Efficacy of recombinant human epidermal growth factor in pressure injury healing: evidence from Chinese randomized controlled trials.

OBJECTIVE: To evaluate the efficacy of recombinant human epidermal growth factor (rhEGF) in healing pressure injuries (PIs). METHODS: A meta-analysis was conducted of randomized controlled trials (RCTs) involving rhEGF in the treatment of PIs that were identified in PubMed, Web of Science, the Cochrane Library, and China National Knowledge Infrastructure (CNKI). The population, intervention, comparison, outcomes, study design (PICOS) strategy was applied to determine analysis eligibility. The Cochrane risk of bias tool was used, and statistical analysis, including sensitivity analysis, was performed of 3 outcomes indicators: the primary outcome was total efficacy of rhEGF in treating PIs, and the secondary outcomes were the proportion of complete healing and the time to complete healing. Total efficacy refers to the proportion of cases that have been cured, obviously effective, or effective. Complete healing refers to cases where the wound has healed, scabbed, and the scab has sloughed off. RESULTS: Sixteen RCTs were included, comprising a total of 1,206 patients. Study and control group size varied by outcomes. The total effective healing rate in rhEGF group was 97.18%, which was significantly higher than 83.38% in control group (OR: 5.69, [95% CI: 3.61, 8.97], z=7.49, P < .001). The proportion of complete healing in the rhEGF group was 73.30%, which was higher than 39.52% in control group (OR: 3.88, [95% CI: 3.01, 5.01], z=10.39, P < .001). Furthermore, the healing time using rhEGF was shorter (SMD: -2.14 days, [95% CI: -2.60, -1.67], z=9.07, P < .001). Sensitivity analyses indicated that the results were robust. CONCLUSIONS: The meta-analysis indicated that rhEGF was effective in healing PIs with few negative effects. Further research beyond Chinese populations involving larger studies and studies that distinguish between results found in using rhEGF alone or in combination are recommended.

Activation of epidermal growth factor receptors in triple-negative breast cancer cells by morphine; analysis through Raman spectroscopy and machine learning.

Triple negative breast cancer (TNBC) is a very aggressive form of breast cancer, and the analgesic drug morphine has been shown to promote the proliferation of TNBC cells. This article investigates whether morphine causes activation of epidermal growth factor receptors (EGFR), the roles of µ-opioid and EGFR receptors on TNBC cell proliferation and migration. While examining the changes with molecular techniques, we also aimed to investigate the analysis ability of Raman spectroscopy and machine learning-based approach. Effects of morphine on the proliferation and migration of MDA.MB.231 cells were evaluated by MTT and scratch wound-healing tests, respectively. Morphine-induced phosphorylation of the EGFR was analyzed by western blotting in the presence and absence of µ-receptor antagonist naltrexone and the EGFR-tyrosine kinase inhibitor gefitinib. Morphine-induced EGFR phosphorylation and cell migration were significantly inhibited by pretreatments with both naltrexone and gefitinib; however, morphine-increased cell proliferation was inhibited only by naltrexone. While morphine-induced changes were observed in the Raman scatterings of the cells, the inhibitory effect of naltrexone was analyzed with similarity to the control group. Principal component analysis (PCA) of the Raman confirmed the epidermal growth factor (EGF)-like effect of morphine and was inhibited by naltrexone and partly by gefitinib pretreatments. Our in vitro results suggest that combining morphine with an EGFR inhibitor or a peripherally acting opioidergic receptor antagonist may be a good strategy for pain relief without triggering cancer proliferation and migration in TNBC patients. In addition, our results demonstrated the feasibility of the Raman spectroscopy and machine learning-based approach as an effective method to investigate the effects of agents in cancer cells without the need for complex and time-consuming sample preparation. The support vector machine (SVM) with linear kernel automatically classified the effects of drugs on cancer cells with ∼95% accuracy.

Regulation of STAT1 and STAT4 Expression by Growth Factor and Interferon Supplementation in Sjögren's Syndrome Cell Culture Models.

Our goal was to investigate the effects of epidermal growth factor (EGF) and interferons (IFNs) on signal transducer and activator of transcription STAT1 and STAT4 mRNA and active phosphorylated protein expression in Sjögren's syndrome cell culture models. iSGECs (immortalized salivary gland epithelial cells) and A253 cells were treated with EGF, IFN-alpha, -beta, -gamma, or mitogen-activated protein kinase p38 alpha (p38-MAPK) inhibitor for 0-24-48-72 h. STAT1 and STAT4 mRNA expression was quantified by qRT-PCR. Untreated and treated cells were compared using the delta-delta-CT method based on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) normalized relative fold changes. phospho-tyrosine-701-STAT1 and phospho-serine-721-STAT4 were detected by Western blot analysis. STAT4 mRNA expression decreased 48 h after EGF treatment in A253 cells, immortalized salivary gland epithelial cells iSGECs nSS2 (sicca patient origin), and iSGECs pSS1 (anti-SSA negative Sjögren's Syndrome patient origin). EGF and p38-MAPK inhibitor decreased A253 STAT4 mRNA levels. EGF combined with IFN-gamma increased phospho-STAT4 and phospho-STAT1 after 72 h in all cell lines, suggesting additive effects for phospho-STAT4 and a major effect from IFN-gamma for phospho-STAT1. pSS1 and nSS2 cells responded differently to type I and type II interferons, confirming unique functional characteristics between iSGEC cell lines. EGF/Interferon related pathways might be targeted to regulate STAT1 and STAT4 expression in salivary gland epithelial cells. Further investigation is required learn how to better target the Janus kinases/signal transducer and activator of transcription proteins (JAK/STAT) pathway-mediated inflammatory response in Sjögren's syndrome.

Growth factor-induced activation of MSK2 leads to phosphorylation of H3K9me2S10 and corresponding changes in gene expression.

Extracellular signals are transmitted through kinase cascades to modulate gene expression, but it remains unclear how epigenetic changes regulate this response. Here, we provide evidence that growth factor-stimulated changes in the transcript levels of many responsive genes are accompanied by increases in histone phosphorylation levels, specifically at histone H3 serine-10 when the adjacent lysine-9 is dimethylated (H3K9me2S10). Imaging and proteomic approaches show that epidermal growth factor (EGF) stimulation results in H3K9me2S10 phosphorylation, which occurs in genomic regions enriched for regulatory enhancers of EGF-responsive genes. We also demonstrate that the EGF-induced increase in H3K9me2S10ph is dependent on the nuclear kinase MSK2, and this subset of EGF-induced genes is dependent on MSK2 for transcription. Together, our work indicates that growth factor-induced changes in chromatin state can mediate the activation of downstream genes.

Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7.

FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. FBXW7 mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

Epidermal Growth Factor Suppresses the Development of GABAergic Neurons Via the Modulation of Perineuronal Net Formation in the Neocortex of Developing Rodent Brains.

Previously, we reported that epidermal growth factor (EGF) suppresses GABAergic neuronal development in the rodent cortex. Parvalbumin-positive GABAergic neurons (PV neurons) have a unique extracellular structure, perineuronal nets (PNNs). PNNs are formed during the development of PV neurons and are mainly formed from chondroitin sulfate (CS) proteoglycans (CSPGs). We examined the effect of EGF on CSPG production and PNN formation as a potential molecular mechanism for the inhibition of inhibiting GABAergic neuronal development by EGF. In EGF-overexpressing transgenic (EGF-Tg) mice, the number of PNN-positive PV neurons was decreased in the cortex compared with that in wild-type mice, as in our previous report. The amount of CS and neurocan was also lower in the cortex of EGF-Tg mice, with a similar decrease observed in EGF-treated cultured cortical neurons. PD153035, an EGF receptor (ErbB1) kinase inhibitor, prevented those mentioned above excess EGF-induced reduction in PNN. We explored the molecular mechanism underlying the effect of EGF on PNNs using fluorescent substrates for matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). EGF increased the enzyme activity of MMPs and ADAMs in cultured neurons. These enzyme activities were also increased in the EGF-Tg mice cortex. GM6001, a broad inhibitor of MMPs and ADAMs, also blocked EGF-induced PNN reductions. Therefore, EGF/EGF receptor signals may regulate PNN formation in the developing cortex.

Hierarchically Assembled Nanofiber Scaffolds with Dual Growth Factor Gradients Promote Skin Wound Healing Through Rapid Cell Recruitment.

To address current challenges in effectively treating large skin defects caused by trauma in clinical medicine, the fabrication, and evaluation of a novel radially aligned nanofiber scaffold (RAS) with dual growth factor gradients is presented. These aligned nanofibers and the scaffold's spatial design provide many all-around "highways" for cell migration from the edge of the wound to the center area. Besides, the chemotaxis induced by two growth factor gradients further promotes cell migration. Incorporating epidermal growth factor (EGF) aids in the proliferation and differentiation of basal layer cells in the epidermis, augmenting the scaffold's ability to promote epidermal regeneration. Concurrently, the scaffold-bound vascular endothelial growth factor (VEGF) recruits vascular endothelial cells at the wound's center, resulting in angiogenesis and improving blood supply and nutrient delivery, which is critical for granulation tissue regeneration. The RAS+EGF+VEGF group demonstrates superior performance in wound immune regulation, wound closure, hair follicle regeneration, and ECM deposition and remodeling compared to other groups. This study highlights the promising potential of hierarchically assembled nanofiber scaffolds with dual growth factor gradients for wound repair and tissue regeneration applications.

Cholesterol suppresses spontaneous activation of EGFR-mediated signal transduction.

Epidermal growth factor receptor (EGFR)-mediated signal transduction controls cell growth and proliferation. The signaling pathway is regulated so that it is activated only by external EGF stimuli, but the mechanisms that prevent EGF-independent spontaneous activation of EGFR-mediated signaling are unknown. Here we report cholesterol depletion activates EGFR-mediated signaling without EGF. We applied automated single-molecule imaging to EGFR and characterized the lateral diffusion and cluster formation on cholesterol-depleted and cholesterol-supplemented membranes. In cells in which cholesterol was depleted by methyl-ß-cyclodextrin (MßCD) treatment, EGFR exhibited a reduction in lateral diffusion, an acceleration of cluster formation, and autophosphorylation without EGF. Concurrently, extracellular signal-regulated kinase (ERK), which is regulated by EGFR-mediated signaling, exhibited phosphorylation and nuclear translocation without EGF. These cholesterol depletion-induced changes were similar, albeit less efficient, to those that occurred with EGF stimulation in normal cells without MßCD, indicating the spontaneous activation of EGFR signaling. The exogenous supplementation of cholesterol suppressed the MßCD-induced spontaneous activation of EGFR and ERK nuclear translocation. Single-molecule imaging of EGFR in a large number of cells revealed cell-to-cell heterogeneity, with a sub-population showing a high ability for spontaneous activation. These results provide evidence that EGFR-mediated signaling is properly regulated by cholesterol metabolism to prevent uncontrolled spontaneous activation.

TCM formula for trauma treatment screening and its role of promoting infectious wound coalescence investigating.

In pet clinics, the number of cases using trauma drugs accounts for >10% of the total number of cases, and most wounds are healing by second intention. The prolongation of wound healing time causes inconvenience and burden to pets and pet owners. Therefore, how to reduce wound healing time and achieve maximum recovery of tissue function and aesthetics is one of the focuses of veterinary clinical practice. Wound suppuration caused by Staphylococcus aureus and Pseudomonas aeruginosa is the main cause of delaying wound healing. Clinically, available antimicrobial treatments are almost exhausted due to the production of large numbers of resistant bacteria. At present, there are no bacteria resistant to traditional Chinese medicine (TCM), which makes TCM have the potential to become an effective drug for the treatment of bacterial infections, so the use of TCM in the treatment of traumatic infections has broad prospects. Based on the characteristics of infection syndrome, three different prescriptions were formulated in our laboratory, and the most effective prescription and dosage form was screened and named Lianrong Healing Cream (LRHC). The results showed that LRHC regulated the expression of fibroblast growth factor-2 (FGF-2), epidermal growth factor-1 (EGF-1), transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor-1 (VEGF-1) genes in wound tissues and fibroblasts, thereby accelerating wound healing and repairing wound appearance and function. The results of this study may be help to develop TCM formulation for traumatic infections.

Searching for EGF Fragments Recreating the Outer Sphere of the Growth Factor Involved in Receptor Interactions.

The aims of this study were to determine whether it is possible to use peptide microarrays obtained using the SPOT technique (immobilized on cellulose) and specific polyclonal antibodies to select fragments that reconstruct the outer sphere of proteins and to ascertain whether the selected peptide fragments can be useful in the study of their protein-protein and/or peptide-protein interactions. Using this approach, epidermal growth factor (EGF) fragments responsible for the interaction with the EGF receptor were searched. A library of EGF fragments immobilized on cellulose was obtained using triazine condensing reagents. Experiments on the interactions with EGFR confirmed the high affinity of the selected peptide fragments. Biological tests on cells showed the lack of cytotoxicity of the EGF fragments. Selected EGF fragments can be used in various areas of medicine.

Collecting duct water permeability inhibition by EGF is associated with decreased cAMP, PKA activity, and AQP2 phosphorylation at Ser269.

Prior studies showed that epidermal growth factor (EGF) inhibits vasopressin-stimulated osmotic water permeability in the renal collecting duct. Here, we investigated the underlying mechanism. Using isolated perfused rat inner medullary collecting ducts (IMCDs), we found that the addition of EGF to the peritubular bath significantly decreased 1-deamino-8-d-arginine vasopressin (dDAVP)-stimulated water permeability, confirming prior observations. The inhibitory effect of EGF on water permeability was associated with a reduction in intracellular cAMP levels and protein kinase A (PKA) activity. Using phospho-specific antibodies and immunoblotting in IMCD suspensions, we showed that EGF significantly reduces phosphorylation of AQP2 at Ser264 and Ser269. This effect was absent when 8-cpt-cAMP was used to induce AQP2 phosphorylation, suggesting that EGF's inhibitory effect was at a pre-cAMP step. Immunofluorescence labeling of microdissected IMCDs showed that EGF significantly reduced apical AQP2 abundance in the presence of dDAVP. To address what protein kinase might be responsible for Ser269 phosphorylation, we used Bayesian analysis to integrate multiple-omic datasets. Thirteen top-ranked protein kinases were subsequently tested by in vitro phosphorylation experiments for their ability to phosphorylate AQP2 peptides using a mass spectrometry readout. The results show that the PKA catalytic-α subunit increased phosphorylation at Ser256, Ser264, and Ser269. None of the other kinases tested phosphorylated Ser269. In addition, H-89 and PKI strongly inhibited dDAVP-stimulated AQP2 phosphorylation at Ser269. These results indicate that EGF decreases the water permeability of the IMCD by inhibiting cAMP production, thereby inhibiting PKA and decreasing AQP2 phosphorylation at Ser269, a site previously shown to regulate AQP2 endocytosis.NEW & NOTEWORTHY The authors used native rat collecting ducts to show that inhibition of vasopressin-stimulated water permeability by epidermal growth factor involves a reduction of aquaporin 2 phosphorylation at Ser269, a consequence of reduced cAMP production and PKA activity.

The optimized priming effect of FGF-1 and FGF-2 enhances preadipocyte lineage commitment in human adipose-derived mesenchymal stem cells.

The cell-assisted lipotransfer technique, integrating adipose-derived mesenchymal stem cells (ADMSCs), has transformed lipofilling, enhancing fat graft viability. However, the multipotent nature of ADMSCs poses challenges. To improve safety and graft vitality and to reduce unwanted lineage differentiation, this study refines the methodology by priming ADMSCs into preadipocytes-unipotent, self-renewing cells. We explored the impact of fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF), either alone or in combination, on primary human ADMSCs during the proliferative phase. FGF-2 emerged as a robust stimulator of cell proliferation, preserving stemness markers, especially when combined with EGF. Conversely, FGF-1, while not significantly affecting cell growth, influenced cell morphology, transitioning cells to a rounded shape with reduced CD34 expression. Furthermore, co-priming with FGF-1 and FGF-2 enhanced adipogenic potential, limiting osteogenic and chondrogenic tendencies, and possibly promoting preadipocyte commitment. These preadipocytes exhibited unique features: rounded morphology, reduced CD34, decreased preadipocyte factor 1 (Pref-1), and elevated C/EBPα and PPARγ, alongside sustained stemness markers (CD73, CD90, CD105). Mechanistically, FGF-1 and FGF-2 activated key adipogenic transcription factors-C/EBPα and PPARγ-while inhibiting GATA3 and Notch3, which are adipogenesis inhibitors. These findings hold the potential to advance innovative strategies for ADMSC-mediated lipofilling procedures.

Chemical mixture that targets the epidermal growth factor pathway impairs human trophoblast cell functions.

Pregnant women are exposed to complex chemical mixtures, many of which reach the placenta. Some of these chemicals interfere with epidermal growth factor receptor (EGFR) activation, a receptor tyrosine kinase that modulates several placenta cell functions. We hypothesized that a mixture of chemicals (Chem-Mix) known to reduce EGFR activation (polychlorinated biphenyl (PCB)-126, PCB-153, atrazine, trans-nonachlor, niclosamide, and bisphenol S) would interfere with EGFR-mediated trophoblast cell functions. To test this, we determined the chemicals' EGFR binding ability, EGFR and downstream effectors activation, and trophoblast functions (proliferation, invasion, and endovascular differentiation) known to be regulated by EGFR in extravillous trophoblasts (EVTs). The Chem-Mix competed with EGF for EGFR binding, however only PCB-153, niclosamide, trans-nonachlor, and BPS competed for binding as single chemicals. The effects of the Chem-Mix on EGFR phosphorylation were tested by exposing the placental EVT cell line, HTR-8/SVneo to control (0.1% DMSO), Chem-Mix (1, 10, or 100 ng/ml), EGF (30 ng/ml), or Chem-Mix + EGF. The Chem-Mix - but not the individual chemicals - reduced EGF-mediated EGFR phosphorylation in a dose dependent manner, while no effect was observed in its downstream effectors (AKT and STAT3). None of the individual chemicals affected EVT cell invasion, but the Chem-Mix reduced EVT cell invasion independent of EGF. In support of previous studies that have explored chemicals targeting a specific pathway (estrogen/androgen receptor), current findings indicate that exposure to a chemical mixture that targets the EGFR pathway can result in a greater impact compared to individual chemicals in the context of placental cell functions.

Effects of recombinant osteopontin expressed in Escherichia coli on the recovery of the endometrial epidermal growth factor profile and fertility in repeat breeder dairy cows.

Endometrial epidermal growth factor (EGF) shows a cyclic change with two peaks on days 2-4 and days 13-14 of the estrous cycle. In repeat breeder cows, loss of the peaks has been associated with reduced fertility. By infusing seminal plasma (SP) and osteopontin (OPN) derived from SP and milk into the vagina, their EGF profile and fertility are restored. However, SP is difficult to obtain, and both SP and OPN can transmit infectious diseases. While OPN can be sourced from recombinant protein without this risk, recombinant bovine OPN (rOPN) expressed in Escherichia coli should be examined for its effects on the EGF profile, since it does not undergo posttranslational modification, which is important for its biological activity. In study 1, PBS, SP (0.5 mL), and rOPN (0.3 mg) were infused into the vagina at estrus (day 0) in 74, 37, and 105 repeat breeder Holstein cows, respectively, with an altered EGF profile. The endometrial EGF concentrations were measured on day 3. Some cows (n = 58, 20, and 83, respectively) were inseminated immediately before the infusion and then diagnosed for pregnancy between days 30 and 35. The normalization rate of the EGF profile and conception rate in the rOPN group (58.1 % and 47.0 %, respectively) were not significantly different from those in the SP group (62.2 % and 45.0 %, respectively) but higher than those in PBS group (29.7 % and 28.1 %, respectively) (P < 0.05). In study 2, repeat breeder cows with an altered EGF profile were infused with PBS (n = 18) and rOPN (n = 17), while fertile controls with a normal EGF profile (n = 18) were infused with PBS. Two or three embryos were transferred into cows on day 7 and then recovered on day 14. Embryo recovery rates of the rOPN and fertile groups were comparable (58.7 % vs. 58.3 %) but higher than that of the PBS group (58.7 % vs. 32.0 %) (P < 0.05). The embryo recovery rate of cows with normalized EGF profile was higher than that of cows with unnormalized EGF profile (64.4 % vs. 16.7 %) (P < 0.05). The embryo sizes of cows in the rOPN and fertile groups were comparable but larger than those in the PBS group (P < 0.05). However, the embryo size was not correlated to the corresponding endometrial EGF concentrations. In conclusion, rOPN without posttranslational modifications normalized the EGF profile in repeat breeder cows. Improved fertility by normalization of the EGF profile could be attributed partly to the increased embryo viability up to day 14.

Comparative evaluation of divergent concoction of NGF, BDNF, EGF, and FGF growth factor's role in enhancing neuronal differentiation of adipose-derived mesenchymal stem cells.

MSCs (Mesenchymal Stem Cells) can differentiate into various lineages, including neurons and glial cells. In the past few decades, MSCs have been well explored in the context of neuronal differentiation and have been reported to have the immense potential to form distinct kinds of neurons. The distinguishing features of MSCs make them among the most desired cell sources for stem cell therapy. This study involved the trans-differentiation of Adipose-derived human Mesenchymal Stem Cells (ADMSCs) into neurons. The protocol employs a cocktail of chemical inducers in different combinations, including Brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), and Nerve growth factor (NGF) Fibroblastic growth factor (FGF), in induction media. Both types have been successfully differentiated into neurons, confirmed by morphological aspects and the presence of neural-specific markers through RT-PCR (Reverse transcription polymerase chain reaction) studies and immunocytochemistry assay. They have shown excellent morphology with long neurites, synaptic connections, and essential neural markers to validate their identity. The results may significantly contribute to cell replacement therapy for neurological disorders.

Roxithromycin and rhEGF Co-loaded Reactive Oxygen Species Responsive Nanoparticles for Accelerating Wound Healing.

BACKGROUND: Bacterial infection can delay wound healing and is therefore a major threat to public health. Although various strategies have been developed to treat bacterial infections, antibiotics remain the best option to combat infections. The inclusion of growth factors in the treatment approach can also accelerate wound healing. The co-delivery of antibiotics and growth factors for the combined treatment of wounds needs further investigation. OBJECTIVE: Here we aimed to develop antibiotic and growth factor co-loaded nanoparticles (NPs) to treat Staphylococcus aureus-infected wounds. METHODS: By using our previously prepared reactive oxygen species-responsive material (Oxi-αCD), roxithromycin (ROX)-loaded NPs (ROX/Oxi-αCD NPs) and recombinant human epidermal growth factor (rhEGF)/ROX co-loaded NPs (rhEGF/ROX/Oxi-αCD NPs) were successfully fabricated. The in vivo efficacy of this prepared nanomedicine was evaluated in mice with S. aureus-infected wounds. RESULTS: ROX/Oxi-αCD NPs and rhEGF/ROX/Oxi-αCD NPs had a spherical structure and their particle sizes were 164 ± 5 nm and 190 ± 8 nm, respectively. The in vitro antibacterial experiments showed that ROX/Oxi-αCD NPs had a lower minimum inhibitory concentration than ROX. The in vivo animal experiments demonstrated that rhEGF/ROX/Oxi-αCD NPs could significantly accelerate the healing of S. aureus-infected wounds as compared to the free ROX drug and ROX/Oxi-αCD NPs (P < 0.05). CONCLUSION: ROX and rhEGF co-loaded NPs can effectively eliminate bacteria in wounds and accelerate wound healing. Our present work could provide a new strategy to combat bacteria-infected wounds.

Epidermal growth factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium.

Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills various types of malignant cells. We used CAP-activated media (PAM) to utilize a range of the generated short- and long-lived reactive species. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in up-regulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells. The proposed approach based on the synergy of CAP and EGFR-targeted therapy may provide new opportunities to improve the clinical management of TNBC.

Reactive Oxygen Species (ROS)-Assisted Nano-Therapeutics Surface-Decorated with Epidermal Growth Factor Fragments for Enhanced Wound Healing.

In this study, stimuli-responsive liberation of an epidermal growth factor fragment (EGFfr) is accomplished using nanofibrous meshes to improve wound healing effects. Electrospun nanofibers are fragmented by mechanical milling, followed by aminolysis to fabricate powdered nanofibrils (NFs). EGFfrs are covalently immobilized on NFs via thioketal linkers (EGFfr@TK@NF) for reactive oxygen species (ROS)-dependent liberation. EGFfr@TK@NF exhibits ROS-responsive liberation of EGFfr from the matrix at hydrogen peroxide (H2 O2 ) concentrations of 0-250 mm. Released EGFfr is confirmed to enhance the migration of HaCaT cell monolayers, and keratinocytic gene expression levels are significantly enhanced when H2 O2 is added to obtain the released fraction of NFs. An in vivo study on the dorsal wounds of mice reveals that EGFfr-immobilized NFs improve the expression levels of keratin1, 5, and 14 for 2 weeks when H2 O2 is added to the wound sites, suggesting that the wounded skin is re-epithelized with the original epidermis. Thus, EGFfrs-immobilized NFs are anticipated to be potential nanotherapeutics for wound treatment in combination with the conventional disinfection process with H2 O2 .

Investigation of the efficacy of epidermal growth factor, boric acid and their combination in cartilage injury in rats: An experimental study.

OBJECTIVES: In this study, we aimed to determine the bioefficacy of epidermal growth factor (EGF), boric acid (BA), and their combination on cartilage injury in rats. MATERIALS AND METHODS: In in vitro setting, the cytotoxic effects of BA, EGF, and their combinations using mouse fibroblast cell (L929), human bone osteosarcoma cell (Saos-2), and human adipose derived mesenchymal stem cells (hAD-MSCs) were determined by applying MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] test. In in vivo setting, 72 rats were randomly divided into four groups. A standard chondral defect was created and microfracture was performed in all groups. Group A was determined as the control group. In addition to the standard procedure, Group B received 100 ng/mL of EGF, Group C received a combination of 100 ng/mL of EGF and 10 µg/mL of BA combination, and Group D 20 µg/mL of BA. RESULTS: The cytotoxic effect of the combinations of EGF dilutions (1, 5, 10, 25, 50, 100, 200 ng/mL) with BA (100, 300, 500 µg/mL) was observed only in the 72-h application period and in Saos-2. The cytotoxic effect of BA was reduced when combined with EGF. There was no significant difference in the histopathological scores among the groups (p=0.13). CONCLUSION: Our study showed that EGF and low-dose BA application had a positive effect on cartilage healing in rats. Significant decreases in recovery scores were observed in the other groups. The combination of EGF and BA promoted osteoblast growth. Detection of lytic lesions in the group treated with 20 µg/mL of BA indicates that BA may have a cytotoxic effect.

Epidermal growth factor: Expression in goat endometrial epithelia during early pregnancy and regulation by interferon tau and FOXO1.

In ruminants, establishment and maintenance of pregnancy depends upon a well-coordinated interaction between the conceptus and the maternal endometrium. Epidermal growth factor (EGF) is important for embryo implantation and pregnancy establishment. However, the regulatory mechanisms of EGF expression remain unclear. FOXO1, a member of the Forkhead box O (FOXO) subfamily of transcription factors, is currently accepted as a novel endometrial receptivity marker for humans and mice owing to its timely and specific expression at the window of implantation. In this study, we examined the spatiotemporal expression profile of EGF in goat uterus during early pregnancy (Day 0 to Day 50 of pregnancy) and verified that EGF expression was regulated by FOXO1 and interferon tau (IFNT). Our results showed that EGF was highly expressed in the luminal epithelium (LE) and the glandular epithelium (GE) during conceptus adhesion (Day 16 to Day 25 of pregnancy). After implantation, EGF protein signals were continuously detected in the endometrial epithelia and appeared in the conceptus trophectoderm. Furthermore, EGF expression could be up-regulated by IFNT in goat uterus and primary endometrial epithelium cells (EECs). The luciferase assay results showed that FOXO1 could promote EGF transcription by binding to its promoter. And FOXO1 positively regulates EGF expression in goat EECs. These findings contribute to better understanding the role and regulation mechanisms of EGF during ruminant early pregnancy.