Interaction effect between low birthweight and resistin gene rs1862513 variant on insulin resistance and type 2 diabetes mellitus in adulthood: Toon Genome Study.

AIMS/INTRODUCTION: Gene-environment interactions are considered to critically influence type 2 diabetes mellitus development; however, the underlying mechanisms and specific interactions remain unclear. Given the increasing prevalence of low birthweight (LBW) influenced by the intrauterine environment, we sought to investigate genetic factors related to type 2 diabetes development in individuals with LBW. MATERIALS AND METHODS: The interaction between 20 reported type 2 diabetes susceptibility genes and the development of type 2 diabetes in LBW (<2,500 g) individuals in a population-based Japanese cohort (n = 1,021) was examined by logistic regression and stratified analyses. RESULTS: Logistic regression analyses showed that only the G/G genotype at the rs1862513 locus of the resistin gene (RETN), an established initiator of insulin resistance, was closely related to the prevalence of type 2 diabetes in individuals with LBW. Age, sex and current body mass index-adjusted stratified analyses showed a significant interaction effect of LBW and the RETN G/G genotype on fasting insulin, homeostatic model assessment 2-insulin resistance, Matsuda index and the prevalence of type 2 diabetes (all P-values for interaction <0.05). The adjusted odds ratio for type 2 diabetes in the LBW + G/G genotype group was 7.33 (95% confidence interval 2.43-22.11; P = 0.002) compared with the non-LBW + non-G/G genotype group. Similar results were obtained after excluding the influence of malnutrition due to World War II. CONCLUSIONS: Simultaneous assessment of LBW and the RETN G/G genotype can more accurately predict the risk of future type 2 diabetes than assessing each of these factors alone, and provide management strategies, including early lifestyle intervention in LBW population.

Effects of different modes and intensities of exercise on longevity proteins in middle-aged mouse skeletal muscle.

Physical exercise represents one of the most effective approaches to anti-aging. The goal of this study was to verify the effects of different modes and intensities of exercise on longevity proteins in the skeletal muscle in midlife. Middle-aged mice were trained in aerobic or resistance exercise for 8 weeks, and the changes in sirtuin 1 (SIRT1), adenosine monophosphate-activated kinase (AMPK), and mammalian target of rapamycin (mTOR) pathways in the skeletal muscle were evaluated by western blotting. Long-term exercise had no effects on skeletal muscle SIRT1 abundance, whereas high-intensity aerobic exercise increased AMPK phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Low-intensity resistance exercise facilitated Akt/mTOR/p70 ribosomal protein kinase S6 (p70S6K) signaling but did not induce muscle hypertrophy. Conversely, high-intensity resistance exercise stimulated muscle hypertrophy without phosphorylation of mTOR signaling-related proteins. These results suggest the importance of setting exercise modes and intensities for anti-aging in midlife.

Effects of uphill and downhill walking on post-traumatic osteoarthritis development in mice.

Using destabilization of the medial meniscus (DMM) to induce models of osteoarthritis (OA), we sought to clarify how flat, uphill and downhill walking affects OA-related inflammation and articular cartilage degeneration. Thirty-two male C57BL/6J mice 7 weeks old underwent DMM surgery in their right knee and sham surgery in their left knee, and were then assigned to either the no walking after DMM group or the flat, uphill or downhill walking after DMM group (n = 8/group). After creating the knee OA model, the mice in the walking groups were subjected to treadmill walking 1 day after surgery, which included walking at 12 m/min for 30 min/day, 7 days/week, at inclines of 0, 20, or -20 degrees. Knee joints were harvested at the end of the intervention period. Non-demineralized frozen sections were prepared and samples were examined histologically. Osteoarthritis Research Society International scores were significantly decreased in both the uphill and flat-walking groups, compared with the no-walking group. Immunohistochemical staining showed increased levels of aggrecan and Sry-related high-mobility group box9; conversely, decreased levels of matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs-5 in both the uphill and flat-walking groups. Micro-CT results showed a higher bone-volume fraction in the uphill and flat-walking groups than that in the no-walking group. Our findings indicate that flat and uphill walking may prevent the progression of OA. KEY POINTS: Flat and uphill treadmill walking can prevent the development of post-traumatic osteoarthritis in mice. Flat and uphill walking increases anabolic proteins and decreases catabolic proteins and inflammatory cytokines in articular cartilage, resulting in protection against cartilage degeneration. Downhill walking increases catabolic proteins and inflammatory cytokines in cartilage, which has negative effects on articular cartilage.

HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis.

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.

Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children.

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m2, melphalan (MEL) 210 mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

Effects of ultrasound, radial extracorporeal shock waves, and electrical stimulation on rat bone defect healing.

Fractures associated with osteoporosis are a major public health concern. Current treatments for fractures are limited to surgery or fixation, leading to long-term bedrest, which is linked to increased mortality. Alternatively, utilization of physical agents has been suggested as a promising therapeutic approach for fractures. Here, we examined the effects of ultrasound, radial extracorporeal shock waves, and electrical stimulation on normal or osteoporotic fracture healing. Femoral bone defects were created in normal or ovariectomized rats. Rats were divided into four groups: untreated, and treated with ultrasound, shock waves, or electrical stimulation after surgery. Samples were collected at 2 or 4 weeks after surgery, and the healing process was evaluated with micro-CT, histological, and immunohistochemical analyses. Ultrasound at intensities of 0.5 and 1.0 W/cm2 , but not 0.05 W/cm2 , accelerated new bone formation. Shock wave exposure also increased newly formed bone, but formed abnormal periosteal callus around the defect site. Conversely, electrical stimulation did not affect the healing process. Ultrasound exposure increased osteoblast activity and cell proliferation and decreased sclerostin-positive osteocytes. We demonstrated that higher-intensity ultrasound and radial extracorporeal shock waves accelerate fracture healing, but shock wave treatment may increase the risk of periosteal callus formation.

Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFalpha in human epidermal keratinocytes (HaCaT).

Glucocorticoids (GCs) are essential drugs administered topically or systematically for the treatment of autoimmune skin diseases such as pemphigus. However, a certain proportion of patients does not respond well to GCs. Although studies on the relationship between cytokines and GC insensitivity in local tissues have attracted attention recently, little is known about the underlying mechanism(s) for GC insensitivity in epidermal keratinocytes. Here, we report that tumor necrosis factor (TNF) alpha reduces GC-induced transactivation of endogenous genes as well as a reporter plasmid which contains GC responsive element (GRE) in human epidermal keratinocyte cells (HaCaT). The GC insensitivity by TNFalpha was not accompanied by changes in mRNA expressions of GR isoforms (alpha or beta). However, we observed that mitogen-activated protein kinase kinase-1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors (PD98059 and U0126) significantly sensitized the GC-induced transactivation of anti-inflammatory genes (glucocorticoid-induced leucine zipper (GILZ) and mitogen-activated protein kinase phosphatase (MKP)-1) and FK506 binding protein (FKBP) 51 gene in the presence of TNFalpha. Additionally, we observed that TNFalpha reduced prednisolone (PSL)-dependent nuclear translocation of GR, which was restored by pre-treatment of MEK-1 inhibitors. This is the first study demonstrating a role of the MEK-1/ERK cascade in TNFalpha-mediated GC insensitivity. Our data suggest that overexpression of TNFalpha leads to topical GC insensitivity by reducing GR nuclear translocation in keratinocytes, and our findings also suggest that inhibiting the MEK-1/ERK cascade may offer a therapeutic potential for increasing GC efficacy in epidermis where sufficient inflammatory suppression is required.