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This study investigated the one-year real-world clinical outcomes of intravitreal faricimab (IVF) in treatment-naïve neovascular age-related macular degeneration (nAMD) and its association with aqueous humor cytokine profiles. Thirty-four eyes of 32 nAMD patients, who received initial IVF at Jichi Medical University were included. These eyes showed significant improvements in central retinal subfield thickness (CST), central choroidal thickness (CCT), and best-corrected visual acuity (BCVA) one year post-IVF (all P  < 0.01). Among 24 measurable cytokines, only VEGF-A was significantly higher in eyes with a dry macula at week 16 ( P  = 0.0030). Three cytokines were significantly higher in eyes with longer injection interval. Higher levels of galectin-1 and VCAM-1, and lower levels of P-selectin, were correlated with greater CST reduction ( P  = 0.020, 0.0061, and 0.012, respectively). Conversely, five cytokines including Ang-1 were correlated with greater BCVA improvement (all P  < 0.05). In conclusion, an anatomical perspective faricimab demonstrated anatomical efficacy for VEGF-driven nAMD in the loading phase, while multiple cytokines associated with vascular instability or fibrosis appear to contribute to its durability. Notably, Ang-1 may be linked to visual improvement, suggesting that the neurotrophic effects of Ang-1 could be enhanced by Ang-2 inhibition.

Angiopoietin-1 (Ang-1) and Vascular Endothelial Growth Factor (VEGF) are central regulators of angiogenesis and are often inactivated in various cardiovascular diseases. VEGF forms complexes with ETS transcription factor family and exerts its action by downregulating multiple genes. Among the target genes of the VEGF-ETS complex, there are a significant number encoding key angiogenic regulators. Phosphorylation of the VEGF-ETS complex releases transcriptional repression on these angiogenic regulators, thereby promoting their expression. Ang-1 interacts with TEK, and this phosphorylation release can be modulated by the Ang-1-TEK signaling pathway. The Ang-1-TEK pathway participates in the transcriptional activation of VEGF genes. In summary, these elements constitute the Ang-1-TEK-VEGF signaling pathway. Additionally, Ang-1 is activated under hypoxic and inflammatory conditions, leading to an upregulation in the expression of TEK. Elevated TEK levels result in the formation of the VEGF-ETS complex, which, in turn, downregulates the expression of numerous angiogenic genes. Hence, the Ang-1-dependent transcriptional repression is indirect. Reduced expression of many target genes can lead to aberrant angiogenesis. A significant overlap exists between the target genes regulated by Ang-1-TEK-VEGF and those under the control of the Ang-1-TEK-TSP-1 signaling pathway. Mechanistically, this can be explained by the replacement of the VEGF-ETS complex with the TSP-1 transcriptional repression complex at the ETS sites on target gene promoters. Furthermore, VEGF possesses non-classical functions unrelated to ETS and DNA binding. Its supportive role in TSP-1 formation may be exerted through the VEGF-CRL5-VHL-HIF-1α-VH032-TGF-β-TSP-1 axis. This review assesses the regulatory mechanisms of the Ang-1-TEK-VEGF signaling pathway and explores its significant overlap with the Ang-1-TEK-TSP-1 signaling pathway.

Background Angiogenesis is important for the progression of gastric cancer (GC). Y-box binding protein 1 (YB-1) predicts advanced disease and indicates neovasculature formation in GC tissues, while the related mechanisms remain elusive. Exosomes mediate intercellular communications via transferring various molecules including proteins, lipids, mRNAs, and microRNAs, while the cargos of GC exosomes and the related mechanisms in GC angiogenesis were rarely reported except for several microRNAs. Methods In this study, human umbilical vein endothelial cells (HUVECs) were, respectively, treated by the exosomes isolated from the YB-1 transfected and the control SGC-7901 cells (SGC-7901-OE-Exo and SGC-7901-NC-Exo), and their apoptosis, proliferation, migration, invasion, and angiogenesis were, sequentially, compared. The levels of angiogenic factors including VEGF, Ang-1, MMP-9 and IL-8 in the exosome-treated HUVECs and the GC-derived exosomes were, separately, detected using PCR and Western blotting as well as RNA sequencing assays. Results We observed the consistent level of YB-1 in the exosomes and their originated GC cells, and the internalization of exosomes into HUVECs. Comparing with SGC-7901-NC-Exo, SGC-7901-OE-Exo significantly inhibited the apoptosis but promoted the proliferation, migration, invasion, and angiogenesis of HUVECs, within which the increased mRNA and protein levels of VEGF, Ang-1, MMP-9 and IL-8 were demonstrated. Meanwhile, mRNA levels of VEGF, Ang-1, MMP-9 and IL-8 showed no significant difference between SGC-7901-NC-Exo and SGC-7901-OE-Exo, although statistically higher mRNA of YB-1 was detected in the SGC-7901-OE-Exo. Conclusions Our findings illustrate YB-1 as the key component of exosome to promote GC angiogenesis by upregulating specific angiogenic factors in the exosome-treated endothelial cells but not in the exosomes themselves.

This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.

Angiopoietin/tyrosine protein kinase receptor Tie-2 signaling in endothelial cells plays an essential role in angiogenesis and wound healing. Angiopoietin-1 (Ang-1) is crucial for blood vessel maturation while angiopoietin-2 (Ang-2), in collaboration with vascular endothelial growth factor (VEGF), initiates angiogenesis by destabilizing existing blood vessels. In healthy people, the Ang-1 level is sustained while Ang-2 expression is restricted. In cancer patients, Ang-2 level is elevated, which correlates with poor prognosis. Ang-2 not only drives tumor angiogenesis but also attracts infiltration of myeloid cells. The latter rapidly differentiate into tumor stromal cells that foster tumor angiogenesis and progression, and weaken the host’s anti-tumor immunity. Moreover, through integrin signaling, Ang-2 induces expression of matrix metallopeptidases (MMPs) to promote tumor cell invasion and metastasis. Many oncogenic viruses induce expression of Ang-2 to promote development of neoplasia associated with viral infection. Multiple Ang-2 inhibitors exhibit remarkable anti-tumor activities, further highlighting the importance of Ang-2 in cancer development.

Objective This study aimed to establish a high-performance liquid chromatography (HPLC) method for the simultaneous quantification of six components in Zhuqi Piantan Granules, and to investigate the protective effect and underlying mechanism of Zhuqi Piantan Granules alone or combined with electroacupuncture on cerebral ischemia-reperfusion injury in rats. Methods Zhuqi Piantan Granules were extracted with 80% methanol. HPLC analysis employed a C18 column and gradient elution using acetonitrile and 0.3% phosphoric acid as the mobile phase. Modeled rats were randomly grouped, given corresponding interventions for 14 days, and evaluated for neurological function, cerebral infarct ratio, vascular density, brain histological changes (hematoxylin-eosin (HE) staining), and Angiopoietin-1/Tyrosine Kinase Receptor-2(Ang-1/Tie-2) protein expressions (Western Blotting). Results All six target components exhibited excellent linear relationships (r ≥ 0.9994). The average recoveries ranged from 97.1% to 99.5%. Both Zhuqi Piantan Granules alone and their combination with electroacupuncture improved neurological function, reduced infarct ratio, increased vascular density, alleviated brain pathological damage, and upregulated Ang-1/Tie-2 expressions—with the combined treatment showing superior efficacy. Conclusion The established HPLC method is reliable and suitable for Zhuqi Piantan Granules quality control. Zhuqi Piantan Granules alone or combined with electroacupuncture alleviates rat cerebral injury by activating the Ang-1/Tie-2 pathway to promote angiogenesis.

(1) Background: The control of angiogenesis is essential in disease treatment. We investigated angiogenesis-promoting or -suppressing factors and their molecular mechanisms. (2) Methods: Angiogenesis from HUVECs was quantitatively analyzed using the Angiogenesis Analysis Kit (Kurabo, Osaka, Japan). Human rAng-1-producing 107-35 CHO cells or mouse DFAT-D1 cells were co-cultured with HUVEC. Antioxidant polyphenols were added to the culture. Gene expression was analyzed by RT-PCR. (3) Results: The addition of rAng-1-producing cells, their culture supernatant, or commercially available rAng-1 showed a promoting effect on angiogenesis. The co-culture of DFAT-D1 cells promoted angiogenesis. Polyphenols showed a dose-dependent inhibitory effect on angiogenesis. Luteolin and quercetin showed remarkable anti-angiogenic effects. The expression of vWF, Flk1, and PECAM-1 was increased by adding rAng-1-producing cell culture supernatant. Polyphenols suppressed these genes. Apigenin and luteolin markedly suppressed α-SMA and Flk1. Resveratrol and quercetin enhanced the expression of PPARγ, and luteolin suppressed the expression of COX-1. The expression of endothelial nitric oxide synthase (eNOS), an oxidative stress-related gene, was slightly increased by luteolin. These results suggest that polyphenols induce ROS reduction. (4) Conclusions: We showed the promoting effect of Ang-1 or DFAT and the suppressing effect of polyphenols on angiogenesis and studied their molecular mechanisms. These results help control angiogenesis in regenerative therapy.

Different housing conditions, including housing space and the physiological and social environment, may affect rodent behavior. Here, we examined the effects of different housing conditions on post-stroke angiogenesis and functional recovery to clarify the ambiguity about environmental enrichment and its components. Male rats in the model groups underwent right middle cerebral artery occlusion (MCAO) followed by reperfusion. The MCAO rats were divided into four groups: the physical enrichment (PE) group, the social enrichment (SE) group, the combined physical and social enrichment (PSE) group and the ischemia/reperfusion + standard conditioning (IS) group. The rats in the sham surgery (SS) group were housed under standard conditions. In a set of behavioral tests, including the modified Neurological Severity Score (mNSS), rotarod test, and adhesive removal test, we demonstrated that the animals in the enriched condition groups exhibited significantly improved neurological functions compared to those in the standard housing group. Smaller infarction volumes were observed in the animals of the PSE group by MRI detection. The enriched conditions increased the microvessel density (MVD) in the ischemic boundary zone, as revealed by CD31 immunofluorescent staining. The immunochemical and q-PCR results further showed that environmental enrichment increased the expression levels of angiogenic factors after ischemia/reperfusion injury. Our data suggest that all three enrichment conditions promoted enhanced angiogenesis and functional recovery after ischemia/reperfusion injury compared to the standard housing, while only exposure to the combination of both physical and social enrichment yielded optimal benefits.

Gradual loss of neuronal structure and function due to impaired blood-brain barrier (BBB) and neuroinflammation are important factors in multiple sclerosis (MS) progression. Our previous studies demonstrated that the C16 peptide and angiopoietin 1 (Ang-1) compound (C + A) could modulate inflammation and vascular protection in many models of MS. In this study, nanotechnology and a novel nanovector of the leukocyte chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) were used to examine the effects of C + A on MS. The acute experimental autoimmune encephalomyelitis (EAE) model of MS was established in Lewis rats. The C + A compounds were conjugated to control nano-carriers and fMLP-nano-carriers and administered to animals by intravenous injection. The neuropathological changes in the brain cortex and spinal cord were examined using multiple approaches. The stimulation of vascular injection sites was examined using rabbits. The results showed that all C + A compounds (C + A alone, nano-carrier C + A, and fMLP-nano-carrier C + A) reduced neuronal inflammation, axonal demyelination, gliosis, neuronal apoptosis, vascular leakage, and BBB impairment induced by EAE. In addition, the C + A compounds had minimal side effects on liver and kidney functions. Furthermore, the fMLP-nano-carrier C + A compound had better effects compared to C + A alone and the nano-carrier C + A. This study indicated that the fMLP-nano-carrier C + A could attenuate inflammation-related pathological changes in EAE and may be a potential therapeutic strategy for the treatment of MS and EAE.

Angiopoietin-1 (Ang-1) is a well-known endothelial growth factor, but its effects on neurons have yet to be elucidated. We show that Ang-1 is rapidly downregulated in the injured brain after controlled cortical impact (CCI), a mouse experimental traumatic brain injury (TBI) model and in etoposide-induced neuronal apoptosis in vitro. Ang-1 treatment inhibits etoposide-induced upregulation of proapoptotic B-cell lymphoma 2 (Bcl-2) family members Noxa, p53 upregulated modulator of apoptosis (Puma), Bcl-2 interacting mediator of cell death (Bim), and Bcl-2-associated X protein (Bax); reduces markers of caspase-dependent (cytochrome c release/caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways; and limits neuronal cell death. Ang-1 treatment phosphorylates receptors Tunica interna endothelial cell kinase 2 (Tie2), and β1-integrin and limits the etoposide-induced decrease in protein kinase B (Akt) activity. Blocking Tie2 and β1-integrin signaling reduces Ang-1 neuroprotective effects. After both TBI and etoposide treatment microRNA (miR)-711 are upregulated, consistent with its putative role as a negative regulator of Ang-1. We show that miR-711 directly targets the Ang-1 messenger RNA (mRNA), decreasing Ang-1 expression. Increased levels of miR-711 and Ang-1 mRNA are found in the RNA-induced silencing complex complex site of miR-mediated degradation of target mRNAs after etoposide treatment and the miR-711mimic downregulates Ang-1. Administration of miR-711 inhibitor elevates Ang-1 after TBI whereas Ang-1 administration increases Akt activation; reduces Puma, Noxa, Bim, and Bax levels; and attenuates caspase-dependent and -independent neuronal apoptosis 24 h after TBI. Ang-1 also attenuates neuronal degeneration, increases gene expression of molecules that maintain blood–brain barrier integrity, and reduces post-traumatic lesion volume/edema 24 h after TBI. Although we only observed short-term neuroprotective effects after Ang-1 administration, miR-711-dependent downregulation of Ang-1, followed by Akt pathway inhibition, may play a role in neuronal cell death after neuronal injury in vitro and after experimental TBI.