scholarly journals Potential of electrospun cationic BSA fibers to guide osteogenic MSC differentiation via surface charge and fibrous topography

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Annamarija Raic ◽  
Frank Friedrich ◽  
Domenic Kratzer ◽  
Karen Bieback ◽  
Joerg Lahann ◽  
...  
Keyword(s):  
Bone Repair ◽  
Bone Cells ◽  
Bone Fractures ◽  
Adhesion Formation ◽  
Treatment Strategies ◽  
Fibrous Scaffold ◽  
New Treatment ◽  
The Stability ◽  
Msc Differentiation

AbstractLarge or complex bone fractures often need clinical treatments for sufficient bone repair. New treatment strategies have pursued the idea of using mesenchymal stromal cells (MSCs) in combination with osteoinductive materials to guide differentiation of MSCs into bone cells ensuring complete bone regeneration. To overcome the challenge of developing such materials, fundamental studies are needed to analyze and understand the MSC behavior on modified surfaces of applicable materials for bone healing. For this purpose, we developed a fibrous scaffold resembling the bone/bone marrow extracellular matrix (ECM) based on protein without addition of synthetic polymers. With this biomimetic in vitro model we identified the fibrous structure as well as the charge of the material to be responsible for its effects on MSC differentiation. Positive charge was introduced via cationization that additionally supported the stability of the scaffold in cell culture, and acted as nucleation point for mineralization during osteogenesis. Furthermore, we revealed enhanced focal adhesion formation and osteogenic differentiation of MSCs cultured on positively charged protein fibers. This pure protein-based and chemically modifiable, fibrous ECM model allows the investigation of MSC behavior on biomimetic materials to unfold new vistas how to direct cells’ differentiation for the development of new bone regenerating strategies.

scholarly journals “Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

2021 ◽  
Vol 22 (4) ◽  
pp. 1824
Author(s):  
Matthias Mietsch ◽  
Rabea Hinkel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Treatment Strategies ◽  
Cardiac Cells ◽  
Aging Effects ◽  
Beneficial Effects ◽  
Micro Rnas ◽  
New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

scholarly journals Tuning the network charge of biohybrid hydrogel matrices to modulate the release of SDF-1

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sebastian Kühn ◽  
Joanna Freyse ◽  
Passant Atallah ◽  
Jörg Rademann ◽  
Uwe Freudenberg ◽  
...  
Keyword(s):  
Bone Repair ◽  
Negative Charge ◽  
Polymer Networks ◽  
Signaling Molecules ◽  
Treatment Modalities ◽  
Precise Control ◽  
Integral Density ◽  
New Treatment ◽  
Two Parameters

Abstract The delivery of chemotactic signaling molecules via customized biomaterials can effectively guide the migration of cells to improve the regeneration of damaged or diseased tissues. Here, we present a novel biohybrid hydrogel system containing two different sulfated glycosaminoglycans (sGAG)/sGAG derivatives, namely either a mixture of short heparin polymers (Hep-Mal) or structurally defined nona-sulfated tetrahyaluronans (9s-HA4-SH), to precisely control the release of charged signaling molecules. The polymer networks are described in terms of their negative charge, i.e. the anionic sulfate groups on the saccharides, using two parameters, the integral density of negative charge and the local charge distribution (clustering) within the network. The modulation of both parameters was shown to govern the release characteristics of the chemotactic signaling molecule SDF-1 and allows for seamless transitions between burst and sustained release conditions as well as the precise control over the total amount of delivered protein. The obtained hydrogels with well-adjusted release profiles effectively promote MSC migration in vitro and emerge as promising candidates for new treatment modalities in the context of bone repair and wound healing.

scholarly journals Metabolic Modeling of Clostridium difficile Associated Dysbiosis of the Gut Microbiota

Processes ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Poonam Phalak ◽  
Michael Henson
Keyword(s):  
Clostridium Difficile ◽  
Treatment Strategies ◽  
E Coli ◽  
Biofilm Model ◽  
Commensal Species ◽  
Species Abundances ◽  
New Treatment ◽  
Biofilm Development

Recent in vitro experiments have demonstrated the ability of the pathogen Clostridium difficile and commensal gut bacteria to form biofilms on surfaces, and biofilm development in vivo is likely. Various studies have reported that 3%–15% of healthy adults are asymptomatically colonized with C. difficile, with commensal species providing resistance against C. difficile pathogenic colonization. C. difficile infection (CDI) is observed at a higher rate in immunocompromised patients previously treated with broad spectrum antibiotics that disrupt the commensal microbiota and reduce competition for available nutrients, resulting in imbalance among commensal species and dysbiosis conducive to C. difficile propagation. To investigate the metabolic interactions of C. difficile with commensal species from the three dominant phyla in the human gut, we developed a multispecies biofilm model by combining genome-scale metabolic reconstructions of C. difficile, Bacteroides thetaiotaomicron from the phylum Bacteroidetes, Faecalibacterium prausnitzii from the phylum Firmicutes, and Escherichia coli from the phylum Proteobacteria. The biofilm model was used to identify gut nutrient conditions that resulted in C. difficile-associated dysbiosis characterized by large increases in C. difficile and E. coli abundances and large decreases in F. prausnitzii abundance. We tuned the model to produce species abundances and short-chain fatty acid levels consistent with available data for healthy individuals. The model predicted that experimentally-observed host-microbiota perturbations resulting in decreased carbohydrate/increased amino acid levels and/or increased primary bile acid levels would induce large increases in C. difficile abundance and decreases in F. prausnitzii abundance. By adding the experimentally-observed perturbation of increased host nitrate secretion, the model also was able to predict increased E. coli abundance associated with C. difficile dysbiosis. In addition to rationalizing known connections between nutrient levels and disease progression, the model generated hypotheses for future testing and has the capability to support the development of new treatment strategies for C. difficile gut infections.

Antiparasitic effects of ethanolic extracts of Piper arboreum and Jatropha gossypiifolia leaves on cercariae and adult worms of Schistosoma mansoni

Parasitology ◽  
2020 ◽  
Vol 147 (14) ◽  
pp. 1689-1699
Author(s):  
Rayan Rubens da Silva Alves ◽  
João Gustavo Mendes Rodrigues ◽  
Andrea Teles-Reis ◽  
Ranielly Araújo Nogueira ◽  
Irlla Correia Lima Licá ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
High Performance ◽  
Treatment Strategies ◽  
Biologically Active ◽  
Internal Damage ◽  
Chemical Screening ◽  
Ethanolic Extracts ◽  
New Treatment ◽  
Jatropha Gossypiifolia

AbstractNew treatment strategies for schistosomiasis should be evaluated, since resistant strains to the only available drug, Praziquantel, have already been described. Thus, we demonstrated antiparasitic effects of ethanolic extracts of Jatropha gossypiifolia and Piper arboreum on cercariae and adult worms of Schistosoma mansoni. The bioassays were performed at 0–10 000 μg mL−1 concentration for 0–72 h. Adult worms were stained with carmine to assess external and internal damage. The chemical screening was performed using high-performance liquid chromatography. P. arboreum displayed the best cercaricidal effect, with a 100% reduction in viability in just 60 min. The extract of J. gossypiifolia was more effective against adult worms, with 100% viability reduction of male and female worms after 12 and 24 h, respectively. P. arboreum and J. gossypiifolia were equally effective in inhibiting the oviposition of S. mansoni (93% reduction) and causing damage to internal and external structures in adult worms. Flavonoids were identified in both the extracts and phenolic compounds and amides only in P. arboreum. Thus, for the first time, it was proven that ethanolic extracts of P. arboreum and J. gossypiifolia leaves are biologically active against cercariae and adult worms of S. mansoni in vitro.

Proteomic analysis of extracellular vesicles from medullospheres reveals a role for iron in the cancer progression of medulloblastoma

2019 ◽  
pp. 1-12
Author(s):  
Maja Larsen ◽  
Matthias Kuhlmann Kuhlmann ◽  
Michael Hvam ◽  
Kenneth Howard
Keyword(s):  
Cell Lines ◽  
Cancer Progression ◽  
Early Stage ◽  
Cell Communication ◽  
Treatment Strategies ◽  
Iron Chelators ◽  
High Morbidity ◽  
New Treatment ◽  
Stem Cell Populations

Background: Medulloblastoma (MB) is the most common malignant childhood brain tumor with the propensity todisseminate at an early stage, and is associated with high morbidity. New treatment strategies are needed toimprove cure rates and to reduce life-long cognitive and functional deficits associated with current therapies.Extracellular Vesicles (EVs) are important players in cell-to-cell communication in health and diseases. A clearerunderstanding of cell-to-cell communication in tumors can be achieved by studying EV secretion inmedullospheres. This can reveal subtle modifications induced by the passage from adherent to non-adherentgrowth, as spheres may account for the adaptation of tumor cells to the mutated environment.Methods: Formation of medullospheres from MB cell lines stabilized in adherent conditions was obtained throughculture conditioning based on low attachment flasks and specialized medium. EVs collected by ultracentrifugation,in adherent conditions and as spheres, were subjected to electron microscopy, NanoSight measurements andproteomics.Results: Interestingly, iron carrier proteins were only found in EVs shed by CSC-enriched tumor cell population ofspheres. We used iron chelators when culturing MB cell lines as spheres. Iron chelators induced a decrease innumber/size of spheres and in stem cell populations able to initiate in vitro spheres formation.Conclusions: This work suggests a not yet identified role of iron metabolism in MB progression and invasion andopens the possibility to use chelators as adjuvants in anti-tumoral chemotherapy.

scholarly journals Sensory nerves directly promote osteoclastogenesis by secreting Cyp40

2021 ◽  
Author(s):  
Guo-Xian Pei ◽  
Liu Yang ◽  
Junqin Li ◽  
Bin Liu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Repair ◽  
Bone Cells ◽  
Critical Role ◽  
Sensory Nerve ◽  
Sensory Nerves ◽  
Blue Staining ◽  
Double Labeling ◽  
Sensory Hypersensitivity

Abstract BackgroundGiven the afferent functions, sensors have been found exerting efferent influences and directly alter organ physiology. Sensory nerves have been found critical in osteoclasts and bone resorption. However, the direct evidence of whether sensory nerve efferent influences osteoclast, remains lacking. MethodsWe treated mice with resiniferatoxin (RTX) or complete Freund’s adjuvant (CFA) to induce sensory hypersensitivity. Bone histomorphometry including micro-ct, three-point bending assay, von kossa staining, calcein double labeling, toluidine blue staining, and trap staining were performed to monitor bone quality and bone cells. Multiple virus vectors were applied to trace signals between sensory nerves and osteoclasts. Sensory neurons (SN) and osteoclasts were cocultured to study the effects and mechanisms of the sensory nerves on osteoclasts in vitro. Isobaric tag for relative and absolute quantitation (iTRAQ) was used to identify secreted proteins in the sensory nerve. ResultsHere, we found sensory hypersensitivity significantly increased osteoclast bone resorption; SN directly promote osteoclastogenesis in vitro; and abundant sensory efferent signals transported into osteoclasts. Then our screening identified a novel neuropeptide Peptidyl-prolyl cis-trans isomerase D (Cyp40), is the reverse signal from the sensory nerve and plays a critical role for osteoclastogenesis, via aryl hydrocarbon receptor (AhR)-Ras/Raf-pErk-NFATc1 pathway. The efferent signals from sensory nerves tend to involves in the rapid feedback process: vast majority of sensory efferent signals (87.28%) present in fast-twitch myofibers. ConclusionThis study revealed a novel mechanism of sensory nerves on osteoclasts: the direct promotion of osteoclastogenesis by the Cyp40. This mechanism may represent a direct, and quick response of sensory nerves to the changes in bone. Targeting the Cyp40 could therefore be a strategy to promote bone repair at the early stage of bone injury.

scholarly journals Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Li ◽  
Shi Xu ◽  
Naixiong Peng ◽  
Zejian Zhang ◽  
Hua He ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Clear Cell ◽  
Tnm Classification ◽  
Treatment Strategies ◽  
Tumor Formation ◽  
Cell Renal Cell Carcinoma ◽  
Functional Studies ◽  
New Treatment

Clear cell renal cell carcinoma (ccRCC) is the most aggressive urologic tumor, and its incidence and diagonosis have been continuously increasing. Identifying novel molecular biomarker for inhibiting the progression of ccRCC will facilitate developing new treatment strategies. Although methyltransferase-like 7B (METTL7B) was identified as a Golgi-associated methyltransferase, the function and mechanism of METTL7B in ccRCC development and progression has not been explored. METTL7B expression were significantly upregulated in ccRCC tissues (n = 60), which significantly associated with TNM classification, tumor size, lymph node metastasis, and poor prognosis for ccRCC patients. Functional studies showed downregulation of METTL7B inhibited cell proliferation, migration in vitro, and xenograft tumor formation in vivo. In addition, METTL7B knockdown promoted cell cycle arrest at G0/G1phase and induced cellular apoptosis. Taken together, downregulation of METTL7B inhibits ccRCC cell proliferation and tumorigenesis in vivo and in vitro. These findings provide a rationale for using METTL7B as a potential therapeutic target in ccRCC patients.

scholarly journals MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Calvin VanOpstall ◽  
Srikanth Perike ◽  
Hannah Brechka ◽  
Marc Gillard ◽  
Sophia Lamperis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Treatment Strategies ◽  
Human Prostate ◽  
Protein Activity ◽  
Prostate Epithelial Cells ◽  
New Treatment ◽  
Hox Protein

The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.

scholarly journals Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
April C. Joice ◽  
Sihyung Yang ◽  
Abdelbasset A. Farahat ◽  
Heidi Meeds ◽  
Mei Feng ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Treatment Strategies ◽  
Parasite Burden ◽  
Pharmacokinetic Analysis ◽  
Content Type ◽  
New Treatment ◽  
Almost All

ABSTRACT Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

scholarly journals In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

2010 ◽  
Vol 54 (11) ◽  
pp. 4596-4604 ◽  
Author(s):  
Urs Duthaler ◽  
Thomas A. Smith ◽  
Jennifer Keiser
Keyword(s):  
Negative Binomial ◽  
Fasciola Hepatica ◽  
Single Agent ◽  
Treatment Strategies ◽  
Drug Combinations ◽  
Antagonistic Effects ◽  
Experimental Drugs ◽  
New Treatment

ABSTRACT Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P = 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.

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