Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.

Literature review on the interdisciplinary biomarkers of multi-target and multi-time herbal medicine therapy to modulate peripheral systems in cognitive impairment.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by the deposition of amyloid-beta (Aß) peptide and neurofibrillary tangles in the brain. The approved drug for AD has certain limitations such as a short period of cognitive improvement effect; moreover, the development of drug for AD therapeutic single target for Aß clearance in brain ended in failure. Therefore, diagnosis and treatment of AD using a multi-target strategy according to the modulation of the peripheral system, which is not only limited to the brain, is needed. Traditional herbal medicines can be beneficial for AD based on a holistic theory and personalized treatment according to the time-order progression of AD. This literature review aimed to investigate the effectiveness of herbal medicine therapy based on syndrome differentiation, a unique theory of traditional diagnosis based on the holistic system, for multi-target and multi-time treatment of mild cognitive impairment or AD stage. Possible interdisciplinary biomarkers including transcriptomic and neuroimaging studies by herbal medicine therapy for AD were investigated. In addition, the mechanism by which herbal medicines affect the central nervous system in connection with the peripheral system in an animal model of cognitive impairment was reviewed. Herbal medicine may be a promising therapy for the prevention and treatment of AD through a multi-target and multi-time strategy. This review would contribute to the development of interdisciplinary biomarkers and understanding of the mechanisms of action of herbal medicine in AD.

Effect of Perioperative Intravenous Iron Supplementation for Complex Cardiac Surgery on Transfusion Requirements: A Randomized, Double-blinded Placebo-controlled Trial.

OBJECTIVES: We investigated whether routine perioperative intravenous iron replenishment reduces the requirement for packed erythrocytes (pRBC) transfusion. SUMMARY OF BACKGROUND DATA: Patients undergoing complex cardiac surgery are at high risk of developing postoperative iron deficiency anemia, thus requiring transfusion, which is associated with adverse outcomes. METHODS: Patients were randomized to receive either ferric derisomaltose 20 mg/kg (n = 103) or placebo (n = 101) twice during the perioperative period: 3 days before and after the surgery. The primary endpoint was the proportion of patients who received pRBC transfusion until postoperative day (POD) 10. Hemoglobin, reticulocyte count, serum iron profile, hepcidin, and erythropoietin were serially measured. RESULTS: pRBC was transfused in 60.4% and 57.2% of patients in the control and iron group, respectively (P = 0.651). Hemoglobin concentration at 3 weeks postoperatively was higher in the iron group than in the control group (11.6 ± 1.5 g/dL vs 10.9 ± 1.4 g/dL, P < 0.001). The iron group showed higher reticulocyte count [205 (150-267)×103/µL vs 164 (122-207)×103/µL, P = 0.003] at POD 10. Transferrin saturation and serum ferritin were significantly increased in the iron group than in the control group (P < 0.001). Serum hepcidin was higher in the iron group than in the control group at POD 3 [106.3 (42.9-115.9) ng/mL vs 39.3 (33.3-43.6) ng/mL, P < 0.001]. Erythropoietin concentration increased postoperatively in both groups (P = 0.003), with no between-group difference. CONCLUSIONS: Intravenous iron supplementation during index hospitalization for complex cardiac surgery did not minimize pRBC transfusion despite replenished iron store and augmented erythropoiesis, which may be attributed to enhanced hepcidin expression.

Neuroprotective effects of ethanolic extract from dry Rhodiola rosea L. rhizomes.

Rhodiola rosea L. rhizome has been used as a traditional medicine to treat fatigue, depression, and cognitive dysfunction. We aimed to authenticate R. rosea L. rhizome using the DNA barcoding technique and to quantify its main compounds, total phenolics, total flavonoids, and antioxidant capacity, and then to investigate their neuroprotective effects. The sequences of internal transcribed spacer and trnH-psbA of R. rosea L. rhizomes showed a 99% identity with those of NCBI GenBank database according to BLAST searches. Analysis using reversed-phase HPLC revealed five main compounds in R. rosea L. rhizome. Rhodiola rosea L. rhizome and two bioactive compounds, salidroside and tyrosol, showed free radical scavenging activity. Rhodiola rosea L. rhizome and its identified compounds protected neuronal PC-12 cells against oxidative stress and showed moderate acetylcholinesterase inhibition. Taken together, these results suggest that R. rosea L. rhizomes with bioactives can be used as a functional ingredient with potential for neuroprotection. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1007/s10068-020-00868-7) contains supplementary material, which is available to authorized users.

Structural and Functional Characteristics of Mitral Paravalvular Leakage Identified by Multimodal Imaging and Their Implication on Clinical Presentation.

OBJECTIVE: Clinical presentation of patients with mitral paravalvular leakage (PVL) varies from asymptomatic to heart failure related with hemolytic anemia or pulmonary hypertension. We aimed to investigate the structural and functional characteristics of mitral PVL by multimodal imaging and their association with the severity of hemolysis and hemodynamic significance. METHODS: A total of 74 patients with mitral PVL who underwent both cardiac computed tomography (CT) and echocardiography from March 2010 to December 2017 was investigated. Location and size of PVL, degree of left atrial (LA) calcification as measured by CT, and hemodynamic variables as measured by echocardiography were comprehensively analyzed. To investigate the degree of hemolysis and pulmonary hypertension, level of lactate dehydrogenase (LDH) and Doppler estimated systolic pulmonary artery pressure (SPAP) were used respectively. RESULTS: Level of LDH was not related to PVL perimeter and was variable, especially in patients with a small PVL. However, it was positively correlated with mean mitral regurgitation velocity. Additionally, SPAP was significantly correlated with PVL perimeter and LA calcium score. In multivariable analysis, mean mitral regurgitation velocity was significantly correlated with levels of LDH (ß = 0.345; p = 0.016), and PVL perimeter and LA calcium score were independently associated with SPAP (ß = 0.249; p = 0.036 and ß = 0.467; p < 0.001, respectively). CONCLUSIONS: Characteristics of mitral PVL and adjacent structures are associated with the severity of hemolysis and pulmonary hypertension. Evaluating the structural and functional characteristics of mitral PVL by complementary multimodal imaging would be important for understanding the clinical presentation and deciding optimal treatments for individual patients.

Gait Disturbance Improvement and Cerebral Cortex Rearrangement by Acupuncture in Parkinson's Disease: A Pilot Assessor-Blinded, Randomized, Controlled, Parallel-Group Trial.

BACKGROUND: Parkinson's disease (PD) leads to impaired mobility and limited independence. OBJECTIVE: We investigated the effects of acupuncture on gait disturbance and analyzed hemodynamic changes caused by acupuncture in the cerebral cortex of patients with PD. METHODS: Participants (n = 26) with gait disturbance due to PD were randomly assigned to the intervention (acupuncture twice a week for 4 weeks + conventional therapy) or control (conventional therapy) groups. We analyzed gait parameters using the GAITRite system and hemodynamic responses in the cerebral cortices using functional near-infrared spectroscopy, Unified Parkinson's Disease Rating Scale (UPDRS) scores, neurotransmitter levels, as well as the immediate effects of acupuncture in patients with PD. RESULTS: The participants tended to walk with hypometric gait (high cadence, short steps) overground. After acupuncture treatment, those in the intervention group showed a significant reduction in cadence and the UPDRS scores involving "walking and balance" compared with those in the control group (P = .004 and P = .020, respectively); the stride, swing, and single support times were significantly increased (P = .006, P = .001, and P = .001, respectively). Oxyhemoglobin levels in the intervention group while walking on a treadmill were significantly increased in the prefrontal and supplementary motor areas. The oxyhemoglobin levels in the prefrontal cortex and swing time revealed significant positive correlations. CONCLUSIONS: Our findings indicated that acupuncture tended to improve hypometric gait and rearranged activation of the cerebral cortex. Thus, acupuncture may be a useful complementary treatment for gait disturbance, including hypometric gait, in patients with PD. Trial Registration Number. Clinical Research Information Service (KCT0002603), https://cris.nih.go.kr/cris/index.jsp.

Ethanol Extract of Ligularia fischeri Inhibits the Lipopolysaccharide-Induced Inflammatory Response by Exerting Anti-Histone Acetyltransferase Activity to Negatively Regulate p65.

Histone acetyltransferase (HAT) activity is well established to regulate inflammatory responses. In contrast, the mechanisms by which natural nutritional extracts influence epigenetic mechanisms to regulate inflammation have not yet been thoroughly investigated. Thus, in the present study, we observed that the anti-HAT activity exerted by an ethanol extract of Ligularia fischeri (ELF) inhibited inflammation. Specifically, we used a cell-free system to show that ELF attenuates HAT activity. We also demonstrated that ELF decreases lipopolysaccharide (LPS)-induced HAT mRNA and protein expression levels in Raw 264.7 cells, and thereby attenuates inflammation-induced patterns of hyperacetylation at nonhistone and histone-H4 proteins. Interestingly, we found that ELF blocked p65 translocation in LPS-stimulated Raw 264.7 cells by attenuating acetylation at lysine residue 310 of p65. Finally, we investigated whether ELF reduces the inflammatory cytokines, IL-6, IL-1ß, and TNFα, using its HAT inhibitor activity. Taken together, these results suggest that ELF negatively regulates inflammatory responses by inhibiting HATs and HAT activity.

Ameliorative Effects of Dendropanax morbifera on Cognitive Impairment Via Enhancing Cholinergic Functions and Brain-Derived Neurotrophic Factor Expression in ß-Amyloid-Induced Mice.

Alzheimer's disease accounts for the majority of dementia and shows hallmarks such as sequential cognitive dysfunction and abnormal behavior. Dendropanax morbifera (DM) has traditionally been used to treat a variety of diseases in East Asia. The aim of this study was to assess the therapeutic effects of DM on brain neuron damage and on cognitive deficit in neuronal cell induced by Aß1-42 in mice. Treatment with DM reduced the levels of intracellular reactive oxygen species and protected against the death of neuronal cells induced by Aß1-42 peptide. In addition, it was also found that pretreatment with DM decreased cognitive damage induced by Aß peptide via enhancing the cholinergic system and antioxidant defense system in mice. Furthermore, the study verified that the change in the expression of both cyclic-adenosine monophosphate response element binding protein and of brain-derived neurotrophic factor in the hippocampus in Aß peptide-treated mice was significantly ameliorated after treatment with DM. Accordingly, these results suggest that pretreatment with DM defends against oxidative stress and cognitive impairment caused by Aß peptide.

Gossypol from Cottonseeds Ameliorates Glucose Uptake by Mimicking Insulin Signaling and Improves Glucose Homeostasis in Mice with Streptozotocin-Induced Diabetes.

Glucose absorption from the gut and glucose uptake into muscles are vital for the regulation of glucose homeostasis. In the current study, we determined if gossypol (GSP) reduces postprandial hyperglycemia or enhances glucose uptake; we also investigated the molecular mechanisms underlying those processes in vitro and in vivo. GSP strongly and concentration dependently inhibited α-glucosidase by functioning as a competitive inhibitor with IC50 value of 0.67 ± 0.44. GSP activated the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathways and enhanced glucose uptake through the translocation of glucose transporter 4 (GLUT4) into plasma membrane in C2C12 myotubes. Pretreatment with a specific inhibitor attenuated the in vitro effects of GSP. We used a streptozotocin-induced diabetic mouse model to assess the antidiabetic potential of GSP. Consistent with the in vitro study, a higher dose of GSP (2.5 mg/kg-1) dramatically decreased the postprandial blood glucose levels associated with the upregulated expressions of GLUT4 and the IRS-1/Akt-mediated signaling cascade in skeletal muscle. GSP treatment also significantly boosted antioxidant enzyme expression and mitigated gluconeogenesis in the liver. Collectively, these data imply that GSP has the potential in managing and preventing diabetes by ameliorating glucose uptake and improving glucose homeostasis.

Trichogenic Photostimulation Using Monolithic Flexible Vertical AlGaInP Light-Emitting Diodes.

Alopecia is considered an aesthetic, psychological, and social issue among modern people. Although laser-induced skin stimulation is utilized for depilation treatment, such treatment has significant drawbacks of high energy consumption, huge equipment size, and limited usage in daily life. Here, we present a wearable photostimulator for hair-growth applications using high-performance flexible red vertical light-emitting diodes (f-VLEDs). Flexible microscale LEDs were effectively fabricated by a simple monolithic fabrication process, resulting in high light output (∼30 mW mm-2), low forward voltage (∼2.8 V), and excellent flexibility for wearable biostimulation. Finally, trichogenic stimulation of a hairless mouse was achieved using high-performance red f-VLEDs with high thermal stability, device uniformity, and mechanical durability.

Obstructive ileus caused by phlebosclerotic colitis.

A 57-year-old man with chronic kidney disease and a history of using numerous herbal medications visited Inje University Ilsan Paik Hospital for abdominal pain and vomiting. An abdominal radiograph showed diffuse small bowel distension containing multiple air-fluid levels and extensive calcifications along the colon. Computed tomography showed colon wall thickening with diffuse calcification along the colonic mesenteric vein and colonic wall. Colonoscopy, performed without bowel preparation, showed bluish edematous mucosa from the transverse to the distal sigmoid colon, with multiple scar changes. At the mid transverse colon, a stricture was noted and the scope could not pass through. A biopsy of the stricture site revealed nonspecific changes. The patient was diagnosed with phlebosclerotic colitis. After the colonoscopy, the obstructive ileus spontaneously resolved, and the patient was discharged without an operation. Currently, after 2 months of follow-up, the patient has remained asymptomatic. Herein, we report the rare case of an obstructive ileus caused by phlebosclerotic colitis with a colon stricture.

Antiobesity Effect of Garlic Extract Fermented by Lactobacillus plantarum BL2 in Diet-Induced Obese Mice.

Obesity is viewed as a serious public health problem. This study aimed to investigate the antiobesity effects of fermented garlic extract by lactic acid bacteria (LAFGE) on obesity. Male C57BL/6J mice were fed with high-fat diet (HFD) to induce obesity. The HFD-induced obese mice were orally administrated with 250 or 500 mg/kg LAFGE for 8 weeks. Feeding HFD-fed mice with 250 or 500 mg/kg LAFGE reduced body weight by 14% and 18%, respectively, compared to HFD. HFD-fed mice with 500 mg/kg LAFGE administration had lower epididymal, retroperitoneal, and mesenteric adipose tissue mass by 36%, 44%, and 63%, respectively, compared to HFD. The concentration of plasma triacylglyceride and total cholesterol was significantly lower in the HFD-fed mice with LAFGE administration. Moreover, LAFGE supplementation suppressed adipogenesis by downregulation in mRNA and protein expression of PPARγ, C/EBPα, and lipogenic proteins, including SREBP-1c, FAS, and SCD-1. Based on these findings, LAFGE may ameliorate diet-induced obesity by inhibiting adipose tissue hypertrophy by suppressing adipogenesis.

The Effect of Oriental Medicine Music Therapy on Idiopathic Chronic Fatigue.

OBJECTIVE: Idiopathic chronic fatigue (ICF), defined as medically unexplained chronic fatigue, is common these days. To date, there is no definite cure for ICF, and alternative therapies are being investigated. Oriental medicine music therapy (OMMT), a novel music therapy that occurs through an active behavioral process, has been applied to various chronic diseases, including ICF. In the present study, we aimed to evaluate the effect of OMMT on ICF. DESIGN: Randomized controlled trial of OMMT compared with the waitlist control (6 sessions each) during a 2-week period. PARTICIPANTS: Thirty participants who had had ICF for at least 6 months before the experiments were recruited. OUTCOME MEASURES: We evaluated fatigue severity scale (FSS), visual analog scale (VAS) for overall fatigue, revised Chalder fatigue scale (RCFS), World Health Organization quality of life scale abbreviated version (WHOQOL-BREF), Buzhongyiqi-Tang questionnaire (BZTQ), and salivary cortisol level at baseline (week 0) and at the end of the study (week 2) in the two groups. RESULTS: FSS, VAS, and RCFS scores were significantly lower, and WHOQOL-BREF scores were significantly higher in the OMMT group than in the waitlist group (p=0.006, p=0.004, p=0.002, and p=0.002, respectively). In contrast, salivary cortisol level and BZTQ scores were not significantly different between the OMMT group and the waitlist group. CONCLUSIONS: The present study suggests that OMMT may be an alternative treatment for ICF. Based on this result, further studies including possible mechanisms are needed.

Effects of oriental medicine music therapy in an ovarian cancer patient with So-Eum-type constitution: a case report.

The cancer incidence in Korea has been increasing, although there is a serious lack of supportive care for the treatment and management of the rapidly increasing number of cancer patients, and there is an immense need for therapeutic interventions to support cancer patients. A 47-year-old So-Eum-type Korean female patient, who was diagnosed with ovarian cancer, had been receiving chemotherapies. She was experiencing pain due to swelling of her hands and feet, and under extreme stress due to hardships of life. During the patient's fourth chemotherapy treatment, she received oriental medicine music therapy twice per week for 2 weeks, for 1 hour each time (4 sessions in total). A self-administered questionnaire and the visual analog scale were used to assess and determine the level of negative and positive feelings. After receiving the oriental medicine music therapy, her negative and positive feelings as well as the visual analog scale score that reflects subjective health conditions have improved and stabilized. This case report suggests the potential of oriental medicine music therapy as a complementary and alternative medical treatment method to promote and enhance quality of life and health conditions of cancer patients in postsurgical care and chemotherapy treatment.

Effect of oriental medicine music therapy on patients with Hwa-byung: a study protocol for a randomized controlled trial.

BACKGROUND: Hwa-byung, a Korean culture-bound syndrome with both psychological and somatic symptoms, is also known as 'anger syndrome'. It includes various physical symptoms including anxiety, a feeling of overheating, a sensation of pressure on the chest, heart palpitations, respiratory stuffiness, insomnia, and anxiety. METHODS/DESIGN: The proposed study is a single-center, double-blind, randomized, controlled trial with two parallel arms: an oriental medicine music therapy (OMMT) group and a control music therapy (CMT) group. In total, 48 patients will be enrolled into the trial. The first visit will be the screening visit. At baseline (visit 2), all participants fulfilling both the inclusion and the exclusion criteria will be split and randomly divided into two equal groups: the OMMT and the CMT (n = 24 each). Each group will receive treatment sessions over the course of 4 weeks, twice per week, for eight sessions in total. The primary outcome is the State-Trait Anxiety Inventory (STAI), and the secondary outcomes are the Hwa-byung scale (H-scale), the Center for Epidemiologic Studies Depression Scale (CES-D), the Hwa-byung visual analogue scale (H-VAS) for primary symptoms, the World Health Organization Quality of Life scale, brief version (WHOQOL-BREF), and levels of salivary cortisol. Patients will be asked to complete questionnaires at the baseline visit (visit 2), after the last treatment session (visit 9), and at 4 weeks after the end of all trial sessions (visit 10). From the baseline (visit 2) through the follow-up (visit 10), the entire process will take a total of 53 days. DISCUSSION: This proposed study targets patients with Hwa-byung, especially those who have exhibited symptoms of anxiety. Therefore, the primary outcome is set to measure the level of anxiety. OMMT is music therapy combined with traditional Korean medicinal theories. Unlike previously reported music therapies, for which patients simply listen to music passively, in OMMT, patients actively move their bodies and play the music. Because Hwa-byung is caused by an accumulation of blocked emotions and anger inside the body, OMMT, because of its active component, is expected to be more efficacious than pre-existing music therapies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11939282.

Enhanced bioavailability of soy isoflavones by complexation with beta-cyclodextrin in rats.

In order to improve the solubility and bioavailability of a soy isoflavone extract (IFE), inclusion complexes (IFE-beta-CD) of the isoflavone extract with beta-cyclodextrin (beta-CD) were prepared and studied for their solubility and bioavailability. The aqueous solubility of the complexes of IFE with beta-CD (2.0 mg/ml) was about 26 times that of IFE itself (0.076 mg/ml). The same dosages of IFE and IFE-beta-CD were orally administered to SD rats (Sprague-Dawley) on an isoflavone glycoside (IFG) basis (daidzin, genistin and glycitin), and the plasma concentrations of daidzein, genistein and glycitein were measured over time to estimate the average AUC (area under the plasma concentration versus time curve) of the isoflavones. After the oral administration, the AUC values for daidzein, genistein and glycitein were 340, 11 and 28 microg x min/ml, respectively. In contrast, the respective AUC values after the administration of IFE-beta-CD were 430, 20 and 48 microg x min/ml. The bioavailability of daidzein in IFE-beta-CD was increased to 126% by the formation of inclusion complexes with beta-CD, compared with that in IFE. Furthermore, the bioavailability of genistein and glycitein in IFE-beta-CD formulation was significantly higher by up to 180% and 170%, respectively, compared with that of IFE p=0.008 and p=0.028, respectively). These results show that the absorption of IFE could be improved by the complexation of IFE with beta-CD (IFE-beta-CD).