[Mechanism of Ganke Granules intervening acute lung injury based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of action in the intervention of acute lung injury(ALI) based on the blood entry components of Ganke Granules in rats and in conjunction with network pharmacology, molecular docking, and animal experimental validation. The blood entry components of Ganke Granules in rats were imported into the SwissTargetPrediction platform to predict drug targets, and ALI-related targets were collected from the disease database. Intersections were taken, and protein-protein interaction(PPI) networks were constructed to screen the core targets, followed by Gene Ontology(GO) functional and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analyses. A "blood entry components-target-pathway-disease" network was constructed, and the core components for disease intervention based on their topological parameters were screened. Molecular docking was used to predict the binding ability of the core components to key targets. The key targets of Ganke Granules in the intervention of ALI were verified by the lipopolysaccharide(LPS)-induced ALI mouse model. Through PPI topological parameter analysis, the top six key targets of STAT3, SRC, HSP90AA1, MAPK3, HRAS, and MAPK1 related to ALI were obtained. GO functional analysis showed that it was mainly related to ERK1 and ERK2 cascade, inflammatory response, and response to LPS. KEGG analysis showed that the main enrichment pathways were MAPK, neutrophil extracellular trap(NET) formation, and so on. Six core components(schizantherin B, schisandrin, besigomsin, harpagoside, isotectorigenin, and trachelanthamine) were filtered out by the "blood entry components-target-pathway-disease" network based on the analysis of topological parameters. Molecular docking results showed that the six core components and Tectoridin with the highest content in the granules had a high affinity with the key targets of MAPK3, SRC, MAPK1, and STAT3. In vivo experiment results showed that compared with the model group, Ganke Granules could effectively alleviate LPS-induced histopathological injury in the lungs of mice and reduce the percentage of inflammatory infiltration. The total protein content, nitric oxide(NO) level, myeloperoxidase(MPO) content, tumor necrosis factor-α(TNF-α), gamma interferon(IFN-γ), interleukin-1ß(IL-1ß), interleukin-6(IL-6), vascular endothelial growth factor(VEGF), and chemokine(C-X-C motif) ligand 1(CXCL1) chemokines in bronchoalveolar lavage fluid(BALF) were decreased, and the expression levels of lymphocyte antigen 6G(Ly6G), citrullinated histones 3(Cit-H3), and phosphorylated proteins SRC, ERK1/2, and STAT3 in lung tissue were significantly down-regulated. In conclusion, Ganke Granules could effectively inhibit the inflammatory response of ALI induced by LPS, protect lung tissue, regulate the release of inflammatory factors, and inhibit neutrophil infiltration and NET formation, and the mechanism of action may be related to inhibiting the activation of SRC/ERK1/2/STAT3 signaling pathway.

The aging lung: microenvironment, mechanisms, and diseases.

With the development of global social economy and the deepening of the aging population, diseases related to aging have received increasing attention. The pathogenesis of many respiratory diseases remains unclear, and lung aging is an independent risk factor for respiratory diseases. The aging mechanism of the lung may be involved in the occurrence and development of respiratory diseases. Aging-induced immune, oxidative stress, inflammation, and telomere changes can directly induce and promote the occurrence and development of lung aging. Meanwhile, the occurrence of lung aging also further aggravates the immune stress and inflammatory response of respiratory diseases; the two mutually affect each other and promote the development of respiratory diseases. Explaining the mechanism and treatment direction of these respiratory diseases from the perspective of lung aging will be a new idea and research field. This review summarizes the changes in pulmonary microenvironment, metabolic mechanisms, and the progression of respiratory diseases associated with aging.

Tracheobronchial mucosal keratosis: A literature review of this rare disorder.

Background: Tracheobronchial mucosal keratosis (TBMK) is a rare airway disease that may cause refractory cough and airway stenosis. The characteristics of this disease remain unknown. In the present study, we describe this disorder based on a review of the current literature, emphasizing its diagnostic and therapeutic aspects. Methods: A comprehensive search of TBMK was performed in Medline, Google Scholar, Web of Science, Cochrane Library (UK), Embase, China National Knowledge Infrastructure (CNKI) (China), and Wan Fang Med Online (China). The following data were collected: patient characteristics, chest imaging findings, bronchoscopy, histopathologic findings, pathogen testing, treatment, and prognosis. Results: As of 2023, eighteen cases of TBMK have been reported. The main clinical manifestations were cough and expectoration. Chest imaging findings were non-specific. The main bronchoscopy findings were nodular protrusion of airway lumen and yellow-white purulent moss above the nodular lesion. The lesions were mainly located in the trachea and mainstem bronchus. The main pathological manifestations include keratinocytes or keratinocyte beads, squamous metaplasia, and mucosal inflammatory changes. The treatments that were administered include antibiotics, symptomatic treatment, and glucocorticoids. All methods were ineffective except for bronchoscopy-guided high-frequency electric knife and recombinant human epidermal growth factor treatment. Conclusions: TBMK is a rare respiratory disease with atypical clinical manifestations and chest computed tomography findings. Bronchoscopy revealed that nodular hyperplasia of the airway and purulent fur-covered lesions are typical manifestations. The final diagnosis needs to be confirmed by histopathological examination. There is a lack of effective treatment for this disease, and bronchoscopy-guided intervention therapy may be a candidate treatment.

Efficacy of Chinese Herbal Injections for Elderly Patients With pneumonia-A Bayesian Network Meta-analysis of Randomized Control Trials.

Background: Pneumonia is a prevalent and complicated disease among adults, elderly people in particular, and the debate on the optimal Chinese herbal injections (CHIs) is ongoing. Our objective is to investigate the comparative effectiveness of various CHIs strategies for elderly patients with pneumonia. Methods: A comprehensive search strategy was executed to identify relevant randomized controlled trials (RCTs) by browsing through several databases from their inception to first, Feb 2020; All of the direct and indirect evidence included was rated by Network meta-analysis under a Bayesian framework. Results: We ultimately identified 34 eligible randomized controlled trials that involved 3,111 elderly participants and investigated 4 CHIs combined with Western medicine (WM) (Xiyanping injection [XYP]+WM, Yanhuning injection [YHN]+WM, Tanreqing injection [TRQ]+WM, Reduning injection [RDN]+WM), contributing 34 direct comparisons between CHIs. Seen from the outcome of Clinical effective rate and time for defervescence, patients taking medicine added with CHIs [Clinical effective rate, XYP + WM(Odd ratio (OR): 0.74, 95%Credible intervals (CrIs):0.55-0.98), YHN + WM(OR: 0.66, 95%CrI: 0.45-0.95), TRQ + WM(OR: 0.65, 95%CrI: 0.50-0.83), RDN + WM(OR: 0.60, 95%CrI: 0.40-0.89); Time for defervescence, YHN + WM(Mean difference (MD): -2.11, 95%CrI: -3.26 to -0.98), XYP + WM(MD: -2.06, 95%CrI: -3.08 to -1.09), RDN + WM(MD: -1.97, 95%CrI: -3.61 to -0.35), TRQ + WM(MD: -1.69, 95%CrI: -2.27 to -1.04)] showed statistically better effect compared with participants in the Control group (CG) who only took WM. Meanwhile, based on the time for disappearance of cough, 3 out of 4 CHIs [TRQ + WM(MD: -2.56, 95%CrI: -3.38 to -1.54), YHN + WM(MD: -2.36, 95%CrI: -3.86 to -1.00) and XYP + WM(MD: -2.21, 95%CrI: -3.72 to -1.10)] strategies indicated improvement of clinical symptoms. Only XYP + WM(MD -1.78, 95%CrI: -3.29 to -0.27) and TRQ + WM (MD: -1.71, 95%CrI: -2.71 to -0.73) could significantly shorten the time for disappearance of pulmonary rales. Conclusion: According to the statistical effect size (The surface under the cumulative ranking), we found that XYP + WM was presumably to be the preferable treatment for treating elderly patients with pneumonia compared with WM alone in terms of clinical effective rate. Our findings were based on very limited evidence and thus should be interpreted with caution. The application of the findings requires further research.

Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms.

Epidemiological studies showed that the metabolic syndromes (MetS) and cardiovascular diseases (CVDs) are responsible for a serious threat to human health worldwide. MetS is a syndromes characterized by fat metabolism disorder, obesity, diabetes, insulin resistance and other risk factors, which increases the risk of CVDs initiation and development. Although certain drugs play a role in lowering blood sugar and lipid, some side effects also occur. Considering the multiple pathogenesis, a great deal of natural products have been attempted to treat metabolic syndromes. Ginsenosides, as the active components isolated from Panax ginseng C.A.Mey, have been reported to have therapeutic effects on MetS and CVDs, of which pharmacological mechanisms were further studied as well. This review aims to systematically summarize current pharmacological effects of ginsenosides on MetS and CVDs, potential mechanisms and clinic trials, which will greatly contribute to the development of potential agents for related disease treatment.

Relation of Helicobacter pylori infection to peripheral arterial stiffness and 10-year cardiovascular risk in subjects with diabetes mellitus.

PURPOSE: This study was conducted to investigate the relation of HP infection to peripheral arterial stiffness and 10-year cardiovascular risk in diabetes mellitus (DM). METHODS: DM subjects who underwent the C13-breath test were enrolled and divided into DMHP+ and DMHP- groups. Peripheral arterial stiffness was measured using brachial to ankle pulse wave velocity (baPWV). Framingham score (FRS) and Chinese evaluation method of ischemic cardiovascular diseases (ICVD) were used to clarify 10-year cardiovascular risk. RESULTS: A total of 6767 subjects were included, baPWV and proportion of subjects with severe peripheral arterial stiffness were lower in DMHP- group than DMHP+ group (1556.68 ± 227.54 vs 2031.61 ± 525.48 cm/s, p < 0.01; 21.9% vs 62.7%, p < 0.01). Multivariate logistic regression analysis demonstrated that HP infection was independently associated with baPWV. Furthermore, cardiovascular risk score and the proportion of subjects with high risk were lower in DMHP- group than DMHP+ group (FRS: 12.09 ± 3.77 vs 13.91 ± 3.77, 17.2% vs 38.8%; ICVD: 8.56 ± 2.99 vs 10.22 ± 3.16, 43.9% vs 65.4%, with all p < 0.05). CONCLUSION: DM subjects with HP infection had more severe peripheral arterial stiffness compared those without HP infection, a higher cardiovascular risk score and 10-year cardiovascular risk stratification were observed in those subjects.

[Effect of catgut implantation at "Yingxiang"(LI20) on lower airway remodeling in allergic rhinitis rats].

OBJECTIVE: To observe the effect of catgut implantation at "Yingxiang"(LI20) on lower airway remodeling and levels of osteopon-tin (OPN) protein in allergic rhinitis (AR) rats, so as to reveal its mechanisms underlying improvement of AR. METHODS: Male SD rats were randomly divided into control, model and catgut implantation groups, with 10 rats in each group. The AR model was established by intraperitoneal injection and nasal drip of ovalbumin. The catgut implantation was applied to bilateral "Yingxiang"(LI20) for 28 days in rats of the catgut implantation group. The total score of allergic symptoms of rats in each group were observed. The histopathological changes of lower airway were observed under light microscope after Hematoxylineosin, Periodic acid-Schiff and Masson staining. The expression of OPN protein was detected by immunohistochemistry and Western blot, separately. RESULTS: The total score of allergic symptoms of nose-wiping, running nose and sneezing, count of lung goblet cells, lung fiber content, and immunoactivity and expression levels of OPN protein were significantly increased in the model group in contrast to the control group (P<0.05). After the intervention, the total score of allergic symptoms, count of lung goblet cells, immunoactivity and expression levels of OPN protein were considerably down-regulated in the catgut implantation group relevant to the model group (P<0.05). H．E. stain showed thickening of partial airway wall, narrowing of lumen, increase of mucus section, widened alveolar septum, infiltration of inflammatory cells, lymphocytes and eosinophil around the bronchus and in the lung interstitium in AR rats, which was milder in the catgut implantation group. The immunoactivity and expression levels of OPN protein were positively related with the lung goblet cells count and lung fiber content (P<0.05，P<0.01). CONCLUSION: Acupoint implantation of catgut can improve pathological changes of lower airway remodeling, which may be related to its effect in down-regulating the expression of OPN protein in the lung tissue.

Relationship between plasma levels of 25-hydroxyvitamin D and arterial stiffness in elderly Chinese with non-dipper hypertension: An observational study.

Elderly individuals with non-dipper hypertension are at high risk of cardiovascular disease because of increased stiffness of peripheral arteries. Since, vitamin D deficiency is prevalent in elderly Chinese. We examined whether reduced plasma levels of 25-hydroxyvitamin D [25(OH)D] may help promote this stiffness.Hypertensive patients at least 60 years old without history of peripheral arterial disease at our hospital were retrospectively divided into dipper and non-dipper groups according to the results of 24-hour ambulatory blood pressure monitoring. Plasma levels of 25(OH)D were measured by enzyme immunoassay. Peripheral arterial stiffness was measured based on the cardio-ankle vascular index (CAVI).Of the 155 patients enrolled, 95 (61.3%) were diagnosed with non-dipper hypertension and these patients had significantly lower plasma levels of 25(OH)D than the 60 patients with dipper hypertension (19.58 ±â€Š5.97 vs 24.36 ±â€Š6.95 nmol/L, P < .01) as well as significantly higher CAVI (8.46 ±â€Š1.65 vs 7.56 ±â€Š1.08 m/s, P < .01). Vitamin D deficiency was significantly more common among non-dipper patients (57.9% vs 31.7%, P < .01). Multivariate regression showed that age and 25(OH)D were independently related to CAVI, with each 1-ng/ml decrease in 25(OH)D associated with a CAVI increase of +0.04 m/s.Non-dipper hypertension is associated with vitamin D deficiency and reduced plasma levels of 25(OH)D. The latter may contribute to stiffening of peripheral arteries, increasing the risk of cardiovascular disease.

Efficacy and safety of acupuncture therapy for urinary incontinence in women: A systematic review and meta- analysis.

BACKGROUND: Urinary incontinence (UI), affects women more frequently than men, with a prevalence to 30-40% of perimenopausal women and almost 50% among women aged over 70 years. caused severe psychological burden and bringing negatively impact to the quality of life, increased caregiver burden and economic cost. Acupuncture is often used to treat them. We aim to conduct a systematic review to evaluate the efficacy of acupuncture for women experiencing UI. METHODS: The following electronic databases will be searched from inception to Jan. 2020: Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Traditional Chinese Medicine, Chinese Biomedical Literature Database (CBM), Wan-Fang Database and Chinese Scientific Journal Database (VIP database).All published randomized controlled trials in English or Chinese related to acupuncture for urinary incontinence in women will be included. The primary outcome will be the change from baseline in the amount of urine leakage measured by the 1-hour pad test. Adverse events will be the secondary outcome. Study selection, data extraction, and assessment of study quality will be performed independently by two reviewers. RevMan V.5.3.5 software will be used for the assessment of risk of bias and data synthesis. RESULTS: This study will provide a high-quality synthesis of current evidence of acupuncture for UI from the 1-hour pad test. CONCLUSION: The conclusion of our study will provide an evidence to judge whether acupuncture is an effective intervention for patients suffered from UI. PROSPERO REGISTRATION NUMBER: CRD42019133195.

Preventive effect on endothelial surface layer damage of Fusu agent in LPS-induced acute lung injury in rats.

Acute lung injury (ALI) is one of major causes of morbidity and mortality in intensive care. In pathophysiological events of ALI, endothelial surface layer (ESL) injury can result in capillary leakage as the initial event. The "Fusu agent", a traditional Chinese medicine, can inhibit inflammatory factors, attenuate lung capillary leak as seen in our previous study. This study was aimed to explore the molecular mechanism of Fusu agent treatment with ALI. Consistent with previous studies, we found that Fusu agent has the protective effect on LPS-induced ALI model rats. Further investigation demonstrated that heparanase activation is necessary for the LPS-induced ALI model to aggravate ESL loss. Fusu agent can inhibit heparanase activation and heparan sulfate proteoglycans' (HSPGs) degradation to mitigate the ESL injury. Furthermore, TNF-α and intercellular adhesion molecule-1 (ICAM-1) were significantly reduced upon Fusu agent pre-treatment to inhibit inflammatory cell influx and neutrophil adhesion in ALI. These findings shed light on the pharmacologic basis for the clinical application of traditional Chinese medicine in treating ALI.

[Cohort Study of EGFR-TKIs Combined with Traditional Chinese Medicine and Single EGFR-TKIs for Advanced NSCLC (Non₋small Cell Lung Cancer)].

OBJECTIVE: To explore the curative effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) combined with Traditional Chinese Medicine (TCM) versus single EGFR-TKIs for Advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 59 NSCLC patients with EGFR mutation were divided (2:1) into treatment group and control group. Patients in treatment group (39 cases) take EGFR-TKIs plus TCM and control group (20 cases) take EGFR-TKIs. Analysis the progression-free survival (PFS), disease control rate (DCR) and treatment-related adverse events of two groups. RESULTS: The DCR of the treatment group and control group was 94.1% and 84.2% respectively (P=0.24). In the total population, PFS was 12.1 months in treatment group and 9.1 months in control group [hazard ratio (HR) 0.46; 95%CI 0.23-0.9; P=0.025]. Among patients with exon 19 deletion (19-del), PFS between treatment group and control group was 10.5 months and 9.5 months respectively (P=0.17). For patients with exon Leu858Arg point mutation (L858R), PFS was significantly longer with treatment group than withcontrol group (median 13.2 months vs. 7.8 months; HR 0.32, 95%CI 0.10-0.97; P=0.046). Grade 3-4 treatment-related adverse events were less common withtreatment-group (8.33 %) than control group (15.00%) (P=0.65). CONCLUSION: For NSCLC patients with EGFR mutation, EGFR-TKIs combined with TCM has a certain effect to prolong PFS, especially for the patients with L858R.

[Effects of ShenFu Injection on Peripheral Neurotoxicity of Paclitaxel].

OBJECTIVE: To investigate the effects and the underlying mechanisms of ShenFu Injection on paclitaxel-induced peripheral neuropathy. METHODS: Twenty-eight adult male Wister rats were randomized into 4 groups (n=7) : control group, paclitaxel group, paclitaxel combined with low or high dose of ShenFu Injection groups. Rats were intraperitoneally injected with paclitaxel 8 mg/kg every 4 d for a total of 4 doses except control group. From Day 1 of the experiment (injection),low dose (4 mL/kg) and high dose (8 mL/kg) of Shenfu Injection were intraperitoneally injected daily in the combination groups for a total of 21 d respectively,while normal saline (NS) was injected in control group in the same way instead. Mechanical withdraw threshold (MWT) and thermal withdraw latency (TWL) of rats' hind paw were measured before (0 d) and after the first injection (6 d,14 d). The level of nerve growth factor (NGF) in the serum was measured at 22 d before the euthanasia,and the ultrastructure of the sciatic nerve was observed with transmission electron microscope. RESULTS: The MWT and TWL of 14 d in paclitaxel group significantly increased compared with those of 0 d and control group ( P<0.05). The combination of paclitaxel with ShenFu Injection,especially the high dose ( P<0.05),significantly reduced the MWT and TWL when compared to paclitaxel group at 14 d. Compared with simultaneous control group,there was no remarkably increased MWT and TWL in the low and high dose of ShenFu Injection (P>0.05) . Compared with control group,the serum NGF level significantly decreased ( P<0.05) in paclitaxel group,while the serum NGF level in low and high dose of ShenFu Injection groups were higher than paclitaxel group,particularly in the high dose group ( P<0.05). When compared to control group,the sciatic nerve fiber structure in the paclitaxel group was generally damaged,including myelin sheath swelling,fragmentation and vacuolization,endoplasmic reticulum swelling and matrix structure disorder in Schwann cells. The structural damages were mitigated in the low dose and high dose groups,especially the latter one,when compared to the paclitaxel group. CONCLUSION: Shenfu Injection can reduce the peripheral neurotoxicity of paclitaxel by promoting the expression of NGF in serum.

Astragaloside IV Enhances Cisplatin Chemosensitivity in Non-Small Cell Lung Cancer Cells Through Inhibition of B7-H3.

BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for human non-small cell lung cancer (NSCLC). Astragaloside IV, the component of Astragalus membranaceus, has been reported to exhibit anti-inflammation, anti-cancer and immunoregulatory properties. In the present study, we investigated the role of astragaloside IV in the chemoresistance to cisplatin in NSCLC cells. METHODS: We established astragaloside IV-suppressed NSCLC cell lines including A549, HCC827, and NCI-H1299 and evaluated their sensitivity to cisplatin in vitro. In addition, we examined the mRNA and protein levels of B7-H3 in response to cisplatin-based chemotherapy. RESULTS: We showed that high doses of astragaloside IV (10, 20, 40 ng/ml) inhibited NSCLC cell growth, whereas low concentrations of astragaloside IV (1, 2.5, 5 ng/ml) had no obvious cytotoxicity on cell viability. Moreover, combined treatment with astragaloside IV significantly increased chemosensitivity to cisplatin in NSCLC cells. On the molecular level, astragaloside IV co-treatment significantly inhibited the mRNA and protein levels of B7-H3 in the presence of cisplatin. In addition, ectopic expression of B7-H3 diminished the sensitization role of astragaloside IV in cellular responses to cisplatin in NSCLC cells. CONCLUSION: These results demonstrate that astragaloside IV enhances chemosensitivity to cisplatin via inhibition of B7-H3 and that treatment with astragaloside IV and inhibition of B7-H3 serve as potential therapeutic approach for lung cancer patients.

Screening study on the anti-angiogenic effects of Traditional Chinese Medicine - Part I: Heat-clearing and detoxicating TCM.

ETHNOPHARMACOLOGICAL RELEVANCE: Few studies have explored the anti-angiogenic effects of TCM - even more so, as it applies to cancer treatment research. Heat-clearing and detoxicating TCM is the most frequently used category in the treatment of cancerous tumors, but lacks sufficient validation studies. AIM OF THE STUDY: The present research (in our series of studies) aims to explore the anti-angiogenic effects of TCM; so we begin with heat-clearing and detoxicating TCM. MATERIALS AND METHODS: Six typical heat-clearing and detoxicating TCM (Philippine Violet Herb, Wild Chrysanthemum, Heartleaf Houttuynia Herb, Chinese Lobelia Herb, Spreading Hedyotis Herb and Uniflower Swisscentaury Root) were decocted, concentrated, sieved and desiccated to attain the water extract. This study utilized the vascular organism research model for Fli1a-EGFP zebrafish, which were raised and maintained under standard conditions. 22h post-fertilization (hpf) embryos were distributed into 12-well plates for a treatment period of 26h. The TCM water extracts which were diluted in 0.1% dimethyl sulfoxide (DMSO), were added to each well at a concentration of 200µg/ml. The positive control was 5µg/ml PTK787 (vatalanib) and the vehicle control was 0.1% DMSO. At 48hpf larvae were tricaine anesthetized and imaged. To demonstrate if TCM shows angiogenesis defects, ten larvae were randomly chosen to conduct a quantitative assay. Quantitative real-time PCR was conducted to dissect the mechanisms involved by analyzing the contributions of signaling pathways and molecules concerning angiogenesis, with a total of ten genes examined. RESULTS: All 30 larvae treated with Wild Chrysanthemum, Uniflower Swisscentaury Root and PTK787 showed angiogenesis defects. Embryos treated with Wild Chrysanthemum and Uniflower Swisscentaury Root showed a lower number of complete intersegmental vessels (ISVs) and there was statistically significant differences between TCM and the vehicle control. Wild Chrysanthemum and Uniflower Swisscentaury Root have a higher inhibition rate and the statistical difference between TCM and the vehicle control was significant. Compared with vehicle controls, Wild Chrysanthemum could significantly modulate the relative mRNA expression of all ten genes. Whereas, Uniflower Swisscentaury Root could significantly regulate the relative mRNA expression of seven genes, it did not show a significant impact on the remaining three genes. CONCLUSIONS: The present research demonstrates that Wild Chrysanthemum and Uniflower Swisscentaury Root have anti-angiogenic effects in zebrafish and that they could regulate both proangiogenic mechanisms and negative angiogenesis regulators. Their anti-angiogenic effects result from effects on negative regulators overriding their effects on proangiogenic mechanisms. The results provide new insights into their clinical application and therapeutic potential for the management of angiogenesis-dependent diseases such as cancer.