Gut microbiota-based prediction for the transition from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) in a remote island cohort study.

AIM: The present cohort study explored whether specific gut microbiota (GM) profile would predict the development of impaired glucose tolerance (IGT) in individuals with normal glucose tolerance (NGT). METHODS: A total of 114 study subjects with NGT in Kumejima island, Japan participated in the present study and underwent 75 g oral glucose tolerance tests at baseline and one year later. We compared the profile of GM at baseline between individuals who consistently maintained NGT (NRN, n = 108) and those who transitioned from NGT to IGT (NTI, n = 6). RESULTS: Within-individual bacterial richness and evenness as well as inter-individual bacterial composition showed no significant differences between NRN and NTI. Of note, however, partial least squares discriminant analyses revealed distinct compositions of GM between groups, with no overlap in their 95 % confidence interval ellipses. Multi-factor analyses at the genus level demonstrated that the proportions of CF231, Corynebacterium, Succinivibrio, and Geobacillus were significantly elevated in NTI compared to NRN (p < 0.005, FDR < 0.1, respectively) after adjusting for age, sex, HbA1c level, and BMI. CONCLUSIONS: Our data suggest that increased proportion of specific GM is linked to the future deterioration of glucose tolerance, thereby serving as a promising predictive marker for type 2 diabetes mellitus.

Post-traumatic pituitary stalk transection syndrome (PSTS) expeditiously manifested after a fall from a height combined with acute traumatic spinal cord injury: a rare case report with review of literature.

Post-traumatic pituitary stalk transection syndrome (PSTS) is an extremely rare cause of combined pituitary hormone deficiency (CPHD), affecting approximately 9 per 100,000 cases of traumatic brain injury. In contrast, pituitary stalk interruption syndrome (PSIS) is also a rare cause of CPHD. Importantly, these conditions are often confused due to their similar names and resembling findings on magnetic resonance imaging (MRI). PSIS has been thought to be a prenatal developmental event resulting from a couple of genetic aberrations. In typical PSIS, anterior pituitary hormone deficiencies are restricted to growth hormone (GH) and gonadotropin during the pediatric age, gradually and generally progressing to panhypopituitarism in most cases. In contrast, global deficiencies of the anterior pituitary hormones in PSTS are temporally associated with trauma. To the best of our knowledge, no case reports of PSTS combined with acute traumatic spinal cord injury have been reported. A 34-year-old female was transferred to our hospital after jumping from the fourth building floor. She was diagnosed as an acute traumatic spinal cord injury and underwent the operation of elective posterior spinal fusion. On postoperative day 7, the blood tests revealed considerable hyperkalemia, hyponatremia and eosinophilia. Notably, menstruation stopped after falling from a height. Pituitary function tests revealed GH deficiency, hypogonadism, hypothyroidism and hypoadrenocorticism. MRI revealed loss of the pituitary stalk, whilst the hyperintense signal from distal axon of hypothalamus was still identified. Based on these findings, she was diagnosed as PSTS. Our case highlights endocrinological landscape of transection of the pituitary stalk by acute trauma.

Profile of gut microbiota and serum metabolites associated with metabolic syndrome in a remote island most afflicted by obesity in Japan.

Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese and obese individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. Results revealed that MUO showed significantly higher levels of genera such as g_Succinivibrio, g_Granulicatella, g_Brachyspira, g_Oribacterium and g_Atopobium in comparison to MHO. Moreover, abundance of g_Succinivibrio, g_Brachyspira and g_Atopobium were positively correlated with value of fasting insulin, HOMA-R, circulating triglycerides, diastolic blood pressure, BMI, body weight, waist circumference and HbA1c. In addition, MUO compared to MHO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

Analysis of spot urine biomarkers and association with body weight in Japanese elementary schoolchildren.

Childhood obesity is rapidly increasing worldwide and is largely the consequence of adoption of unhealthy diets excessive in calories and salt (NaCl) as well as devoid in pivotal micronutrients such as potassium (K) and magnesium (Mg). Education-based programs aiming to encourage healthy food knowledge and behaviors are crucial at a young age, and for this purpose, convenient ways to assess daily dietary intake are warranted. We therefore attempted to evaluate the dietary intake of Okinawan schoolchildren in Japan by analyzing a series of biomarkers in morning spot urine samples and explore whether these biomarkers correlate with body weight and a series of metabolic parameters. We enrolled 98 third-grade elementary schoolchildren in Okinawa, Japan. Morning spot urine samples were collected and analyzed using high-performance liquid chromatography (HPLC) to assess dietary intake. We found that estimated daily NaCl intake was higher in obese/overweight children as compared to healthy-weight children (p = 0.0001). There was also a significant positive correlation between body mass index (BMI) and NaCl intake (Spearman) (ρ = 0.45, p < 0.0001) and a negative correlation between BMI and Mg/Cr (ρ = -0.27, p = 0.01). Furthermore, Na/K ratio was higher in samples collected on Monday (weekend) as compared to samples collected on Thursday or Friday (weekday) (p < 0.0001). CONCLUSION: Via the use of morning spot urine analyses, our results show that NaCl intake was associated with obesity, and Mg excretion negatively correlated with BMI in Japanese schoolchildren, highlighting the potential role of these micronutrients in maintaining a healthy body weight. WHAT IS KNOWN: •Overweight and obesity are largely due to excessive consumption of calories and positively correlated with salt (NaCl) intake. •Spot urine methods are convenient for assessing the nutritional needs and targeting prevention programs in children. WHAT IS NEW: •Utilizing morning spot urine analyses, estimated NaCl intake is positively correlated and Mg/Cr negatively correlated with BMI in Okinawan schoolchildren. •As estimated via morning spot urine samples, a greater proportion of children likely exceeds the recommended NaCl intake on the weekend as compared to weekday.

Fermented brown rice beverage distinctively modulates the gut microbiota in Okinawans with metabolic syndrome: A randomized controlled trial.

Accumulating evidence to date suggests that brown rice is superior to white rice in regard to its beneficial impact on a number of risk factors of the metabolic syndrome (MetS). However, little is known about the influence of fermented brown rice beverage on the gut microbiota in humans. We therefore hypothesized that its impact would beneficially alter the gut microbiota composition of patients with MetS. Using a 4-week randomized, single-arm study design, subjects (n = 40) were advised to consume a daily fermented brown rice beverage (BA) or fermented white rice beverage (WA) as a replacement of their main meal. Clinical and anthropometric measurements as well as fecal samples were collected at baseline and immediately after completion of the intervention. Gut microbiota was analyzed using 16S ribosomal RNA sequencing and capillary electrophoresis-time-of-flight mass spectrometry was used to measure plasma short-chain fatty acids. Interestingly, ingestion of BA in contrast to WA resulted in a unique elevation in the abundance of number of beneficial species belonging to the Clostridia class, associated with reduced inflammation, and increased short-chain fatty acid production: Lactobacillales bacterium DJF B280 (P = .005), Butyrate producing bacterium A2 207 (P = .012), and Firmicutes bacterium DJF VP44 (P = .038). This study demonstrates that consumption of BA is effective to beneficially modulate the gut microbiota compared with WA in patients with MetS.

Maternal Urinary Cotinine Concentrations During Pregnancy Predict Infant BMI Trajectory After Birth: Analysis of 89617 Mother-Infant Pairs in the Japan Environment and Children's Study.

Background: Clinical or epidemiological conclusions remain undecided on the direct effects of active and second-hand smoking during pregnancy on childhood obesity. Urinary cotinine (UC) concentration, an accurate and quantitative marker for smoking, may elucidate the dose-dependent relationship between smoking during pregnancy and childhood obesity. To analyze the relationship between UC concentration and smoking questionnaire (SQ) classes for active and second-hand smoking in pregnant mothers and trajectory of infant Kaup index (body mass index: BMI). Methods: This multicenter prospective cohort study was conducted using a list-wise complete set of 35829 among 89617 mother-infant singleton pairs, recruited between 2011 and 2014, in the Japan Environment and Children's Study (JECS). Pairs were categorized according to UC levels (1 to 4 classes) or SQ (0 to 4 classes). Results: Maternal BMI at delivery was the highest in UC class 4 (highest). Maternal and paternal education of ≥16 years and annual household income were lowest in UC class 4. Infant BMI was lower at birth, but trends in BMI and ΔBMI were higher from six to 36 months step-wise in the UC classes. The above tendency was observed in the list-wise complete dataset but was emphasized after multiple imputations and corrections of cofounders. UC concentration in five SQ classes largely fluctuated, and the relationship between SQ classes and trends in BMI and ΔBMI was not statistically significant. Conclusion: Infants from high UC mothers had a low BMI at birth, increasing from six to 36 months of age. UC concentrations, but not smoking questionnaire classes, predict infant BMI trajectory, suggesting that active and second-hand smoking affect child obesity in a dose-dependent manner.

Specific Expression of KCC2 in the α Cells of Normal and Type 1 Diabetes Model Mouse Pancreatic Islets.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the mature brain; however, it acts excitatory during development. This difference in action depends on the intracellular chloride ion concentration, primarily regulated by potassium chloride co-transporter2 (KCC2). Sufficient KCC2 expression results in its inhibitory action. GABA is also abundant in pancreatic islets, where it acts differentially on the islet cells, and is involved in carbohydrate metabolism. However, the mechanisms underlying the differential action remain unknown. We performed immunohistochemistry for glutamic acid decarboxylase (GAD), a synthetic enzyme for GABA, and KCC2 in normal adult islets. GAD was co-localized with insulin in ß cells, whereas KCC2 was expressed in glucagon-positive α cells. These results are in line with previous observations that GABA decreases glucagon release but increases insulin release, and suggest that GABA and insulin may work together in reducing blood glucose levels under hyperglycemia. Next, we examined the streptozotocin-induced type1 diabetes mellitus mouse model. GAD and insulin expression levels were markedly decreased. KCC2 was expressed in glucagon-positive cells, whereas insulin- and somatostatin-positive cells were KCC2-negative. These findings suggest that in diabetes model, reduced GABA release may cause disinhibition of glucagon release, resulting in increased blood sugar levels and the maintenance of hyperglycemic state.

Impact of anti-diabetic sodium-glucose cotransporter 2 inhibitors on tumor growth of intractable hematological malignancy in humans.

Under the dysfunction of mitochondria, cancer cells preferentially utilize both glycolytic and pentose phosphate pathways rather than electron transport chains to desperately generate adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH), classically recognized as the Warburg effect. Based on this background, the present study tested the hypothesis that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors would exert a tumor-suppressive impact on intractable human hematological malignancies via the modulation of glucose metabolism within cells and cell cycles. The level of mRNA for SGLT2 was remarkably elevated in leukemic cells from patients with adult T-cell leukemia (ATL), one of the most intractable blood cancers in humans, and as well as in two kinds of ATL cell lines (MT-1 and MT-2). Two kinds of SGLT2 inhibitors, Luseogliflozin and Tofogliflozin substantially suppressed the proliferation of MT-1 and MT-2 cells in both adherent and anchorage-independent culture conditions. Such a suppressive effect on tumor cell growth was reproduced by Luseogliflozin in leukemic cells in peripheral blood from patients with ATL. In MT-2 cells, both of SGLT2 inhibitors considerably attenuated glucose uptake, intracellular ATP levels, and NADPH production, resultantly enhancing cell cycle arrest at the G0/G1 phase. From the standpoint of metabolic oncology, the present study suggests that SGLT2 inhibitors would be a promising adjunctive option for the treatment of the most intractable human hematological malignancies like ATL.

Coexistence of sensory qualities and value representations in human orbitofrontal cortex.

Despite the multiple regions and neural networks associated with value-based decision-making, the orbitofrontal cortex (OFC) is possible a particularly important one. Although the role of the OFC in reinforcer devaluation tasks, which assess the ability to represent identity, sensory qualities, and subjective values of the expected outcomes, has been established, the specific aspect represented in this area remains unclear. In this study, using functional magnetic resonance imaging, wherein participants rated the palatability of 128 food items using photographs, we investigated whether the human OFC represents object identity, sensory qualities, or value. Employing many items helped us dissociate object identity from sensory qualities and values; the inferred sensory qualities of identical items were manipulated by a change in metabolic state. Moreover, value differences between items were analytically controlled by employing a technique similar to age adjustment. The palatability ratings for food items significantly decreased after a meal. Using representational similarity analysis, we confirmed that the OFC represents value. Moreover, identical items were represented similarly in the lateral OFC in a given metabolic state; however, these representations were altered post-feeding. Importantly, this change was not explained by subjective value, suggesting that the OFC represents sensory quality and value, but not object identity.

The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma.

On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

Retrospective exploratory analyses on gender differences in determinants for incidence and progression of diabetic retinopathy in Japanese patients with type 2 diabetes mellitus.

Gender differences in risks for macrovascular complications in type 2 diabetes mellitus (T2DM) have been well established. However, the impact of gender differences on diabetic retinopathy (DR) has not been fully elucidated. We therefore retrospectively explored gender-specific determinants for DR in patients with T2DM in a small sized Japanese cohort in Okinawa. There were 214 patients who were diagnosed as no DR (n = 142) and non-proliferative DR (n = 72) in 2009. During the follow-up of median 7 years, 41/142 of incidence, 26/72 of progression, and 67/214 of incidence and progression were observed, respectively. DR was assessed using the modified international clinical DR severity scales. The risks for incidence, progression as well as incidence and progression of DR were comparable between men and women, respectively. Cox proportional hazard models in multivariate analyses demonstrated that the only common determinant in both men and women for DR was the duration of T2DM. Regarding gender-specific determinants, lower level of serum albumin in men as well as higher HbA1c, lower level of estimated glomerular filtration rate, and lower level of serum uric acid in women were extracted, respectively. Although precise mechanisms for such gender-specific determinants of DR still remain unsolved, the present study would highlight a couple of factors associated with gender-specific determinants for DR in a limited numbers of Japanese cohort. Prospective observational studies on gender-specific determinants of DR in a large scale cohort are warranted to further clarify underlying mechanisms.

Extra-virgin olive oil and the gut-brain axis: influence on gut microbiota, mucosal immunity, and cardiometabolic and cognitive health.

Extra-virgin olive oil (EVOO), a popular functional food and major source of fat in the Mediterranean diet, possesses a variety of healthful components, including monounsaturated fatty acids and bioactive phenolic compounds that, individually and collectively, exert beneficial effects on cardiometabolic markers of health and act as neuroprotective agents through their anti-inflammatory and antioxidant activities. The gut microbiota and health of the intestinal environment are now considered important factors in the development of obesity, metabolic disease, and even certain neurodegenerative conditions via the gut-brain axis. Recently, data are emerging which demonstrate that the health-promoting benefits of EVOO may also extend to the gut microbiota. In this review, we aimed to examine findings from recent studies regarding the impact of EVOO on gut microbiota and intestinal health and explore how modulations in composition of gut microbiota, production of microbially produced products, and activity and functioning of the mucosal immune system may lead to favorable outcomes in cardiovascular, metabolic, and cognitive health.

Homeostatic versus hedonic control of carbohydrate selection.

Macronutrient intake is associated with cardiometabolic health, ageing and longevity, but the mechanisms underlying its regulation have remained unclear. Most rodents increase carbohydrate selection under certain physiological and pathological conditions such as fasting. When presented with a choice between a basally preferable high-fat diet (HFD) and a high-carbohydrate diet (HCD) such as a high-sucrose diet, fasted mice first eat the HFD and then switch to the HCD during the first few hours of refeeding and continue to eat the HCD up to 24 h in the two-diet choice approach. Such consumption of an HCD after fasting reverses the fasting-induced increase in the plasma concentration of ketone bodies more rapidly than does refeeding with an HFD alone. 5'-AMP-activated protein kinase (AMPK)-regulated neurons in the paraventricular nucleus of the hypothalamus (PVH) that express corticotropin-releasing hormone (CRH) are necessary and sufficient for the fasting-induced selection of carbohydrate over an HFD in mice. These neurons appear to contribute to a fasting-induced increase in the positive valence of carbohydrate without affecting the preference for more palatable and energy-dense diets such as an HFD. Identification of the neural circuits in which AMPK-regulated CRH neurons in the PVH of mice are embedded should shed new light on the physiological and molecular mechanisms responsible for macronutrient selection.

Metabolically and immunologically beneficial impact of extra virgin olive and flaxseed oils on composition of gut microbiota in mice.

PURPOSE: Extra virgin olive oil (EVOO) and flaxseed oil (FO) contain a variety of constituents beneficial for chronic inflammation and cardio-metabolic derangement. However, little is known about the impact of EVOO and FO on dysbiosis of gut microbiota, intestinal immunity, and barrier. We, therefore, aimed to assess the impact of EVOO and FO on gut microbiota, mucosal immunity, barrier integrity, and metabolic health in mice. METHODS: C57BL/6 J mice were exposed to a low-fat (LF), lard (HF), high fat-extra virgin olive oil (HF-EVOO), or high fat-flaxseed oil (HF-FO) diet for 10 weeks. Gut microbiota assessment was undertaken using 16S rRNA sequencing. Levels of mRNA for genes involved in intestinal inflammation and barrier maintenance in the intestine and bacterial infiltration in the liver were measured by qPCR. RESULTS: HF-EVOO or HF-FO mice showed greater diversity in gut microbiota as well as a lower abundance of the Firmicutes phylum in comparison with HF mice (P < 0.05). The qPCR analyses revealed that mRNA level of FoxP3, a transcription factor, and IL-10, an inducer of regulatory T cells, was significantly elevated in the intestines of mice-fed HF-EVOO in comparison with mice-fed HF (P < 0.05). The mRNA level of the antimicrobial peptide, RegӀӀӀγ, was markedly elevated in the intestines of HF-EVOO and HF-FO compared with HF group (P < 0.05). CONCLUSIONS: Our data suggest that the consumption of EVOO or FO can beneficially impact gut microbiota, enhance gut immunity, and assist in the preservation of metabolic health in mice.

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.

Adipose tissue-derived mesenchymal stem cells ameliorate bone marrow aplasia related with graft-versus-host disease in experimental murine models.

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics.

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axis.

Diabetes mellitus is associated with various disorders of the locomotor system including the decline in mass and function of skeletal muscle. The mechanism underlying this association has remained ambiguous, however. We now show that the abundance of the transcription factor KLF15 as well as the expression of genes related to muscle atrophy are increased in skeletal muscle of diabetic model mice, and that mice with muscle-specific KLF15 deficiency are protected from the diabetes-induced decline of skeletal muscle mass. Hyperglycemia was found to upregulate the KLF15 protein in skeletal muscle of diabetic animals, which is achieved via downregulation of the E3 ubiquitin ligase WWP1 and consequent suppression of the ubiquitin-dependent degradation of KLF15. Our results revealed that hyperglycemia, a central disorder in diabetes, promotes muscle atrophy via a WWP1/KLF15 pathway. This pathway may serve as a therapeutic target for decline in skeletal muscle mass accompanied by diabetes mellitus.