Extracellular vesicles ameliorates sleep deprivation induced anxiety-like behavior and cognitive impairment in mice.

The aim of this research was to explore the therapeutic capabilities of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) that had been subjected to heat shock pretreatment, in treating psychiatric disorders induced by sleep deprivation in mice. The EVs were isolated and characterized, while western blotting was utilized to assess the expression of exosomal markers and heat shock protein 70 (HSP70). To evaluate the impact of EV treatment on anxiety-like behavior and cognitive impairment in sleep-deprived (SD) mice, the open field test, plus maze test, and Y-maze task were conducted. Heat shock pretreatment significantly increased the expression of HSP70 in EVs. Administration of EVs from heat shock-pretreated hUC-MSCs improved anxiety-like behavior and cognitive function in SD mice. Furthermore, EV treatment promoted synaptic protein expression, HSP70 expression and inhibited neuroinflammation in the hippocampus of SD mice. Western blotting analysis also revealed that EV treatment reduced the levels of TLR4 and p65 in the hippocampus. EVs from heat shock-pretreated hUC-MSCs have therapeutic potential for sleep deprivation-induced psychiatric disorders by regulating neuroinflammation and synaptic function in mice.

shinyTempSignal: an R shiny application for exploring temporal and other phylogenetic signals.

The molecular clock model is fundamental for inferring species divergence times from molecular sequences. However, its direct application may introduce significant biases due to sequencing errors, recombination events, and inaccurately labeled sampling times. Improving accuracy necessitates rigorous quality control measures to identify and remove potentially erroneous sequences. Furthermore, while not all branches of a phylogenetic tree may exhibit a clear temporal signal, specific branches may still adhere to the assumptions, with varying evolutionary rates. Supporting a relaxed molecular clock model better aligns with the complexities of evolution. The root-to-tip regression method has been widely used to analyze the temporal signal in phylogenetic studies and can be generalized for detecting other phylogenetic signals. Despite its utility, there remains a lack of corresponding software implementations for broader applications. To address this gap, we present shinyTempSignal, an interactive web application implemented with the shiny framework, available as an R package and publicly accessible at https://github.com/YuLab-SMU/shinyTempSignal. This tool facilitates the analysis of temporal and other phylogenetic signals under both strict and relaxed models. By extending the root-to-tip regression method to diverse signals, shinyTempSignal helps in the detection of evolving features or traits, thereby laying the foundation for deeper insights and subsequent analyses.

Efficacy and safety of adamgammadex for reversing rocuronium-induced deep neuromuscular blockade: A multicenter, randomized, phase IIb study.

The rapid reversal of deep neuromuscular blockade (NMB) is important but remains challenging. This study aimed to evaluate the efficacy and safety of adamgammadex versus sugammadex in reversing deep rocuronium-induced NMB. This multicenter, randomized, phase IIb study included 80 patients aged 18-64 years, American Society of Anesthesiologists (ASA) grade 1-2, undergoing elective surgery under general anesthesia with rocuronium. Patients were randomized to the adamgammadex 7, 8, and 9 mg/kg group or the sugammadex 4 mg/kg group. The primary efficacy variable was the time to recovery of train-of-four ratio (TOFr) to 0.9. The secondary efficacy variables were the time to recovery of TOFr to 0.7, antagonistic success rate of the recovery of TOFr to 0.9 within 5 min, and incidence rate of recurarization within 30 min after drug administration. The explorative efficacy variable was the time to recovery of the corrected TOFr to 0.9 (actual/baseline TOF ratio). Adamgammadex 7, 8, and 9 mg/kg and sugammadex 4 mg/kg groups did not significantly differ in all efficacy variables. Importantly, adamgammadex 9 mg/kg permitted reversal within a geometric mean of 2.9 min. According to the safety profile, adamgammadex achieved good tolerance and low incidence of drug-related adverse events compared with the 4 mg/kg sugammadex. Adamgammadex 7, 8, and 9 mg/kg facilitated rapid reversal of deep rocuronium-induced NMB and had good tolerance and low incidence of drug-related adverse events. Therefore, adamgammadex is a potential and promising alternative to sugammadex.

Short Tandem Repeat Analysis in a Living Related Donor Adult Renal Transplant Recipient with Rare Natural Chimerism.

After renal transplant, immunosuppression therapy is used to reduce the risk of rejection. Here, we describe the case of an adult living related donor renal transplant recipient with rare natural chimerism, as discovered by short tandem repeat sequence analysis. In our process of matching transplant patients, we perform human leukocyte antigen testing and short tandem repeat chimerism testing to decide postoperative immunosuppression strategy for transplant patients. We analyzed the short tandem repeat chimerism status before renal transplant and determined that this patient represented a rare case of natural chimerism. Assessment of organ recipient chimerism can inform physicians regarding a dosage reduction of immunosuppressive agents. Short tandem repeat sequence analysis provides substantial information regarding existing polymorphisms and can identify chimerism, if present, and thereby guide immunosuppression strategies after renal transplant, which may improve the long-term immunosuppression-free survival of renal transplant recipients.

Hsp70 ameliorates sleep deprivation-induced anxiety-like behavior and cognitive impairment in mice.

BACKGROUND: Many neurobehavioral processes, including psychomotor, cognitive, and affection are negatively impacted by sleep deprivation (SD), which may be harmful to a person's physical and mental health. Heat shock proteins (Hsps) have been demonstrated to play a protective role in a number of neurodegenerative diseases and are essential for maintaining intracellular protein homeostasis, but their roles in SD remain elusive. METHODS: A mouse SD model was constructed using a modified multi-platform water environment method. The cognitive function was tested by novel object recognition test and Y-maze test, and anxiety-like behaviors were assessed by open field test (OFT). Protein expression was determined by Western blotting assay and ELISA assay. RESULTS: We found that SD could profoundly enhance anxiety levels and impair cognitive function in mice. SD also reduced the expression levels of p-cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) and increased microglial activation and neuroinflammatory response in the hippocampus of mice. The intranasal injection of human recombinant Hsp70 protein could alleviate SD-induced anxiety and cognitive impairment, as well as restore pCREB and BDNF levels and reduce microglia-induced neuroinflammation in the hippocampus of SD mice. CONCLUSIONS: Hsp70 treatment might serve as a potential treatment for mitigating SD-related unfavorable symptoms.

Apigenin Alleviates Allodynia and Hyperalgesia in a Mouse Model of Chemotherapy-Induced Peripheral Neuropathy via Regulating Microglia Activation and Polarization.

BACKGROUND: Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on chemotherapy-induced peripheral neuropathy (CIPN). METHODS: CIPN mouse model was established using Paclitaxel treatment. Hot plate and tail prick latency tests were performed to examine the allodynia and hyperalgesia behaviors. Anti-inflammatory and anti-oxidative effects of Apigenin on CIPN were determined by enzyme-linked immunosorbent (ELISA) assay, Western blot, and qRT-PCR. Nuclear recruitment of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed to evaluate the underlying mechanisms of the protective effects of Apigenin. RESULTS: Apigenin significantly alleviated CIPN-induced nociceptive behaviors of CIPN mice. It also decreased the TNF-α and IL-1ß levels, suppressed oxidative stress and inflammation in the surgical spinal cord tissues. Mechanistically, Apigenin altered the pro-inflammatory and anti-inflammatory phenotypes ratio of microglia through promoting the nuclear recruitment of NRF2 and activating the NRF2/Antioxidant Response Element (ARE) signaling pathway. CONCLUSIONS: In summary, Apigenin relieves CIPN by regulating microglia activation and polarization, which provides a potential therapeutic strategy for CIPN treatment.

Energy intake restriction significantly improves POCD after internal fixation of tibial fractures in mice.

OBJECTIVE: To investigate the effect of energy intake restriction on postoperative cognitive dysfunction (POCD) after internal fixation of tibial fractures in mice. METHODS: Thirty mice were divided into model groups of internal fixation of tibial fractures with 0%, 20%, 30% and 40% energy intake restriction and sham operation group (n = 6). Novel object recognition task and elevated plus maze test were used to assess the ability of recognition memory and anxiety-related behavior before and one week after surgery. The blood samples were collected from mice on days 1, 3 and 7 after surgery, and the mice were euthanized on the 8th day after surgery. RT-PCR and Western blot were employed to detect the expression of AMPK-SIRT1 pathway-related genes and proteins in the hippocampus. ELISA was used to detect the levels of inflammatory factors in the peripheral blood of mice. Hematoxylin-eosin (H&E) staining and immunofluorescence (IF) staining were used to detect the proliferation, differentiation and injury of hippocampal cells. RESULTS: The results showed that 20% and 30% energy intake restriction significantly improved the POCD after internal fixation of tibial fractures in mice. Significantly, 30% energy intake restriction reduced the expression of AP-1, NF-κB, CD45, IBA-1, and inflammatory factors IL-1ß, IL-6, IL-8 and TNF-α, and increased the expression of AMPK and SIRT1 after the operation. H&E and IF staining showed that 30% energy intake restriction reduced postoperative hippocampal neuronal damage. CONCLUSION: Energy intake restriction can significantly improve POCD after internal fixation of tibial fractures in mice and may provide a new treatment paradigm for POCD patients.

Associated factors of osteoporosis and vascular calcification in patients awaiting kidney transplantation.

INTRODUCTION: Pretransplant osteoporosis and vascular calcification probably increase the risk of fractures and cardiovascular events after kidney transplantation. In the present study, we investigated the related risk factors of osteoporosis and vascular calcification among end-stage renal disease (ESRD) patients awaiting kidney transplantation. METHODS: A total of 221 ESRD patients (age, 43.4 ± 14.3 years; 125 males and 96 females; median dialysis duration, 61.0 m) awaiting kidney transplantation were enrolled in this cross-sectional study. Serum levels of bone turnover markers and intact parathyroid hormone (iPTH) were analyzed from fasting morning blood samples. Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD). Vascular calcification was evaluated by lateral abdominal radiography and plain radiographic films of the pelvis and hands. RESULTS: The osteoporosis prevalence was 27.6% in this cohort of kidney transplantation candidates, and the prevalence of vascular calcification was 51.1%. The related factors for osteoporosis and vascular calcification were similar and included older age, longer dialysis duration, parathyroid hyperplasia, and higher levels of iPTH and bone turnover markers. In the multivariable regression model, age and iPTH were independent risk predictors of both vascular calcification and osteoporosis. There were strong, positive correlations between iPTH and all bone turnover markers. The moderate and severe hyperparathyroidism (iPTH 600-1499 pg/ml and iPTH 1500 pg/ml) were related to reduced serum albumin and hemoglobin levels. CONCLUSION: The involvement of high iPTH levels in vascular calcification, osteoporosis, and malnutrition indicated the need of treating hyperparathyroidism early in patients awaiting kidney transplantation. Prospective studies are needed to further examine the utility of bone turnover markers.

Exploring Epigenomic Datasets by ChIPseeker.

In many aspects of life, epigenetics, or the altering of phenotype without changes in sequences, play an essential role in biological function. A vast number of epigenomic datasets are emerging as a result of the advent of next-generation sequencing. Annotation, comparison, visualization, and interpretation of epigenomic datasets remain key aspects of computational biology. ChIPseeker is a Bioconductor package for performing these analyses among variable epigenomic datasets. The fundamental functions of ChIPseeker, including data preparation, annotation, comparison, and visualization, are explained in this article. ChIPseeker is a freely available open-source package that may be found at https://www.bioconductor.org/packages/ChIPseeker. © 2022 Wiley Periodicals LLC. Basic Protocol 1: ChIPseeker and epigenomic dataset preparation Basic Protocol 2: Annotation of epigenomic datasets Basic Protocol 3: Comparison of epigenomic datasets Basic Protocol 4: Visualization of annotated results Basic Protocol 5: Functional analysis of epigenomic datasets Basic Protocol 6: Genome-wide and locus-specific distribution of epigenomic datasets Basic Protocol 7: Heatmaps and metaplots of epigenomic datasets.

Stemness Analysis Uncovers That The Peroxisome Proliferator-Activated Receptor Signaling Pathway Can Mediate Fatty Acid Homeostasis In Sorafenib-Resistant Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) stem cells are regarded as an important part of individualized HCC treatment and sorafenib resistance. However, there is lacking systematic assessment of stem-like indices and associations with a response of sorafenib in HCC. Our study thus aimed to evaluate the status of tumor dedifferentiation for HCC and further identify the regulatory mechanisms under the condition of resistance to sorafenib. Datasets of HCC, including messenger RNAs (mRNAs) expression, somatic mutation, and clinical information were collected. The mRNA expression-based stemness index (mRNAsi), which can represent degrees of dedifferentiation of HCC samples, was calculated to predict drug response of sorafenib therapy and prognosis. Next, unsupervised cluster analysis was conducted to distinguish mRNAsi-based subgroups, and gene/geneset functional enrichment analysis was employed to identify key sorafenib resistance-related pathways. In addition, we analyzed and confirmed the regulation of key genes discovered in this study by combining other omics data. Finally, Luciferase reporter assays were performed to validate their regulation. Our study demonstrated that the stemness index obtained from transcriptomic is a promising biomarker to predict the response of sorafenib therapy and the prognosis in HCC. We revealed the peroxisome proliferator-activated receptor signaling pathway (the PPAR signaling pathway), related to fatty acid biosynthesis, that was a potential sorafenib resistance pathway that had not been reported before. By analyzing the core regulatory genes of the PPAR signaling pathway, we identified four candidate target genes, retinoid X receptor beta (RXRB), nuclear receptor subfamily 1 group H member 3 (NR1H3), cytochrome P450 family 8 subfamily B member 1 (CYP8B1) and stearoyl-CoA desaturase (SCD), as a signature to distinguish the response of sorafenib. We proposed and validated that the RXRB and NR1H3 could directly regulate NR1H3 and SCD, respectively. Our results suggest that the combined use of SCD inhibitors and sorafenib may be a promising therapeutic approach.

Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects.

Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4, which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay. With improved physicochemical properties and suitable pharmacokinetic properties, compound 4 was advanced into in vivo bioactivity evaluation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 4 showed anti-inflammatory property and reduced the levels of pro-inflammatory cytokines (TNF-α and IL-6). Together, these findings provide evidence that this approach may be promising for further Grp94 drug development efforts.

GIMICA: host genetic and immune factors shaping human microbiota.

Besides the environmental factors having tremendous impacts on the composition of microbial community, the host factors have recently gained extensive attentions on their roles in shaping human microbiota. There are two major types of host factors: host genetic factors (HGFs) and host immune factors (HIFs). These factors of each type are essential for defining the chemical and physical landscapes inhabited by microbiota, and the collective consideration of both types have great implication to serve comprehensive health management. However, no database was available to provide the comprehensive factors of both types. Herein, a database entitled 'Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA)' was constructed. Based on the 4257 microbes confirmed to inhabit nine sites of human body, 2851 HGFs (1368 single nucleotide polymorphisms (SNPs), 186 copy number variations (CNVs), and 1297 non-coding ribonucleic acids (RNAs)) modulating the expression of 370 microbes were collected, and 549 HIFs (126 lymphocytes and phagocytes, 387 immune proteins, and 36 immune pathways) regulating the abundance of 455 microbes were also provided. All in all, GIMICA enabled the collective consideration not only between different types of host factor but also between the host and environmental ones, which is freely accessible without login requirement at: https://idrblab.org/gimica/.

Nalbuphine Exhibited a Better Adjuvant Than Dexmedetomidine in Supraclavicular Brachial Plexus Block in Youths.

OBJECTIVE: Nalbuphine and dexmedetomidine are both used as anesthesia adjuvants for brachial plexus block, but their efficacy and safety in younger patients are not clear. In this study, we aimed to compare the efficacy and side effects of these 2 drugs in young patients undergoing brachial plexus block. METHODS: We recruited 48 young patients aged 18 to 30 years requiring supraclavicular brachial plexus block. Subjects were randomly divided into 2 groups. Patients in group levobupivacaine+nalbuphine received 28 mL of 0.5% levobupivacaine and 10 mg of nalbuphine diluted in 2 mL 0.9% saline. Patients in group levobupivacaine+dexmedetomidine (LD) received 28 mL of 0.5% levobupivacaine and 0.75 µg/kg dexmedetomidine diluted in 2 mL 0.9% saline. Demographic information, types of fracture, onset time of motor and sensory blocks, duration of block, side effects, and analgesic use were recorded. RESULTS: We found that the 2 groups did not differ significantly in the demographic profile and fracture type. Compared with group LD, group LD had significantly shorter sensory and motor block onset time, longer block duration, less analgesic need, and less side effects. CONCLUSION: In summary, our study suggests that nalbuphine is a better anesthesia adjuvant for supraclavicular brachial plexus block in young patients.

Effects of Depth of Anesthesia Monitored by IoC on Patients Undergoing Laparoscopic Radical Resection of Colorectal Cancer.

Index of consciousness (IoC) consisting of IoC1 and IoC2, is a new analgesia monitoring indicator in anesthesia evaluation in the laparoscopic radical resection of colorectal cancer. Although the precise anesthetic dosage adjusted by IoC1 has been confirmed to enhance the recovery and reduce the complications of anesthesia, the most appropriate range of IoC2 during anesthesia remains unclear. To investigate the correlation between IoC2 and peri-operative indicators of patients during laparoscopic radical resection of colorectal cancer, the current randomized, controlled, and single-blinded clinical trial was performed. Participants were divided randomly into three groups with different anesthesia depth monitored by IoC2 during their laparoscopic radical resections. Primary outcomes included the dosage of remifentanil. Secondary outcomes included other physiological indexes and complications. The remifentanil dosage and the awakening time increased as IoC2 decreased. The incidences of hypotension and hypoxemia decreased with the elevated IoC2, but the risk of intra-operative awareness also increased. The impact caused by anesthesia to the immune system and health-related life quality of the patients descended with reduced anesthetic level. The IoC2 range of 35-45 could represent the most appropriate anesthetic depth during laparoscopic radical resection, which provides a new perspective for the clinical treatment of colon cancer.

LncRNA LINC00641 Sponges miR-497-5p to Ameliorate Neural Injury Induced by Anesthesia via Up-Regulating BDNF.

INTRODUCTION: Ketamine, which is widely used in anesthesia, can induce cortical neurotoxicity in patients. This study aims to investigate the effects of long non-coding RNA LINC00641 on the ketamine-induced neural injury. MATERIALS AND METHODS: In this study, rat pheochromocytoma cells (PC12 cells) were used as a cell model and Sprague-Dawley postnatal day 7 rats were used for experiments in vivo. Ketamine-induced aberrant expression levels of LINC00641, miR-497-5p and brain-derived neurotrophic factor (BDNF) were examined by qRT-PCR. The effects of LINC00641 and miR-497-5p on ketamine-induced neural injury were then examined by MTT assays and TUNEL analysis. In addition, the activity of ROS and caspase-3 was measured. The regulatory relationships between LINC00641 and miR-497-5p, miR-497-5p and BDNF were detected by dual-luciferase reporter assay, respectively. RESULTS: Ketamine induced the apoptosis of PC12 cells, accompanied by down-regulation of LINC00641 and BDNF, and up-regulation of miR-497-5p. LINC00641 overexpression enhanced the resistance to the apoptosis of PC12 cells, while transfection of miR-497-5p had opposite effects. Furthermore, LINC00641 could bind to miR-497-5p and reduce its expression, but indirectly increase the BDNF expression, which was considered as a protective factor in neural injury and activated TrkB/PI3K/Akt pathway. CONCLUSION: Collectively, LINC00641/miR-497-5p/BDNF axis was validated to be an important signaling pathway in modulating ketamine-induced neural injury.

Administration of Curcumin Alleviates Neuropathic Pain in a Rat Model of Brachial Plexus Avulsion.

BACKGROUND/AIMS: Brachial plexus avulsion (BPA) generally causes a chronic persistent pain that lacks efficacious treatment. Curcumin has been found to possess anti-inflammatory abilities. However, little is known about the mechanisms and effects of curcumin in an animal model of BPA. METHODS: Mechanical withdrawal thresholds (MWT) were examined by von Frey filaments. Cold allodynia was tested by the acetone spray test. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in rat spinal cords were analyzed by the enzyme-linked immunosorbent assay, and the expression levels of c-Fos and nerve growth factor (NGF) were measured by Western blot. The expression level of glial fibrillary acidic protein (GFAP) was observed by immunofluorescence and Western blot. RESULTS: After curcumin treatment, the MWT showed a significant increase when compared to the BPA group on both hind paws. A remarkable decrease of paw-withdrawal response frequency was observed compared with the BPA group. In addition, curcumin treatment significantly decreased the levels of TNF-α and IL-6 in rat spinal cords that were exceedingly upregulated in the BPA group. The protein levels of c-Fos and NGF were decreased by treatment with curcumin compared with the corresponding protein levels in the BPA group. Besides, curcumin reduced the number of GFAP positive cells and GFAP expression. CONCLUSIONS: Our findings suggest that curcumin significantly extenuates the BPA-induced pain and inflammation by reducing the expression level of proinflammatory cytokines and pain-associated proteins and inhibiting the activity of astrocytes.

Hydromorphone protects CA1 neurons by activating mTOR pathway.

Hydromorphone has been shown to play protective effect in rat glial cell. However, whether hydromorphone plays important roles in ischemia-reperfusion (IR) injury and the involved signaling pathway remains unclear. In this study, we detected whether HM plays protective effect in IR injury mouse model, further followed by the mechanism exploration. Preconditioning with hydromorphone was performed for continuous 4 days at the doe of 2 mg/kg before IR injury induction. Intraperitoneal injection of rapamycin (Rapa) was administrated to examine the role of mTOR in IR injury. The mRNA expression level was detected by RT-PCR, and protein expression level was detected by western blot. Latency time and apoptosis of hippocampal CA1 neurons were detected 72 h after IR injury induction. Preconditioning with hydromorphone significantly increased Latency time, decreased apoptosis of hippocampal CA1 neurons and suppressed IR induced oxidative stress. Mechanically, preconditioning with hydromorphone increased Bcl-2 and p-mTOR expression levels and decreased Bax expression levels. Rapa administration reverses the role of hydromorphone in protecting hippocampal CA1 neurons from IR injury. Hydromorphone protect hippocampal CA1 neurons from IR injury via activating mTOR signaling pathway.

Comparison of neurotoxicity of dexmedetomidine as an adjuvant in brachial plexus block in rats of different age.

Dexmedetomidine is a local anesthetic adjuvant that exerts neuroprotective effects in addition to its sedative and analgesic properties. However, it is not clear whether dexmedetomidine causes any neurotoxicity in neonates. We injected dexmedetomidine alone or in combination with ropivacaine to induce brachial plexus block in rats of different age, corresponding to human neonate, childhood, adolescence and adulthood. We then examined pro-inflammatory cytokines and activated caspase 3 to determine the neurotoxicity effects. We found that high dose of dexmedetomidine significantly reduced IL-6 and TNF-α levels in all aged rat brachial plexus compared to saline treatment, and these levels are similar to that of control brachial plexus at postnatal day 14, 18 and adulthood. Caspase 3 level is not significantly different between dexmedetomidine and control group, except that it is higher in dexmedetomidine treated group at postnatal day 5. We found that this neurotoxicity effect of dexmedetomidine is only present at a high dose. Dexmedetomidine shows minimal neurotoxicity in neonate rats during brachial plexus block when moderate doses are administered. This observation warrants more detailed clinical studies to determine the safety of using dexmedetomidine for brachial plexus block in infant or early childhood patients.

Apigenin attenuates isoflurane-induced cognitive dysfunction via epigenetic regulation and neuroinflammation in aged rats.

PURPOSE OF THE RESEARCH: Post operational cognitive dysfunction (POCD) occurs in patients after anesthesia and surgery. Abnormal histone acetylation and neuroinflammation are key factors in the pathogenesis of cognitive impairment. Apigenin not only has an anti-inflammatory activity but also modifies histone acetylation. We aimed to investigate whether apigenin can attenuate isoflurane exposure-induced cognitive decline by regulating histone acetylation and inflammatory signaling. MATERIALS AND METHODS: Spatial learning and memory were assessed by Morris water maze test. Levels of histone acetylation, BDNF and downstream signaling, and inflammatory components were analyzed. PRINCIPAL RESULTS: Isoflurane exposure in aged rats lead to impaired spatial learning and memory. These rats exhibited dysregulated histone H3K9 and H4K12 acetylation, which was accompanied by reduced BDNF expression and suppressed BDNF downstream signaling pathway. Apigenin restored histone acetylation and BDNF signaling. Apigenin also suppressed isoflurane exposure induced upregulation of proinflammatory cytokines and NFκB signaling pathway. MAJOR CONCLUSIONS: Memory impairment induced by isoflurane exposure is associated with dysregulated histone acetylation in the hippocampus, which affects BDNF expression and hence BDNF downstream signaling pathway. Apigenin recovers cognitive function by restoring histone acetylation and suppressing neuroinflammation.

Melanocortin-4 receptor expression in autonomic circuitry involved in gastric function.

Several studies have shown that CNS provides the regulation of gastric functions. Recent evidence indicated that the activation of melanocortin 4 receptors (MC4R) in brain nuclei played an important role in modulating gastric activity. This study was designed to assess whether MC4R signaling existed in autonomic circuitry modulated the activity of stomach by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV)-614 was injected into the ventral stomach wall in adult male MC4R-green fluorescent protein (GFP) transgenic mice (n = 5). After a survival time of 5 days, the mice were assigned to humanely sacrifice, and spinal cords and caudal brainstem were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the stomach were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML and the dorsal motor nucleus of the vagus nerve (DMV). Our findings support the hypothesis that MC4R signaling in autonomic circuitry may participate in the modulation of gastric activity by the melanocortinergic-sympathetic pathway or melanocortinergic-parasympathetic pathway.