scholarly journals Delivery of Bioactive Compounds to Improve Skin Cell Responses on Microfabricated Electrospun Microenvironments

2021 ◽  
Vol 8 (8) ◽  
pp. 105
Author(s):  
David H. Ramos-Rodriguez ◽  
Sheila MacNeil ◽  
Frederik Claeyssens ◽  
Ilida Ortega Asencio
Keyword(s):  
Bioactive Compounds ◽  
Cell Activity ◽  
Aloe Vera ◽  
Cell Microenvironment ◽  
Cell Responses ◽  
Skin Cell ◽  
Complex Wound ◽  
17Β Estradiol ◽  
Bioactive Agents ◽  
Dose Dependent

The introduction of microtopographies within biomaterial devices is a promising approach that allows one to replicate to a degree the complex native environment in which human cells reside. Previously, our group showed that by combining electrospun fibers and additive manufacturing it is possible to replicate to an extent the stem cell microenvironment (rete ridges) located between the epidermal and dermal layers. Our group has also explored the use of novel proangiogenic compounds to improve the vascularization of skin constructs. Here, we combine our previous approaches to fabricate innovative polycaprolactone fibrous microtopographical scaffolds loaded with bioactive compounds (2-deoxy-D-ribose, 17β-estradiol, and aloe vera). Metabolic activity assay showed that microstructured scaffolds can be used to deliver bioactive agents and that the chemical relation between the working compound and the electrospinning solution is critical to replicate as much as possible the targeted morphologies. We also reported that human skin cell lines have a dose-dependent response to the bioactive compounds and that their inclusion has the potential to improve cell activity, induce blood vessel formation and alter the expression of relevant epithelial markers (collagen IV and integrin β1). In summary, we have developed fibrous matrixes containing synthetic rete-ridge-like structures that can deliver key bioactive compounds that can enhance skin regeneration and ultimately aid in the development of a complex wound healing device.

scholarly journals A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

2021 ◽  
Vol 22 (6) ◽  
pp. 2915
Author(s):  
Manuela Cipolletti ◽  
Stefania Bartoloni ◽  
Claudia Busonero ◽  
Martina Parente ◽  
Stefano Leone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bioactive Compounds ◽  
Estrogenic Activity ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Cellular Models ◽  
Cancer Models ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
Anti Fungal

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

Screening of the Prime bioactive compounds from Aloe vera as potential anti-proliferative agents targeting DNA

2021 ◽  
pp. 105052
Author(s):  
Ranabir Majumder ◽  
Chandan Kanta Das ◽  
Indranil Banerjee ◽  
Bikash Chandra Jena ◽  
Anik Mandal ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Aloe Vera

Time- and dose-dependent differential upregulation of three genes by 17β-estradiol in endothelial cells

2002 ◽  
Vol 92 (3) ◽  
pp. 1064-1073 ◽  
Author(s):  
Amparo C. Villablanca ◽  
Kristine A. Lewis ◽  
John C. Rutledge
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Time Course ◽  
Plasminogen Activator Inhibitor ◽  
Hormone Treatment ◽  
Plasminogen Activator Inhibitor 1 ◽  
Similar Time ◽  
Differential Display Analysis ◽  
17Β Estradiol ◽  
Dose Dependent

The purpose of this study was to identify genetic targets in the vasculature for estrogen by profiling genes expressed in female human aortic endothelial cells exposed to various doses of 17β-estradiol at differing concentrations and for differing periods of time. Our approach employed a RT-PCR-based cloning strategy of DNA differential display analysis, with differential expression verified by semiquantitative PCR performed with gene-specific primers. A significant increase in mRNA expression in response to 17β-estradiol was observed for the following three genes: aldose reductase (3.4-fold), caspase homologue-α protein (4.2-fold), and plasminogen activator inhibitor-1 intron e (2.3-fold). For all three upregulated genes, estradiol-induced upregulation occurred with a similar time course and temporally clustered to the first 24 h after hormone treatment. In addition, the effect of estradiol dose on gene expression was consistent and occurred at physiological concentrations. Our results describe previously uncharacterized estradiol-sensitive time- and dose-dependent regulation of genes with potential importance to vascular function in human endothelial cells.

scholarly journals An Adenovirus-Based Influenza Tablet Vaccine Induces Dose-Dependent T-Cell Responses

2015 ◽  
Vol 2 (suppl_1) ◽  
Author(s):  
Wendy Peters ◽  
Jennifer Brandl ◽  
Leesun Kim ◽  
Sean Tucker
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cell Responses ◽  
Dose Dependent

scholarly journals LARVICIDAL ACTIVITY OFTITHONIA DIVERSIFOLIALEAF EXTRACT ONPERI-URBAN MOSQUITO LARVEA INABAKALIKI; ALTERNATIVE TO INSECTICIDE DEVELOPMENT.

2015 ◽  
Vol 7 (1) ◽  
pp. 1225-1228
Author(s):  
UHUO CA ◽  
OKEREKE CN ◽  
NWELE ED ◽  
OGBONNA S.U ◽  
NWANCHOR K.C ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Adverse Effects ◽  
Bioactive Compounds ◽  
Larvicidal Activity ◽  
Urban Areas ◽  
Insect Pests ◽  
Anopheles Mosquito ◽  
Mosquito Population ◽  
Mosquito Larvae ◽  
Dose Dependent

The bioassay activitiesofTithonia diversifolia leave extract was conducted on the larvae of Anopheles mosquito collected at peri-urban areas of Abakaliki Ebonyi State, using the concentrations of the extract in dilutions at 50/100ml, 40/100ml, 30/100ml and 20/100ml introduced with 10 Anopheles mosquito larvae each in four replicates and allowed for 3hrs. Mean mortality rate of the larvae were observed after the first hour, thus 30%, 10%, 05% and 0% respectively while in the 2nd hour were 60%, 40%, 20% and 10% and in the 3rd hour were 80%, 60%, 50% & 30% respectively. The result thus revealed that the treatment is dose dependent and that the studied specie has some bioactive compounds that can be exploited for insect pests control hence observed to be sensitive in anopheles mosquito larvae. Therefore Tithonia diversifolialeaf extract could be used as a bioassay for the control of mosquito due to its active properties as this has exhibited adverse effects on the larvae thereby reducing the mosquito population and thus reducing the malarious infection associated with the bite of mosquito.

scholarly journals 846 Pre-clinical validation of a FLT3L-fusion protein for dendritic cell expansion and anti-tumor efficacy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A887-A887
Author(s):  
Michelle Kuhne ◽  
Hamlet Chu ◽  
Sarah Ng ◽  
Christopher Clarke ◽  
Brian Carr ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Single Agent ◽  
Tumor Growth Inhibition ◽  
Cell Responses ◽  
Dose Dependent ◽  
Cell Death Protein

BackgroundThe ligand for the receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) plays an importantrole in hematopoiesis. FLT3 signaling is required for the differentiation andexpansion of dendritic cells. In the context of cancer immunity, the conventional dendritic cellsubtype 1 (cDC1) are required for the generation of tumor-specific T cell responses in mousepreclinical models. In human tumors cDC1 are often underrepresented in thetumor microenvironment, supporting the hypothesis that therapeutically increasing their number via FLT3 pathway stimulation has the potential to promote T cell-mediated anti-tumor efficacy.MethodsGS-3583 is a fusion protein composed of the extracellular domain (ECD) of human FLT3 ligand(FLT3L) combined with a modified fragment crystallizable (Fc) region of human IgG4. GS-3583was designed to induce cDC1 expansion and subsequently promote tumor-reactive T cell priming, activation and recruitment into the tumor microenvironment. To evaluate the therapeutic efficacy of FLT3 stimulation in vivo, a mouse surrogate mGS-3583was designed using the ECD of mouse FLT3L fused to an engineered mouse IgG2a Fc withattenuated binding to mouse FcgRs.Results mGS-3583 bound to recombinant mouse FLT3 with an estimated affinity of 15 nM, and to mouse FLT3-expressing cells with an EC50 of 0.15 nM. In vivo, mGS-3583 showed single agent dose-dependent tumor growth inhibition (TGI) in tumors that correlated with peripheral and intratumoral cDC1 expansion. In tumors with no initial immune infiltration, mGS-3583 led to an influx of T cells into the tumors. In addition to single agent efficacy, mGS-3583 combined effectively with programmed cell death protein (ligand)-1 (PD(L)-1) pathway blockade.ConclusionsIn vivo expansion of dendritic cells can convert uninflamed (cold) tumors to immunologically active (hot) tumors and initiate productive anti-tumor immune responses. These findings support the development GS-3583 as a promising candidate for cancer immunotherapy.

scholarly journals A Perspective on Withania somnifera Modulating Antitumor Immunity in Targeting Prostate Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Seema Dubey ◽  
Manohar Singh ◽  
Ariel Nelson ◽  
Dev Karan
Keyword(s):  
Prostate Cancer ◽  
Medicinal Plants ◽  
Bioactive Compounds ◽  
Antitumor Immunity ◽  
Withania Somnifera ◽  
Early Stage ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity

Medicinal plants serve as a lead source of bioactive compounds and have been an integral part of day-to-day life in treating various disease conditions since ancient times. Withaferin A (WFA), a bioactive ingredient of Withania somnifera, has been used for health and medicinal purposes for its adaptogenic, anti-inflammatory, and anticancer properties long before the published literature came into existence. Nearly 25% of pharmaceutical drugs are derived from medicinal plants, classified as dietary supplements. The bioactive compounds in these supplements may serve as chemotherapeutic substances competent to inhibit or reverse the process of carcinogenesis. The role of WFA is appreciated to polarize tumor-suppressive Th1-type immune response inducing natural killer cell activity and may provide an opportunity to manipulate the tumor microenvironment at an early stage to inhibit tumor progression. This article signifies the cumulative information about the role of WFA in modulating antitumor immunity and its potential in targeting prostate cancer.

scholarly journals Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness

2021 ◽  
Vol 12 ◽  
Author(s):  
Laryssa C. Manigat ◽  
Mitchell E. Granade ◽  
Suchet Taori ◽  
Charlotte Anne Miller ◽  
Luke R. Vass ◽  
...  
Keyword(s):  
Wound Healing ◽  
T Cell ◽  
Healing Process ◽  
Cell Activity ◽  
Regulatory Function ◽  
Burned Area ◽  
Wound Healing Process ◽  
Wound Model ◽  
Complex Wound

The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.

scholarly journals Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 (22) ◽  
pp. 12167
Author(s):  
Somayeh S. Tarighat ◽  
Fei Fei ◽  
Eun Ji Joo ◽  
Hisham Abdel-Azim ◽  
Lu Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
High Specificity ◽  
Leukemia Cells ◽  
Cell Precursor ◽  
Cell Responses ◽  
Galectin 3 ◽  
Dose Dependent

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

scholarly journals Prospects of Aloe vera and its Bioactive Compounds in Diabetes: Critical Review

2021 ◽  
Author(s):  
Mukesh Kumar Sharma ◽  
Jagat Chauhan ◽  
Mohan Kumar ◽  
Chetan Kumar Joshi ◽  
Sandeep Sharma ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Aloe Vera ◽  
Underlying Mechanism ◽  
Biologically Active ◽  
Effective Control ◽  
Public Health Issue ◽  
Herbal Products ◽  
Daily Diet ◽  
Significant Public Health ◽  
Control Of Diabetes

Diabetes is a significant public health issue. The global diabetes epidemic has had a tremendous impact on India, and the disease burden has increased dramatically. Diabetes is quickly increasing in prevalence, especially in Indian cities, according to data. Therefore, an ideal drug is sought that has better safety and tolerability and the most effective control of diabetes. Many effective medications come from plant sources. Natural products like onion and garlic can effectively control diabetes. In this review, we should pay attention to Aloe vera and its bioactive compounds, that with the development of traditional medicine, Aloe vera can be used to treat various diseases. Some reports have questioned the safety and efficacy of Aloe vera or its compounds, especially at different doses, and some studies have shown no side effects. In this review we also focus on benefits on human health so that Aloe vera is part of the daily diet in many countries and appears to be non-toxic, it is necessary to investigate whether aloe vera dietary supplement can be a beneficial preventive or nutritional mitigation strategy to reduce the effects of diabetes. This review focuses on Aloe vera and its biologically active compounds that play a role in the treatment or prevention of this morbid disease: diabetes, including its underlying mechanism of blood sugar lowering properties, and herbal products that have been marketed for the treatment of diabetes or the therapeutic effect of diabetes.

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