Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells

Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.

Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant mesothelioma cells

Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.

Analysis of porcine macrophage immune response to antigenic molecules and short chain fatty acids / 동물의과학연구지

Macrophages play an important role in both the innate and adaptive immune responses. These include phagocytosis, killing of microorganisms, antigen presentation, and induction of immune cytokines and antimicrobial genes. Macrophage activity is reported to be controlled by diverse exogenous antigenic or endogenous metabolic molecules, and the underlying mechanisms are well documented in human and mouse macrophage cells. Bacterial lipopolysaccharide (LPS) is known to be one of the most potent stimuli activating macrophages through the toll like receptor 4 (TLR4) signaling pathway. There are other antigenic molecules, such as muramyl dipeptide (MDP) and outer membrane protein A (OmpA), that are also known to activate immune cells. On the other hand, short chain fatty acids (SCFAs) such as acetate and butyrate are produced by gut microbiota and control host energy metabolism and signal transduction through GPR receptors. However, there are few studies demonstrating the effects of these molecules in macrophages from domestic animals, including domestic pigs. In this study, we attempted to characterize gene expression regulation in porcine macrophages (PoM2, Pig Monocytes clone 2) following treatment with LPS, MDP, OmpA, and two short chain fatty acids using porcine genome microarray and RT-PCR techniques. A number of novel porcine genes, including anti-microbial peptides and others, appeared to be regulated at the transcriptional level. Our study reports novel biomarkers such as SLC37A2, TMEN184C, and LEAP2 that are involved in the porcine immune response to bacterial antigen LPS and two short chain fatty acids.

A Case of Mixed Hyperplastic-adenomatous Rectal Polyp with Composition of Invasive Adenocarcinoma

Epithelial colon polyps are largely divided into hyperplastic and adenomatous polyps. Adenomatous polyps are premalignant lesions, whereas hyperplastic polyps are regarded as benign lesions. However, this histological classification has been blurred, as cases of malignant changes in hyperplastic polyposis, mixed hyperplastic adenomatous polyps (MHAPs), and serrated adenomas in the colon have been reported. Rare cases of MHAP have been reported, and are mainly found at the proximal colon with a relatively large size. MHAPs seem to be an intermediate stage of the hyperplastic polyp-adenoma sequence or a collision tumor. Here, we report on a case of a single polyp in the rectum diagnosed with a MHAP combined with an invasive adenocarcinoma.

Tongue bite in a patient with tracheostomy after prone position: A case report / 대한마취과학회지

A 22-year-old man underwent an operation for posterolateral fusion of the lumbar spine at L3-5. He was ventilated via a tracheostomy site in a prone position for 210 minutes. Ventilator function and eyeballs were checked periodically. After changing his position to supine for the wake-up test, it was noticed that his tongue was self-inflicted and looked to be cut unless immediate decompression was applied. After several manual attempts to open the mouth failed, anesthesia depth was deepened with thiopental sodium and neuromuscular blocker to decompress and reposition the tongue into the intraoral cavity. Minimal teeth marks and scarring remained after seven months without any complications.

Involvement of Splenic Hemangioma and Rectal Varices in a Patient with Klippel - Trenaunay Syndrome / 대한소화기학회지

Klippel - Trenaunay syndrome (KTS) is characterized by a cutaneous vascular nevus of the involved extremity, bone and soft tissue hypertrophy of the extremity and venous malformations. We present a case of KTS with splenic hemangiomas and rectal varices. A 29-year-old woman was referred for intermittent hematochezia for several years. She had history with a number of operations for cutaneous and soft tissue hamangiomas since the age of one year old and for increased circumference of her left thigh during the last few months. Abdominal CT revealed multiple hemangiomas in the spleen, fusiform aneurysmal dilatation of the deep veins and soft tissue hemangiomas. There was no evidence of hepatosplenomegaly or liver cirrhosis. Colonoscopy revealed hemangiomatous involvement in the rectum. There were rectal varices without evidence of active bleeding. Upon venography of the left leg, we also found infiltrative dilated superficial veins in the subcutaneous tissue and aneurysmal dilatation of the deep veins. The patient was finally diagnosed with KTS, and treated with oral iron supplementation only, which has been tolerable to date. Intervention or surgery is not required. When gastrointestinal varices or hemangiomatous mucosal changes are detected in a young patient without definite underlying cause, KTS should be considered.

Development of a contralateral acute subdural hematoma during awake craniotomy for glial tumor in a 12-year-old boy: A case report

Contralateral acute subdural hematomas that occur during removal of brain tumors under general anesthesia are extremely rare, and there are no reports of this developing during awake craniotomy for brain tumors. We report a case of a 12-year-old boy who complained of sudden and severe headache and nausea around the completion of removal of a glial tumor of the frontal lobe under awake anesthesia. Postoperative computerized tomography scan revealed the presence of contralateral acute minimal subdural hematoma. We suggest that during craniotomy with awake anesthesia for brain tumors, contralateral acute subdural hematoma may occur, even in the absence of brain bulging or changes in vital signs. Sudden intra-operative headache and nausea should be investigated by immediate postoperative computerized tomography scans to ascertain diagnosis.

Development of a contralateral acute subdural hematoma during awake craniotomy for glial tumor in a 12-year-old boy: A case report

Contralateral acute subdural hematomas that occur during removal of brain tumors under general anesthesia are extremely rare, and there are no reports of this developing during awake craniotomy for brain tumors. We report a case of a 12-year-old boy who complained of sudden and severe headache and nausea around the completion of removal of a glial tumor of the frontal lobe under awake anesthesia. Postoperative computerized tomography scan revealed the presence of contralateral acute minimal subdural hematoma. We suggest that during craniotomy with awake anesthesia for brain tumors, contralateral acute subdural hematoma may occur, even in the absence of brain bulging or changes in vital signs. Sudden intra-operative headache and nausea should be investigated by immediate postoperative computerized tomography scans to ascertain diagnosis.

Malignant Transformation of Gastric Gastrointestinal Stromal Tumor in 44 Months Observational Period: A Case Report / 대한소화기내시경학회지

Gastrointestinal stromal tumor is a common type of gastrointestinal mesenchymal tumor. Depending on the patient's age, compliance and health status, and the level of suspicion of malignancy, tumors < or =3 cm in size are typically monitored annually by endoscopic ultrasonography. The examination interval can be extended if no size change is noted on consecutive examinations. We report here on a 44-year-old female who presented with abdominal discomfort and displayed no size change of her gastrointestinal stromal tumor on three consecutive endoscopies over a 44-month interval. The patient was diagnosed with malignant gastrointestinal stromal tumor on the basis of the evident ulceration seen on esophagogastroduodenoscopy and the inhomogenous echo noted on the endoscopic ultrasonography and the pathologic findings by gastric wedge resection.

The effect of administering colloid solution on the postoperative blood loss in patients who are undergoing total knee arthroplasty: Comparing Hextend with Voluven

BACKGROUND: Total knee arthroplasty (TKR) is associated with a significant loss of blood. Fluid substitution with crystalloid or colloid solutions to correct perioperative hypovolemia is essential. Colloid solutions, and especially hydroxyethyl starches (HES), are used to treat hypovolemia, but they may affect blood coagulation. The purpose of this study was to test the efficacy and the safety of colloid solutions in patients undergoing TKR. METHODS: The patients undergoing TKR were divided into a group that underwent fluid management with Voluven(R) (n = 22) and a group that was managed with Hextend(R) (n = 24). The blood loss, the autotransfused blood volume, the hemoglobin level, the allogenic blood requirement, the urine output and the complications were assessed. RESULTS: There were no significant differences in the amount of blood loss, the autotransfused blood volume, the allogenic requirement, the urine output and the complications between the two groups. CONCLUSIONS: Voluven(R) and Hextend(R) are equally efficacious plasma volume substitutes when performing TKR with an autotransfusion of drained blood.

Small Bowel Obstruction and Capsule Retention by a Small Bowel Ulcer That Was Not Found on Capsule Endoscopy / 대한소화기내시경학회지

Capsule endoscopy (CE) is a valuable modality for directly examining the small bowel in a relatively noninvasive and safe manner. CE is being increasingly used for obscure gastrointestinal bleeding, Crohn's disease, drug induced ulcer and small bowel tumor. Although capsule retention is a relatively infrequent complication, small bowel obstruction and strictures have been considered contraindications to CE. But some authors have reported that capsule endoscopy can be safely used to help identify the etiology and site of small bowel obstruction, and the retention of the capsule indicates the presence of a lesion requiring surgery. We report here on a case of small bowel obstruction and capsule retention by a small bowel ulcer, and the small bowel ulcer was not found when performing capsule endoscopy.

The effect of airway obstruction on systolic arterial and central venous pressure during sedation in patients undergoing total knee replacement / 대한마취과학회지

BACKGROUND: Severe respiratory variations of systolic arterial and central venous pressure (CVP) may increase the risk of embolic event in orthopedic patient. As airway obstruction during sedation can cause this respiratory variation, we evaluated the degree of variations of systolic blood (SBP) and CVP during airway obstruction period. METHODS: Fifteen females who had obstructed airway during total knee replacement (TKR) were included for the study. After regional anesthesia were established, SBP and CVP variations were analyzed according to the three periods; baseline, obstruction, and airway, respectively. Calculated CVP variables were similar to SBP variables as below: DeltaSBP = Expmax (maximal value at expiration) - Inspnadir (minimal value at inspiration), %DeltaSBP = (DeltaSBP/ Exp(max)) x 100. The frequencies of pulsus paradoxus (PP) and negative inspiratory CVP (NIC) were also measured. RESULTS: At obstruction period, DeltaSBP was 21.7 mmHg and 93.3% of patient had PP. Also, DeltaCVP was 19.3 mmHg and 100% of patient showed NIC. %DeltaCVP (140%) was larger than %DeltaSBP (16%). And DeltaCVP was inversely correlated with baseline and obstruction SBP and %DeltaCVP was also inversely correlated with baseline CVP at obstruction period. CONCLUSIONS: During airway obstruction in sedated TKR patients, variations of CVP are larger than those of SBP. So we have to monitor CVP continuously as well as SBP so as not to increase the possible risk of respiratory of variation.

Comparison of Transient Elastography and Hepatic Fibrosis Assessed by Histology in Chronic Liver Disease / 대한소화기학회지

BACKGROUND/AIMS: Transient elastography (Fibroscan, Echosens, France) is a new, simple, and non-invasive method to assess the degree of hepatic fibrosis by measuring liver stiffness. Recent reports have shown that liver stiffness measurement using Fibroscan allowed accurate prediction of hepatic fibrosis in patient with chronic hepatitis C. The aim of this study was to evaluate accuracy of Fibroscan for the detection of hepatic fibrosis in Korea with various etiologies of chronic liver disease by comparison with fibrosis assessed by histologic examination. METHODS: Fifty-four patients with chronic liver diseases, which were histologically confirmed within recent 6 months were enrolled. Etiologies were HBV, HCV infection, autoimmune hepatitis, and non alcoholic steatohepatitis. Hepatic fibrosis was graded on the basis of standard guideline proposed by the Korean Study Group for the Pathology of Digestive Diseases. RESULTS: Fibroscan values were significantly higher in F3 (16.96 kPa) and F4 (19.86 kPa) than others (p=0.003). Liver stiffness measurement was significantly correlated to the fibrosis stage (r=0.614, p<0.0001). CONCLUSIONS: Liver stiffness measurement by Fibroscan is a promising method for the assessment of hepatic fibrosis in chronic liver disease because it accompanies no complication.

The influence of propofol administration time on oxygen-glucose deprivation-reperfusion injury in rat mixed cortical cultures focused on N-Methyl-D-Aspartate (NMDA) receptors / 대한마취과학회지

BACKGROUND: Propofol has been shown to have neuroprotective properties. However, the effect of propofol administration time on neuroprotection is not well understood. This study was conducted to determine if propofol administration time would influence its neuroprotective effects on an in vitro ischemia-reperfusion model, with special attention directed toward NMDA-induced calcium influx. METHODS: Primary mixed cortical cultures of thirteen-day-old rats were exposed to 5 min of oxygen-glucose deprivation (OGD), followed by 2 hr of reperfusion. Propofol (1-100micrometer) was administered before OGD or administered from the time of OGD to the end of the reperfusion period. In the blank and full kill groups, no drug or NMDA 500micrometer treatment was given. The surviving cells were counted using trypan-blue staining, and cell death rate (CDR) was determined. To measure the maximum Ca2+ influx, 50micrometer propofol was pre-treated or co-treated with 100micrometer NMDA. In the control and NMDA 100micrometer groups, no drug or NMDA 100micrometer was given. A P < 0.05 was considered statistically significant. RESULTS: Cells pre-treated with propofol (10-100micrometer) or co-treated (50-100micrometer) at the time of OGD injury had a decreased CDR compared to the blank group. Cells pre-treated (2,713 nA) or co-treated (3,626 nA) with propofol had a decreased maximum Ca2+ influx compared to the 100micrometer NMDA group (4,075 nA). Cells pre-treated with propofol had a decreased maximum Ca2+ influx compared to co-treated rats. CONCLUSIONS: Propofol demonstrated neuroprotective effects at lower concentrations when administered prior to OGD injury. This may be partially attributable to the reduction of Ca2+ influx against NMDA receptor activation.

Hemodynamic Changes after Endotracheal Intubation in Patients with Cerebral Aneurysm

BACKGROUND: Tracheal intubation with a lightwand intubating device (Trachlight) attenuates the hemodynamic stress response to tracheal intubation compared with a direct laryngoscope approach. We compared the effects of the direct laryngoscope (Macintosh blade) and lightwand for intubation in patients with cerebral aneurysm. METHODS: Twenty-four patients undergoing cerebral aneurysm clipping surgery were randomly divided to either the lightwand (Group 1, n = 12) or the laryngoscope (Group 2, n = 12) Group. All patients received fentanyl (2-3microg/kg), midazolam (0.1 mg/kg), and thiopental sodium (2-3microg/kg) followed by vecuronium (0.1- 0.15microg/kg). The lungs were ventilated with 3-4% isoflurane in oxygen, with 1% lidocaine (1-1.5microg/kg) administered before intubation with either the lightwand or the laryngoscope. Systolic, diastolic and mean blood pressures and heart rate were recorded continuously before and for 5 min after intubation. RESULTS: Systolic and mean arterial blood pressure increased significantly (P < 0.05) 1 minute after intubation, but then returned to normal within the next minute. There were no differences in hemodynamic changes between the two groups, and no complications. CONCLUSIONS: Intubation technique did not affect hemodynamic changes in patients with cerebral aneurysm. In patients with aneurysms, appropriate anesthetic levels and pharmacologic manipulation will attenuate the hemodynamic stress response associated with tracheal intubation.

Agreement Evaluation between Noninvasive Oscillometric Blood Pressure Measured by the Tram 800SL Module of Solar 8000M(R) with Invasive Arterial Blood Pressure Measured by the AMK 250 AutoTransducer(R) during General Anesthesia / 대한마취과학회지

BACKGROUND: Blood pressure (BP) varies considerably during general anesthesia. Accurate BP measurement is critical for appropriate treatment, especially during hypotension and hypertension. Here we evaluated whether the noninvasive oscillometric BP measurement technique accurately reflects BP measured by the direct intraarterial technique. METHODS: A total of 256 samples were extracted from 10 patients operated on under general anesthesia. Systolic, diastolic and mean BP were analyzed according to the level of BP; hypotension, normotension, and hypertension. Repeatability of the noninvasive BP measurement were analyzed with repeatability coefficients and percent errors. Agreement between the two BP measurements were analyzed with a Bland-Altman and Modified Bland-Altman analysis. RESULTS: The repeatability coefficient for mean BP of the noninvasive oscillometric BP measurement was 6.34. Percent errors of mean BP were smaller than those of systolic and diastolic BP. All biases were less than 5 mmHg at all BP levels. Most BP agreements were larger than 8 mmHg except all-range mean BP (7.7), hypotensive diastolic BP (6.7), and mean BP (6.2). During hypotension, only mean BP was within the 95% of confidence interval (CI) of bias and limit of agreement. During hypertension, only systolic BP could meet the criteria. CONCLUSIONS: Only mean BP during hypotension and systolic BP during hypertension accurately reflect the direct intraarterial BP. But, diastolic BP does not reflect the direct intraarterial BP over all BPs.

The Effect of Nitrous Oxide on Cerebral Entropy during Isoflurane Inhalational Anesthesia / 대한마취과학회지

BACKGROUND: The bispectral index has limitations in describing the exact depth of anesthesia during nitrous oxide inhalation. This study examined the effect of nitrous oxide on the cerebral entropy measured using an entropy module (M-ENTROPY Module S/5(R), Datex-Ohmeda division, Instrumentarium Corporation, Helsinki, Finland) during the stable anesthetic period with isoflurane inhalation. METHODS: Sixty ASA 1 or 2 adult patients were randomly allocated to three groups. During the stable maintenance period after the skin incision, the baseline entropy values (response entropy, RE; state entropy, SE) were recorded at 2.5 minutes intervals over a 20 minute period on a single frontal channel at 0.9% end-tidal isoflurane. After this, medical air was used continuously (group C) or replaced with nitrous oxide at 40% (group L) or 60% (group H) with continuous hemodynamic and entropy values monitoring. Each of the variables was recorded and analyzed at 2.5 minutes intervals over a 20 minute period. RESULTS: Average values (mean +/-SD) of the RE and SE during experimental period were lower in group H (29.2 +/-12.3 and 28.5 +/-11.7, respectively) than group L (33.9 +/-7.3 and 33.0 +/-7.3, respectively) and the averaged values were lower in group L than in group C (46.6 +/-14.8 and 45.5 +/-14.2, respectively). The percent reduction was larger in group H (42.1 +/-14.2 and 38.7 +/-16.5, respectively) than in group L (25.3 +/-15.1 and 24.4 +/-14.9, respectively) and the percent reduction was larger in group L than in group C (P < 0.01). Conclusions: Added nitrous oxide during the anesthetic maintenance period with isoflurane decreases the level of cerebral entropy.

The Tuberculous Bronchoesophageal Fistula Detected during Induction of General Anesthesia in Brain Abscess Patient: A case report / 대한마취과학회지

We report a case of bronchoesophageal fistula detected during induction of general anesthesia in brain abscess patient. Bubbling sound at substernal area and gas bubble at oral cavity during manually assisted mask ventilation, especially inspiration, were detected. Barium esophagography, gastroscopy and bronchoscophy were performed to know the nature of fistula after neurosurgical operation. The patient had a bronchoesophageal fistula due to unproperly treated old pulmonary tuberculosis. Esophageal opening of fistula located at midesophagus about 27 cm distance from incisor, while bronchial opening located at apical segment of right superior bronchus. It depends on the size, location, and duration of fistula to manifest clinical symptom. In bronchoesophageal fistula, the size of opening tends to be small and gradual symptom onset while relatively large and early in TEF. Therefore, knowledge of the differences of two types of fistula are essential to manage the patient who have these types of fistula.

Prevalence and risk factors of gallstones in a general health screened population / 대한내과학회지

BACKGROUND: Gallstone is the most common disease of the biliary system. Most cases of gallstone are asymptomatic and we incidentally found gallstones during a community health survey. Our study was designed to determine the prevalence and risk factors for gallstone in a population who underwent health screening. METHODS: We enrolled a total of 36,314 persons who visited the health promotion center in Kyungpook National University Hospital in Korea from 1998 to 2004. They had their gallbladder or biliary system examined with using ultrasonography. The body mass index and biochemical parameters from liver function tests, the lipid profiles and the fasting blood sugar were all measured. All the subjects were divided into several groups and the particular prevalence for gallstone disease for each group was calculated. Chi-square tests and logistic regression analysis assessed the risk factors for gallstone disease. RESULTS: Among 36,314 persons, (19,345 males (53.3%) and 16,969 females (46.7%)), gallstone was found in 735 persons (2.0%). On univariate analysis, the risk factors for gallstone disease were age, body mass index, fasting blood sugar, total cholesterol, LDL-cholesterol, triglyceride and serum aspartate aminotransferase. On multivariate logistic regression analysis, the the risk factors were high body mass index, older age and high fasting blood sugar. CONCLUSIONS: The risk factors seem to show a common pathogenesis for gallstone disease. Although the relation between gallstone disease and metabolic syndrome has not been established, it appears to be associated with metabolic syndrome, but further study on a general population is required.

Anaphylactic Shock by Hemocoagulase with Increased Concentration of Mast Cell Tryptase: A case report / 대한마취과학회지

Multiple agents can cause anaphylaxis in a perioperative setting. Identifying the agent responsible is essential for avoiding future adverse reactions as well as to attenuate the progression of anaphylaxis. Being able to distinguish an anaphylactic reaction from an anaphylactoid reaction would help clarify the therapeutic and medicolegal issues. Anaphylaxis generally occurs after reexposure to a specific antigen and requires the release of proinflammatory mediators from mast cells and basophils. An increased concentration of mast cell tryptase is a highly sensitive indicator of anaphylactic reactions during anesthesia. Botropase(R) is a procoagulant hemocoagulase purified from venom of Bothrops jararaca, a Brazilian viper and in wide use in patients with high risk of bleeding. We report a case of suspected anaphylaxis to Botropase(R) in a 67 years old female patient undergoing segmental resection of the liver with elevated concentration of serum mast cell tryptase.