Propolis is a well-known medicinal bee hive product amongst others due to its antiviral properties. Human rhinoviruses (HRVs) are recognized to be responsible for more than 50% of common colds worldwide. This study was performed to determine if kaempferol (KF) and p-coumaric acid (p-CA) extracted from Brazilian propolis and another eight previously known compounds of propolis had antiviral activity toward human rhinovirus (HRV)-2, HRV-3, and HRV-4 in HeLa cells and to determine their mechanism of action using sulforhodamine B assay and real-time reverse transcription polymerase chain reaction. Results were compared with those of a positive control ribavirin. Based on IC₅₀ values, KF, quercetin, chrysin, and luteolin were more pronounced in antiviral activity toward HRV-2 (7.3–37.4 μM), HRV-3 (11.9–20.4 μM), and HRV-4 (12.9–24.4 μM) than a drug reference ribavirin (270.1–323.9 μM). The 35 μM KF and 610 μM p-CA did not interact with the HRV-3 particles. KF and p-CA inhibited HRV-3 infection when added during the early stages (0–4 h) after virus inoculation. These constituents remarkably reduced the RNA replication levels of HRV-3 in the HeLa cell cultures. These findings suggest that KF and p-CA may block or reduce the entrance of the viruses into the cells to protect the cells from the virus destruction and abate virus replication, which may play a crucial role in interfering with expressions of intercellular adhesion molecule-1 and interleukin-6. Further studies about the possible applications of propolis-derived materials as potential products to prevent or treat HRV infection are warranted.

Angiogenesis of brain microvascular endothelial cells (BMECs) is required in the functional restoration of brain injury, such as traumatic brain injury (TBI) and ischemic stroke. Fibroblast growth factor 21 (FGF21) is an angiogenic molecule that functions through the formation of the FGF21/FGFR1/β-klotho complex but does not cause carcinogenic events. The current study was to determine whether recombinant human FGF21 (rhFGF21) could promote angiogenesis and scratch wound healing of human brain microvascular endothelial cells (HBMECs) and the possible underlying mechanism. rhFGF21 promoted angiogenesis and migration of HBMECs. The FGFR1 inhibitor PD173074 was applied to demonstrate that rhFGF21 functions through the formation of FGF21/FGFR1/β-klotho complexes. In addition, the specific PPARγ inhibitor GW9662 and PPARγ activator rosiglitazone were applied to determine that the role of rhFGF21 in increasing angiogenesis is through the PPARγ pathway. In addition, we revealed that the effect of rhFGF21 acts partially through upregulating eNOS expression. In conclusion, our study provides novel evidence that rhFGF21 can enhance the angiogenesis and migration of HBMECs through the formation of the FGF21/FGFR1/β-klotho complex via PPARγ activation and eNOS upregulation, indicating that FGF21 is a potential therapeutic angiogenic agent for the treatment of human brain injury.

Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.

Ischemic strokes account for about 80% of all strokes and are associated with a high risk of mortality. Angiogenesis of brain microvascular endothelial cells may contribute to functional restoration following ischemia. Fibroblast growth factor 1 (FGF1), a member of FGF superfamily, involved in embryonic development, angiogenesis, wound healing, and neuron survival. However, the mitogenic activity of FGF1 is known to contribute to several human pathologies, thereby questioning the safety of its clinical applications. Here, we explored the effects and mechanism of action of non-mitogenic FGF1 (nmFGF1) on angiogenesis in mice after ischemia stroke and an oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) injury model. We found that intranasal administration nmFGF1 significantly promoted angiogenesis in mice after stroke, and significantly increased the formation of matrigel tube and promoted scratch migration in a dose-dependent manner in OGD-induced HBMECs in vitro. However, the co-administration of an FGF receptor 1 (FGFR1)-specific inhibitor PD173074 significantly reversed the effects of nmFGF1 in vitro, suggesting that nmFGF1 functions via FGFR1 activation. Moreover, nmFGF1 activated sphingosine-1-phosphate receptor 1 (S1PR1, S1P1) in mice after stroke in vivo. S1P1 protein antagonist VPC23019 and agonist FTY720 were used to confirm that nmFGF1 promotes angiogenesis in vitro partially through the S1P1 pathway. OGD induced downregulation of S1P1 expression. The S1P1 antagonist VPC23019 blocked the stimulatory effects of nmFGF1, whereas the S1P1 agonist FTY720 exerted effects comparable with those of nmFGF1. Furthermore, PD173074 reversed the effect of nmFGF1 on upregulating S1P1 signaling. In conclusion, nmFGF1 enhanced angiogenesis in mice following stroke and OGD-induced HBMECs through S1P1 pathway regulation mediated via FGFR1 activation. This new discovery suggests the potential therapeutic role of nmFGF1 for the treatment of ischemic strokes.

The human β-site amyloid cleaving enzyme (BACE1) has been considered as an effective drug target for treatment of Alzheimer’s disease (AD). In this study, Urechis unicinctus (U. unicinctus), which is a Far East specialty food known as innkeeper worm, ethanol extract was studied by bioassay-directed fractionation and isolation to examine its potential β-site amyloid cleaving enzyme inhibitory and antimicrobial activity. The following compounds were characterized: hecogenin, cholest-4-en-3-one, cholesta-4,6-dien-3-ol, and hurgadacin. These compounds were identified by their mass spectrometry, ¹H, and ¹³C NMR spectral data, comparing those data with NIST/EPA/NIH Mass spectral database (NIST11) and published values. Hecogenin and cholest-4-en-3-one showed significant inhibitory activity against BACE1 with EC₅₀ values of 116.3 and 390.6 µM, respectively. Cholesta-4,6-dien-3-ol and hurgadacin showed broad spectrum antimicrobial activity, particularly strongly against Escherichia coli (E. coli), Salmonella enterica (S. enterica), Pasteurella multocida (P. multocida), and Physalospora piricola (P. piricola), with minimal inhibitory concentration (MIC) ranging from 0.46 to 0.94 mg/mL. This is the first report regarding those four known compounds that were isolated from U. unicinctus and their anti-BACE1 and antimicrobial activity, highlighting the fact that known natural compounds may be a critical source of new medicine leads. These findings provide scientific evidence for potential application of those bioactive compounds for the development of AD drugs and antimicrobial agents.

Background: Bee pollen (BP) has been used as a traditional medicine and food diet additive due to its nutritional and biological properties. The potential biological properties of bee pollen vary greatly with the botanical and geographical origin of the pollen grains. This study was conducted to characterize the botanical origin and assess the antioxidant effects of ethanol extracts of 18 different bee pollen (EBP) samples from 16 locations in South Korea and their inhibitory activities on human β-amyloid precursor cleavage enzyme (BACE1), acetylcholinesterase (AChE), human intestinal bacteria, and 5 cancer cell lines. Methods: The botanical origin and classification of each BP sample was evaluated using palynological analysis by observing microscope slides. We measured the biological properties, including antioxidant capacity, inhibitory activities against human BACE1, and AChE, and antiproliferative activities toward five cancer cell lines, of the 18 EBPs. In addition, the growth inhibitory activities on four harmful intestinal bacteria, six lactic acid-producing bacteria, two nonpathogenic bacteria, and an acidulating bacterium were also assessed. Results: Four samples (BP3, BP4, BP13 and BP15) were found to be monofloral and presented four dominant pollen types: Quercus palustris, Actinidia arguta, Robinia pseudoacacia, and Amygdalus persica. One sample (BP12) was found to be bifloral, and the remaining samples were considered to be heterofloral. Sixteen samples showed potent antioxidant activities with EC₅₀ from 292.0 to 673.9 μg mL^− 1. Fourteen samples presented potent inhibitory activity against human BACE1 with EC₅₀ from 236.0 to 881.1 μg mL^− 1. All samples showed antiproliferative activity toward the cancer cell lines PC-3, MCF-7, A549, NCI-H727 and AGS with IC₅₀ from 2.7 to 14.4 mg mL^− 1, 0.9 to 12.7 mg mL^− 1, 5.0 to > 25 mg mL^− 1, 2.7 to 17.7 mg mL^− 1, and 2.4 to 8.7 mg mL^− 1, respectively. In addition, total phenol and flavonoid contents had no direct correlation with antioxidant, anti-human BACE1, or antiproliferative activities. Conclusion: Fundamentally, Korean bee pollen-derived preparations could be considered a nutritional addition to food to prevent various diseases related to free radicals, neurodegenerative problems, and cancers. The botanical and geographical origins of pollen grains could help to establish quality control standards for bee pollen consumption and industrial production.