Ursolic acid induces apoptosis and autophagy in oral cancer cells.

Oral squamous cell carcinoma (OSCC) is the fifth common cause of cancer mortality in Taiwan with high incidence and recurrence and needs new therapeutic strategies. In this study, ursolic acid (UA), a triterpenoid, was examined the antitumor potency in OSCC cells. Our results showed that UA inhibited the proliferation of OSCC cells in a dose- and time-dependent manner in both Ca922 and SCC2095 oral cancer cells. UA induced caspase-dependent apoptosis accompanied with the modulation of various biological biomarkers including downregulating Akt/mTOR/NF-κB signaling, ERK, and p38. In addition, UA inhibited angiogenesis as evidenced by abrogation of migration/invasion and blocking MMP-2 secretion in Ca922 cells. Interestingly, UA induced autophagy in OSCC cells, as manifested by LC3B-II conversion and increased p62 expression and accumulation of autophagosomes. Inhibition by autophagy inhibitor enhanced UA-mediated apoptosis in Ca922 cells. The experiment provides a rationale for using triterpenoid in the treatment of OSCC.

Plantar Purpura as the Initial Presentation of Viridians Streptococcal Shock Syndrome Secondary to Streptococcus gordonii Bacteremia.

Viridians streptococcal shock syndrome is a subtype of toxic shock syndrome. Frequently, the diagnosis is missed initially because the clinical features are nonspecific. However, it is a rapidly progressive disease, manifested by hypotension, rash, palmar desquamation, and acute respiratory distress syndrome within a short period. The disease course is generally fulminant and rarely presents initially as a purpura over the plantar region. We present a case of a 54-year-old female hospital worker diagnosed with viridians streptococcal shock syndrome caused by Streptococcus gordonii. Despite aggressive antibiotic treatment, fluid hydration, and use of inotropes and extracorporeal membrane oxygenation, the patient succumbed to the disease. Early diagnosis of the potentially fatal disease followed by a prompt antibiotic regimen and appropriate use of steroids are cornerstones in the management of this disease to reduce the risk of high morbidity and mortality.

Dysphagia aortica: a fatal delay in diagnosis.

Extrinsic esophageal compression leading to dysphagia is an uncommon and late presentation of large thoracic aortic aneurysm named dysphagia aortica. Herein, we report an 86-year-old man who presented with 1-week duration of chest pain, backache, and dysphagia and was eventually diagnosed as dysphagia aortica. Our patient developed progressive dyspnea due to tracheal compression and failed surgery. The case illustrates the importance of early identification of the rare entity of dysphagia especially in elderly cases with cardiovascular disease with complaint of undetermined dysphagia accompanied with chest pain and backache.

Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II.

13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. Molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation.

Application of positive end-expiratory pressure in a case with large laceration on the superior vena cava.

Iatrogenic injury is a difficult situation for a surgeon. Being successful in saving a patient at risk is the major concern in this situation. Once an iatrogenic injury to the superior vena cava (SVC) is found, increasing the intrathoracic pressure is theoretically able to overcome the venous pressure and to alleviate or even stop bleeding from injury. A 76-year-old female patient, who had suffered from end-stage diabetic nephropathy, developed tension hemothorax during insertion of the cuffed hemodialysis catheter. The successful course of resuscitation without emergent operation or endovascular repair is presented here.

Nobiletin Promotes Megakaryocytic Differentiation through the MAPK/ERK-Dependent EGR1 Expression and Exerts Anti-Leukemic Effects in Human Chronic Myeloid Leukemia (CML) K562 Cells.

Differentiation therapy is an alternative strategy used to induce the differentiation of blast cells toward mature cells and to inhibit tumor cell proliferation for cancer treatment. Nobiletin (NOB), a polymethoxyflavone phytochemical, is present abundantly in citrus peels and has been reported to possess anti-cancer activity. In this study, we investigated the anti-leukemic effects of NOB on cell differentiation and its underlying mechanisms in human chronic myeloid leukemia (CML) K562 cells. NOB (100 µM) treatment for 24 and 48 h significantly decreased viability of K562 cells to 54.4 ± 5.3% and 46.2 ± 9.9%, respectively. NOB (10-100 µM) significantly inhibited cell growth in K562 cells. Flow cytometry analysis and immunoblotting data showed that NOB (40 and 80 µM) could modulate the cell cycle regulators including p21, p27, and cyclin D2, and induce G1 phase arrest. NOB also increased the messenger RNA (mRNA) and protein expression of megakaryocytic differentiation markers, such as CD61, CD41, and CD42 as well as the formation of large cells with multi-lobulated nuclei in K562 cells. These results suggested that NOB facilitated K562 cells toward megakaryocytic differentiation. Furthermore, microarray analysis showed that expression of EGR1, a gene associated with promotion of megakaryocytic differentiation, was markedly elevated in NOB-treated K562 cells. The knockdown of EGR1 expression by small interference RNA (siRNA) could significantly attenuate NOB-mediated cell differentiation. We further elucidated that NOB induced EGR1 expression and CD61 expression through increases in MAPK/ERK phosphorylation in K562 cells. These results indicate that NOB promotes megakaryocytic differentiation through the MAPK/ERK pathway-dependent EGR1 expression in human CML cells. In addition, NOB when combined with imatinib could synergistically reduce the viability of K562 cells. Our findings suggest that NOB may serve as a beneficial anti-leukemic agent for differentiation therapy.

Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor.

: Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC50 values of 7.7 µM and 9.5 µM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (N-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.

Extrathoracic bypass of an orifice occlusive lesion in the arch vessels: case reports and literature review.

Arterial occlusive disease of the arch vessels is often associated with flow reversal in the vertebral artery of such patients, the so-called subclavian steal syndrome. We treated two such cases that were diagnosed based on symptoms, physical examination and angiography. In the first case, the occlusive lesion was found at the origin of left subclavian artery, while the occlusion was positioned at the origin of innominate artery in the second case. A carotid-subclavian and a carotid-carotid bypass using 8-mm PTFE grafts were performed, respectively. No complications were noted and the patients have retained a symptom-free status during a follow-up of 5 years. Taking into account the expense of stenting and the patency rate, extrathoracic bypass surgery using a PTFE graft for the treatment of orifice occlusive lesions of arch vessels is cheaper and has an overall better patency rate. Furthermore, because it is the final choice of treatment after percutaneous transluminal angioplasty fails, it should be considered as an ideal therapy for lesions at the origin of arch vessels.

Kaempferol inhibits angiogenic ability by targeting VEGF receptor-2 and downregulating the PI3K/AKT, MEK and ERK pathways in VEGF-stimulated human umbilical vein endothelial cells.

Anti-angiogenesis is one of the most general clinical obstacles in cancer chemotherapy. Kaempferol is a flavonoid phytochemical found in many fruits and vegetables. Our previous study revealed that kaempferol triggered apoptosis in human umbilical vein endothelial cells (HUVECs) by ROS­mediated p53/ATM/death receptor signaling. However, the anti­angiogenic potential of kaempferol remains unclear and its underlying mechanism warranted further exploration in VEGF­stimulated HUVECs. In the present study, kaempferol significantly reduced VEGF­stimulated HUVEC viability. Kaempferol treatment also inhibited cell migration, invasion, and tube formation in VEGF­stimulated HUVECs. VEGF receptor­2 (VEGFR­2), and its downstream signaling cascades (such as AKT, mTOR and MEK1/2­ERK1/2) were reduced as determined by western blotting and kinase activity assay in VEGF­stimulated HUVECs after treatment with kaempferol. The present study revealed that kaempferol may possess angiogenic inhibition through regulation of VEGF/VEGFR­2 and its downstream signaling cascades (PI3K/AKT, MEK and ERK) in VEGF-stimulated endothelial cells.

Hyperin inhibits nuclear factor kappa B and activates nuclear factor E2-related factor-2 signaling pathways in cisplatin-induced acute kidney injury in mice.

Hyperin, a flavonoid compound found in Ericaceae, Guttiferae, and Celastraceae, has been reported to have anti-inflammatory effects. In the present study, we investigated the effects of hyperin on cisplatin-induced acute kidney injury (AKI) in mice. The renal tissue damage induced by cisplatin was detected by H&E staining. Blood urea nitrogen (BUN), creatinine, reactive oxygen species (ROS), and malondialdehyde (MDA) were also detected. Further, the effects of hyperin on cisplatin-induced TNF-α, IL-1ß and IL-6 were detected by ELISA. In addition, the phosphorylation of nuclear factor kappa B (NF-κB) and the expression of nuclear factor E2-related factor-2 (Nrf2) and HO-1 were detected by western blot analysis. The results showed that hyperin attenuated histological changes of kidney induced by cisplatin. The levels of BUN, creatinine, ROS, MDA, TNF-α, IL-1ß and IL-6 induced by cisplatin were also inhibited by hyperin. Cisplatin-induced NF-κB activation was inhibited by hyperin. Additionally, hyperin was found to up regulate the expression of Nrf2 and HO-1. In conclusion, the results suggest that hyperin protects against cisplatin-induced AKI by inhibiting inflammatory and oxidant response.

Original Research: Porcine model for observing changes due to ischemia/reperfusion injury secondary to intra-abdominal endovascular balloon occlusion.

Compared with conventional aortic cross-clamping, endovascular balloon occlusion (EBO) is a valuable strategy in unstable ruptured abdominal aorta aneurysm patients; however, it is unclear how long the balloon may remain safely inflated. Using a porcine model, we evaluated the influence of different EBO time periods on intra-abdominal pressure (IAP) and the association between various pathophysiologic indicators and reperfusion time. Twelve healthy three-month-old domestic piglets were subjected to ischemia/reperfusion injury using EBO within the abdominal aorta. Animals were grouped as A, B, and C based on 30, 60, or 120 min of ischemic time, respectively. Changes in IAP, hemodynamic data, respiratory and renal function, and histology after reperfusion were compared with baseline measurements. All pigs gradually developed intra-abdominal hypertension after ischemia/reperfusion injury. IAP increased significantly after 4 h of reperfusion in all three groups (all P < 0.001) with maximal IAP reaching > 22 mmHg in 10 pigs. However, no significant intergroup differences were found. Cardiac output remained stable, but mixed venous oxygen saturation decreased significantly at 4 h after reperfusion (P < 0.05). The pH decreased significantly at 10 min in all three groups (all P < 0.001). Histological changes in the small intestine, lung, and kidney occurred secondary to aortic ischemia; however, no significant differences were noted between groups (P > 0.05). EBO within the abdominal aorta induced ischemia/reperfusion injury which led to intra-abdominal hypertension, pathological changes within multiple organs, and decreased mixed venous oxygen saturation after only 30 min of abdominal aortic ischemia.

Acute Respiratory Distress Syndrome Manifested by Leptospirosis Successfully Teated by Extracorporeal Membrane Oxygenation (ECMO).

Leptospirosis is recognized as a zoonotic disease that is emerging worldwide. Severe manifestations are associated with high morbidity and mortality rates and may therefore pose an important risk to public health, especially in certain high prevalence areas like Taiwan. The severe pulmonary form of leptospirosis is a lesser known entity and is characterized by intra-alveolar hemorrhage and can lead to acute respiratory failure with resistant hypoxemia, which leads to high mortality rates despite maximally invasive mechanical ventilation and adequate treatment. We herein present a case of severe leptospirosis complicated by massive pulmonary hemorrhage, which was successfully managed by extra corporeal membrane oxygenation.

Hemostatic resuscitation for massive hemorrhage with warm fresh whole blood in a patient with severe blunt trauma.

A 24-year-old male Navy soldier was struck on the left thigh by a ruptured cable and was subsequently thrown into the sea. Initial evaluation showed an Injury Severity Score of 34. Core body temperature was 34.1°C. Laboratory data included a hemoglobin level of 4.5 g/dL and a hematocrit of 13.3%. Prothrombin time was prolonged (>100 seconds), international normalized ratio was elevated (9.99), and partial thromboplastin time was elevated (>180 seconds). The patient was treated for hypothermia, coagulopathy, and metabolic acidosis during resuscitation. The patient was transfused with 16,320 mL of blood during the first 24 hours following the accident, including 4500 mL (18 units) of warm fresh whole blood (WFWB) donated by the patient's military colleagues. The patient was successfully resuscitated, and the injured leg was salvaged. Component therapy can afford replacement of specific deficiencies or requirements, decrease the risk of transfusion-transmitted infectious diseases, and improve resource utilization. However, a protocol of early transfusion with WFWB should be considered during resuscitation following massive hemorrhage in specific conditions such as battle fields or urgent situations.