Epidemiology and clinical characteristics of infection/colonization due to carbapenemase-producing Enterobacterales in neonatal patients.

BACKGROUND: The aim of this study was to elucidate the epidemiological features of carbapenemase-producing Enterobacterales (CPE) in the pediatric and neonatal patients, to describe clinical characteristics of neonatal patients with CPE infections, and to assess risk factors for neonatal rectal colonization with CPE. RESULTS: A total of 439 carbapenem-resistant Enterobacterales (CRE) isolates recovered from 367 infant patients were characterised, including 397 isolates of Klebsiella pneumoniae (KP) and 42 isolates of Escherichia coli (EC). Carbapenemase gene blaNDM-1 was the most commonly detected, accounting for 86.56% (n = 380), followed by blaKPC-2 (9.11%, 40) and blaIMP-4 (4.33%, 19). MLST analysis showed 17 different STs detected within CPKP isolates, with ST20, ST2068, ST36 and ST17 being the most frequently isolated types. Eleven STs were identified within CPEC isolates, with ST325 being the dominant types. Eight isolates of NDM-1 producing KP, belonging to ST23, were identified as having hypervirulent traits. The main infections caused by CPE were pneumonia (n = 90) and sepsis (n = 16). All infected patients received monotherapy, with meropenem and ciprofloxacin being the most commonly used antibiotics. All pneumonia patients were cured or improved after treatment. Of the 16 patients with sepsis, 9 were cured or improved, 3 died, and 4 abandoned treatment without any clinical improvement. The rectal prevalences of CPE in the 0-3 days old (DO), the 4-28 DO, and the 29 DO-1 year old groups were decreased from 15.31%, 27.37% and 14.29% in the first stool screening period to 11.78%, 19.59% and 4.07% in the second stool screening period, respectively. Multivariate analysis showed that cesarean section, acidosis, respiration failure, gastric lavage and enema were independent risk factors for rectal colonization in the 0-3 DO group, whereas cesarean section, cephalosporins, gastric lavage and residence in rural area were independently associated with rectal colonization in the 4-28 DO group. The implementation of a series of evidence-based control measures eventually contained the CPE transmission. CONCLUSIONS: Continued vigilance, epidemiological studies, and multimodal infection prevention strategies are urgently needed due to frequent importations.

O-GlcNAcylation promotes pancreatic tumor growth by regulating malate dehydrogenase 1.

Oncogenic Kras-activated pancreatic ductal adenocarcinoma (PDAC) cells highly rely on an unconventional glutamine catabolic pathway to sustain cell growth. However, little is known about how this pathway is regulated. Here we demonstrate that Kras mutation induces cellular O-linked ß-N-acetylglucosamine (O-GlcNAc), a prevalent form of protein glycosylation. Malate dehydrogenase 1 (MDH1), a key enzyme in the glutamine catabolic pathway, is positively regulated by O-GlcNAcylation on serine 189 (S189). Molecular dynamics simulations suggest that S189 glycosylation on monomeric MDH1 enhances the stability of the substrate-binding pocket and strengthens the substrate interactions by serving as a molecular glue. Depletion of O-GlcNAcylation reduces MDH1 activity, impairs glutamine metabolism, sensitizes PDAC cells to oxidative stress, decreases cell proliferation and inhibits tumor growth in nude mice. Furthermore, O-GlcNAcylation levels of MDH1 are elevated in clinical PDAC samples. Our study reveals that O-GlcNAcylation contributes to pancreatic cancer growth by regulating the metabolic activity of MDH1.

Mechanisms dissection of the combination GRS derived from ShengMai preparations for the treatment of myocardial ischemia/reperfusion injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Recently, a new drug combination GRS comprising ginsenoside Rb1 (G-Rb1), ruscogenin (R-Rus) and schisandrin (S-SA) was screened based on ShengMai preparations, which exhibited a prominent cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury. AIM OF THE STUDY: To investigate their systemic and individual mechanism of each compound in combination GRS. MATERIALS AND METHODS: The mice model of MI/R and hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury were performed to explore the respective characteristics of each compound in GRS against myocardial injury. RESULTS: Each component in the combination GRS attenuated MI/R injury as evidenced by decreased myocardial infarct size, ameliorated histological features, and improved biochemical indicators. Meanwhile, ingredient G, R and S in combination also individually performed a significant decrease of apoptotic index in MI/R mice and H/R-induced cardiomyocytes injury. Mechanistically, component G in GRS could markedly increase the ATP content in cardiomyocytes through activation of AMPKα phosphorylation. Interestingly, the anti-apoptotic actions of G were profoundly attenuated by knockdown of AMPKα, while no alteration was observed on composition R and S. Moreover, component R in GRS significantly reduced the IL-6 and TNF-α mRNA expression, as well as the content of IL-6 via the modulation of NF-κB signaling pathway. Further, component S exhibited the most powerful anti-oxidative capacity in GRS and remarkably decreased the production of MDA and ROS, and potential mechanisms might at least in part through activating the Akt-14-3-3 signaling pathway and inhibiting the phosphorylation of Bad and ERK1/2. CONCLUSIONS: Our results indicated that the respective mechanism of each compound in combination GRS against MI/R injury might closely associated with energy metabolism modulation, suppression of inflammation and oxidative stress.

Antipruritic Effect of Ethyl Acetate Extract from Fructus cnidii in Mice with 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and skin lesions. The exact cause of AD is not yet known and the available therapeutic strategies for AD are limited. Fructus cnidii is commonly used in traditional Chinese medicine as an herb for treating chronic itch. However, the mechanism underlying the antipruritic effects of Fructus cnidii is not well understood. In the present study, we investigated the antipruritic effect of locally administered ethyl acetate extract from Fructus cnidii (EAEFC) to 2,4-dinitrofluorobenzene- (DNFB-) induced AD in a mouse model. The scratching behavior, skin thickness, dermatitis score, weight, blood immunoglobulin E (IgE) level, and itch-related cytokine levels were subsequently monitored and evaluated. Results showed that EAEFC treatment attenuated the DNFB-induced AD-like symptoms by alleviating the skin lesions and decreasing the dermatitis score. Hematoxylin and eosin (H&E) and toluidine blue (TB) staining analyses demonstrated that EAEFC mitigated the DNFB-induced increase in skin thickness and prevented the infiltration of mast cells. Behavioral tests showed that EAEFC decreased the DNFB-induced acute and chronic scratching behaviors. Furthermore, EAEFC reduced the levels of itch-related cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin- (IL-) 17, IL-33, and IL-31, and the DNFB-induced boost in serum IgE. Collectively, these results suggest that EAEFC is a potential therapeutic candidate for the treatment of chronic itch in AD.

YiQiFuMai Powder Injection Attenuates Coronary Artery Ligation-Induced Heart Failure Through Improving Mitochondrial Function via Regulating ROS Generation and CaMKII Signaling Pathways.

The YiQiFuMai powder injection (YQFM), a traditional Chinese medicine (TCM) prescription re-developed based on Sheng-Mai-San, is widely applied for the treatment of cardiovascular diseases. However, its potential molecular mechanism remains obscure. The present study was designed to observe the effects of YQFM and underlying mechanisms on coronary artery ligation (CAL)-induced heart failure (HF) and cell hypoxia of 24 h oxygen-glucose deprivation (OGD) in neonatal rat ventricular myocytes (NRVMs). HF was induced by permanent CAL for 2 weeks in ICR mice. The results demonstrated that YQFM significantly attenuated CAL-induced HF via improving the cardiac function, cardiac systolic function, cardiac structure impairment, cardiac histological features and fibrosis. YQFM markedly attenuated mitochondrial dysfunction through improving mitochondrial morphology, increasing mitochondria membrane potential (Δψm), mitochondrial ROS generation and expression of Mitofusin-2 (Mfn2), meanwhile, decreasing phosphorylation of dynamin-related protein 1 (p-Drp1). Mechanistically, YQFM could significantly decrease the expression of isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NADPH oxidase 2 (NOX2), p67phox and NADPH oxidase 4 (NOX4), ultimately reducing reactive oxygen species (ROS) generation. In addition, YQFM could down-regulate expression of calcium voltage-gated channel subunit α1C (CACNA1C) and phosphorylation of calmodulin dependent protein kinase II (p-CaMKII). These results suggest that YQFM ameliorates mitochondrial function in HF mice, partially through inhibiting ROS generation and CaMKII signaling pathways. Therefore, the present study provided scientific evidence for the underlying mechanism of YQFM.

Insufficient hypothalamic angiotensin-converting enzyme 2 is associated with hypertension in SHR rats.

Angiotensin-Converting Enzyme 2 (ACE2) is a key enzyme in the renin-angiotensin system (RAS), which is implicated in the pathogenesis of hypertension and other cardiovascular diseases. In this study we investigated the expression of ACE2 in the hypothalamus and pituitary tissues and its relationship to hypertension by comparing them in male WKY and SHR rats. We observed that the plasma levels of corticotrophin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and aldosterone (ALD) were all lower in SHR than WKY rats (P<0.05), whereas plasma angiotensin II (AngII) levels were higher in SHR rats (P<0.05). Levels of ACE mRNA and protein were higher in the hypothalamus of SHR than WKY rats (P<0.05). By contrast, hypothalamic expression of ACE2 protein was lower in SHR rats (P<0.05), despite comparable mRNA levels in SHR and WKY rats. There were no differences in the expression levels of ACE, ACE2, AT1 or Mas mRNA in the pituitaries of SHR and WKY rats (P>0.05). These results suggest that insufficiency of hypothalamic ACE2 is associated with hypertension in SHR rats.

Jatrorrhizine hydrochloride attenuates hyperlipidemia in a high-fat diet-induced obesity mouse model.

Jatrorrhizine hydrochloride (JH) is an active component of the traditional Chinese herb Coptis chinensis, which has been used to prevent and treat metabolic disorders. Hyperlipidemia is one of the principal factors underlying numerous metabolic diseases, including diabetes and obesity. Therefore, the aim of the present study was to investigate the lipid lowering effects of JH treatment in vivo in an obesity mouse model. JH-treated hyperlipidemic mice exhibited a reduction in body weight, as well as improved glucose tolerance and insulin sensitivity. In addition, JH­treated hyperlipidemic mice exhibited reduced serum triglyceride, total cholesterol and low­density lipoprotein cholesterol levels, as well as increased high­density lipoprotein cholesterol levels compared with untreated mice fed a high­fat diet. Notably, JH treatment ameliorated the pathophysiological changes observed in the livers of hyperlipidemic mice. At the molecular level, JH downregulated the hepatic mRNA expression levels of SREBP­1c and FAS, and induced PPAR­α and CPT1A mRNA expression in hyperlipidemic mice. These findings suggest that JH ameliorates hyperlipidemia via the suppression of lipogenesis and the enhancement of lipid oxidation in the liver.

Identification and differential expression of hepatopancreas microRNAs in red swamp crayfish fed with emodin diet.

Using high-throughput Illumina Solexa system, the differential miRNA expressions from hepatopancreas in red swamp crayfish (Procambarus clarkii) fed with diets containing 0 (control) and 75 mg emodin kg(-1) (trial) were identified, respectively. As a result, 13,335,928 raw reads from the control sample and 14,938,951 raw reads from the trial sample were obtained while 13,053,344 (98.77%) and 14,517,522 (98.34%) small RNA were identified, respectively. 106 mature miRNAs (belonging to 68 miRNA gene families) were identified. 35 miRNAs displayed significantly differential expressions between two libraries. Of these, comparing to the control library, 6 miRNAs were significantly up-regulated and 29 miRNAs were significantly down-regulated. Moreover, 5 novel miRNAs (2 from control sample, 3 from trial sample) and target genes were predicted. GO analysis suggested that these miRNAs might be involved in innate immune response, growth, metabolism, cellular process, biological regulation and stimulus response. Our knowledge from this study could contribute to a better understanding of the miRNAs roles in regulating innate immune response and the study of miRNA function in crayfish.