CADD Methods for Developing Novel Compounds Synthesized to Inhibit Tyrosine Kinase Receptors.

Growth factors and their receptor tyrosine kinases play a central role in regulating vital cellular processes such as proliferation, differentiation, division, and cell survival, and they are closely associated with the development of various types of cancer, particularly in the context of angiogenesis. Although several small chemical compounds targeting tyrosine kinase receptors have been approved by the FDA for cancer treatment by inhibiting angiogenesis, there is still a need for more effective medications. in silico studies are now crucial tools for the design of new drugs, offering considerable advantages such as cost and time reduction. In this review, we examined recent in silico research carried out between 2022 and 2024, focusing on new drug candidates synthesized to fight cancer, in particular by targeting tyrosine kinase receptors involved in the process of angiogenesis.

The role of extracellular matrix in angiogenesis: Beyond adhesion and structure.

While the extracellular matrix (ECM) has long been recognized for its structural contributions, anchoring cells for adhesion, providing mechanical support, and maintaining tissue integrity, recent efforts have elucidated its dynamic, reciprocal, and diverse properties on angiogenesis. The ECM modulates angiogenic signaling and mechanical transduction, influences the extent and degree of receptor activation, controls cellular behaviors, and serves as a reservoir for bioactive macromolecules. Collectively, these factors guide the formation, maturation, and stabilization of a functional vascular network. This review aims to shed light on the versatile roles of the ECM in angiogenesis, transcending its traditional functions as a mere structural material. We will explore its engagement and synergy in signaling modulation, interactions with various angiogenic factors, and highlight its importance in both health and disease. By capturing the essence of the ECM's diverse functionalities, we highlight the significance in the broader context of vascular biology, enabling the design of novel biomaterials to engineer vascularized tissues and their potential therapeutic implications.

Crosstalk among WEE1 Kinase, AKT, and GSK3 in Nav1.2 Channelosome Regulation.

The signaling complex around voltage-gated sodium (Nav) channels includes accessory proteins and kinases crucial for regulating neuronal firing. Previous studies showed that one such kinase, WEE1-critical to the cell cycle-selectively modulates Nav1.2 channel activity through the accessory protein fibroblast growth factor 14 (FGF14). Here, we tested whether WEE1 exhibits crosstalk with the AKT/GSK3 kinase pathway for coordinated regulation of FGF14/Nav1.2 channel complex assembly and function. Using the in-cell split luciferase complementation assay (LCA), we found that the WEE1 inhibitor II and GSK3 inhibitor XIII reduce the FGF14/Nav1.2 complex formation, while the AKT inhibitor triciribine increases it. However, combining WEE1 inhibitor II with either one of the other two inhibitors abolished its effect on the FGF14/Nav1.2 complex formation. Whole-cell voltage-clamp recordings of sodium currents (INa) in HEK293 cells co-expressing Nav1.2 channels and FGF14-GFP showed that WEE1 inhibitor II significantly suppresses peak INa density, both alone and in the presence of triciribine or GSK3 inhibitor XIII, despite the latter inhibitor's opposite effects on INa. Additionally, WEE1 inhibitor II slowed the tau of fast inactivation and caused depolarizing shifts in the voltage dependence of activation and inactivation. These phenotypes either prevailed or were additive when combined with triciribine but were outcompeted when both WEE1 inhibitor II and GSK3 inhibitor XIII were present. Concerted regulation by WEE1 inhibitor II, triciribine, and GSK3 inhibitor XIII was also observed in long-term inactivation and use dependency of Nav1.2 currents. Overall, these findings suggest a complex role for WEE1 kinase-in concert with the AKT/GSK3 pathway-in regulating the Nav1.2 channelosome.

The growth factor content as an indicator of platelet counts in platelet-rich plasma.

BACKGROUND: Platelet contains growth factors that enhance tissue repair mechanisms, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF-AA and -AB), and transforming growth factor (TGF)-ß. Autologous platelet-rich plasma (PRP) has been shown to significantly improve the treatment of tendon injuries compared with hyaluronic acid and placebo. The topic of agreement between platelet concentrations and growth factors has been covered in some previous studies, but growth factor levels did not correlate well with platelet concentrations. METHOD: In this study, autologous PRP was prepared by concentrating platelets through a J6-MI centrifuge. The automatic hematology analyzer Sysmex XN-20 was used to analyze the platelet concentration in PRP, and the PRP growth factors were determined by ELISA, including PDGF, transforming growth factor- ß1 (TGF-ß1), and EGF. Statistical analysis was conducted on data from 107 patients who received autologous PRP using Pearson correlation analysis. RESULTS: Pearson correlation analysis revealed PDGF, TGF, and EGF had a strong positive correlation with the platelet concentration of the final PRP product (r = 0.697, p < 0.0001; r = 0.488, p < 0.0001; r = 0.572, p < 0.0001, respectively) CONCLUSIONS: There was a strong positive correlation between the concentration of platelets in the final PRP product and the levels of PDGF-AB, TGF-ß, and EGF. These results suggested straightforward and cost-effective growth factor tests can provide valuable information about platelet content in PRP.

Romiplostim in chemotherapy-induced thrombocytopenia: A review of the literature.

Chemotherapy-induced thrombocytopenia (CIT) is a common challenge of cancer therapy and can lead to chemotherapy dose reduction, delay, and/or discontinuation, affecting relative dose intensity, and possibly adversely impacting cancer care. Besides changing anticancer regimens, standard management of CIT has been limited to platelet transfusions and supportive care. Use of the thrombopoietin receptor agonist romiplostim, already approved for use in immune thrombocytopenia, has shown promising signs of efficacy in CIT. In a phase 2 prospective randomized study of solid tumor patients with platelet counts <100 × 109/L for ≥4 weeks due to CIT, weekly romiplostim corrected the platelet count to >100 × 109/L in 93% (14/15) of patients within 3 weeks versus 12.5% (1/8) of untreated patients (p < 0.001). Including patients treated with romiplostim in an additional single-arm cohort, 85% (44/52) of all romiplostim-treated patients responded with platelet count correction within 3 weeks. Several retrospective studies of CIT have also shown responses to weekly romiplostim, with the largest study finding that poor response to romiplostim was predicted by tumor invasion of the bone marrow (odds ratio, 0.029; 95% CI: 0.0046-0.18; p < 0.001), prior pelvic irradiation (odds ratio, 0.078; 95% CI: 0.0062-0.98; p = 0.048), and prior temozolomide treatment (odds ratio 0.24; 95% CI: 0.061-0.96; p = 0.043). Elsewhere, lower baseline TPO levels were predictive of romiplostim response (p = 0.036). No new safety signals have emerged from romiplostim CIT studies. Recent treatment guidelines, including those from the National Comprehensive Cancer Network, now support consideration of romiplostim use in CIT. Data are expected from two ongoing phase 3 romiplostim CIT trials.

Role of Sticky Bone in the Management of Various Alveolar Bone Defects: A Systematic Review.

AIM: This systematic review aimed to evaluate the effectiveness of sticky bone in managing various alveolar bone defects, examining both its benefits and drawbacks. MATERIALS AND METHODS: The review adhered to PRISMA guidelines and employed a thorough search strategy using major databases, medical subject headings (MeSH) keywords, and Boolean operators. As a result, the systematic review identified 12 studies focusing on the efficacy of sticky bone in treating alveolar bone defects. Inclusion criteria consisted of randomized controlled trials and case series reporting on the outcomes of sticky bone use for bone defect treatment. Two examiners meticulously performed screening, data extraction, and bias assessment, with the risk of bias evaluated using the Cochrane tool. RESULT: The findings indicated significant improvements in bone quality, width, height, and volume, with enhanced predictability in socket preservation and implant placement. Sticky bone was particularly effective in ridge augmentation, guided bone regeneration, and filling periodontal defects, often outperforming alternatives like concentrated growth factors (CGFs) and autologous fibrin glue (AFG). It simplified procedures and reduced resorption during healing, underscoring its value as a versatile adjunct in bone reconstruction surgery. CONCLUSION: Sticky bone demonstrated exceptional results in various oral surgeries, effectively addressing issues such as furcation defects, bone loss, and ridge augmentation, with significant clinical and radiographic improvements. Further research is needed to explore its full potential and refine protocols for broader oral surgery and periodontics applications.

Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models.

Premature ovarian insufficiency (POI) means menopause before 40 years of age affecting about 1% of women. Approaches based on cell therapy and the paracrine effects of stem cells or bioproducts such as platelet-rich plasma have been proposed, but concerns remain about undesired systemic effects, as well as the need to optimize delivery methods through bioengineering methods. This study explores the efficacy of decellularized bovine ovarian cortex extracellular matrix (OvaECM) hydrogels alone and as a growth factor (GF) carrier (OvaECM+GF) in a chemotherapy-induced POI murine model. In vitro assays showed a gradual release of GF from the OvaECM sustained for two weeks. Chemotherapy drastically reduced follicle numbers, but OvaECM+GF treatment restored pre-antral follicle development. Moreover, this treatment notably regenerated the ovarian microenvironment by increasing cell proliferation and microvessel density while reducing chemotherapy-induced apoptosis and fibrosis. Whole-ovary RNA sequencing and gene set enrichment analysis revealed an upregulation of regeneration-related genes and a downregulation of apoptotic pathways. The OvaECM+GF treatment also yielded significantly better outcomes following ovarian stimulation and in vitro fertilization. After two consecutive crossbreeding cycles, OvaECM+GF-treated mice showed normal reproductive function. This research showcases the biocompatibility and efficacy of OvaECM to reverse POI in mice, setting a foundation to explore innovative bioengineering-based POI therapies. STATEMENT OF SIGNIFICANCE: Premature ovarian insufficiency (POI) affects about 1% of women worldwide, causing early menopause before 40 years old. Current treatments alleviate symptoms but do not restore ovarian function. This study explores an innovative approach using ovarian cortex extracellular matrix hydrogels to deliver growth factors into the murine ovarian niche and reverse POI. In vitro release kinetic assays demonstrated a gradual and sustained release of growth factors. In a POI-induced mouse model, intraovarian injections of the hydrogel encapsulating growth factors restored pre-antral follicle development, increased cell proliferation, reduced apoptosis and fibrosis, and improved ovarian response and in vitro fertilization outcomes. Long-term benefits included larger litter sizes. This innovative technique shows promise in regenerating the ovarian environment and improving reproductive outcomes.

An In Vitro Model of the Blood-Brain Barrier for the Investigation and Isolation of the Key Drivers of Barriergenesis.

The blood-brain barrier (BBB) tightly regulates substance transport between the bloodstream and the brain. Models for the study of the physiological processes affecting the BBB, as well as predicting the permeability of therapeutic substances for neurological and neurovascular pathologies, are highly desirable. Existing models, such as Transwell utilizing-models, do not mimic the extracellular environment of the BBB with their stiff, semipermeable, non-biodegradable membranes. To help overcome this, we engineered electrospun membranes from poly L-lactic acid in combination with a nanometric coating of poly(ethyl acrylate) (PEA) that drives fibrillogenesis of fibronectin, facilitating the synergistic presentation of both growth factors and integrin binding sites. Compared to commercial semi-porous membranes, these membranes significantly improve the expression of BBB-related proteins in brain endothelial cells. PEA-coated membranes in combination with different growth factors and extracellular protein coatings reveal nerve growth factor (NGF) and fibroblast growth factor (FGF-2) caused formation of better barriers in vitro. This BBB model offers a robust platform for studying key biochemical factors influencing barrier formation that marries the simplicity of the Transwell model with the highly tunable electrospun PEA-fibronectin membranes. This enables the generation of high-throughput drug permeability models without the need of complicated co-culture conditions.

Emerging Role of Hippo-YAP (Yes-Associated Protein)/TAZ (Transcriptional Coactivator with PDZ-Binding Motif) Pathway Dysregulation in Renal Cell Carcinoma Progression.

Although Hippo-YAP/TAZ pathway involvement has been extensively studied in the development of certain cancers, the involvement of this cascade in kidney cancer progression is not well-established and, therefore, will be the focus of this review. Renal cell carcinoma (RCC), the most prevalent kidney tumor subtype, has a poor prognosis and a high mortality rate. Core Hippo signaling inactivation (e.g., LATS kinases) leads to the nuclear translocation of YAP/TAZ where they bind to co-transcriptional factors such as TEAD promoting transcription of genes which initiates various fibrotic and neoplastic diseases. Loss of expression of LATS1/2 kinase and activation of YAP/TAZ correlates with poor survival in RCC patients. Renal-specific ablation of LATS1 in mice leads to the spontaneous development of several subtypes of RCC in a YAP/TAZ-dependent manner. Genetic and pharmacological inactivation of YAP/TAZ reverses the oncogenic potential in LATS1-deficient mice, highlighting the therapeutic benefit of network targeting in RCC. Here, we explore the unique upstream controls and downstream consequences of the Hippo-YAP/TAZ pathway deregulation in renal cancer. This review critically evaluates the current literature on the role of the Hippo pathway in RCC progression and highlights the recent scientific evidence designating YAP/TAZ as novel therapeutic targets against kidney cancer.

In silico modeling the potential clinical effect of growth factor treatment on the metabolism of human nucleus pulposus cells.

Background: While growth factors have the potential to halt degeneration and decrease inflammation in animal models, the literature investigating the effect of dosage on human cells is lacking. Moreover, despite the completion of clinical trials using growth differentiation factor-5 (GDF-5), no results have been publicly released. Aims: The overall objective was to quantitatively assess the effect of three clinically relevant concentrations of GDF-5 (0.25, 1, and 2 mg) as a therapeutic for disc regeneration. Materials and methods: Firstly, this work experimentally determined the effects of GDF-5 concentration on the metabolic and matrix synthesis rates of human nucleus pulposus (NP) cells. Secondly, in silico modeling was employed to predict the subsequent regenerative effect of different GDF-5 treatments (± cells). Results: This study suggests a trend of increased matrix synthesis with 0.25 and 1 mg of GDF-5. However, 2 mg of GDF-5 significantly upregulates oxygen consumption. Despite this, in silico models highlight the potential of growth factors in promoting matrix synthesis compared to cell-only treatments, without significantly perturbing the nutrient microenvironment. Discussion: This work elucidates the potential of GDF-5 on human NP cells. Although the results did not reveal statistical differences across all doses, the variability and response among donors is an interesting finding. It highlights the complexity of human response to biological treatments and reinforces the need for further human research and personalized approaches. Furthermore, this study raises a crucial question about whether these potential biologics are more regenerative in nature or better suited as prophylactic therapies for younger patient groups. Conclusion: Biological agents exhibit unique characteristics and features, demanding tailored development strategies and individualized assessments rather than a one-size-fits-all approach. Therefore, the journey to realizing the full potential of biological therapies is long and costly. Nonetheless, it holds the promise of revolutionizing spinal healthcare and improving the quality of life for patients suffering from discogenic back pain.

Mesoporous silica thin film as effective coating for enhancing osteogenesis through selective proteins adsorption and blood clotting.

The role of blood clot in tissue repair has been identified for a long time whereas its participation in the integration between implants and host tissues has attracted attentions only in recent years. In this work, the mesoporous silica thin film (MSTF) with either vertical or parallel orientation was deposited on titania nanotubes (TNT) surface, resulting in superhydrophilic nanoporous surfaces. Through proteomic analysis of blood plasma adsorption, the MSTF coating could significantly increase the acidic proteins abundance and the coagulation factors (XII and XI) adsorption, with the help of cations (Na+, Ca2+) binding. As a consequent, both platelets activation and the blood clot formation were significantly enhanced on MSTF surface with more condensed fibrin networks. Two classical growth factors of PDGF-AB and TGF-ß were enriched in the blood clots from MSTF surface, which accounted for robust osteogenesis both in vitro and in vivo. In conclusion, the study demonstrates that the MSTF may be a promising coating to enhance osteogenesis through modulating blood clot formation.

Does intra-articular injection of platelet-rich plasma/platelet-rich fibrin improve outcomes after temporomandibular joint arthrocentesis? A systematic review and meta-analysis.

Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have been used as adjuncts to temporomandibular joint (TMJ) arthrocentesis but without any high-quality evidence. This systematic review collated data from published randomised controlled trials (RCTs) to provide level-1 evidence on its efficacy. Trials published on the databases of PubMed, Scopus, Embase, CENTRAL, and Web of Science up to 4 August 2023 and comparing intra-articular PRP/PRF with control after TMJ arthrocentesis were eligible. Primary outcomes were pain and maximal mouth opening (MMO). Twelve RCTs were included. Pooled analysis showed that pain scores were significantly reduced with the use of PRP/PRF as compared with control at one month (MD: -0.96 95% CI: -1.58 to -0.35 I2 = 86%), three months (MD: -1.22 95% CI: -1.86 to -0.59 I2 = 85%), and ≥six months (MD: -1.61 95% CI: -2.22 to -1.00 I2 = 88%). Similarly, MMO was significantly improved in the PRP/PRF group at one month (MD: 2.40 95% CI: 1.02 to 3.77 I2 = 88%), three months (MD: 3.17 95% CI: 1.63 to 4.72 I2 = 91%), and ≥six months (MD: 2.98 95% CI: 1.86 to 4.10 I2 = 75%) as compared with the control group. Subgroup analysis for PRP and PRF failed to show any difference in outcomes. Moderate quality evidence suggests that PRP and PRF may significantly improve pain and MMO when used as adjuncts to TMJ arthrocentesis. Due to the small effect size, the clinical significance of the results is questionable. The high heterogeneity in PRP/PRF preparation methods is a significant limitation.

Effects of combined aerobic and resistance training on the inflammatory profile of children with overweight/obesity: A randomized clinical trial.

BACKGROUND: We assessed the effects of a 20-week combined (aerobic and resistance) exercise training programme on the inflammatory profile of prepubertal children with overweight or obesity. METHODS: Totally 109 participants (10.1 ± 1.1 years, 41% girls) were randomly allocated to an exercise or control group. Adiponectin, C-reactive protein, epidermal growth factor, insulin-like growth factor-1, interleukin (IL)-1ß, IL-6, leptin, tumour necrosis factor-α and vascular endothelial growth factor A (VEGFA) were analysed in plasma. Total white blood cell (WBC) count and immune subpopulations (eosinophils, basophils, neutrophils, lymphocytes and monocytes) were also determined. RESULTS: No intervention effect was found for any of the analysed biomarkers (all p ≥ 0.05). We observed a significant sex by intervention interaction for IL-1ß (p = 0.03). When stratifying the sample by sex, the exercise programme induced a significant effect on IL-1ß levels (mean Z-score difference, 0.66 [95% confidence interval 0.32-1.01]) in girls, but not in boys. A lower number of girls in the exercise group showed a meaningful reduction in IL-1ß (i.e., ≥0.2 standard deviations) than in the control group (15% vs. 85%, p = 0.01). CONCLUSIONS: This exercise programme failed to improve the inflammatory profile in prepubertal children with overweight/obesity. Future studies should explore the effect of longer exercise interventions and in combination with diet.

Plant-based hydrolysates as building blocks for cellular agriculture.

Cellular agriculture, an emerging technology, aims to produce animal-based products such as meat through scalable tissue culture methods. Traditional techniques rely on chemically undefined media using fetal bovine serum (FBS) or chemically defined media utilizing specific growth factors. To be a viable alternative to conventional meat production, cellular agriculture requires cost-effective materials with established supply chains for growth media. Here, we investigate hydrolysates from Kikuyu grass, Alfalfa grass, and cattle rearing pellets. We identified conditions that promote C2C12 myoblast cell growth in media containing 0.1% and 0% serum. These effects are more pronounced in combination with existing growth promoters such as insulin, transferrin, and selenium. Overall, the rearing pellet hydrolysates were most effective in promoting growth particularly when in combination with the growth promoters. Our findings suggest that leveraging these materials, along with known growth factors, can facilitate the development of improved, scalable, and commercially viable media for cellular agriculture.

Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75 min mid-LAD balloon occlusion followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45 µg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated the treatment effect at 8 w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4 w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14 days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

Optimal isolation, culture, and in vitro propagation of spermatogonial stem cells in Huaixiang chicken.

Spermatogonial stem cells (SSCs) comprise the foundation of spermatogenesis and hence have great potential for fertility preservation of rare or endangered species and the development of transgenic animals and birds. Yet, developing optimal conditions for the isolation, culture, and maintenance of SSCs in vitro remains challenging, especially for chicken. The objectives of this study were to (1) find the optimal age for SSC isolation in Huaixiang chicken, (2) develop efficient protocols for the isolation, (3) enrichment, and (4) culture of isolated SSCs. In the present study, we first compared the efficiency of SSC isolation using 11 different age groups (8-79 days of age) of Huaixiang chicken. We found that the testes of 21-day-old chicken yielded the highest cell viability. Next, we compared two different enzymatic combinations for isolating SSCs and found that 0.125% trypsin and 0.02 g/L EDTA supported the highest number and viability of SSCs. This was followed by investigating optimal conditions for the enrichment of SSCs, where we observed that differential plating had the highest enrichment efficiency compared to the Percoll gradient and magnetic-activated cell sorting methods. Lastly, to find the optimal culture conditions of SSCs, we compared adding different concentrations of foetal bovine serum (FBS; 2%, 5%, 7%, and 10%) and different concentrations of GDNF, bFGF, or LIF (5, 10, 20, or 30 ng/mL). We found that a combination of 2% FBS and individual growth factors, including GDNF (20 ng/mL), bFGF (30 ng/mL), or LIF (5 ng/mL), best supported the proliferation and colony formation of SSCs. In conclusion, SSCs can be optimally isolated through enzymatic digestion from testes of 21-day-old chicken, followed by enrichment using differential plating. Furthermore, adding 2% FBS and optimized concentrations of GFNF, bFGF, or LIF in the culture promotes the proliferation of chicken SSCs.

Efficacy of using adipose-derived stem cells and PRP on regeneration of 40 -mm long sciatic nerve defect bridged by polyglycolic-polypropylene mesh in canine model.

BACKGROUND: Sciatic nerve repair becomes a focus of research in neurological aspect to restore the normal physical ability of the animal to stand and walk. Tissue engineered nerve grafts (TENGs) provide a promising alternative therapy for regeneration of large gap defects. The present study investigates the regenerative capacity of PRP, ADSCs, and PRP mixed ADSCs on a long sciatic nerve defect (40-mm) bridged by a polyglycolic polypropylene (PGA-PRL) mesh which acts as a neural scaffold. MATERIALS AND METHODS: The study was conducted on 12 adult male mongrel dogs that were randomly divided into 4 groups: Group I (scaffold group); where the sciatic defect was bridged by a (PGA-PRL) mesh only while the mesh was injected with ADSCs in Group II (ADSCs group), PRP in Group III (PRP group). Mixture of PRP and ADSCs was allocated in Group IV (PRP + ADSCs group). Monthly, all animals were monitored for improvement in their gait and a numerical lameness score was recorded for all groups. 6 months-post surgery, the structural and functional recovery of sciatic nerve was evaluated electrophysiologically, and on the level of gene expression, and both sciatic nerve and the gastrocnemius muscle were evaluated morphometrically, histopathologically. RESULTS: Numerical lameness score showed improvement in the motor activities of both Group II and Group III followed by Group IV and the scaffold group showed mild improvement even after 6 months. Histopathologically, all treated groups showed axonal sprouting and numerous regenerated fascicles with obvious angiogenesis in proximal cut, and distal portion where Group IV exhibited a significant remyelination with the MCOOL technique. The regenerative ratio of gastrocnemius muscle was 23.81%, 56.68%, 52.06% and 40.69% for Group I, II, III and IV; respectively. The expression of NGF showed significant up regulation in the proximal portion for both Group III and Group IV (P ≤ 0.0001) while Group II showed no significant difference. PDGF-A, and VEGF expressions were up-regulated in Group II, III, and IV whereas Group I showed significant down-regulation for NGF, PDGF-A, and VEGF (P ≤ 0.0001). CONCLUSION: ADSCs have a great role in restoring the damaged nerve fibers by secreting several types of growth factors like NGF that have a proliferative effect on Schwann cells and their migration. In addition, PRP therapy potentiates the effect of ADSCs by synthesis another growth factors such as PDGF-A, VEGF, NGF for better healing of large sciatic gap defects.

Impact of concentrated growth factor (CGF) injection on acceleration of orthodontic tooth movement in rabbits.

BACKGROUND: The present study aimed to assess how a concentrated growth factor (CGF) injection affects the rate of orthodontic tooth movement in rabbits. METHODS: This experimental investigation employed a split-mouth configuration. Before orthodontic mesialization of the maxillary first molars, CGF was prepared and administered using submucosal injections on the buccal and palatal sides of the maxillary first molars in one randomly assigned quadrant. The opposite quadrant was used as a control. The study examined four time points:1, 2, 3, and 4 weeks. The measurement of tooth movement was conducted at each follow-up point using a digital caliper. The rabbits were euthanized, and their maxillary segments, specifically the maxillary first molars, were studied histologically to identify any alterations occurring on both the tension and compression sides. RESULTS: Significant tooth movement was observed in the experimental sides versus control sides in the second, third, and fourth week of follow-up periods (p ≤ 0.05). Histologically, on the compression side, the CGF group showed bone resorption and periodontal ligament active reactions from the first week and continued throughout the next three weeks. Also, on the tension side, the CGF group depicted cementoblastic and osteoblastic activities from the first week followed by fibroblastic activities from the second week and all activities continued till the fourth week. CONCLUSIONS: CGF has the potential to effectively enhance orthodontic tooth movement without adverse clinical or histological effects.

Analysis of the causal relationship between gut microbiota and bone remodeling growth factor from the gene association.

BACKGROUND: A growing body of evidence indicates a close association between the gut microbiota (GM) and the bone remodeling (BR) process, raising suspicions that the GM may actively participate in BR by modulating the levels of growth factors. However, the precise causal relationship between them remains unclear. Due to many confounding factors, many microorganisms related to BR growth factors have not been identified. We aimed to elucidate the causal relationship between the GM and BR growth factors. METHODS: We evaluated the genome-wide association study (GWAS) summary statistics for GM and five common growth factors associated with BR: namely, bone morphogenetic proteins (BMP), transforming growth factors(TGF), insulin growth factors (IGFs), epidermal growth factors (EGFs), and fibroblast growth factors (FGF). The causal relationship between the GM and BR growth factors was studied by double-sample Mendelian randomized analysis. We used five Mendelian randomization (MR) methods, including inverse variance-weighted (IVW), MR-Egger, simple mode, weighted median, and weighted model methods. RESULTS: Through MR analysis, a total of 56 bacterial genera were co-identified as associated with BMP, TGF, IGF, EGF, and FGF. Among them, eight genera were found to have a causal relationship with multiple growth factors: Marvinbryantia was causally associated with BMP-6 (P = 0.018, OR = 1.355) and TGF-ß2 (P = 0.002, OR = 1.475); Lachnoclostridium, BMP-7 (P = 0.021, OR = 0.73) and IGF-1 (P = 0.046, OR = 0.804); Terrisporobacter, TGF-ß (P = 0.02, OR = 1.726) and FGF-23 levels (P = 0.016, OR = 1.76); Ruminiclostridium5, TGF-ß levels (P = 0.024, OR = 0.525) and FGFR-2 (P = 0.003, OR = 0.681); Erysipelatoclostridium, TGF-ß2 (P = 0.001, OR = 0.739) and EGF and its receptor (EGFR) (P = 0.012, OR = 0.795); Eubacterium_brachy_group, FGFR-2 (P = 0.045, OR = 1.153) and EGF (P = 0.013, OR = 0.7); Prevotella9 with EGFR (P = 0.022, OR = 0.818) and FGFR-2 (P = 0.011, OR = 1.233) and Faecalibacterium with FGF-23 (P = 0.02, OR = 2.053) and IGF-1 (P = 0.005, OR = 0.843). CONCLUSION: We confirmed the causal relationship between the GM and growth factors related to BR, which provides a new perspective for the study of BR, through targeted regulation of specific bacteria to prevent and treat diseases and growth factor-mediated BR disorders.

A study on the impact of acute exercise on cognitive function in Alzheimer's disease or mild cognitive impairment patients: A narrative review.

This narrative review follows the JBI approach and comprehensively explores the effects and mechanisms of acute exercise on cognitive function in Alzheimer's disease (AD) and Mild cognitive impairment (MCI) patients. The results showed that the combination of acute exercise and cognitive training improved the cognitive function of AD patients better than aerobic exercise or resistance training alone. For patients with MCI, moderate intensity acute aerobic exercise and resistance exercise were beneficial to enhance Inhibitory control (IC), but high-intensity acute exercise was adverse to improve IC; Brain-derived neurotrophic factor (BDNF) and Insulin-like growth factor 1 (IGF-1) may assume the potential mediating mechanism of acute exercise on cognitive function in AD and MCI patients, but more research is needed to further confirm this mechanism.