Vessel Growth Research Articles

Actuation-Mediated Compression of a Mechanoresponsive Hydrogel by Soft Robotics to Control Release of Therapeutic Proteins.

Therapeutic proteins, the fastest growing class of pharmaceuticals, are subject to rapid proteolytic degradation in vivo, rendering them inactive. Sophisticated drug delivery systems that maintain protein stability, prolong therapeutic effects, and reduce administration frequency are urgently required. Herein, a mechanoresponsive hydrogel is developed contained within a soft robotic drug delivery (SRDD) device. In a step-change from previously reported systems, pneumatic actuation of this system releases the cationic therapeutic protein Vascular Endothelial Growth Factor (VEGF) in a bioactive form which is required for therapeutic angiogenesis, the growth of new blood vessels, in numerous clinical conditions. The ability of the SRDD device to release bioactive VEGF in a spatiotemporal manner from the hydrogel is tested in diabetic rats - a model in which angiogenesis is difficult to stimulate. Daily actuation of the SRDD device in the diabetic rat model significantly increased cluster of differentiation 31+ (CD31+) blood vessel number (p=0.0335) and the diameter of alpha-smooth muscle actin+ (α-SMA+) blood vessels (p=0.0025) compared to passive release of VEGF from non-actuated devices. The SRDD device combined with the mechanoresponsive hydrogel offers the potential to deliver an array of bioactive therapeutics in a spatiotemporal manner to mimic their natural release in vivo.

Photothermal Nanozyme‐Encapsulating Microneedles for Synergistic Treatment of Infected Wounds

AbstractPhotothermal therapy (PTT) is widely used in wound healing because it produces heat under near‐infrared irradiation, eliminating bacterial infections. However, excessive production of reactive oxygen species (ROS) occurs during PTT, which causes oxidative stress damage. In this study, a nanozyme, PDA‐MnO2 (PM), is synthesized and encapsulated in the needle tip layer of a bi‐layer GelMA microneedle patch (PbMP), which has excellent mechanical properties and can easily penetrate the skin. In a study involving an SD rat wound model infected with S. aureus, the PbMP significantly accelerated the healing process of bacterially challenged wounds, resulting in better blood vessel growth, cell proliferation, and collagen biosynthesis than other wound dressings. The experiment shows that the PM nanoparticles in PbMP improve photothermal conversion efficiency and activate SOD and CAT, resulting in an efficient cascade enzyme reaction system to eliminate ROS during the PTT process. This study describes a highly effective nanozyme hydrogel microneedle platform with photothermal synergistic antibacterial effects on wound healing.

Pharmacological Insights into Salvia Rosmarinus: A Natural Remedy with Diverse Therapeutic Potential

Rosmarinus officinalis, commonly known as rosemary, is an aromatic herb originating from the Mediterranean region, primarily processed in Murcia, Southeast Spain. It is highly valued in the United States and Europe for its antioxidant properties. Rosemary extracts are renowned for their diverse therapeutic applications, such as liver protection, Alzheimer's disease treatment, and inhibiting the growth of new blood vessels. These extracts also play a vital role in food preservation by preventing oxidation and microbial contamination, offering a natural alternative to synthetic antioxidants. In medicinal use, rosemary helps treat conditions like renal colic, menstrual pain, respiratory disorders, and general pain relief. It aids digestion and bile flow due to its carminative and cholagogue properties and has diuretic effects that enhance urine production. Moreover, rosemary exhibits antiepileptic effects and may benefit fertility. The plant's biosynthetic pathways produce phenolic compounds, including caffeic acid (CA) and dihydroxy-phenyl-lactic acid (DOPL). Shikimic acid is crucial in synthesizing amino acids like phenylalanine, tyrosine, and tryptophan. The process involves converting phenylalanine into cinnamic acid, leading to the formation of Rosmarinus acid (RA), which is an ester of DOPL and has traditionally been used for its liver-protective and bile-stimulating properties, with Rosemary studies confirming its effectiveness in increasing bile flow and protecting against liver toxicity. Rosemary extracts also reduce the formation of malonaldehyde and the release of enzymes in isolated rat liver cells, confirming their hepatoprotective effects. Rosemary also holds promise in cancer prevention, as its dietary non-nutrients effectively inhibit carcinogenesis. RA, absorbed through oral and parenteral routes, has a half-life of 1.8 hours and is detectable in various tissues, especially in the lungs. The herb's antioxidants, including vitamins C and E, and beta carotene, help mitigate oxidative stress, a major factor in many diseases and aging. These antioxidants prevent DNA damage, protein harm, and uncontrolled lipid peroxidation, which are crucial in disease development.

Different Therapeutic Approaches for Dry and Wet AMD.

Age-related macular degeneration (AMD) is the most common cause of irreversible loss of central vision in elderly subjects, affecting men and women equally. It is a degenerative pathology that causes progressive damage to the macula, the central and most vital part of the retina. There are two forms of AMD depending on how the macula is damaged, dry AMD and wet or neovascular AMD. Dry AMD is the most common form; waste materials accumulate under the retina as old cells die, not being replaced. Wet AMD is less common, but can lead to vision loss much more quickly. Wet AMD is characterized by new abnormal blood vessels developing under the macula, where they do not normally grow. This frequently occurs in patients who already have dry AMD, as new blood vessels are developed to try to solve the problem. It is not known what causes AMD to develop; however, certain risk factors (i.e., age, smoking, genetic factors) can increase the risk of developing AMD. There are currently no treatments for dry AMD. There is evidence that not smoking, exercising regularly, eating nutritious food, and taking certain supplements can reduce the risk of acquiring AMD or slow its development. The main treatment for wet AMD is inhibitors of VEGF (vascular endothelial growth factor), a protein that stimulates the growth of new blood vessels. VEGF inhibitors can stop the growth of new blood vessels, preventing further damage to the macula and vision loss. In most patients, VEGF inhibitors can improve vision if macular degeneration is diagnosed early and treated accordingly. However, VEGF inhibitors cannot repair damage that has already occurred. Current AMD research is trying to find treatments for dry AMD and other options for wet AMD. This review provides a summary of the current evidence regarding the different treatments aimed at both forms of AMD with particular and greater attention to the dry form.

Development of nerves and vessels in the penis during the human fetal period.

Although nerves and vessels of the penis play important role in erection, there are few studies on their development in human fetus. Therefore, the objective of the present study is to analyze, quantitatively, in the corpora cavernosa and corpus spongiosum, the development of the nerves and vessels in the fetal penis at different gestational ages. Fifty-six fresh, macroscopically normal human fetuses aged from 13 to 36 weeks post-conception (WPC) were used. Gestational age was determined by the foot length criterion. Penises were immediately fixed in 10% formalin, and routinely processed for paraffin embedding, after which tissue sections from the mid-shaft were obtained. We used immunohistochemical staining to analyze the nerves and vessels in the corpus cavernous and in the corpus spongiosum. These elements were identified and quantified as percentage by using the Image-J software. The quantitative analysis showed that the percentage of nerves varied from 3.03% to 20.35% in the corpora cavernosa and from 1.89% to 23.88% in the corpus spongiosum. The linear regression analysis indicated that nerves growth (incidence) in the corpora cavernosa and corpus spongiosum correlated significantly and positively with fetal age (r2=0.9421, p<0.0001) and (r2=0.9312, p<0.0001), respectively, during the whole fetal period studied. Also, the quantitative analysis showed that the percentage of vessels varies from 2.96% to 12.86% in the corpora cavernosa and from 3.62% to 14.85% in the corpus spongiosum. The linear regression analysis indicated that vessels growth (appearance) in the corpora cavernosa and corpus spongiosum correlated significantly and positively with fetal age (r2=0.8722, p<0.0001) and (r2=0.8218, p<0.0001), respectively, during the whole fetal period studied. In addition, the linear regression analysis demonstrated a more intense growth rate of nerves in the corpus spongiosum during the 2nd trimester of gestation, when compared with nerves in the corpora cavernosa. In addition, the linear regression analysis demonstrated a more intense growth rate of vessels in the corpus spongiosum when compared with the corpora cavernosa, during the whole fetal period studied. In the fetal period, the human penis undergoes major developmental changes, notably in the content and distribution of nerves and vessels. We found strong correlation between nerves and vessels growth (amount) with fetal age, both in the corpora cavernosa and corpus spongiosum. There is significant greater proportional number of nerves than vessels during the whole fetal period studied. Also, nerves and vessels grow in a more intense rate than that of the corpora cavernosa and corpus spongiosum areas.

Bone replacement material with optimized structure, manufactured using additive printing technology

Abstract Additive manufacturing with Arburg Plastic Freeforming (APF), an extrusion-based additive manufacturing process, was used to produce biomimetic bone scaffolds for assistance of osteosynthesis made of poly-caprolactone (PCL) with channel structures for the ingrowth of blood vessels. The specific creation of defined channel structures is very important to support the ingrowth of blood vessels, which significantly supports the regeneration of natural tissue. The tibia model used was divided into the corticalis and the spongiosa to be able to compare the realization of the different requirements of the two natural structures with the printed structures separately. Microtome cuts of the manufactured bone scaffolds with channels were prepared for characterization with light microscopy. Compression tests were carried out on a tensile testing machine. It was found that the channels in the tibial cortex led to a slightly higher stiffness compared to those without channels due to the frame outlines. Overall, however, the stiffness of the Polycaprolactone (PCL) scaffolds was significantly lower than that of natural bone. In the spongiosa scaffolds, the stiffness with channels was lower than that without channels, but still within the physiological range, as was the model without channels. The porosity was within the required range for both scaffold types.

Computer-guided design of Z domain peptides with improved inhibition of VEGF.

Computational protein design is becoming increasingly helpful in the development of new protein therapeutics with enhanced efficacy, specificity, and minimal side effects, for precise modulation of biological pathways. In vascular biology, the interaction between vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1-R3) is a pivotal process underlying blood vessel growth. Dysregulation of this pathway contributes to diseases such as cancer and diabetic retinopathy. Existing VEGFA inhibitors are effective but have limitations, driving interest in peptide-based therapeutics. Peptide inhibitors offer advantages, including reduced toxicity, improved formulation flexibility, and enhanced stability. This study leverages computational tools, particularly ProteinMPNN and Rosetta, to design optimized peptide-based VEGFA inhibitors. Building on the existing peptide templates mini-Z-1 and Z-1-2, new sequences were computationally predicted and experimentally validated. A novel peptide with improved affinity (KD = 6.2 µM) compared to mini-Z-1 (KD = 9.3 µM) was found, requiring only one round of design and testing. The integration of ProteinMPNN and Rosetta enabled a rapid and cost-effective pipeline for designing potent VEGFA inhibitors, underscoring the potential of computational peptide design in developing next-generation therapeutics targeting angiogenesis-dependent diseases.

Design and Biofunctionalization of Cloud Sponge-Inspired Scaffolds for Enhanced Bone Cell Performance.

With the increasing age of our population, which is linked to a higher incidence of musculoskeletal diseases, there is a massive clinical need for bone implants. Porous scaffolds, usually offering a lower stiffness and allowing for the ingrowth of blood vessels and nerves, serve as an attractive alternative to conventional implants. Natural porous skeletons from marine sponges represent an array of evolutionarily optimized patterns, inspiring the design of biomaterials. In this study, cloud sponge-inspired scaffolds were designed and printed from a photocurable polymer, Clear Resin. These scaffolds were biofunctionalized by mussel-derived peptide MP-RGD, a recently developed peptide that contains a cyclic, bioactive RGD cell adhesion motif and catechol moieties, which provide the anchoring of the peptide to the surface. In in vitro cell culture assays with bone cells, significantly higher biocompatibility of three scaffolds, i.e., square, octagon, and hexagon cubes, in comparison to hollow and sphere inside cubes was shown. The performance of the cells regarding signaling was further enhanced by applying an MP-RGD coating. Consequently, these data demonstrate that both the structure of the scaffold and the coating contribute to the biocompatibility of the material. Three out of five MP-RGD-coated sponge-inspired scaffolds displayed superior biochemical properties and might guide material design for improved bone implants.

Iron-based MOF with Catalase-like activity improves the synergistic therapeutic effect of PDT/ferroptosis/starvation therapy by reversing the tumor hypoxic microenvironment

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through “starvation therapy”, cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H2O2). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H2O2, while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future.

ANGI-03. GLIOMA STEM CELLS INDUCE VASECTASIA – A NON-ANGIOGENIC BRAIN TUMOUR NEOVASCULARIZATION PROCESS DRIVEN BY INTERCELLULAR EGFR TRANSFER THROUGH EXTRACELLULAR VESICLES

Abstract Tumour neovascularization in glioblastoma (GBM) is abundant, abnormal and poorly understood, and it likely involves multiple co-existing mechnanisms with distinct modes of regulation. Since glioma stem cells (GSCs) engage in bidirectional interactions with the vasculature we dissected the resulting vascular responses elicited by either proneural (PN), or mesenchymal (MES) GSC subtypes established from patients isolates and able to drive progression of orthotopic intracranial xenografts in mice. We report here that while PN-GSCs elicited mostly angiogenesis-type vascular capillary growth processes, their MES-GSC counterparts elicited non-angiogenic growth of enlarged vessels (vasectesia), paradoxically associated with reduced blood vessel density. Vasectasia was dependent on the expression of oncogenic EGFR/EGFRvIII by MES-GSCs, and on the related kinase/signalling activity, as EGFR/EGFRvIII gene disruption and Dacomitinib treatment suppressed formation of large blood vessels in vivo and resulted in a preponderance of a small calliber (angiogenic) vasculature throughout xenografts. Notably, the analysis of spatial transcriptomes and single cell RNA sequencing revealed distinct molecular traits of endothelial cells asociated with vasectasia and angiogesis, the former enriched in Birc5, but depleted for angiogenic tip cell markers (Vegfr2, Apln). Mechnaistically, vasectasia was linked to the intercellular transfer of EGFR from MES-GSCs to endothelial cells resulting in ectopic activation of EGFR signalling in the endothelial cell bacground, both in vitro and in a model of in vivo blood vessel recruitment into implanted matrigel pellets. Simultaneous pharmacological blockade of both, angiogenesis (anti-VEGR2) and vasectasia (Dacomitinib) lead to a marked increase in survival of mice with aggressive GBM lesions initiated by MES-GSCs. We suggest that, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new, subtype-specific mechanism of GBM neovascularization, and a plausible target for agents aiming to modify vascular tumour microenvironment.

The perspective of ceRNA regulation of circadian rhythm on choroidal neovascularization

Abnormal growth of blood vessels (choroidal neovascularization) can lead to age-related macular degeneration (AMD) and eventually cause vision loss due to detachment of the retinal pigmented epithelium. This indicates that choroidal neovascularization is important for the treatment of AMD. The circadian clock in the mammalian retina is responsible for controlling various functions of the retina, enabling it to adjust to changes in light and darkness. Recent studies have revealed a potential connection between the circadian clock and eye diseases, although a cause-and-effect relationship has not been definitively established. C57BL/6J male mice (aged 6 weeks) were randomly divided into two groups (Control group: 9:00–21:00 light period (300 lx); Jet lag group: 8-hour phase advance once every 4 days). A laser-induced CNV model was created after 2 weeks of feeding in a controlled or jet-lagged environment. Then, full transcriptome sequencing was performed. The pathways regulated by differentially expressed mRNAs were identified by GO analysis and GSEA. Further protein networks were constructed with the STRING database and Cytoscape software. WGCNA was used to further explore the co-expression modules of these differential genes and the correlation between these differential genes and phenotypes. ceRNA networks were constructed with miRanda and TargetScan. The pathways associated with the overlapping differentially expressed mRNAs in the ceRNA network were identified, and the hub genes were validated by qPCR. A total of 661 important DEGs, 31 differentially expressed miRNAs, 106 differentially expressed lncRNAs and 87 differentially expressed circRNAs were identified. GO and GSEA showed that the upregulated DEGs were mainly involved in reproductive structure development and reproductive system development. The STRING database and Cytoscape were used to determine the protein interaction relationships of these DEGs. WGCNA divided the expression of these genes into several modules and screened the hub genes of each module separately. Furthermore, a ceRNA network was constructed. GO analysis and GSEA showed that these target DEmRNAs mainly function in wound healing, cell spreading, epiboly involved in wound healing, epiboly, and morphogenesis of an epithelial sheet. Finally, ten key genes were identified, and their expression patterns were confirmed by real-time qPCR. In this study, we investigated the regulatory mechanism of ceRNAs in choroidal neovascularization according to different light-dark cycles in the eyeball.

Surgical treatment for local recurrence of spinal hemangiomas.

SH is considered to be the most common benign tumor within the human spine. 1-2% of SH get symptomatic with back pain in most cases. Less often, ingrowth of vessels into the spinal canal is seen. In these cases, more invasive surgical treatment is required. Recurrence of SH following surgical treatment is a very rare condition. We present the results of a retrospective chart review, with description of the clinical course of 12 patients with spinal canal invading SH without recurrence and of 5 patients with a recurrent SH. Recurrence was diagnosed 70 months (mean value) after the first procedure. All patients with a recurrent SH had received an incomplete tumor resection as a first treatment. The distribution of gender, age at the diagnosis, levels involved by the tumor, and initial symptoms were comparable in the group of patients with and without recurrence. The patients with recurrent SH were treated with preoperative embolization and en bloc resection or complete piecemeal resection of the affected vertebra. For stabilization, a combined, circumferential fixation was used consisting in a TSM cage filled by bone graft and posterior pedicle screw rod instrumentation in all patients. We followed these patients until 09/ 2023, mean FU 122 months (range 72-184 months). At this time, we found no evidence of tumor recurrence, good clinical conditions in all patients, no signs of implant failure or pseudarthrosis. Thus, radical excision, sufficient stabilization and fusion is considered to be an adequate treatment concept for recurrent SH.

Long-term pulmonary repair in rat lungs after sublobar resection: electrocautery versus stapler methods.

We investigated and compared the long-term (6-month) histologic changes in a rat model of sublobar resection created using electrocautery or stapler techniques. Nine-week-old male rats were anesthetized and intubated; thoracotomy with sublobar resection was performed in the right middle lobe using electrocautery or stapler techniques. Histological examination was performed at 2, 4, 8, 12, and 24weeks post-surgery to assess long-term effects on lung tissue repair and morphologic changes. Lung expansion and alveolar epithelial cell proliferation were evaluated by measuring the mean linear intercept and counting the number of alveolar type I and II cells. The electrocautery group showed signs of lung self-repair at the resected area over time, with inflammatory cell infiltration followed by growth of vessels and bronchioles. Mesothelial cells covered the resected area by 2weeks; elastic fibers gradually connected from both sides by 24weeks. Lung expansion, measured by mean linear intercept, was initially small below the electrocautery resection area at 2weeks but recovered from 4 to 24weeks. The stapler group showed persistently small mean linear intercept over time. In the electrocautery group, the number of alveolar type II cells was higher just below the resection than in other areas from 2 to 24weeks, followed by alveolar type I cells (4 to 24weeks). The stapler group showed a transient alveolar type II cell increase at 2weeks. Compared to the stapler technique, electrocautery mayprovide advantages for postoperative lung repair by promoting lung expansion and alveolar epithelial cell proliferation.

Targeting the histone methyltransferase SETD7 rescues diabetes-induced impairment of angiogenic response by transcriptional repression of semaphorin 3G

Abstract Background Peripheral artery disease (PAD) is highly prevalent in patients with diabetes (DM) and associates with a high rate of limb amputation and poor prognosis. Surgical and catheter-based revascularization have failed to improve outcome in DM patients with PAD. Hence, a need exists to develop new treatment strategies able to promote blood vessel growth in this setting. Mono-methylation of histone 3 at lysine 4 (H3K4me1) - a specific epigenetic signature induced by the histone methyltransferase SETD7 - favours an open chromatin thus enabling gene transcription. Purpose To investigate whether SETD7-dependent epigenetic changes modulate angiogenic response in diabetes. Methodology Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) concentrations for 48 hours. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). In vitro assays, namely cell migration and tube formation were employed to study angiogenic properties in HAECs. SETD7 and H3K4me1 levels were investigated by Western blot and Chromatin immunoprecipitation (ChIP). Pharmacological blockade of SETD7 was achieved by using the highly selective inhibitor (R)-PFI-2. Mice with streptozotocin-induced diabetes were orally treated with (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation for 14 days. Blood flow recovery was analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Our experimental findings were also translated in gastrocnemius muscle samples from patients with and without diabetes. Results RNA-seq in HG-treated HAECs revealed a profound upregulation of the methyltransferase SETD7, an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). SETD7 upregulation in HG-treated HAECs was associated with increased H3K4me1 levels as well as with impaired endothelial cell migration and tube formation. Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G). Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. In diabetic mice with hindlimb ischemia, treatment with (R)-PFI-2 improved limb vascularization and perfusion as compared to vehicle. Finally, SETD7/SEMA3G axis was upregulated in muscle specimens from T2D patients as compared to controls. Conclusion Targeting SETD7 represents a novel epigenetic-based therapy to boost neovascularization in diabetic patients with PAD.

Targeting the VEGFR2 signaling pathway for angiogenesis and fibrosis regulation in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (nAMD) is characterized by abnormal blood vessel growth from the choroid, leading to complications and eventual blindness. Despite anti-VEGF therapy, subretinal fibrosis remains a major concern, as VEGF/VEGF receptor-2 (VEGFR2) signaling can contribute to both angiogenesis and fibrosis. For the identification of the aqueous humor proteome, we performed liquid chromatography with tandem mass spectrometry analysis. To investigate the potential therapeutic effects of targeting the VEGF signaling pathway using apatinib, a highly selective VEGFR2 tyrosine kinase inhibitor, this study employed in vitro (THP-1 conditioned media-treated ARPE-19 cells) and in vivo (laser-induced choroidal neovascularization mouse) models of nAMD. This study revealed elevated VEGFR2 protein levels in the aqueous humor of nAMD patients, suggesting a potential target to mitigate neovascularization and fibrosis in nAMD. Apatinib effectively reduced VEGFA and αSMA levels in both in vitro and in vivo models. Moreover, apatinib showed improvement in laser-induced subretinal hyper-reflective lesions. The action mechanism was linked to the inhibition of VEGFR2 activation, leading to the suppression of both angiogenesis and fibrosis through the downregulation of STAT3 phosphorylation. Therefore, the VEGFR2 signaling pathway appears to play a central role in the development of nAMD by regulating both angiogenesis and fibrosis.

Enhancing bevacizumab efficacy in a colorectal tumor mice model using dextran-coated albumin nanoparticles.

Bevacizumab is a monoclonal antibody (mAb) that prevents the growth of new blood vessels and is currently employed in the treatment of colorectal cancer (CRC). However, like other mAb, bevacizumab shows a limited penetration in the tumors, hampering their effectiveness and inducing adverse reactions. The aim of this work was to design and evaluate albumin-based nanoparticles, coated with dextran, as carriers for bevacizumab in order to promote its accumulation in the tumor and, thus, improve its antiangiogenic activity. These nanoparticles (B-NP-DEX50) displayed a mean size of about 250nm and a payload of about 110µg/mg. In a CRC mice model, these nanoparticles significantly reduced tumor growth and increased tumor doubling time, tumor necrosis and apoptosis more effectively than free bevacizumab. At the end of study, bevacizumab plasma levels were higher in the free drug group, while tumor levels were higher in the B-NP-DEX50 group (2.5-time higher). In line with this, the biodistribution study revealed that nanoparticles accumulated in the tumor core, potentially improving therapeutic efficacy while reducing systemic exposure. In summary, B-NP-DEX can be an adequate alternative to improve the therapeutic efficiency of biologically active molecules, offering a more specific biodistribution to the site of action.

A mathematical model describing the tip-stalk regulation in angiogenesis

Angiogenesis is the process of new blood vessel growth from existing vessels, involving extensive cell signaling. Under normal conditions, new vessels are robust and organized, with a balance among angiogenesis factors. In abnormal conditions, such as tumor development, vessels are stunted and tangled due to an imbalance of these factors. Pathological angiogenesis stimulates rapid vessel growth to feed the oxygen and nutriente starved tumor. Inhibiting angiogenesis can cause side effects like hypertension, thrombosis, and fatigue. To better understand this process, significant effort has gone into studying signaling pathways, contributing to drug development for diseases like cancer. This study presents a mathematical model describing angiogenesis on a microscopic scale, comparing its results with experimental data on vascular network topology. The model, implemented in MatLab®, uses ordinary differential equations to represent cell behavior. Results show that altering VEGF (Vascular Endothelial Growth Factor) disrupts system balance, impacting angiogenesis and possibly explaining differences in network topology seen experimentally.

Intravitreal Metformin Protects Against Choroidal Neovascularization and Light-Induced Retinal Degeneration.

Neovascular age-related macular degeneration (nAMD), a leading cause of blindness in older adults, presents a challenging pathophysiology involving choroidal neovascularization (CNV) and retinal degeneration. Current treatments relying on intravitreal (IVT) administration of anti-angiogenic agents are costly and of moderate effectiveness. Metformin, the common anti-diabetic drug, has been associated with decreased odds of developing AMD. Studies have shown that metformin can mitigate cellular aging, neoangiogenesis, and inflammation across multiple diseases. This preclinical study assessed metformin's impact on vessel growth using choroidal explants before exploring IVT metformin's effects on laser-induced CNV and light-induced retinal degeneration in C57BL/6J and BALB/cJ mice, respectively. Metformin reduced new vessel growth in choroidal explants in a dose-dependent relationship. Following laser induction, IVT metformin suppressed CNV and decreased peripheral infiltration of IBA1+ macrophages/microglia. Furthermore, IVT metformin protected against retinal thinning in response to light-induced degeneration. IVT metformin downregulated genes in the choroid and retinal pigment epithelium which are associated with angiogenesis and inflammation, two key processes that drive nAMD progression. These findings underscore metformin's capacity as an anti-angiogenic and neuroprotective agent, demonstrating this drug's potential as an accessible option to help manage nAMD.

Factors affecting the collateral ingrowth from the superficial temporal artery after Encephalo-Duro-Arterio-Synangiosis in adult patients with Moyamoya disease

BackgroundMultiple factors have been proposed to affect the vessel ingrowth from the superficial temporal artery (STA) after Encephalo-Duro-Arterio-Synangiosis (EDAS). MethodsThis retrospective single-center analyses included patients with Moyamoya Disease (MMD) undergoing EDAS from January 1st, 2013, to December 31st, 2023. Evaluated variables included demographic characteristics, clinical presentation, technical details, modified Rankin Scale (mRS) scores, and radiographic outcomes. Univariate and multivariate analysis was performed to identify factors favoring the ingrowth of collaterals from the STA. ResultsForty adult patients with MMD, most commonly females (77.5 %) with a median age of 48, underwent 56 EDAS. The most common initial presentations were ischemic events (75.0 %), followed by hemorrhagic events (27.5 %) and seizures (7.5 %). Digital angiography performed at a median of 13.7 months post-procedure revealed collateral growth from the STA in 78.6 % of cases, with a Matsushima grade A identified in 35.7 % of the revascularized hemispheres. Univariate analysis showed more collaterals in patients with a larger preoperative STA diameter (p=0.035), higher Suzuki grades (p=0.021) and longer angiographic follow-ups (p=0.048). Patients with occlusion of the internal carotid artery (ICA; p<0.01), middle cerebral artery (MCA; p<0.01), or anterior cerebral artery (ACA; p<0.01) also had more collateral ingrowth. Multivariate analysis revealed that ICA occlusion (OR=6.54; 95 % CI=1.03–41.48) and ACA occlusion (OR=6.52; 95 % CI=1.02–41.67) as predictors of collateral ingrowth from the STA. ConclusionICA and ACA occlusion were associated with success after EDAS. Longer follow-ups and larger STA demonstrated significant association on univariate analysis, but lost significance after adjusting for other procedural characteristics.

Eugenol-Loaded Lipid Nanoparticles-Derived Hydrogels Ameliorate Psoriasis-like Skin Lesions by Lowering Oxidative Stress and Modulating Inflammation.

Psoriasis is a chronic T-cell-mediated autoimmune skin disorder characterized by excessive epidermal thickening, overproliferation of keratinocyte, disruption of epidermal cell differentiation, and increased blood vessel growth in the dermal layer. Despite the common use of corticosteroids in psoriasis treatment, their limited efficacy and numerous side effects pose significant challenges. This research introduces a promising alternative approach by encapsulating eugenol (EU) in soya phosphatidylcholine (SPC) nanoparticles (EUNPs) which showed spherical shape nanoparticles with a hydrodynamic size of approximately 200 nm, polydispersity index 0.23, encapsulation efficiency of 85% having good colloidal stability indicated by ζ-potential of -27 mV. Later on, these EUNPs were formulated into a topical hydrogel system by using Carbopol 974P (EUNPGel), which exhibited superior drug loading, enhanced release kinetics for 48 h, long-term stability, and the ability to scavenge reactive oxygen species (ROS). Furthermore, EUNPs inhibited keratinocyte proliferation, induced apoptosis, and augmented the uptake of IL-6-mediated inflammation in human keratinocyte cells. Application of EUNPs-loaded gels (EUNPGel) to imiquimod-induced psoriatic lesions demonstrated effective dermal penetration, suppressed keratinocyte hyperplasia and restored epidermal growth. This led to a remarkable reduction in the Psoriasis Area and Severity Index (PASI) score from 3.75 to 0.5 within 5 days. This novel approach enhances ROS scavenging capacity, improves cellular uptake, facilitates skin penetration and retention, reduces the activity of hyperactive immune cells, and suggests potential applications for treating other immune-related disorders such as acne and atopic dermatitis.