-Myc downstream-regulated gene-2 in nuclear transcription factor κB-mediated inflammation in ischemia models. METHODS: Mice (n = 6 to 12) with or without nuclear transcription factor κB inhibitor pyrrolidinedithiocarbamate pretreatment were subjected to global cerebral ischemia for 20 min. Pure astrocyte cultures or astrocyte-neuron cocultures (n = 6) with or without pyrrolidinedithiocarbamate pretreatment were exposed to oxygen-glucose deprivation for 4 h or 2 h. Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression, proinflammatory cytokine secretion, neuronal apoptosis and survival, and memory function were analyzed at different time points after reperfusion or reoxygenation. Proinflammatory cytokine secretion was also studied in lentivirus-transfected astrocyte lines after reoxygenation. RESULTS: Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion increased after reperfusion or reoxygenation. Pyrrolidinedithiocarbamate pretreatment significantly reduced N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion in vivo and in vitro, reduced neuronal apoptosis induced by global cerebral ischemia/reperfusion (from 65 ± 4% to 47 ± 4%, P = 0.0375) and oxygen-glucose deprivation/reoxygenation (from 45.6 ± 0.2% to 22.0 ± 4.0%, P < 0.001), and improved memory function in comparison to vehicle-treated control animals subjected to global cerebral ischemia/reperfusion. N-Myc downstream-regulated gene-2 lentiviral knockdown reduced the oxygen-glucose deprivation-induced secretion of proinflammatory cytokines. CONCLUSIONS: Astrocytic N-Myc downstream-regulated gene-2 is up-regulated after cerebral ischemia and is involved in nuclear transcription factor κB-mediated inflammation. Pyrrolidinedithiocarbamate alleviates ischemia-induced neuronal injury and hippocampal-dependent cognitive impairment by inhibiting increases in N-Myc downstream-regulated gene-2 expression and N-Myc downstream-regulated gene-2-mediated inflammation.

Repression of neuronal nitric oxide (nNOS) synthesis by MTA1 is involved in oxidative stress-induced neuronal damage.

The Metastasis-associated protein 1 (MTA1) coregulator, an essential component of the nucleosome remodeling and deacetylase (NuRD) complex, potentiates neuroprotective effects against ischemia/reperfusion (I/R) injury. But the underlying mechanism(s) remain largely unknown. Here, we discovered that neuronal MTA1 was a target of oxidative stress, and stimulation of neurons with oxygen glucose deprivation (OGD) treatment significantly inhibited MTA1 expression. Additionally, MTA1 depletion augmented ischemic oxidative stress and thus promoted oxidative stress-induced neuronal cell death by OGD. While studying the impact of MTA1 status on global neuronal gene expression, we unexpectedly discovered that MTA1 may modulate OGD-induced neuronal damage via regulation of distinct nitric oxide synthase (NOS) (namely neuronal NOS, nNOS) signaling. We provided in vitro evidence that NOS1 is a chromatin target of MTA1 in OGD-insulted neurons. Mechanistically, neuronal ischemia-mediated repression of NOS1 expression is accompanied by the enhanced recruitment of MTA1 along with histone deacetylases (HDACs) to the NOS1 promoter, which could be effectively blocked by a pharmacological inhibitor of the HDACs. These findings collectively reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the neuronal oxidative stress, in the regulation of acute neuronal responses against brain I/R damage. Our study also provides a molecular mechanistic explanation for the previously reported neurovascular protection by selective nNOS inhibitors.

Efficacy and Safety of Esketamine Combined with Antidepressants for Treatment-Resistant Depression: A Meta-Analysis.

Objective: To evaluate the efficacy and safety of esketamine + antidepressant in treatment-resistant depression. Methods: We searched PubMed, Web of Science, Embase, CNKI, and Wanfang databases to obtain published information on esketamine + antidepressant from inception to July 2022. We searched for randomized controlled studies on the treatment of depression with a double-blind induction phase. Outcome indicators included changes in Montgomery-Asberg Depression Rating Scale (MADRS) scores before and after treatment, effective response rate, remission rate, and changes in self-rating depression scale (SDS). We analyzed data using Review Manager 5.4 and assessed the quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis. Results: A total of seven articles were included, including 701 patients in the esketamine + antidepressant group and 551 in the placebo group. Meta-analysis results showed that esketamine + antidepressant could improve the MADRS score in patients with treatment-resistant depression (MD = -2.68, 95% CI -3.98 to -1.37, P < 0.0001), SDS (MD = -2.9, 95% CI -4.01 to -1.79, P < 0.00001), response rate at the end of the double-blind induction period (RR = 1.28, 95% CI 1.12 to 1.46, P = 0.0002), remission rate at the end of the double-blind induction period (RR = 1.39, 95% CI 1.18 to 1.63, P < 0.0001), Five-Dimensional Health Scale (EQ-5D-5L) (MD = 0.05, 95% CI 0.02 to 0.08, P = 0.00009), Visual Analogue Scale of Health Status (EQ-VAS) (MD = 5.54, 95% CI 2.37 to 8.71, P = 0.0006). Conclusion: Esketamine + antidepressant has an obvious curative effect in treatment-resistant depression and can rapidly improve depression in patients, quality of life and satisfaction, but minor adverse reactions can occur.

Comparative efficacy and safety of prophylactic norepinephrine and phenylephrine in spinal anesthesia for cesarean section: A systematic review and meta-analysis with trial sequential analysis.

Background: Phenylephrine is the first-line drug used to maintain blood pressure in cesarean delivery. However, it poses a high risk of bradycardia and depression of cardiac activity in pregnant women. Consequently, norepinephrine has gained popularity over the recent years, as an alternative to Phenylephrine because it is thought that prophylactic use of vasopressors may reduce the incidence of hypotension after spinal anesthesia. This systematic review compared the efficacy of both treatments. Methods: We searched the following databases; CNKI, PubMed, Embase, Web of science, clinicaltrials.gov, Medline and Cochrane Library, for randomized controlled trials comparing the prophylactic efficacy of norepinephrine and phenylephrine on elective cesarean delivery under spinal anesthesia. The search period was from inception to July 2022, and the primary outcome indicator was incidence of bradycardia. Statistical analysis was conducted on Rev manager 5.4, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to evaluate the quality of evidence from each main finding. Results: A total of 12 papers were included in the analysis. The incidence of bradycardia (RR = 0.37, 95% CI: 0.28 to 0.49, p < 0.00001) and reactive hypertension (RR = 0.58, 95% CI 0.40 to 0.83, p = 0.003) was significantly lower in the norepinephrine (NE) group compared with the phenylephrine (PE) category. In contrast, there were no statistical differences in the umbilical cord blood gas analysis pH values between the groups (arterial: MD = 0.00, 95% CI -0.00 to 0.01, p = 0.22, vein: MD = 0.01, 95% CI -0.00 to 0.02, p = 0.06). The incidence of hypotension, nausea, and vomiting did not differ significantly between the NE and PE groups (hypotension: 23% vs. 18%; nausea: 14% vs. 18%; vomiting: 5% vs. 7%, respectively). Conclusion: Prophylactic use of norepinephrine is safe and effective in maintaining maternal hemodynamics without causing adverse events to either the pregnant woman or fetus. Systematic Review Registration: website https://www.crd.york.ac.uk/prospero/, identifier CRD42022347095.

Full-Endoscopic Decompression with the Application of an Endoscopic-Matched Ultrasonic Osteotome for Removal of Ossification of the Thoracic Ligamentum Flavum.

BACKGROUND: Resection of the ossification of the thoracic ligamentum flavum (OTLF) with a high-speed burr may cause a high rate of perioperative complications, such as dural laceration and/or iatrogenic spinal cord injury. OBJECTIVES: The aim of this study was to investigate the safety and feasibility of the endoscopic-matched ultrasonic osteotome in full-endoscopic spinal surgery for direct removal of OTLF. STUDY DESIGN: Retrospective study. SETTING: All data were from Honghui Hospital in Xi'an. METHODS: This study conducted between December 2017 and December 2018, included 27 consecutive patients who met the study criteria, had single-level OTLF, and underwent full-endoscopic decompression under local anesthesia. The postoperative follow-up was scheduled at 1, 3, 6, and 12 months postoperatively. Outcomes evaluations included the Visual Analog Scale (VAS) score for lower extremity pain and the modified Japanese Orthopaedic Association (mJOA) score and improvement rate for the assessment of thoracic myelopathy. Removal of OTLF was measured by comparing the pre- and postoperative computed tomography (CT) and magnetic resonance imaging (MRI) scans. RESULTS: The operation was completed in all patients without conversion to open surgery. The operation time ranged from 65 to 125 minutes (average, 83.7 ± 12.3 minutes). All patients were followed up for 12 to 18 months, with an average follow-up of 14.3 ± 1.3 months. Satisfactory neurologic decompression was confirmed by postoperative CT and MRI, and no revision surgery was required. The VAS and mJOA scores showed statistically higher improvement at the 1-month follow-up and the last follow-up compared with the preoperative assessment (P < 0.05). According to the improvement rate at the final follow-up, 20 cases were classified as good, 6 cases were fair, and 1 case remained unchanged. LIMITATIONS: A single-center, noncontrol study. CONCLUSIONS: The endoscopic-matched ultrasonic osteotome can be considered quite safe and feasible for direct removal of OTLF during full-endoscopic spinal surgery in strictly selected patients, as this allows for effective direct decompression of OTLF while minimizing trauma and instability. In addition, because of the design characteristics of the ultrasonic osteotome, surgical complications, especially dural tears and spinal cord injury, can also be effectively controlled.

Untargeted Lipidomic Analysis of Plasma from High-fat Diet-induced Obese Rats Using UHPLC-Linear Trap Quadrupole-Orbitrap MS.

High-fat diet (HFD)-induced obesity is a primary risk factor for serious health problems. Although much research has been performed at the genomic level, lipidomic studies were limited. In this study, we aim to obtain a comprehensive profile of circulating plasma lipids, which are altered in rodent rat obesity by untargeted liquid chromatography-mass spectrometry. Rats fed with HFD for 8 weeks had increased body weight, liver and adipose tissue weight. The analysis results revealed that polyunsaturated fatty acids (PUFAs) and their corresponding phosphatidylcholine, phosphatidylinositol, and phosphatidylserine were significantly decreased in rats fed with HFD. In contrast, less unsaturated and ether type phosphatidylglycerols were increased. The triacylglycerides (TAGs) having saturated FA were increased in the HFD condition, whereas TAGs having PUFA were decreased. The levels of many plasma lipids were altered, and interestingly PUFA derived lipids were negatively associated with obesity. This signifies the importance of a PUFAs enriched diet to overwhelm obesity associated diseases.

Microbiome Alteration in Type 2 Diabetes Mellitus Model of Zebrafish.

Understanding the gut microbiota in metabolic disorders, including type 2 diabetes mellitus (T2DM), is now gaining importance due to its potential role in disease risk and progression. We previously established a zebrafish model of T2DM, which shows glucose intolerance with insulin resistance and responds to anti-diabetic drugs. In this study, we analysed the gut microbiota of T2DM zebrafish by deep sequencing the 16S rRNA V3-V4 hypervariable regions, and imputed a functional profile using predictive metagenomic tools. While control and T2DM zebrafish were fed with the same kind of feed, the gut microbiota in T2DM group was less diverse than that of the control. Predictive metagenomics profiling using PICRUSt revealed functional alternation of the KEGG pathways in T2DM zebrafish. Several amino acid metabolism pathways (arginine, proline, and phenylalanine) were downregulated in the T2DM group, similar to what has been previously reported in humans. In summary, we profiled the gut microbiome in T2DM zebrafish, which revealed functional similarities in gut bacterial environments between these zebrafish and T2DM affected humans. T2DM zebrafish can become an alternative model organism to study host-bacterial interactions in human obesity and related diseases.