Cisplatin (CP) is a highly effective broad-spectrum chemotherapeutic agent for several solid tumors. However, its clinical use is associated with ovarian toxicity. Icariin (ICA) is a bioactive flavonoid of Epimedium brevicornum with reported protective activities against inflammation, oxidative stress and ovarian failure. This study aimed to explore the protective effects of ICA against CP-associated ovarian toxicity in rats. Rats were randomized into five groups and treated for 17 days: control, ICA (10 mg/kg/day, for 17 days. p.o.), CP (6 mg/kg, i.p. on days 7 and 14), CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 5 mg/kg p.o. daily), and CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 10 mg/kg p.o. daily). Our results indicated that ICA effectively improved ovarian reserve as indicated by attenuating CP-induced histolopathological changes and enhancing serum anti-müllerian hormone (AMH). Furthermore, co-administration of ICA with CP showed restoration of the oxidant-anti-oxidant balance in ovarian tissues, evidenced by decreased malondialdehyde (MDA) concentrations and elevated superoxide dismutase (SOD) and catalase (CAT) activities. Also, ICA suppressed ovarian inflammation as evidenced by down-regulation of the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB). ICA inhibited ovarian apoptosis in CP-treated rats by down-regulation of CASP3 and Bax and up-regulation of Bcl-2 mRNA expression. Further, ICA enhanced PTEN, p-AKT, p-mTOR, and p-AMPKα expression. In conclusion, ICA possesses a protective activity against CP-induced ovarian toxicity in rats by exhibiting antioxidant, antiinflammatory, anti-apoptotic activities and modulating NF-κB expression and PTEN/AKT/mTOR/AMPK axis in ovarian tissues.

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New clinical strategies for treating severe bone and cartilage injuries are required, especially for use in combination with implant procedures. For this purpose, p(VCL-co-HEMA) thermosensitive hydrogels have been activated with icariin-loaded nanoparticles to be used as bone-cell-harvesting platforms. Supercritical CO2-SAS technology has been applied to encapsulate icariin, a small molecule that is involved in osteoblastic differentiation. Thus, physical-chemical analysis, including swelling and transmittance, showed the impact of HEMA groups in hydrogel composition. Moreover, icariin (ICA) release from p(VCL-co-HEMA) platforms, including pVCL@ICA nanoparticles, has been studied to evaluate their efficacy in relevant conditions. Finally, the thermosensitive hydrogels\' cell compatibility, transplant efficiency, and bone differentiation capacity were tested. This study identifies the optimal formulations for icariin-activated hydrogels for both control and HEMA formulations. Using this technique, osteoblastic sheets that were rich in collagen type I were successfully transplanted and recultivated, maintaining an optimal extracellular matrix (ECM) composition. These findings suggest a new cell-sheet-based therapy for bone regeneration purposes using customized and NP-activated pVCL-based cell platforms.

BACKGROUND: Alzheimer\'s disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood.
OBJECTIVE: In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects.
METHODS: We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin.
RESULTS: Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection.
CONCLUSIONS: Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

Icariin (ICA), an active ingredient found in Epimedium, possesses antioxidant and anti-inflammatory properties and has garnered widespread attention in recent years. This study investigated the protective effects of ICA against cadmium (Cd)-induced kidney injury in rats. Healthy male specific pathogen-free Sprague-Dawley rats were randomly divided into a control group, Cd group, a low-dose ICA group, a middle-dose ICA group, and a high-dose ICA group using a random number table. Tissue and blood samples were analyzed for renal function markers, histopathology, and gene expression. We found that ICA intervention ameliorates Cd-induced nephrotoxicity by enhancing glomerular filtration, mitigating renal tubular epithelial cell damage, reducing cellular degeneration and edema, and decreasing oxidative stress. ICA demonstrated anti-apoptotic activity through the regulation of pro- and anti-apoptotic gene transcription and by inhibiting apoptosis, thus protecting the kidneys. ICA also exhibited anti-inflammatory effects by reducing the transcription of Cd-induced pro-inflammatory genes, inhibiting nucleotide oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome formation, and preventing pyroptosis. ICA potentially regulated the Toll-like receptor 4/P2rx7/nuclear factor kappa B signaling pathway, which modulated the activation of the NLRP3 inflammasome and contributed to its anti-inflammatory action. ICA reduced Cd-induced renal injury in rats, likely through a mechanism involving antioxidant, anti-apoptotic, and anti-inflammatory effects.

BACKGROUND: Up to 80 % of chemotherapeutic drugs induce myelosuppression in patients. Chemotherapy not only impairs of hematopoietic stem cells (HSCs) but also damages bone marrow niches (vascular and endosteal). Current treatments for myelosuppression overlook these chemotherapy-induced damages to bone marrow niches and the critical role of niche restoration on hematopoietic regeneration. Ginsenoside protopanaxatriol (PPT) protects vascular endothelium from injury, while icariin (ICA) promotes osteogenic differentiation. The combination of PPT and ICA aims to restore damaged vascular and endosteal niches, thus rejuvenating HSCs for treating myelosuppression.
OBJECTIVE: This study aims to develop effective, bone marrow niche-directed PPT/ICA therapies for treating chemotherapy-induced myelosuppression.
METHODS: 3D cell spheroids were used to investigate the effects of PPT/ICA on cell-cell interactions in vascular niches, osteogenesis, and extracellular matrix (ECM) secretion in endosteal niches. In vitro mimic niche models were designed to access the drug combination\'s efficacy in rejuvenating and mobilizing in HSCs within bone marrow niches. The delivery capability of PPT/ICA to key niche cell types (mesenchymal stromal cells (MSCs), endothelial cells (ECs), and osteoblasts (OBs)) via nanocarriers has been determined. DSS6 peptide-modified nanoparticles (DSS6-NPs) were prepared for specific co-delivery of PPT/ICA into key niche cell populations in vivo.
RESULTS: PPT can prevent vascular niche injury by restoring vascular EC cell-cell adhesion and the intercellular interactions between ECs and MSCs in 5-fluorouracil (5-FU)-damaged cell spheroids. ICA repaired 5-FU-damaged endosteal niches by promoting osteogenesis and ECM secretion. The combination of PPT and ICA restores key HSC niche factor gene expressions, normalizing HSC differentiation and mobilization. The in vitro cellular uptake efficiency of nanocarriers in a mimic niche is positively correlated with their in vivo delivery into bone marrow niche cells. DSS6-NPs greatly enhance the delivery of PPT/ICA into MSCs and OBs within bone marrow niches. Co-loading of PPT/ICA into DSS6-NPs effectively repairs damaged bone marrow niches and promotes HSC rejuvenation in vivo.
CONCLUSIONS: The combination of PPT and ICA effectively prevents injury to the vascular and endosteal niches, thereby promoting hematopoietic regeneration in the bone marrow. This study provides novel niche-directed PPT/ICA therapies for managing chemotherapy-induced myelosuppression.

OBJECTIVE: This study aims to investigate potential beneficial actions of icariin (ICA) on testicular spermatogenic function in male rats with streptozotocin (STZ)-induced diabetes and to explore the underlying mechanisms. Background: ICA was found to reduce blood glucose, regulate the endocrine function of the reproductive system, and improve testicular spermatogenic function.
METHODS: Adult rats were intraperitoneally injected with STZ (65 mg/kg) to induce type 1 diabetes mellitus (T1DM). Diabetic rats were randomly classified intoT1DM (n = 6) and T1DM + ICA (n = 6) groups. Rats without STZ and ICA treatment were assigned as control group (n = 6). The morphology of testicular tissues was examined by histological staining. The mRNA and protein expression levels were determined by quantitative real-time PCR, Western blot and immunostaining, respectively.
RESULTS: Rats from T1DM group showed a reduction in epididymis and testis weight, and a decrease in sperm count when compared to control group (p < 0.01), which was attenuated by ICA treatment (p < 0.05) Diabetic rats from T1DM group also exhibited reduced diameter and area of seminiferous tubules, along with decreased spermatogonia and primary spermatocytes number when compared to control group (p < 0.01), which was partially reversed by ICA treatment (p < 0.05) Rats from T1DM group exhibited down-regulation of PCNA mRNA and protein in the testis when compared to control group (p < 0.01); while ICA treatment up-regulated PCNA expression in the testis of diabetic rats compared to T1DM group (p < 0.05). Rats from T1DM group showed up-regulation of Bax and capase-3 and down-regulation of Bcl-2, PKM2, HK2 and lactate dehydrogenase A in the testes when compared to control group (p < 0.05), which was reversed by ICA treatment (p < 0.05).
CONCLUSIONS: These findings suggest that ICA may exert its protective effects on testicular damage in diabetic rats through modulation of glycolysis pathway and suppression of apoptosis.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by increased sensitivity to environmental allergens and irritants. Icariin, a natural compound extracted from the herb Epimedium, has been traditionally used for its potential anti-inflammatory and antioxidant properties. This study aimed to investigate the regulatory effects of icariin on AD-like symptoms and to elucidate its underlying mechanisms. The effects of icariin on TNF-α/IFN-γ-induced HaCaT cell injury were assessed using various assays, including cell counting kit-8 for cell viability, flow cytometry for reactive oxygen species (ROS) levels, and colorimetric assays for malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. In addition, the study performed enzyme-linked immunosorbent assays to assess cytokines (IL-1β, IL-6, and IL-8) and chemokines (MDC, TARC, and RANTES) levels. Flow cytometry was used to quantify apoptotic rate, while a wound-healing assay was conducted to assess cell migration. The expression of WT1 associated protein (WTAP) and serpin family B member 4 (SERPINB4) at the mRNA and protein levels was determined using qRT-PCR and western blotting, respectively. The associations between WTAP and SERPINB4 were analyzed using RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. Icariin treatment significantly mitigated TNF-α/IFN-γ-induced oxidative stress, inflammatory response, and apoptosis in HaCaT cells, while also reversing the inhibitory effect on cell migration. Icariin reduced the expression of WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Overexpression of WTAP reversed the effects of icariin in TNF-α/IFN-γ-stimulated HaCaT cells. WTAP silencing inhibited the mRNA stability of SERPINB4 through the m6A modification. SERPINB4 overexpression attenuated the effects of WTAP silencing on oxidative stress, inflammatory response, apoptosis, and migration of TNF-α/IFN-γ-stimulated HaCaT cells. Icariin treatment downregulated SERPINB4 expression by regulating WTAP in TNF-α/IFN-γ-stimulated HaCaT cells. Icariin ameliorated TNF-α/IFN-γ-induced human immortalized epidermal cell injury through the WTAP/SERPINB4 axis, highlighting the potential for targeted interventions in AD pathogenesis.

UNASSIGNED: The objectives of this study were to define the superiority of icariin and its derivatives\' anti-inflammatory activities and to create a reference framework for evaluating preclinical evidence. This method combines machine learning and meta-analysis to identify underlying biological pathways.
UNASSIGNED: Data came from PubMed, Embase, Web of Science, and the Cochrane Library. SYRCLE was used to evaluate the risk of bias in a subset of research. Meta-analysis and detailed subgroup analyses, categorized by species, genders, disease type, dosage, and treatment duration, were performed using R and STATA 15.0 software to derive nuanced insights. Employing R software (version 4.2.3) and the tidymodels package, the analysis focused on constructing a model and selecting features, with TNF-α as the dependent variable. This approach aims to identify significant predictors of drug efficacy. An in-depth literature facilitated the synthesis of anti-inflammatory mechanisms attributed to icariin and its constituent compounds.
UNASSIGNED: Following a meticulous search and selection process, 19 studies, involving 370 and 260 animals were included in the meta-analysis and machine-learning assessment, respectively. The findings revealed that icariin and its derivatives markedly reduced inflammation markers, including TNF-α and IL-1β. Additionally, machine-learning outcomes, with TNF-α as the target variable, indicated enhanced anti-inflammatory effects of icariin across respiratory, urological, neurological, and digestive disease types. These effects were more pronounced at doses exceeding 27.52 mg/kg/day and treatment durations beyond 31.22 days.
UNASSIGNED: Strong anti-inflammatory effects are exhibited by icariiin and its derivatives, which are especially beneficial in the management of digestive, neurological, pulmonary, and urinary conditions. Effective for periods longer than 31.22 days and at dosages more than 27.52 mg/kg/day. Subsequent research will involve more targeted animal experiments and safety assessments to obtain more comprehensive preclinical evidence.

UNASSIGNED: Sertoli cells are vital to maintain spermatogenesis and their function decline during aging. Epimedium has the effects of tonifying kidney-yang, strengthening bones and muscles, and expelling wind and dampness, and is commonly used in the treatment of kidney-yang deficiency, impotence and spermatorrhea. Icariin is the main active ingredients from Epimedium exhibiting delaying aging effects and improving male reproductive dysfunction. Whereas, it remains poorly understood how icariin alleviates age-associated decline in testicular function by protecting against the damage of junction function of Sertoli cells.
OBJECTIVE: This study aimed to evaluate the improvement effect of icariin on Sertoli cell junction function damage and explore the underlying mechanisms.
METHODS: Male C57BL/6 mice and mouse Sertoli cell line TM4 cells were utilized to assess the improvement effect of icariin on aging-associated Sertoli cell junction function injury. H&E staining, transmission electron microscopy, qPCR, Western blot, molecular docking, siRNA transfection, and immunofluorescence were performed in this study.
RESULTS: Dietary administration of icariin remarkly attenuated age-associated deterioration in spermatogenic function as evidenced by elevated testicular weight and index, sperm concentration and sperm viability. In addition, icariin protected Sertoli cell junction function from age-associated damage as proven by increased Sertoli cell numbers, improved tight junction ultrastructure, and upregulated junction-related proteins (ZO-1, Occludin and β-Catenin). Moreover, icariin significantly upregulated ERα/c-fos signaling and PKR pathway in testicular Sertoli cells. Similarly, in vitro studies revealed that deletion of ERα, c-fos or PKR abolished the improvement effects of icariin on Sertoli cell junction function damage.
CONCLUSIONS: Icariin effectively mitigates age-associated decline in testicular function by diminished Sertoli cell junction function damage through upregulating PKR pathway via ERα/c-fos signaling. Therefore, attenuating Sertoli cell junction function injury by the upregulation of PKR pathway via ERα/c-fos signaling probably indicates an effective target for the prevention and treatment of testicular spermatogenic function with aging.