Dichloroacetate attenuates brain injury through inhibiting neuroinflammation and mitochondrial fission in a rat model of sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by neuroinflammation, mitochondrial dysfunction, and oxidative stress, leading to cognitive decline and high mortality. The effectiveness of dichloroacetate (DCA) in modulating mitochondrial function provides a novel therapeutic strategy for SAE. In this study, we evaluated the neuroprotective effects of DCA in a rat model of SAE induced by cecal ligation and puncture (CLP). Rats treated with DCA exhibited significant improvements in neurological function and survival, as evidenced by less neuron loss from histopathologic analysis, restored neurologic deficit scores, improved Y-maze alternation percentages, and enhanced recognition index performance. Biochemical analyses showed that DCA administration at 25 mg/kg and 100 mg/kg reduced astrocyte and microglial activation, indicating reduced neuroinflammation. Furthermore, DCA simultaneously reduced the production of circulating and cerebral inflammatory cytokines (including TNF-α, IL-1ß, and IL-10), concomitant with mitigating oxidative stress through down-regulating expression of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) in the brain. Mechanistically, DCA modulated mitochondrial dynamics by suppressing Drp1 and pDrp1 expression, which are indicators of mitochondrial fission. This was corroborated by transmission electron microscopy, quantification of mitochondrial area, and Western blot analyses. Furthermore, DCA treatment improved ATP levels, mitochondrial complex I activity, and NAD+/NADH ratio, indicating a significant attenuation of brain mitochondrial dysfunction. In conclusion, our findings suggest that DCA confers neuroprotection in SAE by curtailing neuroinflammation and mitochondrial fission, outlining a promising therapeutic strategy for treating SAE in critically ill patients.

Beneficial Effects of Ginger Extract on Eye Fatigue and Shoulder Stiffness: A Randomized, Double-Blind, and Placebo-Controlled Parallel Study.

This study aimed to assess ginger extract's impact on ocular and peripheral blood flow and its potential to alleviate eye fatigue and shoulder stiffness. This study included 100 healthy individuals aged 20-73 years with eye fatigue and shoulder stiffness. Participants were randomly assigned to receive either placebo capsules or ginger extract capsules daily for eight weeks. Ocular blood flow, peripheral blood flow, eye fatigue (visual analog scale [VAS]), shoulder stiffness (VAS), body warmth (VAS), and shoulder muscle stiffness were assessed at weeks 0, 4, and 8, respectively. No improvement in ocular blood flow was observed under the study conditions. Conversely, peripheral blood flow in deep areas was enhanced in females (p = 0.033). Subgroup analysis by age (≥51 or <51 years) revealed that ginger's effect on enhancing peripheral blood flow in deep vessels was restricted in females under 51 (p = 0.017). Similarly, subjective complaints of eye fatigue and shoulder stiffness were improved by ginger consumption in females under 51. Body warmth was favorably changed significantly in males ≥51 years due to ginger consumption. The muscle stiffness showed no statistically significant changes. In conclusion, ginger consumption reduces eye fatigue and shoulder stiffness by enhancing peripheral blood flow in relatively young females.

Characterization of regulatory genes Plhffp and Plpif1 involved in conidiation regulation in Purpureocillium lavendulum.

Purpureocillium lavendulum is an important biocontrol agent against plant-parasitic nematodes, primarily infecting them with conidia. However, research on the regulatory genes and pathways involved in its conidiation is still limited. In this study, we employed Agrobacterium tumefaciens-mediated genetic transformation to generate 4,870 random T-DNA insertion mutants of P. lavendulum. Among these mutants, 131 strains exhibited abnormal conidiation, and further in-depth investigations were conducted on two strains (designated as #5-197 and #5-119) that showed significantly reduced conidiation. Through whole-genome re-sequencing and genome walking, we identified the T-DNA insertion sites in these strains and determined the corresponding genes affected by the insertions, namely Plhffp and Plpif1. Both genes were knocked out through homologous recombination, and phenotypic analysis revealed a significant difference in conidiation between the knockout strains and the wild-type strain (ku80). Upon complementation of the ΔPlpif1 strain with the corresponding wildtype allele, conidiation was restored to a level comparable to ku80, providing further evidence of the involvement of this gene in conidiation regulation in P. lavendulum. The knockout of Plhffp or Plpif1 reduced the antioxidant capacity of P. lavendulum, and the absence of Plhffp also resulted in decreased resistance to SDS, suggesting that this gene may be involved in the integrity of the cell wall. RT-qPCR showed that knockout of Plhffp or Plpif1 altered expression levels of several known genes associated with conidiation. Additionally, the analysis of nematode infection assays with Caenorhabditis elegans indicated that the knockout of Plhffp and Plpif1 indirectly reduced the pathogenicity of P. lavendulum towards the nematodes. The results demonstrate that Agrobacterium tumefaciens - mediated T-DNA insertion mutagenesis, gene knockout, and complementation can be highly effective for identifying functionally important genes in P. lavendulum.

Eco-friendly management of Meloidogyne incognita in cadmium-contaminated soil by using nematophagous fungus Purpureocillium lavendulum YMF1.683: Efficacy and mechanism.

Root-knot nematodes (RKNs) are distributed globally, including in agricultural fields contaminated by heavy metals (HM), and can cause serious crop damages. Having a method that could control RKNs in HM-contaminated soil while limit HM accumulation in crops could provide significant benefits to both farmers and consumers. In this study, we showed that the nematophagous fungus Purpureocillium lavendulum YMF1.683 exhibited a high nematocidal activity against the RKN Meloidogyne incognita and a high tolerance to CdCl2. Comparing to the P. lavendulum YMF1.838 which showed low tolerance to Cd2+, strain YMF1.683 effectively suppressed M. incognita infection and significantly reduced the Cd2+ uptake in tomato root and fruit in soils contaminated by 100 mg/kg Cd2+. Transcriptome analyses and validation of gene expression by RT-PCR revealed that the mechanisms contributed to high Cd-resistance in YMF1.683 mainly included activating autophagy pathway, increasing exosome secretion of Cd2+, and activating antioxidation systems. The exosomal secretory inhibitor GW4869 reduced the tolerance of YMF1.683 to Cd2+, which firstly demonstrated that fungal exosome was involved in HM tolerance. The up-regulation of glutathione synthesis pathway, increasing enzyme activities of both catalase and superoxide dismutase also played important roles in Cd2+ tolerance of YMF1.683. In Cd2+-contaminated soil, YMF1.683 limited Cd2+-uptake in tomato by up-regulating the genes of ABCC family in favor of HM sequestration in plant, and down-regulating the genes of ZIP, HMA, NRAMP, YSL families associated with HM absorption, transport, and uptake in plant. Our results demonstrated that YMF1.683 could be a promising bio-agent in eco-friendly management of M. incognita in Cd2+ contaminated soils.

Ethanol mediates the interaction between Caenorhabditis elegans and the nematophagous fungus Purpureocillium lavendulum.

Accurately recognizing pathogens by the host is vital for initiating appropriate immune response against infecting microorganisms. Caenorhabditis elegans has no known receptor to recognize pathogen-associated molecular pattern. However, recent studies showed that nematodes have a strong specificity for transcriptomes infected by different pathogens, indicating that they can identify different pathogenic microorganisms. However, the mechanism(s) for such specificity remains largely unknown. In this study, we showed that the nematophagous fungus Purpureocillium lavendulum can infect the intestinal tract of the nematode C. elegans and the infection led to the accumulation of reactive oxygen species (ROS) in the infected intestinal tract, which suppressed fungal growth. Co-transcriptional analysis revealed that fungal genes related to anaerobic respiration and ethanol production were up-regulated during infection. Meanwhile, the ethanol dehydrogenase Sodh-1 in C. elegans was also up-regulated. Together, these results suggested that the infecting fungi encounter hypoxia stress in the nematode gut and that ethanol may play a role in the host-pathogen interaction. Ethanol production in vitro during fungal cultivation in hypoxia conditions was confirmed by gas chromatography-mass spectrometry. Direct treatment of C. elegans with ethanol elevated the sodh-1 expression and ROS accumulation while repressing a series of immunity genes that were also repressed during fungal infection. Mutation of sodh-1 in C. elegans blocked ROS accumulation and increased the nematode's susceptibility to fungal infection. Our study revealed a new recognition and antifungal mechanism in C. elegans. The novel mechanism of ethanol-mediated interaction between the fungus and nematode provides new insights into fungal pathogenesis and for developing alternative biocontrol of pathogenic nematodes by nematophagous fungi. IMPORTANCE Nematodes are among the most abundant animals on our planet. Many of them are parasites in animals and plants and cause human and animal health problems as well as agricultural losses. Studying the interaction of nematodes and their microbial pathogens is of great importance for the biocontrol of animal and plant parasitic nematodes. In this study, we found that the model nematode Caenorhabditis elegans can recognize its fungal pathogen, the nematophagous fungus Purpureocillium lavendulum, through fungal-produced ethanol. Then the nematode elevated the reactive oxygen species production in the gut to inhibit fungal growth in an ethanol dehydrogenase-dependent manner. With this mechanism, novel biocontrol strategies may be developed targeting the ethanol receptor or metabolic pathway of nematodes. Meanwhile, as a volatile organic compound, ethanol should be taken seriously as a vector molecule in the microbial-host interaction in nature.

m6A-mediated upregulation of miRNA-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the METTL3/ miRNA-193a/BCL2L2 pathway.

The impact of N6-methyladenosine (m6A) modification on pri-miRNA in sepsis-induced cardiomyopathy (SICM), and its underlying regulatory mechanism, have not been fully elucidated. We successfully constructed a SICM mice model through cecal ligation and puncture (CLP). In vitro, a lipopolysaccharide (LPS)-induced HL-1 cells model was also established. The results showed that sepsis frequently resulted in excessive inflammatory response concomitant with impaired myocardial function in mice exposed to CLP, as indicated by decreases in ejection fraction (EF), fraction shortening (FS), and left ventricular end diastolic diameters (LVDd). miR-193a was enriched in CLP mice heart and in LPS-treated HL-1 cells, while overexpression of miR-193a significantly increased the expression levels of cytokines. Sepsis-induced enrichment of miR-193a significantly inhibited cardiomyocytes proliferation and enhanced apoptosis, while this was reversed by miR-193a knockdown. Furthermore, under our experimental conditions, enrichment of miR-193a in SICM could be considered excessively maturated on pri-miR-193a by enhanced m6A modification. This modification was catalyzed by sepsis-induced overexpression of methyltransferase-like 3 (METTL3). Moreover, mature miRNA-193a bound to a predictive sequence within 3'UTRs of a downstream target, BCL2L2, which was further validated by the observation that the BCL2L2-3'UTR mutant failed to decrease luciferase activity when co-transfected with miRNA-193a. The interaction between miRNA-193a and BCL2L2 resulted in BCL2L2 downregulation, subsequently activating the caspase-3 apoptotic pathway. In conclusion, sepsis-induced miR-193a enrichment via m6A modification plays an essential regulatory role in cardiomyocyte apoptosis and inflammatory response in SICM. The detrimental axis of METTL3/m6A/miR-193a/BCL2L2 is implicated in the development of SICM.

Characterization of the complete mitochondrial genome of the nematode-trapping fungus Drechslerella dactyloides.

The complete mitochondrial genome of Drechslerella dactyloides was characterized in this study. This mitogenome is a closed circular molecule of 246860 bp in length with a GC content of 26.16%, including 87 predicted protein-coding genes, 29 transfer RNA genes, and two rRNA gens. Phylogenetic analyses based on concatenated amino acid sequences at 14 conserved mitochondrial protein-coding genes showed that D. dactyloides was closely related to Dactylellina haptotyla.

The Growth and Conidiation of Purpureocillium lavendulum Are Co-Regulated by Nitrogen Sources and Histone H3K14 Acetylation.

Plant-parasitic nematodes cause severe economic losses to agriculture. As important biocontrol agents, nematophagous fungi evolved the ability to obtain nitrogen sources from nematodes. However, the impact of nitrogen sources on the growth and development of these fungi is largely unknown. In this study, we aimed to better understand how nitrogen sources could influence vegetative growth and conidiation through epigenetic regulation in the nematophagous fungus, Purpureocillium lavendulum. Through nutrition screening, we found a phenomenon of the fungus, limited colony extension with a large amount of conidia production when cultured on PDA media, can be altered by adding ammonia nitrate. Characterized by site-directed mutagenesis, the histone H3K14 acetylation was found to be involved in the alternation. Furthermore, the acetyltransferase PlGCN5 was responsible for H3K14 acetylation. Knockout of Plgcn5 severely diminished conidiation in P. lavendulum. Chip-seq showed that H3K14ac distributed in conidiation regulating genes, and genes in the MAPK pathway which may be the downstream targets in the regulation. These findings suggest that histone modification and nitrogen sources coordinated lifestyle regulation in P. lavendulum, providing new insight into the mechanism of growth regulation by nutritional signals for the carnivorous fungus.

Microbiota and functional analyses of nitrogen-fixing bacteria in root-knot nematode parasitism of plants.

BACKGROUND: Root-knot nematodes (RKN) are among the most important root-damaging plant-parasitic nematodes, causing severe crop losses worldwide. The plant rhizosphere and root endosphere contain rich and diverse bacterial communities. However, little is known about how RKN and root bacteria interact to impact parasitism and plant health. Determining the keystone microbial taxa and their functional contributions to plant health and RKN development is important for understanding RKN parasitism and developing efficient biological control strategies in agriculture. RESULTS: The analyses of rhizosphere and root endosphere microbiota of plants with and without RKN showed that host species, developmental stage, ecological niche, and nematode parasitism, as well as most of their interactions, contributed significantly to variations in root-associated microbiota. Compared with healthy tomato plants at different developmental stages, significant enrichments of bacteria belonging to Rhizobiales, Betaproteobacteriales, and Rhodobacterales were observed in the endophytic microbiota of nematode-parasitized root samples. Functional pathways related to bacterial pathogenesis and biological nitrogen fixation were significantly enriched in nematode-parasitized plants. In addition, we observed significant enrichments of the nifH gene and NifH protein, the key gene/enzyme involved in biological nitrogen fixation, within nematode-parasitized roots, consistent with a potential functional contribution of nitrogen-fixing bacteria to nematode parasitism. Data from a further assay showed that soil nitrogen amendment could reduce both endophytic nitrogen-fixing bacteria and RKN prevalence and galling in tomato plants. CONCLUSIONS: Results demonstrated that (1) community variation and assembly of root endophytic microbiota were significantly affected by RKN parasitism; (2) a taxonomic and functional association was found for endophytic nitrogen-fixing bacteria and nematode parasitism; and (3) the change of nitrogen-fixing bacterial communities through the addition of nitrogen fertilizers could affect the occurrence of RKN. Our results provide new insights into interactions among endophytic microbiota, RKN, and plants, contributing to the potential development of novel management strategies against RKN. Video Abstract.

Streptomyces plumbidurans sp. nov., a Pb2+-tolerant actinomycete.

A novel actinobacterium, designated KC 17012T, was isolated from lead zinc tailings collected from Lanping, Yunnan, PR China. Comparative 16S rRNA gene sequencing showed that KC 17012T belonged to the genus Streptomyces and was most closely related to the type strains of Streptomyces neyagawaensis (98.34%), Streptomyces panaciradicis (98.34%) and Streptomyces heilongjiangensis (98.27%). Phylogenetic tree analysis revealed strain KC 17012T formed a distinct clade. The genome size was 8.64 Mbp with a DNA G+C content of 70.8%. Digital DNA-DNA hybridization and average nucleotide identity values between the genome sequence of strain KC 17012T and those of S. neyagawaensis JCM 4796T (25.3 and 81.5 %) and S. panaciradicis NBRC 109811T (30.1 and 85.7 %) were below the thresholds of 70 and 96% for prokaryotic conspecific assignation. The strain formed long straight aerial hyphae which generated regular short rod spores with spiny surfaces. Growth occurred at 10-45 °C, pH 6-8 and with 0-9 % NaCl (w/v). Strain KC 17012T contained ll-diaminopimelic acid and the major whole-cell hydrolysates included glucose, mannose and ribose. The menaquinones were MK-9(H4), MK-9(H6) and MK-9(H8). The major cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside, one unidentified lipid and one unidentified phospholipid. On the basis of the results of a polyphasic taxonomic study, it is concluded that KC 17012T represents a novel species of the genus Streptomyces, for which the name Streptomyces plumbidurans sp. nov., is proposed. The type strain is KC 17012T (CGMCC 4.7704T=JCM 35204T).

Siccirubricoccus soli sp. nov., a novel bacterial species isolated from Jiaozi Mountain soil.

An isolate of Gram-stain-negative and strictly aerobic bacterium, designated KC 17139T, was isolated from Jiaozi Mountain sample in Yunnan, China. Cells were non-motile cocci to oval, catalase-positive and oxidase-positive. Growth occurred at 0-7% NaCl (w/v; optimum, 0%), pH 6.0-8.0 (optimum, pH 7.0) and 15-45 °C (optimum, 28-37 °C). The polar lipids were diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylcholine (PC) and four unidentified aminolipids (UALs). Strain KC 17139T contained summed feature 8 (comprising C18:1 ω7c and/or C18:1 ω6c), C18:1 2OH and C16:0 as major cellular fatty acids (> 5%) and ubiquinone-10 as the sole isoprenoid quinone. The 16S rRNA gene sequence analysis indicated that strain KC 17139T shared highest similarities with Siccirubricoccus phaeus 1-3T (96.7%) and Siccirubricoccus deserti SYSU D8009T (95.0%). Strain KC 17139T clustered with the two Siccirubricoccus type strains, but formed a separate branch in both 16S rRNA gene and genome-scale phylogenetic dendrograms. The genomic DNA G + C content of strain KC 17139T was 71.2%. Genomic comparisons between strain KC 17139T and its close relatives showed the highest digital DNA-DNA hybridisation to S. phaeus (35.5%), highest average nucleotide identity to S. phaeus (88.2%), indicating that strain KC 17139T represents a novel species. On the basis of results of phenotypic, chemotaxonomic and molecular analysis, we report a new bacterium strain KC 17139T belonged to genus Siccirubricoccus, for which the name Siccirubricoccus soli sp. nov. is proposed. The type strain is KC 17139T (= CGMCC 1.18756T = JCM 35132T).

Vitamin C Improves the Outcomes of Cardiopulmonary Resuscitation and Alters Shedding of Syndecan-1 and p38/MAPK Phosphorylation in a Rat Model.

Background Post-resuscitation syndrome, involves a severe inflammatory response following successful cardiopulmonary resuscitation. The potential mechanism of Vitamin C (VitC) after cardiopulmonary resuscitation on myocardial and cerebral function, duration of survival is undefined. Methods and Results A first set of experiments were done in 18 male Sprague-Dawley rats for the investigation of short-term follow-up, randomized into 3 groups: (1) sham; (2) controls; (3) VitC. Ventricular fibrillation was electrically induced and untreated for 6 minutes. Cardiopulmonary resuscitation including chest compression and mechanical ventilation were then initiated and continued for 8 minutes followed by defibrillation. At 5 minutes after return of spontaneous circulation, either VitC (200 mg/kg) or placebo was administered by intravenous infusion with a syringe pump for half an hour. There were significant improvements in myocardial function and buccal microcirculation in rats treated with VitC after return of spontaneous circulation 4 hours compared with controls. VitC inhibited proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α), SDC-1 (Syndecan-1), and hyaluronic acid in plasma compared with controls (P<0.01). VitC decreased reactive oxygen species production and inhibited p38/MAPK (mitogen-activated protein kinase) pathway phosphorylation. A second set with 20 animals was used for assessing the neurological deficit score after return of spontaneous circulation 72 hours, randomized into 2 groups: 1) controls; 2) VitC. The survival rate and neurological deficit score after return of spontaneous circulation 72 hours were improved in VitC-treated animals compared with those of the control group. Conclusions VitC reduces the severity of post-resuscitation myocardial and cerebral dysfunction and improves the survival. The mechanisms may involve inhibiting transcription of inflammatory cytokines and oxidative stress, thus protecting the integrity of the vascular endothelium. Meanwhile VitC reduces shedding of SDC-1 and alters p38/MAPK phosphorylation and microcirculation.

Assessing the effects of Kampo medicine on human skin texture and microcirculation.

In this study, we verified the effectiveness of Kampo medicine by evaluating the changes in the feature values of facial skin texture and microcirculation at two distinct tissue depths (subcutaneous 2 mm and 8 mm). A total of 80 patients who took the Kampo formula participated in this study, and the changes in the feature values of facial skin texture and microcirculation were measured before and after Kampo treatment. The treatment period lasted 6-18 months, according to the doctor's judgment. The total area of the sulci cutis and the average thickness of the sulci cutis significantly decreased (P < 0.05), and the pixels of the grayscale image increased after Kampo treatment (P < 0.05). Moreover, the blood flow velocity at 8 mm depth significantly increased after Kampo treatment (P < 0.05). In this study, we specifically noted changes in the skin texture and microcirculation after Kampo treatment.

Survival and infectivity of second-stage root-knot nematode Meloidogyne incognita juveniles depend on lysosome-mediated lipolysis.

Adaptation to nutrient deprivation depends on the activation of metabolic programs to use reserves of energy. When outside a host plant, second-stage juveniles (J2) of the root-knot nematode (Meloidogyne spp.), an important group of pests responsible for severe losses in the production of crops (e.g., rice, wheat, and tomato), are unable to acquire food. Although lipid hydrolysis has been observed in J2 nematodes, its role in fitness and the underlying mechanisms remain unknown. Using RNA-seq analysis, here, we demonstrated that in the absence of host plants, the pathway for the biosynthesis of polyunsaturated fatty acids was upregulated, thereby increasing the production of arachidonic acid in middle-stage J2 Meloidogyne incognita worms. We also found that arachidonic acid upregulated the expression of the transcription factor hlh-30b, which in turn induced lysosomal biogenesis. Lysosomes promoted lipid hydrolysis via a lysosomal lipase, LIPL-1. Furthermore, our data demonstrated that blockage of lysosomal lipolysis reduced both lifespan and locomotion of J2 worms. Strikingly, disturbance of lysosomal lipolysis resulted in a decline in infectivity of these juveniles on tomato roots. Our findings not only reveal the molecular mechanism of lipolysis in J2 worms but also suggest potential novel strategies for the management of root-knot nematode pests.

Exogenous Nicotinamide Adenine Dinucleotide Attenuates Postresuscitation Myocardial and Neurologic Dysfunction in a Rat Model of Cardiac Arrest.

OBJECTIVES: To investigate the therapeutic potential and underlying mechanisms of exogenous nicotinamide adenine dinucleotide+ on postresuscitation myocardial and neurologic dysfunction in a rat model of cardiac arrest. DESIGN: Thirty-eight rats were randomized into three groups: 1) Sham, 2) Control, and 3) NAD. Except for the sham group, untreated ventricular fibrillation for 6 minutes followed by cardiopulmonary resuscitation was performed in the control and NAD groups. Nicotinamide adenine dinucleotide+ (20 mg/kg) was IV administered at the onset of return of spontaneous circulation. SETTING: University-affiliated research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Nicotinamide adenine dinucleotide+. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and myocardial function were measured at baseline and within 4 hours following return of spontaneous circulation. Survival analysis and Neurologic Deficit Score were performed up to 72 hours after return of spontaneous circulation. Adenosine triphosphate (adenosine triphosphate) level was measured in both brain and heart tissue. Mitochondrial respiratory chain function, acetylation level, and expression of Sirtuin3 and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9 (NDUFA9) in isolated mitochondrial protein from both brain and heart tissue were evaluated at 4 hours following return of spontaneous circulation. The results demonstrated that nicotinamide adenine dinucleotide+ treatment improved mean arterial pressure (at 1 hr following return of spontaneous circulation, 94.69 ± 4.25 mm Hg vs 89.57 ± 7.71 mm Hg; p < 0.05), ejection fraction (at 1 hr following return of spontaneous circulation, 62.67% ± 6.71% vs 52.96% ± 9.37%; p < 0.05), Neurologic Deficit Score (at 24 hr following return of spontaneous circulation, 449.50 ± 82.58 vs 339.50 ± 90.66; p < 0.05), and survival rate compared with that of the control group. The adenosine triphosphate level and complex I respiratory were significantly restored in the NAD group compared with those of the control group. In addition, nicotinamide adenine dinucleotide+ treatment activated the Sirtuin3 pathway, down-regulating acetylated-NDUFA9 in the isolated mitochondria protein. CONCLUSIONS: Exogenous nicotinamide adenine dinucleotide+ treatment attenuated postresuscitation myocardial and neurologic dysfunction. The responsible mechanisms may involve the preservation of mitochondrial complex I respiratory capacity and adenosine triphosphate production, which involves the Sirtuin3-NDUFA9 deacetylation.

UAMC-3203 or/and Deferoxamine Improve Post-Resuscitation Myocardial Dysfunction Through Suppressing Ferroptosis in a Rat Model of Cardiac Arrest.

ABSTRACT: Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 ±â€Š0.060 vs. 0.021 ±â€Š0.016, 1 ±â€Š0.145 vs. 3.338 ±â€Š0.221, 52.010 ±â€Š3.587 ug/g vs. 70.500 ±â€Š3.158 ug/g, all P < 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 ±â€Š0.043, 2.848 ±â€Š0.169, all P < 0.05), (72.43 ±â€Š4.920 ug/g, P  > 0.05)], or Deferoxamine (0.203 ±â€Š0.025, 2.683 ±â€Š0.273, 55.95 ±â€Š2.497 ug/g, all P < 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.

Compression depth of 30 mm has similar efficacy and fewer complications versus 50 mm during mechanical chest compression with miniaturized chest compressor in a porcine model of cardiac arrest.

BACKGROUND: Current guidelines recommend a 50 mm or greater compression depth for manual chest compression in adults. However, whether this uniform compression depth is a suitable requirement for mechanical CPR remains to be determined. We hypothesized that a relatively shallow compression depth (30 mm) would have similar hemodynamic efficacy but fewer complications versus the standard compression depth (50 mm) during mechanical cardiopulmonary resuscitation (CPR) with the miniaturized chest compressor (MCC) in a porcine model. METHODS: In the current study, we used a total of 16 domestic male pigs (38±2 kg). All pigs were exposed to 7 min of ventricular fibrillation (VF) followed by 5 min of CPR. Then the animals were randomly assigned to the shallow (30 mm) group and the standard (50 mm) group. At the second min of CPR, every pig was given epinephrine (20 µg/kg) through the femoral vein and repeated every 3 min. First defibrillation was delivered with a single 120 J shock at 5 min of CPR. Hemodynamics, carotid blood flow (CBF), end-tidal carbon dioxide (ETCO2), coronary perfusion pressure (CPP), intrathoracic pressure (ITP) and arterial blood gas were measured. Rib fractures and lung injuries, as indicated by ground-glass opacification (GGO), as well as intense parenchymal opacification (IPO), were assessed and calculated by quantitative computed tomography (QCT) scan. RESULTS: We found no significant differences in CPP, CBF, or ETCO2 between the both groups throughout the CPR period. After administration of epinephrine, the CPP of all animals increased while ETCO2 and CBF decreased during CPR. A significantly lower intrathoracic positive pressure (ITPP) and systolic artery pressure (SAP) were measured in the shallow group at the first min of CPR. However, we didn't find remarkable differences in these values between the both groups for the next 4 min of CPR. All animals were successfully resuscitated. The shallow group had significantly lower IPO QCT scores compared with the standard group. We found no significant differences in GGO QCT scores after resuscitation between both groups. CONCLUSIONS: Relatively shallow compression depth has similar hemodynamic efficacy but fewer complications versus the standard compression depth.

Sodium-Glucose Co-Transporter 2 Inhibition With Empagliflozin Improves Cardiac Function After Cardiac Arrest in Rats by Enhancing Mitochondrial Energy Metabolism.

Empagliflozin is a newly developed antidiabetic drug to reduce hyperglycaemia by highly selective inhibition of sodium-glucose co-transporter 2. Hyperglycaemia is commonly seen in patients after cardiac arrest (CA) and is associated with worse outcomes. In this study, we examined the effects of empagliflozin on cardiac function in rats with myocardial dysfunction after CA. Non-diabetic male Sprague-Dawley rats underwent ventricular fibrillation to induce CA, or sham surgery. Rats received 10 mg/kg of empagliflozin or vehicle at 10 min after return of spontaneous circulation by intraperitoneal injection. Cardiac function was assessed by echocardiography, histological analysis, molecular markers of myocardial injury, oxidative stress, mitochondrial ultrastructural integrity and metabolism. We found that empagliflozin did not influence heart rate and blood pressure, but left ventricular function and survival time were significantly higher in the empagliflozin treated group compared to the group treated with vehicle. Empagliflozin also reduced myocardial fibrosis, serum cardiac troponin I levels and myocardial oxidative stress after CA. Moreover, empagliflozin maintained the structural integrity of myocardial mitochondria and increased mitochondrial activity after CA. In addition, empagliflozin increased circulating and myocardial ketone levels as well as heart ß-hydroxy butyrate dehydrogenase 1 protein expression. Together, these metabolic changes were associated with an increase in cardiac energy metabolism. Therefore, empagliflozin favorably affected cardiac function in non-diabetic rats with acute myocardial dysfunction after CA, associated with reducing glucose levels and increasing ketone body oxidized metabolism. Our data suggest that empagliflozin might benefit patients with myocardial dysfunction after CA.