The Pathophysiological Importance of Nicotinamide Phosphoribosyltransferase as a Key NAD Biosynthesis Enzyme in Metabolic Homeostasis

Nicotinamide phosphoribosyltransferase: NAMPT) is the rate-limiting enzyme in the NAD biosynthesis pathway in mammals. Interestingly, NAMPT has intra- and extracellular forms: iNAMPT and eNAMPT, respectively), and eNAMPT is secreted from adipose tissue as one of the adipokines. However, the mechanism underlying the regulation of eNAMPT secretion has not been fully understood yet. Here, we have demonstrated that deacetylation on NAMPT by SIRT1 controls its secretion from adipocytes. iNAMPT is acetylated in both brown and white adipose tissues, and the level of acetylation of iNAMPT is decreased during fasting when Sirtuins are activated. We also found that enhancement of eNAMPT secretion under low glucose culture condition in differentiated brown and white adipocytes is completely inhibited by nicotinamide: NAM), an inhibitor of SIRTs, suggesting that deacetylation by SIRTs is required to induce eNAMPT secretion by low glucose stimulus. Consistently, eNAMPT levels in the blood were enhanced after 48 hours fasting in WT but not in Sirt1 KO mice, and iNAMPT acetylation levels are decreased while eNAMPT secretion is increased in differentiated adipocytes by SIRT1 overexpression. In addition, iNAMPT physically interacts with SIRT1 in differentiated adipocytes, and this interaction is enhanced under a low-glucose culture condition, suggesting that SIRT1 deacetylates iNAMPT by direct interaction and increases eNAMPT secretion. We have found five acetylation sites on iNAMPT and only 4 out of 5 were deacetylated. SIRT1 is responsible for deacetylating lysine 53, which results in both increased enzymatic activity and secretion of eNAMPT. These results indicate a novel feedback loop regulating systemic NAD biosynthesis through SIRT1 and eNAMPT in adipose tissues. Next, in an effort to investigate the function of eNAMPT secreted from adipose tissue, we generated adipocyte-specific Nampt KO: ANKO) mice. We first confirmed that female ANKO mice show significant reductions in plasma eNAMPT levels. Interestingly, female ANKO show reduction of NAD levels not only in white and brown adipose tissue but also in the hypothalamus compared to control Namptflox/flox mice, suggesting that loss of Nampt only in adipose tissues could also influence hypothalamic function, including governing glucose homeostasis by lowering NAD levels in this tissue. Consistent with this notion, female ANKO exhibit severely impaired glucose tolerance and glucose-stimulated insulin secretion accompanied by hyperinsulinemia, and administration of NMN partially restores insulin sensitivity but almost completely ameliorates the responsiveness of pancreatic β cells to glucose and hyperinsulinemia in vivo. Taken together, our results suggest the new possibility that adipose tissues play an important role in maintaining glucose homeostasis by controlling eNAMPT secretion and eNAMPT-mediated NAD biosynthesis at a systemic level and provide important insight into therapeutic and preventive intervention for metabolic diseases such as type 2 diabetes

The Protective Effects of Melittin on Propionibacterium acnes–Induced Inflammatory Responses In Vitro and In Vivo

Melittin is the main component in the venom of the honey bee (Apis mellifera). It has multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-inflammatory mechanisms of melittin have not been elucidated in Propionibactierium acnes (P. acnes)–induced keratinocyte or inflammatory skin disease animal models. In this study, we examined the effects of melittin on the production of inflammatory cytokines in heat-killed P. acnes–induced HaCaT cells. Heat-killed P. acnes–treated keratinocytes increased the expression of pro-inflammatory cytokines and Toll-like receptor 2. However, melittin treatment significantly suppressed the expression of these cytokines through regulation of the NF-κB and MAPK signaling pathways. Subsequently, the living P. acnes (1 × 107 CFU) were intradermally injected into the ear of mice. Living P. acnes–injected ears showed cutaneous erythema, swelling, and granulomatous response at 24 hours after injection. However, melittin-treated ears showed markedly reduced swelling and granulomatous responses compared with ears injected with only living P. acnes. These results demonstrate the feasibility of applying melittin for the prevention of inflammatory skin diseases induced by P. acnes

Diagnostic performance of the 2022 KLCA-NCC criteria for hepatocellular carcinoma on magnetic resonance imaging with extracellular contrast and hepatobiliary agents: comparison with the 2018 KLCA-NCC criteria

Background/Aim This study aimed to determine the diagnostic performance of 2022 Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) imaging criteria compared with the 2018 KLCA-NCC for hepatocellular carcinoma (HCC) in high-risk patients using magnetic resonance imaging (MRI). Methods This retrospective study included 415 treatment-naïve patients (152 patients who underwent extracellular contrast agent [ECA]-MRI and 263 who underwent hepatobiliary agent [HBA]-MRI; 535 lesions, including 412 HCCs) with a high risk of HCC who underwent contrast-enhanced MRI. Two readers evaluated all lesions according to the 2018 and 2022 KLCA-NCC imaging diagnostic criteria, and the per-lesion diagnostic performances were compared. Results In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI showed a significantly higher sensitivity for the diagnosis of HCC than ECA-MRI (77.0% vs. 64.3%, P=0.006) without a significant difference in specificity (94.7% vs. 95.7%, P=0.801). On ECAMRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC had significantly higher sensitivity than those of the 2018 KLCA-NCC (85.3% vs. 78.3%, P=0.002) with identical specificity (93.6%). On HBA-MRI, the sensitivity and specificity of “definite” or “probable” HCC categories of both 2018 and 2022 KLCA-NCC were not significantly different (83.3% vs. 83.6%, P>0.999 and 92.1% vs. 90.8%, P>0.999, respectively). Conclusions In “definite” HCC category of both 2018 and 2022 KLCA-NCC, HBA-MRI provides better sensitivity than ECA-MRI without compromising specificity. On ECA-MRI, “definite” or “probable” HCC categories of the 2022 KLCA-NCC may improve sensitivity in the diagnosis of HCC compared with the 2018 KLCA-NCC

Impact of Body Mass Index on the relationship of epicardial adipose tissue to metabolic syndrome and coronary artery disease in an Asian population

<p>Abstract</p> <p>Background</p> <p>In a previous study, we demonstrated that the thickness of epicardial adipose tissue (EAT), measured by echocardiography, was increased in patients with metabolic syndrome (MS) and coronary artery disease (CAD). Several studies on obese patients, however, failed to demonstrate any relationship between EAT and CAD. We hypothesized that body mass index (BMI) affected the link between EAT and MS and CAD.</p> <p>Methods</p> <p>We consecutively enrolled 643 patients (302 males, 341 females; 59 ± 11 years), who underwent echocardiography and coronary angiography. The EAT thickness was measured on the free wall of the right ventricle at the end of diastole. All patients were divided into two groups: high BMI group, ≥27 kg/m²(n = 165), and non-high BMI group, < 27 kg/m²(n = 478).</p> <p>Results</p> <p>The median and mean EAT thickness of 643 patients were 3.0 mm and 3.1 ± 2.4 mm, respectively. In the non-high BMI group, the median EAT thickness was significantly increased in patients with MS compared to those without MS (3.5 vs. 1.9 mm, p < 0.001). In the high BMI group, however, there was no significant difference in the median EAT thickness between patients with and without MS (3.0 vs. 2.5 mm, p = 0.813). A receiver operating characteristic (ROC) curve analysis predicting MS revealed that the area under the curve (AUC) of the non-high BMI group was significantly larger than that of the high BMI group (0.659 vs. 0.506, p = 0.007). When compared to patients without CAD, patients with CAD in both the non-high and high BMI groups had a significantly higher median EAT thickness (3.5 vs. 1.5 mm, p < 0.001 and 4.0 vs. 2.5 mm, p = 0.001, respectively). However, an ROC curve analysis predicting CAD revealed that the AUC of the non-high BMI group tended to be larger than that of the high BMI group (0.735 vs. 0.657, p = 0.055).</p> <p>Conclusions</p> <p>While EAT thickness was significantly increased in patients with MS and CAD, the power of EAT thickness to predict MS and CAD was stronger in patients with BMI < 27 kg/m². These findings showed that the measurement of EAT thickness by echocardiography might be especially useful in an Asian population with a non-high BMI, less than 27 kg/m².</p

Myopericarditis in a Korean Young Male With Systemic Lupus Erythematosus

Myocardial involvement with clinical symptoms is a rare manifestation of systemic lupus erythematosus (SLE), despite the relatively high prevalence of myocarditis at autopsies of SLE patients. In this review, we report the case of a 19-year-old male SLE patient who initially presented with myopericarditis and was successfully treated with high dose of glucocorticoids

Tethered Spinal Cord with Double Spinal Lipomas

Although lumbosacral lipoma is reported to occur in 4-8 of 100,000 patients, and 66% of lipomyelomeningoceles in young patients are accompanied by hypertrophic filum terminale, it is very rare to find two isolated spinal lipomas simultaneously. A 3 month-old baby girl was admitted to the hospital for a protruding, non-tender, soft, subcutaneous 2.5 cm mass of the lumbosacral area that had been present since birth. Simple radiography showed a spinal posterior arch defect from L3 to L5, and magnetic resonance imaging (MRI) demonstrated two isolated spinal lipomas, a transitional type from L3 to L5, and a terminal type below S1 without dural defect. The cornus medullaris was severely tethered descending to the S1, but there was no cerebellar or brain stem herniation on the MRI. We suggest that the presence of a combined spinal lipoma should be a point for careful differentiation in an infant with spinal lipoma

Percutaneous Sclerotherapy of Renal Cysts with a Beta-Emitting Radionuclide, Holmium-166-chitosan Complex

OBJECTIVE: To evaluate the usefulness of a beta-emitting radionuclide (holmium-166-chitosan complex) as a sclerosing agent for the treatment of renal cysts. MATERIALS AND METHODS: Using 10-30 mCi of holmium-166-chitosan complex, 20 renal cysts in 17 patients (14 male and 3 female patients, ranging in age from 47 to 82 years) were treated by percutaneous sclerotherapy under ultrasonographic guidance. The volume of the cysts before and after the sclerotherapy and the percentage change in volume were calculated in order to evaluate the response to therapy, which was classified as either complete regression (invisible), nearly complete regression ( 50 volume%). RESULTS: The follow-up period ranged from 6 to 36 months (mean 28 months). Eighteen cysts (90%) regressed completely (n=11, 55%) or near-completely (n=7, 35%). Partial regression was obtained in one patient (5%) and there was no regression in one patient (5%). No significant complications were encountered. CONCLUSION: The holmium-166-chitosan complex seems to be useful as a new painless sclerosing agent for the treatment of renal cysts with no significant complications.ope

The C677 Mutation in Methylene Tetrahydrofolate Reductase Gene: Correlation with Uric Acid and Cardiovascular Risk Factors in Elderly Korean men

The C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene results in elevated homocysteine levels and, presumably, in increased cardiovascular risk. Moreover, elevated homocysteine levels are reportedly associated with high serum uric acid levels. We evaluated the MTHFR genotype and a panel of biochemical, hematological variables, and lifestyle characteristics in 327 elderly Korean men (age range 40-81 yr; mean, 51.87). This study shows that mutation of the MTHFR gene may be a risk for hyperuricemia. The mean uric acid levels for the C/C, C/T and T/T genotypes were 5.54, 5.91 and 6.33 mg/dL, respectively (p=0.000). The T/T genotype was significantly more frequent in subjects with high uric acid levels (p=0.003). Thus, this mutation of the MTHFR gene is implied by the study results to be a risk factor of hyperuricemia in elderly Korean men. However, the relationship between the MTHFR mutation and uric acid metabolism remains unclear. Therefore, further studies are necessary to explain the associated between the MTHFR mutation and elevated uric acid levels, and to examine potential relationships between it and conventional cardiovascular risk factors