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Objective: To investigate the impact of supragingival scaling on the clinical outcomes of subgingival instrumentation completed after 1 week. Method and materials: In 27 patients with Stage II and Stage III periodontitis, pairs of contralateral quadrants were randomly assigned into test group 1 (single sitting scaling and root planing) and test group 2 (supragingival scaling followed by subgingival instrumentation after lweek). Periodontal parameters were recorded at baseline, 2, 4, and 6months; Gingival crevicular fluid vascular endothelial growth factor (VEGF) estimation was done at baseline in both groups and 7 days after supragingival scaling in test group 2. Results: At 6 months, significantly better improvement in test group 1 at sites with periodontal probing depth (PPD)>5mm; (APPD = 2.32 mm vs 1.41 mm, P= .001; Aclinical attachmen level [CAL] = 2.34 mm vs 1.39 mm, P=.001) was observed. Supragingival scaling resulted in significant reduction in gingival crevicular fluid VEGF (42.46 to 27.88 pg/site) after lweek. Regression analysis explained 14% variance in VEGF to baseline PPD at sites with PPD>4 mm; and 21% variance in CAL improvement to VEGF at sites with PPD>5mm. The percentage of sites with PPD = 5 to 8 mm reachingthe clinical endpoint was 52% and 40%fortest group 1 and test group 2, respectively. Better results were noticed in bleeding on pocket probing-positive sites in both groups. Conclusion: The sites with PPD > 5 mm where supragingival scaling was followed by subgingival instrumentation after 1 weekresulted in less favourable treatment outcomes. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Materials and Methods Results Conclusions Orthodontic treatment involves alveolar bone remodeling in response to mechanical loading, resulting in tooth movement through traction‐side bone formation and compression‐side bone resorption. However, there are conflicting reports regarding alveolar bone resorption during the orthodontic treatment of patients with diabetes.Diabetes was induced in 8‐week‐old C56BL/6J mice using streptozotocin (STZ). Four weeks after the injection of STZ, a mechanical load was applied between the first and second molars on the right side of the upper jaw using the Waldo method with orthodontic elastics in diabetic (DM) and normal (N) mice tooth movement, gene expression, osteoclast counts, alveolar bone residual volume, and bone beam structure were evaluated.The duration until spontaneous elastic loss was significantly longer in the DM group, suggesting that tooth movement may be inhibited in the diabetic state. The number of osteoclasts at 7 days after mechanical loading and the alveolar bone resorption were both significantly lower in the DM group. The gene expression levels of vascular endothelial growth factor (VEGF), a protein related to alveolar bone remodeling, and specificity protein 1 (SP1), a transcription factor of the VEGF gene, were significantly lower in the DM group than in the N group on the compression side of mechanical loading.Mechanical loading‐induced alveolar bone remodeling is suppressed in the diabetic state. Our results suggest that VEGF is a key molecule involved in impaired bone remodeling under mechanical loading in the diabetic state. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) presents a significant clinical challenge, leading to tissue ischemia and potentially resulting in limb necrosis or amputation. Cell‐based regenerative therapies offer promise for improving outcomes in CLI, but their effectiveness is often limited by poor cell survival and engraftment. This study hypothesized that a thermo‐responsive polymer, poly(polyethylene glycol citrate‐co‐N‐isopropylacrylamide) (PPCN), combined with pro‐survival bioactive peptides, can create a protective microenvironment to improve endothelial cell survival and function after their delivery. Through in vitro and in vivo experiments, laminin‐derived peptide A5G81 and vascular endothelial growth factor (VEGF)‐derived peptide QK are identified as effective in promoting endothelial cell spreading, proliferation, and prolonged survival. PPCN's viscoelastic properties protected against shear stress during injection, while the peptides supported endothelial cell behavior through distinct molecular pathways. Importantly, delivery of endothelial cells with PPCN‐A5G81 and PPCN‐QK in a murine hindlimb ischemia model resulted in significant improvements in limb perfusion, tissue preservation, and functional outcomes compared to controls. Additionally, this approach enhanced skeletal muscle remodeling following ischemic injury. This innovative biomaterial platform represents a versatile solution for addressing cell survival challenges and advancing regenerative therapies in CLI and other ischemic conditions. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionTo analyze the efficacy and safety of microsecond pulsing laser therapy (MLT) in the management of central serous chorioretinopathy (CSCR) complicated by choroidal neovascularization (CNV).Patients with CSCR complicated by CNV defined as the presence of characteristic OCT angiography features were randomly assigned to either study or control group. All patients of the study group underwent MLT targeting CNV area using navigated laser system followed by at least 6-month follow-up. Sham treatment was performed in the control group. No other treatment or anti-VEGF therapy was used during the follow-up. Main outcome measure was complete resolution of subretinal fluid at the end of follow-up.Twenty-three eyes (13 males and 10 females, mean age 58.2 ± 8.0 years) with a mean CNV area 0.62 ± 0.77 mm2 were included in the study group. Fourteen (60.9%) patients achieved complete resolution of SRF, five (21.7%) patients demonstrated some reduction of SRF, and four (17.4%) patients demonstrated no improvement after MLT in the study group. Twelve eyes (8 males and 4 females, mean age 59.8 ± 4.6 years) were included in the control group where none of them demonstrated resolution of SRF at the end of the follow-up (p = 0.0018 compared to the study group). No adverse effects, such as changes of CNV size, deterioration of exudation, or decline in visual acuity were observed in the study group.Microsecond pulsing laser is an effective and safe option for the treatment of CSCR complicated by relatively small CNV and achieves complete resolution of SRF in 61% of cases. [ABSTRACT FROM AUTHOR]

Background: Balance dysfunction affects 70% of stroke patients. Emerging neurophysiological approaches, such as virtual reality therapy (VRT) and repetitive transcranial magnetic stimulation (rTMS), have been proven by clinical studies that the balance function of stroke patients can be improved when applied alone, but there are relatively few studies on the combined treatment of balance dysfunction after stroke. This study aimed to evaluate the impact of a 4-week intensive intervention combining VRT and rTMS on both balance function and brain plasticity among stroke patients. Methods: This single-blind, randomized controlled trial was conducted at the Rehabilitation Medical Center of the Rehabilitation General Hospital of Ningxia Medical University. A cohort of 136 stroke patients, with durations of 2 to 24 weeks post-stroke, were enrolled in the study. Participants were randomly allocated in a 1:1:1:1 ratio to four groups: the VR group (n = 34), the rTMS group (n = 34), the combined treatment group receiving both VR and rTMS (n = 34), and the control group undergoing traditional balance training (n = 34). All patients underwent a standardized inpatient rehabilitation program over 4 weeks. The VR group received daily 30-min sessions of VR therapy for 20 days. The rTMS group underwent daily sessions of rTMS stimulation for 20 min, targeting the motor imagery region in the affected hemisphere. The combination group received VR therapy after completing their rTMS treatment. The control group received conventional balance training, with each session lasting 30 min. Additionally, all patients received an extra 60 min of standard rehabilitation therapy twice daily. Assessments were conducted at baseline, 2 weeks, and 4 weeks post-treatment, using the Berg Balance Scale (BBS) as the primary measure, and secondary measures including the Timed Up-and-Go Test (TUGT), Fugl-Meyer Assessment-Lower Extremity (FMA-LE), and 6-m walking test (6MWT), as well as assessments for brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VGEF), tyrosine receptor kinase (TrκB), motor-evoked potential latency (PL), central motor conduction time (CMCT), and amplitude. Discussion: The widespread application of VR technology and rTMS in clinical settings is well-established. However, the potential synergistic effects of combining these modalities on balance function and neuroplasticity in stroke patients remain uncertain. Our hypothesis suggests that the integration of VR with rTMS may result in more pronounced improvements in both balance function and neuroplasticity among stroke patients, surpassing the outcomes achievable with VR alone, rTMS alone, or traditional therapy. The possible mechanism is that VR-based training combined with rTMS plays a superimposed effect, promoting better repair of damaged neurons and ultimately improving balance function in stroke patients. The positive results anticipated from this trial could provide objective evidence advocating for the concurrent use of VR and rTMS in clinical interventions. Trial registration: The study protocol underwent review and approval by the Medical Research Ethics Committee of the General Hospital of Ningxia Medical University on January 26, 2024 (No. KYLL-2024–0162). Subsequently, it was registered in the Chinese Clinical Trial Registry on March 11, 2024 (registration number: ChiCTR2400081775). Currently, the study is still ongoing. [ABSTRACT FROM AUTHOR]

Patients with gastric cancer (GC) are more susceptible to coronavirus disease 2019 (COVID-19), which further worsens their already challenging prognosis. However, there are no effective treatment options for these patients. Lentinan is a potent bioactive component with antiviral and antitumor effects. We hypothesized that lentinan might exert powerful pharmacological effects in patients with GC and COVID-19. In this study, a prognostic model of patients with GC/COVID-19 was constructed and used to apply a network pharmacology approach to reveal biological functions, drug targets, and molecular mechanisms of the action of lentinan against GC/COVID-19. Clinical analysis revealed key prognostic genes in patients with GC/COVID-19. The results of network pharmacology analysis suggested that the therapeutic effect of lentinan on GC/COVID-19 mainly involves the modulation of several neutrophil-related biological processes, as well as the nucleotide-binding and oligomerization domain-like receptor and interleukin-17 signaling pathways. In addition, C-X-C motif chemokine ligand 8, vascular endothelial growth factor A, ribonuclease 3, and F2 were identified as key genes of lentinan against GC/COVID-19. Key prognostic genes were identified in patients with GC/COVID-19 through the construction of a prognostic model. Pharmacological functions and signaling pathways of lentinan against GC/COVID-19 were revealed. These included the regulation of neutrophils and NOD-like receptor signaling pathways. The findings provide the first published evidence of the potential value of lentinan as a complementary therapy for GC/COVID-19. [ABSTRACT FROM AUTHOR]

Background: There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs. Objective: To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT. Study design: TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (Ktrans) of contrast within the BM vascular niche, as well as the fractional volume (vec) of extracellular extravascular tissue (EES). Results: No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, Ktrans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement inmice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery. day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery. [ABSTRACT FROM AUTHOR]

Hypoxic diabetic foot ulcers (HDFUs) pose a challenging chronic condition characterized by oxidative stress damage, bacterial infection, and persistent inflammation. This study introduces a novel therapeutic approach combining ergothioneine (EGT), luteolin (LUT), and quaternized chitosan oxidized dextran (QCOD) to address these challenges and facilitate wound healing in hypoxic DFUs. In vitro, assessments have validated the biosafety, antioxidant, and antimicrobial properties of the ergothioneine‐luteolin‐chitin (QCOD@EGT‐LUT) hydrogel. Furthermore, near‐infrared II (NIR‐II) fluorescence image‐guided the application of QCOD@EGT‐LUT hydrogel in simulated HDFUs. Mechanistically, QCOD@EGT‐LUT hydrogel modulates the diabetic wound microenvironment by reducing reactive oxygen species (ROS). In vivo studies demonstrated increased expression of angiogenic factors mannose receptor (CD206) and latelet endothelial cell adhesion molecule‐1 (PECAM‐1/CD31), coupled with decreased inflammatory factors tumor necrosis factor‐α (TNF‐α) and Interleukin‐6 (IL‐6), thereby promoting diabetic wound healing through up‐regulation of transforming growth factor β‐1 (TGF‐β1). [ABSTRACT FROM AUTHOR]

Background: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. Methods: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. Results: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. Conclusions: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. Trial registration: NCT02674152 and NCT02689505. [ABSTRACT FROM AUTHOR]

Objective To characterize the relationship between gut microbiota and neonatal acute kidney injury biomarkers based on the gut-kidney axis. Study Design The Pubmed database was primarily searched to include relevant literature on gut microbiota and neonatal acute kidney injury biomarkers, which was subsequently organized and analyzed and a manuscript was written. Results Gut microbiota was associated with neonatal acute kidney injury biomarkers. These biomarkers included TIMP-2, IGFBP-7, VEGF, calbindin, GST, B2MG, ghrelin, and clusterin. Conclusion The gut microbiota is strongly associated with neonatal acute kidney injury biomarkers, and controlling the gut microbiota may be a potential target for ameliorating neonatal acute kidney injury. Key Points There is a bidirectional association between gut microbiota and AKI. Gut microbiota is closely associated with biomarkers of nAKI. Manipulation of gut microbiota may improve nAKI. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a crucial role in various physiological and pathological conditions. However, research in equine angiogenesis is relative limited, necessitating the development of suitable in-vitro models. To effectively analyze angiogenesis invitro, it is essential to target the specific cells responsible for this process, namely endothelial cells. Human umbilical vein endothelial cells (HUVECs) are one of the most used in vitro models for studying angiogenesis in humans. Serving as an equivalent to HUVECs, we present a comprehensive isolation protocol for equine umbilical vein endothelial cells (EqUVECs) with relatively minimal requirements, thereby enhancing accessibility for researchers. Umbilical cords obtained from five foals were used to isolate endothelial cells, followed by morphological and immunohistochemical identification. Performance of the cells in various assays commonly used in angiogenesis research was studied. Additionally, EqUVEC expression of vascular endothelial growth factor (VEGF) was assessed using ELISA. EqUVECs exhibited endothelial characteristics, forming a homogeneous monolayer with distinctive morphology. Immunohistochemical staining confirmed positive expression of key endothelial markers including von Willebrand factor (vWF), CD31, and vascular endothelial growth factor receptor-2 (VEGFR-2). Furthermore, performance assessments in in-vitro assays demonstrated the viability, proliferation, migration, tube formation and VEGF-expression capabilities of EqUVECs. The findings suggest that EqUVECs are a promising in-vitro model for studying equine angiogenesis, offering a foundation for further investigations into equine-specific vascular processes and therapeutic interventions. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

The article explores the impact of CCDC88A on hepatocellular carcinoma (HCC) and its regulation of VEGF through miR-101. It highlights that CCDC88A is elevated in HCC tissues and linked to a poor prognosis, with its knockdown inhibiting malignant behaviors in HCC cells by affecting VEGF. The study proposes CCDC88A and VEGF as potential targets for HCC treatment. Additionally, the text delves into the expression and function of VEGF in various cell types, including glomerular endothelial cells, vascular smooth muscle cells, platelets, and human neutrophils, shedding light on its role in angiogenesis and wound healing. [Extracted from the article]

Background: Gastrodia elata Blume, also called Tian Ma (TM), has been used to treat stroke for centuries. However, its effects on inflammation in acute cerebral ischemic injury and underlying mechanisms involved in microglial polarization remain unknown. The present study explored the effects of the TM extract on the modulation of microglial M1/M2 polarization 2 days after transient cerebral ischemia. Methods: Male Sprague Dawley rats were intracerebroventricularly administered with 1% dimethyl sulfoxide 25 min before cerebral ischemia and subsequently intraperitoneally administered 0.25 g/kg (DO + TM-0.25 g), 0.5 g/kg (DO + TM0.5 g), or 1 g/kg (DO + TM-1 g) of the TM extract after cerebral ischemia onset. Results: DO + TM-0.5 g and DO + TM-1 g treatments downregulated the following: phospho-c-Jun N-terminal kinase (p-JNK)/JNK, tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3), TRAF3-interacting JNKactivating modulator (T3JAM), p-nuclear factor-kappa B p65 (p-NF-κB p65)/ NF-κB p65, ionized calcium-binding adapter molecule 1 (Iba1), CD86, TNF-α, interleukin (IL)-1β, and IL-6 expression and toll-like receptor 4 (TLR4)/Iba1, CD86/ Iba1, and p-NF-κB p65/Iba1 coexpression. These treatments also upregulated IL10, nerve growth factor, and vascular endothelial growth factor A expression and YM-1/2/Iba1 and IL-10/neuronal nuclei coexpression in the cortical ischemic rim. The JNK inhibitor SP600125 exerted similar treatment effects as the DO + TM0.5 g and DO + TM-1 g treatments. Conclusion: DO + TM-0.5 g and DO + TM-1 g/kg treatments attenuate cerebral infarction by inhibiting JNK-mediated signaling. TM likely exerts the neuroprotective effects of promoting M1 to M2 microglial polarization by inhibiting JNK/TLR4/T3JAM/NF-κB-mediated signaling in the cortical ischemic rim 2 days after transient cerebral ischemia. [ABSTRACT FROM AUTHOR]

Objective To investigate the application value of Yishen Huayu Xugu prescriptionin the management of osteoporotic lumbar compression fracture among elderly patients. Methods From March 2022 to August 2023, all elderly patients with osteoporotic lumbar compression fractures were enrolled in our hospital and randomly assigned into two groups. The patients were diagnosed with kidney deficiency and blood stasis syndrome through physical identification. After admission, both groups (85 cases each) underwent percutaneous kyphoplasty. The control group received conventional Western medicine treatment post-surgery, while the observation group was administered Yishen Huayu Xugu prescription. This herbal formula was prepared by decocting 300 mL of juice in water, divided into two doses, and taken warmly after breakfast and dinner for a duration of 12 weeks. Therapeutic effects were compared after completion of the 12-week treatment period. Results After treatment, the serum levels of D-dimer (D-dimer, D-D) were (5.02 ± 0.63), interleukin-17 (IL-17) was (53.68 ± 5.47), p-collagen special sequence (p-CTX) was (0.37 ± 0.06, interleukin-6 (IL-6) was (69.38 ± 8.27) compared to the control group; bone morphogenetic protein-2 (BMP-2) was (2.69 ± 0.31), 25-hydroxyvitamin D was (58.93 ± 7.17), and vascular endothelial growth factor (VEGF) was (309.81 ± 51.49) which were higher than those in the control group with more sig-nificant improvement observed in the intervention group (P < 0.05). Bone mineral density (BMD) increased at both week 6 and week12 after treatment with a more pronounced improvement seen in the intervention group (P < 0.05). After treatment, the observation group exhibited a more significant reduction in the total Traditional Chinese Medicine ( TCM ) symptom score, Cobb Angle, and ODI, compared to the control group (P < 0.05 ). Furthermore, the observation group demonstrated a higher total effective rate of 95.29% (81/85) compared to 85.88% (73/85) in the control group after treatment, "with a statistically significant difference between the two groups (P < 0.05). Conclusion The Yishen Huayu Xugu prescription holds significant positive implications for this particular medication, as it exhibits enhanced efficacy in reducing inflammation, regulating bone metabolism, improving lumbar function, promoting disease amelioration, and enhancing clinical outcomes. [ABSTRACT FROM AUTHOR]

Non‐small cell lung cancer comprises up to 85% of lung cancer cases and has a poor prognosis. At present, there are still no effective treatments for this illness. Evidence suggests that the prostaglandin [cyclooxygenase‐2 (COX‐2)] and leukotriene [lipoxygenase‐5 (5‐LOX)] pathways are involved in lung cancer carcinogenesis. Therefore, novel agents that target COX‐2 and 5‐LOX may have therapeutic potential. In the present study, we examined the role of asiatic acid (AA), a triterpenoid saponin, in targeting the protein kinases responsible for lung cancer proliferation and mobility. The experimental data revealed that AA inhibited the growth of lung cancer cells (> 50%) and it significantly impeded the proliferation of lung cancer cells by inhibiting COX‐2, which results in downregulation of the phosphotidyl inositol‐3 kinase/protein kinase B/mammalian target of rapamycin signaling pathway, leading to an induction of cytotoxic autophagy‐mediated apoptosis. Mechanistically, the expression of mitogen‐activated protein kinase/extracellular signal‐regulated kinase, hypoxia‐inducible factor‐1 and vascular endothelial growth factor is downregulated by AA, thereby reducing cell mobility and invasion. It also shows negative osmotic fragility on healthy human erythrocytes. It is concluded that AA may be a viable therapeutic drug for non‐small cell lung cancer treatment, which opens new opportunities for synthesizing analogues. [ABSTRACT FROM AUTHOR]

Bacterial infections, especially those from drug‐resistant strains, pose a significant threat to healing diabetic skin injuries, with current treatments being intricated and often unsatisfactory. Inspired by octopuses, a biomimetic material using α‐cyclodextrin (α‐CD) and polyethylene glycol (PEG) assembled with graphene oxide end‐capped polyrotaxanes (GO‐PR) is developed, where α‐CD mimics the flexible tentacles of an octopus. Further, α‐CD is cationically modified with polyethyleneimine (PEI) to resemble octopus suction cups, creating GO‐PRP, which effectively captures and adheres to bacteria. Importantly, to emulate an octopus's ink defense, GO‐PRP is used as a carrier for nitric oxide (NO), resulting in GO‐PRP/NONOate. Utilizing the photothermal conversion of GO, near‐infrared light exposure triggers rapid heating and NO release, providing efficient antibacterial activity and biofilm dispersion, significantly reducing inflammation in diabetic skin injuries in type I rats. During wound healing, sustained NO release promotes vascular endothelial growth factor production and blood vessel regeneration, enhancing collagen formation and shortening the healing time for diabetic skin infections. Thus, octopus‐inspired GO‐PRP/NONOate emerges as a novel biomaterial for treating drug‐resistant bacterial infections in diabetic wounds in the biomedical field. [ABSTRACT FROM AUTHOR]

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases. [Display omitted] • Meningeal lymphatic vessel ablation causes loss of mature oligodendrocytes • Demyelination due to meningeal lymphatic ablation relies on a competent immune system • Meningeal lymphatic dysfunction affects brain remyelination and aggravates axonal loss • Multiple sclerosis patients have decreased VEGF-C levels in their cerebrospinal fluid The neurophysiological processes regulated by meningeal lymphatic function remain unclear. das Neves et al. showed that meningeal lymphatic dysfunction leads to loss of mature oligodendrocytes and demyelination in the brain. Defective meningeal lymphatics incited a neuroinflammatory environment that limited oligodendrocyte replenishment after a demyelinating insult. This work might have therapeutic implications for the central nervous system demyelinating autoimmune disorders. [ABSTRACT FROM AUTHOR]

Upregulation of vascular endothelial growth factor (VEGF) and enhanced angiogenesis have been implicated in the severe progression of age-related macular degeneration (AMD). Abnormal arachidonate 5-lipoxygenase (ALOX5) is associated with AMD pathogenesis. However, no reports have shown the causal role of ALOX5 in angiogenesis during AMD. In the present study, ARPE-19 cells were exposed to hypoxia, an inducer of VEGF expression. Potential proteins implicated in AMD progression were predicted using bioinformatics. RNA affinity antisense purification-mass spectrometry (RAP-MS) was applied to identify the binding proteins of ALOX5 3′UTR. Expression of ALOX5 and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) was detected by qRT-PCR and western blotting. VEGF expression and secretion were assessed by immunofluorescence and ELISA, respectively. The chicken embryo chorioallantoic membrane (CAM) was used to analyze the effect of ALOX5 on angiogenesis. RNA stability was assayed using the Actinomycin D assay. The results show that hypoxia promoted cell growth and increased VEGF expression in ARPE-19 cells. ALOX5 was associated with AMD progression, and hypoxia upregulated ALOX5 expression in ARPE-19 cells. ALOX5 silencing reduced VEGF expression induced by hypoxia in ARPE-19 cells. Moreover, the conditioned medium of ALOX5-silenced ARPE-19 cells could suppress the viability and migration of HUVECs and diminish angiogenesis in the CAM. Furthermore, YTHDF1 was validated to bind to ALOX5 3′UTR, and YTHDF1 promoted ALOX5 expression by elevating the stability of ALOX5 mRNA. In conclusion, our findings demonstrate that YTHDF1-regulated ALOX5 increases VEGF expression in hypoxia-exposed ARPE-19 cells and enhances the viability, migration, and angiogenesis of vascular endothelial cells. [ABSTRACT FROM AUTHOR]

Retinal neurovascular unit (NVU) is a multi-cellular structure that consists of the functional coupling between neural tissue and vascular system. Disrupted NVU will result in the occurrence of retinal and choroidal vascular diseases, which are characterized by the development of neovascularization, increased vascular permeability, and inflammation. This pathological entity mainly includes neovascular age-related macular degeneration (neovascular-AMD), diabetic retinopathy (DR) retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). Emerging evidences suggest that the angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) signaling pathway is essential for the development of retinal and choroidal vascular. Tie receptors and their downstream pathways play a key role in modulating the vascular development, vascular stability, remodeling and angiogenesis. Angiopoietin 1 (Ang1) is a natural agonist of Tie2 receptor, which can promote vascular stability. On the other hand, angiopoietin 2 (Ang2) is an antagonist of Tie2 receptor that causes vascular instability. Currently, agents targeting the Ang/Tie signaling pathway have been used to inhibit neovascularization and vascular leakage in neovascular-AMD and DR animal models. Particularly, the AKB-9778 and Faricimab have shown promising efficacy in improving visual acuity in patients with neovascular-AMD and DR. These experimental and clinical evidences suggest that activation of Ang/Tie signaling pathway can inhibit the vascular permeability, neovascularization, thereby maintaining the normal function and structure of NVU. This review seeks to introduce the versatile functions and elucidate the modulatory mechanisms of Ang/Tie signaling pathway. Recent pharmacologic therapies targeting this pathway are also elaborated and summarized. Further translation of these findings may afford a new therapeutic strategy from bench to bedside. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults. Objective: To determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis. Methods: Part I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16-18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2-3 months) or aged donors (16-18 months). Results: In older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A. Conclusions: (a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects. [ABSTRACT FROM AUTHOR]

Background: Scarring is one of the most complex outcomes of wound healing which usually replaces normal skin with fibrotic tissue. Scar modulation is a composite biological process involving inflammation, tissue remodeling, and collagen deposition elements. We aimed this study to analyze the expression of Vascular Endothelial Growth Factor (VEGF) in acute wounds and scar modulation following nanofat grafting on an animal model. Methods: This experimental study included 24 male Wistar albino rats. The wounds were divided into a group of nano-fat-treated wounds and a control group receiving saline injections (n=12 rats in each group). Nano fat was prepared by emulsifying harvested fat tissue, which was then injected into the incision wounds of the treatment group. Wound assessment and photographic documentation were made on days 15, 21, and 28 post-surgery. Histological and immunohistochemical evaluations were carried out to evaluate fibrosis and VEGF expression. Results: Nanofat-treated wounds demonstrated a more rapid and organized healing process compared to the control wounds. On day 21, the scars of nanofat-treated wounds were smoother and had a smaller area. In immunohistochemistry, there was substantially more expression for VEGF in the nano-fat-treated scars, and the capillary density was also higher. The positive area for VEGF and the mean VEGF-positive area in the nanofat-treated group were significantly higher than the control group (118072 µm² ±59937, 4.300416% ± 2.136 vs 10302.3 µm² ±16565, and 0.3644% ± 0.583) (p=0.00044, 0.000025 respectively). Conclusion: In conclusion, nanofat grafting improved scar modulation, increased VEGF, and angiogenesis, whereas the quality of scarring increased, and wound-healing time shortened. Detailed mechanisms and potential clinical applications of nanofat grafting in scar treatment require further research. [ABSTRACT FROM AUTHOR]

Simple Summary: The low embryo attachment rate and early embryo loss of dairy cows are important factors restricting the improvement of dairy cow fertility and are also the key scientific problems that need to be solved urgently in dairy cow production and embryo transfer. In this study, we used RT-qPCR, Western blot, immunofluorescence, and so on in cultured bovine endometrial epithelial cells to investigate the mechanism by which melatonin regulates the expression of VEGF and HOXA10 through SIRT1, PI3K, AKT, and miRNA. The results indicate that melatonin regulates the expression of VEGF and HOXA10 through the SIRT1/PI3K/AKT pathway and promotes the establishment of receptivity in bovine endometrial epithelial cells. The results indicate that melatonin negatively regulates the expression of bta-miR-497 and bta-27a-3p in bovine endometrial epithelial cells through the SIRT1/PI3K/AKT pathway and positively regulates the expression of VEGF and HOXA10. In this regulatory network, bta-miR-27a-3p negatively modulates HOXA10 expression, while bta-miR-497 negatively modulates VEGF expression. Melatonin plays a critical role in regulating embryo attachment in ruminants. While numerous studies have investigated its effects on early embryo development in vitro, the precise mechanisms by which melatonin influences the receptivity of endometrial epithelial cells in dairy cows remain unclear. The prerequisite for embryo implantation is the specific physiological condition of the endometrium that allows the embryo to implant, also known as endometrial receptivity. In addition to this, endometrial cells undergo processes such as proliferation, differentiation, and renewal, which makes the embryo more easily implanted. In this study, bovine endometrial epithelial cells were cultured and treated with melatonin, Silent Information Regulator 1 (SIRT1) inhibitor (EX527), and protein kinase B (AKT) phosphorylation inhibitor (periposine). RT-qPCR, Western blot, and immunofluorescence analysis were performed to investigate the effects of melatonin on the expression of target gene (SIRT1); cell proliferative genes, phosphatidylinositol-4,5-bisphosphate 3-Kinase (PI3K), AKT, cyclinD1, cyclinE1; and receptive genes (Leukemia Inhibitory Factor (LIF), Vascular Endothelial Growth Factor (VEGF), Homeobox Structure Gene 10 (HOXA10)). Additionally, microRNA (miRNA) mimics and inhibitors were used to transfect the cells to study the regulatory relationship between miRNA and receptive genes. Results indicated that melatonin activates the PI3K/AKT signaling pathway, upregulates cyclinD1 and cyclinE1, and promotes the proliferation of bovine endometrial epithelial cells. Melatonin also upregulated the expression of VEGF and HOXA10 and downregulated the expression of bta-miR-497 and bta-miR-27a-3p through SIRT1/PI3K/AKT signaling pathway. Further, bta-miR-497 and bta-miR-27a-3p were found to negatively regulate VEGF and HOXA10, respectively. Therefore, melatonin regulates the expression of VEGF and HOXA10 through the SIRT1/PI3K/AKT pathway and promotes the establishment of receptivity in bovine endometrial epithelial cells. [ABSTRACT FROM AUTHOR]

Coronary aneurysms are typically defined as sections of a coronary artery where the diameter is more than 1.5 times that of an adjacent normal segment. In rare circumstances, these aneurysms can become exceedingly large, leading to the classification of giant coronary artery aneurysms. Despite their occurrence, there is no clear consensus on the precise definition of giant coronary artery aneurysms, and their etiology remains somewhat ambiguous. Numerous potential causes have been suggested, with atherosclerosis being the most prevalent in adults, accounting for up to 50% of cases. In pediatric populations, Kawasaki disease and Takayasu arteritis are the primary causes. Although often discovered incidentally, coronary artery aneurysms can lead to severe complications. These complications include local thrombosis, distal embolization, rupture, and vasospasm, which can result in ischemia, heart failure, and arrhythmias. The optimal approach to medical, interventional, or surgical management of these aneurysms is still under debate and requires further clarification. This literature review aims to consolidate current knowledge regarding coronary artery aneurysms' pathophysiology, emphasizing their definition, causes, complications, and treatment strategies. Recent research has begun to explore the molecular mechanisms involved in the formation and progression of coronary artery aneurysms. Various molecules, such as matrix metalloproteinases (MMPs), inflammatory cytokines, and growth factors, play crucial roles in the degradation of the extracellular matrix and the remodeling of vascular walls. Elevated levels of MMPs, particularly MMP-9, have been associated with the weakening of the arterial wall, contributing to aneurysm development. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins (IL-1β and IL-6) have been implicated in promoting inflammatory responses that further degrade vascular integrity. Additionally, growth factors such as vascular endothelial growth factor (VEGF) may influence angiogenesis and vascular remodeling processes. Understanding these molecular pathways is essential for developing targeted therapies aimed at preventing the progression of coronary artery aneurysms and improving patient outcomes. [ABSTRACT FROM AUTHOR]

To evaluate the plasma levels of angiopoietin-1 and vascular endothelial growth factor (VEGF) and their association with macular neovascularization (MNV) in patients with chronic central serous chorioretinopathy (cCSC). Correlations between plasma cytokine levels, CSC duration, and mean choroidal thickness (CT) were also investigated. Of the 59 patients with cCSC, 10 patients with MNV secondary to cCSC and 10 patients with cCSC without MNV were enrolled in the study. The control group included 15 healthy volunteers matched for age, sex, smoking status, and comorbidities. Chronic CSC was diagnosed based on typical findings on swept-source optical coherence tomography (OCT), fundus fluorescein angiography, and indocyanine green angiography. Additionally, all patients underwent OCT angiography to help detect MNV. Plasma angiopoietin-1 and VEGF levels were assessed using multiplex immunoassay. The plasma angiopoietin-1 levels differed between the 3 groups (p = 0.005). The angiopoietin-1 levels were lower in patients with cCSC with MNV than in controls (p = 0.006). There were no differences in the plasma VEGF levels between all the 3 groups (p = 0.329). The VEGF levels were negatively correlated with mean CT in cCSC patients with MNV (rho = −0.683, p = 0.042) but correlated positively with disease duration in patients with cCSC without MNV (rho = 0.886, p = 0.003). Our study confirms that MNV is a common complication of cCSC and provides new insights into the role of angiopoietin-1 in cCSC and MNV. Reduced angiopoietin-1 levels in cCSC patients, regardless of MNV status, highlight the importance of the Ang–Tie2 pathway in disease pathogenesis and may point to new therapeutic targets and future novel treatments to improve the management of these patients. [ABSTRACT FROM AUTHOR]

In the aging population, choroidal vessels grow through the Bruch's membrane, resulting in a loss of central vision due to choroidal neovascularization (CNV). During active neovascularization, CNV is associated with inappropriate levels of apoptosis in multiple cell types, including choroidal endothelial cells (ChECs). Bim is a pro-apoptotic member of the Bcl-2 family. It is essential for cell apoptosis due to exposure to drugs such as dexamethasone or decreased pro-survival factors, including vascular endothelial growth factor (VEGF). To better elucidate the cell autonomous contribution of Bim expression in the integrity and neovascularization of the choroidal vasculature, we isolated ChECs from wild-type and Bim-deficient (Bim−/−) mice. ChECs lacking Bim expression demonstrated increased expression of VEGF, osteopontin, and the inflammatory cytokines Rantes/Ccl5 and IL6. Bim−/− ChECs were more proliferative and demonstrated an increased capacity to undergo capillary morphogenesis. Anti-VEGF had a diminished capacity to disrupt capillary morphogenesis in Bim−/− ChECs. In vivo, utilizing the mouse laser photocoagulation model, anti-VEGF treatment mitigated CNV in wild-type but not Bim−/− mice. We also tested other modalities that are thought to not require the intrinsic death pathway for their function and showed that propranolol, anti-CTGF, and the TSP1-mimetic peptide ABT898 mitigated CNV in mice lacking Bim expression to varying degrees. Thus, in ChECs, Bim expression could impact the effectiveness of treatment modalities that require the intrinsic death pathway to mitigate CNV. [ABSTRACT FROM AUTHOR]

Introduction Programmed death 1 (PD-1) / programmed death 1 ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatments for advanced non-small cell lung cancer (NSCLC), whereas the optimal therapeutic combinations remain uncertain. Methods Our study encompassed phase II/III randomized controlled trials (RCTs) that involved anti-PD-(L)1-based therapies for stage-IV NSCLC. The primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and incidences of adverse events. Subgroup analyses were conducted by treatment lines, PD-L1 expression levels, histological types, and metastatic sites. Results Our analysis incorporated 38 publications, covering 14 therapeutic combinations and involving 18 048 participants. PD-(L)1+chemotherapy (CT), PD-(L)1+ cytotoxic T lymphocyte-associated antigen-4 (CTLA4) +CT, and PD-(L)1+ T-cell immunoglobulin and ITIM domain were notably effective in prolonging OS. Overall, PD-(L)1+CT and PD-(L)1+CT+ vascular endothelial growth factor (VEGF) were significantly beneficial for PFS and ORR. As for the subsequent-line treatments, incorporating radiotherapy can enhance PFS and ORR (ranked fourth among enrolled treatments). For patients with PD-L1 <1%, PD-(L)1+CT+VEGF and PD-(L)1+CTLA4+CT were favorable approaches. Conversely, in patients with PD-L1 ≥50%, PD-(L)1+CT represented an effective treatment. Patients with nonsquamous cell carcinoma or liver metastases might benefit from the addition of VEGF. In cases of squamous cell carcinoma or brain metastases, the combination of PD-(L)1+CTLA4+CT yielded superior benefits. Conclusions This study underscores the enhanced efficacy of combination immunotherapies over monotherapy. It highlights the necessity for personalized treatment, considering individual factors. These insights are vital for clinical decision making in the management of advanced NSCLC. [ABSTRACT FROM AUTHOR]

Objective: To determine whether combining cross‐linked (CL) collagen‐integrated xenogeneic bone blocks stabilized with the fixation of resorbable collagen membranes (CM) can enhance guided bone regeneration (GBR) in the overaugmented calvarial defect model. Materials and Methods: Four circular defects with a diameter of 8 mm were prepared in the calvarium of 13 rabbits. Defects were randomly assigned to receive one of the following treatments: (i) non‐cross‐linked (NCL) porcine‐derived collagen‐embedded bone block covered by a CM without fixation (NCL + unfix group); (ii) NCL bone block covered by CM with fixation using bone‐tack (NCL + fix group); (iii) cross‐linked (CL) porcine‐derived collagen‐embedded bone block covered by CM without fixation (CL + unfix group); and (iv) CL bone block covered by CM with fixation using bone‐tack fixation (CL + fix group). The efficacy of GBR was assessed through histological and molecular analyses after 2 and 8 weeks. Results: At 2 weeks, there were no significant differences in histologically measured areas of newly formed bone among the groups. At 8 weeks, however, the CL + fix group exhibited a larger area of new bone (5.08 ± 1.09 mm2, mean ± standard deviation) compared to the NCL + unfix (1.62 ± 0.42 mm2; p <.0083), NCL + fix (3.97 ± 1.39 mm2) and CL + unfix (2.55 ± 1.04 mm2) groups. Additionally, the expression levels of tumour necrosis factor‐alpha, fibroblast growth factor‐2, vascular endothelial growth factor, osteocalcin and calcitonin receptor were significantly higher in the CL + fix group compared to the other three groups (p <.0083). Conclusion: Cross‐linked bone blocks stabilized with collagen membrane fixation can significantly enhance GBR. [ABSTRACT FROM AUTHOR]

Objectives: Investigation of the therapeutic effect of zoledronic acid (ZA) in a preclinical model of jaw osteosarcoma (JO). Materials and Methods: The effect of 100 μg/kg ZA administered twice a week was assessed in a xenogenic mouse model of JO. The clinical (tumor growth, development of lung metastasis), radiological (bone microarchitecture by micro‐CT analysis), and molecular and immunohistochemical (TRAP, RANK/RANKL, VEGF, and CD146) parameters were investigated. Results: Animals receiving ZA exhibited an increased tumor volume compared with nontreated animals (71.3 ± 14.3 mm3 vs. 51.9 ± 19.9 mm3 at D14, respectively; p = 0.06) as well as increased numbers of lung metastases (mean 4.88 ± 4.45 vs. 0.50 ± 1.07 metastases, respectively; p = 0.02). ZA protected mandibular bone against tumor osteolysis (mean bone volume of 12.81 ± 0.53 mm3 in the ZA group vs. 11.55 ± 1.18 mm3 in the control group; p = 0.01). ZA induced a nonsignificant decrease in mRNA expression of the osteoclastic marker TRAP and an increase in RANK/RANKL bone remodeling markers. Conclusion: The use of bisphosphonates in the therapeutic strategy for JO should be further explored, as should the role of bone resorption in the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

Objectives: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier‐related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. Materials and Methods: A CAL‐27‐LEC co‐culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT‐qPCR detected protein and mRNA expression under different conditions, respectively. CCK‐8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. Results: In high‐glucose co‐culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO‐1 and occludin, two tight‐junction proteins; conversely, the expression of PAR2, a high permeability‐related protein, was increased. Following linagliptin treatment, the expression levels of VEGF‐C, VEGFR‐3, and PAR2 decreased, while those of ZO‐1 and occludin increased. Considerably higher levels of LYVE‐1 expression in individuals with diabetes than in those without diabetes. Conclusions: By ameliorating the high glucose‐induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes. [ABSTRACT FROM AUTHOR]

Objective: Midpalatal expansion (MPE) is routinely employed to treat transverse maxillary arch deficiency. Neutrophils are indispensable for recruiting bone marrow stromal cells (BMSCs) at the initial stage of bone regeneration. This study aimed to explore whether neutrophils participate in MPE and how they function during bone formation under mechanical stretching. Materials and Methods: The presence and phenotype of neutrophils in the midpalatal suture during expansion were detected by flow cytometry and immunofluorescence staining. The possible mechanism of neutrophil recruitment and polarization was explored in vitro by exposing vascular endothelial cells (VECs) to cyclic tensile strain. Results: The number of neutrophils in the distracted suture peaked on Day 3, and N2‐type neutrophils significantly increased on Day 5 after force application. The depletion of circulatory neutrophils reduced bone volume by 43.6% after 7‐day expansion. The stretched VECs recruited neutrophils via a CXCR2 mechanism in vitro, which then promoted BMSC osteogenic differentiation through the VEGFA/VEGFR2 axis. Consistently, these neutrophils showed higher expression of canonical N2 phenotype genes, including CD206 and Arg1. Conclusions: These results suggested that neutrophils participated in early bone formation during MPE. Based on these findings, we propose that stretched VECs recruited and polarized neutrophils, which, in turn, induced BMSC osteogenic differentiation. [ABSTRACT FROM AUTHOR]

Objective: Multitargeted tyrosine kinase inhibitors (TKIs) have been approved as second‐line therapy in refractory sarcoma, prolonging progression‐free survival (PFS) but with short‐lived duration of disease control. Fruquintinib is a TKI that specifically inhibits vascular endothelial growth factor receptor‐1,2,3 with no metabolism by liver enzymes. In this retrospective study, we assessed the efficacy and safety of fruquintinib‐based treatment in patients with refractory sarcoma after developing several lines of TKI resistance. Methods: We retrospectively analyzed the clinical data of patients with refractory sarcoma after they had developed several lines of resistance to TKIs and who received fruquintinib‐based treatment from November 2021 to August 2023. The primary endpoint was the progression‐free survival rate at 4 months (4m‐PFSR). Secondary endpoints were the median PFS, overall survival (OS), objective response rate, disease control rate, and adverse effects (AEs). PFS and OS were estimated using the Kaplan–Meier method. A log‐rank test was used to compare survival curves between different clinical and pathological factors. Cox proportional hazards analysis was performed to identify PFS‐related prognostic factors. Results: We included 124 patients: 56 (45.2%) with osteosarcoma, 28 (22.6%) with Ewing sarcoma, seven (5.6%) with chondrosarcoma, and 33 (26.6%) with soft tissue sarcomas (STS). Only 18 (14.5%) patients received monotherapy with fruquintinib. With a median follow‐up time of 6.8 (interquartile range [IQR], 4.6–9.4) months, 22 (17.7%) patients had partial response and 78 (62.9%) had stable disease. The 4m‐PFSR was 58.4% (95% confidence interval [CI], 49.6%–67.1%). The median PFS and OS were 4.4 (95% CI, 3.9–5.0) months and 11.4 (95% CI, 10.3–12.5) months. In multivariate analysis, a high hazard ratio for progression was associated with target lesions located outside the lung and bone with 1.79 (95% CI, 1.10–2.93; p = 0.020). Eighty‐eight AEs were recorded in 47 (37.9%) patients; the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), oral mucositis (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%). Conclusions: Fruquintinib may be a potential option for patients with refractory sarcoma after developing several lines of TKI resistance, with a satisfactory efficacy and safety profile in combination therapy. However, the degree of contribution of fruquintinib to results is unclear when combined with other effective substances. Additional prospective trials of fruquintinib should be conducted, especially involving different pathological types and combination regimens. [ABSTRACT FROM AUTHOR]

Purpose: To investigate serum levels of VEGF, IGF-1 and FGF-2, and relationships with several clinical characteristics in children and adolescents with autism spectrum disorder (ASD) with and without bipolar disorder (BD). Method: 40 subjects with ASD + BD as study group, and 40 subjects with ASD as control group were included. Serum levels of VEGF, IGF-1, and FGF-2 were measured using commercial enzyme-linked immunosorbent assay kits. Results: The study group was significantly higher than the control group in terms of ASD severity, self-harming behavior and sleep disturbance. Serum VEGF and FGF-2 levels were significantly higher in the ASD + BD group than in the control group. There was no significant difference in serum IGF-1 levels between the two groups. There was no correlation between VEGF, IGF-1 and FGF-2 serum levels and ASD severity in the study group. However there was a negative correlation between VEGF levels and age at first diagnosis of BD, and a positive correlation between IGF-1 levels and the number of bipolar episodes in the study group. Conclusion: Growth factors like VEGF and FGF-2 may be potential biomarkers of bipolar disorder in young subjects with ASD. Given the difficulty of clinical management of BD in young subjects with ASD, potential biomarkers would help clinicians in the diagnosis and follow up of BD in this special population. Further research is needed whether VEGF and FGF-2 can be potential biomarkers in the clinical management of young subjects with ASD and BD. [ABSTRACT FROM AUTHOR]

Background: Long-term results of photodynamic therapy (PDT) combined with vascular endothelial growth factor (VEGF) inhibitors for pachychoroid neovasculopathy (PNV) are not yet clear. Methods: This study is a retrospective, observational case series. We retrospectively examined untreated PNV cases (22 cases, 22 eyes, mean age of 71.0 years) who underwent PDT therapy in combination with VEGF inhibitors followed by additional treatments with pro re nata protocol. Visual acuity, number of treatments, and time to recurrence were examined. In addition, foveal choroidal thickness and choroidal vascularity index (CVI) were evaluated in 13 of 22 patients who were followed up with SpectralisOCTR from baseline. Results: Fifteen (68%) cases had polyps at baseline. LogMAR visual acuity averaged 0.24 ± 0.20 (range, − 0.079 to 0.82) at baseline and significantly improved after 1, 2, and 3 years (p = 0. 004, 0.0003, 0.002, respectively). Fourteen patients (64%) recurred, with an average time to recurrence of 1.8 ± 0.9 years. Foveal choroidal thickness decreased significantly after 1 year (average from 326 μm to 263 μm) and remained unchanged up to 3 years (255 μm). CVI also decreased after 1 year (average from 0.62 to 0.61) and remained unchanged until 3 years later (0.60). Conclusions: We examined the 3-year course of PDT in combination with the VEGF inhibitor for untreated PNV. Visual acuity was improved, foveal choroidal thickness and CVI were decreased after 3 years. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effects of subthreshold micropulse laser (SML) in addition to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). Methods: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were systematically searched for studies that compared anti-VEGF with SML and anti-VEGF monotherapy for DME. Outcome measures were best-corrected visual acuity (BCVA), central macular thickness (CMT), and the number of anti-VEGF injections. Results: Eight studies including 493 eyes were selected. Four studies were randomized controlled, and the other four were retrospective. Meta-analysis showed that there was no significant difference in BCVA (mean difference [MD] -0.04; 95%CI -0.09 to 0.01 logMAR; P = 0.13;). CMT was thinner in the group of anti-VEGF with SML (MD -11.08; 95%CI -21.04 to -1.12 µm; P = 0.03); however, it was due to a single study that weighed higher, and the sensitivity and subcategory analyses did not support the finding. The number of anti-VEGF injections was significantly decreased in the group of anti-VEGF with SML (MD -2.22; 95%CI -3.02 to -1.42; P < 0.0001). Conclusion: Current evidence indicates that adding SML to anti-VEGF therapy could significantly reduce the number of anti-VEGF injections compared to anti-VEGF monotherapy, while achieve similar BCVA and CMT. [ABSTRACT FROM AUTHOR]

Background: Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. Methods: The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. Results: We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. Conclusions: Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the expression of vascular endothelial growth factor (VEGF) in cruciate ligaments from patients with osteoarthritis (OA). It was hypothesized that the expression level of VEGF is associated with the extent of degeneration of the cruciate ligaments. Methods: Remnants of anterior cruciate ligaments (ACLs) from patients with acute ACL injury due to trauma, and ACLs and posterior cruciate ligaments (PCLs) from patients with primary OA were assessed histologically. Samples were immunohistochemically stained with VEGF and tenomodulin, and immunopositive cells were quantitatively assessed by the histological grades of ligament degeneration. Results: Histological analysis showed significant degeneration of the ACLs from OA patients compared with trauma patients, with increased expression of VEGF correlating with higher grades of degeneration. Conversely, tenomodulin expression was lower in more degenerated cruciate ligaments. The percentage of VEGF-positive cells was correlated inversely with that of tenomodulin-positive cells. Conclusions: Increased VEGF expression is associated with degeneration of cruciate ligaments in patients with osteoarthritis of the knee. [ABSTRACT FROM AUTHOR]

The regeneration of hypoxia‐impaired chronic tissue defects has long been challenging, mainly due to the inefficiency of oxygenation and the limited biological activity of existing oxygen delivery systems in regulating dynamic tissue regeneration process. Herein, a novel polyphenol‐copper coordination strategy to fabricate bioactive superoxide dismutase‐catalase self‐cascade nanozymes (SalB‐CuNCs) is reported, which can serve as an in situ oxygenator and induce angiogenesis simultaneously. The copper‐phenolic hydroxyl coordination structure in SalB‐CuNCs plays a critical role in promoting the enzyme‐like cascade reaction via catechol‐mediated Cu valence state transition and substrate capture mechanism. Furthermore, after incorporating SalB‐CuNCs into a Schiff base hydrogel (COC@SalB‐Cu), the resulting system exhibits outstanding antioxidant and robust oxygenation effect in mitigating the hypoxic microenvironment. Benefiting from the intrinsic angiogenic activity of SalB and copper, COC@SalB‐Cu hydrogel can induce a more complete tube formation by up‐regulating the expression level of vascular endothelial growth factor (VEGF), platelet‐endothelial cell adhesion molecule‐1 (CD31), and endothelial nitric oxide synthase (eNOS). In vivo experiments further demonstrate that the COC@SalB‐Cu hydrogel can significantly restore the oxygen and blood supply, leading to fast tissue regeneration. The present strategy holds enormous promise for the treatment of hypoxia‐related chronic tissue defects and vascular injury in the field of regenerative medicine. [ABSTRACT FROM AUTHOR]

Aim: To clarify the association between genetic factors related to angiogenesis and feeling of incomplete bladder emptying among older community‐dwelling individuals. Method: A cross‐sectional study of 1762 (607 men and 1155 women) older Japanese individuals aged 60–79 years with data on rs3025020 was conducted, because vascular endothelial growth factor (VEGF), which contributes to the progression of angiogenesis, has been reported to be positively associated with the minor allele (T) of polymorphism rs3025020. Results: In the study population, 155 (103 men and 52 women) had feeling of incomplete bladder emptying. With rs3025020 (C/C) as the reference group, rs3025020 (T/T) was associated with a significantly higher odds ratio (OR) for feeling of incomplete bladder emptying. The adjusted ORs and 95% confidence intervals were 3.01(1.53, 5.93) in men and 2.48 (1.09, 5.66) in women, respectively. Conclusion: VEGF polymorphism rs3025020 was associated with feeling of incomplete bladder emptying among older community‐dwelling individuals. Development of angiogenesis could be associated with feeling of incomplete bladder emptying in older individuals. Geriatr Gerontol Int 2024; 24: 1039–1044. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to compare the effects of the molecular targeted drugs, sorafenib and lenvatinib, on the survival, invasion, and angiogenesis of hepatocellular carcinoma cells. Additionally, we investigated the involvement of transforming growth factor beta (TGF‐β) signaling in their molecular mechanisms. Methods: To investigate the effects of sorafenib and lenvatinib, we conducted cell viability, invasion, and angiogenesis assays, as well as western blotting analyses. Results: In human hepatocellular carcinoma cells (HepG2), sorafenib demonstrated potent inhibitory effects on cell proliferation, but induced cell invasion similar to TGF‐β. In contrast, lenvatinib showed weaker cytotoxicity compared with sorafenib, but suppressed cell invasion induced by TGF‐β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the TGFβR2/ERK pathway. Moreover, in human umbilical vein endothelial cells, Sorafenib showed weaker cytotoxicity and enhanced the effects of TGF‐β on angiogenesis. Conversely, lenvatinib showed potent cytotoxic abilities and suppressed angiogenesis induced by TGF‐β. The actions of these two molecular targeted drugs were suggested to involve the regulation of the crosstalk between TGF‐β signaling and vascular endothelial growth factor signaling. Conclusions: Our findings indicate that both sorafenib and lenvatinib possess anticancer abilities by inducing the cytotoxicity of hepatocellular carcinoma cells. Furthermore, they show opposing effects on TGF‐β‐induced cell invasion and angiogenesis, thereby enhancing the understanding of the multifaceted functions of molecular targeted drugs in treating hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

This article discusses the disruption of the retinal endothelial cell barrier by direct contact with retinal Müller glial cells (RMGCs) in vitro. The inner blood-retinal barrier plays a crucial role in protecting the neural retina by restricting the passage of solutes and microbes. The study aimed to develop a model for investigating the interactions between human retinal endothelial cells (RECs) and RMGCs to understand the breakdown of the blood-retinal barrier. The results showed that direct contact between RMGCs and RECs led to an activated and leaky retinal endothelium. This model could be useful for studying diseases like diabetic retinopathy and posterior uveitis and evaluating targeted treatments. [Extracted from the article]

Angiogenesis is the critical media for tumor growth and migration. Tissue Inhibitor Matrix Metalloproteinase-1 (TIMP1) acts as an oncogene in colon carcinoma (CC), but the biological effects of TIMP1 on angiogenesis remain an open issue. This study sought to explore the exact function and mechanism of TIMP1 in the angiogenesis of CC. Bioinformatics methods were utilized to analyze the expression of TIMP1 and its upstream transcription factor FOS-like antigen 1 (FOSL1) in the tumor tissue of CC. Meanwhile, in CC cell lines, real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized to verify the expression of TIMP1 and FOSL1. Cell counting kit-8 and tube formation assays were utilized to analyze the proliferation and angiogenesis abilities of human umbilical vein endothelial cells (HUVECs). Western blot was used to detect the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out to explore the specific interaction between FOSL1 and TIMP1. The present study discovered that TIMP1 and FOSL1 were evidently up-regulated in CC tissue and cells. Meanwhile, TIMP1 was found to participate in regulating the signaling pathway of vascular endothelial growth factor (VEGF). Silenced TIMP1 conspicuously suppressed the proliferation and angiogenesis of HUVECs and reduced the protein expression of VEGFA, VEGFR-2, and VEGFR-3. Moreover, FOSL1 could promote TIMP1 transcription by binding with its promoter and the inhibition of TIMP1 expression obviously reversed the promotion effects of FOSL1 overexpression on the proliferation and angiogenesis of HUVECs. FOSL1 activated VEGF pathway by up-regulating TIMP1 expression, thereby advancing CC angiogenesis. We provided theoretical basis that the FOSL1/TIMP1/VEGF pathway might be a novel option for anti-angiogenesis therapy of CC. [ABSTRACT FROM AUTHOR]

Objective: To identify differences in levels of serum biomarkers associated with atherosclerosis between anti-citrullinated protein antibodies (ACPA) positive groups. Methods: Cross-sectional data were used from the Dutch Lifelines Cohort Study combined with data derived from RA risk and early RA studies conducted at the University Medical Center Groningen (UMCG). Serum biomarkers of inflammation, endothelial cell activation, tissue remodeling and adipokine, which were previously associated with atherosclerosis, were measured with Luminex in four ACPA positive groups with different characteristics: without joint complaints, with joint complaints, RA risk and early RA groups. Results: Levels of C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor Receptor 1 (TNFR1) and vascular endothelial growth factor (VEGF) were significantly higher in the RA risk and early RA groups compared to the joint complaints and the no joint complaints groups. The difference remained statistically significant after correcting for renal function, smoking and hypertension in multivariate logistic regression analysis, with focus on ACPA positive with joint complaints group versus RA risk group: CRP OR = 2.67, p = 0.033; IL-6 OR = 3.73, p = 0.019; TNFR1 OR = 1.003, p < 0.001; VGEF OR = 8.59, p = 0.019. Conclusion: Individuals at risk for RA have higher levels of inflammatory markers and VEGF, which suggests that they might also have a risk of higher cardiovascular disease (CVD); however, this does not apply to individuals with ACPA positivity with self-reported joint complaints or without joint complaints only. Therefore, it is important that individuals with RA risk are referred to a rheumatologist to rule in or out arthritis/development of RA and discuss CVD risk. [ABSTRACT FROM AUTHOR]

A substantial increase in colorectal cancer (CRC)–associated fatalities can be attributed to tumor recurrence and multidrug resistance. Traditional treatment options, including radio- and chemotherapy, also exhibit adverse side effects. Ancient treatment strategies that include phytochemicals like resveratrol are now widely encouraged as an alternative therapeutic option. Resveratrol is the natural polyphenolic stilbene in vegetables and fruits like grapes and apples. It inhibits CRC progression via targeting dysregulated cancer-promoting pathways, including PI3K/Akt/Kras, targeting transcription factors like NF-κB and STAT3, and an immunosuppressive tumor microenvironment. In addition, combination therapies for cancer include resveratrol as an adjuvant to decrease multidrug resistance that develops in CRC cells. The current review discusses the biology of resveratrol and explores different mechanisms of action of resveratrol in inhibiting CRC progression. Further, the detrimental role of resveratrol on the immunosuppressive tumor microenvironment of CRC has been discussed. This review illustrates clinical trials on resveratrol in different cancers, including resveratrol analogs, and their efficiency in promoting CRC inhibition. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF)-A is an angiogenic and proinflammatory cytokine with profound effects on microvascular permeability and vasodilation. Several processes may induce VEGF-A expression in brain-dead organ donors. However, it remains unclear whether donor VEGF-A is linked to adverse outcomes after heart transplantation. We examined plasma VEGF-A levels from 83 heart transplant donors as well as the clinical data of these donors and their respective recipients operated between 2010 and 2016. The donor plasma was analyzed using Luminex-based Multiplex and confirmed with a single-target ELISA. Based on donor VEGF-A plasma levels, the recipients were divided into 3 equal-sized groups (low VEGF <500 ng/liter, n = 28; moderate VEGF 500–3000 ng/liter, n = 28; and high VEGF >3000 ng/liter, n = 27). Biochemical and clinical parameters of myocardial injury as well as heart transplant and kidney function were followed-up for one year, while rejection episodes, development of cardiac allograft vasculopathy, and mortality were monitored for 5 years. Baseline parameters were comparable between the donor groups, except for age, where median ages of 40, 45, and 50 were observed for low, moderate, and high donor plasma VEGF levels groups, respectively, and therefore donor age was included as a confounding factor. High donor plasma VEGF-A levels were associated with pronounced myocardial injury (TnT and TnI), a higher inotrope score, and a higher incidence of primary graft dysfunction in the recipient after heart transplantation. Furthermore, recipients with allografts from donors with high plasma VEGF-A levels had a longer length of stay in the intensive care unit and the hospital, and an increased likelihood for prolonged renal replacement therapy. Our findings suggest that elevated donor plasma VEGF-A levels were associated with adverse outcomes in heart transplant recipients, particularly in terms of myocardial injury, primary graft dysfunction, and long-term renal complications. Donor VEGF-A may serve as a potential biomarker for predicting these adverse outcomes and identifying extended donor criteria. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers, as one of the chronic wounds, are a serious challenge in the global healthcare system which have shown notable growth in recent years. DFU is associated with impairment in various stages of wound healing, including angiogenesis. Aberrant expression of microRNAs (miRNAs) involved in the disruption of the balance between angiogenic and anti-angiogenic factors, plays a crucial role in angiogenesis dysfunction. Alteration in the expression of angiomiRNAs (angiomiRs) have the potential to function as biomarkers in chronic wounds. Additionally, considering the rising importance of therapeutic RNAs, there is potential for utilizing angiomiRs in wound healing to induce angiogenesis. This review aims to explore angiogenesis in chronic wounds and investigate the mechanisms mediated by pro- and anti-angiomiRs in the context of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Skin tissue engineering is undergoing tremendous expansion as a result from clinical needs, mandatory replacement of animal models and development of new technologies. Many approaches have been used to produce vascularized skin substitutes for grafting purposes showing the presence of capillary-like structures but with limited analysis of their in vitro maturation and plasticity. Such knowledge is however important for the development of tissue substitutes with improved implantation success as well as for validation of vascularization in vitro models, including as a readout in pharmacological analyses. For optimal interactions of cells with microenvironment and vasculature, we here used a cell sheet approach consisting in the sole production of matrix by the cells. In this context, we limited the density of endothelial cells seeded for self-assembly and rather relied on the stimulation of angiogenesis for the development of an extensive connected microvascular-like network. After detailed characterization of this network, we challenged its plasticity both during and after establishment of the skin substitute. We show that fine tuning of VEGF concentration and time of application differentially affects formation of capillary-like structures and their perivascular coverage. Furthermore, we performed a deep wound assay that displayed tissue repair and angiogenesis with unique characteristics of the physiological process. These studies demonstrate the importance of cell-derived microenvironment for the establishment of mature yet dynamic vascularized skin models allowing a wide range of pharmacological and basic investigations. The significant advancements in organ-on-chips and tissue engineering call for more relevant models including microvascularization with remodeling potential. While vascularized skin substitutes have been developed for years, focus has primarily been on the impact of microvascularization on implantation rather than on its in vitro characterization. We here developed a cell sheet-based vascularized skin substitute relying on angiogenesis, i.e. growth of vessel-like structures within the 3D model, rather than solely on endothelial cell self-assembly. We then characterized :1/ vascularization after modulation of angiogenic factor VEGF during the substitute construction; -2/ angiogenesis associated to tissue repair after deep mechanical wounding. These studies establish a solid physiologically relevant model for further investigation of skin cell interactions and in vitro wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) is a genetic condition characterized by an excessive response to androgens, leading to hairline regression in men and hair thinning at the vertex in women, which can negatively impact self-esteem. Conventional synthetic treatments for AGA are often limited by their side effects. In contrast, Thai medicinal plants offer a promising alternative with fewer adverse effects. This study investigates the synergistic phytochemical and pharmacological effects of a novel Hair RiseTM microemulsion, formulated with bioactive extracts from rice bran (Oryza sativa), shallot bulb (Allium ascalonicum), licorice root (Glycyrrhiza glabra), and corn kernels (Zea mays), for the treatment of hair loss. The microemulsion, in concentrations of 50%, 75%, and 100% (v/v), significantly enhanced the proliferation of human hair follicle dermal papilla cells (HFDPCs) compared to minoxidil. Additionally, it upregulated critical hair growth signaling pathways, including Wnt/β-catenin (CTNNB1), Sonic Hedgehog (SHH, SMO, GLI1), and vascular endothelial growth factor (VEGF), surpassing standard controls such as minoxidil and purmorphamine. The microemulsion also demonstrated potent anti-inflammatory and antioxidant properties by reducing nitric oxide production and oxidative stress, factors that contribute to inflammation and follicular damage in AGA. Furthermore, Hair RiseTM inhibited 5α-reductase (types 1–3), a key enzyme involved in androgen metabolism, in both human prostate cancer cells (DU-145) and HFDPCs. These findings suggest that Hair RiseTM microemulsion presents a promising natural therapy for promoting hair growth and reducing hair loss via multiple synergistic mechanisms, offering a potent, plant-based alternative to synthetic treatments. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) infection can cause condyloma acuminatum (CA), which is characterized by a high incidence and a propensity for recurrence after treatment. Angiogenesis plays an important role in the occurrence and development of CA. Seryl‐tRNA synthetase (SerRS) is a newly identified, potent anti‐angiogenic factor that directly binds to the vascular endothelial growth factor (VEGFA) promoter, thereby suppressing its transcription. Emodin is a natural anthraquinone derivative that can promote SerRS expression. This study aimed to investigate the effects of emodin on CA and explore combined treatment strategies. The HPV‐infected cell line SiHa was treated with either DMSO, emodin, ALA‐PDT or a combination of emodin and ALA‐PDT. We observed the effects on cell proliferation, apoptosis and the SerRS‐VEGFA pathway. Our findings demonstrated that emodin targets angiogenesis through the SerRS‐VEGFA pathway, resulting in the inhibition of SiHa cell proliferation and promotion of apoptosis (p < 0.001). To verify the therapeutic effect of emodin combined with ALA‐PDT on HPV‐associated tumours in vivo, we established an animal xenograft model by subcutaneously inoculating mice with SiHa cells (n = 4). The results showed that the combination of emodin and ALA‐PDT significantly inhibited the expression of VEGFA to inhibit angiogenesis (p < 0.001), thus showing an inhibitory effect on tumour (p < 0.001). Furthermore, we determined that the mechanism underlying the decrease in VEGFA expression after emodin combined with ALA‐PDT in CA may be attributed to the promotion of SerRS expression (p < 0.001). The combination of emodin and ALA‐PDT holds promise as a novel therapeutic target for CA by targeting neovascularization in condyloma tissues. [ABSTRACT FROM AUTHOR]