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¹H NMR spectra of icariin in D2O and DMSO-d6 (50:50, v/v) at 25°C. Abbreviations: ¹H NMR, proton nuclear magnetic resonance; DMSO-d6, deuterated dimethyl sulfoxide; v/v, volume-to-volume; H, hydrogen.
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Icariin is a bioactive herbal ingredient isolated from Herba epimedii, which has been widely used for the treatment of osteoporosis and male sexual dysfunction in traditional Chinese medicine. The major objective of this work is to investigate the different enhancing effects of β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the...
Citations
... These systems enhance solubility, shield ICA from degradation, and facilitate absorption. Lastly, the pharmacokinetic profiles of certain ICA derivatives might deviate from the parent compound, introducing changes in metabolism, absorption, and distribution that affect bioavailability [45,79]. ...
There is an increasing demand for innovative strategies that effectively promote osteogenesis and enhance bone regeneration. The critical process of bone regeneration involves the transformation of mesenchymal stromal cells into osteoblasts and the subsequent mineralization of the extracellular matrix, making up the complex mechanism of osteogenesis. Icariin’s diverse pharmacological properties, such as anti-inflammatory, anti-oxidant, and osteogenic effects, have attracted considerable attention in biomedical research. Icariin, known for its ability to stimulate bone formation, has been found to encourage the transformation of mesenchymal stromal cells into osteoblasts and improve the subsequent process of mineralization. Several studies have demonstrated the osteogenic effects of icariin, which can be attributed to its hormone-like function. It has been found to induce the expression of BMP-2 and BMP-4 mRNAs in osteoblasts and significantly upregulate Osx at low doses. Additionally, icariin promotes bone formation by stimulating the expression of pre-osteoblastic genes like Osx, RUNX2, and collagen type I. However, icariin needs to be effectively delivered to bone to perform such promising functions.
Encapsulating icariin within nanoplatforms holds significant promise for promoting osteogenesis and bone regeneration through a range of intricate biological effects. When encapsulated in nanofibers or nanoparticles, icariin exerts its effects directly at the cellular level. Recalling that inflammation is a critical factor influencing bone regeneration, icariin's anti-inflammatory effects can be harnessed and amplified when encapsulated in nanoplatforms. Also, while cell adhesion and cell migration are pivotal stages of tissue regeneration, icariin-loaded nanoplatforms contribute to these processes by providing a supportive matrix for cellular attachment and movement. This review comprehensively discusses icariin-loaded nanoplatforms used for bone regeneration and osteogenesis, further presenting where the field needs to go before icariin can be used clinically.
... Ica has poor water solubility and low plasma and tissue distribution concentrations [17]. Oral administration of Ica not only requires overcoming the hepatic first-pass effect, but also conquering the abundant P-glycoprotein (P-gp) on the intestinal mucosa and the biological enzymes secreted by intestinal bacteria which affect the absorption and utilization of Ica [18,19]. At the same time, oral administration of non-targeted drugs has the disadvantage of inevitable distribution to other organs. ...
Vascular dementia (VaD) has a serious impact on the patients’ quality of life. Icariin (Ica) possesses neuroprotective potential for treating VaD, yet its oral bioavailability and blood–brain barrier (BBB) permeability remain challenges. This research introduced a PEG–PLGA-loaded chitosan hydrogel-based binary formulation tailored for intranasal delivery, enhancing the intracerebral delivery efficacy of neuroprotective agents. The formulation underwent optimization to facilitate BBB crossing, with examinations conducted on its particle size, morphology, drug-loading capacity, in vitro release, and biodistribution. Using the bilateral common carotid artery occlusion (BCCAO) rat model, the therapeutic efficacy of this binary formulation was assessed against chitosan hydrogel and PEG–PLGA nanoparticles loaded with Ica. Post-intranasal administration, enhanced cognitive function was evident in chronic cerebral hypoperfusion (CCH) rats. Further mechanistic evaluations, utilizing immunohistochemistry (IHC), RT-PCR, and ELISA, revealed augmented transcription of synaptic plasticity-associated proteins like SYP and PSD-95, and a marked reduction in hippocampal inflammatory markers such as IL-1β and TNF-α, highlighting the formulation's promise in alleviating cognitive impairment. The brain-derived neurotrophic factor (BDNF)/tropomyosin related kinase B (TrkB) pathway was activated significantly in the binary formulation compared with the other two. Our study demonstrates that the intranasal application of chitosan hydrogel loaded with Ica-encapsulated PEG–PLGA could effectively deliver Ica into the brain and enhance its neuroprotective effect.
... Two translucent polypropylene cannulae (outside diameter, 4 mm; inside diameter, 3 mm) were introduced through minor incisions at the proximal and distal segments of ileum, and ligated with 3-0 silk. The ileum was pre-equilibrated separately with perfusion solution and the test solutions at a temperature of 37 • C for 15 min each, with a controlled flow rate of 0.2 mL/min maintained using a peristaltic pump (Zhang et al., 2012). Subsequently, a precisely measured test solution was loaded into a pre-weighed EP tube and connected to the inlet of ileum using the polypropylene cannulae. ...
... In UV-visible spectroscopy, the absorption peak of 268 nm can be seen in the curve In the FTIR spectrogram, the characteristic peaks at ≈1650, 1600, 1510, 1070, and 1260 cm can be assigned to free icariin. In differential scanning calorimetry, the endothermic pea at ≈250 °C is related to icariin [97]. ICRN is a light yellow-to-yellow powder. ...
... In the FTIR spectrogram, the characteristic peaks at ≈1650, 1600, 1510, 1070, and 1260 cm −1 can be assigned to free icariin. In differential scanning calorimetry, the endothermic peak at ≈250 • C is related to icariin [97]. ...
Among scaffolds used in tissue engineering, natural biomaterials such as plant-based materials show a crucial role in cellular function due to their biocompatibility and chemical indicators. Because of environmentally friendly behavior and safety, green methods are so important in designing scaffolds. A key bioactive flavonoid of the Epimedium plant, Icariin (ICRN), has a broad range of applications in improving scaffolds as a constant and non-immunogenic material, and in stimulating the cell growth, differentiation of chondrocytes as well as differentiation of embryonic stem cells towards cardiomyocytes. Moreover, fusion of ICRN into the hydrogel scaffolds or chemical crosslinking can enhance the secretion of the collagen matrix and proteoglycan in bone and cartilage tissue engineering. To scrutinize, in various types of cancer cells, ICRN plays a decisive role through increasing cytochrome c secretion, Bax/Bcl2 ratio, poly (ADP-ribose) polymerase as well as caspase stimulations. Surprisingly, ICRN can induce apoptosis, reduce viability and inhibit proliferation of cancer cells, and repress tumorigenesis as well as metastasis. Moreover, cancer cells no longer grow by halting the cell cycle at two checkpoints, G0/G1 and G2/M, through the inhibition of NF-κB by ICRN. Besides, improving nephrotoxicity occurring due to cisplatin and inhibiting multidrug resistance are the other applications of this biomaterial.
... 27 This issue may be resolved by some pharmacological techniques, such as the use of β-cyclodextrin and propyleneglycol-liposomes, which will increase its bioavailability. 34,35 Toxicity of Icariin Because of its structural resemblance to 17-estradiol (E2), ICA is a flavonoid phytoestrogen that can bind to estrogen receptors and have estrogenic effects. 36 As a result, it may have side effects similar to those of estrogen, including uterine hemorrhage, endometrial cancer, breast cancer, and venous thrombosis. ...
Osteoporosis is a metabolic skeletal disorder characterized by increased fragility and fracture risk as s result of reduced bone mineral density and microstructural destruction and caused a heavy burden on families and society. Current medicines, on the other hand, have some limitations, with side effects and doubts regarding long-term efficacy being highlighted. Studies seeking for natural constituents as potential treatment options therefore come into focus. Icariin is a phytochemical derived from a traditional Chinese medicine, Herba epimedium, that has been used to treat orthopedic disorders in ancient China for thousands of years, including osteoporosis, osteoarthritis, and fracture. Icariin belongs to a category of prenylated flavonoids and has been shown to help reduce osteoporosis bone loss while having relatively low side effects. Icariin's anti-osteoporosis properties manifest in a variety of ways, like promoting osteogenesis, suppressing osteoclastogenesis and bone resorption, regulating migration, proliferation, and differentiation of mesenchymal stem cells, enhancing angiogenesis, anti-inflammation, and antioxidation. These procedures entail a slew of critical signaling pathways, such as PPARγ, ERα/AKT/β-catenin, and MAPK. Therefore, icariin can be an applicable alternative to improve osteoporosis although the underlying mechanisms have yet to be fully understood. In this study, we searched using the terms “icariin” and “osteoporosis,” and included 64 articles meeting the inclusion criteria and reviewed the research of icariin in anti-osteoporosis over the last 10 years, and discussed new prospects for future study. Therefore, this review may provide some references for further studies.
... In practice, researchers prefer using HP-beta-CD rather than beta-CD to enhance the bioavailability of insoluble drugs due to the stronger capacity of HP-beta-CD in increasing the water solubility of a compound [39,40]. Moreover, HP-beta-CD was reported to have an inhibitory effect on P-gP ATPase and restrain the efflux of P-gP, while beta-CD did not show any inhibitory activity [41]. In our study, although HP-beta-CD complex of OL permeated through the small intestine a little faster than the beta-CD complex, there was no statistical difference (p > 0.05). ...
Compared to beta-cyclodextrins (beta-CD), hydroxypropyl-beta-cyclodextrins (HP-beta-CD) are a more popular material used to prepare inclusion complexes due to their superior solubility and intestinal absorption. In this study, oleuropein (OL) inclusion complexes with beta-CD (beta-CD:OL) and HP-beta-CD (HP-beta-CD:OL) were prepared and the formation of inclusion complexes was validated by IR, PXRD, and DSC. A phase solubility test showed that the lgK (25 °C) and binding energy of beta-CD:OL and HP-beta-CD:OL was 2.32 versus 1.98, and −6.1 versus −24.66 KJ/mol, respectively. Beta-CD:OL exhibited a more powerful effect than HP-beta-CD:OL in protecting OL from degradation upon exposure to light, high temperature and high humidity. Molecular docking, peak intensity of carbonyls in IR, and ferric reducing power revealed that beta-CD:OL formed more hydrogen bonds with the unstable groups of OL. Both inclusion complexes significantly enhanced the solubility, intestinal permeation and antioxidant activity of OL (p < 0.05). Though HP-beta-CD:OL had higher solubility and intestinal absorption over beta-CD:OL, the difference was not significant (p > 0.05). The study implies that lower binding energy is not always associated with the higher stability of a complex. Beta-CD can protect a multiple-hydroxyl compound more efficiently than HP-beta-CD with the intestinal permeation comparable to HP-beta-CD complex.
... The main challenge for icariin use as a therapeutic option is its very low oral bioavailability because of its physicochemical characteristics [5]. Additionally, icariin efflux in intestinal mucosa mediated by P-glycoprotein is the other reason for its low oral bioavailability [6]. In the small intestine, lactase phlorizin hydrolase and microbiota β-glucosidase activity are important to icariin hydrolysis with concurrent release of its metabolites before absorption [7][8][9]. ...
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.
... The ICA-HPcomplex suppressed the activity of Pgp and increased its water solubility, consequently resulting in a great improvement in the intestinal absorption of ICA. In the case of the ICA-β-CD complex, it showed enhanced solubility but the treatment had no effect on Pgp [67]. ...
... The ICA-HP-complex suppressed the activity of Pgp and increased its water solubility, consequently resulting in a great improvement in the intestinal absorption of ICA. In the case of the ICA-β-CD complex, it showed enhanced solubility but the treatment had no effect on Pgp [67]. ...
In recent years, there has been considerable interest in icariin (ICA) and its derivates, icariside II (ICS) and icaritin (ICT), due to their wide range of potential applications in preventing cancer, cardiovascular disease, osteoporosis, delaying the effects of Alzheimer’s disease, treating erectile dysfunction, etc. However, their poor water solubility and membrane permeability, resulting in low bioavailability, dampens their potential beneficial effects. In this regard, several strategies have been developed, such as pharmaceutical technologies, structural transformations, and absorption enhancers. All these strategies manage to improve the bioavailability of the above-mentioned flavonoids, thus increasing their concentration in the desired places. This paper focuses on gathering the latest knowledge on strategies to improve bioavailability for enhancing the efficacy of icariin, icariside II, and icaritin. We conclude that there is an opportunity for many further improvements in this field. To the best of our knowledge, no such review articles scoping the bioavailability improvement of icariin and its derivates have been published to date. Therefore, this paper can be a good starting point for all those who want to deepen their understanding of the field.
... The icariin inclusion complex was prepared by the freeze-drying method with modification [24]. Briefly, 900 mg HP-b-CD or b-CD was completely dissolved in 60 mL distilled water. ...
... We prepared icariin cyclodextrin complexes as previous description [24] with modification. HP-b-CD and b-CD enhanced the solubility of icariin. ...
... There was no obvious red shift or blue shift. It indicated that no interaction occurred between free icariin and HP-b-CD or b-CD, and certain functional groups of icariin was included in the cavity of HP-b-CD or b-CD molecules [24]. PXRD further evidenced the formation of icariin inclusion complexes. ...
The lower bioavailability after oral administration limited icariin applications in Central Nervous System. Icariin/HP-β-cyclodextrin (HP-β-CD) inclusion complex was prepared for acute severe opening traumatic brain injury (TBI) via facial intradermal(i.d.) in mystacial pad. After fluid percussion-induced TBI, icariin/HP-β-CD at 0.4 mg/kg i.d. preserved more neurons and oligodendrocytes than intranasal injection (i.n.) or intravenous injection via tail vein (i.v.) and decreased microglia and astrocyte activation. Icariin/HP-β-CD i.d. reduced apoptosis in cortical penumbra while i.n. and i.v. showed weak or no effects. Icariin/HP-β-CD i.d. reduced Evans blue leakage and altered CD34, ZO-1, Claudin-5 and beta-catenin expression after TBI. Moreover, icariin/HP-β-CD promoted human umbilical vein endothelial cells proliferation. Thus, Icariin/HP-β-CD i.d. improved TBI, including blood brain barrier opening. Fluorescein 5-isothiocyanate (FITC) and 3,3'-Dioctadecyloxacarbocyanine perchlorate (DiOC18(3)) mimic HP-β-CD and icariin respectively. FITC and DiOC18(3) were similarly delivered to trigeminal epineurium, perineurium and perivascular spaces or tissues, caudal dura mater and scattered in trigeminal fasciculus, indicating that icariin/HP-β-CD was delivered to brain via trigeminal nerve-dura mater-brain pathways. In sum, intradermal injection in mystacial pad might delivered icariin/HP-β-CD to brain and icariin/HP-β-CD improved acute severe opening TBI.
... Icariin has a low bioavailability due to its poor absorption, which poses additional limitations to its clinical application . However, it has been found that the bioavailability of icariin can be improved by pharmacological methods (Zhang et al., 2012). Therefore, the studies on the activation of autophagy to maintain the homeostasis of chondrocytes by icariin are of guidance for the prevention and treatment of OA. ...
Osteoarthritis (OA) is a common degenerative joint disease and is a leading cause of disability and reduced quality of life worldwide. There are currently no clinical treatments that can stop or slow down OA. Drugs have pain-relieving effects, but they do not slow down the course of OA and their long-term use can lead to serious side effects. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Autophagy is an intracellular protective mechanism, and targeting autophagy-related pathways has been found to prevent and treat various diseases. Attenuation of the autophagic pathway has now been found to disrupt cartilage homeostasis and plays an important role in the development of OA. Therefore, modulation of autophagic signaling pathways mediating cartilage homeostasis has been considered as a potential therapeutic option for OA. Phytochemicals are active ingredients from plants that have recently been found to reduce inflammatory factor levels in cartilage as well as attenuate chondrocyte apoptosis by modulating autophagy-related signaling pathways, which are not only widely available but also have the potential to alleviate the symptoms of OA. We reviewed preclinical studies and clinical studies of phytochemicals mediating autophagy to regulate cartilage homeostasis for the treatment of OA. The results suggest that phytochemicals derived from plant extracts can target relevant autophagic pathways as complementary and alternative agents for the treatment of OA if subjected to rigorous clinical trials and pharmacological tests.
