Breathing Behavior and Superprotonic Conductivity of Two-Dimensional Flexible Metal-Organic Frameworks Tuned with Alkoxy Groups.

Flexible metal-organic frameworks (FMOFs) exhibit reversible structural transitions ("breathing" behaviors), which can regulate the proton transport passageway effectively. This property offers remarkable advantages for improving the proton conductivity. Our objective of this work is to design a single-variable flexibility synergistic strategy for the fabrication of FMOFs with high conductivity. Herein, four two-dimensional FMOFs, {[Co(4-bpdb)(R-ip)]·xsolvents}n (x = rich, 1-4), have been successfully designed and assembled (4-bpdb = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and R-ip = MeO/EtO/n-PrO/n-BuO-isophthalate). Upon the release and/or absorption of different solvent molecules, they display reversible breathing behaviors, thereby resulting in the formation of the partial and complete solvent-free compounds {[Co(4-bpdb)(R-ip)]·ysolvents}n (y = free or poor, 1A-4A). This breathing behavior involves the synergistic self-adaption of the dynamic torsion of alkoxy groups and reversible structural transformation, leading to remarkable changes in cell parameters and void space, as evidenced by single-crystal X-ray diffraction, powder X-ray diffraction, and N2 and CO2 adsorption analyses. At 363 K and 98% relative humidity, 2A exhibits the best proton conductivity among the FMOFs. Its conductivity reaches 4.08 × 10-2 S cm-1 and is one of the highest conductivities shown by reported unmodified MOF-based proton conductors.

Investigation of Formation of Bacterial Biofilm upon Dead Siblings.

Biocides can effectively kill bacteria; however, whether the dead bacterial cells left on the surface influence the later growth of biofilm is unknown. In this study, we have cultured Pseudomonas aeruginosa (PAO1) biofilm on their dead siblings and have investigated their evolution by using magnetic force modulation atomic force microscopy (MF-AFM). The time dependence of the biofilm thickness indicates that the deposited dead siblings can slow down the growth of PAO1 biofilm. The biofilm growing on dead bacteria layers is softer in comparison with those upon alive siblings, as reflected by the static elastic modulus ( E) and dynamic stiffness ( kd) scaled to the disturbing frequency ( f) as kd = kd,0 fγ, where kd,0 is the scaling factor and γ is the power-law exponent. We reveal that the smaller population instead of the variation of extracellular polymeric substances (EPS) within the biofilm upon the dead siblings is responsible for the softer biofilm. The present study provides a better understanding of the biofilm formation, thus, making it significant for designing antimicrobial medical materials and antifouling coatings.

Longitudinal surveillance on antibiogram of important Gram-positive pathogens in Southern China, 2001 to 2015.

OBJECTIVES: A longitudinal surveillance aimed to investigate the antibiogram of three genus of important Gram-positive pathogens in Southern China during 2001-2015. METHODS: A total of 3849 Staphylococcus, Enterococcus and Streptococcus strains were isolated from Southern China during 2001-2015. Bacteria identification was performed by colony morphology, Gram staining, the API commercial kit and the Vitek 2 automated system. Antimicrobial susceptibility testing was determined by disk diffusion method and MIC method. RESULTS: As sampling site was concerned, 51.4% of Staphylococcus strains were isolated from sputum, whereas urinary tract remained the dominant infection site among Enterococcus and Streptococcus. According to the antimicrobial susceptibility, three genus of important Gram-positive pathogens showed high resistance against erythromycin, tetracycline, ciprofloxacin and clindamycin. Resistance rates to penicillins (penicillin, oxacillin, ampicillin) were high as well, with the exception of E. faecalis and Streptococcus. Overall, resistance rates against methicillin (oxacillin) were 63.2% in S. aureus and 76.2% in coagulase-negative Staphylococcus (CNS), along with continuous increases during the study. VRSA and vancomycin-resistant coagulase-negative Staphylococcus only appeared in 2011-2015. Sight decline was obtained for the vancomycin resistance of E. faecalis, while vancomycin-resistant E. faecium only appeared in 2011-2015, with its intermediate rate decreasing. Significant decrease in penicillin-resistant Streptococcus pneumonia (PRSP) was observed during studied period. Glycopeptide antibiotic remained highly effective to Staphylococcus, Enterococcus and Streptococcus (resistance rates <5%). CONCLUSIONS: Despite decline obtained for some antibiotic agents resistance during 2001-2015, antimicrobial resistance among Gram-positive pathogens still remained high in Southern China. This study may aid in the guidance for appropriate therapeutic strategy of infections caused by nosocomial pathogens.

Clinical features and antimicrobial resistance profiles of important Enterobacteriaceae pathogens in Guangzhou representative of Southern China, 2001-2015.

OBJECT: This surveillance aimed to investigate the antimicrobial resistance profiles of Enterobacteriaceae pathogens in Southern China during 2001-2015. METHODS: A total of 6858 Enterobacteriaceae isolates were collected, including 4276 E. coli, 1992 K. pneumoniae and 590 Enterobacter spp. Disk diffusion method and minimum inhibitory concentrations method were used for susceptibility testing, with results interpreted by the CLSI (2015). RESULTS: Urinary tract remained the dominant isolated site among E. coli (49.88%), whereas 53.26% K. pneumoniae and 45.25% Enterobacter spp. were from Sputum. The carbapenems maintained the highest antimicrobial activity (resistance rates <15%), followed by piperacillin-tazobactam and amikacin. Gentle increases were obtained in carbapenems-resistant K. pneumoniae and Enterobacter spp. (eg. from 4.5% to 11.2% and 3.2% to 14.5% in imipenem, repestively). The third-generation cephalosporins showed high and stable resistance among Enterobacteriaceae pathogens during the studied period, with ceftazidime as the most active third-generation cephalosporin against Enterobacteriaceae. Isolates from ICU department showed higher or similar resistance rates among Enterobacteriaceae pathogens compared to other wards. CONCLUSION: Carbapenems are the most potent antibiotic agents against Enterobacteriaceae pathogens. Due to the complicated susceptibility profiles, prescribing guidelines should be based on the knowledge of antibiogram of pathogens.

A 16-year retrospective surveillance report on the pathogenic features and antimicrobial susceptibility of Pseudomonas aeruginosa isolates from FAHJU in Guangzhou representative of Southern China.

Pseudomonas aeruginosa is a major pathogen responsible for nosocomial infections. A 16-year retrospective report from 2000 to 2015 was conducted to assess the antimicrobial resistance of P. aeruginosa in Southern China. A total of 1387 P. aeruginosa were collected from inpatients and outpatients. Susceptibility testing results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI, 2015). Piperacillin, piperacillin-tazobactam, ceftazidime, aminoglycosides and carbapenems remained to be active against P. aeruginosa, with resistance rates ranging from 5.6% to 29.7%. Generally, ampicillin, ampicillin-sulbactam, ceftriaxone and trimethoprim-sulfamethoxazole nearly lost the effect on P. aeruginosa, as the resistance rates increase up to 90%. Notably, sputum and blood specimen showed higher resistance rates than other sources in carbapenems, suggesting more caution should be paid on the choice of antibiotic against infections associated with respiratory tract.

Whole-genome resequencing of Bacillus cereus and expression of genes functioning in sodium chloride stress.

Bacillus cereus is one of the most common opportunistic pathogens responsible for various foodborn diseases. To investigate the regulatory mechanism of B. cereus under high osmotic pressure, two B. cereus strains B25 and B26 were isolated from the industrial soy sauce residue containing high-salt concentration. Resequencing was performed by Illumina/Solexa platform and 13,646 SNPs and 434 InDels were identified as common variants between B25 and B26 against reference genome, followed by COG, GO, and KEGG enrichment analysis. Furthermore, 49 key genes involving in Na+/H+,K+ transporter, dipeptide or tripeptide transporter, stress response were selected and classified into 27 groups. Further validation was performed by qRT-PCR, and 4 candidate genes were found most associated with osmotic response. Gene expression of the 4 candidate genes was then analyzed accordingly, and down regulation was obtained for gene BC0669 and BC0754 associated with K+ transport system. However, dramatic up regulation was detected for gene BC2114 involving in glutathione peroxidase, indicating the activation of antioxidant responses by osmotic stress via genetic regulation. As concluded, bioinformatic analysis and gene expression profile represented the basis of further investigation on the genetic and regulatory mechanism of bacterial salt tolerance.

Cannabidiol and its application in the treatment of oral diseases: therapeutic potentials, routes of administration and prospects.

Cannabidiol (CBD), one of the most important active ingredients in cannabis, has been reported to have some pharmacological effects such as antibacterial and analgesic effects, and to have therapeutic potential in the treatment of oral diseases such as oral cancer, gingivitis and periodontal diseases. However, there is a lack of relevant systematic research and reviews. Therefore, based on the etiology and clinical symptoms of several common oral diseases, this paper focuses on the therapeutic potential of CBD in periodontal diseases, pulp diseases, oral mucosal diseases, oral cancer and temporomandibular joint diseases. The pharmacological effects of CBD and the distribution and function of its receptors in the oral cavity are also summarized. In order to provide reference for future research and further clinical application of CBD, we also summarize several possible routes of administration and corresponding characteristics. Finally, the challenges faced while applying CBD clinically and possible solutions are discussed, and we also look to the future.

Sevoflurane causes cognitive impairment by inducing iron deficiency and inhibiting the proliferation of neural precursor cells in infant mice.

AIMS: Numerous studies on animals have shown that exposure to general anesthetics in infant stage may cause neurocognitive impairment. However, the exact mechanism is not clear. The dysfunction of iron metabolism can cause neurodevelopmental disorders. Therefore, we investigated the effect of iron metabolism disorder induced by sevoflurane (Sev) on cognitive function and the proliferation of neural precursor cells (NPCs) and neural stem cells (NSCs) in infant mice. METHODS: C57BL/6 mice of postnatal day 14 and neural stem cells NE4C were treated with 2% Sev for 6 h. We used the Morris water maze (MWM) to test the cognitive function of infant mice. The proliferation of NPCs was measured using bromodeoxyuridine (BrdU) label and their markers Ki67 and Pax6 in infant brain tissues 12 h after anesthesia. Meanwhile, we used immunohistochemical stain, immunofluorescence assay, western blot, and flow cytometer to evaluate the myelinogenesis, iron levels, and cell proliferation in cortex and hippocampus or in NE4C cells. RESULTS: The results showed that Sev significantly caused cognitive deficiency in infant mice. Further, we found that Sev inhibited oligodendrocytes proliferation and myelinogenesis by decreasing MBP and CC-1 expression and iron levels. Meanwhile, Sev also induced the iron deficiency in neurons and NSCs by downregulating FtH and FtL expression and upregulating the TfR1 expression in the cortex and hippocampus, which dramatically suppressed the proliferation of NSCs and NPCs as indicated by decreasing the colocalization of Pax6+ and BrdU+ cells, and caused the decrease in the number of neurons. Interestingly, iron supplementation before anesthesia significantly improved iron deficiency in cortex and hippocampus and cognitive deficiency induced by Sev in infant mice. Iron therapy inhibited the decrease of MBP expression, iron levels in neurons and oligodendrocytes, and DNA synthesis of Pax6+ cells in hippocampus induced by Sev. Meanwhile, the number of neurons was partially recovered in hippocampus. CONCLUSION: The results from the present study demonstrated that Sev-induced iron deficiency might be a new mechanism of cognitive impairment caused by inhaled anesthetics in infant mice. Iron supplementation before anesthesia is an effective strategy to prevent cognitive impairment caused by Sev in infants.

MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in Aspergillus fumigatus.

Aspergillus fumigatus is a major invasive mold pathogen and the most frequent etiologic agent of invasive aspergillosis. The currently available treatments for invasive aspergillosis are limited in both number and efficacy. Our recent work has uncovered that the ß-glucan synthase inhibitors, the echinocandins, are fungicidal against strains of A. fumigatus with defects in septation initiation network (SIN) kinase activity. These drugs are known to be fungistatic against strains with normal septation. Surprisingly, SIN kinase mutant strains also failed to invade lung tissue and were significantly less virulent in immunosuppressed mouse models. Inhibiting septation in filamentous fungi is therefore an exciting therapeutic prospect to both reduce virulence and improve current antifungal therapy. However, the SIN remains understudied in pathogenic fungi. To address this knowledge gap, we characterized the putative regulatory components of the A. fumigatus SIN. These included the GTPase, SpgA, it's two-component GTPase-activating protein, ByrA/BubA, and the kinase activators, SepM and MobA. Deletion of spgA, byrA, or bubA resulted in no overt septation or echinocandin susceptibility phenotypes. In contrast, our data show that deletion of sepM or mobA largely phenocopies disruption of their SIN kinase binding partners, sepL and sidB, respectively. Reduced septum formation, echinocandin hypersusceptibility, and reduced virulence were generated by loss of either gene. These findings provide strong supporting evidence that septa are essential not only for withstanding the cell wall disrupting effects of echinocandins but are also critical for the establishment of invasive disease. Therefore, pharmacological SIN inhibition may be an exciting strategy for future antifungal drug development.IMPORTANCESepta are important structural determinants of echinocandin susceptibility and tissue invasive growth for the ubiquitous fungal pathogen Aspergillus fumigatus. Components of the septation machinery therefore represent promising novel antifungal targets to improve echinocandin activity and reduce virulence. However, little is known about septation regulation in A. fumigatus. Here, we characterize the predicted regulatory components of the A. fumigatus septation initiation network. We show that the kinase activators SepM and MobA are vital for proper septation and echinocandin resistance, with MobA playing an essential role. Null mutants of mobA displayed significantly reduced virulence in a mouse model, underscoring the importance of this pathway for A. fumigatus pathogenesis.

The Aspergillus fumigatus maiA gene contributes to cell wall homeostasis and fungal virulence.

In this study, two distinct in vitro infection models of Aspergillus fumigatus, using murine macrophages (RAW264.7) and human lung epithelial cells (A549), were employed to identify the genes important for fungal adaptation during infection. Transcriptomic analyses of co-incubated A. fumigatus uncovered 140 fungal genes up-regulated in common between both models that, when compared with a previously published in vivo transcriptomic study, allowed the identification of 13 genes consistently up-regulated in all three infection conditions. Among them, the maiA gene, responsible for a critical step in the L-phenylalanine degradation pathway, was identified. Disruption of maiA resulted in a mutant strain unable to complete the Phe degradation pathway, leading to an excessive production of pyomelanin when this amino acid served as the sole carbon source. Moreover, the disruption mutant exhibited noticeable cell wall abnormalities, with reduced levels of ß-glucans within the cell wall but did not show lack of chitin or mannans. The maiA-1 mutant strain induced reduced inflammation in primary macrophages and displayed significantly lower virulence in a neutropenic mouse model of infection. This is the first study linking the A. fumigatus maiA gene to fungal cell wall homeostasis and virulence.

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species.

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.

A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1.

Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.

Association between screen time and suspected developmental coordination disorder in preschoolers: A national population-based study in China.

Introduction: Excessive screen exposure (ESE) is a growing global public health concern. This study aims to investigate the potential association between ESE and suspected developmental coordination disorder (DCD) in Chinese pre-schoolers, with or without siblings. Method: A retrospective cohort study was conducted, involving 126,433 children from 551 cities in China. The Little Developmental Coordination Disorder Questionnaire (LDCDQ) was employed to evaluate motor impairment in children, while parents provided information on their children's screen time in the past year. A mixed and multi-level logistic regression model was used to analyze the associations of all screen exposure measurements from the past year with LDCDQ scores and the risk of suspected DCD. Results: The prevalence of excessive screen exposure was 67.6% (>1 h per day) and 28.9% (>2 h per day) in Chinese pre-schoolers. One hour's increase in weekday daily screen time, weekend daily screen time, and screen time before sleep in the past year was associated with a decreased total score of the LDCDQ (ß were -0.690, -0.398, and -1.587, p < 0.001) and an increased risk of suspected DCD by 15.3%, 9.1%, and 46.8% when adjusting for the child, family and maternal health characteristics. Excessive screen exposure decreased the total LDCDQ scores by 1.335 (>1 vs. ≤1 h) and 1.162 (>2 vs. ≤2 h) and increased risks of suspected DCD by 44.0% (>1 vs. ≤1 h) and 31.1% (>2 vs. ≤2 h) with statistical significance (each p < 0.05). The stratified analysis showed that the association between screen time and LDCDQ score was stronger in children without siblings than in those with siblings. Conclusion: The risk of suspected DCD was highest for screen time exposure before bed compared with average weekday and weekend exposures. Parents should be advised to prevent their children from using electronic screens unsupervised, especially in one-child families.

The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species.

Ergosterol is a critical component of fungal plasma membranes. Although many currently available antifungal compounds target the ergosterol biosynthesis pathway for antifungal effect, current knowledge regarding ergosterol synthesis remains incomplete for filamentous fungal pathogens like Aspergillus fumigatus. Here, we show for the first time that the lipid droplet-associated sterol C-24 methyltransferase, Erg6, is essential for A. fumigatus viability. We further show that this essentiality extends to additional Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Neither the overexpression of a putative erg6 paralog, smt1, nor the exogenous addition of ergosterol could rescue erg6 deficiency. Importantly, Erg6 downregulation results in a dramatic decrease in ergosterol and accumulation in lanosterol and is further characterized by diminished sterol-rich plasma membrane domains (SRDs) at hyphal tips. Unexpectedly, erg6 repressed strains demonstrate wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, repressing erg6 expression reduced fungal burden accumulation in a murine model of invasive aspergillosis. Taken together, our studies suggest that Erg6, which shows little homology to mammalian proteins, is potentially an attractive antifungal drug target for therapy of Aspergillus infections.

Outcome of Extracorporeal Membrane Oxygenation Combined with Intraaortic Balloon Pump Hemodynamic Support during the Percutaneous Coronary Intervention Process for Patients with Cardiac Shock Complicating Acute Myocardial Infarction.

We evaluate the effect of extracorporeal membrane oxygenation combined with intraaortic balloon pump mechanical circulatory support for patients with cardiogenic shock complicating acute myocardial infarction during the PCI process. Extracorporeal membrane oxygenation combined with intraaortic balloon pump hemodynamic support during the percutaneous coronary intervention process for patients with cardiac shock complicating acute myocardial infarction might play a complementary role. Yet, evidence of application of both devices at the same time remains unclear. Patients with cardiogenic shock complicating myocardial infarction who underwent PCI in our hospital from January 2015 to January 2018 were screened. Those who were under hemodynamic support of extracorporeal membrane oxygenation combined with intraaortic balloon pump were enrolled as the ECMO&IABP group, and the patients only under support of intraaortic balloon pump were enrolled as the IABP group. The differences of clinical prognosis between the two groups were compared. A total of 39 patients were enrolled into the study: 10 were in the ECMO&IABP group and 29 in the IABP group. Compared with the IABP group, more patients were complicated with old myocardial infarction (5/10 vs. 2/29, p=0.002), more patients were diagnosed as non-ST elevated myocardial infarction (8/10 vs. 11/29, p=0.002) and left ventricular ejecting fraction was lower (41.1 ± 9.86 vs. 48.55 ± 8.86, p=0.03) in the ECMO&IABP group. Mechanical complications were higher in the ECMO&IABP group (5/10 vs. 5/29, p=0.048), The survive rate in the ECMO&IABP group is higher than that in the IABP group (90.00% vs. 47.83%, p=0.042) at one-year follow-up. Compared with only IABP, ECMO combined with IABP hemodynamic support during the PCI process for patients with cardiogenic shock complicating acute myocardial infarction enjoys better mortality outcome.

A new mechanism of POCD caused by sevoflurane in mice: cognitive impairment induced by cross-dysfunction of iron and glucose metabolism.

Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (µ-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.

Ferritinophagy-Mediated Ferroptosis Involved in Paraquat-Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD.

Parkinson's disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.

Sevoflurane anesthesia during pregnancy in mice induces cognitive impairment in the offspring by causing iron deficiency and inhibiting myelinogenesis.

Maternal anesthetic exposure during pregnancy is associated with an increased risk of cognitive impairment in offspring. The balance of cerebral iron metabolism is essential for the development of brain tissue. Iron deficiency affects the myelinogenesis and nerve tissue development, especially in fetus or infant, which has a key role in cognitive function. We aimed to investigate whether maternal sevoflurane (Sev) exposure caused cognitive impairment in offspring through inducing iron deficiency and inhibiting myelinogenesis. Pregnant mice (gestation stage day 14) were treated with 2% Sev for 6 h. Cognitive function of offspring mice was determined by the Morris water maze and Context fear conditioning test. Iron levels were assayed by Perl's iron staining and synchrotron imaging. Hippocampus and cortex tissues or cerebral microvascular endothelial cells of offspring mice (postnatal day 35) were harvested and subjected to Western blot and/or immunhistochemistry to assess ferritin, transferrin receptor 1(TfR1), Ferroportin-1 (FpN1), myelin basic protein (MBP), tight junction protein ZO-1, occludin, and claudin-5 levels. Beginning with postnatal day 30, the offspring were treated with iron therapy for 30 days, and the indicators above were tested. Our results showed Sev dramatically decreased the iron levels of brain and impaired cognitive function in offspring mice. Sev decreased the expression of heavy chain ferritin (FtH), light chain ferritin (FtL), MBP, ZO-1, occludin, claudin-5, and FpN1, and increased TfR1 in hippocampus and cortex or cerebral microvascular endothelial cells of offspring mice, indicating that Sev caused the iron deficiency and impaired the myelinogenesis in the brain of offspring. Interestingly, iron therapy prompted the myelinogenesis and improved impaired cognitive function at postnatal day 60. Our research uncovered a new mechanism which showed that iron deficiency induced by Sev and myelin formation disorder due to decreased iron of brain may be an important risk factor for cognitive impairment in offspring. It was necessary for offspring to be supplied iron supplement whose mother suffered exposure to sevoflurane during pregnancy.

Propofol prevents oxidative stress and apoptosis by regulating iron homeostasis and targeting JAK/STAT3 signaling in SH-SY5Y cells.

The present study aimed to test the hypothesis that propofol (PRO) could exert a neuroprotective effect via inhibiting oxidative stress induced by iron accumulation. Human SH-SY5Y cells were pretreated with ferric citrate (FAC), and then were protected by PRO. Cell viability was measured by MTT method. Iron levels were assayed by ICP-MS. Cell apoptosis was examined by TUNEL and digital holographic technique. Malondialdehyde (MDA), reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) depolarization were measured by MDA, DCFH-DA and JC-1 kits, respectively. The expression of proteins or genes involved in iron metabolism such as ferritin, TfR1, DMT1, Fpn1 and hepcidin, and other apoptosis-related proteins including Bcl2, Bax, Bid, Cox2, IL-6, JAK1 and STAT3 were detected by western blot. Our results showed low concentration of PRO (5 µM) could significantly prevent FAC induced apoptosis via inhibiting oxidative stress and iron accumulation. PRO suppressed the increase of ROS and MDA and decrease of MMP induced by FAC. PRO significantly down-regulated the expression of ferritin and up-regulated the expression of TfR1and Fpn1, but had no effect of DMT1. Furthermore, this effect was not done by PRO chelating iron. Meanwhile, PRO suppressed the inflammatory response through inhibiting IL-6 and Cox2 expression and activating JAK/STAT3 signaling induced by iron overload. In conclusion, here we demonstrated a new antioxidation mechanism of PRO. PRO could protect against nerve cell injury induced by overload of iron through regulating iron metabolism and inhibiting stress oxidative and inflammation reaction pathways by targeting JAK/STAT3 signaling.

[Clinical research of vasospasm and vagus reflex during radial artery puncture treated with auricular point sticking].

OBJECTIVE: To evaluate the effect and clinical value of auricular point sticking for the diagnosis and treatment of vasospasm and vagus reflex during radial artery puncture, including radial artery spasm (RAS) and coronary artery spasm (CAS). METHODS: A total of 480 patients were randomized into an observation group (224 cases) and a control group (256 cases). Percutaneous coronary intervention and usual care in perioperative period were used in the control group. Auricular point sticking was began to apply 12 h before percutaneous coronary intervention in the observation group at Jiaogan (AH6a), Shenmen (TF4), Pizhixia (AT4), Neifenmi (CO18), Xin (CO15), Shen (CO10), Shenshangxian (TG2p), 1 min a time every point, once every 2 h, 12 h before and after operation. The incidences of vasospasm and vagus reflex during piercing process were compared, and the usage ratios of vasoactive agent were recorded, including glyceryl trinitrate, dopamine and atropine injections. RESULTS: The incidence of angiospasm was 4.9% (11/224) in the observation group, which was lower than 13.3% (34/256) in the control group (P<0.01). The incidence of vagal reflex of the observation group was 7.1% (16/224), which was lower than 19.5% (50/256) of the control group (P<0.01). The usage ratios of glyceryl trinitrate, atropine and dopamine injections were 3.6% (8/224), 7.1% (16/224), 6.3% (14/224) respectively in the observation group, which were lower than 14.8% (38/256), 15.6% (40/256), 15.2% (39/256) in the control group (all P<0.01). . CONCLUSION: Auricular point sticking achieves effect for the diagnosis and treatment of vasospasm and vagus reflex during radial artery puncture.