Modulation of Pro-inflammatory and Anti-inflammatory Cytokines in the Fat by an Aloe Gel-based Formula, QDMC, Is Correlated with Altered Gut Microbiota

Abnormal inflammatory responses are closely associated with intestinal microbial dysbiosis. Oral administration of Qmatrix-diabetes-mellitus complex (QDMC), an Aloe gel-based formula, has been reported to improve inflammation in type 2 diabetic mice; however, the role of the gut microbiota in ameliorating efficacy of QDMC remains unclear. We investigated the effect of QDMC on the gut microbiota in a type 2 diabetic aged mouse model that was administered a high-fat diet. Proinflammatory (TNF-α and IL-6) and anti-inflammatory (IL-4 and IL-10) cytokine levels in the fat were normalized via oral administration of QDMC, and relative abundances of Bacteroides, Butyricimonas, Ruminococcus, and Mucispirillum were simultaneously significantly increased. The abundance of these bacteria was correlated to the expression levels of cytokines. Our findings suggest that the immunomodulatory activity of QDMC is partly mediated by the altered gut microbiota composition.

The Prescribing Patterns of Antipsychotic Drugs and Antiparkinsonian Drugs in Elderly Patients with Dementia

Background@#The number of patients with dementia continues to increase as the age of aging continues to grow. Psychiatric symptoms caused by senile dementia are controlled using antipsychotics. However, these antipsychotics can lead to Parkinson's disease, and abuse of dopamine derivatives such as levodopa among Parkinsonian drugs can lead to psychosis. Therefore, we evaluated the patterns of prescribed antipsychotics and antiparkinsonian drugs in patients with senile dementia. @*Methods@#We used data from the sample of elderly patients from the Health Insurance Review and Assessment Service (HIRA-APS-2016). We analyzed the patterns of prescribing antipsychotics and antiparkinsonian drugs including prescribed daily dosage, period of prescription, and number of patients with both antipsychotics and antiparkinsonian drugs for senile dementia. @*Results@#Among the 159,391 patients with dementia included in this analysis, 4,963 patients (3.1%) and 16,499 patients (10.4%) were prescribed typical and atypical antipsychotic drugs, respectively. The most frequently prescribed typical antipsychotic was haloperidol (4,351 patients with dementia), whereas the atypical agent was quetiapine (12,719 patients). The most frequently prescribed antiparkinsonian drugs were in the order of levodopa/carbidopa, benztropine, and ropinirole. In addition, 1,103 and 3,508 patients prescribed typical and atypical antipsychotics, respectively, were co-prescribed antiparkinsonian drugs. @*Conclusions@#Atypical antipsychotics were the preferred prescription in patients with senile dementia. The prescription dose was relatively low; however, the average treatment duration was mostly long-term. Selection of antipsychotics and/or antiparkinsonian drugs should be made carefully in senile dementia and the causal relationship of adverse drug reactions needs further study.

Needs and Related Factors for Return-to-Work Support in Cancer Survivors / 정신신체의학

Objectives@#：The purpose of this study was to investigate the needs for return-to-work support of cancer survivors and related factors in patients with cancer and their caregivers. @*Methods@#：182 patients and 114 caregivers were recruited. Distress Thermometer and Problem List and scale ranging 0~10 measuring the degree of needs for return-to-work support were utilized. The needs for return-towork support between the patient group and caregiver group (patient’s needs evaluated by the caregiver) were compared, and related factors were investigated using logistic regression analysis. @*Results@#：34.6% and 28.1% of patients and caregivers reported return-to-work support of cancer survivors is “very necessary”. The degree of needs was 6.60±3.365 points in the patient group and 6.17±3.454 points in the caregiver group, with no significant difference (p=0.282). The needs for return-to-work support evaluated by patients was high when they underwent surgery (OR=2.592, p=0.007), has fertility problems (OR=6.137, p=0.025), has appearance problems (OR=2.081, p=0.041), or has fatigue (OR=2.330, p=0.020). The needs for return-towork support of patients evaluated by caregivers was high when patients treated with breast cancer (vs respiratory cancer, OR=13.038, p=0.022 ; vs leukemia/lymphoma, OR=4.517, p=0.025 ; vs other cancer, OR=13.102, p= 0.019), has work/school problems (OR=4.578, p=0.005), or has depression (OR=3.213, p=0.022). @*Conclusions@#：The degree of needs for return-to-work support of cancer survivors was high, and factors related to the needs were different between the two groups. This suggests that return-to-work support of cancer survivors is required, and clinical characteristics, the distress of patients, and differences between patients and their caregivers should be considered in establishing a support plan.

Needs and Related Factors for Return-to-Work Support in Cancer Survivors / 정신신체의학

Objectives@#：The purpose of this study was to investigate the needs for return-to-work support of cancer survivors and related factors in patients with cancer and their caregivers. @*Methods@#：182 patients and 114 caregivers were recruited. Distress Thermometer and Problem List and scale ranging 0~10 measuring the degree of needs for return-to-work support were utilized. The needs for return-towork support between the patient group and caregiver group (patient’s needs evaluated by the caregiver) were compared, and related factors were investigated using logistic regression analysis. @*Results@#：34.6% and 28.1% of patients and caregivers reported return-to-work support of cancer survivors is “very necessary”. The degree of needs was 6.60±3.365 points in the patient group and 6.17±3.454 points in the caregiver group, with no significant difference (p=0.282). The needs for return-to-work support evaluated by patients was high when they underwent surgery (OR=2.592, p=0.007), has fertility problems (OR=6.137, p=0.025), has appearance problems (OR=2.081, p=0.041), or has fatigue (OR=2.330, p=0.020). The needs for return-towork support of patients evaluated by caregivers was high when patients treated with breast cancer (vs respiratory cancer, OR=13.038, p=0.022 ; vs leukemia/lymphoma, OR=4.517, p=0.025 ; vs other cancer, OR=13.102, p= 0.019), has work/school problems (OR=4.578, p=0.005), or has depression (OR=3.213, p=0.022). @*Conclusions@#：The degree of needs for return-to-work support of cancer survivors was high, and factors related to the needs were different between the two groups. This suggests that return-to-work support of cancer survivors is required, and clinical characteristics, the distress of patients, and differences between patients and their caregivers should be considered in establishing a support plan.

Downregulation of IL-18 Expression in the Gut by Metformin-induced Gut Microbiota Modulation

IL-18 is a crucial pro-inflammatory cytokine that mediates chronic intestinal inflammation. Metformin, an anti-diabetic drug, was reported to have ameliorative effects on inflammatory bowel disease. Recently, the mechanism of action of metformin was explained as a modulation of gut microbiota. In this study, fecal microbiota transplantation (FMT) using fecal material from metformin-treated mice was found to upregulate the expression of GLP-1 and pattern-recognition receptors TLR1 and TLR4 for the improvement in hyperglycemia caused by a high-fat diet. Further, FMT downregulated the expression of the inflammatory cytokine IL-18. Within the genera Akkermansia, Bacteroides, and Butyricimonas, which were promoted by metformin therapy, Butyricimonas was found to be consistently abundant following FMT. Our findings suggest that modulation of gut microbiota is a key factor for the anti-inflammatory effects of metformin which is used for the treatment of hyperglycemia.

Restoration of Declined Immune Responses and Hyperlipidemia by Rubus occidenalis in Diet-Induced Obese Mice

Hyperlipidemia, which is closely associated with a fatty diet and aging, is commonly observed in the western and aged society. Therefore, a novel therapeutic approach for this disease is critical, and an immunological view has been suggested as a novel strategy, because hyperlipidemia is closely associated with inflammation and immune dysfunction. In this study, the effects of an aqueous extract of Rubus occidentalis (RO) in obese mice were investigated using immunological indexes. The mice were fed a high-fat diet (HFD) to induce hyperlipidemia, which was confirmed by biochemical analysis and examination of the mouse physiology. Two different doses of RO and rosuvastatin, a cholesterol synthesis inhibitor used as a control, were orally administered. Disturbances in immune cellularity as well as lymphocyte proliferation and cytokine production were significantly normalized by oral administration of RO, which also decreased the elevated serum tumor necrosis factor (TNF)-α level and total cholesterol. The specific immune-related actions of RO comprised considerable improvement in cytotoxic T cell killing functions and regulation of antibody production to within the normal range. The immunological evidence confirms the significant cholesterol-lowering effect of RO, suggesting its potential as a novel therapeutic agent for hyperlipidemia and associated immune decline.

Metformin Down-regulates TNF-alpha Secretion via Suppression of Scavenger Receptors in Macrophages

Obesity is consistently increasing in prevalence and can trigger insulin resistance and type 2 diabetes. Many lines of evidence have shown that macrophages play a major role in inflammation associated with obesity. This study was conducted to determine metformin, a widely prescribed drug for type 2 diabetes, would regulate inflammation through down-regulation of scavenger receptors in macrophages from obesity-induced type 2 diabetes. RAW 264.7 cells and peritoneal macrophages were stimulated with LPS to induce inflammation, and C57BL/6N mice were fed a high-fat diet to generate obesity-induced type 2 diabetes mice. Metformin reduced the production of NO, PGE2 and pro-inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) through down-regulation of NF-kappaB translocation in macrophages in a dose-dependent manner. On the other hand, the protein expressions of anti-inflammatory cytokines, IL-4 and IL-10, were enhanced or maintained by metformin. Also, metformin suppressed secretion of TNF-alpha and reduced the protein and mRNA expression of TNF-alpha in obese mice as well as in macrophages. The expression of scavenger receptors, CD36 and SR-A, were attenuated by metformin in macrophages and obese mice. These results suggest that metformin may attenuate inflammatory responses by suppressing the production of TNF-alpha and the expressions of scavenger receptors.

Pseudostenosis at the Origin of the Vertebral Artery on Contrast-enhanced MRA: Correlation with Aortic Motion on Dynamic 3D Time-Resolved Contrast-Enhanced MRA

PURPOSE: The origin of the vertebral artery (VA) is a frequent site of pseudostenosis on contrast-enhanced MRA (CE-MRA). The purpose of this study is to evaluate the relationship between the motion of the aortic arch and pseudostenosis at the origin of the VA. MATERIALS AND METHODS: Our study had approval of our institutional review board. 47 patients underwent CT angiography (CTA), CE-MRA, and 3D time-resolved contrast-enhanced MRA (TR-CEMRA) within 6.87+/-9.89 days (mean+/-SD). Percent stenosis using the NASCET criteria was measured on CTA and CE-MRA. CTA was used as a reference standard to classify the CE-MRA into pseudostenosis and control group. Pseudostenosis was determined as 50%-99% stenosis observed on CE-MRA but normal to less than 50% stenosis on CTA. Aortic motion (distance between the highest position and lowest position of aortic arch) was measured on TR-CEMRA. Age, route of intravenous contrast media, motion of aortic arch, and normal distal diameter of VA were compared between the two groups. RESULTS: There were 17 patients and 23 vertebral arteries of pseudostenosis. Patients with pseudostenosis showed more aortic motion (3.61+/-1.88 vs. 2.05+/-1.97 mm) and older age (71.29+/-8.88 vs. 62.32+/-13.19 year-old). Route of intravenous contrast media and normal distal diameter of VA were not associated with pseudostenosis. CONCLUSION: VA origin is a frequent site of pseudostenosis. Older age and more motion of aortic arch are associated with pseudostenosis on CE-MRA.

Dietary Aloe Reduces Adipogenesis via the Activation of AMPK and Suppresses Obesity-related Inflammation in Obese Mice

BACKGROUND: Metabolic disorders, including type II diabetes and obesity, present major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes. In this study, we evaluated whether dietary aloe could reduce obesity-induced inflammation and adipogenesis. METHODS: Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. RESULTS: Aloe QDM complex down-regulated fat size through suppressed expression of scavenger receptors on adipose tissue macrophages (ATMs) compared with HFD. Both white adipose tissue (WATs) and muscle exhibited increased AMPK activation through aloe supplementation, and in particular, the Aloe QDM complex. Obesity-induced inflammatory cytokines (IL-1beta and -6) and HIF1alpha mRNA and protein were decreased markedly, as was macrophage infiltration by the Aloe QDM complex. Further, the Aloe QDM complex decreased the translocation of NF-kappaB p65 from the cytosol in the WAT. CONCLUSION: Dietary aloe formula reduced obesity-induced inflammatory responses by activation of AMPK in muscle and suppression of proinflammatory cytokines in the WAT. Additionally, the expression of scavenger receptors in the ATM and activation of AMPK in WAT led to reduction in the percent of body fat. Thus, we suggest that the effect of the Aloe QDM complex in the WAT and muscle are related to activation of AMPK and its use as a nutritional intervention against T2D and obesity-related inflammation.

CT Evaluation of Vocal Cord Paralysis due to Thoracic Diseases: A 10-Year Retrospective Study

PURPOSE: To discuss computed tomography (CT) evaluation of the etiology of vocal cord paralysis (VCP) due to thoracic diseases. MATERIALS AND METHODS: From records from the past 10 years at our hospital, we retrospectively reviewed 115 cases of VCP that were evaluated with CT. Of these 115 cases, 36 patients (23 M, 13 F) had VCP due to a condition within the thoracic cavity. From these cases, we collected the following information: sex, age distribution, side of paralysis, symptom onset date, date of diagnosis, imaging, and primary disease. The etiology of VCP was determined using both historical information and diagnostic imaging. Imaging procedures included chest radiograph, CT of neck or chest, and esophagography or esophagoscopy. RESULTS: Thirty-three of the 36 patients with thoracic disease had unilateral VCP (21 left, 12 right). Of the primary thoracic diseases, malignancy was the most common (19, 52.8%), with 18 of the 19 malignancies presenting with unilateral VCP. The detected malignant tumors in the chest consisted of thirteen lung cancers, three esophageal cancers, two metastatic tumors, and one mediastinal tumor. We also found other underlying etiologies of VCP, including one aortic arch aneurysm, five iatrogenic, six tuberculosis, one neurofibromatosis, three benign nodes, and one lung collapse. A chest radiograph failed to detect eight of the 19 primary malignancies detected on the CT. Nine patients with lung cancer developed VCP between follow-ups and four of them were diagnosed with a progression of malignancy upon CT evaluation of VCP. CONCLUSION: CT is helpful for the early detection of primary malignancy or progression of malignancy between follow-ups. Moreover, it can reveal various non-malignant causes of VCP.

Dietary Aloe Improves Insulin Sensitivity via the Suppression of Obesity-induced Inflammation in Obese Mice

BACKGROUND: Insulin resistance is an integral feature of metabolic syndromes, including obesity, hyperglycemia, and hyperlipidemia. In this study, we evaluated whether the aloe component could reduce obesity-induced inflammation and the occurrence of metabolic disorders such as blood glucose and insulin resistance. METHODS: Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. RESULTS: Aloe QDM lowered fasting blood glucose and plasma insulin compared with HFD. Obesity-induced inflammatory cytokine (IL-1beta, -6, -12, TNF-alpha) and chemokine (CX3CL1, CCL5) mRNA and protein were decreased markedly, as was macrophage infiltration and hepatic triglycerides by Aloe QDM. At the same time, Aloe QDM decreased the mRNA and protein of PPARgamma/LXRalpha and 11beta-HSD1 both in the liver and WAT. CONCLUSION: Dietary aloe formula reduces obesity-induced glucose tolerance not only by suppressing inflammatory responses but also by inducing anti-inflammatory cytokines in the WAT and liver, both of which are important peripheral tissues affecting insulin resistance. The effect of Aloe QDM complex in the WAT and liver are related to its dual action on PPARgamma and 11beta-HSD1 expression and its use as a nutritional intervention against T2D and obesity-related inflammation is suggested.

Immunostimulatory Effects of Cordyceps militaris on Macrophages through the Enhanced Production of Cytokines via the Activation of NF-kappaB

BACKGROUND: Cordyceps militaris has been used in traditional medicine to treat numerous diseases and has been reported to possess both antitumor and immunomodulatory activities in vitro and in vivo. However, the pharmacological and biochemical mechanisms of Cordyceps militaris extract (CME) on macrophages have not been clearly elucidated. In the present study, we examined how CME induces the production of proinflammatory cytokines, transcription factor, and the expression of co-stimulatory molecules. METHODS: We confirmed the mRNA and protein levels of proinflammatory cytokines through RT-PCR and western blot analysis, followed by a FACS analysis for surface molecules. RESULTS: CME dose dependently increased the production of NO and proinflammatory cytokines such as IL-1beta, IL-6, TNF-alpha, and PGE(2), and it induced the protein levels of iNOS, COX-2, and proinflammatory cytokines in a concentration-dependent manner, as determined by western blot and RT-PCR analysis, respectively. The expression of co-stimulatory molecules such as ICAM-1, B7-1, and B7-2 was also enhanced by CME. Furthermore, the activation of the nuclear transcription factor, NF-kappaB in macrophages was stimulated by CME. CONCLUSION: Based on these observations, CME increased proinflammatory cytokines through the activation of NF-kappaB, further suggesting that CME may prove useful as an immune-enhancing agent in the treatment of immunological disease.

Cordycepin Suppresses Expression of Diabetes Regulating Genes by Inhibition of Lipopolysaccharide-induced Inflammation in Macrophages

BACKGROUND: It has been recently noticed that type 2 diabetes (T2D), one of the most common metabolic diseases, causes a chronic low-grade inflammation and activation of the innate immune system that are closely involved in the pathogenesis of T2D. Cordyceps militaris, a traditional medicinal mushroom, produces a component compound, cordycepin (3'-deoxyadenosine). Cordycepin has been known to have many pharmacological activities including immunological stimulating, anti-cancer, and anti-infection activities. The molecular mechanisms of cordycepin in T2D are not clear. In the present study, we tested the role of cordycepin on the anti-diabetic effect and anti-inflammatory cascades in LPS-stimulated RAW 264.7 cells. METHODS: We confirmed the levels of diabetes regulating genes mRNA and protein of cytokines through RT-PCR and western blot analysis and followed by FACS analysis for the surface molecules. RESULTS: Cordycepin inhibited the production of NO and pro-inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha in LPS-activated macrophages via suppressing protein expression of pro-inflammatory mediators. T2D regulating genes such as 11beta-HSD1 and PPARgamma were decreased as well as expression of co-stimulatory molecules such as ICAM-1 and B7-1/-2 were also decreased with the increment of its concentration. In accordance with suppressed pro-inflammatory cytokine production lead to inhibition of diabetic regulating genes in activated macrophages. Cordycepin suppressed NF-kappaB activation in LPS-activated macrophages. CONCLUSION: Based on these observations, cordycepin suppressed T2D regulating genes through the inactivation of NF-kappaB dependent inflammatory responses and suggesting that cordycepin will provide potential use as an immunomodulatory agent for treating immunological diseases.

Activation of Macrophages by the Components Produced from Cordyceps militaris

BACKGROUND: Cordyceps militaris have been reported to modify the immune and inflammatory responses both in vivo and in vitro. Macrophages play important roles in the innate immunity through the phagocytosis of antigens. This study examined the effects of Cordyceps militaris on the activation of murine macrophage RAW 264.7 cells and primary macrophages. METHODS: The components contained in culture broth of Cordyceps militaris were purified by propyl alcohol extraction and HP 20 column chromatography to CMDB, CMDBW, CMDB5P, and CMDB25P. The amounts of nitric oxide (NO) were determined by using ELISA, Griess reagent respectively. The amounts of some cytokines were determined by using ELISA, western blot, and RT-PCR. The expression levels of cell surface molecules (ICAM-1, B7-1 and B7-2) were measured by flow cytometric analysis. RESULTS: All the components of Cordyceps militaris produced significant amounts of NO. In particular, CMDB produced much more NO in RAW 264.7 cells and primary macrophages than other fractions of Cordyceps militaris. CMDB increased significantly the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 dose-dependently in RAW 264.7 cells. Examination of the gene expression level also showed that the enhanced production of cytokines was correlated with the up-regulation of i-NOS expression, cycloxygenase (COX)-2 expression, IL-1beta and IL-6 expression, and TNF-alpha expression on the expression of mRNAs by semi-quantitative RT-PCR. Western blot analysis also confirmed that CMDB enhances the expression level of these cytokines. CONCLUSION: These results show that CMDB stimulates the production of NO and pro-inflammatory cytokines and can also up-regulate the gene expression levels in macrophages.