miR­3120/Hsc70 participates in forced swim stress­induced mechanical hyperalgesia in rats in an inflammatory state.

The heat shock cognate 71 kDa protein (Hsc70) is a stress­inducible ATPase that can protect cells against harmful stimuli. Transient receptor potential vanilloid 1 (TRPV1) is a well­documented nociceptor. Notably, Hsc70 can inhibit TRPV1 expression and function, suggesting that Hsc70 may have pain regulation potential. However, the role of Hsc70 in stress­induced hyperalgesia remains unclear. In the present study, the participation of Hsc70 and its regulator microRNA (miR)­3120 were investigated in forced swim (FS) stress­induced mechanical hyperalgesia in rats in an inflammatory state. Complete Freund's adjuvant (CFA) hind paw injection was performed to induce inflammatory pain in rats (CFA rats). Furthermore, in FS + CFA rats, FS stress was performed for 3 days before CFA injection. The levels of Hsc70, miR­3120 and their downstream molecule TRPV1 were measured in the dorsal root ganglion (DRG) with western blotting, immunofluorescence, reverse transcription­quantitative polymerase chain reaction and fluorescence in situ hybridization. The results revealed that FS stress significantly exacerbated CFA­induced mechanical pain. Furthermore, CFA upregulated Hsc70 and TRPV1 expression, which was partially inhibited or further enhanced by FS stress, respectively. In FS + CFA rats, intrathecal injection of a lentiviral vector overexpressing Hsc70 (LV­Hsc70) could decrease TRPV1 expression and improve the mechanical pain. Additionally, the expression levels of miR­3120, a regulator of Hsc70, were markedly upregulated on day 3 following FS stress. Finally, miR­3120 was identified to be colocalized with Hsc70 and expressed in all sizes of DRG neurons. In CFA rats, DRG injection of miR­3120 agomir to induce overexpression of miR­3120 resulted in similar TRPV1 expression and behavioral changes as those caused by FS stress, which were abolished in the presence of LV­Hsc70. These findings suggested that miR­3120/Hsc70 may participate in FS stress­induced mechanical hyperalgesia in rats in an inflammatory state, possibly via disinhibiting TRPV1 expression in the DRG neurons.

Pathogenetic detection, retrospective and pathogenicity analysis of a fatal case of Vibrio vulnificus in Shenzhen, China.

We report a 36-year-old male patient died of V. vulnificus-induced septicaemia and multiple organ failure syndrome after oyster consumption at a restaurant. We isolated and identified V. vulnificus vv16015 from the patient's blood sample and antibiotic susceptibility tests indicated sensitivity to all 21 antibiotics. Oyster samples were subsequently collected from the restaurant's supplier and three strains of V. vulnificus were isolated. Whole genome sequencing and analysis revealed vv16015 to be distantly related to these strains and confirmed that V. vulnificus contamination was present in the seafood of the restaurant and supplier. Using a Galleria mellonella larvae infection model, the virulence of vv16015 was determined to be higher than that of comparison strains isolated from a surviving patient (vv15018) and an oyster (vv220015). The human and environment distribution of V. vulnificus in Shenzhen is sporadic and heterogeneous, and vv16015 is highly virulent compared to other strains.

Research Trends and Hot Spots of Allopregnanolone Research in the Last 20 Years: A Bibliometric Analysis.

Background: Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABAA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years. Methods: We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/). Results: A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included "depression", "postpartum depression", "GABAA receptor", and so on. Conclusion: Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.

Distribution of drug-resistant genes in alveolar lavage fluid from patients with psittacosis and traceability analysis of causative organisms.

Background: Chlamydia psittaci is a small bacterium often found in birds, including poultry, and domesticated mammals, which causes psittacosis (or parrot fever) in humans. Different strains of C. psittaci respond variably to antibiotics, suggesting a possible risk of antibiotic resistance. In general, different genotypes of C. psittaci have relatively stable hosts and different pathogenicity. Methods: Macrogenomic sequencing was performed using nucleic acids extracted from psittacosis patients' alveolar lavage fluid samples and analyzed for genetic variability and antibiotic resistance genes. Nucleic acid amplification sequences specific to the core coding region of the C. psittaci ompA gene were used, and a phylogenetic tree was constructed with C. psittaci genotypic sequences from other sources, including Chinese published sources. The C. psittaci found in each patient were genotyped by comparing ompA gene sequences. In addition, to better illustrate the relationship between genotype and host of C. psittaci, 60 bird fecal samples were collected from bird-selling stores for screening and C. psittaci typing. Results: Macrogenomic sequence alignment revealed the presence of resistance genes in varying abundance in samples from all three patients, including C. psittaci resistance gene sequences from two patients that matched those previously published on NCBI. Based on ompA genotyping, two patients were infected with C. psittaci genotype A and one patient was infected with genotype B. All five C. psittaci-positive samples obtained from bird-selling stores were genotype A. Both genotypes are reported to be infectious to humans. The host origin of the samples and the previously reported main sources of each genotype suggested that all but one of the C. psittaci genotype A in this study were derived from parrots, while genotype B was probably derived from chickens. Conclusion: The presence of bacterial resistance genes in psittacosis patients may affect the efficacy of clinical antibiotic therapy. Focusing on the developmental progression of bacterial resistance genes and differences in the therapeutic efficacy may facilitate effective treatment of clinical bacterial infections. Pathogenicity genotypes (e.g., genotype A and genotype B) are not limited to one animal host, suggesting that monitoring the development and changes of C. psittaci may help prevent transmission to humans.

Satellite glial cell-secreted exosomes after in-vitro oxaliplatin treatment presents a pro-nociceptive effect for dorsal root ganglion neurons and induce mechanical hypersensitivity in naïve mice.

BACKGROUND: The pathophysiological mechanism underlying chemotherapy-induced neuropathic pain (CINP) remains unclear. Sensory neuronal hypersensitivity in the dorsal root ganglion (DRG) is essential for the onset and maintenance of chronic pain. Satellite glial cells (SGCs) in the DRG potentially affect the function of sensory neurons, possibly by mediating extracellular or paracrine signaling. Exosomes play an essential role in cell-cell communication. However, the role of SGC-secreted exosomes in glia-neuron communication and CINP remains unclear. METHODS: SGCs and sensory neurons were cultured from the DRG of mice. The SGCs were treated with 4 µM oxaliplatin for 24 h. Glial fibrillary acid protein (GFAP) and connexin-43 (Cx-43) expressions in the SGCs were examined with immunocytochemistry (ICC). Enzyme-linked immunosorbent assay (ELISA) detected cytokine release in the SGCs after oxaliplatin treatment. Subsequently, SGC-secreted exosomes were collected using ultracentrifugation and identified by nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Subsequently, DRG neurons were incubated with SGC-secreted exosomes for 24 h. The percentage of reactive oxygen species (ROS)-positive neurons was detected using flow cytometry, and acid-sensing ion channel 3 (ASIC3) and transient receptor potential vanilloid 1 (TRPV1) expression were examined by western blotting. SGC-secreted exosomes were intrathecally injected into naïve mice. The mechanical withdrawal threshold was assessed 24, 48, and 72 h following the injection. TRPV1 expression in the DRG was examined 72 h after intrathecal injection. Furthermore, differentially expressed (DE) miRNAs within the SGC-secreted exosomes were detected using RNA sequencing and bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses were performed to predict the function of the target genes of DE miRNAs. Finally, the DE miRNAs with pain regulation potential were identified in silico. RESULTS: After in-vitro oxaliplatin treatment, ICC showed an increase in the immunoreactivity of GFAP and Cx-43 in the SGCs. ELISA results suggested an increased release of tumor necrosis factor-α and interleukin (IL)-1ß, but a decreased release of IL-10. Oxaliplatin treatment increased the secretion of exosomes in the SGCs from 4.34 to 5.99 × 1011 (particles/ml). The exosome-specific markers CD9 and TSG101 were positive, whereas calnexin was negative for the obtained exosomes. Additionally, the SGC-secreted exosomes were endocytosed by DRG neurons after co-incubation. Moreover, after incubation with conditioned SGC-secreted exosomes (after 4 µM oxaliplatin treatment), the percentage of ROS-positive DRG neurons increased and ASIC3 and TRPV1 expressions were upregulated. After the intrathecal injection of the conditioned SGC-secreted exosomes, the mice presented with mechanical hypersensitivity and TRPV1 expression upregulation in the DRG. Notably, 25 and 120 significantly upregulated and downregulated miRNAs, respectively, were identified in the conditioned SGC-secreted exosomes. When predicting the function of target genes of DE miRNAs, certain GO terms, such as synapse organization, neurogenesis regulation, histone modification, and pain-related KEGG or Reactome pathways, including vascular endothelial growth factor A-vascular endothelial growth factor receptor 2, mammalian target of rapamycin, and mitogen-activated protein kinase signaling pathways, related to nervous system function were predicted. Finally, 27 pain regulation-related miRNAs, including miR-324-3p, miR-181a-5p, and miR-122-5p, were identified in silico. CONCLUSION: Our study demonstrates that SGC-secreted exosomes after in-vitro oxaliplatin treatment present a pro-nociceptive effect for DRG neurons and induce mechanical hypersensitivity in naïve mice, possibly via the contained miRNA cargo. Identifying the candidate miRNAs and verifying their functions in vivo are required to elucidate the exosomes mediating 'glia-neuron' communication under CINP condition.

Epidemiological and genomic analyses of human isolates of Streptococcus suis between 2005 and 2021 in Shenzhen, China.

Streptococcus suis (S. suis) is an important food-borne zoonotic pathogen that causes swine streptococcosis, which threatens human health and brings economic loss to the swine industry. Three-quarters of human S. suis infections are caused by serotype 2. A retrospective analysis of human S. suis cases in Shenzhen, a megacity in China, with high pork consumption, between 2005 and 2021 was conducted to understand its genomic epidemiology, pathogen virulence, and drug resistance characteristics. The epidemiological investigation showed that human cases of S. suis in Shenzhen were mainly associated with people who had been in close contact with raw pork or other swine products. Whole-genome sequence analysis showed that 33 human isolates in Shenzhen were dominated by serotype 2 (75.76%), followed by serotype 14 (24.24%), and the most prevalent sequence types (STs) were ST7 (48.48%) and ST1 (39.40%). ST242 (9.09%) and ST25 (3.03%), which were rarely reported, were also found. Phylogenetic analysis showed that the Shenzhen human isolates had close genetic relatedness to isolates from Guangxi (China), Sichuan (China), and Vietnam. We found a new 82 KB pathogenicity island (PAI) in the serotype 2 isolate that may play a role in sepsis. Similarly, a serotype 14 isolate, containing 78 KB PAI, was isolated from a patient presenting with streptococcal toxic shock syndrome (STSLS) who subsequently died. Multi-drug resistance (MDR) was high in human isolates of S. suis from Shenzhen. Most human isolates were resistant to tetracycline, streptomycin, erythromycin, and clindamycin, and 13 isolates had intermediate resistance to penicillin. In conclusion, swine importation from Guangxi, Sichuan, and Vietnam should be more closely monitored, and the use of antibiotics limited to reduce the potential for antimicrobial resistance (AMR).

The role of green financing to enhance tourism growth by mitigating carbon emission in China.

The tourism industry has undergone rapid inquiry in modern times. Based on climatic importance, current research intends to inquire about the role of green financing in enhancing tourism growth by mitigating carbon emissions in China. The study used Data Envelopment Analysis to infer the efficiency of the study model in the study context based on research topicality. Our findings highlighted that China's local tourism destination, renowned for its health and wellness tourism, indicated tourist inspiration to visit climate-supporting visit stations. Study results extended that using green financing for climate change mitigation in a Chinese tourist destination is essential. Empirical results confirmed that green funding directly mitigated climate change and enhanced tourism growth in Chinese settings by solving related issues. On such findings, the study yielded the practical implications for green financing institutions, climate change policymakers and Chinese officials for tourism development.

Pathogenetic characterization of a Micrococcus luteus strain isolated from an infant.

Purpose: To explore the clinical characteristics of Micrococcus luteus bloodstream infection in an infant and characterize the phenotype and genotype of the isolated strains, as well as seek suitable infection models for assessing virulence. Methods: Clinical data was collected from an infant patient diagnosed with M. luteus bloodstream infection. Metagenomic sequencing was performed on the isolated blood sample. The strain was isolated and underwent mass spectrometry, biochemical tests, antibiotic susceptibility assays, and whole-genome sequencing. The Galleria mellonella infection model was used to assess M. luteus virulence. Results: Patient responded poorly to cephalosporins, but recovered after Linezolid treatment. Metagenomic sequencing identified M. luteus as the predominant species in the sample, confirming infection. They were identified as M. luteus with a high confidence level of 98.99% using mass spectrometry. The strain showed positive results for Catalase, Oxidase, and Urea tests, and negative results for Mannose, Xylose, Lactose, Mannitol, Arginine, and Galactose tests, consistent with the biochemical profile of M. luteus reference standards. M. luteus susceptibility to 15 antibiotics was demonstrated and no resistance genes were detected. Predicted virulence genes, including clpB, were associated with metabolic pathways and the type VI secretion system. The infection model demonstrated dose-dependent survival rates. Conclusion: The infant likely developed a bloodstream infection with M. luteus due to compromised immunity. Although the isolated strain is sensitive to cephalosporin antibiotics and has low pathogenicity in infection models, clinical treatment with cephalosporins was ineffective. Linezolid proved to be effective, providing valuable guidance for future clinical management of such rare infections.

Concomitant Gastric Acid Suppressants on the Survival of Patients with Non-Small-Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis.

Background: The influence of concomitant use of gastric acid suppressants (AS) on survival of patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inconsistent according to previous studies. We performed a meta-analysis to evaluate the effect of additional AS in patients with NSCLC taking TKIs. Methods: Relevant observational studies were identified by a search of Medline, Embase, and Web of Science databases. Only studies with multivariate analyses were included. A random-effect model was used to combine the results. Results: Thirteen retrospective studies with 12259 patients were included. Pooled results showed that concomitant use of AS was associated with worse progression-free survival (PFS, adjusted hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.31 to 1.89, P < 0.001; I 2 = 65%) and overall survival (OS, adjusted HR: 1.38, 95% CI: 1.19 to 1.61, P < 0.001; I 2 = 70%) in NSCLC patients taking TKIs. Sensitivity analysis limited to studies including NSCLC with EGFR mutation showed consistent results (HR for PFS: 1.53, P=0.003; HR for OS: 1.43, P=0.001). Subgroup analyses indicated that the association between concomitant use of AS and poor survival was not significantly affected by the category of AS used (proton pump inhibitors or histamine type-2 receptor antagonists) or the country of the study (Asian or non-Asian, P for subgroup analysis all >0.05). Conclusions: Concomitant use of AS in patients with NSCLC taking TKIs may be associated with poor survival outcomes.

Downregulation of microRNA­29c reduces pain after child delivery by activating the oxytocin­GABA pathway.

A significant decrease in the expression of spinal microRNA­29c (miR­29c), which is responsible for the regulation of oxytocin receptor (OXTR) expression, was observed in nerve injury pain during childbirth. The present study investigates whether spinal miR­29c could be a potential target for the treatment of pain, via the oxytocin (OT)­Î³­aminobutyric acid (GABA) pathway. A spared nerve injury (SNI) rat model was established to induce neuropathic pain, simulating hyperalgesia. Spinal neurons were treated with OT to mimic the hormonal changes in the central nervous system after delivery. A change in the neuronal miniature inhibitory postsynaptic currents (mIPSCs) was observed in neurons, following the silencing of miR­29c or OT treatment with or without OXTR antagonist. The Von­Frey apparatus was used to measure the animal behaviors. Molecular biological experiments and electrophysical recordings in vivo and in vitro were performed to reveal the potential analgesic mechanisms. miR­29c was significantly downregulated (more than 8­fold) in the spinal dorsal horn of delivery+SNI rats compared with the SNI rats. The silencing of miR­29c resulted in increased pain threshold in SNI rats. Bioinformatics analysis indicated that OXTR was a potential target gene of miR­29c. The delivery+SNI rats presented with higher levels of OT in the cerebrospinal fluid compared with SNI rats, which indicated that the OT signaling pathway may participate in pain relief response. The increased expression of OXTR and GABA in delivery+SNI rats were observed in the miR­29c­silenced SNI rat model, suggesting that the silencing of miR­29c can mediate pain relief by enhancing the OT­GABA pathway. In addition, an electrophysiology assay was performed to assess the mIPSCs in neurons. The silencing of miR­29c in neurons increased the frequency and amplitude of mIPSCs but there was no influence on the decay time, which suggested that the spinal inhibitory neurons became more active, subsequently reducing the feeling of pain. The inhibition of OXTR reversed the enhanced inhibitory postsynaptic currents, indicating a crucial role for OXTR in the miR­29c­associated pain regulation. Taken together, the results of the present study suggested that spinal oxytocinergic inhibitory control plays an important role in pain relief in the neuropathic pain rat model undergoing vaginal delivery. Silencing spinal miR­29c may be a potential target for pain relief through the OT­GABA pathway.

Concerned topics of epidural labor analgesia: labor elongation and maternal pyrexia: a systematic review.

OBJECTIVE: Labor is a complex process and labor pain presents challenges for analgesia. Epidural analgesia (EA) has a well-known analgesic effect and is commonly used during labor. This review summarized frequently encountered and controversial problems surrounding EA during labor, including the labor process and maternal intrapartum fever, to build knowledge in this area. DATA SOURCES: We searched for relevant articles published up to 2019 in PubMed using a range of search terms (eg, "labor pain," "epidural," "analgesia," "labor process," "maternal pyrexia," "intrapartum fever"). STUDY SELECTION: The search returned 835 articles, including randomized control trials, retrospective cohort studies, observational studies, and reviews. The articles were screened by title, abstract, and then full-text, with a sample independently screened by two authors. Thirty-eight articles were included in our final analysis; 20 articles concerned the labor process and 18 reported on maternal pyrexia during EA. RESULTS: Four classic prospective studies including 14,326 participants compared early and delayed initiation of EA by the incidence of cesarean delivery. Early initiation following an analgesia request was preferred. However, it was controversial whether continuous use of EA in the second stage of labor induced adverse maternal and neonatal outcomes due to changes in analgesic and epidural infusion regimens. There was a high incidence of maternal pyrexia in women receiving EA and women with placental inflammation or histologic chorioamnionitis compared with those receiving systemic opioids. CONCLUSIONS: Early EA (cervical dilation ≥1 cm) does not increase the risk for cesarean section. Continuous epidural application of low doses of analgesics and programmed intermittent epidural bolus do not prolong second-stage labor duration or impact maternal and neonatal outcomes. The association between EA and maternal pyrexia remains controversial, but pyrexia is more common with EA than without. A non-infectious inflammatory process is an accepted mechanism of epidural-related maternal fever.

Bolus norepinephrine and phenylephrine for maternal hypotension during elective cesarean section with spinal anesthesia: a randomized, double-blinded study.

BACKGROUND: In recent years, norepinephrine has attracted increasing attention for the management of maternal hypotension during elective cesarean section with spinal anesthesia. Intermittent bolus is a widely used administration paradigm for vasopressors in obstetric anesthesia in China. Thus, in this randomized, double-blinded study, we compared the efficacy and safety of equivalent bolus norepinephrine and phenylephrine for rescuing maternal post-spinal hypotension. METHODS: In a tertiary women's hospital in Nanjing, China, 102 women were allocated with computer derived randomized number to receive prophylactic 8 µg norepinephrine (group N; n = 52) or 100 µg phenylephrine (group P; n = 50) immediately post-spinal anesthesia, followed by an extra bolus of the same dosage until delivery whenever maternal systolic blood pressure became lower than 80% of the baseline. Our primary outcome was standardized maternal cardiac output (CO) reading from spinal anesthesia until delivery analyzed by a two-step method. Other hemodynamic parameters related to vasopressor efficacy and safety were considered as secondary outcomes. Maternal side effects and neonatal outcomes were collected as well. RESULTS: Compared to group P, women in group N had a higher CO (standardized CO 5.8 ±â€Š0.9 vs. 5.3 ±â€Š1.0 L/min, t = 2.37, P = 0.02) and stroke volume (SV, standardized SV 73.6 ±â€Š17.2 vs. 60.0 ±â€Š13.3 mL, t = 4.52, P < 0.001), and a lower total peripheral resistance (875 ±â€Š174 vs. 996 ±â€Š182 dyne·s/cm, t = 3.44, P < 0.001). Furthermore, the incidence of bradycardia was lower in group N than in group P (2% vs. 14%, P = 0.023), along with an overall higher standardized heart rate (78.8 ±â€Š11.6 vs. 75.0 ±â€Š7.3 beats/min, P = 0.049). Other hemodynamics, as well as maternal side effects and neonatal outcomes, were similar in two groups (P > 0.05). CONCLUSIONS: Compared to equivalent phenylephrine, intermittent bolus norepinephrine provides a greater CO for management of maternal hypotension during elective cesarean section with spinal anesthesia; however, no obvious maternal or neonatal clinical advantages were observed for norepinephrine.

A randomized double-blind study comparing prophylactic norepinephrine and ephedrine infusion for preventing maternal spinal hypotension during elective cesarean section under spinal anesthesia: A CONSORT-compliant article.

BACKGROUND: Studies have shown the efficacy of norepinephrine in the treatment of maternal hypotension during cesarean section by comparing it to treatment with phenylephrine. However, few studies have compared the efficacy of norepinephrine to ephedrine. METHODS: Ninety-seven women undergoing elective cesarean section were administered norepinephrine at 4 µg/minute (group N; n = 48) or ephedrine at 4 mg/minute (group E; n = 49) immediately postspinal anesthesia, with an on-off titration to maintain systolic blood pressure (SBP) at 80% to 120% of baseline. A rescue bolus of 8 µg norepinephrine was given whenever SBP reached the predefined lower limit. Our primary outcome was the incidence of tachycardia. Secondary outcomes included the incidence of bradycardia, hypertension, hypotension, severe hypotension, hypotensive episodes, number of rescue top-ups, hemodynamic performance error including median performance error (MDPE), and median absolute performance error (MDAPE). Neonatal Apgar scores and umbilical arterial (UA) blood gas data were also collected. RESULTS: Women in group N experienced fewer cases of tachycardia (4.2% vs 30.6%, P = .002, odds ratio: 0.11 [95% confidence interval, CI: 0.02-0.47]), a lower standardized heart rate (HR) (70.3 ±â€Š11 vs 75 ±â€Š11, P = .04, difference: 4.7 ±â€Š2.2 [95% CI: 0.24-9.1]), and a lower MDPE for HR (1.3 ±â€Š9.6 vs 8.4 ±â€Š13.5 bpm, P = .003, difference: 3.1 ±â€Š1.8 [95% CI: -0.6-6.7]). In addition, the lowest or the highest HR was lower in group N compared to group E (both P < .05). Meanwhile, the standardized SBP in group N was lower than that in group E (P = .04). For neonates, the UA blood gas showed a higher base excess (BE) and a lower lactate level in group N compared to E (both P < .001). Other hemodynamic variables, maternal, and neonatal outcomes were similar. CONCLUSION: Infusion of 4 µg/minute norepinephrine presented fewer cases of tachycardia, less fluctuation and a lower HR compared to baseline values, as well as a less stressed fetal status compared to ephedrine infusion at 4 mg/minute. In addition, norepinephrine infusion presented a lower standardized SBP compared to ephedrine.

PTEN-Induced Putative Kinase 1 (PINK1)/Parkin-Mediated Mitophagy Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity.

BACKGROUND The pathogenesis of chemotherapy-induced neuropathy, a dose-dependent adverse effect of cisplatin, involves mitochondrial dysfunction. PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy removes damaged mitochondria under various pathological conditions. The objective of this study was to determine mitophagy status and its effects on mitochondrial function and neuronal cell damage after cisplatin treatment using an in vitro model of cisplatin-induced neurotoxicity. MATERIAL AND METHODS PC12 cells were transfected with Parkin or Parkin siRNA using lentiviral particles and Lipofectamine 3000™, respectively, and then were exposed to 10 µM cisplatin. The expression of autophagic proteins was measured by Western blot analysis. Mitophagy in PC12 cells was detected by confocal microscopy analysis of mitochondria-lysosomes colocalization and autophagic flux. The effects of PINK1/Parkin-mediated mitophagy on cisplatin-induced neurotoxicity were assessed via mitochondrial function, neuritic length, nuclear diameter, and apoptosis. RESULTS Cisplatin activated PINK1/Parkin-mediated mitophagy in PC12 cells. Autophagic flux analysis revealed that cisplatin inhibits the late stage of the autophagic process. The knockdown of Parkin suppressed cisplatin-induced mitophagy, aggravating cisplatin-induced depolarization of mitochondria, cellular ATP deficits, reactive oxygen species outburst, neuritic shortening, nuclear diameter reduction, and apoptosis, while Parkin overexpression enhanced mitophagy and reversed these effects. CONCLUSIONS PINK1/Parkin-regulated mitophagy can protect against cisplatin-related neurotoxicity, suggesting therapeutic enhancement of mitophagy as a potential intervention for cisplatin-induced peripheral neuropathies. The interference of cisplatin with autophagosome-lysosome fusion may be partly responsible for cisplatin-induced neurotoxicity.

The etiological contribution of GABAergic plasticity to the pathogenesis of neuropathic pain.

Neuropathic pain developing after peripheral or central nerve injury is the result of pathological changes generated through complex mechanisms. Disruption in the homeostasis of excitatory and inhibitory neurons within the central nervous system is a crucial factor in the formation of hyperalgesia or allodynia occurring with neuropathic pain. The central GABAergic pathway has received attention for its extensive distribution and function in neural circuits, including the generation and development of neuropathic pain. GABAergic inhibitory changes that occur in the interneurons along descending modulatory and nociceptive pathways in the central nervous system are believed to generate neuronal plasticity, such as synaptic plasticity or functional plasticity of the related genes or proteins, that is the foundation of persistent neuropathic pain. The primary GABAergic plasticity observed in neuropathic pain includes GABAergic synapse homo- and heterosynaptic plasticity, decreased synthesis of GABA, down-expression of glutamic acid decarboxylase and GABA transporter, abnormal expression of NKCC1 or KCC2, and disturbed function of GABA receptors. In this review, we describe possible mechanisms associated with GABAergic plasticity, such as central sensitization and GABAergic interneuron apoptosis, and the epigenetic etiologies of GABAergic plasticity in neuropathic pain. Moreover, we summarize potential therapeutic targets of GABAergic plasticity that may allow for successful relief of hyperalgesia from nerve injury. Finally, we compare the effects of the GABAergic system in neuropathic pain to other types of chronic pain to understand the contribution of GABAergic plasticity to neuropathic pain.

RNA-Sequencing and Bioinformatics Analysis of Long Noncoding RNAs and mRNAs in the Prefrontal Cortex of Mice Following Repeated Social Defeat Stress.

BACKGROUND: Repeated or continuous chronic psychological stress may induce diverse neuropsychiatric disorders; however, the underlying mechanisms remain unclear. In this study, we explored the expression profiles of long noncoding RNAs (lncRNAs) and mRNAs, along with their biological function and regulatory network, in mice after repeated social defeat (RSD) stress to explore their potential involvement in the development of anxiety-like behaviors. MAIN METHODS: RNA-sequencing was used to screen all differentially expressed (DE) lncRNAs and mRNAs between the RSD and control groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for confirmation of the RNA-sequencing results. The function of DE lncRNAs was predicted by Gene Ontology (GO) enrichment and pathway analyses of target mRNAs. In addition, the functional regulatory network of the target mRNAs was constructed to reveal potential relationships between lncRNAs and their target genes with bioinformatics approaches. KEY FINDINGS: In mice experiencing RSD, 373 and 454 lncRNAs, along with 1142 and 654, mRNAs were significantly upregulated and downregulated, respectively. The detailed regulatory network included 126 eligible lncRNA-mRNA pairs. Among them, 14 genes such as Arhgef1, Chchd2, Fam107a, Dlg1, Nova2, Dpf1, and Shank3 involved in neurite growth, neural development, and synaptic plasticity were direct targets of the DE lncRNAs. qRT-PCR of four of the DE lncRNAs and mRNAs confirmed the reliability of RNA-sequencing. GO clustering analyses showed that the top enriched biological process, cellular component, and molecular function terms were synaptic transmission, neuron spine, and glutamate receptor binding, respectively. Further, the top three significant enriched pathways were synaptic adhesion-like molecule (SALM) protein interactions at the synapses, trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as glutamate binding, activation of AMPA receptors, and synaptic plasticity. SIGNIFICANCE: Hundreds of lncRNAs and mRNAs are dysregulated after RSD, and many of these lncRNAs might participate in the development of anxiety-like behaviors via multiple complex mechanisms such as target regulation. Available informatics evidence highlighted the likely role of synapse dysfunction and abnormal synaptic neurotransmission in these behaviors. Thus, our findings provide potential candidate biomarkers or intervention targets for chronic psychological stress-induced neuropsychiatric disorders.

A Comparative Study of Bolus Norepinephrine, Phenylephrine, and Ephedrine for the Treatment of Maternal Hypotension in Parturients with Preeclampsia During Cesarean Delivery Under Spinal Anesthesia.

BACKGROUND This study aimed to compare the efficacy and safety of bolus norepinephrine, phenylephrine, and ephedrine in parturient with preeclampsia who had hypotension during cesarean delivery under spinal anesthesia. MATERIAL AND METHODS One hundred and sixty-six parturient women with preeclampsia who had a baseline systolic blood pressure (SBP) <80% during spinal anesthesia for cesarean section were divided into three treatment groups; bolus norepinephrine 4 µg (group N) (n=56), phenylephrine 50 µg (group P) (n=55), and ephedrine 4 mg (group E) (n=55). Primary outcomes included overall SBP and heart rate (HR) until delivery. Secondary outcomes included the incidence of tachycardia (HR >120 bpm), bradycardia (HR <60 bpm), hypertension (SBP >120% baseline), number of boluses of vasopressor required and episodes of hypotension, maternal side effects, and neonatal outcome. RESULTS Overall HR in group N was significantly increased compared with group P (80.5±12 vs. 76.6±6.9 bpm; P=0.04), and significantly lower compared with group E (80.5±12 vs. 84.9±7.1 bpm; P=0.02). Parturients in group N had fewer episodes of bradycardia compared with group P (3.6% vs. 21.8%; RR=0.26l; 95% CI, 0.07-0.73; P=0.004) and fewer episodes of tachycardia compared with group E (16.1% vs. 36.4%; RR 0.54; 95% CI, 0.29-0.90; P=0.02). CONCLUSIONS A bolus dose of norepinephrine showed similar efficacy to phenylephrine but improved maternal and neonatal safety in parturients with preeclampsia with hypotension during cesarean section under spinal anesthesia.

Efficacy and safety of norepinephrine versus phenylephrine for the management of maternal hypotension during cesarean delivery with spinal anesthesia: A systematic review and meta-analysis.

BACKGROUND: Phenylephrine is the current "gold standard' vasopressor used to treat maternal hypotension in women undergoing cesarean delivery with spinal anesthesia. Since 2015, various studies have explored the use of norepinephrine to manage maternal hypotension. We conducted this systematic review and meta-analysis of available randomized controlled trials (RCTs) to compare the efficacy and safety of norepinephrine and phenylephrine for the prevention and treatment of maternal hypotension. METHODS: A systematic literature search was conducted using electronic databases, including PubMed, MEDLINE, Embase (Embase.com), and the Cochrane CENTRAL register of controlled trials. Parturients underwent cesarean delivery with spinal anesthesia and received norepinephrine to prevent or treat hypotension were considered. Maternal outcomes, including incidences of hypotension, hypertension, bradycardia, intraoperative nausea and vomiting (IONV), maternal cardiac output (CO), and blood pressure (BP) control precision, as well as neonatal Apgar scores and umbilical cord blood analyses, were compared between groups. RESULTS: Three RCTs in 4 reports published between 2015 and 2018 were finally identified with a total of 294 parturients. We found there was no difference in effectiveness between norepinephrine and phenylephrine for the treatment of maternal hypotension (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.37-1.10, P = .11), and there was no difference in the occurrence of hypertension (OR 0.74; 95% CI 0.33-1.62, P = .45). Of note, compared to the phenylephrine group, parturients in the norepinephrine group were less likely to experience bradycardia (OR 0.29; 95% CI 0.12-0.68, P = .005) and IONV (OR 0.54; 95% CI, 0.29-0.99, P = .04). Further, we did not observe a difference between the two vasopressors in the incidence of neonatal Apgar scores < 7 at 1  and 5 minutes or in umbilical vein (UV) blood gas. However, evidence is insufficient to draw conclusions regarding the greater maternal CO and better BP control precision with the use of norepinephrine. CONCLUSION: This systematic review and meta-analysis shows norepinephrine provides similar efficacy to manage maternal hypotension compared to phenylephrine; additionally, showing advantage regarding certain side effects like bradycardia and IONV reduction. Accordingly, norepinephrine is a promising alternative to phenylephrine. However, before routine clinical application, more studies are warranted.

The etiological changes of acetylation in peripheral nerve injury-induced neuropathic hypersensitivity.

Neuropathic pain is a common chronic pain condition with mechanisms far clearly been elucidated. Mounting preclinical and clinical studies have shown neuropathic pain is highly associated with histone acetylation modification, which follows expression regulation of various pain-related molecules such as mGluR1/5, glutamate aspartate transporter, glutamate transporter-1, GAD65, Nav1.8, Kv4.3, µ-opioid receptor, brain-derived neurotrophic factor, and certain chemokines. As two types of pivotal enzymes involved in histone acetylation, histone deacetylases induce histone deacetylation to silence gene expression; in contrast, histone acetyl transferases facilitate histone acetylation to potentiate gene transcription. Accordingly, upregulation or blockade of acetylation may be a promising intervention direction for neuropathic pain treatment. In fact, numerous animal studies have suggested various histone deacetylase inhibitors, Sirt (class III histone deacetylases) activators, and histone acetyl transferases inhibitors are effective in neuropathic pain treatment via targeting specific epigenetic sites. In this review, we summarize the characteristics of the molecules and mechanisms of neuropathy-related acetylation, as well as the acetylation upregulation and blockade for neuropathic pain therapy. Finally, we will discuss the current drug advances focusing on neuropathy-related acetylation along with the underlying treatment mechanisms.

Macrophage migration inhibitory factor mediates peripheral nerve injury-induced hypersensitivity by curbing dopaminergic descending inhibition.

Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1. In cultured dopaminergic neurons, rMIF enhanced the recruitment of G9a and SUV39H1, followed by an increase in H3K9me2/H3K9me3. These molecular changes correspondingly exhibited alterations in Th promoter CpG site methylation and pain behaviors. In summary, MIF functions as a braking factor in curbing dopaminergic descending inhibition in peripheral nerve injury-induced hypersensitivity by mediating Th gene methylation through G9a/SUV39H1-associated H3K9 methylation.