The Vascular Component of Melasma: A Systematic Review of Laboratory, Diagnostic, and Therapeutic Evidence.

BACKGROUND: Melasma is a common acquired disorder of hyperpigmentation, classically manifesting as symmetric brown patches on the face. Although the exact pathogenesis is not fully understood, vascular abnormalities have been implicated in melasma. OBJECTIVE: To evaluate the laboratory and clinical evidence regarding the safety and efficacy of antivascular agents for the treatment of melasma. METHODS: A systematic review of PubMed, EMBASE, and Cochrane was conducted on May 13, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Original research articles investigating the role of vascularity and/or evaluating the use of antivascular therapeutics in melasma were included. Clinical recommendations were based on the American College of Physicians guidelines. RESULTS: A total of 34 original research articles as follows were identified: 4 laboratory studies, 15 diagnostic studies, and 15 therapeutic studies. CONCLUSION: There is promising evidence supporting the use of tranexamic acid and laser/light therapies to treat the vascular component of melasma, and more rigorous clinical trials are needed to validate their efficacy. Clinicians may consider treatment with one or more antivascular therapeutics in patients with melasma. Further research is warranted to characterize the role of cutaneous vascularization in melasma and may provide insights for novel therapies.

Short-Term Oral Sorafenib for Therapy of Intratumoral Shunts of Hepatocellular Carcinoma to Enable Intraarterial Treatment.

INTRODUCTION: Significant intratumoral shunts between tumor-supplying arteries and portal or liver veins are a contraindication for transarterial therapy of HCC because interventional treatment of these shunts is frequently insufficient. Sorafenib has anti-angiogenic effects and is indicated for palliative treatment of patients with HCC. Here, we report our experience with the use of sorafenib for the closure of intratumoral shunts in patients scheduled for transarterial therapy of HCC. MATERIALS AND METHODS: Three patients with HCC, aged 65, 82 and 79 years, exhibited a significant intratumoral shunting from tumor artery to portal (n = 1) or liver veins (n = 2). In all cases, intratumoral shunting had already been suspected based on pre-interventional CT angiography, and DSA confirmed the shunt. Oral sorafenib (800 mg/day) was administered for at least four weeks, only and specifically to occlude the shunt. Hereafter, patients were re-evaluated by CT and DSA. RESULTS: All patients tolerated the full prescribed dose for at least 4 weeks. In one case, therapy was prolonged with an adapted dose (400 mg/day) due to sorafenib-related hand-foot syndrome. After sorafenib treatment, CT and DSA confirmed a complete closure of intratumoral shunts for all patients. No tumor progression was observed. All three patients hereafter underwent successful transarterial treatment by TACE (n = 2) or TARE (n = 1) without complications. Progression-free survival according to mRECIST was 501, 397 and 599 days, respectively. CONCLUSION: Even short-term oral sorafenib seems to effectively close intratumoral shunts in patients with HCC and thus might enable transarterial treatment of these patients.

EphrinB2 activation enhances angiogenesis, reduces amyloid-ß deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats.

Cerebral infarction causes secondary neurodegeneration and angiogenesis in thalamus, which impacts functional recovery after stroke. Here, we hypothesize that activation of ephrinB2 could stimulate angiogenesis and restore the secondary neurodegeneration in thalamus after cerebral infarction. Focal cerebral infarction was induced by middle cerebral artery occlusion (MCAO). Secondary damage, angiogenesis, amyloid-ß (Aß) deposits, levels of ephrinB2 and receptor for advanced glycation end product (RAGE) in the ipsilateral thalamus were determined by immunofluorescence and immunoblot. The contribution of ephrinB2 to angiogenesis was determined by siRNA-mediated knockdown of ephrinB2 and pharmacological activation of ephrinB2. The results showed that formation of new vessels and ephrinB2 expression was markedly increased in the ipsilateral thalamus at seven days after MCAO. EphrinB2 knockdown markedly suppressed angiogenesis coinciding with increased Aß accumulation, neuronal loss and gliosis in the ipsilateral thalamus. In contrast, clustered EphB2-Fc significantly enhanced angiogenesis, alleviated Aß accumulation and the secondary thalamic damage, which was accompanied by accelerated function recovery. Additionally, activation of ephrinB2 significantly reduced RAGE levels in the ipsilateral thalamus. Our findings suggest that activation of ephrinB2 promotes angiogenesis, ameliorates Aß accumulation and the secondary thalamic damage after cerebral infarction. Additionally, RAGE might be involved in Aß clearance by activating ephrinB2 in the thalamus.

Angiogenesis and Hepatic Fibrosis: Western and Chinese Medicine Therapies on the Road.

Hepatic fibrosis is a common feature of almost all chronic liver diseases. Formation of new vessels (angiogenesis) is a process strictly related to the progressive fibrogenesis which leads to cirrhosis and liver cancer. This review mainly concerns the relationship between angiogenesis and hepatic fibrosis, by considering the mechanism of angiogenesis, cells in angiogenesis, anti-angiogenic and Chinese medicine therapies.

Nanosecond Pulsed Electric Fields Enhance the Anti-tumour Effects of the mTOR Inhibitor Everolimus against Melanoma.

The PI3K/mTOR/AKT pathway is activated in most melanomas, but mTOR inhibitors used singly have limited activity against advanced melanomas. The application of nanosecond pulsed electric fields (nsPEFs) is a promising cancer therapy approach. In this study, we evaluated the synergistic anti-tumour efficacy of the mTOR inhibitor everolimus in conjunction with nsPEFs against melanoma. The combined treatment of nsPEFs and everolimus gradually decreased cell growth concurrent with nsPEF intensity. nsPEFs alone or combined with everolimus could promote melanoma cell apoptosis, accompanied with a loss in cellular mitochondrial membrane potential and an increase in Ca2+ levels. In vivo experiments showed that a combination of the mTOR inhibitor everolimus and nsPEFs improved the inhibitory effect, and all skin lesions caused by nsPEFs healed in 1 week without any observed adverse effect. Combination treatment induced caspase-dependent apoptosis through the upregulation of the pro-apoptotic factor Bax and downregulation of the anti-apoptotic factor Bcl-2. Everolimus and nsPEFs synergistically inhibited angiogenesis by decreasing the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and CD34. Our findings indicate that nsPEFs in combination with an mTOR inhibitor can be used as a potential treatment approach for advanced melanoma.

Effects of tongxinluo on angiogenesis in the carotid adventitia of hyperlipidemic rabbits.

Atherosclerosis, as a common arterial disease with high morbidity rate, is reported to be closely associated with adventitia angiogenesis. The present study aimed to investigate the effect of tongxinluo (TXL) on angiogenesis in the carotid adventitia of hyperlipidemic rabbits and the underlying mechanism. A total of 90 experimental rabbits were randomly assigned into the following six groups (n=15 per group): Normal group, model group, low­dose TXL group, moderate-dose TXL group, high­dose TXL group and atorvastatin group. The normal group was fed with a standard diet. The model and treatment groups were on a high cholesterol diet for 4 weeks. The serum lipid level of the model group was significantly higher compared with the normal group. TXL serum lipid level compared with the model group. Hematoxylin and eosin, and CD31 staining demonstrated that TXL inhibited adventitia angiogenesis in a dose­dependent manner. The dihydroethidium probe and fluorescence in situ hybridization results indicated that TXL reduced O2­ level and positive signal of gp91phox and p22phox mRNA in adventitia. Reverse transcription­polymerase chain reaction and western blot analysis determined that TXL treatment significantly downregulated the expression levels of the gp91phox, p22phox genes and the vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2) proteins compared with the model group. TXL exhibited a dose­dependent inhibitory effect on angiogenesis in the carotid adventitia of hyperlipidemic rabbits. This may be associated with the downregulation of reactive oxygen species generation in the adventitia and the suppression of VEGF/VEGFR-2 expression.

Inhibition of pathological angiogenesis of Chinese medicine against liver fibrosis.

Pathological angiogenesis of liver which includes liver sinusoidal capillarization due to lose of fenestraes of liver sinusoidal endothelial cells (LSECs) and formation of new vascular, is a crucial mechanism responsible for origination and development of liver fifibrosis and closely involves in the development of cirrhosis and hepatic cancer. Anti-neovascularization medicine such as sorafenib can decrease portosystemic shunts, improve splanchnic hyperdynamic circulation, lower portal hypertension, while it can not be applied in clinic due to its serious toxic and side reactions. Chinese herbal formula can effectively inhibit pathological angiogenesis of liver, improve microcirculation of liver, and decrease the probability of gastrointestinal hemorrhage in cirrhotic patients. Different Chinese herbal formula are of different characteristics on inhibiting pathological angiogenesis in liver fifibrosis, which partly explains synergistic effect of different compatibility of Chinese materia medica and opens up good vista for Chinese medicine against liver fifibrosis through inhibiting angiogenesis.

Preclinical Assessment of the Efficacy of Anti-Angiogenic Therapies in Hepatocellular Carcinoma.

Diffuse hepatocellular carcinoma (HCC) is a complex affliction in which comorbidities can bias global outcome of cancer therapy. Better methods are thus warranted to directly assess effects of therapy on tumor angiogenesis and growth. As tumor angiogenesis is invariably associated with changes in local blood flow, we assessed the utility of ultrasound imaging in evaluation of the efficacy of anti-angiogenic therapy in a spontaneous transgenic mouse model of HCC. Blood flow velocities were measured monthly in the celiac trunk before and after administration of sorafenib or bevacizumab at doses corresponding to those currently used in clinical practice. Concordant with clinical experience, sorafenib, but not bevacizumab, reduced microvascular density and suppressed tumor growth relative to controls. Evolution of blood flow velocities correlated with microvascular density and with the evolution of tumor size. Ultrasound imaging thus provides a useful non-invasive tool for preclinical evaluation of new anti-angiogenic therapies for HCC.

Anticancer activities of citrus peel polymethoxyflavones related to angiogenesis and others.

Citrus is a kind of common fruit and contains multiple beneficial nutrients for human beings. Flavonoids, as a class of plant secondary metabolites, exist in citrus fruits abundantly. Due to their broad range of pharmacological properties, citrus flavonoids have gained increased attention. Accumulative in vitro and in vivo studies indicate protective effects of polymethoxyflavones (PMFs) against the occurrence of cancer. PMFs inhibit carcinogenesis by mechanisms like blocking the metastasis cascade, inhibition of cancer cell mobility in circulatory systems, proapoptosis, and antiangiogenesis. This review systematically summarized anticarcinogenic effect of citrus flavonoids in cancer therapy, together with the underlying important molecular mechanisms, in purpose of further exploring more effective use of citrus peel flavonoids.

Non-invasively evaluating therapeutic response of nanorod-mediated photothermal therapy on tumor angiogenesis.

Gold nanorod-mediated photothermal therapy has been widely explored for cancer treatment. However, timely evaluation of the therapeutic response is difficult as current diagnostic approaches are largely based on measurements of tumor volume. The present study developed a non-invasive imaging strategy to rapidly assess the efficacy of photothermal therapy in mice bearing human tumor xenografts. In this study, gold nanorods modified with carboxylated bovine serum albumin showed both anti-tumor and anti-angiogenesis effects under near-infrared laser irradiation. An α(v)ß3 integrin-targeted multi-modal nanoprobe, Dendrimer-arginine-glycine-aspartic acid (Den-RGD), was designed and intravenously injected into mice bearing tumor xenografts at 24 h after photothermal therapy. Magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging demonstrated that the Den-RGD not only visualized the tumors with high target-to-background ratio, but also showed the ability to evaluate the therapeutic response by monitoring the tumor neovasculature. Additionally, the target-to-background ratio on MRI and NIRF imaging correlated with the microvessel density in the Den-RGD groups. Immunofluorescence staining confirmed the targeting specificity of Den-RGD to the neovasculature at the tumor periphery. This dual-modal imaging method holds the promise of evaluating therapeutic efficacy in vivo. Nanomedicine provides a multi-functional platform for treatment of cancer and image-guided assessment of anti-cancer therapy.

670nm photobiomodulation as a novel protection against retinopathy of prematurity: evidence from oxygen induced retinopathy models.

INTRODUCTION: To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR). MATERIALS AND METHODS: During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670 nm light for 3 minutes a day (9J/cm²). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed. RESULTS: 670 nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670 nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670 nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670 nm light-exposed animals, and no adverse effects of exposure to 670 nm light were detected. DISCUSSION: Low levels of exposure to 670 nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity.

Ischemia-induced copper loss and suppression of angiogenesis in the pathogenesis of myocardial infarction.

Myocardial ischemia is a primary cause for the loss of vital components such as cardiomyocytes in the heart, leading to myocardial infarction and eventual cardiac dysfunction or heart failure. Suppressed angiogenesis plays a determinant role in the pathogenesis of myocardial infarction. In response to myocardial ischemia, hypoxia-inducible factor-1α and 2α (HIF-1α and HIF-2α) accumulate in cardiomyocytes and other cell types. This would up-regulate the expression of genes involved in angiogenesis such as vascular endothelial growth factor (VEGF); however, it is often observed that the angiogenic capacity is suppressed rather than enhanced. Ischemic toxicity, which has not been fully recognized, is highly responsible for the compromised angiogenic capacity. One of the toxic effects resulting from myocardial ischemia is the loss of copper content in the heart. Although the reason for this loss has not been elucidated, the essential role of copper in the regulation of HIF-1 transcriptional activity has been described. Copper does not affect the accumulation of HIF-1α in the cell, but is required for the HIF-1 transcriptional complex formation and its interaction with the hypoxia-responsive element in target genes. Copper supplementation can stimulate the transcriptional activity of HIF-1 and restore angiogenic capacity, leading to increased capillary density in the heart. The recognition of ischemic toxicity and the effort to overcome the toxic effect would help develop alternative approaches in the treatment of ischemic heart disease.

Bisphosphonates in preclinical bone oncology.

Bisphosphonates, especially nitrogen-containing bisphosphonates, are widely used to block bone destruction in cancer patients with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. In addition to their antiresorptive effects, preclinical evidence strongly suggests that nitrogen-containing bisphosphonates exert direct and indirect anticancer activities through inhibition of tumor cell functions, enhancement of the cytotoxic activity of chemotherapy agents, inhibition of tumor angiogenesis, and stimulation of antitumor immune reactions. This review examines the current evidence and provides insights into ongoing preclinical research on anticancer activities of these bisphosphonates in animal models of tumorigenesis and metastasis.

Emerging therapeutic approaches in the management of retinal angiogenesis and edema.

Conditions resulting in retinal angiogenesis and edema (exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity) are major causes of visual impairment, with significant impact on quality of life. There has been increasing clinical usage of anti-vascular endothelial growth factor (anti-VEGF) agents to stop retinal angiogenesis and resolve intraretinal fluid arising from these conditions. However, anti-VEGFs have not been completely successful in curing these conditions, and a range of emerging treatments aimed at supplementing or competing with anti-VEGF agents are being developed. We will discuss the proposed merits these emerging agents bring to the treatment arsenal and how they compare with anti-VEGFs with regards to therapeutic activity, potency, specificity and safety. This review will also highlight recent pre-clinical research findings and suggest where future research might be directed.

Angiogenesis in bladder cancer--prognostic marker and target for future therapy.

Angiogenesis is the process by which tumours induce a blood supply, crucial for growth and metastasis. Evidence for its role in bladder carcinogenesis, its usefulness as a marker of patient prognosis, and potential anti-angiogenic therapies for future development are discussed in this chapter.

Angiogénesis en el cáncer de cérvix uterino / Angiogenesis in cancer of the uterine cervix

La angiogénesis es necesaria para el crecimiento tumoral. En los exámenes histológicos de especímenes tumorales se precisa unificar criterios en los métodos de recuento de microvasos/campo para comparar resultados clínicos. Se produce un incremento de la densidad de microvasos (MVD), factores de crecimiento endotelial vascular y receptores asociados a la gravedad de lesiones intraepiteliales de cérvix (CIN-III frente a epitelio normal), relación que es clara respecto al carcinoma invasor. Considerando las publicaciones analizadas, se puede decir que en el cáncer de cérvix, la densidad de microvasos no tiene relación con los estadios de la FIGO (tamaño tumoral, profundidad de invasión de la estroma, invasión corporal, infiltración vaginal, invasión parametrial y estado ganglionar), invasión del espacio linfovascular, variedades histológicas y grados de diferenciación histológica. En el cáncer del cérvix uterino, la alta MVD es un factor de riesgo de recidiva; las pacientes cuyos tumores poseen alta MVD tienen peores tasas de supervivencia global y supervivencia libre de enfermedad. En la mayoría de los estudios de análisis de multivariables, la MVD fue un factor significativo para tasas de supervivencias (AU)