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Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus. [ABSTRACT FROM AUTHOR]

Silk fibroin (SF) has been utilized in various applications, including as, in bone, cartilage, nerve, skin regeneration, owing to its biocompatibility, controllable biodegradability, minimal inflammation, and tunable mechanical properties. Excellent neovascularization of silk matrices is prerequisite for the success of promoting wound healing in different tissues. Neovascularization of SF can provide a nutrient supply to the newly developed granulation tissue at the wound site and accelerate vessel formation and remodeling. In this review, we summarize the neovascularization of SF in different forms and dissolution by recombining different composites, modifying active peptides, and adding growth factors in the treatment of various wound healing processes. [ABSTRACT FROM AUTHOR]

It has been reported that the effective inhibition of vascular endothelial growth factor (VEGF) can prevent the progression of ovarian hyperstimulation syndrome (OHSS). The present study aimed to investigate the mechanism underlying the effect of vitamin D3 (VD3) on OHSS in mouse models and granulosa cells. The effects of VD3 administration (16 and 24 IU) on ovarian permeability were determined using Evans blue. In addition, ovarian pathology, corpus luteum count, inflammatory responses, and hormone and VEGFA levels were assessed using pathological sections and ELISA. Molecular docking predicted that pentraxin 3 (PTX3) could be a potential target of VD3, and therefore, the effects of human chorionic gonadotropin (hCG) and VD3 as well as PTX3 overexpression on the production and secretion of VEGFA in granulosa cells were also investigated using western blotting and immunofluorescence. Twenty-four IU VD3 significantly reversed the increase in ovarian weight and permeability in mice with OHSS. Additionally, VD3 diminished congestion and the number of corpus luteum in the ovaries and reduced the secretion levels of inflammatory factors and those of estrogen and progesterone. Notably, VD3 downregulated VEGFA and CD31 in ovarian tissues, while the expression levels of PTX3 varied among different groups. Furthermore, VD3 restored the hCG-induced enhanced VEGFA and PTX3 expression levels in granulosa cells, whereas PTX3 overexpression abrogated the VD3-mediated inhibition of VEGFA production and secretion. The present study demonstrated that VD3 could inhibit the release of VEGFA through PTX3, thus supporting the beneficial effects of VD3 administration on ameliorating OHSS symptoms. [ABSTRACT FROM AUTHOR]

Macrophages play a role in nephrolithiasis, offering the possibility of developing macrophage-mediated preventive therapies. To establish a system for screening drugs that could prevent the formation of kidney stones, we aimed to develop a model using human induced pluripotent stem cell (iPSC)-derived macrophages to study phagocytosis of calcium oxalate monohydrate (COM) crystals. Human iPSCs (201B7) were cultured. CD14+ monocytes were recovered using a stepwise process that involved the use of growth factors and cytokines. These cells were then allowed to differentiate into M1 and M2 macrophages. The macrophages were co-cultured with COM crystals and used in the phagocytosis experiments. Live cell imaging and polarized light observation via super-resolution microscopy were used to visualize phagocytosis. Localization of phagocytosed COM crystals was observed using transmission electron microscopy. Intracellular fluorescence intensity was measured using imaging cytometry to quantify phagocytosis. Human iPSCs successfully differentiated into M1 and M2 macrophages. M1 macrophages adhered to the culture plate and moved COM crystals from the periphery to cell center over time, whereas M2 macrophages did not adhere to the culture plate and actively phagocytosed the surrounding COM crystals. Fluorescence assessment over a 24-h period showed that M2 macrophages exhibited higher intracellular fluorescence intensity (5.65-times higher than that of M1 macrophages at 4.5 h) and maintained this advantage for 18 h. This study revealed that human iPSC-derived macrophages have the ability to phagocytose COM crystals, presenting a new approach for studying urinary stone formation and highlighting the potential of iPSC-derived macrophages as a tool to screen nephrolithiasis-related drugs. [ABSTRACT FROM AUTHOR]

The efficacy of growth factor gene–modified stem cells in treating spinal cord injury (SCI) remains unclear. This study aims to evaluate the effectiveness of growth factor gene–modified stem cells in restoring motor function after SCI. Two reviewers searched four databases, including PubMed, Embase, Web of Science, and Scopus, to identify relevant records. Studies on rodents assessing the efficacy of transplanting growth factor gene–modified stem cells in restoring motor function after SCI were included. The results were reported using the standardized mean difference (SMD) with a 95% confidence interval (95% CI). Analyses showed that growth factor gene–modified stem cell transplantation improved motor function recovery in rodents with SCI compared to the untreated (SMD = 3.98, 95% CI 3.26–4.70, I2 = 86.8%, P < 0.0001) and stem cell (SMD = 2.53, 95% CI 1.93–3.13, I2 = 86.9%, P < 0.0001) groups. Using growth factor gene–modified neural stem/histone cells enhanced treatment efficacy. In addition, the effectiveness increased when viral vectors were employed for gene modification and high transplantation doses were administered during the subacute phase. Stem cells derived from the human umbilical cord exhibited an advantage in motor function recovery. However, the transplantation of growth factor gene–modified stem cells did not significantly improve motor function in male rodents (P = 0.136). Transplantation of growth factor gene–modified stem cells improved motor function in rodents after SCI, but claims of enhanced efficacy should be approached with caution. The safety of gene modification remains a significant concern, requiring additional efforts to enhance its clinical translatability. [ABSTRACT FROM AUTHOR]

Physical evolution of cosmological models can be tested by using expansion data, while growth history of these models is capable of testing dynamics of the inhomogeneous parts of energy density. The growth factor, as well as its growth index, gives a clear indication of the performance of cosmological models in the regime of structure formation of early Universe. In this work, we explore the growth index in several leading f(T) cosmological models, based on a specific class of teleparallel gravity theories. These have become prominent in the literature and lead to other formulations of teleparallel gravity. Here we adopt a generalized approach by obtaining the Mészáros equation without immediately imposing the subhorizon limit, because this assumption could lead to over-simplification. This approach gives avenue to study at which k modes the subhorizon limit starts to apply. We obtain numerical results for the growth factor and growth index for a variety of data set combinations for each f(T) model. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the effect of injecting chemical factors compared to conventional distraction osteogenesis (DO) treatment on the bone formation of the distracted area of the maxillofacial region in human and animal studies. Method: Electronic search was done in PubMed, Scopus, Embase, and Cochrane database for studies published until September 2021. The studies' risk of bias (ROB) was assessed using the Cochrane Collaborations and NIH quality assessment tools. Meta-analyses were performed to assess the difference in the amount of bone formation and maximal load tolerance. Results: Among a total of 58 included studies, eight studies analyzed the bone formation rate of the distracted area in human models and others in animal models. Results of the human studies showed acceptable outcomes in the case of using bone morphogenic protein-2 (BMP-2), autologous bone-platelet gel, and calcium sulfate. However, using platelet reach plasma does not increase the rate of bone formation significantly. Quantitative analyses showed that both BMP-2 (SMD = 26.57; 95% CI = 18.86 to 34.28) and neuron growth factor (NGF) (SMD = 16.19; 95% CI = 9.64 to 22.75) increase the amount of bone formation. Besides, NGF increased the amount of load tolerance significantly (SMD = 30.03; 95% CI = 19.91 to 40.16). Additionally, BMP-2 has no significant impact on the post-treatment maxillary length (SMD = 9.19; 95% CI = − 2.35 to 20.73). Conclusion: Limited number of human studies with low quality used chemical factors to enhance osteogenesis and showed acceptable results. However, more studies with higher quality are required. [ABSTRACT FROM AUTHOR]

This paper is devoted to the accuracy and stability of quaternion Gaussian elimination (qGE). First, considering the noncommutativity of quaternion multiplications, we establish the rules of quaternion floating-point operations. After that, roundoff error analyses of quaternion LU and qGE with partial pivoting (qGEPP) are presented to show the backward stability of qGEPP is affected by the growth factor. Then, the upper bounds for growth factors of qGE with partial or complete pivoting, and the quaternion matrices with maximal growth factor are investigated. Finally, growth factors of some special matrices are also studied, and the theoretical results are confirmed through several numerical experiments. A conjecture about the growth factor of quaternion Hadamard matrix is given. [ABSTRACT FROM AUTHOR]

Background: Diabetic retinopathy (DR) is a common diabetic neurodegenerative disease that affects vision in severe cases. Current therapeutic drugs are ineffective for some patients with severe side effects, and ginsenoside-Rg1 (GRg1) has been shown to protect against DR and may serve as a new potential drug for DR. This study aimed to confirm the protective effect of GRg1 against DR and its molecular mechanism. Methods: Human retinal microvascular endothelial cells (hRMECs) and rats were used to construct DR models in vitro and in vivo. Cell proliferation was detected by BrdU assays, the cell cycle was detected by flow cytometry, and TNF-α, IL-6 and IL-1β levels were detected by ELISA. qRT‒PCR, Western blotting and immunohistochemistry were used to detect the expression of related genes and proteins, and angiogenesis assays were used to assess angiogenesis. RIP and RNA pull down assays were used to determine the relationship between miR-216a-5p and TLR4; retinal structure and changes were observed by HE staining and retinal digestive spread assays. Results: GRg1 effectively inhibited HG-induced hRMEC proliferation, cell cycle progression and angiogenesis and reduced the levels of intracellular inflammatory cytokines and growth factors. HG downregulated the expression of miR-216a-5p and upregulated the expression of TLR4/NF-kB signaling pathway-related proteins. Importantly, GRg1 inhibited TLR4/NF-kB signaling pathway activation by upregulating miR-216a-5p, thereby inhibiting HG-induced cell proliferation, cell cycle progression, angiogenesis, and the production of inflammatory cytokines and growth factors. In addition, animal experiments confirmed the results of the cell experiments. Conclusions: GRg1 inhibits TLR4/NF-kB signaling by upregulating miR-216a-5p to reduce growth factors and inflammatory cytokines in DR, providing a potential therapeutic strategy for DR. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated clinically and histologically the efficacy of modified perforated collagen membrane (PCM) and/or leukocyte- and platelet-rich fibrin (L-PRF) in combination with xenogeneic block bone graft in the vertical alveolar ridge augmentation. Materials and methods: Six adult mongrel dogs were enrolled in this randomized blinded study. After defect preparation, xenogeneic screw-fixed block graft was covered by an occlusive collagen membrane in group 1 that represented the control group (Block + CM). In group 2, L-PRF membrane was added first before top coverage by occlusive collagen membrane (Block + L-PRF + CM). Groups 3 (Block + PCM) and 4 (Block + L-PRF + PCM) were identical to the first two groups except that the occlusive collagen membrane was replaced by a perforated one. Following a healing period of 2 months, the dogs were submitted to the surgical reentry phase for clinical and histological evaluation. Results: Clinically, no significant differences were found among all groups regarding vertical and horizontal ridge dimensions (p = 0.155, 0.492, respectively). Histomorphometric analysis revealed that the percentage of the total bone area and mature bone was significantly higher in group 4 (69.36 ± 2.72, 33.11 ± 5.18) compared to the control group (59.17 ± 4.27, 21.94 ± 2.86) (p = 0. 027, p = 0.029). Conclusion: The use of xenogenic block grafts in combination with a double-layered perforated collagen L-PRF membrane in vertical ridge augmentation appeared to improve the inductive power of this challenging defect type. Clinical relevance: Size and number of perforations may affect the mechanical and handling properties of the membrane. [ABSTRACT FROM AUTHOR]

Objective: Topical injection of growth factor (GF) for facial rejuvenation is unauthorized, but it is commonly performed in China, leading to emerging and challenging complications. The purpose of this study is to investigate the clinical, imaging, and histopathologic characteristics of complications caused by facial GF injection, as well as their treatments and outcomes. Methods: We performed a retrospective single-centered case series study on consecutive patients who were treated for complications following facial injection of GF. The primary outcome was the recurrence over follow-up period. The secondary outcomes were the subjective evaluations of the facial aesthetic, symptomatic, and psychological improvements using the Global Aesthetic Improvement Scale (GAIS) and a patient-reported outcome measurement (PROM). Kaplan–Meier analysis and log-rank test were performed to investigate the recurrence. Results: A total of 32 females with an average age of 42.6 ± 9.4 years were included. Most patients received GF injections in non-medical institutes such as beauty spas and presented with uncontrollable soft tissue hyperplasia, diffuse subcutaneous swelling, and skin redness. Ultrasonography showed heterogeneous hypoechoic or echogenic areas in a thickened and disorganized subcutaneous tissue hierarchy. MRI showed flaky isointensive or hypointensive signals on T1WI and hyperintensive signals on T2WI. 37.5% patient underwent triamcinolone acetonide injection, whereas 62.5% patients underwent surgical interventions. Lipoma-like hyperplastic tissue was found during surgery. HE staining confirmed intramuscular lipoma and fibrolipomatous tissue hyperplasia. Recurrence was found in 37.5% patients over a median follow-up of 6 months. KM curves and log-rank test demonstrated no significant difference in the recurrence between patients who underwent nonsurgical or surgical interventions (p = 0.77). GAIS and PROM scores indicated substantial aesthetic, symptomatic, and psychological improvements in 70%, 91.7%, and 75% patients, respectively. Conclusions: Both surgical and nonsurgical interventions are feasible and effective treatment options for GF-induced complications. Although recurrence rate was relatively high, aesthetic, symptomatic, and psychological improvements were achieved in most patients. We developed a workflow that might help diagnose and treat complications following unknown dermal filler injections. Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Previous studies indicated that nerve growth factor (NGF) and proNGF differentially regulate the phenotype of macrophages and microglia via actions at tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptors (p75NTR), respectively. The ability of HIV gp120 and virions to induce the secretion of factors toxic to neurons was suppressed by NGF and enhanced by proNGF, suggesting the potential for neurotrophin based "anti-inflammatory" interventions. To investigate the "anti-inflammatory" potential of the p75NTR ligand, LM11A-31, we treated cultured macrophages and microglia with HIV gp120 in the presence or absence of the ligand and evaluated the morphological phenotype, intrinsic calcium signaling, neurotoxic activity and proteins in the secretome. LM11A-31 at 10 nM was able to suppress the release of neurotoxic factors from both monocyte-derived macrophages (MDM) and microglia. The protective effects correlated with a shift in morphology and a unique secretory phenotype rich in growth factors that overrode the actions of HIV gp120. The protein pattern was generally consistent with anti-inflammatory, phagocytic and tissue remodeling functions. Although the toxic factor(s) and the source of the neuroprotection were not identified, the data indicated that an increased degradation of NGF induced by HIV gp120 was likely to contribute to neuronal vulnerability. Although substantial work is still needed to reveal the functions of many proteins in the mononuclear phagocyte secretome, such as growth and differentiation factors, the data clearly indicate that the ligand LM11A-31 has excellent therapeutic potential due to its ability to induce a more protective phenotype that restricts activation by HIV. [ABSTRACT FROM AUTHOR]

Background: The cellular and biochemical composition of the platelet rich plasma (PRP) may impact its regenerative capacity. PRP composition have been shown to vary substantially among different separation systems and protocols. The type and the dose of anticoagulant might affect the content of PRP. Objective: The objective of this study was to evaluate the effect of anticoagulant use, on cellular composition and the amount of growth factors in fresh PRP. Methods: Three different methods were used to prepare PRP from 12 healthy participants. The protocol 1 included standart dose sodium citrate (SC) (0.9 ml, 3.8%), protocol 2 included 0.5 ml SC and no anticoagulant was used in protocol 3. The PRP's were compared in regards to cellular content, capture efficiency of platelets (CE), concentrations and total doses of fresh studied vascular endothelial growth factor (VEGF), platelet derived growth factor -BB, (PDGF-BB), transforming growth factor β1 (TGF-β1) levels. Results: The CE and total platelet count were highest in protocol 1. The white blood cells (WBC) and VEGF were highest in protocol 3. The highest total TGF-β1 and total PDGF levels were obtained with protocol 1, while the highest total VEGF levels were obtained with protocol 3. Conclusion: The results of this study revealed that the use and the dose of SC affects the cellular content of PRP and GFs measured in fresh PRP. The CE and platelet dose increases while the WBC and VEGF decreases with the use of SC. [ABSTRACT FROM AUTHOR]

Purpose: To determine the clinical efficacy and safety of growth factors in the treatment of tympanic membrane (TM) perforations from randomized controlled trials (RCTs). Methods: Databases, including PubMed, EMBASE, Cochrane library, Ebsco, Ovid, Scopus, and Web of Science, were searched for articles in any language about studies on the treatment of TM perforations with growth factors. Inclusion criteria were: (1) randomized controlled trials (RCTs); (2) only patients with TM perforations included; and (3) any kinds of growth factors or related products were used as an intervention. Exclusion criteria were: (1) study was not reported as a full paper, only as an abstract; (2) review studies and case reports; and (3) an inability to extract valid data. Outcomes of interest included perforation closure rate, closure time, hearing improvement, and complications. Results: Nineteen RCTs with a total of 1335 participants were included. Growth factors effectively increased the rate of perforation closure [risk ratio (RR): 1.21 95% confidence interval (1.12, 1.30), p < 0.01] and shortened closure time [mean difference (MD): − 16.71 (− 22.74, − 10.15), p < 0.01]. There was no significant difference in hearing improvement [MD: 0.10 (− 0.50, 0.70), p = 0.74] or complications [RR: 1.49 (0.96, 2.32), p = 0.07] between the growth factor intervention group and the control group. Conclusion: Growth factors are effective and safe in the treatment of TM perforations. However, better designed clinical trials should be carried out in the future to obtain more robust findings about the effectiveness of growth factors in the treatment of TM perforations. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Our aim was to study the association between duration of breastfeeding and circulating immunological markers during the first 3 years of life in children with HLA-conferred susceptibility to type 1 diabetes. Methods: We performed a longitudinal analysis of 38 circulating immunological markers (cytokines, chemokines and growth factors) in serum samples from Finnish (56 individuals, 147 samples), Estonian (56 individuals 148 samples) and Russian Karelian children (62 individuals, 149 samples) at 3, 6, 12, 18, 24 and 36 months of age. We also analysed gut inflammation markers (calprotectin and human β defensin-2) at 3 (n = 96) and 6 months (n = 153) of age. Comparisons of immunological marker medians were performed between children who were breastfed for 6 months or longer vs children who were breastfed for less than 6 months. Results: Breastfeeding for 6 months or longer vs less than 6 months was associated with lower median of serum immunological markers at 6 months (granulocyte-macrophage colony-stimulating factor [GMCSF], macrophage inflammatory protein [MIP-3α]), 12 months (IFN-α2, vascular endothelial growth factor, GMCSF, IFN-γ, IL-21), 18 months (FGF-2, IFN-α2) and 24 months of age (CCL11 [eotaxin], monocyte chemoattractant protein-1, TGFα, soluble CD40 ligand, IL-13, IL-21, IL-5, MIP-1α) (all p < 0.01) but not at 36 months of age. Breastfeeding was not associated with gut inflammation markers at 3 and 6 months of age. Conclusions/interpretation: Children who were breastfed for 6 months or longer had lower medians for 14 immunological markers at one or more age points during the first 2 years of life compared with children who were breastfed for less than 6 months. The clinical meaning of the findings is not clear. However, the present study contributes to the understanding of immunological differences in children that have been breastfed longer, and thus provides a mechanistic suggestion for the previously observed associations between breastfeeding and risk of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Purpose of Review: Tissue regenerative solutions for musculoskeletal disorders have become increasingly important with a growing aged population. Current growth factor treatments often require high dosages with the potential for off-target effects. Growth factor immobilization strategies offer approaches towards alleviating these concerns. This review summarizes current growth factor immobilization techniques (encapsulation, affinity interactions, and covalent binding) and the effects of immobilization on growth factor loading, release, and bioactivity. Recent Findings: The breadth of immobilization techniques based on encapsulation, affinity, and covalent binding offer multiple methods to improve the therapeutic efficacy of growth factors by controlling bioactivity and release. Growth factor immobilization strategies have evolved to more complex systems with the capacity to load and release multiple growth factors with spatiotemporal control. Summary: The advancements in immobilization strategies allow for development of new, complex musculoskeletal tissue treatment strategies with improved spatiotemporal control of loading, release, and bioactivity. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is a chronic metabolic disorder, increasing in the number of patients and poses a severe threat to human health. Significant advances have been made in DM treatment; the most important of which is differentiation and proliferation of beta cells from IPSCs. Methods: Data were collected from PUBMED at various time points up to the academic year of 2020. The related keywords are listed as follows: "Induced pluripotent stem cell", "Proliferation", "Growth factor", "Small molecule", "cardiotoxicity" and "Scaffold." Result: The use of growth factors along with small molecules can be a good strategy for beta-cell proliferation. Also, proliferation of beta cells on nanofibers scaffolds can create a similar in vivo environment, that leads to increased function of beta-cell. Some transcription factors that cause beta cells proliferation play an important role in inflammation; so, it is essential to monitor them to prevent inflammation. Conclusion: Finally, the simultaneous use of growth factors, micronutrients and scaffolds can be an excellent strategy to increase the proliferation and function of beta cells derived from IPSCs. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common cancer among men in the USA. A peptide derived from the active site of alpha-fetoprotein (AFP), known as AFPep, has been shown to be efficacious in inhibiting breast cancer growth. The role of this derived peptide AFPep in the development of prostate cancer has yet to be studied. To investigate the role of AFPep on prostate cancer, we used the PC-3 and DU-145 cell lines. We found that through key anti-apoptosis and pro-proliferation molecules, AFPep enhances the proliferation of DU-145 prostate cancer cells. The anti-proliferative molecules p18, p21, and p27, along with the pro-apoptotic molecules Fas and Bax, were all down-regulated in DU-145 cell lines treated with AFPep. Conversely, AFPep was not found to have a proliferative effect on the PC-3 prostate cancer cell line. This finding suggests the effects of AFPep to be cell line-specific in prostate cancer. Further investigation into the effects of AFPep could lead to new areas of treating prostate cancer. [ABSTRACT FROM AUTHOR]

Exogenous electrical fields have been explored in regenerative medicine to increase cellular expression of pro-regenerative growth factors. Adipose-derived stem cells (ASCs) are attractive for regenerative applications, specifically for neural repair. Little is known about the relationship between low-level electrical stimulation (ES) and ASC regenerative potentiation. In this work, patterns of ASC expression and secretion of growth factors (i.e., secretome) were explored across a range of ES parameters. ASCs were stimulated with low-level stimulation (20 mV/mm) at varied pulse frequencies, durations, and with alternating versus direct current. Frequency and duration had the most significant effects on growth factor expression. While a range of stimulation frequencies (1, 20, 1000 Hz) applied intermittently (1 h × 3 days) induced upregulation of general wound healing factors, neural-specific factors were only increased at 1 Hz. Moreover, the most optimal expression of neural growth factors was achieved when ASCs were exposed to 1 Hz pulses continuously for 24 h. In evaluation of secretome, apparent inconsistencies were observed across biological replications. Nonetheless, ASC secretome (from 1 Hz, 24 h ES) caused significant increase in neurite extension compared to non-stimulated control. Overall, ASCs are sensitive to ES parameters at low field strengths, notably pulse frequency and stimulation duration. [ABSTRACT FROM AUTHOR]

Neural stem/progenitor cells (NSPCs) rely on internal and external cues determining their lineage decisions during brain development. The progenitor cells of the embryonic mammalian forebrain reside in the ventricular and subventricular zones of the lateral ventricles, where they proliferate, generate neurons and glial cells, and respond to external cues like growth factors. The extracellular matrix (ECM) surrounds NSPCs and influences the cell fate by providing mechanical scaffold, trophic support, and instructive signals. The ECM molecule tenascin-C (Tnc) is expressed in the proliferative zones of the developing forebrain and involved in the proliferation and maturation of NSPCs. Here, we analyzed the regulation of the Tnc gene expression by NSPCs cultivated under the influence of different growth factors. We observed that the epidermal growth factor (EGF) and the fibroblast growth factor (FGF)-2 strongly increased the expression of Tnc, whereas the transforming growth factor (TGF)β 1 had no effect on Tnc gene expression, in contrast to previous findings in cell cultures of neural and non-neural origin. The stimulation of the Tnc gene expression induced by EGF or FGF-2 was reversible and seen in constantly treated as well as short term stimulated NSPC cultures. The activation depended on the presence of the respective receptors, which was slightly different in cortical and striatal NSPC cultures. Our results confirm the influence of extracellular stimuli regulating the expression of factors that form a niche for NSPCs during embryonic forebrain development. [ABSTRACT FROM AUTHOR]

Growth factors such as bone morphogenetic protein-2 (BMP-2) are potent tools for tissue engineering. Three-dimensional (3D) printing offers a potential strategy for delivery of BMP-2 from polymeric constructs; however, these biomolecules are sensitive to inactivation by the elevated temperatures commonly employed during extrusion-based 3D printing. Therefore, we aimed to correlate printing temperature to the bioactivity of BMP-2 released from 3D printed constructs composed of a model polymer, poly(propylene fumarate). Following encapsulation of BMP-2 in poly(dl-lactic-co-glycolic acid) particles, growth factor-loaded fibers were fabricated at three different printing temperatures. Resulting constructs underwent 28 days of aqueous degradation for collection of released BMP-2. Supernatants were then assayed for the presence of bioactive BMP-2 using a cellular assay for alkaline phosphatase activity. Cumulative release profiles indicated that BMP-2 released from constructs that were 3D printed at physiologic and intermediate temperatures exhibited comparable total amounts of bioactive BMP-2 release as those encapsulated in non-printed particulate delivery vehicles. Meanwhile, the elevated printing temperature of 90 °C resulted in a decreased amount of total bioactive BMP-2 release from the fibers. These findings elucidate the effects of elevated printing temperatures on BMP-2 bioactivity during extrusion-based 3D printing, and enlighten polymeric material selection for 3D printing with growth factors. [ABSTRACT FROM AUTHOR]

The prevalence of rheumatic and musculoskeletal diseases (RMDs) including osteoarthritis (OA) and low back pain (LBP) in aging societies present significant cost burdens to health and social care systems. Intervertebral disc (IVD) degeneration, which is characterized by disc dehydration, anatomical alterations, and extensive changes in extracellular matrix (ECM) composition, is an important contributor to LBP. IVD cell homeostasis can be disrupted by mitochondrial dysfunction. Mitochondria are the main source of energy supply in IVD cells and a major contributor to the production of reactive oxygen species (ROS). Therefore, mitochondria represent a double-edged sword in IVD cells. Mitochondrial dysfunction results in oxidative stress, cell death, and premature cell senescence, which are all implicated in IVD degeneration. Considering the importance of optimal mitochondrial function for the preservation of IVD cell homeostasis, extensive studies have been done in recent years to evaluate the efficacy of small molecules targeting mitochondrial dysfunction. In this article, we review the pathogenesis of mitochondrial dysfunction, aiming to highlight the role of small molecules and a selected number of biological growth factors that regulate mitochondrial function and maintain IVD cell homeostasis. Furthermore, molecules that target mitochondria and their mechanisms of action and potential for IVD regeneration are identified. Finally, we discuss mitophagy as a key mediator of many cellular events and the small molecules regulating its function. [ABSTRACT FROM AUTHOR]

Spirulina platensis (Sp) or Amphora coffeaeformis (Am) are good candidates as an in-feed antibiotic substitute for broilers. This work was performed to investigate the effects of Sp and Am on the growth performance, intestinal microbial population, physiological responses, and blood biochemical constituents in broiler chickens. Fifty-one-day old Cobb broilers (with initial body weights 50–55 g) were allocated to five groups. Each treatment group had five replicate pens with two birds each. The experiments lasted for 35 days. The 1st group had basal diet (control group). The 2nd and 3rd groups received basal diet, along with 5- or 10-g/kg Sp as a feed ingredient, respectively. While the 4th and 5th groups received basal diet, along with 5- or 10-g/kg Am as a feed ingredient, respectively. Data analysis revealed significantly higher body weight gains (P ≤ 0.05) with higher Sp or Am levels and, in turn, linear improvements (P ≤ 0.05) in feed conversion values. In addition, intestinal Lactobacillus sp. was increased, and Escherichia coli populations were decreased by both dietary Sp levels or Am levels. Furthermore, the liver (% body weight) was significantly decreased (P ≤ 0.05) and the heart (% body weight) was significantly increased (P ≤ 0.05) with higher Sp or Am levels in comparison with untreated control. In conclusion, dietary inclusion with 10 g/kg of Sp and Am could improve the growth performance, serum biochemical parameters and intestinal microbial population in broiler chickens. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) disrupts the axonal pathways and abruptly affects sensory, motor, and autonomic functions below the injury. Physical disabilities in injured persons linked with the type, severity, the level of the spinal cord at which injury occurs, and the axonal pathways that damaged due to injury. SCI initiates the cascade of secondary damage to neuronal and non-neuronal cells and causing the degeneration of the axonal pathways, which ultimately leads to functional deficits. A variety of therapeutic strategies and training paradigm alone or in combination, have been used to promote regeneration in the experimental model of SCI. These regenerative strategies categorized into three categories. The first category of regenerative strategies consists of molecules that are used to block or neutralize the growth inhibitory molecule, such as chondroitin sulfate proteoglycans (CSPGs) Nogo, Myelin-associated glycoprotein (MAG), and oligodendrocytes myelin glycoprotein (OMgp). The second category of regenerative strategies focusses on the application of various growth factors such as brain-derived neurotrophic factors (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) to promote axonal regeneration. And the third category of regenerative strategies focusses on transplantation of various types of cells such as Schwann cells, induced pluripotent stem cells (IPS), embryonic stem cells (ESCs), and olfactory ensheathing cells (OECs). This review provides an overview of current researches to enhance the growth of severed axonal pathways, which ultimately help to develop an effective therapy to restore sensory and motor function following SCI. [ABSTRACT FROM AUTHOR]

Evidence suggests that some systemic and local factors, including cytokines and growth factors in patients with traumatic brain injury (TBI), can play an essential role in accelerating fracture healing. The purpose of this study was to evaluate serum levels of some inflammatory cytokines and growth factors in patients with fracture and TBI as well as healthy subjects. In this study, a total number of 30 patients with a femoral fracture, 30 cases with TBI, 30 patients with TBI and a femoral fracture (fracture + TBI group), and 30 healthy subjects were recruited. The Glasgow Coma Scale (GCS) scores were also determined upon their admission. Then, the serum levels of fibroblast growth factor 2 (FGF-2), transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), bone morphogenetic protein 2 (BMP-2), insulin-like growth factor 1 (IGF-1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were measured via enzyme-linked immunosorbent assay (ELISA) technique, 12 h and 4 weeks after injury and hospital admission. The study results demonstrated that the serum levels of BMP-2, FGF-2, IL-1β, and PDGF in the femoral fracture + TBI group increased significantly over 12 h and after 4 weeks compared with other groups, but the serum levels of IGF-I, IL-6, and TGF-β in this group increased in a significant manner at 12 h compared with other studied groups. The findings also showed that the time to union of a femoral fracture was shorter in the fracture + TBI group than in cases with a femoral fracture alone (p = 0.03). Accordingly, it seems that elevated serum levels of BMP-2, PDGF, FGF-2, and IL-1β may be associated with healing acceleration in fracture + TBI patients. However, further studies are needed to confirm this claim. [ABSTRACT FROM AUTHOR]

A novel insulin-like growth factor (igf3), which is exclusively expressed in the gonads, has been widely identified in fish species. Recent studies have indicated that Igf3 regulates spermatogonia proliferation and differentiation in zebrafish; however, detailed information on the role of this Igf needs further in vivo investigation. Here, using Nile tilapia (Oreochromis niloticus) as an animal model, we report that igf3 is required for spermatogenesis and reproduction. Knockout of igf3 by CRISPR/Cas9 severely inhibited spermatogonial proliferation and differentiation at 90 days after hatching, the time critical for meiosis initiation, and resulted in less spermatocytes in the mutants. Although spermatogenesis continued to occur later, more spermatocytes and less spermatids were observed in the igf3−/− testes when compared with wild type of testes at adults, indicating that Igf3 regulates spermatocyte to spermatid transition. Importantly, a significantly increased occurrence of apoptosis in spermatids was observed after loss of Igf3. Therefore, igf3−/− males were subfertile with drastically reduced semen volume and sperm count. Conversely, the overexpression of Igf3 in XY tilapia enhanced spermatogenesis leading to more spermatids and sperm count. Transcriptomic analysis revealed that the absence of Igf3 resulted in dysregulation of many genes involved in cell cycle, meiosis and pluripotency regulators that are critical for spermatogenesis. In addition, in vitro gonadal culture with 17α-methyltetosterone (MT) and 11-ketotestosterone (11-KT) administration and in vivo knockout of cyp11c1 demonstrated that igf3 expression is regulated by androgens, suggesting that Igf3 acts downstream of androgens in fish spermatogenesis. Notably, the igf3 knockout did not affect body growth, indicating that this Igf specifically functions in reproduction. Taken together, our data provide genetic evidence for fish igf3 in the regulation of reproductive capacity by controlling spermatogenesis. [ABSTRACT FROM AUTHOR]

Purpose of Review: The decreased contact area, edge loading, and increased stress in the adjacent area cartilage resulting from chondral defects are believed to predispose this tissue to degenerative changes that have significant economic implications, especially when considering its progression to osteoarthritis of the knee. Growth factors are considered therapeutic possibilities to enhance healing of chondral injuries and modify the progression to degenerative arthritis. Thus, the purposes of this review are to first to summarize important points for defect preparation and recent advances in techniques for marrow stimulation and second, and to identify specific growth factors and cytokines that have the capacity to advance cartilage regeneration and the treatment of osteoarthritis in light of recent laboratory and clinical studies. Recent Findings: TGF-β, BMP-2, BMP-7, IGF-1, as IL-1 receptor antagonist, and recombinant human FGF-18 are some of the promising growth factor/cytokine treatments with pioneering and evolving clinical developments. The bulk of the review describes and discusses these developments in light of fundamental basic science. It is crucial to also understand the other underlying advances made in the surgical management of cartilage defects prior to onset of OA. These advances are in techniques for defect preparation and marrow stimulation, a common cartilage repair procedure used in combination with growth factor/cytokine augmentation. Summary: Multiple growth factor/cytokine modulation therapies are currently undergoing clinical trial investigation including Invossa (currently in phase III study), Kineret (currently in phase I study), and Sprifermin (currently in phase II study) for the treatment of symptomatic osteoarthritis. [ABSTRACT FROM AUTHOR]

The aim of this study was to replace fetal bovine serum (FBS) with platelet-rich plasma (PRP) for in vitro production of bovine embryos. The maturation media (TCM-199 medium) for the cumulus-oocyte complexes (COCs) was supplemented with 5% (G5) and 10% (G10) PRP or 10% FBS (GC). After fertilization, the presumed zygotes were randomly distributed in culture medium supplemented with 5% (G5) and 10% (G10) PRP or 10% FBS (GC) for 7 days. Cumulus cell (CC) expansion was greater (P < 0.05) in the GC (88.9%) group than in G5 (34.1%) or G10 (50.0%). Nevertheless, the expansion of CCs in group G10 was greater than in G5 (P < 0.05). Cleavage was higher in group G5 (86.0%) than in G10 (79.0%) (P < 0.05) and did not differ from group GC (82.0%). The percentage of blastocysts in group G5 (50.0%) was higher than in CG (40.2%) and G10 (34.2%) (P < 0.05). In addition, the number of blastomeres was higher in G5 (159.0 ± 4.18) than in GC (132.4 ± 4.11) and in G10 (127.1 ± 5.88) (P < 0.05). The addition of PRP into the oocytes maturation medium is not beneficial. On the other hand, the PRP addition into the embryo culture medium at 5% concentration is recommended where it increased the quantity and quality of in vitro–produced bovine embryos. [ABSTRACT FROM AUTHOR]

Heart disease represents a significant public health burden and is associated with considerable morbidity and mortality at the level of the individual. Current therapies for pathologies such as myocardial infarction, cardiomyopathy and heart failure are unable to repair damaged tissue to an extent that provides restoration of function approaching that of the pre-diseased state. Novel approaches to repair and regenerate the injured heart include cell therapy and the use of exogenous factors. Improved understanding of the role of growth factors in endogenous cardiac repair processes has motivated the investigation of their potential as therapeutic agents for cardiac pathology. Despite the disappointing performance of other growth factors in historical clinical trials, insulin-like growth factor 1 (IGF-1), neuregulin and platelet-derived growth factor (PDGF) have recently emerged as new candidate therapies. These growth factors elicit tissue repair through anti-apoptotic, pro-angiogenic and fibrosis-modulating mechanisms and have produced clinically significant functional improvement in preclinical studies. Early human trials suggest that IGF-1 and neuregulin are well tolerated and yield dose-dependent benefit, warranting progression to later phase studies. However, outstanding challenges such as short growth factor serum half-life and insufficient target-organ specificity currently necessitate the development of novel delivery strategies. [ABSTRACT FROM AUTHOR]

The cartilage of joints, such as meniscus and articular cartilage, is normally long lasting (i.e., permanent). However, once damaged, especially in large animals and humans, joint cartilage is not spontaneously repaired. Compensating the lack of repair activity by supplying cartilage-(re)forming cells, such as chondrocytes or mesenchymal stromal cells, or by transplanting a piece of normal cartilage, has been the basis of therapy for biological restoration of damaged joint cartilage. Unfortunately, current biological therapies face problems on a number of fronts. The joint cartilage is generated de novo from a specialized cell type, termed a 'joint progenitor' or 'interzone cell' during embryogenesis. Therefore, embryonic chondroprogenitors that mimic the property of joint progenitors might be the best type of cell for regenerating joint cartilage in the adult. Pluripotent stem cells (PSCs) are expected to differentiate in culture into any somatic cell type through processes that mimic embryogenesis, making human (h)PSCs a promising source of embryonic chondroprogenitors. The major research goals toward the clinical application of PSCs in joint cartilage regeneration are to (1) efficiently generate lineage-specific chondroprogenitors from hPSCs, (2) expand the chondroprogenitors to the number needed for therapy without loss of their chondrogenic activity, and (3) direct the in vivo or in vitro differentiation of the chondroprogenitors to articular or meniscal (i.e., permanent) chondrocytes rather than growth plate (i.e., transient) chondrocytes. This review is aimed at providing the current state of research toward meeting these goals. We also include our recent achievement of successful generation of "permanent-like" cartilage from long-term expandable, hPSC-derived ectomesenchymal chondroprogenitors. [ABSTRACT FROM AUTHOR]

The graft of human amniotic membrane (HAM) contributes to the healing of corneal perforating ulcers and so to save a large number of eyes suffering of severe chemical burns. This biological material is used for the treatment of ocular surface diseases because of its capacity to reduce inflammation and promote a quicker wound healing. For clinical use, the HAM is denuded from its spongy layer, but this layer can be an important source of growth factors which promote re-epithelialization. The aim of our study is to provide a general view of protein expression of the HAM and the spongy layer and therefore to determine if the spongy layer and/or a specific part of HAM have a beneficial role in the process of wound healing in patients with corneal ulcers. For this study, human placentas were obtained from healthy women after vaginal delivery or caesarean section after signing the consent form. Mapping of protein expression is done by dividing the placenta in 2 equal parts, one with spongy layer and another without (conventional HAM). Each part is also divided in 3 zones depending on the distance from the umbilical cord. The proteomic analysis was done by ELISA, targeting growth factors (EGF, HGF, KGF, NGF and TGF-beta1) and pro inflammatory cytokine TNF-α in the HAM without spongy layer and in the spongy layer. In this study we observed significant difference in the total amount of protein extract between the different donors. We do not observe a significant difference in the growth factor level between the conventional HAM and the spongy layer. No variation was observed in the expression of HGF, KGF and NGF in different zone of HAM and neither between conventional HAM and spongy layer in each zone. (*p value < 0.05, **p value<0.01,***p value < 0.001). We do detect very low dose of TNF-α and no correlation with the amount of growth factors. In our study we demonstrated that keeping the spongy layer in conventional method of handling HAM can add more GF, and so probably have a positive affect the wound healing process. Variation in some growth factors expression has been observed between the placentas and therefore this may explain the variation in clinical results. No indicator for the selection of placentas with a higher rate of growth factor was found. [ABSTRACT FROM AUTHOR]

Male reproductive organ plays an important role in sperm production, maintenance and entry to the female reproductive tract, as well as generation and secretion of male sex hormones responsible for the health of male reproductive system. The purpose of this paper is to discuss the experimental and clinical evidence on the utilization of tissue engineering techniques in treating male infertility. Tissue engineering (TE) and regenerative medicine have developed new approaches to treat patients with reproductive disorders such as iatrogenic injuries, congenital abnormalities, and trauma. In some cases, including congenital defects and undescended testis or hypogonadism, the sperm samples are not retrieved. This makes TE a possible future strategy for restoration of male fertility. Here, we have summarized the recent advances in experimental and clinical application of cell-, tissue-, and organ-based regenerative medicine in male reproductive disorders. [ABSTRACT FROM AUTHOR]

The 5-year mortality rate for heart failure borders on 50%. The main cause is an ischaemic cardiac event where blood supply to the tissue is lost and cell death occurs. Over time, this damage spreads and the heart is no longer able to pump efficiently. Increasing vascularisation of the affected area has been shown to reduce patient symptoms. The growth factors required to do this have short half-lives making development of an efficacious therapy difficult. Herein, the angiogenic growth factor Vascular Endothelial Growth Factor (VEGF) is complexed electrostatically with star-shaped or linear polyglutamic acid (PGA) polypeptides. Optimised PGA-VEGF nanomedicines provide VEGF encapsulation of > 99% and facilitate sustained release of VEGF for up to 28 days in vitro. The star-PGA-VEGF nanomedicines are loaded into a percutaneous delivery compliant hyaluronic acid hydrogel. Sustained release of VEGF from the composite nano-in-gel system is evident for up to 35 days and the released VEGF has comparable bioactivity to free, fresh VEGF when tested on both Matrigel® and scratch assays. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. Therefore, we report the development of novel, self-assembling PGA-VEGF nanomedicines and their incorporation into a hyaluronic acid hydrogel that is compatible with medical devices to enable minimally invasive delivery to the heart. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. This formulation provides the basis for optimal spatiotemporal delivery of an angiogenic growth factor to the ischaemic myocardium. [ABSTRACT FROM AUTHOR]

Objective: To systematically assess the effects of platelet-rich fibrin (PRF) on in vitro cellular behavior. Methods: A systematic electronic search using MEDLINE database was performed. In vitro studies using PRF were considered and articles published up to June 31, 2018 were screened. Eligible studies were selected based on the use of human PRF. Results: In total, 1746 titles were identified with the search terms, from these 37 met the inclusion criteria and were chosen for data extraction. In addition, 16 new studies, mainly published in 2019, were also included in the analysis resulting in 53 studies. No meta-analysis could be performed due to the heterogeneity of study designs. Included studies show that PRF enhances proliferation, migration, adhesion, and osteogenic differentiation on a variety of cell types along with cell signaling activation. Furthermore, PRF reduces inflammation, suppresses osteoclastogenesis, and increases the expression of various growth factors in mesenchymal cells. Summary and conclusions: Despite some notable differences of the studies, the overall findings suggest a positive effect of PRF on cell proliferation, migration, adhesion, differentiation, and inflammation pointing towards a therapeutic potential in regenerative dentistry. Clinical relevance: PRF serves as a reservoir of bioactive molecules to support wound healing and bone regeneration. Although the cellular mechanisms by which PRF supports the clinical outcomes remain unclear, in vitro research provides possible explanations. This systematic review aims to provide an update of the existing research on how PRF affects basic physiological processes in vitro. The overall findings suggest that PRF induces cell proliferation, migration, adhesion, and differentiation along with possessing anti-inflammatory properties further supporting its therapeutic potential in wound healing and bone regeneration. [ABSTRACT FROM AUTHOR]

Hypertension has been linked with peripheral and central reductions in vascular density, and with devastating effects on brain function. However, the underlying mechanisms in the relationship between blood pressure and cognitive impairment have yet to be fully elucidated. Here, we review compelling evidence from two lines of inquiry: one that links microvascular rarefaction with insulin-like growth factor 1 (IGF-1) deficiencies, and another which posits that vascular dysfunction precedes hypertension. Based on the findings from experimental and clinical studies, we propose that these lines of evidence converge, and suggest that age-related declines in IGF-1 concentrations precede microvascular rarefaction, initiate an increase in vascular resistance, and therefore are causally linked to onset of hypertension. Physical exercise provides a relevant model for supporting our premise, given the well-established effects of exercise in attenuating vascular dysfunction, hypertension, IGF-1 deficiency, and cognitive decline. We highlight here the role of exercise-induced increases in blood flow in improving vascular integrity and enhancing angiogenesis via the actions of IGF-1, resulting in reversal of rarefaction and hypertension, and enhancement of cerebral blood flow and cognition. [ABSTRACT FROM AUTHOR]

Regenerative medicine that had emerged as a scientific and medical discipline at end of 20th century uses cultured cells and tissue-engineered structures for transplantation into human body to restore lost or damaged organs. However, practical achievements in this field are far from the promising results obtained in laboratory experiments. Searching for new directions has made apparent that successful solution of practical problems is impossible without understanding the fundamental principles of the regulation of development, renewal, and regeneration of human tissues. These aspects have been extensively investigated by cell biologists, physiologists, and biochemists working in a specific research area often referred to as regenerative biology. It is known that during regeneration, growth factors, cytokines, and hormones act beyond the regulation of individual cell functions, but rather activate specific receptor systems and control pivotal tissue repair processes, including cell proliferation and differentiation. These events require numerous coordinated stimuli and, therefore, are practically irreproducible using single proteins or low-molecular-weight compounds, i.e., cannot be directed by applying classical pharmacological approaches. Our review summarizes current concepts on the regulatory mechanisms of renewal and regeneration of human tissues with special attention to certain general biological and evolutionary aspects. We focus on the biochemical regulatory mechanisms of regeneration, in particular, the role of growth factors and cytokines and their receptor systems. In a separate section, we discussed practical approaches for activating regeneration using small molecules and stem cell secretome containing a broad repertoire of growth factors, cytokines, peptides, and extracellular vesicles. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to differentiate and characterize fibroblast-like cells from stem cells from human exfoliated deciduous teeth (SHED). Materials and methods: The differentiation of fibroblast-like cells from SHED was carried out by using specific human recombinant connective tissue growth factor (CTGF). To characterize fibroblastic differentiation, the induced cells were subjected to morphological changes, proliferation rate, gene expression analysis using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and immunofluorescence staining. The commercial primary human gingival fibroblasts served as positive control in this study. Results: The results from characterization analysis were compared with that of commercial cells to ensure that the cells differentiated from SHED were fibroblast-like cells. The results showed the inductive effect of CTGF for fibroblastic differentiation in SHED. SHED-derived fibroblasts were successfully characterized despite having similar morphological appearance, i.e., (i) significant proliferation rate between fibroblast-like cells and SHED, (ii) high expression of fibroblast-associated markers in qRT-PCR analysis, and (iii) positive staining against collagen type 1, fibroblast-specific protein 1, and human thymic fibroblasts in flow cytometry analysis and immunofluorescence staining. The same expression patterns were found in primary human gingival fibroblasts, respectively. SHED as negative control showed lower expression or no signal, thus confirming the cells differentiated from SHED were fibroblast-like cells. Conclusions: Taken together, the protocol adopted in this study suggests CTGF to be an appropriate inducer in the differentiation of SHED into fibroblast-like cells. Clinical relevance: The fibroblast-like cells differentiated from SHED could be used in future in vitro and in vivo dental tissue regeneration studies as well as in clinical applications where these cells are needed. [ABSTRACT FROM AUTHOR]

Stem cell therapy is considered to be a promising future treatment for intractable neurological diseases, although all the clinical trials using stem cells have not yet shown any good results. Early passage mesenchymal stem cells (MSCs) have been used in most clinical trials because of the issues on safety and efficacy. However, it is not easy to get plenty of cells enough for the treatment and it costs too much. Lots of late passage MSCs can be obtained at lower cost but their efficacy would be a big hurdle for clinical trials. If late passage MSCs with better efficacy could be used in clinical trials, it could be a new and revolutionary solution to reduce cost and enhance easier clinical trials. In the present study, it was investigated whether late passage MSCs could be induced into glia-like cells (ghMSCs); ghMSCs had better efficacy and they protected neurons and the brain from ischemia, and insulin-like growth factor binding protein-4 (IGFBP-4) played a critical role in beneficial effect of ghMSCs. ghMSCs were induced from MSCs and treated in in vitro and in vivo models of ischemia. They effectively protected neurons from ischemia and restored the brain damaged by cerebral infarction. These beneficial effects were significantly blocked by IGFBP-4 antibody. The current study demontsrated that late passage hMSCs can be efficiently induced into ghMSCs with better neuroprotective effect on ischemic stroke. Moreover, the results indicate that IGFBP-4 released from ghMSCs may serve as one of the key neuronal survival factors secreted from ghMSCs. [ABSTRACT FROM AUTHOR]

It has been demonstrated that interstitial fluid (IF) flow can play a crucial role in tumor cell progression. Swartz and collaborators (Cancer Cell 11: 526–538, Shields et al. 2007) demonstrated that cells that secrete the lymphoid homing chemokines CCL21/CCL19 and express their receptor CCR7 could use flow to bias the secreted chemokine, causing pericellular gradients that stimulate cells to migrate in the direction of the flow. In a further work by Shieh et al. (Cancer Res 71: 790–800, 2011), a synergetic enhancement of tumor cell invasion caused by interaction between tumor cells and fibroblasts in the presence of fluid flow was reported. In the present work, we extend a previous proposed cell-fluid mathematical model for autologous chemotaxis (Chem Eng Sci 191: 268–287, Waldeland and Evje 2018) to also include fibroblasts. This results in a cell-fibroblast-fluid model. Motivated by the experimental findings by Shieh et al, the momentum balance equation for the fibroblasts involves (1) a stress term that accounts for chemotaxis in the direction of positive gradients in secreted growth factor TGF- β ; (2) a fibroblast–ECM interaction term; (3) a cancer cell–fibroblast interaction term. Imposing reasonable simplifying assumptions, we derive an explicit expression for the cancer cell velocity u c that reveals a balance between a fluid-generated stress term, a chemotactic-driven migration term (autologous chemotaxis), and a new term that accounts for the possible mechanical interaction between fibroblasts and cancer cells. Similarly, the model provides an expression for the fibroblast velocity u f as well as the IF velocity u w . The three-phase model is then used for comparison of the simulated output with experimental results to elucidate some of the possible mechanism(s) behind the reported fibroblast-enhanced tumor cell invasion. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to compare the effects of drying and fresh-freezing on human amniotic membrane (HAM) and amnion/chorion membrane (HACM) in terms of histological and structural characteristics and cytokine levels. HAM and HACM samples, obtained from six placentae, were investigated. HAM and HACM were dried, electron beam-irradiated (dehydration group; d-HAM/d-HACM), or fresh-frozen (freezing group; f-HAM/f-HACM). Luminex assay was used to assay the levels of 15 cytokines. The ultrastructural characteristics of HAM and HACM were evaluated using light and transmission electron microscopies. Total cytokine contents did not show the statistical difference between dehydration and fresh-freezing process. Significantly higher levels of total cytokines were observed in HACM than in HAM. Epidermal growth factor (EGF) level was significantly higher in d-HAM than in the other samples. The levels of most of the other growth factors were higher in HACM than in HAM, but there was no statistical difference between the dehydration process and the fresh-freezing process. The levels of the cytokines, other than the growth factors, were higher in HACM than in HAM, and higher concentrations of cytokines were observed in the freezing group than in the dehydration group. Histological examination revealed that the dehydration group had thinner tissues than the freezing group, but the structural stability, including the basement membrane, did not differ between the two groups. Microscopic structures such as microvilli and nuclei were well-preserved in the freezing group, based on the results of the transmission electron microscopy. Our dehydration process maintained the histological structure of HAM/HACM and a variety of growth factors and cytokines were identified. Especially, the HAM, processed with the dehydration method, had a higher EGF level than that processed with the fresh-freezing method. Therefore, dehydration method can be used to effectively promote wound repair. [ABSTRACT FROM AUTHOR]

Intervertebral disc (IVD) degeneration (IDD) is considered as one of the major causes for low back pain (LBP). However, conventional surgical approaches for treating LBP do not aim to counter the degeneration. Biological interventions have been investigated with an attempt to regenerate the IVD by restoring its matrices and cell activities. This review summarizes the current clinical trials that explore the efficacy of covering cell-, growth factor-, and small molecule-based approaches. While investigations of growth factor- and small molecule-based therapies are still preliminary, intradiscal delivery of mesenchymal stromal cells has been more widely adopted and shown positive results in addressing the pain and the associated physical disability, albeit to a lower extent than observed in previous animal studies. Strategies that potentiate the endogenous disc progenitors may offer a valid alternative to the exogenous cell transplantation. Identification of the novel biologics to arrest IDD phenotype may potentiate disc repair in future. Large-scale, high-quality long-term trials should be conducted to clarify the safety and efficacy of these therapies. [ABSTRACT FROM AUTHOR]

Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration. [ABSTRACT FROM AUTHOR]

Identification of new drug and cell therapy targets for disease treatment will be facilitated by a detailed molecular understanding of normal and disease development. Human pluripotent stem cells can provide a large in vitro source of human cell types and, in a growing number of instances, also three-dimensional multicellular tissues called organoids. The application of stem cell technology to discovery and development of new therapies will be aided by detailed molecular characterisation of cell identity, cell signalling pathways and target gene networks. Big data or 'omics' techniques—particularly transcriptomics and proteomics—facilitate cell and tissue characterisation using thousands to tens-of-thousands of genes or proteins. These gene and protein profiles are analysed using existing and/or emergent bioinformatics methods, including a growing number of methods that compare sample profiles against compendia of reference samples. This review assesses how compendium-based analyses can aid the application of stem cell technology for new therapy development. This includes via robust definition of differentiated stem cell identity, as well as elucidation of complex signalling pathways and target gene networks involved in normal and diseased states. [ABSTRACT FROM AUTHOR]

Abstract Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator‐3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3‐depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild‐type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells.

The inducible repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) eliminates O6-methylguanine adducts in DNA and protects the cells from damaging effects of alkylating agents. We have found that anti-MGMT antibodies recognize both the MGMT protein with a mol. weight ~ 24 kDa and a protein with a mol. weight ~ 48 kDa, which was named MARP (anti-methyltransferase antibody recognizable protein). A number of growth factors and cytokines were shown to regulate the expression of MGMT and MARP proteins. The ranges of concentrations of several growth factors and cytokines that caused increasing or decreasing protein amounts in human cell cultures were determined. The results of special biological experiments have allowed us to assume a possible role of MARP in the repair of alkyl adducts in human cells. [ABSTRACT FROM AUTHOR]

Background/aims: Finding differences in systemic inflammatory response in ulcerative colitis (UC), UC with Clostridium difficile infection (CDI), and CDI could lead to a better ability to differentiate between UC with symptomatic CDI and UC with C. difficile colonization, and could identify specific inflammatory pathways for UC or CDI, which could be therapeutic targets.Methods: We prospectively collected sera from symptomatic UC patients whose stools were tested for toxigenic C. difficile, and from CDI patients who did not have UC (CDI-noUC). The UC patients with positive tests (UC-CDI) were further categorized into responders to CDI treatment (UC-CDI-R) and non-responders (UC-CDI-NR). We compared serum inflammatory mediators among groups using unadjusted and adjusted multivariable statistics.Results: We included 117 UC [27 UC-CDI, 90 UC without CDI (UC-noCDI)] and 16 CDI-noUC patients. Principal component analysis (PCA) did not reveal significant differences either between UC-CDI and UC-noCDI groups, or between UC-CDI-R and UC-CDI-NR groups. In contrast, the PCA showed significant separation between the UC and CDI-noUC groups (P = 0.002). In these two groups, hepatocyte growth factor (HGF) and chemokine (C-C motif) ligand 2 (CCL2) levels were significantly lower and IL-23 levels were higher in UC patients in multivariable analyses. The model to distinguish UC from CDI including IL-23, HGF, CCL2, age, gender, and HGB had an AuROC of 0.93.Conclusion: Inflammatory profiles could not distinguish UC-CDI from UC-noCDI, and UC-CDI-R from UC-CDI-NR. However, the UC and CDI-noUC groups were significantly different. Future work should examine whether therapeutic agents inhibiting IL-23 or stimulating HGF can treat UC. [ABSTRACT FROM AUTHOR]

Psychological factors have been shown to influence the process of wound healing. This study examined the effect of Mindfulness-Based Stress Reduction (MBSR) on the speed of wound healing. The local production of pro-inflammatory cytokines and growth factors was studied as potential underlying mechanism. Forty-nine adults were randomly allocated to a waiting-list control group (n = 26) or an 8-week MBSR group (n = 23). Pre- and post-intervention/waiting period assessment for both groups consisted of questionnaires. Standardized skin wounds were induced on the forearm using a suction blister method. Primary outcomes were skin permeability and reduction in wound size monitored once a day at day 3, 4, 5, 6, 7, and 10 after injury. Secondary outcomes were cytokines and growth factors and were measured in wound exudates obtained at 3, 6, and 22 h after wounding. Although there was no overall condition effect on skin permeability or wound size, post hoc analyses indicated that larger increases in mindfulness were related to greater reductions in skin permeability 3 and 4 days after wound induction. In addition, MBSR was associated with lower levels of interleukin (IL)-8 and placental growth factor in the wound fluid 22 h after wound induction. These outcomes suggest that increasing mindfulness by MBSR might have beneficial effects on early stages of wound healing. Trial Registration NTR3652, http://www.trialregister.nl [ABSTRACT FROM AUTHOR]

Laser- or light-assisted therapies have been used to improve the perifollicular environment by upregulating the expression of growth factors and signaling molecules for hair restoration. The aim of our study was to preclinically and clinically evaluate the therapeutic efficacy and safety of a 1927-nm fractionated thulium laser on pattern hair loss (PHL). An in vivo hairless mouse study and an in vivo human skin environmental scanning electron microscopy (ESEM) study were performed with different power and energy settings. Thereafter, an evaluator-blinded, split-scalp study was conducted to evaluate hair thickness and density in 10 PHL patients treated with 12 sessions of fractionated thulium laser treatment with or without post-laser treatment application of a growth factor-containing (GF) solution. In in vivo hairless mouse skin, inverted cone-shaped zones of thulium laser-induced tissue coagulation (LITC) were noted immediately after treatment in the epidermis and upper to mid-dermis without remarkable ablative tissue injury. The ESEM study revealed round to oval-shaped zones of non-ablative LITC on the surface of the stratum corneum of a human subject immediately after laser irradiation. In PHL patients, 12 sessions of thulium laser monotherapy at 1-week intervals resulted in significantly increased hair density and thickness. Post-laser treatment application of GF solution offered additional therapeutic efficacy by improving hair density and thickness on the split scalp. The use of a fractionated thulium laser with or without post-laser therapy application of GF solution to treat PHL elicited remarkable improvements in hair thickness and hair counts. [ABSTRACT FROM AUTHOR]

Introduction: Spheroids of mesenchymal stem cells (MSCs) in cartilage tissue engineering have been shown to enhance regenerative potential owing to their 3D structure. In this study, we explored the possibility of priming spheroids under different media to replace the use of inductive surface coatings for chondrogenic differentiation.Methods: Rat bone marrow-derived MSCs were organized into cell spheroids by the hanging drop technique and subsequently cultured on hyaluronic acid (HA) coated or non-coated well plates under different cell media conditions. Endpoint analysis included cell viability, DNA and Glycosaminoglycan (GAG) and collagen content, gene expression and immunohistochemistry.Results: For chondrogenic applications, MSC spheroids derived on non-coated surfaces outperformed the spheroids derived from HA-coated surfaces in matrix synthesis and collagen II gene expression. Spheroids on non-coated surfaces gave rise to the highest collagen and GAG when primed with medium containing insulin-like growth factor (IGF) for 1 week during spheroid formation. Spheroids that were grown in chondroinductive raw material-inclusive media such as aggrecan or chondroitin sulfate exhibited the highest Collagen II gene expression in the non-coated surface at 1 week.Conclusion: Media priming by growth factors and raw materials might be a more predictive influencer of chondrogenesis compared to inductive-surfaces. Such tailored bioactivity of the stem cell spheroids in the stage of the spheroid formation may give rise to a platform technology that may eventually produce spheroids capable of chondrogenesis achieved by mere media manipulation, skipping the need for additional culture on a modified surface, that paves the way for cost-effective technologies. [ABSTRACT FROM AUTHOR]