Linking alterations in estrogen receptor expression to memory deficits and depressive behavior in an ovariectomy mouse model.

The high risk of neurological disorders in postmenopausal women is an emerging medical issue. Based on the hypothesis of altered estrogen receptors (ERα and ß) after the decline of estrogen production, we investigated the changes in ERs expressions across brain regions and depressive/amnesic behaviors. C57BL/6J female mice were ovariectomized (OVX) to establish a menopausal condition. Along with behavior tests (anxiety, depression, and memory), the expression of ERs, microglial activity, and neuronal activity was measured in six brain regions (hippocampus, prefrontal cortex, striatum, raphe nucleus, amygdala, and hypothalamus) from 4 to 12 weeks after OVX. Mice exhibited anxiety- and depressive-like behaviors, as well as memory impairment. These behavioral alterations have been linked to a suppression in the expression of ERß. The decreased ERß expression coincided with microglial-derived neuroinflammation, as indicated by notable activations of Ionized calcium-binding adapter molecule 1 and Interleukin-1beta. Additionally, the activity of brain-derived neurotrophic factor (BDNF), particularly in the hippocampus, decreased in a time-dependent manner from 4 to 12 weeks post-OVX. Our study provides evidence shedding light on the susceptibility to memory impairment and depression in women after menopause. This susceptibility is associated with the suppression of ERß and alteration of ERα in six brain regions.

A Capsicum annuum L. seed extract exerts anti-neuroexcitotoxicity in HT22 hippocampal neurons.

The hippocampal memory deficit stands out as a primary symptom in neurodegenerative diseases, including Alzheimer's disease. While numerous therapeutic candidates have been proposed, they primarily serve to delay disease progression. Given the irreversible brain atrophy or injury associated with these conditions, current research efforts are concentrated on preventive medicine strategies. Herein, we investigated whether the extracts of Capsicum annuum L. seeds (CSE) and Capsicum annuum L. pulp (CPE) have preventive properties against glutamate-induced neuroexcitotoxicity (one of the main causes of Alzheimer's disease) in HT22 hippocampal neuronal cells. Pretreatment with CSE demonstrated significant anti-neuroexcitotoxic activity, whereas CPE did not exhibit such effects. Specifically, CSE pretreatment dose-dependently inhibited the elevation of excitotoxic elements (intracellular calcium influx and reactive oxygen species; ROS) and apoptotic elements (p53 and cleaved caspase-3). In addition, the glutamate-induced alterations of neuronal activity indicators (brain-derived neurotrophic factor; BDNF and cAMP response element-binding protein phosphorylation; CREB) were significantly attenuated by CSE treatment. We also found that luteolin is the main bioactive compound corresponding to the anti-neuroexcitotoxic effects of CSE. Our results strongly suggest that Capsicum annuum L. seeds (but not its pulp) could be candidates for neuro-protective resources especially under conditions of neuroexcitotoxicity. Its underlying mechanisms may involve the amelioration of ROS-mediated cell death and BDNF-related neuronal inactivity and luteolin would be an active compound.

Reflect, Inspire, Strengthen, and Empower 2.0 Program: Advancing Careers and Leadership for Women Physician Staff in an Academic Institution.

Background: To study the effects of the Reflect, Inspire, Strengthen, and Empower (RISE) 2.0 Program designed for professional development of women staff. Topics included emotional intelligence, appreciative coaching, resilience, and strategic career development. Methods: The RISE 2.0 program was held between September 2020 and February 2021. After each session, program satisfaction surveys were sent to evaluate whether session objectives were met. Professional network, professional mentor, and professional goals were surveyed at the introductory session and at 1 month after the program ended. Survey data about leadership self-efficacy, motivation to lead, and well-being were collected at the introductory session (baseline) and at months 1 and 3 to evaluate the sustainability of program outcomes. Results: Of the 71 notified, 41 (58%) committed to the program. Results increased for having a robust professional network from baseline to month 1 for very good (7.3% to 13.3%) and excellent (19.5% to 40%). Those who responded favorably to setting and attaining ambitious goals increased from 78.1% to 93.3%. For leadership self-efficacy, all except 2 respondents reported an increase in ratings from baseline to month 3. Motivation to lead changed only slightly. Well-being scores fluctuated as affected by daily needs and fulfillment. For 10 of 15 respondents, well-being increased overall from baseline to month 1 or 3, from month 1 to 3. Conclusions: Based on participant evaluations and feedback, the RISE 2.0 program received positive responses overall in achieving its learning goals. The program exhibited promise in fostering career advancement and leadership development, particularly when assessed using indicators predictive of successful leadership, such as self-efficacy, motivation to lead, and overall wellbeing.

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology.

OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date. METHODS: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models. RESULTS: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown. CONCLUSIONS: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Do Organizational Values and Leadership Impact Staff Engagement, Wellbeing, and Patient Satisfaction?

Purpose: Organizational culture has been shown to be an important characteristic that influences behaviors of groups and individuals within an organization. This study seeks to examine the relationships among various organizational values, staff engagement, staff wellbeing, and patient satisfaction in community hospitals. Participants and Methods: Organizational values and engagement data were retrieved from all-staff survey results from 387 clinical units at Mayo Clinic Health Systems. For patient satisfaction data, Press Ganey scores were matched with data for 17 outpatient units from the all-staff survey. Cluster analysis was used to create constructs from the staff satisfaction survey. Reliability was obtained using Cronbach's alpha. Structural equation modeling (SEM) was used to create the measurement model for prediction of constructs. Correlation was used to examine the relationship between culture and patient satisfaction. Results: From the all-staff survey results, we identified nine constructs related to organizational cultural values, staff well-being, and employee engagement. We were able to determine a structural equation model for values and engagement that had an excellent fit. Staff's sense of fairness had a significant impact on how staff provide service excellence. Cultural values of excellence and innovation were positively correlated with large effect size in ten out of eleven patient satisfaction measurement domains and all were statistically significant. Conclusion: Values of excellence had a larger positive relationship with patient satisfaction than all other variables. How staff perceive the level of the organization's commitment to its values had impact on both staff engagement and wellbeing. This study also showed that the construct of wellbeing and patient satisfaction scores are not correlated. Staff will strive to provide excellent experience and good patient care regardless of their state of wellbeing.

Epileptic seizures associated with progressive multifocal leukoencephalopathy in HIV-infected patients in Korea.

We investigated the incidence and risk factors of seizures related to progressive multifocal leukoencephalopathy (PML) in Korean patients infected with HIV. Of the 34 patients, 14 (41.2%) developed epileptic seizures during a median follow-up of 82 months. The median time from PML diagnosis to seizure onset was 44 months, ranging from 0 to 133 months. Patients with PML who developed seizures more commonly had cognitive impairment and multiple or diffuse lesions on brain MRI. These findings highlight the increased seizure risk among HIV-infected patients with PML at any stage of the disease, particularly in cases with extensive involvement.

Ginseng Sprouts Attenuate Mortality and Systemic Inflammation by Modulating TLR4/NF-κB Signaling in an LPS-Induced Mouse Model of Sepsis.

Sepsis leads to multi-organ failure due to aggressive systemic inflammation, which is one of the main causes of death clinically. This study aimed to evaluate whether ginseng sprout extracts (GSE) can rescue sepsis and explore its underlying mechanisms. C57BL/6J male mice (n = 15/group) were pre-administered with GSE (25, 50, and 100 mg/kg, p.o) for 5 days, and a single injection of lipopolysaccharide (LPS, 30 mg/kg, i.p) was administered to construct a sepsis model. Additionally, RAW264.7 cells were treated with LPS with/without GSE/its main components (Rd and Re) to explain the mechanisms corresponding to the animal-derived effects. LPS injection led to the death of all mice within 38 h, while GSE pretreatment delayed the time to death. GSE pretreatment also notably ameliorated LPS-induced systemic inflammation such as histological destruction in both the lung and liver, along with reductions in inflammatory cytokines, such as TNF-α, IL-6, and IL-1ß, in both tissues and serum. Additionally, GSE markedly diminished the drastic secretion of nitric oxide (NO) by suppressing the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) in both tissues. Similar changes in TNF-α, IL-1ß, NO, iNOS, and COX2 were observed in LPS-stimulated RAW264.7 cells, and protein expression data and nuclear translocation assays suggested GSE could modulate LPS-binding protein (LBP), Toll-like receptor 4 (TLR4), and NF-κB. Ginsenoside Rd could be a major active component in GSE that produces the anti-sepsis effects. Our data support that ginseng sprouts could be used as an herbal resource to reduce the risk of sepsis. The corresponding mechanisms may involve TLR4/NF-κB signaling and a potentially active component.

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors.

Microglia are emerging as important targets for the treatment of neuropsychiatric disorders. The phagocytic microglial phenotype and the resulting neuroinflammation lead to synaptic loss and neuronal cell death. To explore potential candidates that inhibit microglial hyperactivation, we first investigated ten candidate extracts of traditional Chinese medicine (TCM) using lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Among the candidates, Pinus spp. succinum extract (PSE) was superior; thus, we further investigated its pharmacological activity and underlying mechanisms both in vitro and in vivo. Pretreatment with PSE (10, 20, and 40 µg/ml) attenuated the increases in inflammatory factors (nitric oxide and tumor necrosis factor-α), translocation of nuclear factor-kappa B (NF-κB), and phenotypic transformations (phagocytic and migratory) in a dose-dependent manner. These inhibitory effects of PSE on microglia were supported by its regulatory effects on the CX3C chemokine receptor 1 (CX3CR1)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. In particular, intragastric administration of PSE (100 mg/kg) considerably improved sickness, anxiety, and depressive-like behaviors in mice subjected to chronic restraint stress (CRS). Our results suggest that PSE has strong antineuroinflammatory and antidepressant properties, and the underlying mechanisms may involve not only the regulation of NF-κB translocation but also the normalization of the CX3CR1/Nrf2 pathway.

Korean Red Ginseng Ameliorates Fatigue via Modulation of 5-HT and Corticosterone in a Sleep-Deprived Mouse Model.

Central fatigue, which is neuromuscular dysfunction associated with neurochemical alterations, is an important clinical issue related to pathologic fatigue. This study aimed to investigate the anti-central fatigue effect of Korean red ginseng (KRG) and its underlying mechanism. Male BALB/c mice (8 weeks old) were subjected to periodic sleep deprivation (SD) for 6 cycles (forced wakefulness for 2 days + 1 normal day per cycle). Simultaneously, the mice were administered KRG (0, 100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg). After all cycles, the rotarod and grip strength tests were performed, and then the changes regarding stress- and neurotransmitter-related parameters in serum and brain tissue were evaluated. Six cycles of SD notably deteriorated exercise performance in both the rotarod and grip strength tests, while KRG administration significantly ameliorated these alterations. KRG also significantly attenuated the SD-induced depletion of serum corticosterone. The levels of main neurotransmitters related to the sleep/wake cycle were markedly altered (serotonin was overproduced while dopamine levels were decreased) by SD, and KRG significantly attenuated these alterations through relevant molecules including brain-derived neurotropic factor and serotonin transporter. This study demonstrated the anti-fatigue effects of KRG in an SD mouse model, indicating the clinical relevance of KRG.

Gelfoam embolization for distal, medium vessel injury during mechanical thrombectomy in acute stroke: A case report.

BACKGROUND: Arterial perforation has inevitably increased as endovascular treatments have become more common for intracranial large vessel occlusions, and even distal, medium vessel occlusions. A distal, medium vessel has a tortuous course and thinner wall compared to large arteries, making it more susceptible to damage. Here, we review the treatment strategies for arterial perforation during mechanical thrombectomy, and we report the case of a patient treated with gelfoam embolization. CASE SUMMARY: A 63-year-old woman presented to the emergency department with sudden neurologic symptoms of right hemiparesis and global aphasia. The initial National Institutes of Health Stroke Scale score was 15. Computed tomography (CT) and CT angiography revealed hyperacute infarction and emergent arterial occlusion of the left middle cerebral artery M2-3 portion. During endovascular mechanical thrombectomy, arterial rupture occurred. The patient's vital signs were stable, but delayed angiography showed persistent active bleeding. Therefore, selective embolization of the injured artery was performed using gelfoam. Subsequent left vertebral and internal carotid angiography was performed to confirm hemostasis. A localized subarachnoid hemorrhage (SAH) was confirmed on a follow-up CT scan. A repeated CT scan after 12 d showed resolution of the SAH, and rebleeding did not occur. CONCLUSION: Rescue embolization with gelfoam could be considered an additional option in distal, medium vessel perforation.

Aquilariae Lignum Methylene Chloride Fraction Attenuates IL-1ß-Driven Neuroinflammation in BV2 Microglial Cells.

Microglial hyperactivation and neuroinflammation are known to induce neuronal death, which is one of the main causes of neurodegenerative disorders. We previously found that Aquilariae Lignum extract attenuated both neuronal excitotoxicity and neuroinflammation in vivo and in vitro. For further analysis, we extracted the methylene chloride fraction of Aquilariae Lignum to determine the bioactive compounds. In this study, we investigated the anti-neuroinflammatory effects and underlying mechanisms of the Aquilariae Lignum fraction (ALF) using lipopolysaccharide (LPS)-stimulated BV2 microglial cells. BV2 cells were pretreated with ALF (0.5, 1, and 2.5 µg/mL) before treatment with LPS (1 µg/mL). Pretreatment with ALF significantly attenuated the LPS-induced overproductions of nitric oxide (NO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and interleukin (IL)-1ß. These anti-inflammatory effects were supported by ALF-mediated modulation of the nuclear factor-kappa B (NF-κB) pathway. Furthermore, ALF exerted strong anti-inflammasome effects, as shown by IL-1ß-specific inhibitory activity, but not activity against tumor necrosis factor (TNF)-α, along with inhibition of caspase-1 activity and NACHT, LRR, and PYD domain-containing protein 3 (NLRP3)-related molecules. These results indicate the potent anti-neuroinflammatory activity of ALF and that its underlying mechanism may involve the regulation of NLRP3 inflammasome-derived neuroinflammation in microglial cells.

Ethyl Acetate Fraction of Amomum xanthioides Ameliorates Nonalcoholic Fatty Liver Disease in a High-Fat Diet Mouse Model.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and has continued to increase; however, no drugs have yet been approved for NAFLD treatments. The ethyl acetate fraction of Amomum xanthioides (EFAX) was previously reported to have an anti-hepatic fibrosis effect, but its effects on steatosis or steatohepatitis remain unclear. This study investigated the anti-fatty liver of EFAX using a high-fat diet mouse model. High-fat diet intake for 8 weeks induced hepatic steatosis with mild inflammation and oxidative damage and increased the adipose tissue weight along with the development of dyslipidemia. EFAX treatment significantly ameliorated the steatohepatic changes, the increased weight of adipose tissues, and the altered serum lipid profiles. These observed effects were possibly due to the lipolysis-dominant activity of EFAX on multiple hepatic proteins including sterol regulatory element-binding protein (mSREBP)-1c, peroxisome proliferator-activated receptor (PPAR)-α, AMP-activated protein kinase, and diglyceride acyltransferases (DGATs). Taken together, these results show that EFAX might be a potential therapeutic agent for regulating a wide spectrum of NAFLDs from steatosis to fibrosis via multiple actions on lipid metabolism-related proteins. Further studies investigating clear mechanisms and their active compounds are needed.

Relationships Among Organizational Values, Employee Engagement, and Patient Satisfaction in an Academic Medical Center.

OBJECTIVE: To examine the relationships among various organizational values, employee engagement, and patient satisfaction in an academic medical center. PARTICIPANTS AND METHODS: Organizational values and engagement data were retrieved from 2015 all-staff survey results from 1876 clinical units at Mayo Clinic. For patient satisfaction data, Press Ganey scores from visits from July 1, 2015, through January 1, 2016, were matched with data for 26 outpatient units from the all-staff survey. The study was performed from January 1, 2016, through December 31, 2017. RESULTS: From the all-staff survey results, we identified seven constructs related to values and employee engagement, all of which showed high positive correlation with each other. We were able to determine a structural equation model for values and engagement that had an excellent fit (comparative fit index, 0.957). Empowering leadership was positively correlated with the largest number of patient satisfaction items, followed by employee engagement and psychological safety/trust. All items from the care provider category had positive correlations with empowering leadership and psychological safety/trust. CONCLUSION: All the organizational values studied showed positive correlation with employee engagement, and all the organizational values and engagement were predictors of excellence and innovation either directly or indirectly. This affirms that honoring organizational values related to respect, psychological safety/trust, empowering leadership, and fairness has a positive influence on employee engagement and desire to pursue excellence. Organizational values, engagement, and empowering leadership behavior were positively correlated with many patient satisfaction items.

Schwannoma of the thyroid bed: A case report and review of the literature.

RATIONALE: Schwannomas involving the thyroid gland are very rare and only a few cases have been reported in the literature. However, previous reports did not distinguish between thyroid bed schwannomas and intrathyroidal schwannomas. Here, we report a thyroid bed schwannoma mimicking a malignant thyroid nodule and review the literature on thyroid bed schwannomas. PATIENT CONCERNS: A 33-year-old woman presented at our hospital with mild neck swelling. DIAGNOSIS: Thyroid ultrasound revealed a well-defined, oval-shaped, markedly hypoechoic solid nodule with echogenic foci suggesting macro- and microcalcifications in the left thyroid gland. The lesion was considered a "highly suspicious" intrathyroidal nodule, based on the guidelines for the assessment of thyroid nodules. Fine needle aspiration was performed twice, but the cytological results were nondiagnostic. INTERVENTIONS: Left thyroidectomy was performed, and schwannoma of the thyroid bed was confirmed on histopathologic analysis. OUTCOMES: The patient was in a stable condition after surgery, and the thyroid function test results were within the normal range. LESSONS: Diagnosis of a schwannoma of the thyroid bed is challenging because its incidence is extremely low, and it is often misdiagnosed as an intrathyroidal nodule on ultrasonography. Therefore, it is advisable to adopt a diagnostic strategy to perform additional core needle biopsy in cases of thyroid nodules with nondiagnostic fine needle aspiration results and to consider the location of the lesion more carefully to determine the suitable therapy.

A Comparison of Isolation Stress and Unpredictable Chronic Mild Stress for the Establishment of Mouse Models of Depressive Disorder.

This study aimed to help to understand the influence of stress on depression, which reflects the social environments of especially solitary life and the increasing prevalence of depressive disorders. To determine the distinguishable features of two-representative animal models of stress-induced depressive disorder, we compared isolation stress (IS) and unpredictable chronic mild stress (UCMS). After 4-week of stress, both models showed significant depressive- and anxiety-like behaviors in an open field test (OFT; p < 0.01 for IS, p < 0.01 for UCMS), forced swimming test (FST; p < 0.01 for IS, p < 0.01 for UCMS), and tail suspension test (TST; p < 0.01 for IS, p < 0.05 for UCMS) along with alterations in serum corticosterone levels, serotonin activity in the dorsal raphe nuclei (DRN) and microglial activity in the dentate gyrus of the hippocampus (p < 0.05 for both parameters). In a comparison of the two stress models, IS strongly induced depressive and anxiety features, as indicated by all parameters: behavior test scores (p < 0.05 for OFT, FST, and TST), serum corticosterone levels (p < 0.05), immunohistological alterations for serotonin activity (p < 0.05) and microglial activity (p = 0.072). Our results indicate the suitability of IS for the development of animal models of depressive disorders and may reveal the medical impact of social isolation environment in modern society.

Multiscale architectured materials with composition and grain size gradients manufactured using high-pressure torsion.

The concept of multiscale architectured materials is established using composition and grain size gradients. Composition-gradient nanostructured materials are produced from coarse grained interstitial free steels via carburization and high-pressure torsion. Quantitative analyses of the dislocation density using X-ray diffraction and microstructural studies clearly demonstrate the gradients of the dislocation density and grain size. The mechanical properties of the gradient materials are compared with homogeneous nanostructured carbon steel without a composition gradient in an effort to investigate the gradient effect. Based on the above observations, the potential of multiscale architecturing to open a new material property is discussed.

The analgesic and anti-inflammatory effect of WIN-34B, a new herbal formula for osteoarthritis composed of Lonicera japonica Thunb and Anemarrhena asphodeloides BUNGE in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicera japonica Thunb and Anemarrhena asphodeloides BUNGE have been used for the treatment of a variety of inflammatory diseases, cold and infective diseases in many countries, including Korea and China. AIM OF THE STUDY: This study aimed to assess the anti-nociceptive and anti-inflammatory activities of n-butanol fraction (WIN-34B) prepared from dried flowers of Lonicera japonica and dried roots of Anemarrhena asphodeloides as potential novel treatment of osteoarthritis. MATERIALS AND METHODS: Anti-nociceptive activities of WIN-34B (100, 200 and 400 mg/kg, p.o.) were measured using acetic acid-induced writhing response, formalin-induced paw licking, hot plate, radiant heat tail-flick, carrageenan-induced paw pressure, and Hargreaves tests, respectively. Anti-inflammatory activities of WIN-34B (100, 200 and 400 mg/kg, p.o.) were assessed using acetic acid-induced vascular permeability, carrageenan-induced paw edema, and croton oil-induced ear edema. Anti-osteoarthritis effect of WIN-34B was analyzed using monosodium iodoacetate (MIA)-induced osteoarthritis animal model. RESULTS: WIN-34B exhibited better anti-inflammatory activity than that of celecoxib in carrageenan at the dose of 200 mg/kg and croton oil-induced paw edema and ear edema at the doses of 200 and 400 mg/kg. WIN-34B exhibited significant anti-inflammatory effects on vascular permeability. WIN-34B also exhibited significant anti-nociceptive activities in the late phase of formalin-induced paw licking and writhing response model in mice. In radiant heat tail-flick and carrageenan-induced paw pressure tests, WIN-34B at the dose of 400 mg/kg and at the doses of 200 and 400 mg/kg presented similar activities to indomethacin and celecoxib. Compared to indomethacin WIN-34B at 400mg/kg showed similar or better anti-nociceptive activities after 1 and 2h of theraphy in the hot plate test and better anti-nociceptive activity than that of celecoxib in Hargreves test. In the MIA-induced osteoarthritis animal models, WIN-34B at 400 mg/kg exhibited similar or better anti-nociceptive property than that of celecoxib throughout the pain measurement periods. CONCLUSION: When compared to celecoxib, WIN-34B exhibited similar or better anti-nociceptive and anti-inflammatory activities in osteoarthritic animal models, which may become a potential novel treatment for osteoarthritis.

Sesquiterpenoids isolated from the flower buds of Tussilago farfara L. inhibit diacylglycerol acyltransferase.

Inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT), which is a key enzyme in triglyceride synthesis in eukaryotic organisms, has been proposed as one of the drug targets for treating obesity, type II diabetes mellitus, and metabolic syndrome. Bioassay-guided fractionation of EtOH extract of the flower buds of Tussilago farfara , using an in vitro DGAT enzyme assay, resulted in the isolation of four known sesquiterpenoids, tussilagonone (1), tussilagone (2), 7beta-(3-ethyl-cis-crotonoyloxy)-1alpha-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (3), and 8-angeloylxy-3,4-epoxy-bisabola-7(14),10-dien-2-one (4). DGAT1 inhibitory activity was studied by in vitro DGAT assay using rat liver microsomes and HepG2 cell microsomes. They showed DGAT1 inhibition with IC(50) values of 99.2 (1), 18.8 (2), 47.0 (3), and 211.1 (4) microM (for rat liver microsomes) and >1 mM (1), 49.1 (2), 160.7 (3), and 294.4 (4) microM (for HepG2 cell microsomes), respectively. Compound 2 showed the most potent inhibition against microsomal DGAT1 derived from rat liver and human hepatocellular carcinoma HepG2 cells and also significantly inhibited triglyceride synthesis by suppressing incorporation of [(14)C]acetate or [(14)C]glycerol into triglycerides in HepG2 cells. These findings suggest that tussilagone is a potential lead compound in the treatment of obesity and type 2 diabetes.

ACAT inhibition of alkamides identified in the fruits of Piper nigrum.

In this study, via a bioactivity-guided fractionation of MeOH extracts of the fruits of Piper nigrum, alkamide (5) and five previously-identified alkamides were isolated. Their structures were elucidated via spectroscopic analysis ((1)H, (13)C NMR and ESI-MS), as follows: retrofractamide A (1), pipercide (2), piperchabamide D (3), pellitorin (4), dehydroretrofractamide C (5) and dehydropipernonaline (6). The IC(50) values determined for the compounds were 24.5 (1), 3.7 (2), 13.5 (3), 40.5 (4), 60 (5) and 90 microM (6), according to the results of an ACAT enzyme assay system using rat liver microsomes. These compounds all inhibited cholesterol esterification in HepG2 cells.

Glabrol, an acyl-coenzyme A: cholesterol acyltransferase inhibitor from licorice roots.

Acyl-coenzyme A: cholesterol acyltransferase (ACAT) esterifies free cholesterol in the liver and the intestine. It has relations with production of lipoproteins and accumulation of cholesteryl esters of the atheroma. Therefore, ACAT inhibitors may act as antihypercholesterolemic and antiatherosclerotic agents. One isoprenyl flavonoid was isolated from ethanol extract of licorice roots. On the basis of spectral evidences, the compound was identified as glabrol (1). Compound 1 inhibited rat liver microsomal ACAT activity with an IC(50) value of 24.6 microM and decreased cholesteryl ester formation with an IC(50) value of 26.0 microM in HepG2 cells. In addition, 1 showed a non-competitive type of inhibition against ACAT.