Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

Effect of the incorporation of gallium ions into silver indium sulfide nanocrystals.

Gallium ion incorporation into silver indium gallium sulfide nanocrystals is investigated by various methods, including photoluminescence (PL) and X-ray photoelectron spectroscopy. The ZnS shell-growth enhances a PL quantum yield of up to 16%, with which the quantum dot light-emitting diode was successfully fabricated.

In-depth correlation analysis between tear glucose and blood glucose using a wireless smart contact lens.

Tears have emerged as a promising alternative to blood for diagnosing diabetes. Despite increasing attempts to measure tear glucose using smart contact lenses, the controversy surrounding the correlation between tear glucose and blood glucose still limits the clinical usage of tears. Herein, we present an in-depth investigation of the correlation between tear glucose and blood glucose using a wireless and soft smart contact lens for continuous monitoring of tear glucose. This smart contact lens is capable of quantitatively monitoring the tear glucose levels in basal tears excluding the effect of reflex tears which might weaken the relationship with blood glucose. Furthermore, this smart contact lens can provide an unprecedented level of continuous tear glucose data acquisition at sub-minute intervals. These advantages allow the precise estimation of lag time, enabling the establishment of the concept called 'personalized lag time'. This demonstration considers individual differences and is successfully applied to both non-diabetic and diabetic humans, as well as in animal models, resulting in a high correlation.

C-C Bond Cleavage-Induced C- to N-Acyl Transfer for Synthesis of Amides.

A new approach for the preparation of amides was developed using C-C bond cleavage that initiates C- to N-acyl transfer, employing activated ketones as acylation reagents and amine nucleophiles. The reaction was operational under the coupling reagent system that is commonly utilized for peptide bond formations. The method enables practical preparation of amides using linear and cyclic ketone substrates under mild conditions.

A self-powered and supercapacitive microneedle continuous glucose monitoring system with a wide range of glucose detection capabilities.

Continuous detection of sudden changes in blood glucose is essential for individuals with diabetes who have difficulty in maintaining optimal control of their blood glucose levels. Hypoglycemic shock or a hyperglycemic crisis are likely to occurs in patients with diabetes and poses a significant threat to their lives. Currently, commercial continuous glucose monitoring (CGM) has limits in the glucose concentration detection range, which is 40-500 mg/dL, making it difficult to prevent the risk of hyperglycemic shock. In addition, current CGMs are invasive, cause pain and irritation during usage, and expensive. In this research, we overcome these limitations by introducing a novel mechanism to detect glucose concentration using supercapacitors. The developed CGM, which is self-powered and minimally invasive due to the use of microneedles, can detect a wider range of glucose concentrations than commercial sensors. In addition, efficacy and stability were proven through in vitro and in vivo experiments. Thus, this self-powered, microneedle and supercapacitive-type CGM can potentially prevent both hypoglycemic and complications of hyperglycemia without pain and with less power consumption than current commercial sensors.

Clinical and radiological outcomes of non-window-type bioactive glass-ceramic cage in single-level ACDF versus PEEK cage filled with autologous bone.

Bioactive glass-ceramic (BGC) cage is a substitute for polyether ether ketone (PEEK) cages in anterior cervical discectomy and fusion (ACDF). Only a few comparative studies exist using PEEK and non-window-type BGC cages (CaO-SiO2-P2O5-B2O3) in single-level ACDF. This study compared PEEK cages filled with autologous iliac bone grafts and BGC cages regarding clinical safety and effectiveness. A retrospective case series was performed on 40 patients who underwent single-level ACDF between October 2020 and July 2021 by a single orthopedic spine surgeon. The spacers used in each ACDF were a PEEK cage with a void filled with an autologous iliac bone graft and a non-window-type BGC cage in 20 cases. The grafts were compared pre-operatively and post-operatively at 6 weeks and 3, 6, and 12 months. Post-operative complications were investigated in each group. Clinical outcome was measured, including Visual Analog Scale (VAS) scores of neck and arm pains, Japanese Orthopedic Association score (JOA), and Neck Disability Index (NDI). Dynamic lateral radiographs were used to assess the inter-spinous motion (ISM) between the fusion segment and subsidence. The fusion status was evaluated using a computed tomography (CT) scan. Overall, 39 patients (19 and 20 patients in the PEEK and BGC groups, respectively) were recruited. Eighteen (94.7%) and 19 (95.0%) patients in the PEEK and BGC groups, respectively, were fused 12 months post-operatively, as assessed by ISM in dynamic lateral radiograph and bone bridging formation proven in CT scan. The PEEK and BGC groups showed substantial improvement in neck and arm VAS, JOA, and NDI scores. No substantial difference was found in clinical and radiological outcomes between the PEEK and BGC groups. However, the operation time was considerably shorter in the BGC group than in the PEEK group. In conclusion, a non-window-type BCG cage is a feasible substitute for a PEEK cage with an autologous iliac bone graft in single-level ACDF.

Mortality in metabolic dysfunction-associated steatotic liver disease: A nationwide population-based cohort study.

BACKGROUND: A new fatty liver disease nomenclature, steatotic liver disease (SLD) has been proposed; however, there are no data on clinical outcomes. We investigated the impact of SLD with metabolic dysfunction (MD; SLD-MD) on all-cause mortality. METHODS: We evaluated nationally representative participants aged ≥19 years using data from the Korea National Health and Nutrition Examination Survey 2007-2015 and their linked death data through 2019. The presence of fatty liver disease was assessed by liver fat score, fatty liver index and significant liver fibrosis was evaluated by the Fibrosis-4 Index, and fibrosis score. SLD-MD was categorized into three groups: metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic alcoholic liver disease (MetALD); and SLD with other combination etiologies. RESULTS: Among 26734 individuals (11561 men and 15173 women, mean age 48.8 years), 1833 (6.9 %) died during a mean follow-up period of 110.6 ± 33.9 months. Mortality risk was significantly higher in individuals with SLD-MD (hazard ratio [HR] = 1.35) than in those without (P < 0.001). Among the three groups, MASLD (HR = 1.32) and SLD with other combination etiologies (HR = 2.06) independently increased mortality risk (all P < 0.001). When individuals with SLD-MD had significant liver fibrosis or diabetes, mortality risk increased further (HR = 1.68 and 1.85, respectively; all P < 0.001). SLD-MD with both significant liver fibrosis and diabetes showed the highest mortality risk (HR = 2.29, P < 0.001). When applied fatty liver index and fibrosis score, similar results were observed. CONCLUSIONS: SLD-MD is associated with a higher mortality risk. When SLD-MD was combined with significant liver fibrosis or diabetes, the mortality risk became much higher. Treatment strategies to reduce fibrotic burden and improve glycemic control in individuals with MASLD are needed.

Alanine to glycine ratio is a novel predictive biomarker for type 2 diabetes mellitus.

AIM: We aimed to evaluate the metabolite ratios that could predict the clinical incidence or remission of type 2 diabetes mellitus (T2D). METHODS: The Cox proportional hazards regression model was used to assess 1813 individuals without T2D to test the predictive value of metabolite ratios for T2D incidence and 451 newly diagnosed T2D for remission. The receiver operating characteristic curve analysis was performed to determine the best cut-off values for the metabolite ratios. Survival analyses were performed to compare the four subgroups defined by baseline metabolite ratios and clinical status of obesity. RESULTS: The alanine/glycine was the most significant marker for T2D incidence (hazard ratio per SD: 1.24; p < .001). On the other hand, metabolite hydroxy sphingomyelin C22:2 was most specific for T2D remission (hazard ratio per SD: 1.32; p = .029). Survival analysis of T2D incidence among the subgroups defined by the combination of alanine/glycine and obesity showed the group with a high alanine/glycine and obesity had the highest risk of T2D incidence (p < .001). The alanine/glycine as a T2D risk marker was also validated in the independent external data. CONCLUSIONS: The combination of obesity and the alanine/glycine ratio can be used to evaluate the diabetes risk.

Moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with metabolic syndrome and atherosclerotic cardiovascular disease: A post-hoc analysis of the RACING trial.

AIM: This study evaluated the safety and efficacy of a moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with metabolic syndrome (MetS) and atherosclerotic cardiovascular disease. MATERIALS AND METHODS: In this post-hoc subgroup analysis of the RACING trial, patients were analysed based on the presence of MetS. MetS was defined as meeting at least three of the five following criteria: (a) elevated waist circumference; (b) elevated triglycerides; (c) reduced high-density lipoprotein cholesterol; (d) elevated blood pressure; and (e) elevated fasting glucose. The primary outcome was a 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke. RESULTS: Of the 3780 patients enrolled in the RACING trial, 1703 (45.1%) had MetS at baseline. The primary outcome rate was 10.1% and 10.3% in patients with MetS receiving ezetimibe combination therapy versus high-intensity statin monotherapy (hazard ratio = 0.97; 95% confidence interval = 0.72-1.32; p = .868). Lower rates of intolerance-related drug discontinuation or dose reduction (3.9% vs. 8.0%; p < .001) and lower low-density lipoprotein cholesterol levels (57 vs. 65 mg/dl; p < .001) were observed with ezetimibe combination therapy versus high-intensity statin monotherapy. Furthermore, the rate of new-onset diabetes was 18.5% and 19.1% in each group (p = .822). There were no significant interactions between MetS and therapy regarding study outcomes in the total population. CONCLUSIONS: In patients with MetS and atherosclerotic cardiovascular disease, a moderate-intensity statin with ezetimibe combination therapy had comparable cardiovascular benefits with those of high-intensity statin monotherapy. Meanwhile, ezetimibe combination therapy was associated with lower drug intolerance and low-density lipoprotein cholesterol levels, but there was no apparent between-group difference in new-onset diabetes.

Carboxylate-Directed Pd-Catalyzed ß-C(sp3)-H Arylation of N-Methyl Alanine Derivatives for Diversification of Bioactive Peptides.

This study presents a Pd(II)-catalyzed method for the ß-C(sp3)-H arylation of N-Cbz- or N-Fmoc-protected N-methyl alanines, providing ready access to building blocks for N-methylated peptide synthesis. For this transformation, the native carboxylate was exploited as the directing group, attributing its success to the use of a monoprotected amino-pyridine ligand. Its synthetic utility was demonstrated by facile generation of nine analogues of the naturally occurring N-methylated cyclic peptide cycloaspeptide A.

Appendicular Skeletal Muscle Mass to Visceral Fat Area Ratio Predicts Hepatic Morbidities.

Background/Aims: : Reports on the association between sarcopenic visceral obesity and non-alcoholic fatty liver disease (NAFLD)-associated morbidities remain scarce. We investigated the association between sarcopenia and visceral obesity, and the influence of this association on hepatic and coronary comorbidities. Methods: : The appendicular skeletal muscle mass to visceral fat area ratio (SV ratio) was evaluated using bioelectric impedance analysis. NAFLD and significant liver fibrosis were assessed using transient elastography, and high atherosclerotic cardiovascular disease (ASCVD) risk was defined as a 10-year ASCVD risk score >10%. Sarcopenia was defined as appendicular skeletal muscle mass adjusted by body mass index (<0.789 for men and <0.512 for women). Results: : In total, 82.0% (n=1,205) of the entire study population had NAFLD, and 14.6% of these individuals (n=176) exhibited significant liver fibrosis. Individuals with the lowest SV ratio had a significantly increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk (all p<0.05). Individuals with both the lowest SV ratio and sarcopenia had the highest risk of developing NAFLD (odds ratio [OR]=3.11), significant liver fibrosis (OR=2.03), and high ASCVD risk (OR=4.15), compared with those with a higher SV ratio and without sarcopenia (all p<0.05). Conclusions: : Low SV ratio combined with sarcopenia was significantly associated with an increased risk of NAFLD, significant liver fibrosis, and high ASCVD risk among individuals with a high risk of NAFLD.

SGLT2 and DPP4 inhibitors improve Alzheimer's disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid ß (Aß) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aß accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.

Assessing the Potential Distribution of Oxalis latifolia, a Rapidly Spreading Weed, in East Asia under Global Climate Change.

Oxalis latifolia, a perennial herbaceous weed, is a highly invasive species that poses a threat to agricultural lands worldwide. East Asia is under a high risk of invasion of O. latifolia under global climate change. To evaluate this risk, we employed maximum entropy modeling considering two shared socio-economic pathways (SSP2-4.5 and SSP5-8.5). Currently, a small portion (8.02%) of East Asia is within the O. latifolia distribution, with the highest coverages in Chinese Taipei, China, and Japan (95.09%, 9.8%, and 0.24%, respectively). However, our projections indicated that this invasive weed will likely be introduced to South Korea and North Korea between 2041 and 2060 and 2081 and 2100, respectively. The species is expected to cover approximately 9.79% and 23.68% (SSP2-4.5) and 11.60% and 27.41% (SSP5-8.5) of the total land surface in East Asia by these time points, respectively. South Korea and Japan will be particularly susceptible, with O. latifolia potentially invading up to 80.73% of their territory by 2081-2100. Mongolia is projected to remain unaffected. This study underscores the urgent need for effective management strategies and careful planning to prevent the introduction and limit the expansion of O. latifolia in East Asian countries.

Comparisons of the prediction models for undiagnosed diabetes between machine learning versus traditional statistical methods.

We compared the prediction performance of machine learning-based undiagnosed diabetes prediction models with that of traditional statistics-based prediction models. We used the 2014-2020 Korean National Health and Nutrition Examination Survey (KNHANES) (N = 32,827). The KNHANES 2014-2018 data were used as training and internal validation sets and the 2019-2020 data as external validation sets. The receiver operating characteristic curve area under the curve (AUC) was used to compare the prediction performance of the machine learning-based and the traditional statistics-based prediction models. Using sex, age, resting heart rate, and waist circumference as features, the machine learning-based model showed a higher AUC (0.788 vs. 0.740) than that of the traditional statistical-based prediction model. Using sex, age, waist circumference, family history of diabetes, hypertension, alcohol consumption, and smoking status as features, the machine learning-based prediction model showed a higher AUC (0.802 vs. 0.759) than the traditional statistical-based prediction model. The machine learning-based prediction model using features for maximum prediction performance showed a higher AUC (0.819 vs. 0.765) than the traditional statistical-based prediction model. Machine learning-based prediction models using anthropometric and lifestyle measurements may outperform the traditional statistics-based prediction models in predicting undiagnosed diabetes.

Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.

Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.

Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.