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Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant.

Background Ankle sprains are one of the most common musculoskeletal injuries. To guide management decisions, a clear insight into the relevant subgroups of patients with a potentially better or worse prognosis is important. This study aimed to evaluate injury severity, using ultrasonography (US), as a prognostic factor of acute ankle sprain and other possible factors including age, sex, body mass index (BMI), level of job activity, and level of sports activity. Materials and methods We retrospectively reviewed 28 patients with acute ankle sprain who reported at initial examination with an acutely twisted ankle. All patients had received a standard physical examination, radiography and standard ultrasound, to diagnose specific ligament injuries and their ankle sprain had been treated using standard conservative management. Various data including age, sex, BMI, level of sports activity, level of daily job activity, and final functional score (Foot and Ankle Outcome Scores, FAOS) were obtained. Mean comparison and correlations were used to assess risk factors. Risk factors associated with functional outcomes were evaluated using a multiple linear regression test. Results At final follow-up as 1 year after injury, FAOS differed significantly for injury severity, age, and BMI. There were no significant differences in sex, job activity, and exercise levels. The factor most affecting FAOS for both pain (FAOS-Pain) and symptoms (FAOS-Sx) was the number of completely torn ligaments. Age was the most important factor affecting the FAOS-Daily Living Activity (ADL). BMI was the most important factor for sports activity level (FAOS-Sports). Age and the number of completely torn ligaments were both important to FAOS-Sports and quality of life (FAOS-QOL). Conclusion The severity of injury, defined using US, was a prognostic factor for long-term outcome following acute ankle sprain. Therefore, US imaging of acute ankle ligament injury may be important to predict prognosis of acute ankle sprain.

Background Previous quantitative proteomic study from our laboratory had identified leucine-rich-alpha-2-glycoprotein 1 (LRG1) as the most prominent marker for colorectal cancer (CRC). This marker was significantly up-regulated in the serum of late-stage CRC patients and present in a stage-dependent manner in the CRC cells. Many studies have linked autophagy to cancer, but none had explored the relationship between LRG1 and autophagy in CRC. This study (FRGS/1/2018/SKK08/UKM/03/3) is aimed to investigate the effect of LRG1 modulation on the autophagy mechanism in colorectal cancer. Methods Colorectal adenocarcinoma cells, HT29 (low-grade CRC) with the lowest endogenous level of LRG1 were chosen for the over-expression of human LRG1 gene, whereas colorectal carcinoma cells, HCT116 (high-grade CRC) with the highest endogenous level of LRG1 were used for the LRG1 knockdown experiment. The cells were stably transduced with lentivirus containing LRG1 open reading frame (ORFs) and short hairpin RNA (shRNA), respectively. The selection was carried out with Blasticidin S and Puromycin, respectively prior to RNA extraction and gene expression assessment via RT-qPCR. Statistical analysis of Independent T-test was performed using GraphPad Prism 8.0.1. Results Over-expression of LRG1 in HT29 increased cell proliferation by activation of Ki67 mRNA (p 0.05), but several autophagy markers (Beclin-1, ATG4D, ATG5, LC3 and GABARAP, except ATG3) were in a decreasing trend. Conclusions In summary, LRG1 enhanced the survival of low-grade colorectal cancer and tumour progression by suppression of autophagy but failed to reverse the mechanism in the knockdown model of high-grade cancer. More related works are currently on-going.

Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.

Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.

Fused in sarcoma (FUS) is a DNA/RNA-binding protein that is involved in DNA repair and RNA processing. FUS is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the molecular mechanisms underlying FUS-mediated neurodegeneration are largely unknown. Here, using a Drosophila model, we showed that the overexpression of glutathione transferase omega 2 (GstO2) reduces cytoplasmic FUS aggregates and prevents neurodegenerative phenotypes, including neurotoxicity and mitochondrial dysfunction. We found a FUS glutathionylation site at the 447

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.

In the present study, we examined whether Lactobacillus johnsonii CJLJ103 (LJ) could alleviate cholinergic memory impairment in mice. Oral administration of LJ alleviated scopolamine-induced memory impairment in passive avoidance and Y-maze tasks. Furthermore, LJ treatment increased scopolamine-suppressed BDNF expression and CREB phosphorylation in the hippocampi of the brain, as well as suppressed TNF-α expression and NF-κB activation. LJ also increased BDNF expression in corticosterone-stimulated SH-SY5Y cells and inhibited NF-κB activation in LPS-stimulated microglial BV2 cells. However, LJ did not inhibit acetylcholinesterase activity. These findings suggest that LJ, a member of human gut microbiota, may mitigate cholinergic memory impairment by increasing BDNF expression and inhibiting NF-κB activation.

BACKGROUND/OBJECTIVE There is intense interest in soy isoflavone as a hormone replacement therapy for the prevention of postmenopausal osteoporosis. A new kind of isoflavone-enriched whole soy milk powder (I-WSM) containing more isoflavones than conventional whole soy milk powder was recently developed. The aim of this study was to investigate the effects of I-WSM on bone metabolism in ovariectomized mice. MATERIALS/METHODS Sixty female ICR mice individually underwent ovariectomy (OVX) or a sham operation, and were randomized into six groups of 10 animals each as follows: Sham, OVX, OVX with 2% I-WSM diet, OVX with 10% I-WSM diet, OVX with 20% I-WSM diet, and OVX with 20% WSM diet. After an 8-week treatment period, bone mineral density (BMD), calcium, alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) 5b, osteocalcin (OC), procollagen 1 N-terminal propeptide (P1NP), and osteoprotegenin (OPG) were analyzed. RESULTS BMD was significantly lower in the OVX group compared to the Sham group but was significantly higher in OVX + 10% I-WSM and OVX + 20% I-WSM groups compared to the OVX group (P < 0.05). Serum calcium concentration significantly increased in the OVX + 10% and 20% I-WSM groups. Serum ALP levels were significantly lower in the OVX + 10% and 20% I-WSM groups compared to the other experimental groups (P < 0.05). OC was significantly reduced in the OVX group compared to the Sham group (P < 0.05), but a dose-dependent increase was observed in the OVX groups supplemented with I-WSM. P1NP and OPG levels were significantly reduced, while TRAP 5b level was significantly elevated in the OVX group compared with the Sham group, which was not affected by I-WSM (P < 0.05). CONCLUSIONS This study suggests that I-WSM supplementation in OVX mice has the effect of preventing BMD reduction and promoting bone formation. Therefore, I-WSM can be used as an effective alternative to postmenopausal osteoporosis prevention.

The aim of the present study was to evaluate the physiochemical properties and resorption progress of two cross-linked, porcine skin-derived collagen membranes and compare their features with those of a membrane without cross-linking (Bio-Gide® [BG], Geistlich Biomaterials, Wolhusen, Switzerland). Three porcine skin-derived collagen membranes, dehydrothermally (DHT) cross-linked (experimental), DHT and 1-ethyl-3(3-dimethylaminopropyl)-carbodiimide (DHT/EDC) cross-linked (experimental) and BG were investigated for their morphology, enzyme resistance, and tensile strength in vitro and biodegradation in vivo. DHT and DHT/EDC membranes exhibited irregular, interconnected macro- and micropores that formed a 3D mesh, whereas BG exhibited individual collagen fibrils interlaced to form coarse collagen strands. In enzyme resistance and tensile strength tests, DHT and DHT/EDC membranes demonstrated good resistance and mechanical properties compared with BG. In vivo, all three membranes were well integrated into the surrounding connective tissue. Thus, the DHT membrane exhibited its potential as a barrier membrane for guided bone and tissue regeneration.

Exposure to excessive lipopolysaccharide (LPS) by the gut microbiota disturbance causes ulcerative colitis and memory impairment. Therefore, we isolated anti-inflammatory Lactobacillus johnsonii CJLJ103 (LJ) from human fecal microbiota as an inhibitor for Escherichia coli growth and LPS production and investigated anti-colitic and memory impairment-ameliorating effects in mice. Oral administration of LJ inhibited 2,3,6-trinitrobenzenesulfonic acid (TNBS)-induced colon shortening, colonic myeloperoxidase activity, and NF-κB activation in mice. Furthermore, LJ inhibited TNBS-induced TNF and IL-1β expression in the colon but increased TNBS-suppressed expression of IL-10 and tight-junction proteins. Treatment with LJ inhibited fecal LPS levels and proteobacteria/bacteroidetes ratio in mice with TNBS-induced colitis. Furthermore, LJ ameliorated LPS-induced memory impairment in mice. LJ also suppressed LPS-induced NF-κB activation in the hippocampus and increased LPS-suppressed brain-derived neurotrophic factor expression. These findings suggest that LJ, a member of human gut microbiota, may ameliorate colitis and memory impairment, thereby acting as a useful probiotic.

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

Gynostemma pentaphyllum is widely used in Asia as a herbal medicine to treat type 2 diabetes, dyslipidemia, and inflammation. Here, we investigated the anti-obesity effect and underlying mechanism of G. pentaphyllum extract (GPE) enriched in gypenoside L, gypenoside LI, and ginsenoside Rg3 and obtained using a novel extraction method. Five-week-old male C57BL/6N mice were fed a control diet (CD), high-fat diet (HFD), HFD + 100 mg/kg body weight (BW)/day GPE (GPE 100), HFD + 300 mg/kg BW/day GPE (GPE 300), or HFD + 30 mg/kg BW/day Orlistat (Orlistat 30) for 8 weeks. The HFD-fed mice showed significant increases in body weight, fat mass, white adipose tissue, and adipocyte hypertrophy compared to the CD group, but GPE inhibited those increases. GPE reduced serum levels of triglyceride, total cholesterol, and LDL-cholesterol, without affecting HDL-cholesterol. GPE significantly increased AMPK activation and suppressed adipogenesis by decreasing the mRNA expression of CCAAT/enhancer binding protein-&alpha, (C/EBP&alpha, ), peroxisome proliferator-activated receptor-&gamma, (PPAR&gamma, ), sterol regulatory element-binding protein-1c (SREBP1c), PPAR&gamma, coactivator-1&alpha, fatty acid synthase (FAS), adipocyte protein 2 (AP2), and sirtuin 1 (SIRT1) and by increasing that of carnitine palmitoyltransferase (CPT1) and hormone- sensitive lipase (HSL). This study demonstrated the ameliorative effect of GPE on obesity and elucidated the underlying molecular mechanism.

Aronia melanocarpa are a rich source of anthocyanins that have received considerable interest for their relations to human health. In this study, the anti-adipogenic effect of cyanidin-3-O-galactoside-enriched Aronia melanocarpa extract (AM-Ex) and its underlying mechanisms were investigated in an in vivo system. Five-week-old male C57BL/6N mice were randomly divided into five groups for 8-week feeding with a control diet (CD), a high-fat diet (HFD), or a HFD with 50 (AM-Ex 50), 100 (AM-Ex 100), or 200 AM-Ex (AM-Ex 200) mg/kg body weight/day. HFD-fed mice showed a significant increase in body weight compared to the CD group, and AM-Ex dose-dependently inhibited this weight gain. AM-Ex significantly reduced the food intake and the weight of white fat tissue, including epididymal fat, retroperitoneal fat, mesenteric fat, and inguinal fat. Treatment with AM-Ex (50 to 200 mg/kg) reduced serum levels of leptin, insulin, triglyceride, total cholesterol, and low density lipoprotein (LDL)-cholesterol. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that AM-Ex suppressed adipogenesis by decreasing CCAAT/enhancer binding protein α, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma coactivator-1α, acetyl-CoA carboxylase 1, ATP-citrate lyase, fatty acid synthase, and adipocyte protein 2 messenger RNA (mRNA) expressions. These results suggest that AM-Ex is potentially beneficial for the suppression of HFD-induced obesity by modulating multiple pathways associated with adipogenesis and food intake.

In the present study, we isolated Bifidobacterium longum CH57, which suppresses macrophage activation, from human gut microbiota and Lactobacillus brevis CH23, which inhibit Th17 cell differentiation, from kimchi, and investigated anti-inflammatory effects of CH23, CH57, and their probiotic mixture (PM) in mice with TNBS-induced colitis. CH57 inhibited NF-κB activation in LPS-stimulated macrophages. Oral administration of CH57 in mice attenuated TNBS-induced colitis and TNF-α expression. CH23 inhibited IL-17 and RORγt expression in splenic T cells. Oral administration of CH23 in mice inhibited TNBS-induced colon shortening, myeloperoxidase activity, and Th17 cell differentiation and induced TNBS-suppressed Treg differentiation. PM increased TNBS-suppressed claudin, occludin, and ZO-1 expression and Treg differentiation, while CH57 inhibited Th17 cell differentiation and RORγt and IL-17 expression. PM inhibited TNBS-induced macrophage activation. Moreover, CH23 and CH57 synergistically inhibited macrophage activation and Th17 cell differentiation in vitro. The PM may synergistically ameliorate colitis by inhibiting macrophage activation and restoring Th17/Treg balance.

The type II C-type lectin CLEC4C is a transmembrane protein selectively expressed on plasmacytoid dendritic cells (PDCs). Although its mechanism of action remains unclear, triggering of the extracellular C-terminal C-type carbohydrate recognition region of CLEC4C regulates the secretion of proinflammatory cytokines and type I IFNs in PDCs. Applying whole-exome sequencing in a patient with juvenile amyotrophic lateral sclerosis (ALS) and both healthy parents, we identified a de novo CLEC4C variant (c.629_631delAGA; p.Lys210del). In this study, we report that the deletion of a lysine residue at the extracellular region of CLEC4C yields a C-terminal dilysine motif that results in endoplasmic reticulum (ER) retention of the protein in transfected HeLa and Jurkat T lymphoma cell models. As a consequence, a decrease in the surface expression of CLEC4C and the ER localization of the mutant construct were observed. Furthermore, depletion of the cell surface CLEC4C level was also observed in the patient PDCs, further suggesting that the variant p.Lys210del CLEC4C may contribute to juvenile ALS susceptibility.

Background Anemarrhena asphodeloides (Liliaceae family) and Mangifera indica L. (Anacardiaceae family) contain neomangiferin as the main active constituent and have been used to treat inflammation, asthma, and pain. Purpose A preliminary study found that neomangiferin inhibited splenic T cell differentiation into Th17 cells and promoted Treg cell production in vitro. Therefore, we examined its anti-colitic effects in vitro and in vivo. Methods Splenocytes isolated from C57BL/6 J mice were treated with neomangiferin. Colitis was either induced in vivo by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to C57BL/6 J mice or occurred spontaneously in colitis caused by interleukin (IL)-10 knockout at age of 13 weeks. Mice were treated daily with neomangiferin or sulfasalazine. Inflammatory markers, cytokines, enzymes and transcription factors were measured by enzyme-linked immunosorbent assay, immunoblot, and flow cytometry. Results Neomangiferin suppressed retinoic acid receptor-related orphan receptor gamma t (RORγt) and IL-17 expression in IL-6/transforming growth factor β-stimulated Th17 splenocytes and increased IL-10 expression in vitro. Mouse TNBS-induced colon shortening, macroscopic score, and myeloperoxidase activity were inhibited by neomangiferin, which also reduced TNBS-induced activation of nuclear factor-κB and extracellular signal-regulated kinases, as well as expression of inducible nitric oxide synthase and cyclooxygenase-2. In addition, neomangiferin inhibited TNBS-induced expression of tumor necrosis factor-α, IL-17, IL-6, and IL-1β, and increased IL-10 expression. Neomangiferin inhibited TNBS-induced differentiation to Th17 cells and promoted the development of Treg cells. Moreover, in IL-10−/− mice, neomangiferin inhibited colonic myeloperoxidase activity, suppressed Th17 cell differentiation, and reduced levels of TNF-α and IL-17. Conclusion Neomangiferin may restore the balance between Th17/Treg cells by suppressing IL-17 and RORγt expression and inducing IL-10 and forkhead box P3 expression, thus ameliorating colitis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation., Graphical Abstract

Recently, studies on the relationship between gut dysbiosis and Parkinson’s disease (PD) have increased, but whether a specific gut bacterium may cause PD remains unexplored. Here, we report, for the first time, that a specific gut bacterium directly induces PD symptoms and dopaminergic neuronal damage in the mouse brain. We found that the number of Enterobacteriaceae, particularly Proteus mirabilis, markedly and commonly increased in PD mouse models. Administration of P. mirabilis isolated from PD mice significantly induced motor deficits, selectively caused dopaminergic neuronal damage and inflammation in substantia nigra and striatum, and stimulated α-synuclein aggregation in the brain as well as in the colon. We found that lipopolysaccharides, a virulence factor of P. mirabilis, may be associated in these pathological changes via gut leakage and inflammatory actions. Our results suggest a role of P. mirabilis on PD pathogenesis in the brain.

Orally administered probiotics change gut microbiota composition and enzyme activities. Thus, coadministration of probiotics with drugs may lead to changes in the pharmacokinetic parameters of the drugs. In this study, we investigated the pharmacokinetics of acetaminophen in mice treated with probiotics. Oral administration of probiotics changed the gut microbiota composition in the mice. Of these probiotics, Lactobacillus reuteri K8 increased the numbers of clostridia, bifidobacteria, and enterococci, and Lactobacillus rhamnosus K9 decreased the number of bifidobacteria, determined by culturing in selective media. Next, we performed a pharmacokinetic study of acetaminophen in mice orally treated with K8 and K9 for 3 days. Treatment with K8 reduced the area under the curve (AUC) of orally administered acetaminophen to 68.4% compared with normal control mice, whereas K9 did not affect the AUC of acetaminophen. Oral administration to mice of K8, which degraded acetaminophen, increased the degradation of acetaminophen by gut microbiota, whereas K9 treatment did not affect it. Treatment with K8 increased the number of L. reuteri adhered in the upper small intestine, whereas the number of L. rhamnosus was not affected by treatment with K8 or K9. K8 increased the number of cyanobacteria, whereas K9 increased the number of deferribacteres. These results suggest that the intake of probiotics may make the absorption of orally administered drugs fluctuate through the disturbance of gut microbiota-mediated drug metabolism and that the subsequent impact on microbiota metabolism could result in altered systemic concentrations of the intact drug.

Vaccination is the most efficient method for infectious disease prevention. Parenteral injections such as intramuscular, intradermal, and subcutaneous injections have several advantages in vaccine delivery, but there are many drawbacks. Thus, the development of a new vaccine delivery system has long been required. Recently, microneedles have been attracting attention as new vaccination tools. Microneedle is a highly effective transdermal vaccine delivery method due to its mechanism of action, painlessness, and ease of use. Here, we summarized the characteristics of microneedles and the possibilities as a new vaccine delivery route.

Proinflammatory cytokines have been implicated in the production of neuropathic pain. We have previously reported that several ginsenosides produce antinoception. Especially, we have previously demonstrated that ginsenosides administered supraspinally reduce pain behaviors induced by proinflmmatory cytokines administered spinally. However, spinal action of ginsenosides in the regulation of proinflammtory cytokine-induced pain behavior has not been characterized yet. In the present study, we investigated the effects of ginsenosides following intrathecal treatment on pain behaviors induced by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ) injected intrathecally. The ginsenosides such as Rb1, Rb2, Rc, Rf, Rg1, and Rg3 pretreated intrathecally reduced the pain behavior induced by TNF-α, IL-1β, and IFN-γ injection. However, ginsenoside Rd and Re treated intrathecally did not affect the pain behavior induced by proinflammatory cytokines i...

We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β1-adrenergic receptor agonist) or terbutaline (β2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β1-adrenergic receptor antagonist) or butoxamine (β2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β1- and β2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves.

In the present study, the antinociceptive profiles of coumarin were examined in ICR mice. Coumarin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of coumarin maintained at least for 60 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 µg) or glutamate (20 µg) injection was not affected by coumarin. In addition, intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration with coumarin (10-40 µg) attenuated acetic acid-induced writhing response in a dose dependent manner. Intraperitoneal (i.p.) pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by coumarin in the writhing test. Furthermore, i.c.v. or i.t. pretreatment with naloxone (5 µg) reversed the decreased acetic acid-induced writhing response. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an α2-adrenergic receptor antagonist) did not affect antinociception induced by coumarin in the writhing test. Our results suggest that coumarin exerts a selective antinociceptive property in the acetic acid-induced visceral-derived pain model. Furthermore, the antinociceptive effect of coumarin may be mediated by activation of central opioid receptors, but not serotonergic and adrenergic receptors.

// Su Min Lim 1,2,* , Byung-Ok Choi 3,* , Seong-il Oh 4,* , Won Jun Choi 5 , Ki-Wook Oh 2,6 , Minyeop Nahm 2 , Yuanchao Xue 7 , Jae Hyeok Choi 2 , Ji Young Choi 2 , Young-Eun Kim 8 , Ki Wha Chung 9 , Xiang-Dong Fu 10 , Chang-Seok Ki 11 and Seung Hyun Kim 2,6 1 Biomedical Research Institute, Hanyang University, Seoul, Republic of Korea 2 Cell Therapy Center, Hanyang University Hospital, Seoul, Republic of Korea 3 Department of Neurology and Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 4 Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea 5 Department of Neurology, Sheikh Khalifa Specialty Hospital, Ras Al Khaimah, United Arab Emirates 6 Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea 7 Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 8 Green Cross Genome, Yongin, Republic of Korea 9 Department of Biological Sciences, Gongju National University, Gongju, Republic of Korea 10 Department of Cellular Molecular Medicine, University of California, San Diego, La Jolla, CA, USA 11 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence: Chang-Seok Ki, email: // Seung Hyun Kim, email: // Keywords : krabbe disease; globoid cell leukodystrophy; β-galactosylceramidase; psychosine; induced neuron; Gerotarget Received : October 17, 2015 Accepted : October 14, 2016 Published : October 21, 2016 Abstract Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective β-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult-onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology.

The regulation of microglial cell phenotype is a potential therapeutic intervention in neurodegenerative disease. Previously, we reported that transforming growth factor-β (TGF-β) levels in mesenchymal stromal cells (MSCs) could be used as potential biological markers to predict the effectiveness of autologous MSC therapy in patients with amyotrophic lateral sclerosis. However, the underlying mechanism of TGF-β in MSCs was not fully elucidated in determining the functional properties of microglia. In this study, we aimed to clarify the role of TGF-β that is involved in MSC effectiveness, especially focusing on microglia functional properties that play a pivotal role in neuroinflammation. We found that MSC-conditioned media (MSC-CM) inhibited proinflammatory cytokine expression, restored alternative activated microglia phenotype markers (fractalkine receptor, mannose receptor, CD200 receptor), and enhanced phagocytosis in lipopolysaccharide (LPS)-stimulated microglia. In addition, TGF-β in MSC-CM played a major role in these effects by inhibiting the nuclear factor-κB pathway and restoring the TGF-β pathway in LPS-stimulated microglia. Recombinant TGF-β also induced similar effects to MSC-CM in LPS-stimulated microglia. Therefore, we propose that MSCs can modulate the functional properties of microglia via TGF-β secretion, switching them from a classically activated phenotype to an inflammation-resolving phenotype. The latter role may be associated with the inhibition of neuroinflammatory processes in neurodegenerative disorders. Significance The results of this study showed that microglia functional properties may be modulated depending on the composition and quantity of mesenchymal stromal cell (MSC)-secreting factors. Transforming growth factor (TGF)-β is proposed as a modulator of microglia functional properties among MSC-secreting factors, and this study aligns with a previous clinical study by these same authors. TGF-β releasing capacity could be an important factor enhancing the therapeutic efficacy of MSCs in clinical trials.

We investigated the effect of DWac on the gut microbiota composition in mice with 2,3,6-trinitrobenzenesulfonic acid- (TNBS-) induced colitis. Treatment with DWac restored TNBS-disturbed gut microbiota composition and attenuated TNBS-induced colitis. Moreover, we examined the effect of DWac in mice with mesalazine-resistant colitis (MRC). Intrarectal injection of TNBS in MRC mice caused severe colitis, as well as colon shortening, edema, and increased myeloperoxidase activity. Treatment with mesalazine (30 mg/kg) did not attenuate TNBS-induced colitis in MRC mice, whereas treatment with DWac (30 mg/kg) significantly attenuated TNBS-induced colitis. Moreover, treatment with the mixture of mesalazine (15 mg/kg) and DWac (15 mg/kg) additively attenuated colitis in MRC mice. Treatment with DWac and its mixture with mesalazine inhibited TNBS-induced activation of NF-κB and expression of M1 macrophage markers but increased TNBS-suppressed expression of M2 macrophage markers. Furthermore, these inhibited TNBS-induced T-bet, RORγt, TNF-α, and IL-17 expression but increased TNBS-suppressed Foxp3 and IL-10 expression. However, Th2 cell differentiation and GATA3 and IL-5 expression were not affected. These findings suggest that DWac can ameliorate MRC by increasing the polarization of M2 macrophage and correcting the disturbance of gut microbiota and Th1/Th17/Treg, as well as additively attenuating MRC along with mesalazine.

Glucosyltransferases GtfB, GtfC, and GtfD of Streptococcus mutans are virulent factors involved in dental caries. Consequently, they are considered to be target molecules in the development of vaccines against dental caries. Among them, GtfD plays a significant role in the sucrose-dependent cellular adhesion of S. mutans, and a number of studies have suggested that the N-terminus of GtfD is an important part of its role in enzymatic activity. In this study, we generated monoclonal antibodies against the N-terminus of GtfD (anti-GtfDN antibody) in an initial attempt to investigate its preventive efficacy against dental caries. To obtain anti-GtfDN monoclonal antibodies, the gene for the N-terminus of gtfD (2 kb) was cloned into an Escherichia coli expression vector, pQE30; then the expressed protein (about 75 kDa) was purified. The purified GtfDN protein was injected into BALB/c mice, and hybridoma clones were established. We obtained three hybridoma clones (HDN9, HDN11, and HDN28) capable of producing anti-GtfDN antibodies. Their binding specificity was characterized by ELISA, dot blot, and Western blot analysis after purification using affinity column chromatography. The isotype of the monoclonal antibodies was confirmed to be IgG2a.

In the previous study, the rhizome mixture of Anemarrhena asphodeloides and Coptis chinensis (DW2007), improved TNBS-, oxazolone-, or DSS-induced colitis in mice by regulating macrophage activation. Therefore, to understand the effect of DW2007 on the T cell differentiation involved in the adaptive immunity, we measured its effect on both Th17 and Treg cell differentiation in splenocytes, in the lamina propria of mice with DSS-induced colitis (DIC), and in the spleens of mice with collagen-induced arthritis (CIA). Results showed that DW2007 potently inhibited the differentiation of splenocytes into Th17 cells, but increased Treg cell differentiation in vitro. In the colon of wild type and TLR4-/- mice with DIC, DW2007 potently suppressed DSS-induced colon shortening and myeloperoxidase activity. DW2007 also suppressed collagen-induced paw thickening, clinical index, and myeloperoxidase activity in CIA mice. Overall, DW2007 potently suppressed Th17 cell differentiation in mice with CIA and DIC, but increased Treg cell differentiation. Moreover, DW2007 strongly inhibited the expression of TNF-α and IL-1β, as well as the activation of NF-κB. Based on these findings, DW2007 may ameliorate inflammatory diseases by regulating the innate immunity via the inhibition of macrophage activation and the adaptive immunity via the correction of disturbed Th17/Treg cells.

Background Mutations in the fused in sarcoma (FUS) gene have been linked to amyotrophic lateral sclerosis (ALS). ALS patients with FUS mutations exhibit neuronal cytoplasmic mislocalization of the mutant FUS protein. ALS patients’ fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons have been developed as models for understanding ALS-associated FUS (ALS-FUS) pathology; however, pathological neuronal signatures are not sufficiently present in the fibroblasts of patients, whereas the generation of iPSC-derived neurons from ALS patients requires relatively intricate procedures. Results Here, we report the generation of disease-specific induced neurons (iNeurons) from the fibroblasts of patients who carry three different FUS mutations that were recently identified by direct sequencing and multi-gene panel analysis. The mutations are located at the C-terminal nuclear localization signal (NLS) region of the protein (p.G504Wfs*12, p.R495*, p.Q519E): two de novo mutations in sporadic ALS and one in familial ALS case. Aberrant cytoplasmic mislocalization with nuclear clearance was detected in all patient-derived iNeurons, and oxidative stress further induced the accumulation of cytoplasmic FUS in cytoplasmic granules, thereby recapitulating neuronal pathological features identified in mutant FUS (p.G504Wfs*12)-autopsied ALS patient. Importantly, such FUS pathological hallmarks of the patient with the p.Q519E mutation were only detected in patient-derived iNeurons, which contrasts to predominant FUS (p.Q519E) in the nucleus of both the transfected cells and patient-derived fibroblasts. Conclusions Thus, iNeurons may provide a more reliable model for investigating FUS mutations with disrupted NLS for understanding FUS-associated proteinopathies in ALS. Electronic supplementary material The online version of this article (doi:10.1186/s13024-016-0075-6) contains supplementary material, which is available to authorized users.

We investigated the effect of DWac on the gut microbiota composition in mice with 2,3,6-trinitrobenzenesulfonic acid- (TNBS-) induced colitis. Treatment with DWac restored TNBS-disturbed gut microbiota composition and attenuated TNBS-induced colitis. Moreover, we examined the effect of DWac in mice with mesalazine-resistant colitis (MRC). Intrarectal injection of TNBS in MRC mice caused severe colitis, as well as colon shortening, edema, and increased myeloperoxidase activity. Treatment with mesalazine (30 mg/kg) did not attenuate TNBS-induced colitis in MRC mice, whereas treatment with DWac (30 mg/kg) significantly attenuated TNBS-induced colitis. Moreover, treatment with the mixture of mesalazine (15 mg/kg) and DWac (15 mg/kg) additively attenuated colitis in MRC mice. Treatment with DWac and its mixture with mesalazine inhibited TNBS-induced activation of NF-κB and expression of M1 macrophage markers but increased TNBS-suppressed expression of M2 macrophage markers. Furthermore, these inhibited TNBS-induced T-bet, RORγt, TNF-α, and IL-17 expression but increased TNBS-suppressed Foxp3 and IL-10 expression. However, Th2 cell differentiation and GATA3 and IL-5 expression were not affected. These findings suggest that DWac can ameliorate MRC by increasing the polarization of M2 macrophage and correcting the disturbance of gut microbiota and Th1/Th17/Treg, as well as additively attenuating MRC along with mesalazine.

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 µg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.

In the present study, the antinociceptive profiles of hop extract were characterized in ICR mice. Hop extract administered orally (from 25 to 100 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Antinociceptive action of hop extract was maintained at least for 60 min. Moreover, cumulative response time of nociceptive behaviors induced with intraplantar formalin injection was reduced by hop extract treatment during the 2nd phases. Furthermore, the cumulative nociceptive response time for intrathecal injection of substance P (0.7 µg) or glutamate (20 µg) was diminished by hop extract. Intraperitoneal pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by hop extract in the writhing test. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an α(2)-adrenergic receptor antagonist) did not affect antinociception induced by hop extract in the writhing test. Our results suggest that hop extract shows an antinociceptive property in various pain models. Furthermore, the antinociceptive effect of hop extract may be mediated by opioidergic receptors, but not serotonergic and α(2)-adrenergic receptors.

Background: Overweight in Korean adolescents has continuously increased over the past few years and it is recognized as a public health problem. We investigated the relationship between socioeconomic status and overweight in Korean adolescents. Methods: The data was obtained from the 2007 Korean Youth’s Risk Behavior Web-based Study. We included adolescents aged 12 to 18 yearswho were ≥ 5th percentile of the BMI cut-off point based on the Korean child growth curve. Logistic regression analysis was performed to examine the association between socioeconomic status and overweight. Results: The adjusted odds ratios for overweight were 1.116 (95% confidence interval [CI],1.021 to 1.220), 1.390 (95% CI, 1.242 to 1.555) in girls having middle and low grade family affluence scale (FAS), respectively, compared in girls having high grade FAS (P < 0.05). However, in boys, there was no significant relationship between FAS and overweight. In both gender, perceived household economic status and parental education level were negatively related to overweight in adolescents (P < 0.05). Conclusion: Lower socioeconomic status increased the risk of overweight in Korean adolescents. Efforts to reduce socioeconomic disparities in adolescents should be initiated for overweight prevention.

Background: Low high density lipoprotein-cholesterol (HDL-C) is one of the major risk factors for coronary heart disease. Using data from the Korean National Health and Nutrition Examination Survey (KNHANES), we assessed trend of the prevalence of low HDL-C and the factors which are associated with low HDL-C in Korean men. Methods: We analyzed three serial KNHANES data which were conducted in year 1998, 2001, and 2005. Among all survey participants, we included men aged 30-79 years with laboratory data. Low HDL-C was defined by serum HDL-C < 40 mg⁄dL. We used multiple logistic regression analysis to assess the association between low HDL-C and related factors. We investigated trend of the prevalence of low HDL-C and associated factors among Korean men. Results: The prevalence of low HDL-C in Korean men was increasing from 26.3% (1998) to 38.8% (2001) and 45.9% (2005). Low HDL-C was associated with non-alcohol drinker, current smoking, sedentary physical activity, obesity and hypertriglyceridemia. The prevalence of current smoking decreased linearly. The prevalence of sedentary physical activity and hypertriglyceridemia increased from year 1998 to year 2001, but decreased from year 2001 to year 2005. However, the prevalence of non-alcohol drinker and obesity increased continuously. The patterns of the increasing prevalence of low HDL-C were compatible to the increasing prevalence of obesity according to age in Korean men. Conclusion: From year 1998 to year 2005, the prevalence of low HDL-C in Korean men has increased. Obesity and nonalcohol drinking might be contributing factors of increasing prevalence of low HDL-C in Korean men. Management of obesity is needed to prevent increasing the prevalence of low HDL-C among Korean men.