Analysis of perinatal risk factors for massive pulmonary hemorrhage in very low birth weight infant: A nationwide large cohort database.

OBJECTIVE: To determine perinatal risk factors for Massive pulmonary hemorrhage (MPH) and MPH-caused mortality to guide clinicians in implementing preventive measures at the beginning of life for improving the survival of very low birth weight infant (VLBWIs). STUDY DESIGN: A total of 13,826 VLBWIs born between 2013 and 2020 in the Korean Neonatal Network database were included. RESULTS: MPH occurred in 870 (6.3 %) VLBWIs. Among infants with MPH, 162 (18.6 %) VLBWIs died due to MPH. In the multivariate logistic regression analysis, independent risk factors for MPH were identified as small for gestational age, multiple gestation, high CRIB-II score, use of surfactant, and symptomatic patent ductus arteriosus (sPDA) in VLBIWs. Independent risk factors for MPH-caused mortality were identified as multiple gestation in VLBWIs. Receiving a complete course of antenatal corticosteroids (ACS) was found to be a significant independent protective factor for MPH-caused mortality in VLBWIs. CONCLUSION: Proactive managements for reducing unnecessary use of pulmonary surfactant and for decreasing the risk of sPDA at the beginning of life could be recommended as preventive strategies to reduce the risk of MPH in extremely preterm infants. ACS therapy is highly recommended for women with a high likelihood of giving birth preterm to reduce the risk of mortality caused by MPH.

Particulate matter induces arrhythmia-like cardiotoxicity in zebrafish embryos by altering the expression levels of cardiac development- and ion channel-related genes.

Air pollution is a risk factor that increases cardiovascular morbidity and mortality. In this study, we investigated the cardiotoxicity of particulate matter (PM) exposure using a zebrafish embryo model. We found that PM exposure induced cardiotoxicity, such as arrhythmia, during cardiac development. PM exposure caused cardiotoxicity by altering the expression levels of cardiac development (T-box transcription factor 20, natriuretic peptide A, and GATA-binding protein 4)- and ion-channel (scn5lab, kcnq1, kcnh2a/b, and kcnh6a/b)-related genes. In conclusion, this study showed that PM induces the aberrant expression of cardiac development- and ion channel-related genes, leading to arrhythmia-like cardiotoxicity in zebrafish embryos. Our study provides a foundation for further research on the molecular and genetic mechanisms of cardiotoxicity induced by PM exposure.

Morbidity and Mortality Trends in Preterm Infants of <32 Weeks Gestational Age with Severe Intraventricular Hemorrhage : A 14-Year Single-Center Retrospective Study.

OBJECTIVE: Owing to advances in critical care treatment, the overall survival rate of preterm infants born at a gestational age (GA) <32 weeks has consistently improved. However, the incidence of severe intraventricular hemorrhage (IVH) has persisted, and there are few reports on in-hospital morbidity and mortality. Therefore, the aim of the present study was to investigate trends surrounding in-hospital morbidity and mortality of preterm infants with severe IVH over a 14-year period. METHODS: This single-center retrospective study included 620 infants born at a GA <32 weeks, admitted between January 2007 and December 2020. After applying exclusion criteria, 596 patients were included in this study. Infants were grouped based on the most severe IVH grade documented on brain ultrasonography during their admission, with grades 3 and 4 defined as severe. We compared in-hospital mortality and clinical outcomes of preterm infants with severe IVH for two time periods : 2007-2013 (phase I) and 2014-2020 (phase II). Baseline characteristics of infants who died and survived during hospitalization were analyzed. RESULTS: A total of 54 infants (9.0%) were diagnosed with severe IVH over a 14-year period; overall in-hospital mortality rate was 29.6%. Late in-hospital mortality rate (>7 days after birth) for infants with severe IVH significantly improved over time, decreasing from 39.1% in phase I to 14.3% in phase II (p=0.043). A history of hypotension treated with vasoactive medication within 1 week after birth (adjusted odds ratio, 7.39; p=0.025) was found to be an independent risk factor for mortality. When comparing major morbidities of surviving infants, those in phase II were significantly more likely to have undergone surgery for necrotizing enterocolitis (NEC) (29.2% vs. 0.0%; p=0.027). Additionally, rates of late-onset sepsis (45.8% vs. 14.3%; p=0.049) and central nervous system infection (25.0% vs. 0.0%; p=0.049) were significantly higher in phase II survivors than in phase I survivors. CONCLUSION: In-hospital mortality in preterm infants with severe IVH decreased over the last decade, whereas major neonatal morbidities increased, particularly surgical NEC and sepsis. This study suggests the importance of multidisciplinary specialized medical and surgical neonatal intensive care in preterm infants with severe IVH.

Myelin toxicity of chlorhexidine in zebrafish larvae.

BACKGROUND: Chlorhexidine gluconate (CHG) is a topical antiseptic solution recommended for skin preparation before central venous catheter placement and maintenance in adults and children. Although CHG is not recommended for use in children aged <2 months owing to limited safety data, it is commonly used in neonatal intensive care units worldwide. We used zebrafish model to verify the effects of early-life exposure to CHG on the developing nervous system, highlighting its impact on oligodendrocyte development and myelination. METHODS: Zebrafish embryos were exposed to different concentrations of CHG from 4 h post fertilization to examine developmental toxicity. The hatching rate, mortality, and malformation of the embryos/larvae were monitored. Oligodendrocyte lineage in transgenic zebrafish embryos was used to investigate defects in oligodendrocytes and myelin. Myelin structure, locomotor behavior, and expression levels of genes involved in myelination were investigated. RESULTS: Exposure to CHG significantly induced oligodendrocyte defects in the central nervous system, delayed myelination, and locomotor alterations. Ultra-microstructural changes with splitting and fluid-accumulated vacuoles between the myelin sheaths were found. Embryonic exposure to CHG decreased myelination, in association with downregulated mbpa, plp1b, and scrt2 gene expression. CONCLUSION: Our results suggest that CHG has a potential for myelin toxicity in the developing brain. IMPACT: To date, the neurodevelopmental toxicity of chlorhexidine gluconate (CHG) exposure on the developing brains of infants remains unknown. We demonstrated that CHG exposure to zebrafish larvae resulted in significant defects in oligodendrocytes and myelin sheaths. These CHG-exposed zebrafish larvae exhibited structural changes and locomotor alterations. Given the increased CHG use in neonates, this study is the first to identify the risk of early-life CHG exposure on the developing nervous system.

Association of delayed initiation of non-invasive respiratory support with pulmonary air leakage in outborn late-preterm and term neonates.

The frequency of non-invasive respiratory support use has increased in neonates of all gestational ages with respiratory distress (RD). However, the impact of delayed initiation of non-invasive respiratory support in outborn neonates remains poorly understood. This study aimed to identify the impact of the delayed initiation of non-invasive respiratory support in outborn, late-preterm, and term neonates. Medical records of 277 infants (gestational age of ≥ 35 weeks) who received non-invasive respiratory support as primary respiratory therapy < 24 h of age between 2016 and 2020 were retrospectively reviewed. Factors associated with respiratory adverse outcomes were investigated in 190 outborn neonates. Infants with RD were divided into two groups: mild (fraction of inspired oxygen [FiO2] ≤ 0.3) and moderate-to-severe RD (FiO2 > 0.3), depending on their initial oxygen requirements from non-invasive respiratory support. The median time for the initiation of non-invasive respiratory support at a tertiary center was 3.5 (2.2-5.0) h. Male sex, a high oxygen requirement (FiO2 > 0.3), high CO2 level, and respiratory distress syndrome were significant factors associated with adverse outcomes. Subgroup analysis revealed that in the moderate-to-severe RD group, delayed commencement of non-invasive respiratory support (≥ 3 h) was significantly associated with pulmonary air leakage (p = 0.033). CONCLUSION: Our study shows that outborn neonates with moderate-to-severe RD, who were treated with delayed non-invasive respiratory support, were associated with an increased likelihood of pulmonary air leakage. Additional prospective studies are required to establish the optimal timing and methods of non-invasive respiratory support for outborn, late-preterm, and term infants. WHAT IS KNOWN: • Non-invasive respiratory support is widely used in neonates of all gestational ages. • Little is known on the impact of delayed initiation of non-invasive respiratory support in outborn, late preterm, and term neonates. WHAT IS NEW: • Male sex, high oxygen requirement (FiO2 >0.3), high initial CO2 level, and respiratory distress syndrome significantly correlated with adverse outcomes. • Outborn late-preterm and term neonates with high oxygen requirement who were treated with delayed non-invasive respiratory support indicated an increased likelihood of pulmonary air leakage.

DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts.

Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated ß-galactosidase (SA-ß-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21 Waf1/Cip1 , and p16 Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.

Conservative Treatment Without Any Intervention Compared With Other Therapeutic Strategies for Symptomatic Patent Ductus Arteriosus in Extremely Preterm Infants: A Nationwide Cohort Study in Korea.

Objective: Although symptomatic treatment is the most preferred treatment strategy for proven symptomatic patent ductus arteriosus (PDA), a considerable number of infants only received conservative treatment without any pharmacological or surgical interventions in the lower gestational age and lower birth weight group in Korea. We compared in-hospital outcomes of infants treated conservatively without any intervention and those of infants managed by other therapeutic strategies in extremely preterm infants with symptomatic PDA. Methods: A prospectively collected cohort study for 2,303 infants with gestational ages <28 weeks from the Korean Neonatal Network database. These infants were classified into four groups according to the presence of PDA-related symptoms and therapeutic treatment strategy: prophylactic treatment group, pre-symptomatic treatment (PST) group, symptomatic treatment (ST) group, and conservative treatment (CT) without any intervention group. Results: In multivariable logistic regression analysis, the risk of death was significantly decreased in the PST group (adjusted odds ratio [aOR] = 0.507; 95% confidence interval [CI] 0.311-0.826) and ST group (aOR = 0.349; 95% CI: 0.230-0.529) compared with the CT group. However, the risk of composite outcome of severe bronchopulmonary dysplasia or death had not increased in the PST group and ST group. Neonatal death due to pulmonary hemorrhage or neurological disease was significantly higher in the CT group than in the PST group or ST group. Conclusion: In extremely preterm infants, who are at highest risk of PDA-related morbidities and mortality, even less interventional approach for PDA can be allowed; the rescued pharmacological or surgical interventions are necessary if they met the criteria for hemodynamically significant PDA.

Risk factors and prognosis in very low birth weight infants treated for hypotension during the first postnatal week from the Korean Neonatal Network.

Hypotension in the early stages of life appears in 20% of very low birth weight (VLBW) infants. The gestational age and birth weight are the risk factors highly related to the postnatal hypotension. Other risk factors slightly differ between different studies. So, we evaluated the risk factors and prognosis that are associated with infants treated with hypotension in the early stages of life, after excluding the influences of gestational age and small for gestational age (SGA). VLBW infants registered in the Korean Neonatal Network between 2013 and 2015 treated for hypotension within a week after their birth were selected as study subjects. The rest were used as a control group. Risk factors and the prevalence of severe complications, including mortality, were investigated and compared after matching for gestational age and SGA. The treatment rate for hypotension within the first postnatal week was inversely related to decreasing gestational ages and birth weights. In particular, 63.4% of preterm infants born at ≤ 24 weeks' gestation and 66.9% of those with a birth weight < 500 g were treated for hypotension within a week of birth. Regression analysis after matching showed that 1-minute Apgar score, neonatal cardiac massage or epinephrine administration, symptomatic patent ductus arteriosus, early onset sepsis, and chorioamnionitis were significantly associated with hypotension. In the hypotension group, mortality, grade 3 or higher intraventricular hemorrhage, periventricular leukomalacia, and moderate to severe bronchopulmonary dysplasia rates were significantly higher after the matching for gestational age and SGA. Hypotension during the first postnatal week is very closely related to the prematurity and the condition of the infant shortly after birth. Regular prenatal care including careful monitoring and appropriate neonatal resuscitation are very crucial to decrease the risk of hypotension in the early stages of life.

Luteolin inhibits H2O2-induced cellular senescence via modulation of SIRT1 and p53.

Luteolin, a sort of flavonoid, has been reported to be involved in neuroprotective function via suppression of neuroinflammation. In this study, we investigated the protective effect of luteolin against oxidative stress-induced cellular senescence and its molecular mechanism using hydrogen peroxide (H2O2)-induced cellular senescence model in House Ear Institute-Organ of Corti 1 cells (HEI-OC1). Our results showed that luteolin attenuated senescent phenotypes including alterations of morphology, cell proliferation, senescence-associated ß-galactosidase expression, DNA damage, as well as related molecules expression such as p53 and p21 in the oxidant challenged model. Interestingly, we found that luteolin induces expression of sirtuin 1 in dose- and time-dependent manners and it has protective role against H2O2-induced cellular senescence by upregulation of sirtuin 1 (SIRT1). In contrast, the inhibitory effect of luteolin on cellular senescence under oxidative stress was abolished by silencing of SIRT1. This study indicates that luteolin effectively protects against oxidative stress-induced cellular senescence through p53 and SIRT1. These results suggest that luteolin possesses therapeutic potentials against age-related hearing loss that are induced by oxidative stress.

Size of Patent Ductus Arteriosus and Echocardiographic Markers of Shunt Volume in Preterm Infants Based on Postnatal Age.

Objective: This study was conducted in order to compare the strength of correlation between echocardiographic markers of shunt volume and patent ductus arteriosus (PDA) diameter based on postnatal age. Methods: This retrospective study focused on preterm infants (aged <32 weeks of gestation) admitted to the Neonatal Intensive Care Unit of Korea University Ansan Hospital, between April 2014 and December 2017, who studied serial targeted neonatal echocardiography (TNE) for PDA during hospitalization. The association between echocardiographic characteristics and duct size was divided into the following days: within 3 days (very early, VE), 4-7 days after birth (early, E), and after 8 days of birth (late, L). Results: We found 113 assessments conducted on 57 infants in the VE period, 92 assessments on 40 infants in the E period, and 342 assessments on 37 infants in the L period. Median gestational age and birth weight were 28+2 weeks of gestation and 1,115 g, respectively. In the univariate regression analysis, we found a statistically significant correlation between PDA diameter and all TNE markers in the E and L days, but not in the VE period. Only ductal velocity [coefficient of determination (R 2) = 0.224], antegrade left pulmonary artery diastolic flow velocity (R 2 = 0.165), left ventricular output (LVO)/superior vena cava (SVC) flow ratio (R 2 = 0.048), and E/A wave ratio (R 2 = 0.092) showed weak correlations with PDA diameter in the VE period. The slopes of the regressions showed significant changes based on postnatal age in the maximum ductal velocity, left atrium/aorta ratio, LVO/SVC flow ratio, and LVO. Conclusions: It is difficult to predict the echocardiographic markers of shunt volume based on the PDA diameter in preterm infants younger than 4 days. A better understanding of the changes in the hemodynamic consequences of PDA based on postnatal age is needed when considering treatment.

Apigenin Alleviates Oxidative Stress-Induced Cellular Senescence via Modulation of the SIRT1-NAD[Formula: see text]-CD38 Axis.

Oxidative stress-induced cellular senescence is now regarded as an important driving mechanism in chronic lung diseases-particularly chronic obstructive pulmonary disease (COPD). 4[Formula: see text],5,7-trihydroxyflavone (Apigenin) is a natural flavonoid product abundantly present in fruits, vegetables, and Chinese medicinal herbs. It has been known that apigenin has anti-oxidant, anti-inflammatory and liver-protecting effects. The efficacy of apigenin for lung aging, however, has not been reported. In this study, we selected the hydrogen peroxide (H2O[Formula: see text]- or doxorubicin (DOXO)-induced senescence model in WI-38 human embryonic lung fibroblast cells to determine the potential anti-aging effects of apigenin in vitro and associated molecular mechanisms. We found that apigenin reduced senescence-associated [Formula: see text]-galactosidase (SA-[Formula: see text]-gal) activity and promoted cell growth, concomitant with a decrease in levels of Acetyl (ac)-p53, p21[Formula: see text], and p16[Formula: see text] and an increase in phospho (p)-Rb. Apigenin also increased the activation ratio of silent information regulator 1 (SIRT1), nicotinamide adenine dinucleotide (NAD[Formula: see text], and NAD[Formula: see text]/NADH and inhibited cluster of differentiation 38 (CD38) activity in a concentration-dependent manner. SIRT1 inhibition by SIRT1 siRNA abolished the anti-aging effect of apigenin. In addition, CD38 inhibition by CD38 siRNA or apigenin increased the SIRT1 level and reduced H2O2-induced senescence. Our findings suggest that apigenin is a promising phytochemical for reducing the impact of senescent cells in age-related lung diseases such as COPD.

Changes in gene expression of cervical collagens, metalloproteinases, and tissue inhibitors of metalloproteinases after partial cervical excision-induced preterm labor in mice.

We investigated changes in gene expression of cervical collagens, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) during pre-gestational uterine cervical excision and/or inflammation-induced preterm labor in mice. Forty sexually mature female mice were uniformly divided into four groups: sham, cervical excision, lipopolysaccharide (LPS) injection, and cervical excision plus LPS injection. Partial cervical tissue excision was performed at five weeks of age before mating. LPS was injected into the lower right uterine horn near the cervix on gestational day 16. Mice were sacrificed immediately postpartum. Uterine cervices were collected and subjected to quantitative real-time PCR. Col4α1 and Col5α1 expression increased significantly in the cervical excision plus LPS injection group compared to the sham group (p < 0.01 and p = 0.024, respectively). MMP-14 expression levels increased in the cervical excision plus LPS injection group compared to the sham group (p < 0.01). TIMP-1 expression was not significantly decreased in this group. Increased expression levels of Col4α1, Col5α1, and MMP-14 were associated with cervical excision plus inflammation-induced preterm labor. Thus, pre-gestational cervical remodeling through specific collagen metabolism and MMP activation may involve the pathogenesis of spontaneous preterm labor.

Perinatal Outcomes Associated with Latency in Late Preterm Premature Rupture of Membranes.

This study aims to evaluate the perinatal outcomes of preterm premature rupture of membrane (PPROM) with latency periods at 33 + 0-36 + 6 weeks of gestation. This retrospective case-control study included women with singleton pregnancies who delivered at 33 + 0-36 + 6 weeks at Korea University Ansan Hospital in South Korea between 2006-2019. The maternal and neonatal characteristics were compared between different latency periods (expectant delivery ≥72 h vs. immediate delivery <72 h). Data were compared among 345 women (expectant, n = 39; immediate delivery, n = 306). There was no significant difference in maternal and neonatal morbidities between the groups, despite the younger gestational age in the expectant delivery group. Stratified by gestational weeks, the 34-week infants showed a statistically significant lower exposure to antenatal steroids (73.4% vs. 20.0%, p < 0.001), while the incidence of respiratory distress syndrome (12.8%) and the use of any respiratory support (36.8%) was higher than those in the 33-week infants, without significance. Our study shows that a prolonged latency period (≥72 h) did not increase maternal and neonatal morbidities, and a considerable number of preterm infants immediately delivered at 34 weeks experienced respiratory complications. Expectant management and antenatal corticosteroids should be considered in late preterm infants with PPROM.

Hemodynamics of different volumes of red blood cell transfusion in preterm infants.

BACKGROUND: Although many controversies exist regarding the risk of red blood cell (RBC) transfusions, half of preterm infants born at <32 weeks of gestational age receive such transfusions because of anemia of prematurity. Because of the costs and risks associated with multiple transfusions, it has been suggested that a large transfusion volume reduces the number of transfusions. However, there have been persistent concerns that RBC transfusion might lead to volume overload. METHODS: We examined the impacts of large (20 mL/kg) compared to standard volume (15 mL/kg) transfusions on the hemodynamic variables of stable, electively transfused, preterm infants, by serially measuring echocardiographic parameters and plasma B-type natriuretic peptide levels. RESULTS: A total of 39 infants born at <34 weeks of gestation and aged >2 weeks at the time of enrollment were randomly allocated to either a standard volume (15 mL/kg) or a large volume (20 mL/kg) group. Significant reductions in cardiac output and transient increases in plasma B-type natriuretic peptide levels were found after RBC transfusion in both the standard and large volume (20 mL/kg) groups. However, these changes were not significantly different between the two groups. CONCLUSIONS: Large-volume transfusions could be tolerable in stable preterm infants with anemia.

6,4'-dihydroxy-7-methoxyflavanone protects against H2O2-induced cellular senescence by inducing SIRT1 and inhibiting phosphatidylinositol 3-kinase/Akt pathway activation.

6, 4'-Dihydroxy-7-methoxyflavanone (DMF) has been shown to possess anti-inflammatory, anti-oxidative, and neuroprotective activities. However, its effect on oxidative stress-induced aging remains undemonstrated. This study aimed at investigating the anti-senescence effect of DMF on hydrogen peroxide (H2O2)-induced premature senescence, and associated molecular mechanisms in human dermal fibroblasts (HDFs). The cells were DMF pretreated with small interfering RNA (siRNAs) of control or sirtuin 1 (SIRT1) before H2O2 exposure, and western blot analysis, senescence-associated ß-galactosidase (SA-ß-gal) activity, cell counting, gene silencing, and SIRT1 activity assay were performed. Pretreatment with DMF inhibited H2O2-induced senescence phenotypes, which showed decreased SA-ß-gal activity and increased cell growth in comparison with H2O2-treated HDFs. Meanwhile, the decreases in ac-p53, p21Cip1/WAF1, and p16Ink4a and the increases in pRb and cyclin D1 were observed. DMF was also found to induce SIRT1 expression and activity level concentration- and time-dependently. Moreover, SIRT1 inhibition abrogated DMF senescence prevention. Additionally, Akt and ERK were activated with different kinetics after H2O2 exposure, and Akt activity inhibition attenuated SA-ß-gal activity augmentation. We also found that DMF inhibited H2O2-induced Akt phosphorylation. This study indicates that DMF effectively protects against oxidative stress-induced premature senescence through SIRT1 expression up-regulation and Akt pathway inhibition in HDFs. These results suggest that DMF can be a potential therapeutic molecule for age-related diseases, or a protective agent against the aging process.

Isoparvifuran isolated from Dalbergia odorifera attenuates H2O2-induced senescence of BJ cells through SIRT1 activation and AKT/mTOR pathway inhibition.

Isoparvifuran is a benzofuran compound isolated from the heartwood of Dalbergia odorifera. Related research reported that isoparvifuran has antioxidant property. However, it is unclear whether isoparvifuran has anti-aging effects. In this research, we established an aging model, hydrogen peroxide (H2O2)-induced BJ cell senescence, to explore the protective effect of isoparvifuran on cell senescence and its related mechanisms. Our results revealed that isoparvifuran obviously attenuated H2O2-induced cell senescence, increased the cell proliferation rate,and reversed senescence-associated molecular markers expression such as cyclin D1, pRb, caveolin-1, ace-p53, p21 and p16. Moreover, isoparvifuran dose and time dependently increased the expression level of Sirtuin 1 (SIRT1) in BJ cells. The inhibition of SIRT1 obviously reversed the reduction of SA-ß-gal activity and the alteration of senescence-associated molecular markers induced by isoparvifuran. Additionally, isoparvifuran also inhibited H2O2-induced AKT and S6 phosphorylation and increase of SA-ß-gal activity. In summary, isoparvifuran protects BJ cells from H2O2-induced premature senescence, the anti-senescence effect of isoparvifuran is associated with the activation of SIRT1 and the suppression of AKT/mTOR signaling pathway.

The Extract of Arctium lappa L. Fruit (Arctii Fructus) Improves Cancer-Induced Cachexia by Inhibiting Weight Loss of Skeletal Muscle and Adipose Tissue.

BACKGROUND: Cachexia induced by cancer is a systemic wasting syndrome and it accompanies continuous body weight loss with the exhaustion of skeletal muscle and adipose tissue. Cancer cachexia is not only a problem in itself, but it also reduces the effectiveness of treatments and deteriorates quality of life. However, effective treatments have not been found yet. Although Arctii Fructus (AF) has been studied about several pharmacological effects, there were no reports on its use in cancer cachexia. METHODS: To induce cancer cachexia in mice, we inoculated CT-26 cells to BALB/c mice through subcutaneous injection and intraperitoneal injection. To mimic cancer cachexia in vitro, we used conditioned media (CM), which was CT-26 colon cancer cells cultured medium. RESULTS: In in vivo experiments, AF suppressed expression of interleukin (IL)-6 and atrophy of skeletal muscle and adipose tissue. As a result, the administration of AF decreased mortality by preventing weight loss. In adipose tissue, AF decreased expression of uncoupling protein 1 (UCP1) by restoring AMP-activated protein kinase (AMPK) activation. In in vitro model, CM increased muscle degradation factors and decreased adipocytes differentiation factors. However, these tendencies were ameliorated by AF treatment in C2C12 myoblasts and 3T3-L1 cells. CONCLUSION: Taken together, our study demonstrated that AF could be a therapeutic supplement for patients suffering from cancer cachexia.

Protective effects of Coenzyme Q10 against acute pancreatitis.

Acute pancreatitis (AP) refers to inflammation in the pancreas, which may lead to death in severe cases. Coenzyme Q10 (Q10), generally known to generate energy, plays an important role as an anti-oxidant and anti-inflammatory effector. Here, we showed the effect of Q10 on inflammatory response in murine AP model. For this study, we induced AP by injection of cerulein intraperitoneally or pancreatic duct ligation (PDL) in mice. The level of cytokines and digestive enzymes were measured in pancreas, and blood. All pancreatic tissues were excised for investigation such as histological changes, infiltration of immune cells. Administration of Q10 attenuated the severity of AP and its associated pulmonary complication as shown by reduction of acinar cell death, parenchymal edema, inflammatory cell infiltration and alveolar thickening in both cerulein-induced AP and PDL-induced AP. Moreover, reduction of the cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were observed in pancreas and pancreatic acinar cells by Q10. Furthermore, Q10 reduced the infiltration of immune cells such as monocytes and neutrophils and augmentation of chemokines such as CC chemokine-2 (CCL2) and C-X-C chemokine-2 (CXCL2) in pancreas of AP mice. In addition, Q10 deactivates the phosphorylation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in pancreas. In conclusion, these observations suggest that Q10 could attenuate the pancreatic damage and its associated pulmonary complications via inhibition of inflammatory cytokines and inflammatory cell infiltration and that the deactivation of ERK and JNK by Q10 might contribute to the attenuation of AP.

Preventive Effects of Gardenia jasminoides on Cerulein-Induced Chronic Pancreatitis.

Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1[Formula: see text]g/kg) or saline (control group) were intraperitoneally injected 1[Formula: see text]h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.