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Heme oxygenase (HO)-1, the inducible isoform of the heme-degrading enzyme HO, plays a critical role in inflammation and iron homeostasis. Regulatory functions of HO-1 are mediated via ...the catalytic breakdown of heme, which is an iron-containing tetrapyrrole complex with potential pro-oxidant and pro-inflammatory effects. In addition, the HO reaction produces the antioxidant and anti-inflammatory compounds carbon monoxide (CO) and biliverdin, subsequently converted into bilirubin, along with iron, which is reutilized for erythropoiesis. HO-1 is up-regulated by a plethora of stimuli and injuries in most cell types and tissues and provides salutary effects by restoring physiological homeostasis. Notably, HO-1 exhibits critical immuno-modulatory functions in macrophages, which are a major cell population of the mononuclear phagocyte system. Macrophages play key roles as sentinels and regulators of the immune system and HO-1 in these cells appears to be of critical importance for driving resolution of inflammatory responses. In this review, the complex functions and regulatory mechanisms of HO-1 in macrophages will be high-lighted. A particular focus will be the intricate interactions of HO-1 with its substrate heme, which play a contradictory role in distinct physiological and pathophysiological settings. The therapeutic potential of targeted modulation of the macrophage heme-HO-1 system will be discussed in the context of inflammatory disorders.
Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and ...cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.
SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury ...and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel "proof of concept" studies in the context of COVID-19.
Polyisocyanopeptide (PIC) hydrogels are proposed as promising wound dressings. These gels are thermo-sensitive, allow application as a cold liquid, and rely on gelation through body heat. It is ...supposed that the gel can be easily removed by reversing the gelation and washing it away with a cold irrigation solution. The impact on wound healing of the regular application and removal of PIC dressings is compared to a single application of PIC and the clinically used Tegaderm™ in murine splinted full-thickness wounds for up to 14 days. SPECT/CT analysis of
In-labelled PIC gels showed that, on average, 58% of the PIC gel could be washed out of the wounds with the employed method, which is, however, heavily influenced by personal technique. Evaluation with photography and (immuno-)histology showed that wounds in which PIC dressings were regularly removed and replaced were smaller at 14 days post-injury but performed on par with the control treatment. Moreover, the encapsulation of PIC in wound tissue was less severe and occurred less often when PIC was regularly refreshed. In addition, no morphological damage related to the removal procedure was observed. Thus, PIC gels are atraumatic and perform similarly to currently employed wound dressing materials, offering possible future benefits for both clinicians and patients.
The driving factors causing fibrosis and scar formation include fibroblast differentiation into myofibroblasts and hampered myofibroblast apoptosis, which ultimately results in collagen accumulation ...and tissue contraction. Currently, only very few drugs are available for fibrosis treatment, and there is an urgent demand for new pharmaceutical products. High-throughput in vitro fibrosis models are necessary to develop such drugs. In this study, we developed such a novel model based on synthetic polyisocyanide (PIC-RGD) hydrogels. The model not only measures contraction but also allows for subsequent molecular and cellular analysis. Fibroblasts were seeded in small (10 μL) PIC-RGD gels in the absence or presence of TGFβ1, the latter to induce myofibroblast differentiation. The contraction model clearly differentiates fibroblasts and myofibroblasts. Besides a stronger contraction, we also observed α-smooth muscle actin (αSMA) production and higher collagen deposition for the latter. The results were supported by mRNA expression experiments of αSMA, Col1α1, P53, and Ki67. As proof of principle, the effects of FDA-approved antifibrotic drugs nintedanib and pirfenidone were tested in our newly developed fibrosis model. Both drugs clearly reduce myofibroblast-induced contraction. Moreover, both drugs significantly decrease myofibroblast viability. Our low-volume synthetic PIC-RGD hydrogel platform is an attractive tool for high-throughput in vitro antifibrotic drug screening.
Abstract
Background
Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is ...needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk.
Methods
To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg
E. coli
lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within < 24 h) and severe septic shock (norepinephrine dose > 0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula.
Results
Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L,
p
= 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls,
p
= 0.0139).
Conclusions
Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients.
Graphical abstract
Orofacial soft tissue wounds caused by surgery for congenital defects, trauma, or disease frequently occur leading to complications affecting patients' quality of life. Scarring and fibrosis prevent ...proper skin, mucosa and muscle regeneration during wound repair. This may hamper maxillofacial growth and speech development. To promote the regeneration of injured orofacial soft tissue and attenuate scarring and fibrosis, intraoral and extraoral stem cells have been studied for their properties of facilitating maintenance and repair processes. In addition, the administration of stem cell-derived extracellular vesicles (EVs) may prevent fibrosis and promote the regeneration of orofacial soft tissues. Applying stem cells and EVs to treat orofacial defects forms a challenging but promising strategy to optimize treatment. This review provides an overview of the putative pitfalls, promises and the future of stem cells and EV therapy, focused on orofacial soft tissue regeneration.
There is a high degree of uncertainty regarding the appropriate force level that should be applied during orthodontic tooth movement (OTM). As a result, orthodontic treatments may take longer than ...necessary, leading to unwanted side effects. This review aimed to identify an optimal force range with the rate of OTM as the primary outcome. External apical root resorption and pain were evaluated as secondary outcomes, and the influence of growth was examined.
Five electronic databases were searched (MEDLINE via PubMed, Embase via OVID, Cochrane Library, CINAHL, and Web of Science) with no publication date or language restrictions. Inclusion eligibility screening, quality assessment, and data extraction were performed by 3 investigators. Each retrieved record was assessed by 2 observers independently. Only randomized controlled trials and randomized split-mouth studies were included.
A total of 12 articles satisfied the inclusion criteria—two randomized controlled trials and 10 randomized split-mouth studies. Only 1 study showed a low risk of bias, whereas the remaining 11 were unclear. The qualitative analysis showed that forces between 50 cN and 250 cN produced a similar OTM rate; forces >250 cN yielded a slightly higher rate but were accompanied by adverse effects. Because of considerable heterogeneity in methodology, clinical diversity with varying forces between 18 cN and 360 cN, and poor statistical reporting, a meta-analysis was deemed inappropriate.
Forces between 50 cN and 100 cN seem optimal for OTM, patient comfort and potentially exhibit fewer side effects. Nevertheless, careful data interpretation is necessary because of the lack of strong evidence. Protocol registration: PROSPERO CRD42016039985.
•Two randomized controlled trials and 10 randomized split-mouth studies were assessed in this systematic review.•Risk of bias was low in 1 study, unclear in 11.•Forces of 50 cN-100 cN seem optimal for orthodontic tooth movement, patient comfort, and potentially exhibit fewer side effects.•Due to considerable heterogeneity in methodology, clinical diversity with varying forces between 18 cN-360 cN and poor statistical reporting, a meta-analysis was deemed inappropriate.
In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in ...preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM.
In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 μmol/L (0.4 mg/dL) to 64 μmol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed.
Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.
Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections. Novel therapies demonstrating simultaneously antiviral activity and improved wound healing are warranted. The aim ...of this study was to investigate the efficacy of medical-grade honey (MGH) for treating HSV-induced cold sores. A crossover trial was performed in patients with recurrent cold sores (
= 29). The majority (65.6%) of these patients experience four or more episodes per year, thus forming a valid self-control group. In this study, patients applied an MGH-based formulation (L-Mesitran Soft) on their cold sore at the onset of symptoms (62.1%) or appearing of blister (37.9%) and compared it to their conventional treatments. After complete healing, patients filled in a questionnaire evaluating healing, pain, and itching. The average absolute healing time was 72.4% slower with conventional treatment (10.0 days) compared to MGH (5.8 days). After MGH treatment, 86.2% of all patients experienced faster objective healing (6.9% similar and 6.9% slower) and the subjective healing score was higher in 79.3% of the patients (20.7% similar). If the patients normally experience pain and itching during their cold sores, these levels were lower with MGH therapy compared to conventional treatment in 72.7% and 71.4% of the patients, respectively. Moreover, 100% of the patients prefer MGH treatment over conventional treatment and will use it again on future cold sores. MGH is a promising alternative treatment for cold sores, likely by combining both increased antiviral and wound healing activities while alleviating pain and itching.
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