Neurohumoral mechanisms of keratinocytes regulation in diabetes mellitus

The extent of damage to the nervous, vascular and microcirculatory systems in diabetic patients determine the regulation of physiological events that lead to the formation of chronic wounds, reduction of patient quality of life and increase of the financial value of medical care. Successful physiological repair is impossible without the successive phases of inflammation, proliferation and wound healing. Keratinocytes are the major cellular barrier components of the epidermis. These cells play an important role in physiological repair, as suggested by recent research, with many cells able to secrete steroid hormones de novo. Damage to the integrity of the skin leads to keratinocyte activation, triggering a cascade of reactions that contribute to changes in epidermal cell phenotype and lead to their proliferation and migration, analogous to changes in cellular adhesion and configuration of the cytoskeleton. An open question remains as to how the keratinocyte cell cycle, which is altered under conditions of hyperglycemia, and neurotransmitter metabolism during different stages of physiological repair are regulated. Understanding these processes will provide a scientific basis for the development of new targets for pharmacotherapies.

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Vaccarin Regulates Diabetic Chronic Wound Healing through FOXP2/AGGF1 Pathways

International Journal of Molecular Sciences ◽

10.3390/ijms21061966 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1966

Author(s):

Yixiao Liu ◽

Jiangnan Sun ◽

Xinyu Ma ◽

Shuangshuang Li ◽

Min Ai ◽

...

Keyword(s):

Wound Healing ◽

High Glucose ◽

Chronic Wounds ◽

Chronic Wound ◽

Angiogenic Factor ◽

Cell Counting ◽

Sensory Loss ◽

Diabetic Patients ◽

And Migration ◽

Proliferation And Migration

Background: Diabetes mellitus is a growing global health issue nearly across the world. Diabetic patients who are prone to develop diabetes-related complications often exhibit progressive neuropathy (painless and sensory loss). It is usual for small wounds to progress to ulceration, which especially worsens with peripheral arterial disease and in the presence of anaerobic bacteria, culminating into gangrene. In our study, vaccarin (VAC), the main active monomer extracted from Chinese herb vaccariae semen, is proven to have a role in promoting diabetic chronic wound healing through a cytoprotective role under high glucose conditions. Materials and methods: We constructed a pressure ulcer on both VAC-treated and control mice based on a type 1 diabetes (T1DM) model. The wound healing index was evaluated by an experimental wound assessment tool (EWAT). We also determined the effect of VAC on the proliferation and cell migration of human microvascular endothelial cells (HMEC-1) by a cell counting kit (CCK-8), a scratch and transwell assay. Results: The results demonstrated that VAC could promote the proliferation and migration of high glucose-stimulated HMEC-1 cells, which depend on the activation of FOXP2/AGGF1. Activation of the angiogenic factor with G patch and FHA domains 1 (AGGF1) caused enhanced phosphorylation of serine/threonine kinase (Akt) and extracellular regulated protein kinases (Erk1/2). By silencing the expression of forkhead box p2 (FOXP2) protein by siRNA, both mRNA and protein expression of AGGF1 were downregulated, leading to a decreased proliferation and migration of HMEC-1 cells. In addition, a diabetic chronic wound model in vivo unveiled that VAC had a positive effect on chronic wound healing, which involved the activation of the above-mentioned pathways. Conclusions: In summary, our study found that VAC promoted chronic wound healing in T1DM mice by activating the FOXP2/AGGF1 pathway, indicating that VAC may be a promising candidate for the treatment of the chronic wounds of diabetic patients.

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Fabrication of Hybrid Nanofibers from Biopolymers and Poly (Vinyl Alcohol)/Poly (ε-Caprolactone) for Wound Dressing Applications

Polymers ◽

10.3390/polym13132104 ◽

2021 ◽

Vol 13 (13) ◽

pp. 2104

Author(s):

Sibusiso Alven ◽

Blessing Atim Aderibigbe

Keyword(s):

Mechanical Properties ◽

Wound Healing ◽

Vinyl Alcohol ◽

Wound Dressing ◽

Chronic Wounds ◽

Cellular Adhesion ◽

Wound Dressings ◽

Poly Vinyl Alcohol ◽

High Porosity ◽

Hybrid Nanofibers

The management of chronic wounds is challenging. The factors that impede wound healing include malnutrition, diseases (such as diabetes, cancer), and bacterial infection. Most of the presently utilized wound dressing materials suffer from severe limitations, including poor antibacterial and mechanical properties. Wound dressings formulated from the combination of biopolymers and synthetic polymers (i.e., poly (vinyl alcohol) or poly (ε-caprolactone) display interesting properties, including good biocompatibility, improved biodegradation, good mechanical properties and antimicrobial effects, promote tissue regeneration, etc. Formulation of these wound dressings via electrospinning technique is cost-effective, useful for uniform and continuous nanofibers with controllable pore structure, high porosity, excellent swelling capacity, good gaseous exchange, excellent cellular adhesion, and show a good capability to provide moisture and warmth environment for the accelerated wound healing process. Based on the above-mentioned outstanding properties of nanofibers and the unique properties of hybrid wound dressings prepared from poly (vinyl alcohol) and poly (ε-caprolactone), this review reports the in vitro and in vivo outcomes of the reported hybrid nanofibers.

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Effects of High Glucose Concentration on Pericyte-Like Differentiated Human Adipose-Derived Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22094604 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4604

Author(s):

Giuliana Mannino ◽

Anna Longo ◽

Florinda Gennuso ◽

Carmelina Daniela Anfuso ◽

Gabriella Lupo ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

High Glucose ◽

Angiogenic Factors ◽

Diabetic Patients ◽

Ros Production ◽

Migration Ability ◽

And Migration

A pericyte-like differentiation of human adipose-derived mesenchymal stem cells (ASCs) was tested in in vitro experiments for possible therapeutic applications in cases of diabetic retinopathy (DR) to replace irreversibly lost pericytes. For this purpose, pericyte-like ASCs were obtained after their growth in a specific pericyte medium. They were then cultured in high glucose conditions to mimic the altered microenvironment of a diabetic eye. Several parameters were monitored, especially those particularly affected by disease progression: cell proliferation, viability and migration ability; reactive oxygen species (ROS) production; inflammation-related cytokines and angiogenic factors. Overall, encouraging results were obtained. In fact, even after glucose addition, ASCs pre-cultured in the pericyte medium (pmASCs) showed high proliferation rate, viability and migration ability. A considerable increase in mRNA expression levels of the anti-inflammatory cytokines transforming growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) was observed, associated with reduction in ROS production, and mRNA expression of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and angiogenic factors. Finally, a pmASC-induced better organization of tube-like formation by retinal endothelial cells was observed in three-dimensional co-culture. The pericyte-like ASCs obtained in these experiments represent a valuable tool for the treatment of retinal damages occurring in diabetic patients.

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Treatment of de novo coronary artery lesions with paclitaxel drug coated balloons (DCB) in diabetic and non-diabetic patients

European Heart Journal ◽

10.1093/ehjci/ehaa946.1486 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K.M.Z Mohd Saad Jalaluddin

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

De Novo ◽

Target Lesion ◽

Diabetic Group ◽

Target Lesion Revascularization ◽

Diabetic Patients ◽

Coronary Artery Lesions ◽

Artery Disease

Abstract Background Drug-coated balloon has been widely used to treat In-Stent Restenosis as recommended by ESC/EACT coronary intervention guideline. However, trials of effectiveness of DCB in treating de novo lesions in diabetic patients are limited. This study will highlight the impact of DCB in diabetic patients with only de novo lesions against non-diabetic patients. Aim To compare the outcomes of Paclitaxel Drug Coated Balloon (DCB) in Diabetic and non-diabetic patients with only de novo coronary artery disease. Methods A retrospective, single center study was conducted from January 2016 till December 2018. All diabetic and non-diabetic patients underwent angioplasty to only de novo coronary artery lesions were included in the study. Patients' baseline characteristic, angiographic data, post procedural and 12 months follow-up outcomes including major adverse coronary artery event (MACE), target lesion revascularization (TLR) and myocardial infarction (MI) are compared. Results A total of 1257 patients (726 diabetic and 531 non-diabetic patients) with total 1385 de novo coronary artery lesions (791 lesions in diabetic group and 594 lesions in non-diabetic group) were included in this study. Mean age for non-diabetic group was 57.6±10.6 years and diabetic group was 59.6±9.6 years with male predominance (91.1% in non-diabetic group, n=484 and 79.2% in diabetic group, n=575). Majority of diabetic group has hypertension (83.7%, n=608 vs 58.6%, n+311), chronic renal failure (10.3%, n=75 vs 1.9%, n=10), documented coronary artery disease (55.6%, n=404 vs 47.5%, n=252) and previous coronary angioplasty 39.5%, n=287 vs 28.8%, n=153). Adequate pre-dilatation was done in both groups (98.5%, n=585 in non-diabetic group and 99.4%, n=786 in diabetic group; p=0.000). Mean DCB diameter and length were almost similar in both groups. Mean residual stenosis after DCB was 11.15±16.9% in non-diabetic group and 13.13±13.4% in the diabetic group (p=0.008). 74.6% of non-diabetic group (n=396) and 77.1% of diabetic group (n=560) were on double antiplatelet therapy for 12 months. 86.8% (n=461) of non-diabetic and 88.4% (n=642) of diabetic patients were available for follow up. MACE events were significantly higher (p=0.000) in diabetic group (4.3%, n=31) as compare to non-diabetic group (0.6%, n=3). Target lesion revascularization (TLR) and myocardial infarction (MI) was also significantly higher in diabetic group (TLR 1.4%, N=10 vs 0.6%, n=3, p=0.049; MI 2.6%, n=19 vs 0.4%, n=2, p=0.002). Conclusion Treating de novo coronary lesions in diabetic patients with DCB associated with significantly higher MACE events, target lesion revascularization and myocardial infarction. Diabetic patients appear to have a greater volume of atherosclerotic plaque and increased propensity for atherosclerotic plaque rupture. Funding Acknowledgement Type of funding source: None

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Migration and Proliferation Effects of Thymoquinone-Loaded Nanostructured Lipid Carrier (TQ-NLC) and Thymoquinone (TQ) on In Vitro Wound Healing Models

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/9725738 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Henna Roshini Alexander ◽

Sharifah Sakinah Syed Alwi ◽

Latifah Saiful Yazan ◽

Fatin Hanani Zakarial Ansar ◽

Yong Sze Ong

Keyword(s):

Wound Healing ◽

Nigella Sativa ◽

Drug Carrier ◽

Healing Process ◽

Diabetic Patients ◽

Nanostructured Lipid Carrier ◽

Impaired Wound Healing ◽

And Migration ◽

Proliferation And Migration

Wound healing is a regulated biological event that involves several processes including infiltrating leukocyte subtypes and resident cells. Impaired wound healing is one of the major problems in diabetic patients due to the abnormal physiological changes of tissues and cells in major processes. Thymoquinone, a bioactive compound found in Nigella sativa has been demonstrated to possess antidiabetic, anti-inflammatory, and antioxidant effects. Today, the rapidly progressing nanotechnology sets a new alternative carrier to enhance and favour the speed of healing process. In order to overcome its low bioavailability, TQ is loaded into a colloidal drug carrier known as a nanostructured lipid carrier (NLC). This study aimed to determine the effect of TQ-NLC and TQ on cell proliferation and migration, mode of cell death, and the antioxidant levels in normal and diabetic cell models, 3T3 and 3T3-L1. Cytotoxicity of TQ-NLC and TQ was determined by MTT assay. The IC10 values obtained for 3T3-L1 treated with TQ-NLC and TQ for 24 hours were 4.7 ± 3.3 and 5.3 ± 0.6 μM, respectively. As for 3T3, the IC10 values obtained for TQ-NLC and TQ at 24 hours were 4.3 ± 0.17 and 3.9 ± 2.05 μM, respectively. TQ-NLC was observed to increase the number of 3T3 and 3T3-L1 healthy cells (87–95%) and gradually decrease early apoptotic cells in time- and dose-dependant manner compared with TQ. In the proliferation and migration assay, 3T3-L1 treated with TQ-NLC showed higher proliferation and migration rate (p<0.05) compared with TQ. TQ-NLC also acted as an antioxidant by reducing the ROS levels in both cells after injury at concentration as low as 3 μM. Thus, this study demonstrated that TQ-NLC has better proliferation and migration as well as antioxidant effect compared with TQ especially on 3T3-L1 which confirms its ability as a good antidiabetic and antioxidant agent.

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Intracoronary Brachytherapy After Stenting De Novo Lesions in Diabetic Patients

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2004.02.061 ◽

2004 ◽

Vol 44 (3) ◽

pp. 520-527 ◽

Cited By ~ 21

Author(s):

Manel Sabaté ◽

Gela Pimentel ◽

Carlos Prieto ◽

José María Corral ◽

Camino Bañuelos ◽

...

Keyword(s):

De Novo ◽

Diabetic Patients ◽

Intracoronary Brachytherapy

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Science-Driven Societal Transformation, Part III: Design

Sustainability ◽

10.3390/su13020726 ◽

2021 ◽

Vol 13 (2) ◽

pp. 726

Author(s):

John C. Boik

Keyword(s):

System Design ◽

De Novo ◽

Cognitive Architecture ◽

Development Program ◽

Transformational Change ◽

Biodiversity Loss ◽

Cognitive Capacity ◽

Original Research ◽

Self Identity ◽

And Migration

Climate change, biodiversity loss, and other major social and environmental problems pose severe risks. Progress has been inadequate and scientists, global policy experts, and the general public increasingly conclude that transformational change is needed across all sectors of society in order to improve and maintain social and ecological wellbeing. At least two paths to transformation are conceivable: (1) reform of and innovation within existing societal systems (e.g., economic, legal, and governance systems); and (2) the de novo development of and migration to new and improved societal systems. This paper is the final in a three-part series of concept papers that together outline a novel science-driven research and development program aimed at the second path. It summarizes literature to build a narrative on the topic of de novo design of societal systems. The purpose is to raise issues, suggest design possibilities, and highlight directions and questions that could be explored in the context of this or any R&D program aimed at new system design. This paper does not present original research, but rather provides a synthesis of selected ideas from the literature. Following other papers in the series, a society is viewed as a superorganism and its societal systems as a cognitive architecture. Accordingly, a central goal of design is to improve the collective cognitive capacity of a society, rendering it more capable of achieving and sustainably maintaining vitality. Topics of attention, communication, self-identity, power, and influence are discussed in relation to societal cognition and system design. A prototypical societal system is described, and some design considerations are highlighted.

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Diabetic wound regeneration using heparin-mimetic peptide amphiphile gel in db/db mice

Biomaterials Science ◽

10.1039/c7bm00251c ◽

2017 ◽

Vol 5 (7) ◽

pp. 1293-1303 ◽

Cited By ~ 11

Author(s):

Berna Senturk ◽

Burak M. Demircan ◽

Alper D. Ozkan ◽

Sehmus Tohumeken ◽

Tuncay Delibasi ◽

...

Keyword(s):

High Risk ◽

Chronic Wounds ◽

Diabetic Patients ◽

Diabetic Wound ◽

Peptide Amphiphile ◽

Efficient Treatment ◽

Mimetic Peptide ◽

Leg Amputation

There is an urgent need for more efficient treatment of chronic wounds in diabetic patients especially with a high risk of leg amputation.

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Posttranscriptional down-regulation of ras oncogene expression by inhibitors of cellular glutathione

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4416-4422.1993 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4416-4422

Author(s):

A C Miller ◽

J Gafner ◽

E P Clark ◽

D Samid

Keyword(s):

Transcriptional Activation ◽

De Novo ◽

Drug Effects ◽

Human Tumor ◽

Cell Phenotype ◽

Similar Drug ◽

Ras Family ◽

Steady State Levels ◽

Or Gene ◽

Nih 3T3

Alterations in intracellular glutathione (GSH) content are known to affect intrinsic responses to ionizing radiation. More recently, it became apparent that radiation responses may depend also on the expression of specific oncogenes, including ras. These findings, suggesting a possible link between GSH and ras, led us to examine the effect of various GSH modulators on ras expression. Treatment of c-Ha-ras-transformed NIH 3T3 cells with L-buthionine S'R'-sulfoximine, dimethylfumarate, or N',N'-1,3-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea resulted in dose- and time-dependent reduction in ras mRNA steady-state levels followed by a decrease in ras-encoded p21 protein production. The effect on ras correlated with the extent of GSH decline, was common to different members of the ras family, and was independent of the mode of oncogene activation or cell phenotype. Indeed, similar drug effects were observed with murine cells in which overexpression of the c-Ha-ras proto-oncogene was due to transcriptional activation (PR4, nontumorigenic) or gene amplification (NIH 136, tumorigenic) and with malignant cells expressing a mutated Ha-ras (RS504). Moreover, N-ras, EJras, and Ki-ras in human tumor cells were similarly affected. Molecular analysis revealed a significant decrease in ras mRNA half-life in cells subjected to GSH inhibition, an effect that required de novo protein synthesis, but there was no change in the rate of gene transcription. These results indicate that pharmacological manipulation of cellular GSH content can down-regulate ras expression at the posttranscriptional level by destabilizing ras transcripts. The potential clinical implications are discussed.

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Effects of a New Bioceramic Material on Human Apical Papilla Cells

Journal of Functional Biomaterials ◽

10.3390/jfb9040074 ◽

2018 ◽

Vol 9 (4) ◽

pp. 74 ◽

Cited By ~ 16

Author(s):

Diana Sequeira ◽

Catarina Seabra ◽

Paulo Palma ◽

Ana Cardoso ◽

João Peça ◽

...

Keyword(s):

Wound Healing ◽

Mineral Trioxide Aggregate ◽

Cellular Adhesion ◽

Cellular Migration ◽

Cellular Viability ◽

Migration Rates ◽

Apical Papilla ◽

And Migration ◽

Proliferation And Migration

Background: The development of materials with bioregenerative properties is critically important for vital pulp therapies and regenerative endodontic procedures. The aim of this study was to evaluate the cytocompatibility and cytotoxicity of a new endodontic biomaterial, PulpGuard, in comparison with two other biomaterials widely used in endodontic procedures, ProRoot Mineral Trioxide Aggregate (MTA) and Biodentine. Methods: Apical papilla cells (APCs) were isolated from third molars with incomplete rhizogenesis from patients with orthodontic indication for dental extraction. Cultured APCs were incubated for 24, 48, or 72 h with different dilutions of eluates prepared from the three materials. Cellular viability, mobility, and proliferation were assessed in vitro using the Alamar Blue assay and a wound-healing test. The cells were also cultured in direct contact with the surface of each material. These were then analyzed via Scanning Electron Microscopy (SEM), and the surface chemical composition was determined by Energy-Dispersive Spectroscopy (EDS). Results: Cells incubated in the presence of eluates extracted from ProRoot MTA and PulpGuard presented rates of viability comparable to those of control cells; in contrast, undiluted Biodentine eluates induced a significant reduction of cellular viability. The wound-healing assay revealed that eluates from ProRoot MTA and PulpGuard allowed for unhindered cellular migration and proliferation. Cellular adhesion was observed on the surface of all materials tested. Consistent with their disclosed composition, EDS analysis found high relative abundance of calcium in Biodentine and ProRoot MTA and high abundance of silicon in PulpGuard. Significant amounts of zinc and calcium were also present in PulpGuard discs. Concerning solubility, Biodentine and ProRoot MTA presented mild weight loss after eluate extraction, while PulpGuard discs showed significant water uptake. Conclusions: PulpGuard displayed a good in vitro cytocompatibility profile and did not significantly affect the proliferation and migration rates of APCs. Cells cultured in the presence of PulpGuard eluates displayed a similar profile to those cultured with eluates from the widely used endodontic cement ProRoot MTA.

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