Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression.

Pro-inflammatory cytokine production by the retinal pigment epithelium (RPE) is a key etiology in retinal degenerative diseases, yet the underlying mechanisms are not well understood. TMEM97 is a scarcely studied transmembrane protein recently implicated in retinal degeneration. BAH domain coiled coil 1 (BAHCC1) is a newly discovered histone code reader involved in oncogenesis. A role for TMEM97 and BAHCC1 in RPE inflammation was not known. Here we found that they constitute a novel axis regulating pro-inflammatory cytokine expression in RPE cells. Transcriptomic analysis using a TMEM97-/- ARPE19 human cell line and the validation via TMEM97 loss- and gain-of-function revealed a profound role of TMEM97 in promoting the expression of pro-inflammatory cytokines, notably IL1ß and CCL2, and unexpectedly BAHCC1 as well. Moreover, co-immunoprecipitation indicated an association between the TMEM97 and BAHCC1 proteins. While TMEM97 ablation decreased and its overexpression increased NFκB (p50, p52, p65), the master transcription factor for pro-inflammatory cytokines, silencing BAHCC1 down-regulated NFκB and downstream pro-inflammatory cytokines. Furthermore, in an RPE-damage retinal degeneration mouse model, immunofluorescence illustrated down-regulation of IL1ß and CCL2 total proteins and suppression of glial activation in the retina of Tmem97-/- mice compared to Tmem97+/+ mice. Thus, TMEM97 is a novel determinant of pro-inflammatory cytokine expression acting via a previously unknown TMEM97- > BAHCC1- > NFκB cascade. SYNOPSIS: Retinal pigment epithelium (RPE) inflammation can lead to blindness. We identify here a previously uncharacterized cascade that underlies RPE cell production of pro-inflammatory cytokines. Specifically, transmembrane protein TMEM97 positively regulates the recently discovered histone code reader BAHCC1, which in turn enhances pro-inflammatory cytokine expression via the transcription factor NFκB.

Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Serum YKL-40 in coronary heart disease: linkage with inflammatory cytokines, artery stenosis, and optimal cut-off value for estimating major adverse cardiovascular events.

Objective: YKL-40, previously known as chitinase-3-like protein 1 (CHI3L1), is an inflammation-related glycoprotein that promotes atherosclerosis, but its application and optimal cut-off value as a prognostic biomarker in coronary heart disease (CHD) require more clinical evidence. Thus, this prospective study aimed to evaluate the linkage of serum YKL-40 with disease features, inflammatory cytokines, and major adverse cardiovascular events (MACEs) in CHD patients. Methods: A total of 410 CHD patients were enrolled for serum YKL-40 determination via enzyme-linked immunosorbent assay. Meanwhile, serum YKL-40 levels in 100 healthy controls (HCs) were also quantified. Results: YKL-40 level was higher in CHD patients compared with that in HCs (P < 0.001). YKL-40 was positively linked with hyperlipidemia (P = 0.014), diabetes mellitus (P = 0.001), fasting blood glucose (P = 0.045), C-reactive protein (P < 0.001), the Gensini score (P < 0.001), and stenosis degree (graded by the Gensini score) (P < 0.001) in CHD patients. In addition, an elevated YKL-40 level was associated with increased levels of tumor necrosis factor alpha (P = 0.001), interleukin (IL)-1ß (P = 0.001), IL-6 (P < 0.001), and IL-17A (P = 0.002) in CHD patients. The 1-/2-/3-year cumulative MACE rates of CHD patients were 5.5%, 14.4%, and 25.0%, respectively. Regarding the prognostic capability, YKL-40 ≥100 ng/ml (the median cut-off value) (P = 0.003) and YKL-40 ≥150 ng/ml (the third interquartile cut-off value) (P = 0.021) reflected an elevated accumulating MACE rate, whereas accumulating MACE was not different between CHD patients with YKL-40 ≥80 and <80 ng/ml (the first interquartile cut-off value) (P = 0.083). Conclusion: Serum YKL-40 is positively linked with inflammatory cytokines and the Gensini score, whose high expression cut-off by 100 and 150 ng/ml estimates a higher MACE risk in CHD patients.

Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer.

Prostate cancer (PCa) seriously threatens male health, and targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been verified to reduce PCa burden, while the research progress on the DYRK2 inhibitors was relatively slow. In this work, we discovered DYRK2 inhibitor 12 (IC50 = 9681 nM) through virtual screening. Subsequently, we performed systematic structural optimization to obtain 54 (IC50 = 14 nM). Compound 54 exhibited high selectivity among 215 kinases and significantly suppressed the proliferation and metastasis of PCa cells in vitro. Moreover, compound 54 displayed high safety, favorable bioavailability, and potent tumor growth inhibitory activity in vivo, which could be used as a potential candidate in the discovery of novel anti-PCa drugs.

X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.

Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.

Discovery of diaminotriazine carboxamides as potent inhibitors of hematopoetic progenitor kinase 1.

Hematopoietic progenitor kinase 1 (HPK1), a member of mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of Ste20 serine/threonine kinases, is a negative regulator of T-cell receptor (TCR) signaling. Inactivating HPK1 kinase has been reported to be sufficient to elicit antitumor immune response. Therefore, HPK1 has attracted much attention as a promising target for tumor immunotherapy. A few of HPK1 inhibitors have been reported, and none of them have been approved for clinical applications. Hence, more effective HPK1 inhibitors are needed. Herein, a series of structurally novel diaminotriazine carboxamides were rationally designed, synthesized and evaluated for their inhibitory activity against HPK1 kinase. Most of them exhibited potent inhibitory potency against HPK1 kinase. In particular, compound 15b showed more robust HPK1 inhibitory activity than that of 11d developed by Merck in kinase activity assay (IC50 = 3.1 and 8.2 nM, respectively). The significant inhibitory potency against SLP76 phosphorylation in Jurkat T cells further confirmed the efficacy of compound 15b. In human peripheral blood mononuclear cell (PBMC) functional assays, compound 15b more significantly induced the production of interleukin 2 (IL-2) and interferon γ (IFN-γ) relative to 11d. Furthermore, 15b alone or in combination with anti-PD-1 antibodies showed potent in vivo antitumor efficacy in MC38 tumor-bearing mice. Compound 15b represents a promising lead for the development of effective HPK1 small-molecule inhibitors.

Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC.

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

Nickel-Catalyzed Amidation of Aryl Alkynyl Acids with Tetraalkylthiuram Disulfides: A Facile Synthesis of Aryl Alkynyl Amides.

Nickel-catalyzed amidation of aryl alkynyl acids using tetraalkylthiuram disulfides as the amine source is described, affording a series of aryl alkynyl amides in good to excellent yields under mild conditions. This general methodology provides an alternative pathway for the synthesis of useful aryl alkynyl amides in an operationally simple manner, which shows its practical synthetic value in organic synthesis. The mechanism of this transformation was explored through control experiments and DFT calculations.

Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.

Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.

Dendrobium officinale polysaccharide-induced neuron-like cells from bone marrow mesenchymal stem cells improve neuronal function a rat stroke model.

Various methods have been used to induce the neuronal differentiation of marrow mesenchymal stem cells (MSCs). However, the limited induction efficiency of cells in vitro has restricted their use. Therefore, identifying a simple and efficient treatment method is necessary. Dendrobium officinale is an important traditional Chinese medicine, and its main component, polysaccharides, has many pharmacological activities. However, the effects of D. officinale polysaccharide (DOP) on the neuronal differentiation of bone marrow mesenchymal stem cells (BMSCs) and treatment of ischaemic stroke remain unknown. We found that DOP promoted the neuronal differentiation of BMSCs by increasing the expression levels of neural markers, and the optimal concentration of DOP was 25 µg/mL. Additionally, the Notch signalling pathway was inhibited during the neuronal differentiation of BMSCs induced by DOP, and this effect was strengthened using an inhibitor of this pathway. The Wnt signalling pathway was activated during the differentiation of BMSCs, and inhibition of the Wnt signalling pathway downregulated the expression of neuronal genes. Furthermore, the transplantation of neuron-like cells induced by DOP improved neuronal recovery, as the brain infarct volume, neurologic severity scores and levels of inflammatory factors were all significantly reduced in vivo. In conclusion, DOP is an effective inducer of the neuronal differentiation of BMSCs and treatment option for ischaemic stroke.

Modified axial computed tomography classification of cervical ossification of the posterior longitudinal ligament: selecting the optimal operating procedure and enhancing the accuracy of prognosis.

BACKGROUND: Cervical ossification of the posterior longitudinal ligament (OPLL) causes spinal cord compression, which can lead to myelopathy or radiculopathy. Non-surgical treatments have little effect on this condition. Current OPLL classification systems offer little guidance on the selection of an appropriate operating procedure. In this study, we developed a modified axial computed tomography classification (MACTC) scheme. We then examined the usefulness of the MACTC scheme and two other existing classification schemes in guiding OPLL operation choice. METHODS: Following screening in which a defined exclusion criteria was used, a total of 91 patients with OPLL participated in the study. Patients' follow-up data for at least 2 years were obtained. The recovery rate of the Japanese Orthopaedic Association (JOA) scores was compared to two other classification schemes. RESULTS: According to the MACTC, central-sharp-type OPLL had a lower recovery rate of the JOA score than that of central-gentle-type OPLL (36.05±32.38 vs. 83.90±23.52, P≤0.05). The recovery rate of the JOA scores in the ipsilateral open-door OPLL group was significantly lower than that in the contralateral group of the lateral-steep type (36.67±41.5 vs. 88.89±17.21, P=0.04), but not of that in the lateral-gentle type. There was no significant difference in the recovery rates of the JOA scores between groups when using either existing classification scheme (P>0.05). CONCLUSIONS: The MACTC scheme can assist surgeons to choose the most appropriate operating procedure, and provide an accurate prognosis. If operations on central-sharp-type OPLL are not performed using both the posterior and anterior approaches, prognosis will be poor. The contralateral side should be the first choice for door opening in laminoplasty, especially for patients with lateral-steep-type OPLL. Severe OPLL may not be an absolute contraindication for the posterior approach.

Interleukin-17A promotes the differentiation of bone marrow mesenchymal stem cells into neuronal cells.

Ischemia or hemorrhagic stroke is one of the leading causes of death and permanent disability in the worldwide population. As a consequence of the potential increasing in stroke, stem cell therapy is currently an area of intense focus. However, there are less data available regarding the promotion of healing efficacy after stroke. The present study aimed to investigate whether the cytokine interleukin-17A (IL-17A) could have a role in promoting the neuronal differentiation of mesenchymal stem cells (MSCs) and to investigate the associated molecular mechanism. Firstly, different concentration of IL-17A at range from 5-40 ng/mL was applied to stimulate bone marrow MSCs (BMSCs) during the course of neurogenic differentiation. Then reverse transcription-PCR, histological analyses and immunofluorescence assays were used to determine the optimum concentration of IL-17A in promoting the neuronal differentiation of BMSCs, which was 20 ng/mL. Mechanistically, Wnt signaling pathway was activated and Notch signaling pathway was suppressed. In addition, there were antergic effect of these two signaling pathways modulating the neurogenic differentiation of BMSCs induced by IL-17A. The present study demonstrated the potential role of IL-17A-based BMSCs strategy for promoting neuronal differentiation in vitro. However, the treatment efficacy could be considerably confirmed in animals with ischemia stroke. Therefore, a more sophisticated strategy that addresses the complicated treatment associated with stroke is needed.

BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.

The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation. Cholesterol deprivation was induced in ARPE19 cells using a blocker of lysosomal cholesterol export. This condition up-regulated S2R mRNA and protein, and also SREBP2 but not SREBP1, both transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD3 or BRD4 (though widely deemed a master regulator) averted S2R up-regulation that was induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, endogenous BRD2 co-immunoprecipitated with the transcription-active N-terminal half of SREBP2, and chromatin immunoprecipitation-qPCR signified co-occupancy of BRD2, H3K27ac (histone acetylation), and SREBP2Nterm at the S2R gene promoter. In summary, this study reveals a previously unrecognized BRD2/SREBP2 cooperative regulation of S2R transcription, thus shedding new light on signaling in response to cholesterol deprivation.

Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity.

Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.

Comparison of the differentiation of dental pulp stem cells and periodontal ligament stem cells into neuron-like cells and their effects on focal cerebral ischemia.

Recent studies have reported an increasing incidence of ischemic stroke, particularly in younger age groups. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are the most common stem cells acquired from the teeth of adults, even elderly people. However, there are no detailed reports on whether DPSCs or PDLSCs are suitable for the treatment of ischemic stroke. In this study, the in vitro differentiation of DPSCs and PDLSCs into neuron-like cells was evaluated. Then, we established a rat model of cerebral ischemia. DPSCs or PDLSCs were administered to animals, and the therapeutic effects of these two types of cells were investigated. The results showed that PDLSCs had a higher differentiation rate than DPSCs. Immunofluorescence studies showed that the expression of the neuronal differentiation marker Thy-1 was higher in PDLSCs than in DPSCs, and other gene markers of neuronal differentiation showed corresponding trends, which were confirmed by western blot analysis. In this process, the Notch and Wnt signaling pathways were inhibited and activated, respectively. Finally, rats with transient occlusion of the right middle cerebral artery were used as a model to assess the therapeutic effect of PDLSCs and DPSCs on ischemia. The results showed that rats in the PDLSC-treated group emitted significantly greater red fluorescence signal than the DPSC-treated group. PDLSC transplantation promoted the recovery of neurological function more effectively than DPSC transplantation. Hence, PDLSCs represent an autogenous source of adult mesenchymal stem cells with desirable biological properties and may be an ideal candidate for clinical applications.

Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA-424 in osteosarcoma.

BACKGROUND: This study aimed to evaluate the association of circular RNA La-related RNA-binding protein 4 (circ-LARP4) with clinical features and prognosis in osteosarcoma patients, and further explore its effect on chemosensitivity in osteosarcoma cells. METHODS: Seventy-two osteosarcoma patients with Enneking stage IIA-IIB who underwent resection were consecutively enrolled, and then, tumor tissues and non-tumor tissues were obtained. Circ-LARP4 in tumor tissue/non-tumor tissue was detected by quantitative polymerase chain reaction. After circ-LARP4 overexpression and negative control overexpression plasmid transfection, relative cell viability (%) was evaluated by Cell Counting Kit-8 in MG63 cells treated by different concentrations of cisplatin, methotrexate, and doxorubicin, and IC50 was calculated. RESULTS: Circ-LARP4 was downregulated in tumor tissue compared with non-tumor tissue and had a good value in distinguishing tumor tissue from non-tumor tissue with an area under curve of 0.829 (95% CI: 0.762-0.859). Meanwhile, tumor circ-LARP4 was negatively correlated with the Enneking stage. After resection, circ-LARP4 high expression patients showed an increased tumor cell necrosis rate to adjuvant chemotherapy compared to circ-LARP4 low expression patients, and circ-LARP4 high expression correlated with prolonged disease-free survival and overall survival. In vitro experiments revealed that circ-LARP4 overexpression elevated the chemosensitivity of MG63 cells to cisplatin and doxorubicin but not methotrexate, with decreased cisplatin IC50 and doxorubicin IC50 concentrations than negative control. Besides, miR-424 overexpression attenuated the chemosensitivity in circ-LARP4 overexpression-treated MG63 cells. CONCLUSION: Circ-LARP4 high expression correlates with decreased Enneking stage and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging miR-424 in osteosarcoma.

SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance.

Autophagosome-lysosome fusion is a common critical step in various forms of macroautophagy/autophagy including mitophagy, the selective degradation of mitochondria. Regulations of this fusion process remain poorly defined. Here we have determined the role of SIGMAR1, a unique endoplasmic reticulum membrane protein. Knockout of Sigmar1 impaired mitochondrial clearance without altering the PINK1-PRKN/Parkin signaling, in mouse retinal explants and cultured cells treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) for induction of mitophagy. SIGMAR1 depletion also caused accumulation of autophagosome markers LC3-II and SQSTM1, but did not change the levels of BECN1 and ATG7, proteins associated with autophagosome biogenesis. Lysosomal pH and protease activities were not negatively affected. However, sigmar1 knockout partially compromised autophagosome-lysosome fusion in CCCP-treated NSC34 cells, as revealed by reduced GFP fluorescence quenching of GFP-RFP-LC3-II puncta and co-localization of lysosomes with mitochondria. Furthermore, SIGMAR1 co-immunoprecipitated with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome-lysosome membrane fusion. Re-expressing SIGMAR1 in the null background rescued clearance of mitochondria and autophagosomes. In summary, we started out finding that sigmar1 knockout impaired the clearance of mitochondria and autophagosomes, and then narrowed down the SIGMAR1 modulation to the autophagosome-lysosome fusion step. This study may shed new light on understanding autophagy-associated cyto-protection and disease mechanisms. Abbreviations: APEX2, a genetically engineered peroxidase; BiFC, bimolecule fluorescence complementation; CCCP, a mitophagy inducing compound; CRISPR, clustered regularly interspaced short palindromic repeats; EM, electron microscopy; ER, endoplasmic reticulum; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; SIGMAR1, sigma non-opioid intracellular receptor 1.

A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells.

BACKGROUND: The 90-kDa heat shock protein HSP90AA1 is critical for the stability of several proteins that are important for tumor progression and thus, is a promising target for cancer therapy. Selenosemicarbazone metal complexes have been shown to possess anticancer activity through an unknown molecular mechanism. METHODS: The MTT assay, fluorescence-activated cell sorting, and fluorescent microscopy were used to analyze the mechanism of the anti-cancer activity of the selenosemicarbazone metal complexes. Additionally, RNA-seq was applied to identify transcriptional gene changes, and in turn, the signaling pathways involved in the process of 2-24a/Cu-induced cell death. Last, the expression of HSP90AA1, HSPA1A, PIM1, and AKT proteins in 2-24a/Cu-treated cells were investigated by western blot analysis. RESULTS: A novel selenosemicarbazone copper complex (2-24a/Cu) efficiently induced G2/M arrest and was cytotoxic in cancer cells. 2-24a/Cu significantly induced oxidative stress in cancer cells. Interestingly, although RNA-seq revealed that the transcription of HSP90AA1 was increased in 2-24a/Cu-treated cells, western blotting showed that the expression of HSP90AA1 protein was significantly decreased in these cells. Furthermore, down-regulation of HSP90AA1 led to the degradation of its client proteins (PIM1 and AKT1), which are also cancer therapy targets. CONCLUSION: Our results showed that 2-24a/Cu efficiently generates oxidative stress and down-regulates HSP90AA1 and its client proteins (PIM1, AKT1) in U2os and HeLa cells. These results demonstrate the potential application of this novel copper complex in cancer therapy.

Monitoring dynamic reactions of red blood cells to UHF electromagnetic waves radiation using a novel micro-imaging technology.

Multiple state-of-the-art techniques, such as multi-dimensional micro-imaging, fast multi-channel micro-spetrophotometry, and dynamic micro-imaging analysis, were used to dynamically investigate various effects of cell under the 900 MHz electromagnetic radiation. Cell changes in shape, size, and parameters of Hb absorption spectrum under different power density electromagnetic waves radiation were presented in this article. Experimental results indicated that the isolated human red blood cells (RBCs) do not have obviously real-time responses to the ultra-low density (15 µW/cm(2), 31 µW/cm(2)) electromagnetic wave radiation when the radiation time is not more than 30 min; however, the cells do have significant reactions in shape, size, and the like, to the electromagnetic waves radiation with power densities of 1 mW/cm(2) and 5 mW/cm(2). The data also reveal the possible influences and statistical relationships among living human cell functions, radiation amount, and exposure time with high-frequency electromagnetic waves. The results of this study may be significant on protection of human being and other living organisms against possible radiation affections of the high-frequency electromagnetic waves.

A novel model of intimal hyperplasia with graded hypoosmotic damage.

BACKGROUND: The purpose was to develop a rabbit model of intimal hyperplasia with controllable lesion. METHODS: Following 1 week of a 2% cholesterol diet, 32 New Zealand White male rabbits underwent right femoral arteries surgical perfusion with distilled water for 1, 3, 5, or 7 min (n=8/group). After a further 4 weeks of the same diet, serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein were measured in all rabbits. Intimal hyperplasia in histological sections of arteries were assessed by intimal proliferation ratio. Macrophage numbers and levels of proteins matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 2, and alpha smooth muscle actin in lesions were analyzed by immunohistochemistry. RESULTS: Serum lipids levels showed no statistical difference between experimental groups. Intimal proliferation ratio increased gradually with perfusion time, and a positive linear correlation was calculated between intimal proliferation ratio and duration of distilled water perfusion. Similarly, number of macrophages and levels of matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 2, and alpha smooth muscle actin in lesions increased with perfusion time. CONCLUSIONS: A novel model of intimal hyperplasia was established by intravascular distilled water perfusion in high-cholesterol-fed rabbits. Importantly, this model exhibits time-dependent neointimal proliferation lesions that can be readily controlled in terms of extent, thus providing an avenue for further studies.