Significant advancements have been made in diagnostic methods for early‐stage diabetic polyneuropathy. Early and accurate diagnosis of diabetic polyneuropathy is crucial for preventing further ...complications and enabling timely intervention. Furthermore, there is a need for an objective numerical value to evaluate the early stage of diabetic polyneuropathy.
The expectations for the clinical application of stem cell therapy for diabetic microvascular complications are increasing, as stem cell transplantation improves histopathological abnormalities ...mainly through angiogenesis/protection, nerve elongation/protection, and anti‐inflammatory effects.
Evidence suggests the involvement of trained immunity in metabolic memory under the diabetic condition. High glucose‐induced trained immunity is a possible key player in “metabolic memory” among ...patients with diabetes. Increased aerobic glycolysis plays an important role in inducing trained immunity in diabetes.
COVID‐19 patients with diabetes are reported to have higher mortality compared with non‐diabetic COVID‐19 patients. However, recent investigations showed the importance of better glycemic control ...among diabetes patients to avoid death from COVID‐19.
Schwann cells maintain peripheral nerve structure and function by ensheathment of unmyelinated axons, myelination of myelinated axons, and secretion of neurotrophic factors, and these cells also play ...a crucial role in the pathogenic mechanisms of diabetic neuropathy. A decrease in unmyelinated and small myelinated axons appeared earlier than a decrease in large myelinated fibers in diabetic neuropathy. Electron microscopic studies of human diabetic neuropathy demonstrated edematous cell cytoplasm, aggregates of glycogen particles, and hyperplasia of the surrounding basal lamina in Schwann cells. Diabetic conditions also induces metabolic disorders, such as polyol pathway hyperactivity, activation of protein kinase C, and increased advanced glycosylation end products in Schwann cells, followed by the depletion of neurotrophic factor production.Cell transplantation using progenitor or stem cells is expected to cure diabetic neuropathy. Many studies demonstrated that the paracrine effect of abundant secreted factors from transplanted stem cells was crucial for the success of cell transplantation in diabetic neuropathy. Transplantation of progenitor or stem cells in diabetic animal models ameliorated impaired nerve conduction velocity, nerve blood flow, sensory disorders, and intraepidermal nerve fiber density, with an increase of myelin thickness. The supernatant from cultured dental pulp stem cells increased the proliferation and production of myelin-related protein in Schwann cells, suggesting that Schwann cells is the main target of cell transplantation for diabetic neuropathy.
Extracellular vesicles (EVs) are known to be secreted by various cells. In particular, mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have tissue repair capacity and anti-inflammatory properties. ...Dental pulp stem cells (DPSCs), which are MSCs isolated from pulp tissue, are less invasive to the body than other MSCs and can be collected from young individuals. In this study, we investigated the efficacy of EVs secreted by DPSCs (DPSC-EVs) for bone formation.
DPSC-EVs were isolated from the cell culture medium of DPSCs. DPSC-EVs were unilaterally injected along with collagen (COL), beta-tricalcium phosphate (β-TCP) or hydroxyapatite (HA) into rat calvarial bone defects. The effects of DPSC-EVs were analyzed by micro-computed tomography (micro-CT) and histological observation.
Micro-CT showed that administration of DPSC-EVs with the abovementioned scaffolds resulted in bone formation in the periphery of the defects. DPSC-EVs/COL specifically resulted in bone formation in the center of the defects. Histological observation revealed that DPSC-EVs/COL promoted new bone formation. Administration of DPSC-EVs/COL had almost the same effect on the bone defect site as transplantation of DPSCs/COL.
These results suggest that DPSC-EVs may be effective tools for bone tissue regeneration.
Atherosclerosis is a major cause of mortality worldwide. The initial change in atherosclerosis is intimal thickening due to muscle cell proliferation and migration. A correlation has been observed ...between periodontal disease and atherosclerosis. Here, we investigated the proliferation and migration of human aortic smooth muscle cells (HASMCs) using
-derived LPS (
-LPS). To elucidate intracellular signaling, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) of HASMCs were knocked down, and the role of these molecules in
-LPS-stimulated proliferation and migration was examined. The role of mitogen-activated protein kinase (MAPK) in HASMC proliferation and migration was further elucidated by MAPK inhibition.
-LPS stimulation increased the proliferation and migration of HASMCs and activated the TLR4/MyD88 pathway. TLR4 knockdown inhibited
-LPS stimulated HASMCs proliferation and migration.
-LPS stimulation led to the phosphorylation of P38 MAPK, JNK, and ERK, and MyD88 knockdown inhibited the phosphorylation of P38 MAPK and JNK but not ERK. P38 MAPK and SAPK/JNK inhibition did not suppress the proliferation of HASMCs upon
-LPS stimulation, but ERK inhibition significantly inhibited proliferation. SAPK/JNK and ERK inhibition suppressed
-LPS-stimulated migration of HASMCs. In conclusion, our findings suggest that
-LPS may promote atherosclerosis via the activation of MAPK through TLR4.
Aims/Introduction
Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity ...and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves.
Materials and Methods
DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated.
Results
Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells.
Conclusions
These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy.
Effects of DPSC transplantation on the inflammatory mRNA expressions in sciatic nerves. Transplantation of DPSCs significantly decreased TNF‐α gene expression and increased the CD206 gene expression in the sciatic nerves compared with the vehicle‐injected side in diabetic rats.
Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The ...physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this study. By using immortalized adult Fischer rat Schwann cells (IFRS1), we investigated the mechanism of the stimulating effects of insulin on the cell proliferation and expression of myelin proteins (myelin protein zero (MPZ) and myelin basic protein (MBP). The application of insulin to IFRS1 cells increased the proliferative activity and induced phosphorylation of Akt and ERK, but not P38-MAPK. The proliferative potential of insulin-stimulated IFRS1 was significantly suppressed by the addition of LY294002, a PI3 kinase inhibitor. The insulin-stimulated increase in MPZ expression was significantly suppressed by the addition of PD98059, a MEK inhibitor. Furthermore, insulin-increased MBP expression was significantly suppressed by the addition of LY294002. These findings suggest that both PI3-K/Akt and ERK/MEK pathways are involved in insulin-induced cell growth and upregulation of MPZ and MBP in IFRS1 Schwann cells.
Development of cardiovascular disease (CVD), including coronary artery disease, arrhythmia, and ischemic stroke, depends on environmental and genetic factors. To investigate the epigenetic basis of ...myocardial infarction (MI), we performed an epigenome-wide association study for this condition in elderly Japanese subjects. A total of 192 case subjects with MI and 192 control subjects were recruited from hospital attendees and the general population, respectively. Genome-wide DNA methylation (DNAm) profiles for DNA isolated from whole blood were obtained by analysis with an Infinium HumanMethylation450 BeadChip. The relation of DNAm sites found to be significantly associated with MI to nearby single nucleotide polymorphisms (SNPs) previously shown to be associated with CVD was assessed in the control group.
Three DNAm sites (cg06642177, cg07786668, cg17218495) showed genome-wide significant associations with MI (
= 4.33 × 10
, 3.96 × 10
, and 3.77 × 10
, respectively). Two of these sites (cg07786668, cg17218495) still showed such associations after adjustment for classical risk factors of MI (
= 1.04 × 10
and 6.60 × 10
, respectively). The DNAm sites cg07786668 and cg17218495 are located in
(zinc finger homeobox 3) and
(SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) genes, respectively. SNPs in
or
that were previously found to be associated with CVD were not significantly associated with these DNAm sites in our control subjects.
We identified two DNAm sites-cg07786668 in
and cg17218495 in
- that are independently and significantly associated with MI. Our results suggest that the development of MI might be influenced by changes in DNAm at these sites via a pathway that differs from that affected by CVD-associated SNPs in these genes. The Kita-Nagoya Genomic Epidemiology (KING) study, which was the source of control samples in the present study, was registered in ClinicalTrials.gov (NCT00262691) on 6 December 2005.
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