Search

Implants with deficient papillae and black triangles are common findings. The treatment of these esthetic complications is considered to be challenging with limited predictability. Therefore, the present report aims to describe a novel technique for papilla augmentation: the "iceberg" connective tissue graft (iCTG) after extraction and interproximal bone reconstruction in the anterior region. A 35-year-old patient presented with a hopeless tooth with interproximal clinical attachment loss extending to the apical third of the adjacent tooth. Interproximal bone reconstruction was performed through alveolar ridge preservation by directly applying recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to the exposed root surface of the adjacent tooth. A mixture of autogenous bone chips (obtained from the ramus) and bovine bone xenograft particles (previously mixed with the growth factor) was also used. The patient was able to return for implant therapy only 2 years later, at which time an incomplete regeneration of the interproximal bone was observed. Therefore, to compensate the interproximal deficiency, the iCTG approach was utilized, involving a double layer of CTG with different origins. Two small grafts from the tuberosity were sutured to the mesial and distal ends of a wider CTG harvested from the palate, aiming to gain additional volume at the interproximal sites. The composite graft was then sutured on top of the implant platform, and the flap was then released and closed by primary intention. After conditioning the peri-implant tissues, the case was finalized with a satisfactory outcome. The described iCTG could be an effective approach for reconstructing peri-implant papillae following interproximal bone reconstruction. [ABSTRACT FROM AUTHOR]

Background: Platelet-rich fibrin (PRF) is used to prepare "sticky bone" by combining it with bone graft material. The present study investigated the ability of different bone grafts to absorb growth factors from the PRF and release them over time. Materials and Methods: Human blood was collected from 10 healthy volunteers for liquid PRF preparation. Bovine bone, allograft (mineralized and demineralized), and synthetic bone were each mixed with the PRF to prepare a sticky bone. All sticky bone samples were incubated for up to 4 days. The absorption and release pattern kinetics of two selective growth factors within the PRF--platelet-derived growth factor (PDGF) and bone morphogenetic protein-2 (BMP-2)--were quantified with immunofluorescence staining and enzyme-linked immunoassay (ELISA) testing. Results: All bone graft materials adsorbed the examined growth factors from the PRF. ß-TCP showed the highest adsorption levels, followed by the xenograft, and the allografts showed the lowest adsorption levels. Furthermore, PDGF showed a fast-release pattern from the grafts, whereas BMP-2 was released at a later stage. Similar to the adsorption pattern, the ß-TCP and xenograft were better able to sustain the release of the PRF growth factors from the graft than the allografts. Conclusions: The adsorption of PDGF and BMP-2 differ between graft materials, with superior results for ß-TCP, followed by xenograft, then allograft materials. [ABSTRACT FROM AUTHOR]

This canine in vivo study assessed the effect of recombinant human platelet-derived growth factor (rhPDGF) on the healing of periapical tissues following apical surgery. From a total of 96 premolar teeth, 64 teeth from six beagle dogs (2 years old) were classified as experimental and were randomly assigned to four experimental groups (16 teeth per group). After having the pulp extirpated, leaving teeth open to the oral cavity for 1 week, and sealing with an immediate restorative material for 8 weeks, nonsurgical endodontic treatment was performed. A split-mouth design was used, and intra-animal randomization of treatment sides was applied to the groups as follows: apical curettage + 1.5-mm root-end resection (Group 1); apicoectomy + mineral trioxide aggregate (MTA) root-end filling (Group 2); apicoectomy + MTA root-end filling + rhPDGF (Group 3); and apical curettage + rhPDGF (Group 4). The animals were sacrificed 24 months after apical surgery, and histologic and µCT analyses were performed for bone volume loss (BVL). Group 1 showed partial resolution of the periapical lesions without signs of tissue regeneration (BVL: 49.09 ± 10.97 mm3). Group 2 had minimal bone regeneration and showed cementum reformation in 9 teeth, with no direct attachment to the MTA (BVL: 35.34 ± 10.97 mm3). Group 3 showed regeneration of all damaged apical tissues without direct contact between the cementum and MTA (BLV: 4.51 ± 1.55 mm3). Group 4 showed regeneration of PDL, bone, and cementum and attachment of functional cementum fibers (BVL: 2.82 ± 2.3 mm3). The difference in BVL was statistically significant only for Groups 1 and 2 (P < .05). rhPDGF may help regenerate apical tissue structures following apical surgery. [ABSTRACT FROM AUTHOR]

Traditional GBR procedures have been associated with frequent complications and compromised peri-implant esthetics. Tunneling techniques have been proposed as a promising alternative in this regard. More recently, a subperiosteal minimally invasive aesthetic ridge augmentation technique (SMART) was reported to have been clinically successful in a prospective case series. This technique includes the use of a bone graft/recombinant human platelet-derived growth factor-BB combination delivered to the site by a tunneling method. However, published histologic information regarding the nature of the regenerated tissue has been limited. The current study evaluated the histologic and histomorphometric findings of four human specimens harvested at 2, 5, 9, and 14 months after ridge augmentation using the SMART method. Evaluations of the wound healing and bone regeneration sequence over time found that the ridge augmentation was the result of extensive new bone formation that progressed through the woven bone to lamellar bone stages, with remodeling of the xenogeneic graft material and replacement by patient bone. This is the first study utilizing sequential human specimens to histologically examine the chronology of wound healing following alveolar ridge augmentation. [ABSTRACT FROM AUTHOR]

Objective: The predictability and long-term success of periodontal regeneration begins with oral hygiene education, disease management, and an individually tailored periodontal maintenance protocol. The treatment outcomes could be enhanced when biologics and bone grafts are combined. The aim of this report was to describe the outcome of two complex infrabony defects in the same patient treated with recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and freeze-dried bone allograft (FDBA) over 10 years. Case presentation: Two complex infrabony defects were treated following guided tissue regeneration principles and procedures. Fullthickness flaps were raised to allow visualization of the defects. The areas were debrided, and exposed root surfaces were planed. FDBA and rhPDGF-BB were combined to fill both defects. A collagen membrane was used over the bone graft in one case. The flaps were reapproximated to achieve primary closure. The patient was seen for regular periodontal maintenance visits and clinical and radiographic follow-ups over 10 years. Throughout the examination periods, the probing depths improved without bleeding on probing, and there was radiographic evidence of bone regeneration. Conclusion: The growth factorinfused bone graft was successfully utilized for periodontal regeneration in complex bony defects. [ABSTRACT FROM AUTHOR]

Conditioned media (CM) is derived from mesenchymal stem cells (MSC) culture and contains biologically active components. CM is easy to handle and reduces inflammation while repairing injured joints. Combination therapy of the CM with cross-linked hyaluronic acid (HA) could ameliorate the beneficial effect of HA in treating degenerative changes of articulating surfaces associated with arthritic rats' temporomandibular joints (TMJs). This study aimed to evaluate the therapeutic potential of HA hydrogel combined with bone marrow stem cells-conditioned medium (BMSCs-CM) on the articulating surfaces of TMJs associated with complete Freund's adjuvant (CFA)-induced arthritis. Fifty female Sprague-Dawley rats were divided randomly into five equal groups. Rats of group I served as the negative controls and received intra-articular (IA) injections of 50 µl saline solution, whereas rats of group II were subjected to twice IA injections of 50 µg CFA in 50 µl; on day 1 of the experiment to induce persistent inflammation and on day 14 to induce arthritis. Rats of group III and IV were handled as group II and instead, they received an IA injection of 50 µl HA hydrogel and 50 µl of BMSCs-CM, respectively. Rats of group V were given combined IA injections of 50 µl HA hydrogel and BMSCs-CM. All rats were euthanized after the 4th week of inducing arthritis. The joints were processed for sectioning and histological staining using hematoxylin and eosin, Masson's trichrome and toluidine blue special staining, and immunohistochemical staining for nuclear factor-kappa B (NF-κB). SPSS software was used to analyze the data and one-way analysis of variance followed by post-hoc Tukey statistical tests were used to test the statistical significance at 0.05 for alpha and 0.2 for beta. In the pooled BMSC-CM, 197.14 pg/ml of platelet-derived growth factor and 112.22 pg/ml of interleukin-10 were detected. Compared to TMJs of groups III and IV, TMJs of group V showed significant improvements (P = 0.001) in all parameters tested as the disc thickness was decreased (331.79 ± 0.73), the fibrocartilaginous layer was broadened (0.96 ± 0.04), and the amount of the trabecular bone was distinctive (19.35 ± 1.07). The mean values for the collagen amount were increased (12.29 ± 1.38) whereas the mean values for the NF-κB expression were decreased (0.62 ± 0.15). Combination therapy of HA hydrogel and BMSCs-CM is better than using HA hydrogel or BMSCs-CM, separately to repair degenerative changes in rats' TMJs associated with CFA-induced arthritis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the effect of moxibustion at Governor Vessel (GV) acupoints, including Baihui (GV 20), Shenting (GV 24) and Dazhui (GV 14) for 14 days on glial vascular unit (GVU) in rats with multiple microinfarctions (MMI), and to explore its action mechanism. Methods: The effect and mechanism of moxibustion on vascular dementia (VD) were studied in MMI rats by means of behavioral and molecular biology experiments. Results: Rats receiving MMI showed impairment of memory function, reduction of cerebral blood flow, damage of blood-brain barrier (BBB) integrity and increased brain mass. MMI also increased neuronal degeneration in the hippocampus. Notably, levels of glial fibrillary acidic protein (GFAP) and complement component 3 significantly increased, but those of Connexin43 (CX43) and platelet derived growth factor receptor β (PDGFRβ) significantly decreased in the hippocampus of the rats receiving MMI. Moxibustion, as well as oxiracetam (ORC) treatment improved memory function and neuronal degeneration, ameliorated BBB integrity, increased cerebral blood flow and decreased brain mass. In addition, moxibustion as well as oxiracetam (ORC) treatment reduced the decrease of CX43 protein and increased PDGFRβ protein level in the hippocampus of MMI rats. Moreover, moxibustion treatment reversed MMI-induced increase of the GFAP/CX43 ratio in vascular structural units. Importantly, after PDGFRβ inhibition, VD rats treated with moxibustion had impaired learning and memory, decreased cerebral blood flow, and BBB disruption. Conclusion: Moxibustion treatment at various GV acupoints improved cerebral blood flow and repaired BBB function in rats with MMI, likely through protecting GVU. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited effective therapies. Interstitial macrophages (IMs), especially those derived from monocytes, play an unknown role in IPF pathogenesis. By using single-cell RNA sequencing (scRNA-seq), bleomycin (BLM)-induced pulmonary fibrosis mouse lungs were analyzed to characterize the cellular landscape and heterogeneity of macrophages in this model. scRNA-seq was used to identify distinct interstitial macrophage subpopulations in fibrotic lungs, with monocyte-derived macrophages exhibiting a pro-fibrotic gene expression profile enriched in wound healing, extracellular matrix (ECM) remodeling, and pro-fibrotic cytokine production functions. A pseudotime analysis revealed that IMs originated from monocytes and differentiated along a specific trajectory. A cell–cell communication analysis demonstrated strong interactions between monocyte-derived interstitial macrophages (Mo-IMs) and fibroblasts through the transforming growth factor beta (TGFβ), secreted phosphoprotein 1 (SPP1), and platelet-derived growth factor (PDGF) signaling pathways. Flow cytometry validated the presence and expansion of Mo-IMs subpopulations in BLM-treated mice. This study reveals the cellular heterogeneity and developmental trajectory of lung macrophages in early BLM-induced pulmonary fibrosis, highlighting the crucial role of Mo-IMs with a pro-fibrotic phenotype in IPF pathogenesis via interactions with fibroblasts. Targeting these specific macrophage subpopulations and associated signaling pathways may provide novel therapeutic strategies for IPF. [ABSTRACT FROM AUTHOR]

The development of effective biomaterials for tissue regeneration has led to the exploration of blood derivatives such as leucocyte- and platelet-rich fibrin (L-PRF). A novel variant, Albumin-Enriched Platelet-Rich Fibrin (Alb-PRF), has been introduced to improve structural stability and bioactivity, making it a promising candidate for bone regeneration. This study aimed to evaluate Alb-PRF's capacity for cytokine and growth factor release, along with its effects on the proliferation, differentiation, and mineralization of human osteoblasts in vitro. Alb-PRF membranes were analyzed using histological, scanning electron microscopy, and fluorescence microscopy techniques. Cytokine and growth factor release was quantified over seven days, and osteoinductive potential was evaluated with MG-63 osteoblast-like cells. Structural analysis showed Alb-PRF as a biphasic, highly cellularized material that releases lower levels of inflammatory cytokines and higher concentrations of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) compared to L-PRF. Alb-PRF exhibited higher early alkaline phosphatase activity and in vitro mineralization (p < 0.05) and significantly increased the OPG/RANKL mRNA ratio (p < 0.05). These results indicate that Alb-PRF has promising potential as a scaffold for bone repair, warranting further in vivo and clinical assessments to confirm its suitability for clinical applications. [ABSTRACT FROM AUTHOR]

Infantile haemangioma (IH) – the most common vascular tumour of infancy – is comprised of diverse cell types, including endothelial cells, pericytes, fibroblasts and immune cells. IH is characterized by rapid proliferation followed by slow involution over 1–10 years. Most lesions regress spontaneously, but up to 10% can be disfiguring, with complications that require further medical treatment. Recent research has revealed the biological characteristics of IH, highlighting the involvement of angiogenesis and vasculogenesis during tumour formation. Gene expression profiling has provided vital insights into the underlying biological processes, with some of the key IH-related pathways identified, including vascular endothelial growth factor, the renin–angiotensin–aldosterone system, hypoxia-inducible factor 1α, Notch, platelet-derived growth factor, phosphoinositide 3-kinase/Akt/mammalian target of rapamycin, Janus kinase/signal transducers and activators of transcription, fibroblast growth factor, peroxisome proliferator-activated receptor-γ and insulin-like growth factor. Further evidence suggests extracellular matrix factors and hormone receptors regulate IH progression. In this review, we explore the molecular mechanisms involved in the proliferating, plateau and involuting phases of IH, identifying differentially expressed genes, targeted proteins and key signalling pathways. This knowledge will increase the broader understanding of vascular development, tissue remodelling and angiogenesis. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate the role of high-intensity interval training (HIIT) in promoting myelin sheath recovery during the remyelination phase in cuprizone (CPZ)-induced demyelination mice and elucidate the mechanisms involving the Wnt/β-catenin pathway. Methods: After 5 weeks of a 0.2% CPZ diet to induce demyelination, a 4-week recovery phase with a normal diet was followed by HIIT intervention. Mice body weight was monitored. Morris water maze (MWM) gauged spatial cognition and memory, while the open field test (OFT) assessed anxiety levels. Luxol fast blue (LFB) staining measured demyelination, and immunofluorescence examined myelin basic protein (MBP) and platelet-derived growth factor receptor-alpha (PDGFR-α). Western blotting analyzed protein expression, including MBP, PDGFR-α, glycogen synthase kinase-3β (GSK3β), β-catenin, and p-β-catenin. Real-time PCR detected mRNA expression levels of CGT and CST. Results: HIIT promoted remyelination in demyelinating mice, enhancing spatial cognition, memory, and reducing anxiety. LFB staining indicated decreased demyelination in HIIT-treated mice. Immunofluorescence demonstrated increased MBP fluorescence intensity and PDGFR-α+ cell numbers with HIIT. Western blotting revealed HIIT reduced β-catenin levels while increasing p-β-catenin and GSK3β levels. Real-time PCR demonstrated that HIIT promoted the generation of new myelin sheaths. Additionally, the Wnt/β-catenin pathway agonist, SKL2001, decreased MBP expression but increased PDGFR-α expression. Discussion: HIIT promotes remyelination by inhibiting the Wnt/β-catenin pathway and is a promising rehabilitation training for demyelinating diseases. It provides a new theoretical basis for clinical rehabilitation and care programs. [ABSTRACT FROM AUTHOR]

Background: In the context of spinal cord injury (SCI), infiltrating macrophages assume prominence as the primary inflammatory cells within the lesion core, where the fibrotic scar is predominantly orchestrated by platelet-derived growth factor receptor beta (PDGFRβ+) fibroblasts. Galectin-3, a carbohydrate-binding protein of the lectin family, is notably expressed by infiltrating hematogenous macrophages and mediates cell-cell interactions. Although Galectin-3 has been shown to contribute to the endocytic internalization of PDGFRβ in vitro, its specific role in driving fibrotic scar formation after SCI has not been determined. Methods: We employed a crush mid-thoracic (T10) SCI mouse model. Galectin-3 inhibition after SCI was achieved through intrathecal injection of the Galectin-3 inhibitor TD139 or in situ injection of lentivirus carrying Galectin-3-shRNA (Lv-shLgals3). A fibrosis-induced mice model was established by in situ injection of platelet-derived growth factor D (PDGFD) or recombinant Galectin-3 (rGalectin-3) into the uninjured spinal cord. Galectin-3 internalization experiments were conducted in PDGFRβ+ fibroblasts cocultured in conditioned medium in vitro. Results: We identified the spatial and temporal correlation between macrophage-derived Galectin-3 and PDGFRβ in fibroblasts from 3 to 56 days post-injury (dpi). Administration of TD139 via intrathecal injection or in situ injection of Lv-shLgals3 effectively mitigated fibrotic scar formation and extracellular matrix deposition within the injured spinal cord, leading to better neurological outcomes and function recovery after SCI. Furthermore, the fibrosis-inducing effects of exogenous PDGFD in the uninjured spinal cord could be blocked by TD139. In vitro experiments further demonstrated the ability of PDGFRβ+ fibroblasts to internalize Galectin-3, with Galectin-3 inhibition resulting in reduced PDGFRβ expression. Conclusions: Our finding underscores the pivotal role of macrophage-derived Galectin-3 in modulating the sustained internalized activation of PDGFRβ within fibroblasts, providing a novel mechanistic insight into fibrotic scarring post-SCI. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are multipotent stem cells that are under investigation for use in clinical trials because they are capable of self-renewal and differentiating into different cell types under defined conditions. Nonetheless, the therapeutic effects of MSCs have been constrained by low engraftment rates, cell fusion, and cell survival. Various strategies have been explored to improve the therapeutic efficacy of MSCs, with platelet-derived growth factor (PDGF)-BB emerging as a promising candidate. To enhance our comprehension of the impact of PDGF-BB on the gene expression profile and chromosomal accessibility of MSCs, RNA-sequencing and analysis of chromatin accessibility profiles were conducted on three human primary MSCs in culture, both with and without stimulation by PDGF-BB. Results: Integrative analysis of gene expression and chromatin accessibility demonstrated that PDGF-BB treatment modified the chromatin accessibility landscape, marking regions for activation or repression through the AP-1 family transcription factors TEAD, CEBP, and RUNX2. These changes in AP-1 transcription factor expression, in turn, led to cell proliferation and differentiation potential towards osteoblasts, adipocytes, or chondrocytes. The degree of MSC differentiation varies among cells isolated from different donors. The presence of an enrichment of exosome-related genes is also noted among all the differentially expressed genes. Conclusions: In conclusion, the observed changes in AP-1 transcription factor expression not only induced cellular proliferation and differentiation, but also revealed variations in the degree of MSC differentiation based on donor-specific differences. Moreover, the enrichment of exosome-related genes among differentially expressed genes suggests a potential significant role for PDGF-BB in facilitating intercellular communication. [ABSTRACT FROM AUTHOR]

The platelet-derived growth factor (PDGF) family contributes to the progression of steatohepatitis; however, changes in and the characteristics of isoform-specific expression remain unclear. Since diabetes is a major driver of metabolic dysfunction-associated steatohepatitis (MASH), we characterized the mouse model of diabetic MASH (dMASH) by focusing on PDGF signaling. Pdgfa-d expression was markedly higher in hepatic stellate cells among flow-sorted cells in control mice and also increased in dMASH. In contrast, a reanalysis of human single-cell RNA-Seq data showed the distinct distribution of each PDGF isoform with disease progression. Furthermore, inflammation and fibrosis in the liver were less severe in diabetic MASH using tamoxifen-induced PDGF receptor β (PDGFRβ)-deficient mice (KO) than in control dMASH using floxed mice (FL) at 12 weeks old. Despite the absence of tumors, the expression of tumor-related genes was lower in KO than in FL. Tumorigenesis was significantly lower in 20-week-old KO. An Ingenuity Pathway Analysis of differentially expressed miRNA between FL and KO identified functional networks associated with hepatotoxicity and cancer. Therefore, PDGFRβ signals play important roles in the progression of steatohepatitis and tumorigenesis in MASH, with the modulation of miRNA expression posited as a potential underlying mechanism. [ABSTRACT FROM AUTHOR]

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear. Methods and results: In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models. Conclusions: Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH. Highlights: (1) Que can significantly improve the hemodynamic changes, RVH and pulmonary vascular remodeling in MCT induced PAH rats. (2) Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by regulating TGF-β1/Smad2/Smad3 pathway, thus playing a protective role in PAH pulmonary vascular remodeling. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications. [ABSTRACT FROM AUTHOR]

The abnormal proliferation and differentiation of oral mucosal fibroblasts (FBs) is the key to the progression of oral submucosal fibrosis. To clarify the mechanism of platelet-derived growth factor (PDGF-BB)-induced FBs fibrosis in oral mucosa, real-time quantitative polymerase chain reaction and Western blot were used in this study to detect the expression of miR-503 and the expression of p-MEK, p-ERK, miR-503, RAF, smooth actin and type I collagen under different time and concentration stimulation of PDGF-BB. The effects of overexpression of miR-503 or RAF on the proliferation and migration of FBs were detected by cell counting kit 8 and cell scratch assay, respectively. A dual luciferase reporter gene assay was used to verify the targeting effect of miR-503 on RAF. The results showed that miR-503 was downregulated in a dose- and time-dependent manner in PDGF-BB-induced FBs. In addition, RAF is a direct target of miR-503 and can be negatively regulated. Overexpression of RAF can promote FB proliferation, migration, differentiation, collagen synthesis, and activation of downstream molecules (MEK/ERK), while overexpression of miR-503 can partially reverse the effects of RAF. Therefore, miR-503 regulates the biological behavior of PDGF-BB-induced oral mucosal FBs by influencing the activation of the RAS/RAF/MEK/ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: Renin and prorenin promote the proliferation of vascular smooth muscle cells (VSMCs) through the (pro)renin receptor, or (P)RR, to promote restenosis occurrence. This study aimed to explore whether prorenin promoted the proliferation of VSMCs in a (P)RR-mediated Ang II-independent manner. Methods : Losartan and PD123319 were used to block the interaction between (P)RR and angiotensin in vitro. Cells were treated with renin, platelet-derived growth factor (PDGF), or RNAi-(P)RR, either jointly or individually. Cell proliferation was measured via Cell Counting Kit-8 (CCK-8) and flow cytometry methods; moreover, real-time polymerase chain reaction (RT–PCR) and Western blot (WB) assays were used to detect the expression of cyclin D1, proliferating cell nuclear antigen (PCNA), (P)RR, NOX1, and phosphatidylinositol 3-kinase (PI3K)/AKT signaling proteins. Immunofluorescence staining was conducted to measure the expression of (P)RR, and the levels of renin, PDGF-BB, inflammatory factors, and oxidative stress were determined by using enzyme-linked immunosorbent assay (ELISA). Moreover, a balloon catheter was used to enlarge the carotid artery of the Sprague Dawley rats. PRO20 was applied to identify angiotensin II (Ang II). The hematoxylin and eosin, RT–PCR, and WB results validated the cell assay results. Results : Renin promoted the proliferation of rat VSMCs by enhancing cell viability and cell cycle protein expression when Ang II was blocked, but silencing (P)RR inhibited this effect. Furthermore, renin enhanced NOX1-mediated oxidative stress and inflammation by activating the extracellular signal-regulated kinase 1/2 (ERK1/2)-AKT pathway in vitro. Similarly, the inhibition of (P)RR resulted in the opposite phenomenon. Importantly, the inhibition of (P)RR inhibited neointimal hyperplasia in vivo after common carotid artery injury by restraining NOX1-mediated oxidative stress through the downregulation of the ERK1/2-AKT pathway. The animal study confirmed these findings. Conclusion : Renin and (P)RR induced VSMC proliferation and neointimal hyperplasia by activating oxidative stress, inflammation, and the ERK1/2-AKT pathway in an Ang II-independent manner. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic fibrosis develops as a response to chronic liver injury, resulting in the formation of fibrous scars. This process is initiated and driven by collagen-producing activated myofibroblasts which reportedly express high levels of platelet derived growth factor receptor-β (PDGFRβ). We therefore regard PDGFRβ as an anchor for diagnosis and therapy. The Fibrobody® SP02SP26-ABD is a biparatopic VHH-construct targeting PDGFRβ. Here, we explore its potential as a theranostic vector for liver fibrosis. Methods: Specificity, cross-species binding, and cellular uptake of SP02SP26-ABD was assessed using human, mouse and rat PDGFRβ ectodomains and PDGFRβ-expressing cells. Cellular uptake by PDGFRβ-expressing cells was also evaluated by equipping the Fibrobody® with auristatinF and reading out in vitro cytotoxicity. The validity of PDGFRβ as a marker for active fibrosis was confirmed in human liver samples and 3 mouse models of liver fibrosis (DDC, CCl4, CDA-HFD) through immunohistochemistry and RT-PCR. After radiolabeling of DFO*-SP02SP26-ABD with 89Zr, its in vivo targeting ability was assessed in healthy mice and mice with liver fibrosis by PET-CT imaging, ex vivo biodistribution and autoradiography. Results: SP02SP26-ABD shows similar nanomolar affinity for human, mouse and rat PDGFRβ. Cellular uptake and hence subnanomolar cytotoxic potency of auristatinF-conjugated SP02SP26-ABD was observed in PDGFRβ-expressing cell lines. Immunohistochemistry of mouse and human fibrotic livers confirmed co-localization of PDGFRβ with markers of active fibrosis. In all three liver fibrosis models, PET-CT imaging and biodistribution analysis of [89Zr]Zr-SP02SP26-ABD revealed increased PDGFRβ-specific uptake in fibrotic livers. In the DDC model, liver uptake was 12.15 ± 0.45, 15.07 ± 0.90, 20.23 ± 1.34, and 20.93 ± 4.35%ID/g after 1,2,3 and 4 weeks of fibrogenesis, respectively, compared to 7.56 ± 0.85%ID/g in healthy mice. Autoradiography revealed preferential uptake in the fibrotic (PDGFRβ-expressing) periportal areas. Conclusion: The anti-PDGFRβ Fibrobody® SP02SP26-ABD shows selective and high-degree targeting of activated myofibroblasts in liver fibrosis, and qualifies as a vector for diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

[Display omitted] • First episode major dysmood disorder (FE-MDMD) is a severe subtype of depression. • FE-MDMD is characterized by activation of the immune-inflammatory response (IRS) • Activated IRS pathways are primarily driven by Th-1 polarization and interleukin-16. • Elevated tumor necrosis factor signaling is another important pathway in FE-MDMD. • IL-16 or CD4 activation are promising novel drug targets to treat FE-MDMD. Immune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD). This study investigated the immune profiles of 71 patients with the acute phase of first-episode major depressive disorder (FE-MDMD) and 40 healthy controls. We measured 48 cytokines/chemokines/growth factors, classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles. FE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-β. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56–60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6, and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naïve FE-MDMD patients. FE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the efficacy of autologous blood preparations, namely Platelet-Rich Plasma (PRP), Platelet-Rich Fibrin (PRF), and Concentrated Growth Factor (CGF), in maxillary sinus floor elevation surgery. The focus was on their impact on new bone formation, maxillary sinus floor height, and soft tissue healing. Methods: A systematic search was conducted across PubMed/MEDLINE, Web of Science, Embase, and Scopus databases up to April 2024. This systematic review included both randomized clinical trials (RCTs) and controlled clinical trials (CCTs) that evaluated the efficacy of autologous blood preparations in maxillary sinus floor elevation surgery. The primary outcomes measured were the percentage of new bone formation, maxillary sinus floor height, and he percentage of soft tissue area. Data from the selected studies were extracted and analyzed to determine the impact of autologous blood preparations on these outcomes. The risk of bias was assessed using Cochrane's risk of bias tool and ROBINS-I, and meta-analyses were performed using Review Manager 5.4 software to calculate effect sizes and integrate results from multiple studies. Results: Among the 507 screened articles, 30 studies met the inclusion criteria. The results indicated that the application of PRP significantly increased new bone formation during maxillary sinus floor elevation surgery (primary outcome, MD = 4.40, CI = 0.37 to 8.44, P = 0.03), as well as improving maxillary sinus floor height elevation (secondary outcome, MD = 1.00, CI = 0.78 to 1.23, P < 0.00001). The absence of PRP during surgery had a statistically significant effect on the percentage of soft tissue area (secondary outcome, MD= -5.25, CI= -7.29 to 3.20, P < 0.00001). However, based on the research findings, PRF did not show significant effects on enhancing new bone formation, maxillary sinus floor height elevation, and promoting soft tissue regeneration. Conclusions: PRP demonstrates efficacy in maxillary sinus floor elevation surgery by enhancing new bone formation and increasing sinus height. Further studies are needed to validate the outcomes of PRF and CGF. [ABSTRACT FROM AUTHOR]

Background: The human endometrium, lining the inner uterus, regenerates over 400 times uniquely during a woman's reproductive life. Endometrial stem cells (eSCs) enrich the tissue, resulting in a dense vascular network, significant angiogenic potential, and effective regeneration power. Being of natural angiogenic properties and proven effective in the treatment of vascular disorders, eSCs can be considered safe, reliable, and superior to other post-natal stem cells. Cluster of Differentiation 146 (CD146) has emerged as a pivotal marker associated with pericytes and endothelial cells for promoting angiogenesis. Endometrial cells with high CD146 expression could proliferate and differentiate into multiple lineages. This study will explore the role of CD146 in eSCs, focusing on the potential to boost the angiogenic and regenerative functions of the cells. The novelty of this study lies in the investigation of CD146 on eSC function, which may open new possibilities for eSC-based therapy in regenerative medicine and vascular disorders. Methods: The study involved obtaining endometrial biopsies from active reproducing women to isolate and cultivate eSCs. eSCs were assessed for growth factor secretion pattern, characterized for their mesenchymal properties. Finally, eSCs were tested for their angiogenic potential by angiogenic gene expression profile and in-ovo chick embryo model. As aimed, to check the role of CD146 in eSC angiogenesis, CD146+ cells were magnetically sorted and cultured. The sorted cells underwent various analyses, including flowcytometry to identify mesenchymal markers and human growth factor panel to analyze growth factor secretion profiles The study evaluated the angiogenic potential of CD146 + cells using functional assays, including ring formation, endothelial differentiation, and wound scratch assays, to evaluate cell migration and healing capabilities. Molecular insights were obtained through chemokine and cytokine investigations In-ovo Chick model assay was conducted to check the angiogenic potential and evaluated through macroscopic as well as through immunohistochemistry. Result: Endometrial stem cells (eSCs) were successfully isolated using a combination of mechanical and enzymatic digestion, followed by culturing in complete DMEM media. The secretion profile of eSCs revealed significant production of various angiogenic growth factors, including Granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), Vascular endothelial growth factor (VEGF), Fibroblast growth factors (FGF), and Platelet derived growth factor AA (PDGF-AA). The angiogenic gene profile indicated upregulation of several angiogenic genes in eSCs. The mesenchymal nature of eSCs was demonstrated through surface marker analysis (Cluster of differentiation 73, Cluster of differentiation 90, Cluster of differentiation 105) and trilineage differentiation. The in-ovo chick model confirmed the angiogenic potential of eSCs. CD146+ cells, isolated via magnetic sorting, exhibited enhanced angiogenic potential. These cells secreted significant levels of angiogenic growth factors such as VEGF. In Matrigel assays, CD146+ cells formed endothelial ring structures more rapidly and persistently than unsorted eSCs. Semi-quantitative PCR confirmed their endothelial differentiation. CD146+ cells express various angiogenic chemokines such as CXCL5, CXCL8, CCL3, and CCL20 and cytokines such as GM-CSF, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), PDGF AA/BB, Epidermal growth factor (EGF), Endothelin 1, Angiopoietin. In-ovo chick model assay showed that CD146+ cells had superior angiogenesis, with more nodes, junctions, and segments compared to eSCs and controls. Immunohistochemistry confirmed increased expression of endothelial markers (Cluster of differentiation 31, VEGF, Vascular associated protein (VAP), Von Willebrand factor (vWF) in CD146+ cells. Conclusion: The study highlights the angiogenic potential of endometrial stem cells, particularly the CD146+ cell population. These cells promote angiogenesis, secreting growth factors and forming stable blood vessel structures. CD146+ cells have higher expression levels of VEGF and TGF-α, key factors in angiogenesis. This suggests CD146+ eSCs may be promising for therapeutic applications in vascular diseases requiring angiogenesis. Further research is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently, delivering nanoparticles to hard-to-reach tumor sites remains a challenge in nanomedicine. Mesenchymal stem cells are an innovative strategy for targeting tumors, and genetic engineering could enable them to release antitumor agents and/or nanomaterials at tumor sites. Therefore, combining radiosensitizing agents with mesenchymal stem cells represents a promising strategy in the fight against cancer. Still, evaluating whether nanoparticles can modulate mesenchymal stem cells' behavior is essential. This study assessed the impact of new Fe3O4@Au nanoparticles on human pulmonary mesenchymal stem cells to determine whether they can be used as carriers for radiosensitizer agents to cancer sites. This study focused on the markers related to cell death, redox and proinflammatory status, and tumorigenesis. Background/Objectives: Metallic nanoparticles (NPs) exhibit interesting radiosensitizing effects, and finding a way to accurately deliver them appears to be crucial. Due to their tumor tropism, mesenchymal stem cells (MSCs) represent a strategic approach. Therefore, we aimed to evaluate the impact of core–shell Fe3O4@Au NPs on the functionality of human pulmonary MSCs (HPMSCs). Methods/Results: The results showed that 100 µg/mL Fe3O4@Au NPs, accumulated in HPMSCs (revealed by Prussian blue staining), did not alter cell viability as assessed by cell counting, MTT, and LDH assays. However, caspase 9 and Bcl2 gene expression, evaluated by RT-qPCR, was regulated 72 h after exposure to the NPs. Moreover, the NPs also decreased proinflammatory cytokine/chemokine secretions, except for CXCL8 (ELISA). These modulations were associated with the downregulation of AMPK gene expression at 24 h. In contrast, the NPs did not modulate VEGF, PI3K, or PDGF gene expression. Nevertheless, a decrease in VEGF secretion was observed after 24 h of exposure to the NPs. Interestingly, the Fe3O4@Au NPs did not modulate Nrf2 gene expression, but they did regulate the expression of the genes encoding Nox4 and HMOX-1. Additionally, the NPs increased ROS production, suggesting a redox imbalance. Conclusions: Finally, the Fe3O4@Au NPs did not affect the HPMSCs' viability or proangiogenic/tumorigenic markers. These findings are encouraging for investigating the effects of Fe3O4@Au NPs delivered by HPMSCs to tumor sites in combination with radiation. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. Cancer‐associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non‐metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high‐resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease‐specific mortality. Increased stromal expression of fibroblast activation protein (FAP), α‐smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet‐derived growth factor receptor‐β (PDGFRβ) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFRβ and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFRα−/PDGFRβ+/FAP+, was associated with invasion and metastasis, and independently predicted poor disease‐specific survival. These results identify high PDGFRβ expression alone and multimarker combination PDGFRα−/PDGFRβ+/FAP+ by CAFs as potential biomarkers for risk of metastasis and poor prognosis. [ABSTRACT FROM AUTHOR]

Platelet-rich plasma (PRP) is an autologous blood-derived product utilized nowadays as a treatment for various non-hemostatic, orthopedic, and muscular injuries. Although the exact mechanism of PRP use and effectivity is not yet fully understood, PRP applications are extensively developing and expanding. PRP, as the name implies, contains mostly platelets; thus, platelets are the main players in this therapeutic management for numerous tissue disorders and conditions. Platelets are known to facilitate wound healing and tissue repair through the various growth factors present in their granules. The growth factors in platelets also act on cells found in tissues other than those involved in wound repair, resulting in an increased interest in PRP use as a regenerative therapy for various disorders. In this paper, we discussed platelets and its morphology, and the various growth factors present within the platelet granules. The effects of these growth factors on tissue recovery are highlighted. PRP components, preparation considerations and classifications are presented here to showcase PRP differences and complexity. [ABSTRACT FROM AUTHOR]

Background: Visceral adipose tissue in individuals with obesity is an independent cardiovascular risk indicator. However, it remains unclear whether adipose tissue influences common cardiovascular diseases, such as atherosclerosis, through its secreted exosomes. Methods: The exosomes secreted by adipose tissue from diet-induced obesity mice were isolated to examine their impact on the progression of atherosclerosis and the associated mechanism. Endothelial apoptosis and the proliferation and migration of vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque were evaluated. Statistical significance was analyzed using GraphPad Prism 9.0 with appropriate statistical tests. Results: We demonstrate that adipose tissue-derived exosomes (AT-EX) exacerbate atherosclerosis progression by promoting endothelial apoptosis, proliferation, and migration of VSMCs within the plaque in vivo. MicroRNA-132/212 (miR-132/212) was detected within AT-EX cargo. Mechanistically, miR-132/212-enriched AT-EX exacerbates palmitate acid-induced endothelial apoptosis via targeting G protein subunit alpha 12 and enhances platelet-derived growth factor type BB-induced VSMC proliferation and migration by targeting phosphatase and tensin homolog in vitro. Importantly, melatonin decreases exosomal miR-132/212 levels, thereby mitigating the pro-atherosclerotic impact of AT-EX. Conclusion: These data uncover the pathological mechanism by which adipose tissue-derived exosomes regulate the progression of atherosclerosis and identify miR-132/212 as potential diagnostic and therapeutic targets for atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored. Methods and results We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)−/−) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein–metabolism-associated gene expression in Nfat5 -deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)—a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth—in capillary MLEC of hypoxia-exposed Nfat5(EC)−/− mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries. Conclusion Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis (HF) is a common pathological repair response occurring after liver injury and is a critical stage in the progression of chronic liver diseases towards cirrhosis. The molecular mechanisms of HF occurrence are complex. Liver injury triggers the release of various cytokines by multiple cell types, and initiates the downstream signaling pathways to activate the hepatic stellate cells (HSCs) and transform them into myofibroblasts (MFBs). MFBs can release large quantities of extracellular matrix (ECM), thereby disrupt the normal liver architecture and lead to the occurrence and development of HF. The potential therapeutic targets for HF are still in the experimental animal phase, and there are no clinical applications yet. This review summarizes the signaling pathways and related factors involving HSCs and ECM in HF, such as the transforming growth factor-β(TGF-β) /Smad signaling pathway, platelet-derived growth factor (PDGF), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and connective tissue growth factor (CTGF). It also discusses the related therapeutic targets, and provids the theoretical basis for the development of new drugs for HF. [ABSTRACT FROM AUTHOR]

Aim To establish an efficient and stable isolation method of primary mouse brain vascular smooth muscle cells and endothelial cells, and provide experimental materials for the investigation of pathogenesis and treatment of brain vascular diseases. Methods Brain vascular smooth muscle cells were isolated by dextran gradient centrifugation with enzymatic digestion, and endothelial cells were isolated by immunomagnetic beads sorting. Morphology and growth characteristics of two types of cells were observed with an inverted phase contrast microscope, their purity were identified by immunofluorescence, and their proliferation characteristics were observed by CCK-8 assay. At the level of cellular function, angiogenic capacity of endothelial cell was assessed by angiogenesis assay and smooth muscle cell responsiveness to platelet-derived growth factor (PDGF) was assessed by migration assay. Results The two types of cells isolated using this method grew vigorously and were in good condition. Smooth muscle cells exhibited typical "peak valley" growth, and immunofluorescence results showed cytoplasmic specific smooth muscle α-SMA and SM22α expression was positive. Endothelial cells exhibited typical "cobblestone like" growth, with positive expression of platelet endothelial cell adhesion molecule CD31 and atresia zone protein 1. Conclusion This study established a reliable and efficient method for simultaneously isolating two types of cerebrovascular cells, the isolated cells have high purity, good activity, and stable characteristics after passage, which were sufficient to meet the needs of subsequent experiments. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the efficacy of N-acetylcysteine as an adjuvant therapy in chronic obstructive pulmonary disease (COPD) with pulmonary interstitial fibrosis (PIF), and its effect on inflammatory factors and serum vascular endothelial growth factor (VEGF) levels. Methods: A total of 94 patients with COPD-PIF from May 2020 to May 2022 in Wuhan Fourth Hospital, China were equally randomized into study and control groups. Control group was administered conventional treatment while the study group was given N-acetylcysteine in addition to conventional treatment. Therapeutic efficacy, forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, blood gas, pulmonary fibrosis, and oxidative stress were evaluated. Changes in inflammatory factors, serum vascular endothelial growth factor (VEGF), and incidence of adverse drug reactions were compared. Results: The study group showed significantly higher efficacy, FEV1, FVC, FEV1/FVC compared to control group (p < 0.05). Also, study group showed significantly higher partial pressure of oxygen (PaO2), blood oxygen saturation, superoxide dismutase (SOD), and glutathione (GSH) levels after treatment compared to control group (p < 0.05). Platelet-derived growth factor (PDGF), transforming growth factor (TGF-ß), vascular cell adhesion molecule (VCAM), tumor necrosis factor (TNF), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) levels after treatment were significantly lower in the study group than in the control group (p < 0.05). Conclusion: N-acetylcysteine as an adjuvant therapy for COPD-IF is highly effective, improves lung function and oxidative stress, reduces airway inflammation, and VEGF, and attenuates the degree of hypoxia and pulmonary fibrosis with no serious adverse effects. A larger sample size, multicenter, randomized trials to validate these findings and evaluate the downstream regulatory mechanism of Nacetylcysteine in COPD-PIF. [ABSTRACT FROM AUTHOR]

AIM: To investigate the pathological mechanism by which abnormal activation of sphingosine-1-phosphate (S1P)/S1P receptor 2 (S1PR2) signaling pathway induces pericyte loss and subsequently affects blood-brain barrier dysfunction in neuropsychiatric systemic lupus erythematosus (NPSLE) mice using MRL/lpr mouse model. METHODS: Behavioral changes in female MRL/lpr mice from 6 weeks of age were assessed using open-field test (OFT), novel object recognition test (NORT) and forced swimming test (FST). The mice with neurobehavioral changes exceeding 20% compared with baseline were defined as NPSLE mice and were randomly divided into 3 groups each with 6 mice: NPSLE-S1P antagonist group, NPSLE-S1PR2 blocker group, and NPSLE saline treatment group. Additional 6 mice with no abnormal behavioral changes served as control group. The mice in NPSLE-S1P antagonist group were treated with S1P antagonist FTY720 (2 mg/kg, orally), those in NPSLE-S1PR2 blocker group received treatment with S1PR2 blocker JTE-013 (8 mg/kg, intraperitoneally), while those in NPSLE saline treatment group and control group received an equivalent volume of saline. Treatments were conducted 3 times per week for 3 weeks. Behavioral changes were reassessed using OFT, NORT and FST. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of S1P, interleukin-6 (IL-6) and interferon-α (IFN-α). Blood-brain barrier permeability changes were evaluated by Evans blue staining. He-matoxylin-eosin (HE) staining was employed to observe brain tissue inflammation, Nissl staining was used to examine neuronal damage, and immunofluorescence staining was performed to assess the expression of pericyte marker neural/glial antigen 2 (NG2) and endothelial cell marker CD31 in microvessels. Western blot analysis was conducted to detect the expression levels of S1P, S1PR2, platelet-derived growth factor receptor-β (PDGFR-β) and zonula occludens-1 (ZO-1) in brain tissues, while RT-qPCR was utilized to measure S1PR2 and PDGFR-β mRNA levels. RESULTS: Compared with model group, the mice in S1P antagonist and S1PR2 blocker groups exhibited reduced latency and immobility time in the water (P<0. 05) and increased central zone exploration distance (P<0. 05). There was reduced inflammatory exudation and neuronal damage in the ventricles, along with attenuated retention of pericytes (NG2, green) and endothelial cells (CD31, red). Serum levels of S1P, IL-6 and IFN-α were significantly decreased (P<0. 05). The S1PR2 mRNA expression was significantly reduced, whereas PDGFR-β mRNA expression was significantly increased (P<0. 05). Protein expression levels of S1P and S1PR2 were significantly decreased, while PDGFR-β and ZO-1 protein levels were significantly incr eased (P<0. 05). CONCLUSION: Inhibition of the S1P/S1PR2 pathway attenuates neurobehavioral symptoms, reduces blood-brain barrier permeability, and suppresses inflammation in NPSLE mice. [ABSTRACT FROM AUTHOR]

This article discusses the role of microRNAs (miRNAs) carried by extracellular vesicles (EVs) in the context of anaphylaxis, a severe allergic reaction. The study focuses on children with food-mediated anaphylaxis and examines the levels of miR-21-3p and miR-487b-3p in EVs during the acute phase of the reaction compared to the basal phase. The results show an increase in miR-21-3p levels in EVs during anaphylaxis, suggesting its potential as a mediator of the condition. The study also highlights the involvement of miR-21-3p and miR-375-3p in immune and cardiovascular processes related to anaphylaxis. These findings contribute to a better understanding of the molecular mechanisms underlying anaphylaxis and may inform future research on targeted therapies. [Extracted from the article]

Non‐union during healing of bone fractures affects up to ~5% of patients worldwide. Given the success of recombinant human platelet‐derived growth factor‐B chain homodimer (rhPDGF‐BB) in promoting angiogenesis and bone fusion in the hindfoot and ankle, rhPDGF‐BB combined with bovine type I collagen/β‐TCP matrix (AIBG) could serve as a viable alternative to autografts in the treatment of non‐unions. Defects (~2 mm gaps) were surgically induced in tibiae of skeletally mature New Zealand white rabbits. Animals were allocated to one of four groups—(1) negative control (empty defect, healing for 8 weeks), (2 and 3) acute treatment with AIBG (healing for 4 or 8 weeks), and (4) chronic treatment with AIBG (injection 4 weeks post defect creation and then healing for 8 weeks). Bone formation was analyzed qualitatively and semi‐quantitatively through histology. Samples were imaged using dual‐energy X‐ray absorptiometry and computed tomography for defect visualization and volumetric reconstruction, respectively. Delayed healing or non‐healing was observed in the negative control group, whereas defects treated with AIBG in an acute setting yielded bone formation as early as 4 weeks with bone growth appearing discontinuous. At 8 weeks (acute setting), substantial remodeling was observed with higher degrees of bone organization characterized by appositional bone growth. The chronic healing, experimental, group yielded bone formation and remodeling, with no indication of non‐union after treatment with AIBG. Furthermore, bone growth in the chronic healing group was accompanied by an increased presence of osteons, osteonal canals, and interstitial lamellae. Qualitatively and semiquantitatively, chronic application of AI facilitated complete bridging of the induced non‐union defects, while untreated defects or defects treated acutely with AIBG demonstrated a lack of complete bridging at 8 weeks. [ABSTRACT FROM AUTHOR]

Introduction: The release of pro-inflammatory cytokines in critically ill patients with sepsis leads to endothelial dysfunction resulting in cardiocirculatory insufficiency. Their extracorporeal elimination using the cytokine adsorber CytoSorb® (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data about the adsorption capacity as well as a potential harmful adsorption of anti-inflammatory cytokines are missing so far. Methods: The prospective Cyto-SOLVE-study included 15 patients with sepsis or other hyperinflammatory conditions (interleukin 6 > 500 pg/ml), continuous kidney replacement therapy, and the application of CS. Various cytokines and chemokines were measured pre- and post-CS as well as in patients' blood at predefined timepoints. Significant changes in the concentrations were detected with the Wilcoxon test with associated samples. Clearance of the adsorber (ml/min) was calculated with: b l o o d f l o w ∗ c o n c e n t r a t i o n p r e - p o s t c o n c e n t r a t i o n pre . Results: Most of the inflammatory mediators showed a high initial extracorporeal clearance of 70–100 ml/min after CS installation, which dropped quickly to 10-30 ml/min after 6 h of treatment. No difference in clearance was observed between pro- and anti-inflammatory cytokines. Despite extracorporeal adsorption, a significant (p < 0.05) decrease in the blood concentration after 6 h was only observed for the pro-inflammatory cytokines tumor necrosis factorα (TNF-α) (median 284 vs. 230 pg/ml), vascular endothelial growth factor (VEGF) (median 294 vs. 252 pg/ml), macrophage inflammatory protein 1a (MIP-1a) (median 11.1 vs. 9.0 pg/ml), and regulated upon activation, normal T cell expressed and secreted (RANTES) (median 811 vs. 487 pg/ml) as well as the anti-inflammatory cytokines interleukin 4 (median 9.3 vs. 6.4 pg/ml), interleukin 10 (median 88 vs. 56 pg/ml), and platelet-derived growth factor (PDGF) (median 177 vs. 104 pg/ml). A significant (p < 0.05) decrease in patients' blood after 12 h was only detected for interleukin 10. Conclusions: CS can adsorb pro- as well as anti-inflammatory mediators with no relevant difference regarding the adsorption rate. A fast saturation of the adsorber resulted in a rapid decrease of the clearance. The potential clinical benefit or harm of this unspecific cytokine adsorption needs to be evaluated in the future. Trial Registration: ClinicalTrials.gov NCT04913298, registration date June 4, 2021. [ABSTRACT FROM AUTHOR]

The article "Extracellular vesicles and interstitial lung disease in systemic sclerosis: State of the art!" published in the journal "Rheumatology & Immunology Research" discusses the role of extracellular vesicles (EVs) in systemic sclerosis-related interstitial lung disease (SSc-ILD). EVs play a crucial role in intercellular communication and may contribute to endothelial dysfunction, inflammation, fibrosis, and hypercoagulation in SSc-ILD. Clinical studies on the association between circulating EVs and SSc-ILD are limited and conflicting, highlighting the need for further research to explore EVs as potential biomarkers and therapeutic targets for SSc-ILD. [Extracted from the article]

High-grade oligodendroglioma (HGOG) is the most common type of glioma in dogs and expresses platelet-derived growth factor receptor-α (PDGFR-α). Microvascular proliferation is often observed in HGOG. Therefore, the present study investigated the functional relationships between PDGFR-α, microvascular proliferation, and tumor cell proliferation in canine HGOG. The expression of PDGFR-α and PDGF-subunit A (PDGF-A) in tumor cells, as well as endothelial cells and pericytes of tumor-associated microvascular proliferations, in 45 canine HGOGs were examined immunohistochemically. Microvascular proliferation was observed in 24/45 cases (53%). PDGFR-α expression in tumor cells and microvascular proliferations was observed in 45/45 (100%) and 2/24 cases (8%), respectively. Furthermore, PDGF-A expression in tumor cells and microvascular proliferations was detected in 13/45 (29%) and 24/24 cases (100%), respectively. In vitro, stimulation of the canine HGOG cell line AOFB-01 with PDGF-A showed that the doubling time of AOFB-01 cells was significantly shorter with PDGF-A than without PDGF-A. Crenolanib (a PDGFR inhibitor) inhibited AOFB-01 cell proliferation. In vivo, the AOFB-01 xenograft mouse model was treated with crenolanib. Tumor xenografts were smaller in crenolanib-treated mice than in untreated control mice. PDGFR-α expression in tumor cells and PDGF-A expression in microvascular proliferations and tumor cells suggest autocrine and paracrine effects of PDGF-A in canine HGOG. The results of in vitro assays indicate that canine HGOG expresses functional PDGFR-α, which responds to PDGF-A. Therefore, PDGF-A produced by microvascular proliferations and tumor cells may promote the proliferation of PDGFR-α-expressing tumor cells in canine HGOG. PDGFR-α signaling has potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Plasma derivatives have extensive applications in the field of regenerative medicine. Platelet-rich plasma (PRP) is a blood component acquired through centrifugation and can be administered through periwound injection or direct application to the wound bed area. PRP aids in shifting the healing process from chronic to acute, fostering regeneration in traumatic and surgical wounds. Here, we present seven cases of challenging wounds in paediatric patients that were treated using PRP at our institution. [ABSTRACT FROM AUTHOR]

The present work investigates the potential role of metformin nanoparticles (MTF-NPs) as a radio-protector against cardiac fibrosis and inflammation induced by gamma radiation via CXCL1/TGF-β pathway. Lethal dose fifty of nano-metformin was determined in mice, then 21 rats (male albino) were equally divided into three groups: normal control (G1), irradiated control (G2), and MTF-NPs + IRR (G3). The possible protective effect of MTF-NPs is illustrated via decreasing cardiac contents of troponin, C-X-C motif Ligand 1 (CXCL1), tumor growth factor β (TGF-β), protein kinase B (AKT), and nuclear factor-κB (NF-κB). Also, the positive effect of MTF-NPs on insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) in heart tissues using immunohistochemical technique is illustrated in the present study. Histopathological examination emphasizes the biochemical findings. The current investigation suggests that MTF-NPs might be considered as a potent novel treatment for the management of cardiac fibrosis and inflammation in patients who receive radiotherapy or workers who may be exposed to gamma radiation. [ABSTRACT FROM AUTHOR]

Growth factors are considered an important component for periodontal wound healing and a key element in the periodontal regeneration triad. Randomized controlled clinical trials have demonstrated that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in combination with bone graft materials is effective in treating intrabony periodontal defects. Many clinicians are currently using rhPDGF-BB in combination with xenogeneic or allogeneic bone. Therefore, the purpose of this case series was to assess the clinical effectiveness of combining rhPDGF-BB with xenogeneic bone substitutes to treat severe intrabony periodontal defects. Three patients with challenging deep and wide intrabony defects were treated using a combination of rhPDGF-BB and xenogeneic graft matrix. Probing depth (PD) reduction, bleeding on probing (BOP), mobility reduction, and radiographic bone fill (RBF) were observed for 12 to 18 months. PD decreased from 9 mm to 4 mm, BOP was eliminated, mobility decreased, and RBF ranged from 85% to 95% over the postsurgical observation period. These results indicate that combination of rhPDGF-BB with xenogeneic bone substitutes is a safe and effective graft that leads to favorable clinical and radiographic outcomes for treating severe intrabony periodontal defects. Larger case series or randomized studies will further elucidate the clinical predictability of this treatment protocol. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of platelet-derived growth factor (PDGF) on the activity and invasion ability of choroidal melanoma (CM) cells. Methods CM cells were divided into groups A and B and were transfected with empty vector and PDGF knockdown lentivirus, respectively. RT-qPCR was used to measure the relative expression level of PDGF mRNA; XTT assay was used to measure cell activity; Transwell assay was used to test the invasion ability of cells in the two groups; Western blot was used to measure the relative expression levels of epithelial-mesenchymal transition (EMT) marker proteins and matrix metalloproteinases (MMPs). GEPIA database was used to investigate the association between PDGF and the prognosis of CM patients. Results Compared with group A, group B had significant reductions in the relative expression level of PDGF RNA (t=176.30,P

Background. Applying autologous growth factors and diode laser in periodontal therapy enhances fibroblast-mediated new attachment and osteoblastic differentiation. Hence, this study compared and evaluated the effectiveness of concentrated growth factor (CGF) alone and with diode laser application in managing intrabony periodontal defects. Methods. Ten patients with stage III periodontitis were included in this study. All the patients underwent an open flap debridement (OFD) procedure followed by CGF membrane placement in the intrabony defect in site A, whereas, in site B, after OFD, all the patients underwent diode laser irradiation before CGF membrane placement. Plaque and gingival bleeding index (PI & GBI), PPD, and clinical attachment level (CAL) were evaluated at baseline and 3 and 6 months later. Bone fill (BF), BF%, bone crest changes (BCC), and BCC% were assessed radiographically at six months postoperatively. Results. Significant reductions in PI and GBI scores, probing pocket depth (PPD), and CAL gain were observed at both sites 3 and 6 months from baseline. A significant reduction in PPD and CAL gain was noted between sites, which were higher in site B than in site A with a mean difference of 0.70±0.05 mm and 1.30±0.18 mm, 0.90±1.89 mm at 3 and 6 months, respectively. Radiographic measurement showed better BF, BF%, BCC, and BCC% at both sites at six months, which were higher at site B than at site A but statistically insignificant. Conclusion. The combination of CGF and diode laser application has demonstrated successful and promising results in terms of regeneration, improving the clinical and radiographic parameters.

Objective To analyze the changes in important indicators such as P-selectin, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and pH value in platelet-rich plasma (PRP) after short-term cryopreservation at -80 ℃, and to provide a theoretical basis for the low-temperature storage of PRP. Methods Each of PRP samples prepared from the blood from 30 healthy donors was divided into 5 aliquots, with 0.5 mL retained per aliquot. These samples were de-signated as group A (fresh sample) and groups B to E (cryopreservation for 5, 10, 15, and 20 d, respectively). The pH values of the five groups were measured. The concentrations of P-selectin, PDGF, and VEGF in each group were determined by the ELISA method. The effect of groups A and E on the vascular formation capacity of human umbilical vein endothelial cells (HUVEC) was determined by the angiogenesis assay. Results No significant differences were observed in the concentrations of P-selectin, PDGF, and VEGF as well as the pH values between group A and groups B to E (P >0.05). Compared with the fresh sample (group A), the number of vessels formed from HUVECs in the sample frozen for 20 d (group E) was basically the same, with no significant differences (P>0.05). Conclusion The cryopreservation of PRP at -80 ℃ has no significant effects on its pH value and concentrations of P-selectin, VEGF, and PDGF, thus extending the clinical application time of PRP.

Lung regeneration after fibrosis requires formation of functional new vasculature, which is essential for gas exchange and cellular cross-talk with other lung cells. It remains unknown how the lung vasculature can be regenerated without fibrosis. Here, we tested the role of N6-methyladenosine (m6A) modification of forkhead box protein O1 (Foxo1) mRNA in lung regeneration after pneumonectomy (PNX) in mice, a model for lung regrowth after surgical resection. Endothelial cell (EC)–specific knockout of methyltransferase-like 3 (Mettl3) and Foxo1 caused nonproductive intussusceptive angiogenesis (IA), which impaired regeneration and enhanced fibrosis. This nonproductive IA was characterized by enhanced endothelial proliferation and increased vascular splitting with increased numbers of pillar ECs. Endothelial-selective knockout of Mettl3 in mice stimulated nonproductive IA and up-regulation of profibrotic factors after PNX, promoting regeneration to fibrotic transition. EC-specific mutation of m6A modification sites in the Foxo1 gene in mice revealed that endothelial Mettl3 modified A504 and A2035 sites in the Foxo1 mRNA to maintain pro-regenerative endothelial glycolysis, ensuring productive IA and lung regeneration without fibrosis. Suppression of Mettl3-Foxo1 signaling stimulated a subset of hyperglycolytic and hyperproliferative 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3)+, Ras homolog family member J (Rhoj)+, and platelet-derived growth factor subunit B (Pdgfb)+ ECs in both human and mouse lungs with fibrosis. Inhibiting this Pfkfb3+Rhoj+Pdgfb+ EC subset normalized IA, alleviated fibrosis, and restored regeneration in bleomycin (BLM)–injured mouse lungs. We found that m6A modification of Foxo1 in the mouse vasculature promoted lung regeneration over fibrosis after PNX and BLM injury. Editor's summary: Lung regeneration after injury or transplantation is limited by fibrosis. Ma et al. showed that a subset of glycolytic endothelial cells that express Ras homolog family member J (Rhoj) was responsible for impaired lung regeneration and intussusceptive angiogenesis or split blood vessels in response to injury. Forkhead box protein O1 (Foxo1) loss or loss of Foxo1 mRNA N6-methyladenosine (m6A) modification resulted in improved lung function and less fibrosis after left lung lobe removal in mice. Rhoj-expressing endothelial cells in fibrotic lung tissue was associated with poor lung function in humans, and genetic inhibition of Rhoj in mice led to improved lung function and fibrosis. Therefore, RHOJ may be a target for promoting lung regeneration. —Brandon Berry [ABSTRACT FROM AUTHOR]

Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane. [ABSTRACT FROM AUTHOR]

Background Reemergence of human herpesvirus 8 (HHV-8)–induced Kaposi sarcoma (KS) in people living with HIV (PLWH) despite antiretroviral therapy (ART) poses a clinical challenge because they already have favorable CD4 T-cell numbers and undetectable viral loads. We observed that clinical presentation in PLWH on ART resembled classic KS found in older HIV-uninfected patients and hypothesized that immunosenescence may thus play a role in occurrence of KS on ART. We compared viral and immune factors implicated in the development of KS in ART-treated PLWH (HIV KS) and HIV-uninfected classic KS patients (cKS), compared to controls without KS (HIV Control, cControls respectively). Methods Plasma, peripheral blood mononuclear cell, and skin tissues were obtained from 11 HIV KS and 11 cKS patients and 2 groups of age-matched controls. Results HIV KS participants were younger than cKS (aged 53 vs 75 years). HHV-8 genotypes did not differ between groups. Despite the younger age and a lower CD4/CD8 ratio, activated, exhausted, and senescent T-cell frequencies were similar between HIV KS and cKS. Anti–HHV-8 immunoglobulin G levels were higher and circulating HHV-8 DNA lower in HIV KS compared with cKS. Circulating platelet-derived growth factors AA-BB and granulocyte colony-stimulating factors were higher in HIV KS We observed similar levels of HHV-8 DNA and PD-1 expression in skin lesions from HIV KS and cKS patients. Conclusions Altogether, early immune senescence could be involved in the development of KS in ART-treated PLWH. Higher anti–HHV-8 immunoglobulin G levels could be linked with lower circulating viral load. Such insights should help developing therapeutical strategies to prevent development and treat KS in PLWH on ART. [ABSTRACT FROM AUTHOR]

Variants (pathogenic) of the LMNA gene are a common cause of familial dilated cardiomyopathy (DCM), which is characterised by early-onset atrioventricular (AV) block, atrial fibrillation and ventricular tachyarrhythmias (VTs), and progressive heart failure. The unstable internal nuclear lamina observed in LMNA-related DCM is a consequence of the disassembly of lamins A and C. This suggests that LMNA variants produce truncated or alternative forms of protein that alter the nuclear structure and the signalling pathway related to cardiac muscle diseases. To date, the pathogenic mechanisms and phenotypes of LMNA-related DCM have been studied using different platforms, such as patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) and transgenic mice. In this review, point variants in the LMNA gene that cause autosomal dominantly inherited forms of LMNA-related DCM are summarised. In addition, potential therapeutic targets based on preclinical studies of LMNA variants using transgenic mice and human iPSC-CMs are discussed. They include mitochondria deficiency, variants in nuclear deformation, chromatin remodelling, altered platelet-derived growth factor and ERK1/2-related pathways, and abnormal calcium handling. [ABSTRACT FROM AUTHOR]

To assess the effectiveness of the autologous plasma-rich fibrin plug technique for repairing small tympanic membrane perforations. Platelet rich fibrin (PRF) is also called second generation platelet rich plasma due to its high amount of growth factors which could be used in tympanic perforation closure. Being autologous, it is readily available with no immunogenic reactions. PRF membrane has a strong elastin fibrin structure containing growth factors and hence can be considered as an ideal sealing material or an adjuvant to the graft in repairing tympanic membrane perforations. Ours is a prospective study. A total of 52 patients with dry small tympanic membrane perforation were included in the study. In this technique, 10 ml of blood is withdrawn from the patient, processed in a centrifuge machine, and platelet-rich fibrin (PRF) is separated from the mixture for use in the repair of small tympanic membrane defects. Out of the 52 patients, 42 experienced successful repair (full closure) of the tympanic membrane. The mean time of closure of the perforation was around 2 weeks. However, five of them encountered failure. Although the size of the perforation decreased compared to the preoperative size. Additionally, two patients developed granulations on the tympanic membrane. No major side effects were noted. Autologous PRF is a product derived from whole blood through the process of centrifugation. It is safe and effective in promoting the natural process of wound healing by incorporating a high concentration of platelet-derived growth factors as well as fibrin into the graft mixture. This facilitates the rapid healing of tympanic membrane perforation. [ABSTRACT FROM AUTHOR]

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts. [ABSTRACT FROM AUTHOR]