Clinical research progress of fruquintinib in the treatment of malignant tumors.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

Intravitreal faricimab for treatment naïve patients with neovascular age-related macular degeneration: a real-world prospective study.

BACKGROUND: Intravitreal faricimab, a bispecific antibody targeting both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A), was recently introduced for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema and cystoid macular oedema secondary to retinal vein occlusion. The aim of our study was to assess the efficacy, safety and durability of intravitreal faricimab in a real-world cohort of treatment-naïve patients with nAMD. METHODS: Single-centre, prospective cohort study of 21 eyes from 19 treatment-naïve nAMD patients who were treated with intravitreal faricimab from October 2022 to April 2024. Patients underwent a loading dose (LD) of 4 monthly faricimab injections followed by a treat-and-extend regimen. Primary outcomes included best-corrected visual acuity (BCVA) and structural parameters from spectral-domain optical coherence tomography (SD-OCT). Secondary outcomes included the proportion of eyes achieving a dry macula, maximal fluid-free interval and intended interval at last follow-up. RESULTS: The study included 21 eyes of 19 patients (mean age 83.1 years). After LD, 93.3% of eyes achieved a dry macular SD-OCT scan within a median time of 8 weeks. At the first extension, 53% of eyes remained dry, while 47% showed fluid recurrence. Long-term analysis (n = 14) revealed significant reductions in macular volume (MV), central subfield thickness (CST), and pigment epithelial detachment (PED) height over a median follow-up of 64.9 weeks, with sustained visual and anatomical improvements. Median BCVA, CST, and MV at the final follow-up were significantly improved from baseline (p < 0.01). The intended interval between injections was ≥ 12 weeks in 42.86% of eyes. No cases of intraocular inflammation were observed, although 10% experienced retinal pigment epithelial tears. CONCLUSIONS: Intravitreal faricimab demonstrated favourable efficacy, safety, and durability outcomes in a real-world cohort of treatment-naïve nAMD patients.

Exploring the Association of VEGF-A and ANGPTL2 with the Prognosis of Non-proliferative and Proliferative Diabetic Retinopathy.

Introduction Diabetic retinopathy (DR) is a microvascular ailment that can arise from the long-term effects of diabetes mellitus. It can potentially cause retinal damage that could endanger vision and cause blindness. The worsening of DR is mainly linked to poor glycemic control, uncontrolled hypertension, and dyslipidemia. There is a need for alternative and clinically significant novel molecules involved in the pathogenesis of DR because the diagnostic and prognostic markers have reached a limit. Materials and method This study included sex and age-matched diabetic patients with proliferative stage (N = 70), non-proliferative stage (N = 80), and control (N = 80, without the sign of DR). These patients were recruited from outpatients in the Department of Ophthalmology, Sri Ramachandra Institute of Higher Education and Research, Chennai, India. A random blood sample was collected from each study participant, and the serum was separated after centrifugation and stored at -80 °C for batch analysis. The biomarkers vascular endothelial growth factor (VEGF-A) and angiopoietin-like protein-2 (ANGPTL2) were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) technique, and the laboratory parameters such as fasting blood sugar (FBS), lipid profile, blood urea nitrogen (BUN), creatine, and glycated hemoglobin (HbA1C) were also assessed. Results We observed statistically significant differences in the duration of diabetes, FBS, total cholesterol (TC), triglyceride level (TGL), BUN, and creatine (p<0.05), and the mean age of study participants was 52.95±8.20 years in the control group, 53.85±10.20 years in the proliferative diabetic retinopathy (PDR) group, and 55.02±7.65 in the non-proliferative diabetic retinopathy (NPDR) group. Furthermore, ANGPTL2 levels were statistically significant according to the severity of the disease (p<0.001*), and they were also linked (p<0.05) with established markers such as VEGF-A. Conclusion Thus, our research implies that the up-regulated markers might be linked to the disease's advancement and could serve as a prognostic indicator or therapeutic target for DR.

Diagnostic value of serum vascular endothelial growth factor and interleukin-17 in primary hepatocellular carcinoma.

BACKGROUND: Despite significant advancements in the medical treatment of primary hepatocellular carcinoma (PHC) in recent years, enhancing therapeutic effects and improving prognosis remain substantial challenges worldwide. AIM: To investigate the expression levels of serum vascular endothelial growth factor (VEGF) and interleukin (IL)-17 in patients with PHC and evaluate their diagnostic value while exploring their relationship with patients' clinical characteristics. METHODS: The study included 50 patients with confirmed PHC who visited Wuhan Hanyang Hospital from January 2021 to January 2022, and 50 healthy individuals from the same period served as the control group. Serum VEGF and IL-17 levels in both groups were measured by Enzyme-Linked Immunosorbent Assay, and their diagnostic value was assessed using receiver operating characteristic (ROC) curves. Pearson correlation analysis was performed to examine the relationship between serum VEGF and IL-17 levels. Pathological data of the PHC patients were analyzed to determine the relationship between serum VEGF and IL-17 levels and pathological characteristics. RESULTS: Serum VEGF and IL-17 levels were significantly higher in the study group compared to the control group (P < 0.05). No significant association was observed between serum VEGF and IL-17 levels and gender, age, combined cirrhosis, tumor diameter, or degree of differentiation (P > 0.05). However, there was a significant relationship between clinical TNM stage, tumor metastasis, and serum VEGF and IL-17 levels (P < 0.05). Correlation analysis revealed a positive correlation between serum VEGF and IL-17 (P < 0.05). ROC analysis demonstrated that both serum VEGF and IL-17 had good diagnostic efficacy for PHC. CONCLUSION: Serum VEGF and IL-17 levels were significantly higher in PHC patients compared to healthy individuals. Their levels were closely related to pathological features such as tumor metastasis and clinical TNM stage, and there was a significant positive correlation between VEGF and IL-17. These biomarkers may serve as valuable reference indicators for the early diagnosis and treatment guidance of PHC.

Nomogram for predicting short-term response to anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration: An observational study.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is critical for managing neovascular age-related macular degeneration (nAMD), but understanding factors influencing treatment efficacy is essential for optimizing patient outcomes. AIM: To identify the risk factors affecting anti-VEGF treatment efficacy in nAMD and develop a predictive model for short-term response. METHODS: In this study, 65 eyes of exudative AMD patients after anti-VEGF treatment for ≥ 1 mo were observed using optical coherence tomography angiography. Patients were classified into non-responders (n = 22) and responders (n = 43). Logistic regression was used to determine independent risk factors for treatment response. A predictive model was created using the Akaike Information Criterion, and its performance was assessed with the area under the receiver operating characteristic curve, calibration curves, and decision curve analysis (DCA) with 500 bootstrap re-samples. RESULTS: Multivariable logistic regression analysis identified the number of junction voxels [odds ratio = 0.997, 95% confidence interval (CI): 0.993-0.999, P = 0.010] as an independent predictor of positive anti-VEGF treatment outcomes. The predictive model incorporating the fractal dimension, number of junction voxels, and longest shortest path, achieved an area under the curve of 0.753 (95%CI: 0.622-0.873). Calibration curves confirmed a high agreement between predicted and actual outcomes, and DCA validated the model's clinical utility. CONCLUSION: The predictive model effectively forecasts 1-mo therapeutic outcomes for nAMD patients undergoing anti-VEGF therapy, enhancing personalized treatment planning.

[Diagnosis and management of POEMS syndrome].

POEMS syndrome is a plasma cell neoplasm that presents with peripheral neuropathy, organomegaly, fluid retention, skin manifestations, osteosclerotic lesions, and λ-type M-proteinemia. The pathogenesis of POEMS syndrome is poorly understood, as the genetic profile of plasma cells in POEMS syndrome differs from that of myeloma. In most cases, POEMS syndrome is difficult to distinguish from chronic inflammatory demyelinating polyneuropathy (CIDP). Consequently, it is essential not to miss characteristic signs of POEMS syndrome such as M-protein, VEGF, pleural effusion, and osteosclerotic lesions. Novel agents for myeloma, such as thalidomide, lenalidomide, and bortezomib, are effective. For younger patients, these agents followed by autologous transplantation with high-dose melphalan is the standard of care. More relapses are now being reported in results of long-term observation, and treatment strategies for relapsed disease must be established.

Duration of Vascular Endothelial Growth Factor Suppression after Intravitreal Injection of Faricimab in Macaque Eyes.

Purpose: To evaluate the duration of vascular endothelial growth factor (VEGF) suppression in the aqueous humor of macaque eyes after intravitreal faricimab (IVF) injection. Methods: Faricimab (6 mg/50 µL) was injected into the vitreous cavity of the right eye of 6 macaques. Aqueous humor samples (150 µL) were collected from both eyes immediately before injection and on days 1, 3, 7, 14, 21, 28, 42, 56, 84, and 112 after injection. The VEGF concentrations in the aqueous humor were measured using an enzyme-linked immunosorbent assay. Results: The VEGF was undetectable until 4 weeks after IVF injection in 4 eyes and until 6 weeks in the remaining 2 eyes. The mean duration of complete VEGF suppression was 4.7 weeks (range, 4-6 weeks). The VEGF concentration did not decrease in the aqueous humor of the non-injected fellow eyes. Conclusions: Faricimab effectively suppressed the VEGF concentrations in the aqueous humor of macaques for an average of 4.7 weeks after a single intravitreal injection. It did not reduce the VEGF concentrations in the aqueous humor of the fellow eyes.

Increased vascular endothelial growth factor expression is associated with cruciate ligament degeneration in patients with osteoarthritis of the knee.

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.

Evaluation of Foveal Vasculature by Optical Coherence Tomography Angiography after Pan-Retinal Photocoagulation versus Intravitreal Anti-VEGF Injections.

Purpose: This study aimed to compare macular vascular changes one and three months after treatment with either panretinal photocoagulation (PRP) or intravitreal bevacizumab (IVB). Methods: A total of 62 eyes with very severe non-proliferative diabetic retinopathy or early proliferative diabetic retinopathy without center-involved diabetic macular edema, were included in this retrospective study. Thirty-nine eyes were allocated to the PRP group, while 23 eyes were treated with IVB. Optical coherence tomography angiography (OCTA) was performed to measure foveal avascular zone (FAZ) characteristics as well as the densities of superficial and deep capillary plexuses (SCP and DCP). Results: In the IVB group, the FAZ area and perimeter expanded at month one but returned to baseline level after three months. In the PRP group, however, the FAZ area and perimeter were rather steady. Changes in the FAZ area were significantly different between the treatment groups at month one (P = 0.02), but not at month three (P = 0.31). There was no significant difference in the change in FAZ circularity index between the two groups at each time point (P = 0.55 and P = 0.31). Similarly, changes in SCP density were not statistically significant between the two groups at both time points (all Ps > 0.05). A comparison of the two treatment arms based on the mean change in DCP density revealed a significant difference at month one, but not at month three (P = 0.01 and P = 0.49, respectively). Conclusion: Although bevacizumab and PRP have different short-term macular vascular responses, both therapies have the ability to normalize or stabilize vascular measures over time.

A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers.

Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.

Efficacy and Safety of Aflibercept and Ranibizumab in the Treatment of Retinopathy of Prematurity.

PURPOSE: To compare the efficacy, recurrence rate, and recurrence interval of intravitreal injection of aflibercept (IVA) and ranibizumab (IVR) in patients with retinopathy of prematurity (ROP). METHODS: This is a single-center retrospective study of neonates hospitalized from January 2018 to March 2023 in the Department of Neonatology of the First Affiliated Hospital of Zhengzhou University who received intravitreal injection of anti-vascular endothelial growth factor owing to type 1 prethreshold ROP, threshold ROP, or aggressive posterior ROP. Clinical data were collected to record the cure, recurrence, number of injections, and side effects of ROP. FINDINGS: A total of 224 neonates (444 eyes) were enrolled in this study, of which 121 (241 eyes) received IVA and 103 (203 eyes) received IVR. There were no significant differences in the general characteristics of infants between the two groups (P > 0.05). The corrected gestational age of the first injection was 37.27 ± 3.07 weeks in the IVA group and 37.20 ± 4.89 weeks in the IVR group (P = 0.582). The recurrence rate was 15.8% in the IVA group and 14.9% in the IVR group (P = 0.841). For relapsed infants, the postmenstrual age (PMA) was 34.89 ± 3.49 weeks in the IVA group and 35.28 ± 4.43 weeks in the IVR group at the first treatment. The PMA was 43.69 ± 4.57 and 40.96 ± 4.98 weeks at the second treatment in the IVA and IVR groups, respectively (P = 0.185). There were two children in the IVA group that required a third treatment, with PMAs of 58.71 and 57.29 weeks at the time of surgery, and one child in the IVR group, with a PMA of 43.14 weeks at the time of injection (P = 0.221). No complications were recorded in either group. IMPLICATIONS: The efficacies of aflibercept and ranibizumab in treating ROP are similar, and the safety of the medications was good. Further research should be conducted in large-scale, prospective clinical trials, providing ophthalmologists with new options for the treatment of ROP.

Choroidal thickness after anti-VEGF in typical neovascular age-related macular degeneration - A systematic review and meta-analysis.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world and anti-vascular endothelial growth factor (VEGF) injections have been the standard of care for the wet/neovascular variant since 2004. Currently, there are conflicting reports regarding its effect on the choroid, which supplies outer retina with oxygen and other nutrients. We synthesize available information of anti-VEGF on choroidal thickness (CT) in treatment-naïve typical neovascular AMD patients during the initial 12-week loading phase. We found 43 studies involving 1901 eyes from 1878 patients were included. Meta-analysis of 35 studies reporting CT at baseline and after 12 weeks suggested a significant decrease in CT with anti-VEGF treatment. A greater mean change with aflibercept compared to ranibizumab was found in subgroup analyses of sub-foveal CT in types 1 and 2 macular neovascularization. The long-term consequences of reduced CT in neovascular AMD remain unclear and require further targeted studies.

VEGFB promotes adipose tissue thermogenesis by inhibiting norepinephrine clearance in macrophages.

Adipokines play key roles in adaptive thermogenesis of beige adipocytes, though its detailed regulatory mechanisms are not fully understood. In the present study, we identify a critical function of vascular endothelial growth factor B (VEGFB)/vascular endothelial growth factor receptor 1 (VEGFR1) signaling in improving thermogenesis in white adipose tissue (WAT). In mouse subcutaneous WAT (scWAT), thermogenesis activation leads to the up-regulation of VEGFB in adipocytes and its receptor VEGFR1 in macrophages. Ablation of adipocyte VEGFB results in deficiency in murine WAT browning. Meanwhile, supplementation of VEGFB promotes WAT thermogenesis, but this effect is blocked by knockout of macrophage VEGFR1. Mechanistic studies show that the VEGFB-activated VEGFR1 inhibits p38 MAPK signaling through its dissociation with receptor for activated C kinase 1, thereby preventing norepinephrine transporter (solute carrier family 6 member 2) and norepinephrine-degrative monoamine oxidase a mediated norepinephrine clearance in macrophages. Our findings demonstrate that VEGFB/VEGFR1 circuit contributes to the WAT thermogenesis.

Insights to Ang/Tie signaling pathway: another rosy dawn for treating retinal and choroidal vascular diseases.

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.

Muscle Atrophy and mRNA-miRNA Network Analysis of Vascular Endothelial Growth Factor (VEGF) in a Mouse Model of Denervation-Induced Disuse.

BACKGROUND: Skeletal muscle atrophy is frequently caused by the disuse of muscles. It impacts quality of life, especially in aging populations and those with chronic diseases. Understanding the molecular mechanisms underlying muscle atrophy is crucial for developing effective therapies. OBJECTIVE: To investigate the roles of vascular endothelial growth factor (VEGF) and various microRNAs (miRNAs) in muscle atrophy using a mouse model of denervation (DEN)-induced disuse, and to elucidate their interactions and regulatory functions through comprehensive network analysis. METHODS: The right sciatic nerve of C57BL/6J mice (n=6) was excised to simulate DEN, with the left serving as a sham surgery control (Sham). Following a two-week period, wet muscle weight was measured. Total RNA was extracted from the tibialis anterior muscle for microarray analysis. Significant expression changes were analyzed via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and miRNet for miRNAs. RESULTS: Denervated limbs showed a significant reduction in muscle weight. Over 1,000 genes displayed increased expression, while 527 showed reductions to less than half of control levels. VEGF, along with specific miRNAs such as miR-106a-5p, miR-mir20a-5p, mir93-5p and mir17-5p, occupied central regulatory nodes within the gene network. Functional analysis revealed that these molecules are involved in key biological processes including regulation of cell migration, vasculature development, and regulation of endothelial cell proliferation. The increased miRNAs were subjected to further network analysis that revealed significant regulatory interactions with target mRNAs. CONCLUSION: VEGF and miRNAs play crucial roles in the progression of skeletal muscle atrophy, offering potential targets for therapeutic interventions aimed at reducing atrophy and enhancing muscle regeneration.

Homocysteine decreases VEGF, EGF, and TrkB levels and increases CCL5/RANTES in the hippocampus: Neuroprotective effects of rivastigmine and ibuprofen.

Homocysteine (Hcy) is produced through methionine transmethylation. Elevated Hcy levels are termed Hyperhomocysteinemia (HHcy) and represent a risk factor for neurodegenerative conditions such as Alzheimer's disease. This study aimed to explore the impact of mild HHcy and the neuroprotective effects of ibuprofen and rivastigmine via immunohistochemical analysis of glial markers (Iba-1 and GFAP). Additionally, we assessed levels of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), chemokine ligand 5 (CCL5/RANTES), CX3C chemokine ligand 1 (CX3CL1), and the NGF/p75NTR/tropomyosin kinase B (TrkB) pathway in the hippocampus of adult rats. Mild chronic HHcy was induced chemically in Wistar rats by subcutaneous administration of Hcy (4 mg/kg body weight) twice daily for 30 days. Rivastigmine (0.5 mg/kg) and ibuprofen (40 mg/kg) were administered intraperitoneally once daily. Results revealed elevated levels of CCL5/RANTES and reduced levels of VEGF, EGF, and TrkB in the hippocampus of HHcy-exposed rats. Rivastigmine mitigated the neurotoxic effects of HHcy by increasing TrkB and VEGF levels. Conversely, ibuprofen attenuated CCL5/RANTES levels against the neurotoxicity of HHcy, significantly reducing this chemokine's levels. HHcy-induced neurochemical impairment in the hippocampus may jeopardize neurogenesis, synapse formation, axonal transport, and inflammatory balance, leading to neurodegeneration. Treatments with rivastigmine and ibuprofen alleviated some of these detrimental effects. Reversing HHcy-induced damage through these compounds could serve as a potential neuroprotective strategy against brain damage.

Long-term stability of frozen platelet-rich plasma under -80 °C storage condition.

Platelet rich plasma (PRP) is increasingly used in various fields of medicine, aiming to regeneration and repair damaged tissues, cells and organs. High concentration of bioactive molecules including growth factors, cytokines and chemokines are the rationale of using PRP. The aim of this study is to analyze the effect of frozen on the levels of growth factors. In our study, PRP samples were isolated from 50 healthy volunteers using the Trima Accel blood cell separator. The concentration of growth factors such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF-1) and platelet factor 4 (PF-4) were assessed in fresh PRP and frozen PRP stored at -80 °C for one to twelve months. The study found that count of platelet in all fresh and frozen PRP samples was significantly increased compared to whole blood baseline. There was no significant difference in the concentrations of PDGF-BB, bFGF, VEGF, and PF-4 between fresh and frozen samples. The concentrations of EGF and IGF in Frozen-PRP group were significantly higher than those in Fresh-PRP group. And the storage condition of -80 °C is suitable for PRP, which will not lead to a decrease in growth factors concentration for at least 6 months.

Dynamics of serum cytokines in preeclampsia.

The aim of the present study was to evaluate the diagnostic significance of the dynamics of cytokines and growth factors during pregnancy with and without preeclampsia. The study included 168 pregnant women at risk of hypertensive disorders. The levels of biomarkers of all pregnant women were studied at 12-16 weeks, 28-30 weeks and 36-38 weeks. These included cytokines (tumour necrosis factor-α, interferon-, γinterleukin-4) and growth factors (placental growth factor, vascular endothelial growth factor). All pregnant women were divided into two groups: 124 patients with preeclampsia and 44 without preeclampsia (control group). In patients with preeclampsia, an increase in the level of tumour necrosis factorα- was observed, compared with the control group: a 6.1-fold increase at 12-16 weeks and a 5.9-fold increase at 36-38 weeks. The level of interferon-γ was also increased, by 44.3% in the first trimester of pregnancy and by 46.8% at 28-30 weeks, compared to the control group. The level of interleukin-4 did not significantly differ between the studied groups. The level of placental growth factor was reduced in pregnant women with preeclampsia at all stages of gestation, and at 28-30 weeks was reduced by 67.9% compared to the control group. The level of vascular endothelial growth factor was also reduced, by 75%, compared with the control group. An increase in the level of pro-inflammatory cytokines and decrease in growth factors may therefore be considered as potential predictors of the development of preeclampsia, and evaluation of these factors may be advocated in pregnant women with risk factors of preeclampsia.

Development of pial collaterals by extension of pre-existing artery tips.

Pial collaterals provide protection from ischemic damage and improve the prognosis of stroke patients. The origin or precise sequence of events underlying pial collateral development is unclear and has prevented clinicians from adapting new vascularization and regeneration therapies. We use genetic lineage tracing and intravital imaging of mouse brains at cellular resolution to show that during embryogenesis, pial collateral arteries develop from extension and anastomoses of pre-existing artery tips in a VegfR2-dependent manner. This process of artery tip extension occurs on pre-determined microvascular tracks. Our data demonstrate that an arterial receptor, Cxcr4, earlier shown to drive artery cell migration and coronary collateral development, is dispensable for the formation and maintenance of pial collateral arteries. Our study shows that collateral arteries of the brain are built by a mechanism distinct from that of the heart.