Novel Plant Extract Ameliorates Metabolic Disorder through Activation of Brown Adipose Tissue in High-Fat Diet-Induced Obese Mice.

Obesity is characterized by excessive body fat accumulation due to unbalanced energy intake and expenditure. Potential therapeutic targets for anti-obesity include the inhibition of white adipose tissue (WAT) hypertrophy and hyperplasia and the activation of brown adipose tissue (BAT). Not only the activation of BAT but also the browning of WAT have gained increasing attention in research fields as an alternative method in the prevention and treatment of obesity. Here, we investigated possible mechanisms underlying the anti-obesity effect of Phlomis umbrosa Turcz. root ethanol extract (PUE) in an obesogenic animal model. PUE treatment can reduce diet-induced obesity and modulate obesity-associated metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation. In the liver, PUE improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption while increasing biliary sterol excretion and hepatic fatty acid oxidation compared to the high-fat group. Moreover, PUE increased energy expenditure and regulated fecal lipid excretion, leading to reduced body weight gain. In particular, PUE remarkably activated the browning of subWAT via upregulation of the browning-related protein and gene expression and promoted BAT activation. In conclusion, these findings provide the potential therapeutic usefulness into the effects of PUE in the treatment of obesity and metabolic disorders. Furthermore, it suggests that PUE treatment can regulate energy metabolism via activating BAT and browning subWAT.

Applications and Functions of γ-Poly-Glutamic Acid and its Derivatives in Medicine.

BACKGROUND: γ-Poly-Glutamic Acid (γ-PGA) is a naturally occurring homo-polyamide produced by various strains of Bacillus. It is made from repeating units of L-glutamic acid, D-glutamic acid, or both connected through amide linkages between α-amino and γ-carboxylic acid groups. As a biopolymer substance, the attractive properties of γ-PGA are that it is water-soluble, biodegradable, biocompatible, non-toxic, non-immunogenic, and edible. Therefore, it can be used as a green and environmentally friendly biological material. METHODS: The review concentrates on the reports revealing the functions and potential use of γ-PGA and its derivatives in medicine. RESULTS & DISCUSSION: γ-PGA is described to possess several properties that may be exploited in medicine. The biopolymer reportedly has been successfully applied not only as a metal chelator, drug carrier/ deliverer, and gene vector, but also used safely as a vaccine adjuvant, tissue engineering material, and contrast agent. CONCLUSION: γ-PGA could be potentially considered as a potential biomedical material in the field of medicine.

Thirteen-week oral toxicity study of fermented ginseng, GBCK25, in Sprague-Dawley rats.

Ginseng (Panax ginseng) is commonly used in Asia as a medicinal herb. In particular, fermented ginseng, GBCK25, has been recently developed to increase ginsenoside absorption. It also has other beneficial biological effects such as hemodynamic and anti-inflammation functions. Here, we investigated the potential toxicity of GBCK25 in Sprague-Dawley rats following 13 weeks of GBCK25 treatment by oral gavage at doses of 250, 500, or 1000 mg/kg/day and reversible toxic effects over a 4-week recovery phase. Ten male and female rats per group were randomly allocated to the main toxicology groups and five male and female rats per group were allocated to the 0 and 1000 mg/kg/day recovery groups, respectively. There was no mortality; significant clinical toxicity or microscopic findings; and changes in body weight, food consumption, hematological parameters, serum biochemistry, or absolute and relative organ weights in any of the groups. In conclusion, there were no toxicological changes upon repeated oral gavage of GBCK25 at doses of 250, 500, or 1000 mg/kg/day in Sprague-Dawley rats over 13 weeks. The no-observed-adverse-effect level of GBCK25 was 1000 mg/kg/day in both sexes of Sprague-Dawley rat.

Double-Blind, Randomized, Placebo-Controlled Trial of DA-9701 in Parkinson's Disease: PASS-GI Study.

OBJECTIVES: This study aimed to assess the efficacy of DA-9701 on gastrointestinal symptom-related quality of life in patients with Parkinson's disease on stable dopaminergic medications. METHODS: This multicenter, double-blind, placebo-controlled, phase 4 trial included a total of 144 patients with Parkinson's disease with gastrointestinal dysfunctions based on predefined criteria. Participants were randomized to take either DA-9701 or placebo for 4 weeks, and then both groups were administered DA-9701 for an additional 8 weeks while antiparkinsonian medications were unchanged. The primary outcome measure was gastrointestinal symptoms and related quality-of-life changes assessed on the Korean Nepean dyspepsia index after 4 and 12 weeks of therapy. We also evaluated the impact of DA-9701 therapy on parkinsonian motor symptoms at each time point. RESULTS: The gastrointestinal symptom-related quality-of-life score significantly improved in the DA-9701-treated group compared with the placebo-treated group after 4weeks (adjusted P = 0.012 by linear mixed effect model analysis). The overall gastrointestinal symptom and dyspepsia sum scores improved at 12 weeks after intervention in the DA-9701-first treated group (adjusted P = 0.002 and 0.014, respectively) and also in the placebo-first treated group (adjusted P = 0.019 and 0.039) compared with the baseline. Parkinsonian motor severity was not significantly affected by DA-9701 treatment in both groups at 4 and 12 weeks after intervention. There were no drug-related serious adverse events throughout the trial. CONCLUSIONS: DA-9701 therapy improved gastrointestinal symptom-related quality of life, and 12 weeks of daily administration can relieve the overall severity of gastrointestinal symptoms in patients with Parkinson's disease without affecting motor symptoms. (Clinical trial identifier: NCT02775591.) © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amoxicillin or tetracycline in bismuth-containing quadruple therapy as first-line treatment for Helicobacter pylori infection.

AIM: To compare the efficacy and safety between modified quadruple- and bismuth-containing quadruple therapy as first-line eradication regimen for Helicobacter pylori infection. METHODS: This study was a multicenter, randomized-controlled, non-inferiority trial. Subjects endoscopically diagnosed with H. pylori infection were randomly allocated to receive modified quadruple- (rabeprazole 20 mg bid, amoxicillin 1 g bid, metronidazole 500 mg tid, bismuth subcitrate 300 mg qid [elemental bismuth 480 mg]; PAMB) or bismuth-containing quadruple therapy (rabeprazole 20 mg bid, bismuth subcitrate 300 mg qid, metronidazole 500 mg tid, tetracycline 500 mg qid; PBMT) for 14 days. Rates of eradication success and adverse events were investigated. Antibiotic resistance was determined using the agar dilution and DNA sequencing of the clarithromycin resistance point mutations in the 23 S rRNA gene of H. pylori. RESULTS: In total, 233 participants were randomized, 27 were lost to follow-up, and four violated the protocol. Both regimens showed an acceptable eradication rate in the intention-to-treat (PAMB: 87.2% vs. PBMT: 82.8%, P = .37), modified intention-to-treat (96.2% vs. 96%, P > .99), and per-protocol (96.2% vs. 96.9%, P > .99) analyses. Non-inferiority in the eradication success between PAMB and PBMT was confirmed. The amoxicillin-, metronidazole-, tetracycline-, clarithromycin-, and levofloxacin-resistance rates were 8.3, 40, 9.4, 23.5, and 42.2%, respectively. Antimicrobial resistance did not significantly affect the efficacy of either therapy. Overall compliance was 98.1%. Adverse events were not significantly different between the two therapies. CONCLUSION: Modified quadruple therapy comprising rabeprazole, amoxicillin, metronidazole, and bismuth is an effective first-line treatment for the H. pylori infection in regions with high clarithromycin and metronidazole resistance.

Eupatolide inhibits the TGF-ß1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5.

The epithelial-mesenchymal transition (EMT) is a hallmark of cancer metastasis, and the associated molecular signaling pathways are regarded as therapeutic targets for cancer treatment. Thus, suppressing EMT with a natural chemical compound may be of therapeutic benefit. Eupatolide is a natural chemical compound extracted from the medicinal plant Inula britannica, which is used in Eastern Asia to treat bronchitis, disorders of the digestive system and inflammation. Besides the anti-inflammatory function of eupatolide, the present study found that eupatolide suppressed the migration and invasion of breast cancer cells, which was associated with the downregulation of vimentin in MDA-MB-231 cells and the upregulation of E-cadherin in MCF-7 cells. Treatment with eupatolide also significantly inhibited the migration and invasion of breast cancer cells that had been stimulated with transforming growth factor-ß1 (TGF-ß1). Eupatolide also suppressed TGF-ß1-induced EMT via downregulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and transcriptional repression of TGF-ß receptor 1 (ALK5). In addition to this canonical pathway, the non-canonical protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways were also inhibited by eupatolide treatment. In summary, the results suggest that eupatolide suppresses the migration and invasion of breast cancer cells by blocking the canonical ALK5-SMAD3 signaling pathway and the non-canonical ERK and AKT signaling pathways.

Combined Treatment of Herbal Mixture Extract H9 with Trastuzumab Enhances Anti-tumor Growth Effect.

Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC.

Evaluation of toxicity to triclosan in rats following 28 days of exposure to aerosol inhalation.

The present study was conducted to investigate the potential subchronic toxicity of triclosan (TCS) in rats following 28 days of exposure by repeated inhalation. Four groups of six rats of each sex were exposed to TCS-containing aerosols by nose-only inhalation of 0, 0.04, 0.13, or 0.40 mg/L for 6 h/day, 5 days/week over a 28-day period. During the study period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 0.40 mg/L, rats of both sexes exhibited an increase in the incidence of postdosing salivation and a decrease in body weight. Histopathological alterations were found in the nasal septum and larynx. There were no treatment-related effects in rats of either sex at ⩽0.13 mg/L. Under the present experimental conditions, the target organs in rats were determined to be the nasal cavity and larynx. The no-observed-adverse-effect concentration in rats was determined to be 0.13 mg/L.

Difference of the naltrexone's effects in social drinkers by spicy food preference.

The purpose of this study was to investigate the differences in subjective acute effects of alcohol and naltrexone among those who prefer spicy food to varying degrees. Acute biphasic alcohol effects scale (BAES), visual analogue scale for craving (VAS-C), blood alcohol concentration (BAC) and food preference scale were measured in 26 men. Repeated measures ANOVA (2 preference groups×4 time blocks) on the stimulative subscale of BAES revealed a significant group by block interaction in naltrexone condition (N+) (P<0.001), but not in non-naltrexone condition (N-). Furthermore, repeated measures ANOVA (2 drug groups×4 time blocks) on the stimulative subscale of BAES revealed a significant group by block interaction in strong preference for spicy food (SP) (P<0.001), but not in lesser preference for spicy food (LP). The paired t-test revealed that significant suppression of the stimulative subscale of BAES was observed at 15 min (P<0.001) and 30 min (P<0.001) after drinking when N+ compared with N- in SP. For those who prefer spicy food, the stimulative effect of acute alcohol administration was suppressed by naltrexone. This result suggests that the effect of naltrexone may vary according to spicy food preference.

Luteolin supplementation modulates mammary tumor growth in C3H mice fed diet with high- and low-fat content.

In this study we investigated the effects of luteolin supplementation (0.05% w/w) on mammary tumor growth in C3H mice, a strain of mouse mammary tumor virus negative, fed either high-fat (45% fat of energy) or low-fat diet (15% fat of energy). Animals (n = 12/group) were allocated into 4 experimental groups (low-fat diet, low-fat diet + luteolin supplementation, high-fat diet, high-fat diet + luteolin supplementation). Experimental diet were fed for 13 wk and 7,12-dimethylbenz[a]anthracene was administered once a week for 6 wk starting at Week 1 to induce mammary tumors. Study results showed that animals on low-fat diet supplemented with luteolin exhibited longer tumor latency and lower tumor weights and sizes compared to the other groups. Animals fed high-fat diet showed increased serum IGF-1 levels and the elevated mammary tissue expression of Ki-67, IRS-1, pp38, Cdk4, and Cdk6. Luteolin inhibited IRS-1, Cdk4, and Cdk6 expression in high-fat fed animals. The expression of pp38, cyclinD1, and Bcl-xL was suppressed by luteolin supplementation both in the low-fat and high-fat diet groups. These results suggest that excess energy supply increases the risk of mammary tumor formation and luteolin suppresses tumor formation regardless of dietary fat content through its cell cycle regulatory and proapoptotic activity.

The Evaluation of the Body Weight Lowering Effects of Herbal Extract THI on Exercising Healthy Overweight Humans: A Randomized Double-Blind, Placebo-Controlled Trial.

We investigated the effects of herbal extracts, a mixture of Scutellariae Radix and Platycodi Radix containing the active ingredients Baicalin and Saponin (target herbal ingredient (THI)), on lowering body weight. The present study was a prospective, randomized, double-blind, and placebo-controlled trial carried out at the outpatient department of a hospital over a period of 2 months. Group 1 patients (n = 30) received THI, and group 2 patients (n = 23) received placebo three times a day before meals. Weight, waist circumference, BMI, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and glucose were measured at baseline and again at the 2nd month. For safety evaluation, various hematological and biochemical parameters were assessed. Values of mean change of weight in the THI-treated group were -1.16 ± 1.41 kg and in the placebo-treated group were -0.24 ± 1.70 kg, respectively. The difference in mean change of weight in the THI-treated group compared with that in the placebo-treated group was statistically significant (P < 0.05). The incidence of subjective and objective adverse drug reactions was insignificant (P > 0.05). THI was statistically significant in its effectiveness on the weight loss.

Hwanggeumchal sorghum extract enhances BMP7 and GH signaling through the activation of Jak2/STAT5B in MC3T3­E1 osteoblastic cells.

Sorghum is a principal cereal food in a number of parts of the world and is critical in folk medicine in Asia and Africa. However, its effects on bone are unknown. Growth hormone (GH) is a regulator of bone growth and bone metabolism. GH activates several signaling pathways, including the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathways, thereby regulating expression of genes, including insulin­like growth factor (IGF)­1. Bone morphogenetic proteins (BMPs) induce the differentiation of cells of the osteoblastic lineage, increasing the pool of IGF­1 target cells, the mature osteoblasts. In the present study, the effects of Hwanggeumchal sorghum extracts (HSE) on GH signaling via the Jak/STAT pathway in osteoblasts were investigated. HSE was not observed to be toxic to osteoblastic cells and increased the expression of BMP7 and GH­related proteins, including STAT5B, p­STAT5B, IGF­1 receptor (IGF-1R), growth receptor hormone (GHR) and Jak2 in MC3T3­E1 cells. In addition, HSE increased BMP7 and GHR mRNA expression in MC3T3­E1 cells. The expression of HSE­induced BMP7 and GHR was inhibited by AG490, a Jak2 kinase inhibitor. The observations indicate that HSE­induced signaling is similar to GH signaling via the GHR­Jak2 signaling axis. Using small interference RNA (siRNA) analysis, STAT5B was found to play an essential role in HSE­induced BMP7 and GH signaling in MC3T3­E1 cells. Results of the current study indicate that HSE promotes bone growth through activation of STAT5B.

Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.

BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

A mixture of Trachelospermi caulis and Moutan cortex radicis extracts suppresses collagen-induced arthritis in mice by inhibiting NF-κB and AP-1.

OBJECTIVES: We aimed to determine the anti-arthritis effect and its mechanism of a combination of herbal extracts from Trachelospermi caulis (TC) and Moutan cortex radicis (MC) (TCMC). METHODS: The anti-arthritis activity of TCMC was assessed using a mouse model of type II collagen-induced arthritis (CIA). Reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA) and other biological assays were performed. KEY FINDINGS: TCMC significantly ameliorated various inflammatory parameters, such as clinical arthritis index, histological deformation of joints, serum levels of rheumatoid arthritis biomarkers (cartilage oligomeric matrix protein, serum amyloid P and anti-collagen type II IgG antibody), and Th1-related responses (T cell proliferation, and production of Interferon-γ and interleukin (IL)-2 in splenocytes isolated from CIA mice). The production of matrix metalloproteinases (MMPs), pro-inflammatory cytokines (tumour necrosis factor-α, IL-1ß and IL-6) and chemokines (macrophage inflammatory protein-1, monocyte chemoattractant protein-1, and Regulated upon Activation, Normal T-cell Expressed, and Secreted) was suppressed by TCMC in CIA mice. In addition, the number of osteoclasts in the hind tibia was significantly decreased. With regard to the mechanism, TCMC suppressed the activation of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1. CONCLUSIONS: TCMC exerts an anti-arthritis effect in CIA mice by suppression of the production of various inflammatory factors and the formation of osteoclasts through the inhibition of NF-κB and AP-1 activation.

Antiobesity effects of a sulfur compound thiacremonone mediated via down-regulation of serum triglyceride and glucose levels and lipid accumulation in the liver of db/db mice.

Garlic is widely used as a spice. Garlic extracts exert anticancer and antiinflammatory effects, but its antiobesity efficacy studies have produced conflicting results. The antiobesity effects of thiacremonone, a sulfur compound isolated from garlic, was evaluated in obese db/db mice. Thiacremonone was orally administrated to mice for 3 weeks. The thiacremonone-treated db/db mice showed a loss of body weight and decrease in blood triglyceride and glucose levels compared with the control mice. Histological analysis further revealed that thiacremonone significantly decreased lipid accumulation in the fatty livers of treated db/db mice. It was observed that GLUT-4 expression and glucose uptake were up-regulated by thiacremonone in 3T3-L1 adipocytes. Thiacremonone treatment also suppressed expression levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which are involved in lipid metabolism, in the liver of db/db mice. In addition, thiacremonone enhanced peroxisome proliferator-activated receptor γ (PPARγ) expression in the fatty liver. Taken together, these results suggest that thiacremonone may play a vital role in improving the management of obesity and related metabolic syndromes via inhibition of lipid accumulation.

Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes.

Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. Estimated hepatic clearance (Cl(h)) for BIBX1382, carbazeran, O6-benzylguanine, zaleplon, and XK-469 using cryopreserved hepatocytes was 18, 17, 12, <4.3, and <4.3 ml · min⁻¹ · kg⁻¹, respectively. The observed metabolic clearance in cryopreserved hepatocytes was confirmed to be a result of AO-mediated metabolism via two approaches. Metabolite identification after incubations in the presence of H2¹8O confirmed that the predominant oxidative metabolite was generated by AO, as expected isotope patterns in mass spectra were observed after analysis by high-resolution mass spectrometry. Second, clearance values were efficiently attenuated upon coincubation with hydralazine, an inhibitor of AO. The low exposure after oral doses of BIBX1382 and carbazeran (∼5% F) would have been fairly well predicted using simple hepatic extraction (f(h)) values derived from cryopreserved hepatocytes. In addition, the estimated hepatic clearance value for O6-benzylguanine was within ∼80% of the observed total clearance in humans after intravenous administration (15 ml · min⁻¹ · kg⁻¹), indicating a reasonable level of quantitative activity from this in vitro system. However, a 3.5-fold underprediction of total clearance was observed for zaleplon, despite the 5-oxo metabolite being clearly observed. These data taken together suggest that the use of cryopreserved hepatocytes may be a practical approach for assessing AO-mediated metabolism in discovery and potentially useful for predicting hepatic clearance of AO substrates.

Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate.

KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, is a novel compound to be effective on mouse systemic lupus erythematosus.

B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4-carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF-BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mouse. When 5 or 10mg/kg KR33426 was intraperitoneally administered to MRL(lpr/lpr) mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220(+) B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43(-)IgM(+) immature pro-B and a decrease in CD21(+) IgM(+) T2-B and IgD(+) IgM(-)recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF-BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF-BAFF-R interactions, specifically.

A prospective evaluation of adult men with iron-deficiency anemia in Korea.

OBJECTIVE: Iron-deficiency anemia (IDA) is the most common nutritional deficiency worldwide. However, the information concerning various causes of IDA in adult men is still insufficient. The aim of our study was to evaluate adult men with IDA. METHODS: We prospectively studied 206 adult men with IDA. All subjects had a direct history taken and underwent a physical examination. Esophagogastroduodenoscopy was performed in most patients, and colonoscopy was conducted if no lesion causing IDA was found or the fecal occult blood test was positive. RESULTS: The history of prior gastrectomy and blood-letting cupping therapy that probably had caused IDA were reported in 24 (11.7%) and 11 (5.3%) patients, respectively. In terms of potential causes of IDA, 68 (33.0%) patients were found to have upper gastrointestinal disorders (34 peptic ulcers, 17 erosive gastritis, 16 gastric cancers, and one gastrointestinal stromal tumor). Colonoscopy showed 42 (20.4%) clinically relevant lesions that probably caused IDA: colon cancer (five patients), colon polyps (14 patients), ulcerative colitis (one patient), and hemorrhoids (22 patients). One small bowel tumor was detected at small bowel series. Concerning malignant lesions that were responsible for IDA, 22 malignant lesions were found in patients of 50 years or older, accounting for 16.8% (22 of 131 patients), while only one (1.3%) early gastric cancer was found in the younger patients. CONCLUSION: This study demonstrated that gastrointestinal blood loss is the main cause of IDA in adult men, and that there is a high rate of malignancy in men older than 50 years, emphasizing the need for a complete, rigorous gastrointestinal examination in this group of patients. Considering blood-letting cupping therapy, there is a need to consider culture-specific procedures as a possible cause of IDA.