Identification and characterization of the cupin_1 domain-containing proteins in ma bamboo (Dendrocalamus latiflorus) and their potential role in rhizome sprouting.

Cupin_1 domain-containing protein (CDP) family, which is a member of the cupin superfamily with the most diverse functions in plants, has been found to be involved in hormone pathways that are closely related to rhizome sprouting (RS), a vital form of asexual reproduction in plants. Ma bamboo is a typical clumping bamboo, which mainly reproduces by RS. In this study, we identified and characterized 53 Dendrocalamus latiflorus CDP genes and divided them into seven subfamilies. Comparing the genetic structures among subfamilies showed a relatively conserved gene structure within each subfamily, and the number of cupin_1 domains affected the conservation among D. latiflorus CDP genes. Gene collinearity results showed that segmental duplication and tandem duplication both contributed to the expansion of D. latiflorus CDP genes, and lineage-specific gene duplication was an important factor influencing the evolution of CDP genes. Expression patterns showed that CDP genes generally had higher expression levels in germinating underground buds, indicating that they might play important roles in promoting shoot sprouting. Transcription factor binding site prediction and co-expression network analysis indicated that D. latiflorus CDPs were regulated by a large number of transcription factors, and collectively participated in rhizome buds and shoot development. This study significantly provided new insights into the evolutionary patterns and molecular functions of CDP genes, and laid a foundation for further studying the regulatory mechanisms of plant rhizome sprouting.

Risk factors for bronchopulmonary dysplasia infants with respiratory score greater than four: a multi-center, prospective, longitudinal cohort study in China.

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity involving both pre- and post-natal factors. A large, prospective, longitudinal cohort study was conducted to determine whether inflammation-related factors are associated with an increased risk of BPD in preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and respiratory score > 4. The study included infants from 25 participating hospitals in China between March 1, 2020 and March 31, 2022. The primary outcomes were BPD and severity of BPD at 36 weeks post-menstrual age. A total of 1362 preterm infants were enrolled in the study. After exclusion criteria, the remaining 1088 infants were included in this analysis, of whom, 588 (54.0%) infants were in the BPD group and 500 (46.0%) were in the non-BPD group. In the BPD III model, the following six factors were identified: birth weight (OR 0.175, 95% CI 0.060-0.512; p = 0.001), surfactant treatment (OR 8.052, 95% CI 2.658-24.399; p < 0.001), mean airway pressure (MAP) ≥ 12 cm H2O (OR 3.338, 95% CI 1.656-6.728; p = 0.001), late-onset sepsis (LOS) (OR 2.911, 95% CI 1.514-5.599; p = 0.001), ventilator-associated pneumonia (VAP) (OR 18.236, 95% CI 4.700-70.756; p < 0.001) and necrotizing enterocolitis (NEC) (OR 2.725, 95% CI 1.182-6.281; p = 0.019). Premature infants remained at high risk of BPD and with regional variation. We found that post-natal inflammation-related risk factors were associated with an increased risk of severe BPD, including LOS, VAP, NEC, MAP ≥ 12 cm H2O and use of surfactant.

Whole-genome resequencing of wild and cultivated cannabis reveals the genetic structure and adaptive selection of important traits.

BACKGROUND: Cannabis is an important industrial crop species whose fibre, seeds, flowers and leaves are widely used by humans. The study of cannabinoids extracted from plants has been popular research topic in recent years. China is one of the origins of cannabis and one of the few countries with wild cannabis plants. However, the genetic structure of Chinese cannabis and the degree of adaptive selection remain unclear. RESULTS: The main morphological characteristics of wild cannabis in China were assessed. Based on whole-genome resequencing SNPs, Chinese cannabis could be divided into five groups in terms of geographical source and ecotype: wild accessions growing in the northwestern region; wild accessions growing in the northeastern region; cultivated accessions grown for fibre in the northeastern region; cultivated accessions grown for seed in northwestern region, and cultivated accessions in southwestern region. We further identified genes related to flowering time, seed germination, seed size, embryogenesis, growth, and stress responses selected during the process of cannabis domestication. The expression of flowering-related genes under long-day (LD) and short-day (SD) conditions showed that Chinese cultivated cannabis is adapted to different photoperiods through the regulation of Flowering locus T-like (FT-like) expression. CONCLUSION: This study clarifies the genetic structure of Chinese cannabis and offers valuable genomic resources for cannabis breeding.

Maternal Ureaplasma exposure during pregnancy and the risk of preterm birth and BPD: a meta-analysis.

PURPOSE: Perinatal Ureaplasma infection is associated with a variety of adverse outcomes and neonatal diseases. This meta-analysis is to evaluate current evidence evaluating the association between Ureaplasma and adverse pregnancy outcomes and bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: We searched for published articles on Ureaplasma, preterm and BPD in PubMed, the Cochrane Library, and Embase databases posted before August 28, 2021. In addition, the references of these articles were screened. A random/fixed-effect model was used to synthesize predefined outcomes. RESULTS: A total of 19 cohort studies involving 11,990 pregnancy women met our inclusion criteria. Pregnancy Ureaplasma positive increased the risk of preterm birth [odds ratios (OR) 2.76, 95% confidence intervals (CI) 1.63-4.68], BPD (OR 2.39 95% CI 1.73-3.30), chorioamnionitis (OR 2.71, 95% CI 2.02-3.64) and premature rupture of membranes (PROM, OR 2.19, 95% CI 1.34-3.58). CONCLUSIONS: Pregnancy Ureaplasma positive may increase the risk of developing preterm birth, chorioamnionitis, PROM and BPD in the preterm infant. The evidence base is, however, of low quality and well-designed studies are needed.

Risk factors for peripherally inserted central catheterization-associated bloodstream infection in neonates. / ç»å¤–å‘¨é™è„‰ç©¿åˆºä¸­å¿ƒé™è„‰ç½®ç®¡æ‚£å„¿ç›¸å ³æ€§è¡€æºæ„ŸæŸ“çš„å±é™©å› ç´ åˆ†æž.

OBJECTIVES: To study the features of catheter-related bloodstream infection (CRBSI) or central line-associated bloodstream infection (CLABSI) after peripherally inserted central catheterization (PICC) in neonates admitted to the neonatal intensive care unit (NICU) and the risk factors for CRBSI or CLABSI. METHODS: A retrospective analysis was performed on the medical data of the neonates who were treated and required PICC in the NICU of the Children's Hospital, Zhejiang University School of Medicine from June 1, 2018 to May 1, 2020. The catheterization-related data were collected, including placement time, insertion site, removal time, and antimicrobial lock of PICC. The multivariate logistic regression model was used to investigate the risk factors for CRBSI or CLABSI in the neonates. RESULTS: A total of 446 neonates were enrolled, with a mean gestational age of (30.8±4.0) weeks, a mean birth weight of (1 580±810) g, a median age of 9 days, and a median duration of PICC of 18 days. The incidence rates of CLABSI and CRBSI were 5.6 and 1.46 per 1 000 catheter days, respectively. Common pathogens for CLABSI caused by PICC included Staphylococcus epidermidis (n=19) and Klebsiella pneumoniae (n=11), and those for CRBSI caused by PICC included Klebsiella pneumoniae (n=6). The risk of CLABSI caused by PICC increased significantly with prolonged durations of PICC and antibiotic use, and the PICC-related infection probability at head and neck was significantly lower than that in the upper and low limbs (P<0.05), while the above conditions were more obvious in neonates with a birth weight of <1 500 g. The risk of CRBSI caused by PICC decreased with the increase in gestational age (P<0.05). CONCLUSIONS: CRBSI and CLABSI remain serious issues in NICU nosocomial infection. The identification of the risk factors for CRBSI and CLABSI provides a basis for improving the quality of clinical care and management.

USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2.

TET2 DNA dioxygenase is frequently mutated in human hematopoietic malignancies and functionally inactivated in many solid tumors through a nonmutational mechanism. We recently found that TET2 mediates the interferon-JAK-STAT pathway to stimulate chemokine expression and tumor infiltration of lymphocytes (TILs). TET2 is monoubiquitylated at K1299, which promotes its activity. Here, we report that USP15 is a TET2 deubiquitinase and inhibitor. USP15 catalyzes the removal of K1299-linked monoubiquitin and negatively regulates TET2 activity. Gene expression profiling demonstrates that TET2 and USP15 oppositely regulate genes involved in multiple inflammatory pathways, and TET2 is a major target of USP15 function. Deletion of Usp15 in melanoma stimulates chemokine expression and TILs in a TET2-dependent manner, leading to increased response to immunotherapy and extended life span of tumor-bearing mice. These results reveal a previously unknown regulator of TET2 activity and suggest USP15 as a potential therapeutic target for immunotherapy of solid tumors.

Inoculation Pneumonia Caused by Coagulase Negative Staphylococcus.

RATIONALE: Although frequently retrieved in tracheal secretions of critically ill patients on mechanical ventilation, the existence of pneumonia caused by coagulase-negative staphylococci (CoNS) remains controversial. OBJECTIVE: To assess whether Staphylococcus haemolyticus (S. haemolyticus) inoculated in mice's trachea can infect normal lung parenchyma, increasing concentrations of S. haemolyticus were intratracheally administered in 221 immunocompetent mice. METHODS: Each animal received intratracheally phosphate-buffered saline (PBS) (n = 43) or live (n = 141) or inactivated (n = 37) S. haemolyticus at increasing load: 1.0 × 106, 1.0 × 107, and 1.0 × 108 colony forming units (CFU). Forty-three animals were sacrificed at 12 h and 178 were sacrificed at 36 h; 64 served for post-mortem lung histology, 157 served for pre-mortem bronchoalveolar lavage (BAL) analysis, and 42 served for post-mortem quantitative bacteriology of lung tissue. The distribution of biofilm-associated genes was investigated in the S. haemolyticus strain used in our in vivo experiment as well as among 19 other clinical S. haemolyticus strains collected from hospitals or nursing houses. MEASUREMENTS AND MAIN RESULTS: Intratracheal inoculation of 1.0 × 108 CFU live S. haemolyticus caused macroscopic and histological confluent pneumonia with significant increase in BAL white cell count, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein (MIP)-2. At 12 h, high concentrations of S. haemolyticus were identified in BAL. At 36 h, lung injury and BAL inflammation were less severe than at 12 h and moderate concentrations of species belonging to the oropharyngeal flora were identified in lung tissue. The inoculation of 1.0 × 106 and 1.0 × 107 CFU live S. haemolyticus caused histologic interstitial pneumonia and moderate BAL inflammation. Similar results were observed after inoculation of inactivated S. haemolyticus. Moreover, biofilm formation was a common phenotype in S. haemolyticus isolates. The low prevalence of the ica operon in our clinical S. haemolyticus strain collection indicated icaA and icaD independent-biofilm formation. CONCLUSION: In immunocompetent spontaneously breathing mice, inoculation of S. haemolyticus causes concentration-dependent lung infection that spontaneously recovers over time. icaA and icaD independent biofilm formation is a common phenotype in S. haemolyticus isolates.

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy.

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased TH1-type chemokines and tumor-infiltrating lymphocytes (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-JAK-STAT-TET signaling pathway that mediates tumor response to anti-PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.

[Source Apportionment and Pollution Characteristics of PM2.5 During the Two Heavy Pollution Episodes in the Winter of 2016 in a Typical Logistics City].

To characterize the chemical composition of PM2.5 and the formation of pollution during a heavy pollution episode in the winter in a typical logistics city, PM2.5 samples were collected from December 2016 to January 2017 at six sampling sites, and the water-soluble ions, elements, and carbon components were determined. The results showed that the average concentration of PM2.5 was (145.2±87.8) µg·m-3 during the whole sampling period, of which 82% of daily average concentrations were above class Ⅱ of the national standards. The average concentrations of PM2.5 during the two heavy pollution episodes were (187.3±79.8) and (205.3±92.0) µg·m-3, which were 5.4 and 5.9 times, respectively, as high as class Ⅱ of the national standard. The results of the chemical composition of the PM2.5 showed that secondary water-soluble inorganic ions (SO42-, NO3-, and NH4+) were the main components of PM2.5 in winter (51.2% of PM2.5 mass concentration), followed by organic matter (OM, 23.8%), and mineral dust (12.7%). Combined with the change trend and accumulation rate of chemical components during the pollution episode, we discovered that the increasing of SNA and OM led to PM2.5 pollution in the first episode, while the growth of SNA caused the second pollution episode. This was further verified by the synchronous change of SOR, NOR, and the OC/EC ratio. PMF analysis indicated that mixed sources of secondary particulate matter and biomass combustion (50.0%), coal combustion (16.8%), vehicles (12.9%), fugitive dust (10.0%), industry (5.3%) and soil dust (5.0%), were the main sources of PM2.5 of Linyi city in the winter. Compared with the average concentration over the whole sampling period, the contribution of secondary particles during the two pollution episodes was significantly increased. This indicates that the formation and accumulation of secondary particulate matter under static and humid meteorological conditions were the main influencing factors during the heavy pollution episodes.

The Impact of Renal Denervation on the Progression of Heart Failure in a Canine Model Induced by Right Ventricular Rapid Pacing.

Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson's trichrome staining and the expression of transforming growth factor-ß1 (TGF-ß1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin-angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.

Atypical CHARGE associated with a novel frameshift mutation of CHD7 in a Chinese neonatal patient.

BACKGROUND: CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7, which has been estimated to occur in 1:10,000 births worldwide. It is a genetic disorder closely resembles other pattern of anomalies. Genetic testing should be pointed out as a useful method for clinical diagnosis. CASE PRESENTATION: A female infant was the second child born to a 33-year-old, gravida 3, para 2 mother. The infant was born at 37 + 4 weeks of gestation with a birth weight of 2440 g (- 1.1 S.D.). Clinical examination showed atypical CHARGE syndrome, with choanal atresia, a heart defect, and sensorineural deafness. Genomic DNA was extracted from peripheral venous blood sample using molecular biological technique. We used the Illumina TruSigt One sequencing panel on the MiSeq next- generation sequencing (NGS) platform for mutation screening and found a novel frameshift mutation in chromodomain helicase DNA binding protein 7 (CHD7; c.4656dupT). This mutation results in a new reading frame ending in p.(Ile1553fs). At the first month of age, the patient had a posterior nostril plasty operation by nasal endoscope. At the second month of age, she had patent ductus arteriosus ligation surgery. At the 4th month of age, she was discharged from the hospital. CONCLUSIONS: Our findings further reveal that patients should not be rejected for CHD7 mutational analysis even if they do not fulfill CHARGE syndrome Verloes criteria.

Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.

Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.

Hesperetin alleviates renal interstitial fibrosis by inhibiting tubular epithelial-mesenchymal transition in vivo and in vitro.

Hesperetin (HES) is a flavonoid that has been reported to exert protective effects against cardiac remodeling, lung fibrosis and hepatic fibrosis. However, reports on the effects and potential mechanisms of HES in renal fibrosis are limited. In the present study, a unilateral ureteric obstruction (UUO) mouse model and a transforming growth factor (TGF)-ß1-activated normal rat kidney (NRK)-52E cell model were established. HES was subsequently administered to these models to evaluate its anti-fibrotic effects and potential underlying mechanisms of action. The results demonstrated that HES reduced obstruction-induced renal injury and deposition of the extracellular matrix components collagen-I and fibronectin in UUO mouse kidneys (P<0.05). Furthermore, HES treatment significantly suppressed EMT, as evidenced by decreased expression of α-smooth muscle actin and E-cadherin, (P<0.05). Additionally, HES inhibited the hedgehog signaling pathway in UUO mice and TGF-ß1-treated NRK-52E cells. The present findings indicate that HES treatment may inhibit EMT and renal fibrosis in vivo and in vitro by antagonizing the hedgehog signaling pathway.

MiR-126a-5p is involved in the hypoxia-induced endothelial-to-mesenchymal transition of neonatal pulmonary hypertension.

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by increased medial and adventitial thickness of the lung vasculature. The underlying mechanisms that regulate the cell phenotype alteration during PPHN remodeling are largely unknown. We randomly selected newborn rats that were exposed to hypoxia (10-12%) or room air for 2 weeks and used a microarray to identify the lung tissue microRNAs (miRNAs) involved in PPHN progression. The role of a key miRNA that affects the endothelial-to-mesenchymal transition (EndMT) in primary cultured rat pulmonary microvascular endothelial cells (RPMECs) was investigated. The expression of miR-126a-5p was elevated in the PPHN model according to microarray analysis. The relative expression of miR-126a-5p in RPMECs increased when they were exposed to hypoxia (P<0.05), consistent with the microarray results. Pecam1 expression decreased, whereas alpha-smooth muscle actin (α-SMA) increased in the hypoxic RPMECs. Knockdown of miR-126a-5p in RPMECs followed by treatment with hypoxia for 48 h resulted in a significant increase in the expression of Pecam1 and a reduction in α-SMA expression, with a simultaneous increase in PI3K (p85ß) and phosphorylation of AKT at serine 473 compared with the negative control. Finally, the circulating miR-126a-5p concentration was upregulated in the PPHN model compared with healthy neonates. We concluded that hypoxia changed the cell homeostasis and that miR-126a-5p was upregulated in PPHN, which is partly responsible for hypoxia-induced EndMT. The mechanism underlying the upregulation of miR-126a-5p by hypoxia probably acts through the p85-ß/p-AKT pathway.

Bronchopulmonary Dysplasia in Preterm Infants Born at Less Than 32 Weeks Gestation.

OBJECTIVES: Bronchopulmonary dysplasia (BPD) is a chronic pulmonary disorder affecting preterm infants. We studied the factors and echocardiographic evidence of early pulmonary hypertension (PH) associated with moderate or severe BPD. METHODS: We retrospectively reviewed preterm infants who were born at <32 weeks gestation and admitted to the neonatal intensive care unit at the Children's Hospital of Zhejiang University School of Medicine between July 2013 and July 2015. RESULTS: Forty-two preterm infants were enrolled in the study. All the patients received oxygen treatment for a mean of 62.5 ± 28.0 days. The grades of BPD were classified as follows: severe, 35.7%; moderate, 40.5%; and mild, 23.8%. The time of ventilator and oxygen supplementation was longer in infants who developed PH. Severe BPD was related to PH at 28 days. CONCLUSIONS: These findings support the notion that early pulmonary vascular disease and long-term infection in preterm infants contributes to increased susceptibility for severe BPD.

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-ß1-Smad3 pathway.

This study investigated whether oxymatrine (OMT) treatment can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) mice model. Moreover, the potential mechanisms of such treatment were analyzed. Twenty-four C57/BL6 mice were randomly divided into three groups, namely sham group, vehicle plus unilateral ureteral obstruction (UUO)-treated group, and 100 mg/kg/d OMT plus UUO-treated group. All mice were euthanized seven days after surgery, and their kidneys were harvested. Renal injury, fibrosis, expression of proinflammatory cytokines, and the transforming growth factor-ß1/Smads (TGF-ß/Smads) and nuclear factor-kappa B (NF-κB)-signaling pathways were assessed. The results showed OMT significantly prevented kidney injury and fibrosis, as evidenced by decreased expression of collagen-1 and fibronectin. Furthermore, OMT administration inhibited the release of inflammatory factors including tumor necrosis factor-α, (TNF-α) interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as phosphorylated NF-κB p65. In addition, OMT blocked the activation of myofibroblasts by inhibiting the TGF-ß/Smad3-signaling pathway. The findings indicate that OMT-attenuated renal fibrosis and inflammation, and this renoprotective effect may be ascribed to the inactivation of the TGF-ß/Smad3 and NF-κB p65 pathways.

Association between UCP3 gene polymorphisms and nonalcoholic fatty liver disease in Chinese children.

AIM: To confirm the hypothesis that polymorphisms of the uncoupling protein 3 (UCP3) gene are associated with the occurrence of nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 250 NAFLD patients (147 males and 103 females) and 200 healthy individuals who served as controls (control, 109 males and 91 females), aged between 6 and 16 years were enrolled in this study. The four non-synonymous single nucleotide polymorphisms (SNPs) in the UCP3 gene polymorphisms of rs1726745, rs3781907, rs11235972 and rs1800849, were genotyped using MassArray. Body mass index (BMI), waist and hip circumference, blood pressure (BP), fasting blood glucose (FBG), insulin and lipid profiles were measured and B-ultrasound examination was performed in all subjects. RESULTS: NAFLD patients showed risk factors for metabolic syndrome: elevated BMI, waist-to-hip ratio, BP, FBG, homeostasis model assessment-estimated insulin resistance, total triglyceride, total cholesterol and low-density lipoprotein-cholesterol, while decreased high-density lipoprotein-cholesterol level compared with the control group. The GG genotype distributions of rs11235972 in the NAFLD group differed significantly from that in the control group. We found that waist circumference between CC (58.76 ± 6.45 cm) and CT+TT (57.00 ± 5.59 cm), and hip circumference between CC (71.28 ± 7.84 cm) and CT+TT genotypes (69.06 ± 7.75 cm) were significantly different with and without rs1800849 variation (P < 0.05). CONCLUSION: A higher prevalence of rs11235972 GG genotype was observed in the NAFLD group compared with the control group. No differences were observed for the other SNPs. However, there was a significant difference in body height in addition to waist and hip circumference between the CC (mutant type group) and CT+TT group with and without rs1800849 variation.

Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization.

Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylation-mimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.