icaritin and Disease-Models--Animal

An ischemic stroke is brain damage caused by interruption of blood supply to the brain that can cause death and long-term disability. New medical strategies or therapies are urgently needed for ischemic stroke. Icaritin (ICT) is a metabolite of icariin (ICA), which are two active flavonoid components extracted from

Topics: Animals; Apoptosis; Brain Ischemia; Disease Models, Animal; Flavonoids; Infarction, Middle Cerebral Artery; Ischemic Stroke; Mice; Neuroprotective Agents; Reperfusion; Reperfusion Injury; Stroke

Recent studies have demonstrated that splenic extramedullary hematopoiesis (EMH) is an important mechanism for the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissues, and thus contributes to disease progression. Icaritin, a prenylflavonoid derivative from plants of the

Topics: Animals; Antineoplastic Agents, Phytogenic; Biomarkers; Carcinoma, Hepatocellular; Cell Line, Tumor; Disease Models, Animal; Fetal Blood; Flavonoids; Humans; Immunomodulation; Immunophenotyping; Kaplan-Meier Estimate; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Mice; Myeloid-Derived Suppressor Cells; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Animals; Astrocytes; Cells, Cultured; Disease Models, Animal; Flavonoids; Humans; Lipopolysaccharides; Mesencephalon; Mice; Neuroinflammatory Diseases; Primary Cell Culture; Receptor, IGF Type 1; Signal Transduction

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Depression is a chronic, severe, and often life-threatening disease accompanied with impaired neurogenesis. Evidence showed that neuroinflammation played a key role in the process of depression. High mobility group protein box 1 (HMGB1) has been proved to function as a pro-inflammatory cytokine. In this study, we used a social defeat (SD) stress to induce inflammatory response, aiming to explore the relationship between HMGB1 and neuroinflammation. We found that the expression of HMGB1 decreased in mice exposure to SD stress, but showed a high expression of cytoplasmic HMGB1 and a high expression of RAGE, which could be rescued by ICA and ICT. So, we speculated that the translocation of HMGB1 from the nucleus to the cytoplasm might play an important role in neuroinflammatory process, and HMGB1-RAGE signaling was involved in this process. Furthermore, we also found that TLR4-XBP1s-ER stress related NF-κB signaling activation was also involved in HMGB1-related neuroinflammation. However, ICA and ICT treatment activated NF-κB signaling, and we also observed the translocation of HMGB1 into the nucleus and the increased number of neurons in mice hippocampus, indicating that the activation of NF-κB signaling might be related to neuroregeneration. Moreover, recombinant human HMGB1 protein (rHMGB1) pretreatment could suppress HMGB1-RAGE signaling and TLR4-XBP1s-ER stress related NF-κB signaling, resulted in a suppressed microglia activation in mice hippocampus. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and show neuroprotective effects via activating TLR4- NF-κB signaling at the same time, resulting in improving depressive behaviors in mice.

Topics: Animals; Anti-Inflammatory Agents; Behavior, Animal; Cytokines; Disease Models, Animal; Flavonoids; Hippocampus; HMGB1 Protein; Male; Mice, Inbred C57BL; Neuroprotective Agents; NF-kappa B; Receptor for Advanced Glycation End Products; Signal Transduction; Stress, Psychological

Prostate cancer (PCa) is one of the most common health-related issues in the male individuals of western countries. Icaritin (ICT) is a traditional Chinese herbal medicine that exhibits antitumor efficacy in variety of cancers including PCa. However, the precise function and detailed molecular mechanism of ICT in the regression of PCa remain unclear. Ubiquitin-conjugating enzyme E2C (UBE2C) is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin conjugating enzyme, which acts as an oncogene in PCa progression. The function of ICT in PCa was investigated in transgenic adenocarcinoma mouse prostate (TRAMP) mice using survival analysis, hematoxylin and eosin (HE) staining, TUNEL assay, and immunohistochemistry and in human PCa cell lines using various molecular techniques and functional assays including plasmid construction and transfection. Bioinformatic analyses were performed to identify the interaction between miRNA and UBE2C via the TargetScan algorithm. We demonstrated that ICT inhibited the development and progression of PCa in TRAMP mice by improving the survival rate and tumor differentiation. Furthermore, we found that ICT could significantly inhibit cell proliferation and invasion and induce apoptosis in PCa cells. Consistently, downregulation of UBE2C suppressed the proliferation and invasion of PCa cells. Moreover, a luciferase reporter assay confirmed that UBE2C was a direct target of miR-381-3p. Meanwhile, ICT simultaneously downregulated UBE2C expression and upregulated miR-381-3p levels in human PCa cells. Altogether, our findings provide a strong rationale for the clinical application of ICT as a potential oncotherapeutic agent against PCa via a novel molecular mechanism of regulating the miR-381-3p/UBE2C pathway.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Flavonoids; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Male; MicroRNAs; Prostatic Neoplasms; RNA Interference; Ubiquitin-Conjugating Enzymes; Xenograft Model Antitumor Assays

Inflammation is a defensive response of the body and is at the center of many diseases' process like depression. High mobility group protein box 1 (HMGB1), has been proved to function as a pro-inflammatory cytokine. We aim to explore the role of HMGB1 played in the neuroinflammation here. In this study, we used LPS to induce an acute inflammatory response, and to measure the anti-neuroinflammation effect of icariin (ICA) and icaritin (ICT). We found that LPS could increase the expression of HMGB1 in serum and hippocampus, along with a high expression of HMGB1 in the cytoplasm and a high expression of RAGE, which could be rescued by ICA and ICT, and ethyl pyruvate (EP) pretreatment showed similar effects here. We speculated that the translocation of HMGB1 from the nucleus to the cytoplasm played an important role in neuroinflammatory process, and HMGB1-RAGE signal was involved in this process. Furthermore, we found that ICA and ICT treatment activated TLR4-XBP1s related NF-κB signal, which we thought was relevant with the neuroprotective effect of ICA and ICT. However, EP pretreatment suppressed TLR4-XBP1s- endoplasmic reticulum stress related NF-κB signal to anti-inflammatory response, which was almost absolutely opposite with ICA and ICT treatment. We speculated that it might be caused by the duration of inflammation. We supposed that ICA and ICT could ameliorate neuroinflammation in hippocampus via suppressing HMGB1-RAGE signaling and might show a neuroprotective effect via activating TLR4-XBP1s related NF-κB signal at the same time, making it possible to act as an anti-neuroinflammatory drugs.

Topics: Animals; Anti-Inflammatory Agents; Disease Models, Animal; Flavonoids; Hippocampus; HMGB1 Protein; Inflammation; Interleukin-10; Lipopolysaccharides; Male; Mice, Inbred C57BL; Neuroprotective Agents; Receptor for Advanced Glycation End Products; Tumor Necrosis Factor-alpha

Icaritin, a traditional Chinese medicine, possesses antitumor activity. The current study aimed to investigate icaritin effect and potential mechanism on oral squamous cell carcinoma (OSCC) development. OSCC cells proliferation, apoptosis, and autophagy were analyzed after incubation with icaritin at different concentrations and incubation times. The expressions of proteins related to proliferation, apoptosis, and autophagy, as well as signal transducer and activator of transcription 3 (STAT3) signal network, were also evaluated by western blot. Furthermore, STAT3 was knocked down by siRNA transfection to determine STAT3 role in OSCC cell proliferation and apoptosis. An oral specific carcinogenesis mouse model was used to explore icaritin effect on OSCC in vivo. Icaritin significantly inhibited OSCC proliferation in vitro and reduced the expression of both the cell-cycle progression proteins cyclin A2 and cyclin D1. Besides, icaritin increased cleaved caspase 3 and cleaved poly-(ADP-ribose) polymerase expression leading to apoptosis, and it activated autophagy. Icaritin significantly inhibited the expression of phospho-STAT3 (p-STAT3) in a dose- and time-dependent manner. In the in vivo experiment, the number of malignant tumors in the icaritin-treated group was significantly lower than the control. Overall, icaritin suppressed proliferation, promoted apoptosis and autophagy, and inhibited STAT3 signaling in OSCC in vitro and in vivo. In conclusion, icaritin might be a potential therapeutic agent against OSCC development.

Topics: Animals; Apoptosis; Autophagy; Blotting, Western; Carcinoma, Squamous Cell; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclins; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Flavonoids; Humans; Mice, Inbred C57BL; Mouth Neoplasms; Phosphorylation; Poly(ADP-ribose) Polymerases; RNA Interference; Signal Transduction; STAT3 Transcription Factor; Time Factors

Counteracting muscle atrophy induced by mechanical unloading/inactivity is of great clinical need and challenge. A therapeutic agent that could counteract muscle atrophy following mechanical unloading in safety is desired. This study showed that natural product Icaritin (ICT) could increase the phosphorylation level of Phosphatidylinositol 3 kinase (PI3K) at p110 catalytic subunit and promote PI3K/Akt signaling markers in C2C12 cells. This study further showed that the high dose ICT treatment could significantly attenuate the decreases in the phosphorylation level of PI3K at p110 catalytic subunit and its downstream markers related to protein synthesis, and inhibit the increases in protein degradation markers at mRNA and protein levels in rat soleus muscle following 28-day hindlimb unloading. In addition, the decreases in soleus muscle mass, muscle fiber cross-sectional area, twitch force, specific force, contraction time and half relaxation time could be significantly attenuated by the high dose ICT treatment. The low dose ICT treatment could moderately attenuate the above changes induced by unloading. Wortmannin, a specific inhibitor of PI3K at p110 catalytic subunit, could abolish the above effects of ICT in vitro and in vivo, indicating that PI3K/Akt signaling could be required by ICT to counteract skeletal muscle atrophy following mechanical unloading.

Topics: Animals; Biomarkers; Cell Line; Disease Models, Animal; Flavonoids; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Organ Size; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Biosynthesis; Protein Subunits; Proteolysis; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

We aimed to investigate whether icaritin (ICT) would inhibit serum proinflammatory cytokines and postpone prostate cancer (PCa) development and progression in both normal diet and high-fat diet (HFD) transgenic adenocarcinoma mouse prostate (TRAMP) mice.. TRAMP mice were randomly divided into four groups: normal diet with/without ICT group and HFD with/without ICT group. Each TRAMP mouse received intraperitoneal injection of ICT solution at the dose of 30 mg/kg 5 times per week.. ICT treatment could significantly increase the survival when compared with those in normal diet group (P = 0.015, log-rank test) and HFD group (P = 0.009, log-rank test). Proinflammatory cytokine levels, including IL-1α, IL-1β, IL-6, and TNF-α, were decreased more or less in ICT-treated TRAMP mice. Moreover, significant higher inflammation scores were detected in normal diet group and HFD group compared with their relevant ICT treatment groups (P = 0.026 and P = 0.006, respectively). Meanwhile, the incidences of well-differentiated tumor tissue in two ICT treatment groups (39.13 and 31.82 %) were moderately higher than control groups (29.41 and 20.00 %, respectively), though no significant difference was observed.. Taken together, our findings indicate that ICT could inhibit the development and progression of PCa in TRAMP mice via inhibiting proinflammatory cytokines.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cytokines; Diet, High-Fat; Disease Models, Animal; Disease Progression; Flavonoids; Inflammation; Male; Mice; Mice, Transgenic; Prostatic Neoplasms; Signal Transduction

Icaritin, an intestinal metabolite of prenylflavonoids from Herba Epimedii, has been known to regulate many cellular processes. The purpose of this study was to investigate the protective effects of icaritin on inflammation in lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages in vitro and zymosan induced peritonitis model in vivo. The release of Nitric oxide (NO) was measured by a Griess reagent system. The phagocytosis, the expression of CD69, the production of inflammatory cytokines and the leukocytes numbers were determined by flow cytometry. The Ca(2+) influx was recorded by confocal microscopy. The phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) was determined by Western blot. The results showed that icaritin significantly inhibited the NO, IL-6, IL-10 TNF-α, and MCP-1 production both in vitro and in vivo. Icaritin efficiently diminished the uptake of nonopsonized pHrodo™-labeled Escherichia coli bacteria on the LPS-stimulated macrophages. In addition, icaritin significantly inhibited the expression of CD69 on CD11b(+) macrophages. Icaritin pretreatment significantly inhibited the elevation of intracellular Ca(2+) induced by LPS. Furthermore, icaritin markedly decreased phospho-p38 and JNK protein expression in LPS-stimulated mouse peritoneal macrophages. In vivo study, it was also observed that icaritin prolonged survival of peritonitis mice, and inhibited massive leukocyte influx into the peritoneal cavity. These results suggest that icaritin possesses significant anti-inflammatory effects that may be mediated through the regulation of inflammatory cytokines and phosphorylation of p38 and JNK.

Topics: Animals; Anti-Inflammatory Agents; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Calcium; Cell Survival; Cells, Cultured; Disease Models, Animal; Female; Flavonoids; Lectins, C-Type; Leukocyte Count; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases; Nitric Oxide; Peritonitis; Phagocytosis

Icariin is a major constituent of flavonoids isolated from Herba Epimedii. Several previous studies have demonstrated the antidepressant-like effects of icariin. After oral administration of icariin, 19 metabolites of icariin were detected in rat plasma. Icaritin is one such of metabolite of icariin. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the effects of icaritin administration on social avoidance are investigated. The data indicates that icaritin (5mg/kg and 10mg/kg) oral administration opposes the development of social aversion after defeat stress. In vitro corticosterone sensitivity assay demonstrated that icaritin partially restored social defeat-induced impairment of glucocorticoid sensitivity. The expressions of GR mRNA and BDNFmRNA in the hippocampus were increased after icaritin treatment. Meanwhile, the social defeat-induced increases in CRH mRNA in hypothalamus were restored by icaritin administration. Our data also suggests that icaritin administration remarkably attenuated the increases in serum IL-6 and TNF-α level that occur following exposure to social defeat. In conclusion, icaritin is a novel antidepressant. It partially restored social defeat-induced impairment of glucocorticoid sensitivity, HPA axis hyperactivity. These effects are at least partially attributed to normalization of the GR function and increases in BDNF expression.

Topics: Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Flavonoids; Hypothalamus; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Receptors, Glucocorticoid; RNA, Messenger; Social Dominance; Stress, Psychological; Tumor Necrosis Factor-alpha

This study was designed to develop a bioactive scaffold to enhance bone defect repair in steroid-associated osteonecrosis (SAON). Icaritin, a metabolite of the herb Epimedium, has been identified as an angiogenic and osteogenic phytomolecule. Icaritin was homogenized into poly lactic-co-glycolic acid/tricalcium phosphate (PLGA/TCP) to form an icaritin-releasing porous composite scaffold (PLGA/TCP/icaritin) by fine-spinning technology. In vitro, high performance liquid chromatography was used to determine the release of icaritin during degradation of PLGA/TCP/icaritin. The osteogenic effects of PLGA/TCP/icaritin were evaluated using rat bone marrow mesenchymal stem cells (BMSCs). In vivo, the osteogenic effect of PLGA/TCP/icaritin was determined within a bone tunnel after core decompression in SAON rabbits and angiography within scaffolds was examined in rabbit muscle pouch model. In vitro study confirmed the sustainable release of icaritin from PLGA/TCP/icaritin with the bioactive scaffold promoting the proliferation and osteoblastic differentiation of rat BMSCs. In vivo study showed that PLGA/TCP/icaritin significantly promoted new bone formation within the bone defect after core decompression in SAON rabbits and enhanced neovascularization in the rabbit muscle pouch experiment. In conclusion, PLGA/TCP/icaritin is an innovative local delivery system that demonstrates sustainable release of osteogenic phytomolecule icaritin enhancing bone repair in an SAON rabbit model. The supplement of scaffold materials with bioactive phytomolecule(s) might improve treatment efficiency in challenging orthopedic conditions.

Topics: Animals; Bone Marrow Cells; Calcium Phosphates; Cells, Cultured; Disease Models, Animal; Femoral Fractures; Flavonoids; Fracture Healing; Lactic Acid; Male; Neovascularization, Physiologic; Osteogenesis; Osteonecrosis; Phytoestrogens; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rabbits; Rats; Tissue Engineering; Tissue Scaffolds