Application of concentrated growth factor in mandibular third molar extraction: A protocol for systematic review and meta-analysis.

OBJECTIVE: We will perform the systematic review to evaluate the effect of applying concentrated growth factor (CGF) on relieving postoperative complications and promoting wound healing following mandibular third molar extraction. METHODS: The PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Biology Medicine Disc (CBM), and VIP Databases will be comprehensively searched up to May 31, 2024. Randomized controlled trials (RCTs) examining the application of CGF after mandibular third molar extraction will be included. The protocol was registered in PROSPERO, and the registration ID was CRD42023463234. Two reviewers will conduct the literature search, eligible study selection, data extraction, and bias risk assessment (using the Cochrane Risk of Bias 2.0 tool). Data analysis will be performed with RevMan software (version 5.4). RESULTS: The results of this study will be available in a peer-reviewed journal. CONCLUSION: Our study will provide scientific evidence regarding the efficacy of applying CGF in mandibular third molar extraction.

Bone Regeneration Facilitated by Autologous Bioscaffold Material: Liquid Phase of Concentrated Growth Factor with Dental Follicle Stem Cell Loading.

The application of bioengineering techniques for achieving bone regeneration in the oral environment is an increasingly prominent field. However, the clinical use of synthetic materials carries certain risks. The liquid phase of concentrated growth factor (LPCGF), as a biologically derived material, exhibits superior biocompatibility. In this study, LPCGF was employed as a tissue engineering scaffold, hosting dental follicle cells (DFCs) to facilitate bone regeneration. Both in vivo and in vitro experimental results demonstrate that this platform significantly enhances the expression of osteogenic markers in DFCs, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and type I collagen (Col1a1). Simultaneously, it reduces the expression of inflammation-related genes, particularly interleukin-6 (IL-6) and interleukin-8 (IL-8), thereby alleviating the negative impact of the inflammatory microenvironment on DFCs. Further investigation into potential mechanisms reveals that this process is regulated over time by the WNT pathway. Our research results demonstrate that LPCGF, with its favorable physical characteristics, holds great potential as a scaffold. It can effectively carry DFCs, thereby providing an optimal initial environment for bone regeneration. Furthermore, LPCGF endeavors to closely mimic the mechanisms of bone healing post-trauma to facilitate bone formation. This offers new perspectives and insights into bone regeneration engineering.

Enhanced Vascular-like Network Formation of Encapsulated HUVECs and ADSCs Coculture in Growth Factors Conjugated GelMA Hydrogels.

Tissue engineering primarily aimed to alleviate the insufficiency of organ donations worldwide. Nonetheless, the survival of the engineered tissue is often compromised due to the complexity of the natural organ architectures, especially the vascular system inside the organ, which allows food-waste transfer. Thus, vascularization within the engineered tissue is of paramount importance. A critical aspect of this endeavor is the ability to replicate the intricacies of the extracellular matrix and promote the formation of functional vascular networks within engineered constructs. In this study, human adipose-derived stem cells (hADSCs) and human umbilical vein endothelial cells (HUVECs) were cocultured in different types of gelatin methacrylate (GelMA). In brief, pro-angiogenic signaling growth factors (GFs), vascular endothelial growth factor (VEGF165) and basic fibroblast growth factor (bFGF), were conjugated onto GelMA via an EDC/NHS coupling reaction. The GelMA hydrogels conjugated with VEGF165 (GelMA@VEGF165) and bFGF (GelMA@bFGF) showed marginal changes in the chemical and physical characteristics of the GelMA hydrogels. Moreover, the conjugation of these growth factors demonstrated improved cell viability and cell proliferation within the hydrogel construct. Additionally, vascular-like network formation was observed predominantly on GelMA@GrowthFactor (GelMA@GF) hydrogels, particularly on GelMA@bFGF. This study suggests that growth factor-conjugated GelMA hydrogels would be a promising biomaterial for 3D vascular tissue engineering.

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study.

INTRODUCTION: Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. METHODS: A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg-1.min-1, and serial doses of apelin-13 (50, 150 and 450 µg.kg-1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. RESULTS: Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). CONCLUSION: Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

Inconsequential role for chemerin-like receptor 1 in the manifestation of ozone-induced lung pathophysiology in male mice.

We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a Gi/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-ß-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.

Cytotoxic effect of dental luting cement on human gingival mesenchymal stem cell and evaluation of cytokines and growth factor release - An in vitro study.

AIM: In routine dental care, various dental luting cements are utilized to cement the dental prosthesis. Thus, the aim of the current study was to assess the Cytotoxic effect of three different dental luting cements on human gingival mesenchymal stem cell and evaluation of cytokines and growth factors release. SETTINGS AND DESIGN: Cytotoxicity of glass ionomer cement (GIC), resin modified glass ionomer cement (RMGIC) and resin cement (RC) on the human gingival mesenchymal stem cells (HGMSCs) was evaluated. Amongst the cements tested, least cytotoxic cement was further tested for the release of cytokines and growth factors. MATERIALS AND METHODS: MTT test was used to evaluate the cytotoxicity of the dental luting cements at 1 h, 24 h, and 48 h on HGMSCs. Cytokines such as interleukin (IL) 1α & IL 8 and growth factors such as platelet derived growth factor & transforming growth factor beta release from the least cytotoxic RC was evaluated using flow cytometry analysis. STATISTICAL ANALYSIS USED: The mean absorbance values by MTT assay and cell viability at various time intervals between four groups were compared using a one way analysis of variance test and Tukey's post hoc test. The least cytotoxic RC group and the control group's mean levels of cytokines and growth factors were compared using the Mann-Whitney test. RESULT: As exposure time increased, the dental luting cement examined in this study were cytotoxic. RC was the least cytotoxic, RMGIC was moderate and glass ionomer cement showed the highest cytotoxic effect. Concomitantly, a significant positive biological response of gingival mesenchymal stem cells with the release of ILs when exposed to the RC was observed. CONCLUSION: For a fixed dental prosthesis to be clinically successful over the long term, it is imperative that the biocompatibility of the luting cement be taken into account in order to maintain a healthy periodontium surrounding the restoration.

Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation.

The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6-/- mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.

SHH regulates penile morphology and smooth muscle through a mechanism involving BMP4 and GREM1.

BACKGROUND: The cavernous nerve (CN) is frequently damaged in prostatectomy and diabetic patients with erectile dysfunction (ED), initiating changes in penile morphology including an acute and intense phase of apoptosis in penile smooth muscle and increased collagen, which alter penile architecture and make corpora cavernosa smooth muscle less able to relax in response to neurotransmitters, resulting in ED. AIM: Sonic hedgehog (SHH) is a critical regulator of penile smooth muscle, and SHH treatment suppresses penile remodeling after CN injury through an unknown mechanism; we examine if part of the mechanism of how SHH preserves smooth muscle after CN injury involves bone morphogenetic protein 4 (BMP4) and gremlin1 (GREM1). METHODS: Primary cultures of smooth muscle cells were established from prostatectomy, diabetic, hypertension and Peyronie's (control) (N = 18) patients. Cultures were characterized by ACTA2, CD31, P4HB, and nNOS immunohistochemical analysis. Patient smooth muscle cell growth was quantified in response to BMP4 and GREM1 treatment. Adult Sprague Dawley rats underwent 1 of 3 surgeries: (1) uninjured or CN-injured rats were treated with BMP4, GREM1, or mouse serum albumin (control) proteins via Affi-Gel beads (N = 16) or peptide amphiphile (PA) (N = 26) for 3 and 14 days, and trichrome stain was performed; (2) rats underwent sham (N = 3), CN injury (N = 9), or CN injury and SHH PA treatment for 1, 2, and 4 days (N = 9). OUTCOMES: Western analysis for BMP4 and GREM1 was performed; (3) rats were treated with 5E1 SHH inhibitor (N = 6) or IgG (control; N = 6) for 2 and 4 days, and BMP4 and GREM1 localization was examined. Statistics were performed by analysis of variance with Scheffé's post hoc test. RESULTS: BMP4 increased patient smooth muscle cell growth, and GREM1 decreased growth. In rats, BMP4 treatment via Affi-Gel beads and PA increased smooth muscle at 3 and 14 days of treatment. GREM1 treatment caused increased collagen and smooth muscle at 3 days, which switched to primarily collagen at 14 days. CN injury increased BMP4 and GREM1, while SHH PA altered Western band size, suggesting alternative cleavage and range of BMP4 and GREM1 signaling. SHH inhibition in rats increased BMP4 and GREM1 in fibroblasts. CLINICAL IMPLICATIONS: Understanding how SHH PA preserves and regenerates penile morphology after CN injury will aid development of ED therapies. STRENGTHS AND LIMITATIONS: SHH treatment alters BMP4 and GREM1 localization and range of signaling, which can affect penile morphology. CONCLUSION: Part of the mechanism of how SHH regulates corpora cavernosa smooth muscle involves BMP4 and GREM1.

Engineering Lymphangiogenesis-On-Chip: The Independent and Cooperative Regulation by Biochemical Factors, Gradients, and Interstitial Fluid Flow.

Despite the crucial role of lymphangiogenesis during development and in several diseases with implications for tissue regeneration, immunity, and cancer, there are significantly fewer tools to understand this process relative to angiogenesis. While there has been a major surge in modeling angiogenesis with microphysiological systems, they have not been rigorously optimized or standardized to enable the recreation of the dynamics of lymphangiogenesis. Here, a Lymphangiogenesis-Chip (L-Chip) is engineered, within which new sprouts form and mature depending upon the imposition of interstitial flow, growth factor gradients, and pre-conditioning of endothelial cells with growth factors. The L-Chip reveals the independent and combinatorial effects of these mechanical and biochemical determinants of lymphangiogenesis, thus ultimately resulting in sprouts emerging from a parent vessel and maturing into tubular structures up to 1 mm in length within 4 days, exceeding prior art. Further, when the constitution of the pre-conditioning cocktail and the growth factor cocktail used to initiate and promote lymphangiogenesis are dissected, it is found that endocan (ESM-1) results in more dominant lymphangiogenesis relative to angiogenesis. Therefore, The L-Chip provides a foundation for standardizing the microfluidics assays specific to lymphangiogenesis and for accelerating its basic and translational science at par with angiogenesis.

Photo-Polymerizable Autologous Growth-Factor Loaded Silk-Based Biomaterial-Inks toward 3D Printing-Based Regeneration of Meniscus Tears.

Meniscus tears in the avascular region undergoing partial or full meniscectomy lead to knee osteoarthritis and concurrent lifestyle hindrances in the young and aged alike. Here they reported ingenious photo-polymerizable autologous growth factor loaded 3D printed scaffolds to potentially treat meniscal defects . A shear-thinning photo-crosslinkable silk fibroin methacrylate-gelatin methacrylate-polyethylene glycol dimethacrylate biomaterial-ink is formulated and loaded with freeze-dried growth factor rich plasma (GFRP) . The biomaterial-ink exhibits optimal rheological properties and shape fidelity for 3D printing. Initial evaluation revealed that the 3D printed scaffolds mimic mechanical characteristics of meniscus, possess favourable porosity and swelling characteristics, and demonstrate sustained GFRP release. GFRP laden 3D scaffolds are screened with human neo-natal stem cells in vitro and biomaterial-ink comprising of 25 mg mL-1 of GFRP (GFRP25) is found to be amicable for meniscus tissue engineering. GFRP25 ink demonstrated rigorous rheological compliance, and printed constructs demonstrated long term degradability (>6 weeks), GFRP release (>5 weeks), and mechanical durability (3 weeks). GFRP25 scaffolds aided in proliferation of seeded human neo-natal stem cellsand their meniscus-specific fibrochondrogenic differentiation . GFRP25 constructs show amenable inflammatory response in vitro and in vivo. GFRP25 biomaterial-ink and printed GFRP25 scaffolds could be potential patient-specific treatment modalities for meniscal defects.

Safety of Plasma Rich in Growth Factors (PRGF) as additive to healthy human sperm samples: a pilot study.

OBJECTIVE: The aim of our study was to assess if the addition of PRGF to healthy human sperm affects its motility and vitality. METHODS: This was a prospective study, with 44 sperm donors on whom sperm analysis was performed. Nine mL of blood was collected and PRGF was obtained using PRGF-Endoret® technology. The influence of different dilutions of PRGF (5%, 10%, 20%, 40%) applied to 15 sperm donors was compared, and sperm motility was assessed after 30 minutes. In the second part of the study, 29 sperm donors were studied to analyze the influence of 20% dilution of PRGF at 15, 30 and 45 minutes in fresh and thawed sperm samples. Motility was assessed after the addition of PRGF and after analysis each aliquot was frozen. After thawing, concentration and motility were assessed at the same time periods. RESULTS: There were no differences in sperm motility in fresh samples between dilutions of PRGF when assessed 30 minutes after administration, nor between them, nor when compared to the control group immediately prior to treatment. No trend was observed between motility and PRGF dilution in linear regression analysis. There were no significant differences in thawed samples. CONCLUSIONS: The administration of 20% PRGF dilution had no effect on sperm motility compared to samples without PRGF. In addition, there was no change in sperm vitality when comparing samples with and without PRGF. More studies focusing on subnormal sperm samples, analyzing different PRGF concentrations and increasing the number of study variables are needed.

The impact of apelin-13 on cisplatin-induced endocrine pancreas damage in rats: an in vivo study.

Apelin-13 is a peptide hormone that regulates pancreatic endocrine functions, and its benefits on the endocrine pancreas are of interest. This study aims to investigate the potential protective effects of apelin-13 in cisplatin-induced endocrine pancreatic damage. Twenty-four rats were divided into four groups: control, apelin-13, cisplatin, and cisplatin + apelin-13. Caspase-3, TUNEL, and Ki-67 immunohistochemical staining were used as markers of apoptosis and mitosis. NF-κB/p65 and TNFα were used to show inflammation. ß-cells and α-cells were also evaluated with insulin and glucagon staining in the microscopic examination. Pancreatic tissue was subjected to biochemical analyses of glutathione (GSH) and malondialdehyde (MDA). Apelin-13 ameliorated cisplatin-induced damage in the islets of Langerhans. The immunopositivity of apelin-13 on ß-cells and α-cells was found to be increased compared to the cisplatin group (p = 0.001, p = 0.001). Mitosis and apoptosis were significantly higher in the cisplatin group (p = 0.001). Apelin-13 reduced TNFα, NF-κB/p65 positivity, and apoptosis caused by cisplatin (p = 0.001, p = 0.001, p = 0.001). While cisplatin caused a significant increase in MDA levels (p = 0.001), apelin caused a significant decrease in MDA levels (p = 0.001). The results demonstrated a significant decrease in pancreatic tissue GSH levels following cisplatin treatment (p = 0.001). Nevertheless, apelin-13 significantly enhanced cisplatin-induced GSH reduction (p = 0.001). On the other hand, the serum glucose level, which was measured as 18.7 ± 2.5 mmol/L in the cisplatin group, decreased to 13.8 ± 0.7 mmol/L in the cisplatin + apelin-13 group (p = 0.001). The study shows that apelin-13 ameliorated cisplatin-induced endocrine pancreas damage by reducing oxidative stress and preventing apoptosis.

Phosphatidylserine accelerates wound healing and reduces necrosis in the rats: Growth factor activation.

To examine the effect of topical phosphatidylserine (PS) on wound healing factors and tissue necrosis in in vivo models. Topical PS was applied to evaluate aspects of the wound healing process and growth factors production of vascular endothelial growth factors (VEGF) as well a necrosis reduction in the skin flap of rat models. Moreover, phenytoin (PHT) and cyclosporine A (CsA) were used topically as positive control treatments in wound and necrosis models, respectively. Immunohistochemistry (IHC) VEGF, transforming growth factor-ß (TGF-ß), fibroblast growth factor (FGF) and histopathology were analysed on the wounds of rats. In the necrosis assessment, necrotic areas were determined on photography taken from the back skin of rats. Results indicated that PS topically enhanced significantly (P < 0.05) numbers of fibroblasts and endothelium while inhibiting the neutrophils and macrophages during the 14 days of wound treatment. Moreover, higher values of collagen deposition and epithelialization scores as well as wound recovery percentage (near 80%) were determined significantly (P < 0.05) in the PS group compared with the control. IHC analysis determined that FGF and VEGF cytokine factors were elevated in the wound site by topical PS. Moreover, the necrotic area was significantly (P < 0.05) improved in the PS group. Our experiment indicated that wound improvement and flap survival values in PS treatments were superior to PHT and CsA control groups, respectively. In conclusion, these findings suggest the potential of PS application in the healing of wounds and control of necrosis development after surgery or skin injuries.

Apelin-13 alleviates osteoclast formation and osteolysis through Nrf2-pyroptosis pathway.

Wear particle-induced periprosthetic osteolysis is the key to aseptic loosening after artificial joint replacement. Osteoclastogenesis plays a central role in this process. Apelin-13 is a member of the adipokine family with anti-inflammatory effects. Here, we report that apelin-13 alleviates RANKL-mediated osteoclast differentiation and titanium particle-induced osteolysis in mouse calvaria. Mechanistically, apelin-13 inhibits NLRP3 inflammasome-mediated pyroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In summary, apelin-13 is expected to be a potential drug for relieving aseptic osteolysis. RESEARCH HIGHLIGHTS: This study reveals the molecular mechanism by which apelin-13 inhibits NLRP3 inflammasome activation and pyroptosis by promoting Nrf2. This study confirms that apelin-13 alleviates osteoclast activation by inhibiting pyroptosis. In vivo studies further confirmed that apelin-13 alleviated mouse skull osteolysis by inhibiting the activation of NLRP3 inflammasome.

Vascular stent with immobilized anti-inflammatory chemerin 15 peptides mitigates neointimal hyperplasia and accelerates vascular healing.

Endovascular stenting is a safer alternative to open surgery for use in treating cerebral arterial stenosis and significantly reduces the recurrence of ischemic stroke, but the widely used bare-metal stents (BMSs) often result in in-stent restenosis (ISR). Although evidence suggests that drug-eluting stents are superior to BMSs in the short term, their long-term performances remain unknown. Herein, we propose a potential vascular stent modified by immobilizing clickable chemerin 15 (C15) peptides on the stent surface to suppress coagulation and restenosis. Various characterization techniques and an animal model were used to evaluate the surface properties of the modified stents and their effects on endothelial injury, platelet adhesion, and inflammation. The C15-immobilized stent could prevent restenosis by minimizing endothelial injury, promoting physiological healing, restraining the platelet-leukocyte-related inflammatory response, and inhibiting vascular smooth muscle cell proliferation and migration. Furthermore, in vivo studies demonstrated that the C15-immobilized stent mitigated inflammation, suppressed neointimal hyperplasia, and accelerated endothelial restoration. The use of surface-modified, anti-inflammatory, endothelium-friendly stents may be of benefit to patients with arterial stenosis. STATEMENT OF SIGNIFICANCE: Endovascular stenting is increasingly used for cerebral arterial stenosis treatment, aiming to prevent and treat ischemic stroke. But an important accompanying complication is in-stent restenosis (ISR). Persistent inflammation has been established as a hallmark of ISR and anti-inflammation strategies in stent modification proved effective. Chemerin 15, an inflammatory resolution mediator with 15-aa peptide, was active at picomolar through cell surface receptor, no need to permeate cell membrane and involved in resolution of inflammation by inhibiting inflammatory cells adhesion, modulating macrophage polarization into protective phenotype, and reducing inflammatory factors release. The implications of this study are that C15 immobilized stent favors inflammation resolution and rapid re-endothelialization, and exhibits an inhibitory role of restenosis. As such, it helps the decreased incidence of ISR.

Method to obtain a plasma rich in platelet- and plasma-growth factors based on water evaporation.

Platelet-Rich Plasma, also known as PRP, is an autologous biologic product used in medicine as a treatment for tissue repair. Nowadays, the majority of PRP obtention methods enrich only platelets, not considering extraplatelet biomolecules, which take part in several cell processes. In the present work, a novel PRP preparation method was developed to obtain a PRP rich in both platelet and plasma extraplatelet molecules. The method is based on the evaporation of the water of the plasma using a rotary evaporator. With this new methodology an increase in plasmatic growth factors and, as a consequence, a better dermal fibroblast cell viability was achieved, compared to a standard PRP formulation. This novel PRP product obtained with this new methodology showed promising results in vitro as an improved PRP treatment in future application.

Dual Growth Factor Delivery Using Photo-Cross-Linkable Gelatin Hydrogels for Effectively Reinforced Regeneration of the Rotator Cuff Tendon.

Rotator cuff tears are currently treated with drugs (steroids and nonsteroidal anti-inflammatory drugs) and surgery. However, the damaged rotator cuff requires a considerable amount of time to regenerate, and the regenerated tissue cannot restore the same level of function as that before the damage. Although growth factors can accelerate regeneration, they are difficult to be used alone because of the risk of degradation and the difficulties in ensuring their sustained release. Thus, hydrogels such as gelatin are used, together with growth factors. Gelatin is a biocompatible and biodegradable hydrogel derived from collagen; therefore, it closely resembles the components of native tissues and can retain water and release drugs continuously, while also showing easily tunable mechanical properties by simple modifications. Moreover, gelatin is a natural biopolymer that possesses the ability to form hydrogels of varying compositions, thereby facilitating effective cross-linking. Therefore, gelatin can be considered to be suitable for rotator-to-tendon healing. In this study, we designed photo-cross-linkable gelatin hydrogels to enhance spacing and adhesive effects for rotator cuff repair. We mixed a ruthenium complex (Ru(II)bpy32+) and sodium persulfate into gelatin-based hydrogels and exposed them to blue light to induce gelation. Basic fibroblast growth factor and bone morphogenetic protein-12 were encapsulated in the gelatin hydrogel for localized and sustained release into the wound, thereby enhancing the cell proliferation. The effects of these dual growth factor-loaded hydrogels on cell cytotoxicity and tendon regeneration in rotator cuff tear models were evaluated using mechanical and histological assessments. The findings confirmed that the gelatin hydrogel was biocompatible and that treatment with the dual growth factor-loaded hydrogels in in vivo rotator cuff tear models promoted regeneration and functional restoration in comparison with the findings in the nontreated group. Therefore, growth factor-loaded gelatin-based hydrogels may be suitable for the treatment of rotator cuff tears.

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice.

Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Liraglutide binds to the G-protein-coupled receptor and activates an adenylyl cyclase and the associated classic growth factor signaling pathway, which acts growth factor-like and neuroprotective properties. The underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on the emotion and memory ability of alcohol-withdrawal mice, and synaptic morphology in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the relapse-like drinking of alcohol-withdrawal mice. The alcohol-withdrawal group was reintroduced to a 20% v/v alcohol and water through the two-bottle choice for four consecutive days, a period referred to as alcohol re-drinking. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory proficiency, and anxiety-like behavior were evaluated using the Morris water maze, open field, and elevated plus maze paradigms. Furthermore, synaptic morphology and the levels of synaptic transport-related proteins were assessed via Golgi staining and Western Blot analysis after a two-week alcohol deprivation period. Alcohol re-drinking of alcohol-withdrawal mice was also evaluated using a two-bottle choice paradigm. Our findings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) in the alcohol group and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01) of alcohol-withdrawal mice. Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transport-related proteins in mice subjected to alcohol withdrawal (p < 0.01). The study findings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxiety induced by alcohol withdrawal. The therapeutic efficacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions and thus prevented relapse-like drinking in alcohol-withdrawal mice.

The combination treatment of methylprednisolone and growth factor-rich serum ameliorates the structural and functional changes after spinal cord injury in rat.

STUDY DESIGN: Preclinical pharmacology. OBJECTIVES: Our study aims to evaluate the combined effect of Methylprednisolone (MP) and growth factor-rich serum (GFRS) on structural and functional recovery in rats following spinal cord injury (SCI). SETTING: Shiraz University of Medical Sciences, Shiraz, Iran METHODS: Male Sprague-Dawley rats were randomly assigned to five groups: sham group (laminectomy); SCI group (the spinal cord clip compression model); SCI-MP group (30 mg/kg MP was administrated intraperitoneally (IP) immediately after SCI); SCI-GFRS group (GFRS (200 µl, IP) was administrated for six consecutive days); and SCI-MP + GFRS group (the rats received MP (30 mg/kg, IP) immediately after SCI, and GFRS (200 µl, IP) for six consecutive days). Motor function was assessed weekly using the Basso, Beattie, and Bresnahan (BBB) scale. After 4 weeks, we conducted the rotarod test, then removed and prepared the spinal cords (including the epicenter of injury) for stereological and histological estimation, and biochemical assays. RESULTS: The results showed that MP and GFRS combining treatment enhanced functional recovery, which was associated with a decrement in lesion volume, increased spared white and gray matter volume, reduced neuronal loss, as well as decreased necrosis and hemorrhage after SCI. Moreover, administration of MP and GFRS inhibited lipid peroxidation (malondialdehyde (MDA) content), and increased antioxidant enzymes including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) after rat SCI. CONCLUSIONS: We suggests that the combination treatment of MP and GFRS may ameliorate the structure and functional changes following SCI by reducing oxidative stress, and increasing the level of antioxidants enzymes.