Adipose Derived Stem Cells Affect miR-145 and p53 Expressions of Co-Cultured Hematopoietic Stem Cells.

In this article published in Cell J, Vol 19, No 4, Jan-Mar (Winter) 2018, on pages 654-659, the authors found that Figures 2 and 3 had some errors that accidentally happened during organizing figures. Because of mislabeling of some images and saving them in an incorrect folder, the following figures' legends are corrected. The authors would like to apologies for any inconvenience.

Synthetic Small Molecules Induce Insulin Secretion and Pancreatic Beta-Cell-Specific Gene Expression.

Despite various efficient pharmaceuticals which are already used to manage diabetes, new drugs are needed to preserve and restore the function of pancreatic ß-cells (pßCs) including cell-specific gene expression and insulin production and secretion. Newly developed small molecules (SMs) with potential anti-diabetic activity need to be preliminarily tested. Mice insulinoma MIN6 cells can be utilized as an in vitro screening model. These cells have pßC characteristics and can secrete insulin in response to glucose level changes. As well, the ß-cell-specific gene expression pattern of these cells is similar to that of mouse pancreatic islet cells. It is possible to use this cell line as a research tool to study the function of pßCs. To date, approximately 60 genes have been identified which are effective in the pßC embryonic development and insulin production and secretion during puberty, including pancreas/duodenum homeobox protein 1 (Pdx1), neuronal differentiation 1 (Neurod1), neurogenin3 (Ngn3), and insulin-1 precursor (Ins1). In this study, a family of new SMs that are structurally similar to glinides was synthesized through 3 different synthetic methods and categorized into 3 categories (C1-C3). Then, these novel SMs were characterized by testing their effects on cell viability, pßC-specific gene expression, and insulin secretion in MIN6 in 4 different concentrations and at 3 time points (24, 48, and 72 h). According to our results, SMs of C1 (1j, 1k, and 1l) and 2 SMs of C3 (1f, 1i), at 200 µM concentration, were able to increase the expression levels of Pdx1, Neurod1, Ngn3, and Ins1 as well as the insulin secretion after 24 h. However, C2 (1a, 1b, 1c, and 1d) did not show significant bioactivity of MIN6 cells. These investigated molecules can provide a tool for exploring pseudo-islet functionality in MIN6 cells or provide a possible basis for future therapeutic interventions for diabetes.

P38 initiates degeneration of midbrain GABAergic and glutamatergic neurons in diabetes models.

Diabetes mellitus may cause tau protein hyperphosphorylation and neurodegeneration, but the exact mechanism by which diabetic conditions induce tau pathology remains unclear. Tau protein hyperphosphorylation is considered a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau-directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed different techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in in vivo and in vitro models. We showed that diabetes-related stresses and glucose metabolism deficiency could induce cis P-tau (an early driver of the tau pathology) accumulation in the midbrain and corpus callosum of the diabetic mice models and cells treated with 2-deoxy-D-glucose, respectively. We found that the active phosphorylated level of P38 was increased in the treated cells and diabetic mice models. We observed that oxidative stress activated P38, which directly and indirectly drove tau pathology in the GABAergic and glutamatergic neurons of the midbrain of the diabetic mice after 96 h, which accumulated in the other neighboring brain areas after 2 months. Notably, P38 inhibition suppressed tau pathogenicity and risk-taking behaviors in the animal models after 96 h. The data establish P38 as a central mediator of diabetes mellitus-induced tau pathology. Our findings provide mechanistic insight into the consequences of this metabolic disorder on the nervous system.

Potential Impact of Diabetes and Obesity on Alveolar Type 2 (AT2)-Lipofibroblast (LIF) Interactions After COVID-19 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new emerging respiratory virus, caused evolving pneumonia outbreak around the world. In SARS-Cov-2 infected patients, diabetes mellitus (DM) and obesity are two metabolic diseases associated with higher severity of SARS-CoV-2 related complications, characterized by acute lung injury requiring assisted ventilation as well as fibrosis development in surviving patients. Different factors are potentially responsible for this exacerbated response to SARS-CoV-2 infection. In patients with DM, base-line increase in inflammation and oxidative stress represent preexisting risk factors for virus-induced damages. Such factors are also likely to be found in obese patients. In addition, it has been proposed that massive injury to the alveolar epithelial type 2 (AT2) cells, which express the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), leads to the activation of their stromal niches represented by the Lipofibroblasts (LIF). LIF are instrumental in maintaining the self-renewal of AT2 stem cells. LIF have been proposed to transdifferentiate into Myofibroblast (MYF) following injury to AT2 cells, thereby contributing to fibrosis. We hypothesized that LIF's activity could be impacted by DM or obesity in an age- and gender-dependent manner, rendering them more prone to transition toward the profibrotic MYF status in the context of severe COVID-19 pneumonia. Understanding the cumulative effects of DM and/or obesity in the context of SARS-CoV-2 infection at the cellular level will be crucial for efficient therapeutic solutions.

A Possible Neurodegeneration Mechanism Triggered by Diabetes.

Several conditions result in neurodegeneration; among which diabetes mellitus (DM) is of crucial importance. Tau (τ) malfunction is a major pathological process participating in neurodegeneration. Despite extensive considerations, the actual causative link between DM and τ abnormalities remains uncertain thus far. Phosphorylated (p)-τ at Thr-Pro motifs can exist in the two distinct cis and trans conformations. cis is neurotoxic, and is accumulated upon various stress conditions, such as nutrition depletion. We assume that pathogenic cis p-τ is the central mediator of neurodegeneration in DM, and propose why different brain areas give various responses to stress conditions. We herein juxtapose recent approaches in diabetic neurodegeneration and propose a therapeutic target to stop neuronal loss during DM.

Type 1 Diabetes Mellitus: Cellular and Molecular Pathophysiology at A Glance.

Type 1 diabetes mellitus (T1DM) is a disease where destruction of the insulin producing pancreatic beta-cells leads to increased blood sugar levels. Both genetic and environmental factors play a part in the development of T1DM. Currently, numerous loci are specified to be the responsible genetic factors for T1DM; however, the mechanisms of only a few of these genes are known. Although several environmental factors are presumed responsible for progression of T1DM, to date, most of their mechanisms remain undiscovered. After several years of hyperglycemia, late onsets of macrovascular (e.g., cardiovascular) and microvascular (e.g., neurological, ophthalmological, and renal) complications may occur. This review and accompanying figures provides an overview of the etiological factors for T1DM, its pathogenesis at the cellular level, and attributed complications.

Adipose Derived Stem Cells Affect miR-145 and p53 Expressions of Co-Cultured Hematopoietic Stem Cells.

OBJECTIVES: Umbilical cord blood is used for transplantation purposes in regenerative medicine of hematological disorders. MicroRNAs are important regulators of gene expression that control both physiological and pathological processes such as cancer development and incidence. There is a new relation between p53 (tumor suppressor gene) and miR-145 (suppressor of cell growth) upregulation. In this study, we have assessed how adipose-derived stem cells (ADSCs) affect the expansion of hematopoietic stem cells (HSCs), as well as miR-145 and p53 expressions. MATERIALS AND METHODS: In this experimental study, we cultured passage-3 isolated human ADSCs as a feeder layer. Flow cytometry analysis confirmed the presence of ADSC surface markers CD73, CD90, CD105. Ex vivo cultures of cordblood CD34+ cells were cultured under the following 4 culture conditions for 7 days: i. Medium only supplemented with cytokines, ii. Culture on an ADSCs feeder layer, iii. Indirect culture on an ADSCs feeder layer (Thin Cert™ plate with a 0.4 µm pore size), and iv. Control group analyzed immediately after extraction. Real-time polymerase chain reaction (PCR) was used to determine the expressions of the p53 and miR-145 genes. Flow cytometry analysis of cells stained by annexin V and propidium iodide (PI) was performed to detect the rate of apoptosis in the expanded cells. RESULTS: ADSCs tested positive for mesenchymal stem cell (MSC) markers CD105, CD90, and CD73, and negative for HSC markers CD34 and CD45. Our data demonstrated the differentiation potential of ASCs to osteoblasts by alizarin red and alkaline phosphatase staining. MTT assay results showed a higher proliferation rate of CD34+cells directly cultured on the ADSCs feeder layer group compared to the other groups. Direct contact between HSCs and the feeder layer was prevented by a microporous membrane p53 expression increased in the HSCs group with indirect contact of the feeder layer compared to direct contact of the feeder layer. p53 significantly downregulated in HSCs cultured on ADSCs, whereas miR-145 significantly upregulated in HSCs cultured on ADSCs. CONCLUSIONS: ADSCs might increase HSCs proliferation and self-renewal through miR-145, p53, and their relationship.