Signaling modality within gp130 receptor enhances tissue regeneration

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease.

Download Full-text

Decellularized bone extracellular matrix in skeletal tissue engineering

Biochemical Society Transactions ◽

10.1042/bst20190079 ◽

2020 ◽

Vol 48 (3) ◽

pp. 755-764

Author(s):

Benjamin B. Rothrauff ◽

Rocky S. Tuan

Keyword(s):

Tissue Engineering ◽

Bone Regeneration ◽

Tissue Regeneration ◽

Animal Studies ◽

Tumor Resection ◽

Regenerative Capacity ◽

Skeletal Tissue ◽

Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

Download Full-text

Transplantation of Adipose-derived Cells for Periodontal Regeneration: A Systematic Review

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666181105144430 ◽

2019 ◽

Vol 14 (6) ◽

pp. 504-518 ◽

Cited By ~ 3

Author(s):

Dilcele Silva Moreira Dziedzic ◽

Bassam Felipe Mogharbel ◽

Priscila Elias Ferreira ◽

Ana Carolina Irioda ◽

Katherine Athayde Teixeira de Carvalho

Keyword(s):

Systematic Review ◽

Animal Models ◽

Platelet Rich Plasma ◽

Periodontal Regeneration ◽

In Vitro Studies ◽

In Vivo Studies ◽

Cell Sources ◽

Study Designs

This systematic review evaluated the transplantation of cells derived from adipose tissue for applications in dentistry. SCOPUS, PUBMED and LILACS databases were searched for in vitro studies and pre-clinical animal model studies using the keywords “ADIPOSE”, “CELLS”, and “PERIODONTAL”, with the Boolean operator “AND”. A total of 160 titles and abstracts were identified, and 29 publications met the inclusion criteria, 14 in vitro and 15 in vivo studies. In vitro studies demonstrated that adipose- derived cells stimulate neovascularization, have osteogenic and odontogenic potential; besides adhesion, proliferation and differentiation on probable cell carriers. Preclinical studies described improvement of bone and periodontal healing with the association of adipose-derived cells and the carrier materials tested: Platelet Rich Plasma, Fibrin, Collagen and Synthetic polymer. There is evidence from the current in vitro and in vivo data indicating that adipose-derived cells may contribute to bone and periodontal regeneration. The small quantity of studies and the large variation on study designs, from animal models, cell sources and defect morphology, did not favor a meta-analysis. Additional studies need to be conducted to investigate the regeneration variability and the mechanisms of cell participation in the processes. An overview of animal models, cell sources, and scaffolds, as well as new perspectives are provided for future bone and periodontal regeneration study designs.

Download Full-text

Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22041514 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1514 ◽

Cited By ~ 1

Author(s):

Akihiro Yachie

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Heme Oxygenase ◽

Inflammatory Diseases ◽

Cell Types ◽

Pharmacological Intervention ◽

Heme Oxygenase 1 ◽

Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Download Full-text

Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models

mAbs ◽

10.1080/19420862.2021.1954136 ◽

2021 ◽

Vol 13 (1) ◽

pp. 1954136

Author(s):

Sujatha Kumar ◽

Srimoyee Ghosh ◽

Geeta Sharma ◽

Zebin Wang ◽

Marilyn R. Kehry ◽

...

Keyword(s):

Animal Models ◽

Immune Function ◽

Cellular Assays ◽

In Vivo Animal Models

Download Full-text

Techniques for the Assessment of In Vitro and In Vivo Antifungal Combinations

Journal of Fungi ◽

10.3390/jof7020113 ◽

2021 ◽

Vol 7 (2) ◽

pp. 113

Author(s):

Anne-Laure Bidaud ◽

Patrick Schwarz ◽

Guillaume Herbreteau ◽

Eric Dannaoui

Keyword(s):

Animal Models ◽

Fungal Infections ◽

Acquired Resistance ◽

Adequate Treatment ◽

Combination Treatments ◽

Target Organs ◽

Fungal Load ◽

Time Kill

Systemic fungal infections are associated with high mortality rates despite adequate treatment. Moreover, acquired resistance to antifungals is increasing, which further complicates the therapeutic management. One strategy to overcome antifungal resistance is to use antifungal combinations. In vitro, several techniques are used to assess drug interactions, such as the broth microdilution checkerboard, agar-diffusion methods, and time-kill curves. Currently, the most widely used technique is the checkerboard method. The aim of all these techniques is to determine if the interaction between antifungal agents is synergistic, indifferent, or antagonistic. However, the interpretation of the results remains difficult. Several methods of analysis can be used, based on different theories. The most commonly used method is the calculation of the fractional inhibitory concentration index. Determination of the usefulness of combination treatments in patients needs well-conducted clinical trials, which are difficult. It is therefore important to study antifungal combinations in vivo, in experimental animal models of fungal infections. Although mammalian models have mostly been used, new alternative animal models in invertebrates look promising. To evaluate the antifungal efficacy, the most commonly used criteria are the mortality rate and the fungal load in the target organs.

Download Full-text

Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model

Molecules ◽

10.3390/molecules26144221 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4221

Author(s):

Aage Kristian Olsen Alstrup ◽

Svend Borup Jensen ◽

Ole Lerberg Nielsen ◽

Lars Jødal ◽

Pia Afzelius

Keyword(s):

Animal Model ◽

Animal Models ◽

Porcine Model ◽

Animal Experiments ◽

Radioactive Tracers ◽

The Individual ◽

Selection Of

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

Download Full-text

The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

Cancers ◽

10.3390/cancers13040855 ◽

2021 ◽

Vol 13 (4) ◽

pp. 855

Author(s):

Paola Serrano Martinez ◽

Lorena Giuranno ◽

Marc Vooijs ◽

Robert P. Coppes

Keyword(s):

Signaling Pathways ◽

Progenitor Cells ◽

Tissue Regeneration ◽

Normal Tissue ◽

Cellular Response ◽

Adult Tissue ◽

Tissue Specific ◽

Radiation Induced

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this.

Download Full-text

Current Knowledge on Functionality and Potential Therapeutic Uses of Donkey Milk

Animals ◽

10.3390/ani11051382 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1382

Author(s):

Mina Martini ◽

Iolanda Altomonte ◽

Domenico Tricò ◽

Riccardo Lapenta ◽

Federica Salari

Keyword(s):

Animal Models ◽

Randomized Clinical Trials ◽

Current Knowledge ◽

Saturated Fatty Acids ◽

Cow Milk ◽

Donkey Milk ◽

Alpha Linolenic Acid ◽

High Concentration

The increase of knowledge on the composition of donkey milk has revealed marked similarities to human milk, which led to a growing number of investigations focused on testing the potential effects of donkey milk in vitro and in vivo. This paper examines the scientific evidence regarding the beneficial effects of donkey milk on human health. Most clinical studies report a tolerability of donkey milk in 82.6–98.5% of infants with cow milk protein allergies. The average protein content of donkey milk is about 18 g/L. Caseins, which are main allergenic components of milk, are less represented compared to cow milk (56% of the total protein in donkey vs. 80% in cow milk). Donkey milk is well accepted by children due to its high concentration of lactose (about 60 g/L). Immunomodulatory properties have been reported in one study in humans and in several animal models. Donkey milk also seems to modulate the intestinal microbiota, enhance antioxidant defense mechanisms and detoxifying enzymes activities, reduce hyperglycemia and normalize dyslipidemia. Donkey milk has lower calorie and fat content compared with other milks used in human nutrition (fat ranges from 0.20% to 1.7%) and a more favourable fatty acid profile, being low in saturated fatty acids (3.02 g/L) and high in alpha-linolenic acid (about 7.25 g/100 g of fat). Until now, the beneficial properties of donkey milk have been mostly related to whey proteins, among which β-lactoglobulin is the most represented (6.06 g/L), followed by α-lactalbumin (about 2 g/L) and lysozyme (1.07 g/L). So far, the health functionality of donkey milk has been tested almost exclusively on animal models. Furthermore, in vitro studies have described inhibitory action against bacteria, viruses, and fungi. From the literature review emerges the need for new randomized clinical trials on humans to provide stronger evidence of the potential beneficial health effects of donkey milk, which could lead to new applications as an adjuvant in the treatment of cardiometabolic diseases, malnutrition, and aging.

Download Full-text

Synthesis and Activity of New Schiff Bases of Furocoumarin

Heterocyclic Communications ◽

10.1515/hc-2020-0115 ◽

2020 ◽

Vol 26 (1) ◽

pp. 176-184

Author(s):

Huijun Xie ◽

Chao Niu ◽

Zeyang Chao ◽

Nuramina Mamat ◽

Haji Akber Aisa

Keyword(s):

Animal Models ◽

Amphotericin B ◽

Molecular Mechanism ◽

Schiff Bases ◽

Positive Control ◽

Excellent Performance ◽

Activation Rate ◽

Antibacterial Spectrum ◽

Better Than

AbstractFurocoumarins, such as 8-MOP, are the most common medications used to relieve the symptoms of vitiligo clinically. Some furocoumarins also showed excellent performance in an anti-bacterial assay. This paper describes the synthesis of a series of novel Schiff bases (6a-6k), and their promotion in melanogenesis and anti-bacterial properties were studied in vitro.The pigment production of B16 cells and bacterial inhibition ring assay were applied for the bioactivity of 6a-6k. According to the results, a stronger promotion on pigment content was observed, when six compounds co-cultured with cells, compared with positive control (8-MOP). Significantly, compound 6k (237%) as the most active was found to increase the amount of melanin more than 1.7 times compared with 8-MOP activation rate (136%). All the compounds could moderately retard C. albicans growth. Interestingly, aldehyde 5, which possessed a broader antibacterial spectrum, showed the highest inhibition against C. albicans as well and much better than the positive control (Amphotericin B).Studies of 6k in animal models of vitiligo and related molecular mechanism are presently under way, with the aim of discovering an anti-vitiligo leading compound.

Download Full-text

Generalizing game-changing species across microbial communities

ISME Communications ◽

10.1038/s43705-021-00022-2 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Jie Deng ◽

Marco Tulio Angulo ◽

Serguei Saavedra

Keyword(s):

Microbial Communities ◽

Context Dependency ◽

Heuristic Rules ◽

Resident Species ◽

Experimental Systems ◽

Environment And Health ◽

Structuralist Theory ◽

Context Specific

AbstractMicrobes form multispecies communities that play essential roles in our environment and health. Not surprisingly, there is an increasing need for understanding if certain invader species will modify a given microbial community, producing either a desired or undesired change in the observed collection of resident species. However, the complex interactions that species can establish between each other and the diverse external factors underlying their dynamics have made constructing such understanding context-specific. Here we integrate tractable theoretical systems with tractable experimental systems to find general conditions under which non-resident species can change the collection of resident communities—game-changing species. We show that non-resident colonizers are more likely to be game-changers than transients, whereas game-changers are more likely to suppress than to promote resident species. Importantly, we find general heuristic rules for game-changers under controlled environments by integrating mutual invasibility theory with in vitro experimental systems, and general heuristic rules under changing environments by integrating structuralist theory with in vivo experimental systems. Despite the strong context-dependency of microbial communities, our work shows that under an appropriate integration of tractable theoretical and experimental systems, it is possible to unveil regularities that can then be potentially extended to understand the behavior of complex natural communities.

Download Full-text