Intelligent, Flexible Artificial Throats with Sound Emitting, Detecting, and Recognizing Abilities.

In recent years, there has been a notable rise in the number of patients afflicted with laryngeal diseases, including cancer, trauma, and other ailments leading to voice loss. Currently, the market is witnessing a pressing demand for medical and healthcare products designed to assist individuals with voice defects, prompting the invention of the artificial throat (AT). This user-friendly device eliminates the need for complex procedures like phonation reconstruction surgery. Therefore, in this review, we will initially give a careful introduction to the intelligent AT, which can act not only as a sound sensor but also as a thin-film sound emitter. Then, the sensing principle to detect sound will be discussed carefully, including capacitive, piezoelectric, electromagnetic, and piezoresistive components employed in the realm of sound sensing. Following this, the development of thermoacoustic theory and different materials made of sound emitters will also be analyzed. After that, various algorithms utilized by the intelligent AT for speech pattern recognition will be reviewed, including some classical algorithms and neural network algorithms. Finally, the outlook, challenge, and conclusion of the intelligent AT will be stated. The intelligent AT presents clear advantages for patients with voice impairments, demonstrating significant social values.

Comparing the antibacterial activity of chitin nanocrystals with chitin: exploring the feasibility of chitin nanocrystals as novel pesticide nanocarriers in agriculture.

BACKGROUND: In recent years, nanomaterials-based pesticide carriers have garnered significant attention and sparked extensive research. However, most studies have primarily focused on investigating the impact of physical properties of nanomaterials, such as size and modifiable sites, on drug delivery efficiency of nano-pesticides. The limited exploration of biologically active nanomaterials poses a significant obstacle to the advancement and widespread adoption of nano-pesticides. In this study, we prepared chitin nanocrystals (ChNC) based on acid hydrolysis and systematically investigated the differences between nano- and normal chitin against plant bacteria (Pseudomonas syringae pv. tabaci). The primary objective was to seek out nanocarriers with heightened biological activity for the synthesis of nano-pesticides. RESULTS: Zeta potential analysis, Fourier Transform infrared spectrometry (FTIR), X-Ray diffraction (XRD), Atomic force microscopy (AFM) and Transmission electron microscopy (TEM) identified the successful synthesis of ChNC. ChNC showcased remarkable bactericidal activity at comparable concentrations, surpassing that of chitin, particularly in its ability to inhibit bacterial biofilm formation. Furthermore, ChNC displayed heightened effectiveness in disrupting bacterial cell membranes, resulting in the leakage of bacterial cell contents, structural DNA damage, and impairment of DNA replication. Lastly, potting experiments revealed that ChNC is notably more effective in inhibiting the spread and propagation of bacteria on plant leaves. CONCLUSION: ChNC exhibited higher antibacterial activity compared to chitin, enabling efficient control of plant bacterial diseases through enhanced interaction with bacteria. These findings offer compelling evidence of ChNC's superior bacterial inhibition capabilities, underscoring its potential as a promising nanocarrier for nano-pesticide research. © 2023 Society of Chemical Industry.

Constructing Active Cu2+-O-Fe3+ Sites at the CuO-Fe3O4 Interface to Promote Activation of Surface Lattice Oxygen.

Activating surface lattice oxygen (Olatt) through the modulation of metal-oxygen bond strength has proven to be an effective route for facilitating the catalytic degradation of volatile organic compounds (VOCs). Although this strategy has been implemented via the construction of the TM1-O-TM2 (TM represents a transition metal) structure in various reactions, the underlying principle requires exploration when using different TMs. Herein, the Cu2+-O-Fe3+ structure was created by developing CuO-Fe3O4 composites with enhanced interfacial effect, which exhibited superior catalytic activity to their counterparts, with T90 (the temperature of toluene conversion reaching 90%) decreasing by approximately 50 °C. Structural analyses and theoretical calculations demonstrated that the active Cu2+-O-Fe3+ sites at the CuO-Fe3O4 interface improved low-temperature reducibility and oxygen species activity. Particularly, X-ray absorption fine structure spectroscopy revealed the contraction and expansion of Cu-O and Fe-O bonds, respectively, which were responsible for the activation of the surface Olatt. A mechanistic study revealed that toluene can be oxidized by rapid dehydrogenation of methyl assisted by the highly active surface Olatt and subsequently undergo ring-opening and deep mineralization into CO2 following the Mars-van Krevelen mechanism. This study provided a novel strategy to explore interface-enhanced TM catalysts for efficient surface Olatt activation and VOCs abatement.

Washout-Resistant, pH-Responsive Anti-TMV Nanoimmune Inducer Based on Cellulose Nanocrystals.

The application of antiplant virus agents on leaf surfaces faces challenges due to their vulnerability to wear, instability, and limited duration, which in turn jeopardizes plant health and yield. In recent years, high-aspect-ratio nanomaterials have gained prominence as powerful carriers for disease treatment, thanks to their exceptional penetrability and precise drug delivery capabilities. Here, we synthesized a pH-responsive nanoimmune inducer (CNC-AMO) with strong leaf adhesion through a Schiff base reaction, achieved by grafting amino-oligosaccharides (AMOs) on the surface of aldehyde-based CNC (CNC-CHO). Fourier transform infrared spectrometry, zeta potential, X-ray photoelectron spectroscopy, X-ray diffraction, transmission electron microscopy, atomic force microscopy, scanning electron microscopy, thermogravimetric analysis, and elemental analysis were used to characterize the CNC-AMO. The CNC-AMO displayed the capability for pH-responsive AMO release, showcasing its potential for targeted and controlled delivery. When applied to plants, the CNC-AMO exhibited impressive anti-TMV efficacy during a weeklong observation period. Meanwhile, the CNC-AMO exhibited remarkable adhesion and scouring resistance on the surfaces of the plant leaves. We strongly believe that the synergy of environmentally friendly synthetic materials, efficient plant virus control, and streamlined scalability positions CNC-AMOs as a promising pesticide for plant virus therapy.

Synthesis of chitin nanocrystals supported Zn2+ with high activity against tobacco mosaic virus.

Chitin is a kind of natural nitrogenous organic polysaccharide. It contains antibacterial and antiviral properties, and it can induce plant disease resistance and promote plant growth. However, its application is constrained due to its insolubility and intricate molecular structure. Tobacco mosaic disease is caused by tobacco mosaic virus (TMV) infection, which seriously harms tobacco production. Zinc-containing chemical agents are commonly used to control tobacco mosaic disease, but overuse of chemical agents will cause serious environmental pollution. In this study, a novel nanomaterial (ChNC@Zn) was prepared by using chitin nanocrystals loaded with Zn2+, which has the function of inducing disease resistance to plants and reducing virus activity. When the Zn2+ concentration of ChNC@Zn is 105.6 µg/mL, it shows higher resistance to TMV than Lentinan (LNT). ChNC@Zn can improve the enzymes activities of peroxidase (POD) and catalase (CAT) in tobacco, and reduce the damage of reactive oxygen species (ROS) caused by TMV infection, thereby inducing resistance to TMV in tobacco. Besides, it can promote the growth of tobacco. As a result, ChNC@Zn can exhibit strong antiviral activity at low Zn2+ concentration and minimize the pollution of Zn2+ to the environment, which has high potential application value in the control of virus disease.

(1R,3S)-THCCA-Asn: To show the discovery of selective inhibitor of thrombin by successfully combining virtual screening and biological assay.

Thrombin is the most potent platelet aggregator. To discover the selective inhibitor of thrombin that is important to curing platelet aggregation-related diseases, docking experiments were performed to dock (1R,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1R,3S)-THCCA], and (1S,3S)-2,3,4,9-tetrahydro-ß-carboline-3- carboxylic acid, [(1S,3S)-THCCA], into the p pocket of bovine thrombin. The ideal match supported that (1R,3S)-THCCA could be used as a potential lead compound. In this case 20 natural amino acids were theoretically introduced into the 3-carboxyl of (1R,3S)-THCCA and 20 derivatives, (1R,3S)-THCCA-amino acids, were docked into p pocket of bovine thrombin to perform virtual screening. The screening revealed that comparing to (1R,3S)-THCCA itself the DockScores of 16 derivatives were higher, and (1R,3S)-THCCA-Asn (4j) got the highest DockScore. Thus, 16 derivatives were synthesized for experimental study. The in vitro anti-platelet aggregation assay showed that at 100 µM of concentration the 16 derivatives failed to inhibit the platelet aggregation induced by both adenosine diphosphate and arachidonic acid. On the other hand, however, the IC50 value of the 16 derivatives inhibiting the platelet aggregation induced by platelet activating factor and thrombin ranged from 9.44 µM to 194.64 µM and from 0.07 µM to 9.56 µM, respectively. The in vitro anti-platelet aggregation assay suggested that the 16 derivatives selectively inhibited the platelet aggregation induced by thrombin. In particular, the IC50 of (1R,3S)-THCCA-Asn (4j) had the lowest value. On rat model at 1 nmol/kg of dosage the 16 derivatives effectively prevented thrombus formation. It is worth pointing out that even at 0.01 nmol/kg of dosage, 4j still effectively prevented thrombus formation. 4j hardly has effects on the proliferation of mammalian cells and rat tail bleeding time. In conclusion, the combination of virtual screening and biological assays successfully lead to the discovery of 4j as a promising candidate of selective inhibitor of thrombin.

Exploring the action of RGDV-gemcitabine on tumor metastasis, tumor growth and possible action pathway.

The coupling of Arg-Gly-Asp-Val (RGDV) and gemcitabine led to a hypothesis that the conjugate (RGDV-gemcitabine) could inhibit tumor metastasis. To confirm this hypothesis the activities of RGDV-gemcitabine inhibiting tumor metastasis in vitro and in vivo were presented for the first time. AFM (atomic force microscopy) imaged that RGDV-gemcitabine was able to adhere onto the surface of serum-starved A549 cells, to block the extending of the pseudopodia. Thereby RGDV-gemcitabine was able to inhibit the invasion, migration and adhesion of serum-starved A549 cells in vitro. On C57BL/6 mouse model RGDV-gemcitabine dose dependently inhibited the metastasis of planted tumor towards the lung and the minimal dose was 0.084 µmol/kg/3 days. The decrease of serum TNF-α (tumor necrosis factor), IL-8 (interleukin-8), MMP-2 (matrix metalloprotein-2) and MMP-9 (matrix metalloprotein-9) of the treated C57BL/6 mice was correlated with the action pathway of RGDV-gemcitabine inhibiting the metastasis of the planted tumor towards lung.

Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo.

The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 µmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application.

Development of 13-Cys-BBR as an Agent Having Dual Action of Anti-Thrombosis and Anti-Inflammation.

BACKGROUND: There is a correlation between tumor and inflammation. The activity of 13-[CH2CO-Cys(Bzl)-OBzl]-berberine (13-Cys-BBR) slowing tumor growth is higher than that of BBR. Whether the anti-inflammation activity of 13-Cys-BBR is higher than that of BBR remains unknown. There is a correlation between thrombosis and inflammation. Whether 13-Cys-BBR is an inhibitor of thrombosis remains unknown. PURPOSE: The object of this investigation is to compare the activities of 13-Cys-BBR inhibiting thrombosis and inflammation to those of BBR. METHODS: In vivo anti-thrombosis assay was performed on rat model of arterial and venous thrombosis. In vivo anti-inflammation assay was performed on mouse model of xylene induced ear edema. RESULTS: At oral dose of 66.7 nmol/kg, 13-Cys-BBR, but not BBR, inhibited the rats to form both venous thrombus and arterial thrombus. At oral dose of 2 µmol/kg, 13-Cys-BBR, but not BBR, inhibited the ears of the mice to occur edema. CONCLUSION: The anti-venous thrombosis activity, anti-arterial thrombosis activity and anti-inflammation activity of 13-Cys-BBR were significantly higher than those of BBR. 13-Cys-BBR is a promising preclinical candidate.

Modifying ICCA with Trp-Phe-Phe to Enhance in vivo Activity and Form Nano-Medicine.

BACKGROUND: 1-(4-isopropylphenyl)-ß-carboline-3-carboxylic acid (ICCA) was modified by Trp-Phe-Phe to form 1-(4-isopropylphenyl)-ß-carboline-3-carbonyl-Trp-Phe-Phe (ICCA-WFF). PURPOSE: The object of preparing ICCA-WFF was to enhance the in vivo efficacy of ICCA, to explore the possible targeting action, and to visualize the nano-feature. METHODS: The advantages of ICCA-WFF over ICCA were demonstrated by a series of in vivo assays, such as anti-tumor assay, anti-arterial thrombosis assay, anti-venous thrombosis assay, P-selectin expression assay, and GPIIb/IIIa expression assay. The nano-features of ICCA-WFF were visualized by TEM, SEM and AFM images. The thrombus targeting and tumor-targeting actions were evidenced by FT-MS spectrum analysis. RESULTS: The minimal effective dose of ICCA-WFF slowing tumor growth and inhibiting thrombosis was 10-fold lower than that of ICCA. ICCA-WFF, but not ICCA, formed nano-particles capable of safe delivery in blood circulation. In vivo ICCA-WFF, but not ICCA, can target thrombus and tumor. In thrombus and tumor, ICCA-WFF released Trp-Phe-Phe and/or ICCA. CONCLUSION: Modifying ICCA with Trp-Phe-Phe successfully enhanced the anti-tumor activity, improved the anti-thrombotic action, formed nano-particles, targeted tumor tissue and thrombus, and provided an oligopeptide modification strategy for heterocyclic compounds.

13-[CH2CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein.

BACKGROUND: The discovery of novel derivative of berberine (BBR) having higher anti-tumor activity in vivo is of clinical importance. In this profile, 13-[CH2CO-Cys-(Bzl)-OBzl]-berberine (13-Cys-BBR) was prepared for related assays. PURPOSE: The object of preparation and evaluation is to show the advantages of 13-Cys-BBR over BBR in both in vitro and in vivo anti-tumor actions, furthermore to correlate the proliferation of cancer cells with ROS formation and anti-apoptosis protein (XIAP) expression inside cancer cells. METHODS: Transwell chamber was used to simulate the intestinal and cell wall for bioavailability evaluation; MTT assay was used to evaluate the in vitro anti-proliferation activity; fluorescein isothiocyanate content was used to represent ROS level in HCT-8 cells; Western blot assay was used to quantify the expression of XIAP, caspase-3, and poly ADP-ribose polymerase in HCT-8 cells; and S180 mouse model was used to evaluate the in vivo anti-tumor activity. RESULTS: In vitro the IC50 values (~15-40 µM) of 13-Cys-BBR against the proliferation of eight cancer cell lines were significantly lower than those of BBR (~25-140 µM); the content of ROS formed inside HCT-8 cells treated by 13-Cys-BBR was ~3.44-folds higher than that inside HCT-8 cells treated by BBR; the expression of XIAP in HCT-8 cells treated by 13-Cys-BBR was ~1.21-folds lower than that in HCT-8 cells treated by BBR; the tumor weight of S180 mice orally treated by 2 µmol/kg/day of 13-Cys-BBR (~1.5 g) was significantly lower than that of S180 mice orally treated by 2 µmol/kg/day of BBR (~2.5 g); and the active pocket of XIAP was more suitable for 13-Cys-BBR than for BBR. CONCLUSION: The anti-tumor action correlates with ROS and apoptosis protein, which suggests 13-Cys-BBR is a promising candidate for preclinical study.

RGDV-modified gemcitabine: a nano-medicine capable of prolonging half-life, overcoming resistance and eliminating bone marrow toxicity of gemcitabine.

BACKGROUND: Gemcitabine has been widely used as a chemotherapeutic drug. However, drug resistance, short half-life and side effects seriously decrease its chemotherapeutic efficacy. PURPOSE: The object of preparing RGDV-gemcitabine was to prolong the half-life, to overcome drug resistance and to eliminate bone marrow toxicity of gemcitabine. METHODS: Arg-Gly-Asp-Val was coupled with gemcitabine, forming 4-(Arg-Gly-Asp-Val-amino)-1-[3,3-difluoro-4-hydroxy-5-(hydroxylmethyl)oxo-lan-2-yl]pyrimidin-2-one (RGDV-gemcitabine) involving 9-step reactions. The advantages of RGDV-gemcitabine to gemcitabine were demonstrated by a series of assays, such as in vitro half-life assay, in vitro drug resistance assay, in vivo anti-tumor assay, in vivo kidney toxicity assay, in vivo liver toxicity assay and in vivo marrow toxicity assay. The nano-features of RGDV-gemcitabine were visualized by TEM, SEM and AFM images. The tumor-targeting action and release of RGDV-gemcitabine were evidenced by FT-MS spectra. RESULTS: Half-life and anti-tumor activity of RGDV-gemcitabine were 17-fold longer and 10-fold higher than that of gemcitabine, respectively. RGDV-gemcitabine, but not gemcitabine, showed no kidney toxicity, no liver toxicity, no marrow toxicity and no drug resistance. The advantages attributed to the nanofeatures of RGDV-gemcitabine were targeting tumor tissue and releasing gemcitabine in tumor tissue. CONCLUSION: RGDV-gemcitabine successively overcame the defects of gemcitabine and provided a practical strategy of nano-medicine.

Nano-scaled MTCA-KKV: for targeting thrombus, releasing pharmacophores, inhibiting thrombosis and dissolving blood clots in vivo.

BACKGROUND: In vitro (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxyl-Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (MTCA-KKV) adheres activated platelets, targets P-selectin and GPIIb/IIIa. This led to the development of MTCA-KKV as thrombus targeting nano-medicine. METHODS: MTCA-KKV was characterized by nano-feature, anti-thrombotic activity, thrombolytic activity, thrombus target and targeting release. RESULTS: In vivo 0.01 µmol/kg of MTCA-KKV formed nano-particles less than 100 nm in diameter, targeted thrombus, released anti-thrombotic and thrombolytic pharmacophores, prevented thrombosis and dissolved blood clots. CONCLUSION: Based on the profiles of targeting thrombus, targeting release, inhibiting thrombosis and dissolving blood clots MTCA-KKV is a promising nano-medicine.

BCESA: a nano-scaled intercalator capable of targeting tumor tissue and releasing anti-tumoral ß-carboline-3-carboxylic acid.

Background: In the discovery of DNA intercalators, ß-carbolines compose one member of the most interesting alkaloid family and are of clinical importance. In the efforts, N-(3-benzyloxycarbonyl-ß-carboline-1-yl)ethyl-Ser-Ala-OBzl (BCESA) was designed as a nano-scaled DNA intercalator without Dox-like toxicity. Methods: Based on the structural analysis and CDOCKER energy comparison, BCESA was rationally designed as such a nano-scaled intercalator. The anti-tumor activity, the toxicity and the tumor targeting action of BCESA were evaluated on mouse models. Results: The in vitro proliferation of cancer cells, but not non-cancer cells, was effectively inhibited by BCESA. On S180 mouse model BCESA dose-dependently slowed the tumor growth, and 0.01 µmol/kg/day was found as a minimal effective dose. Both BCESA and its moiety were found in the tumor tissue, but not in the organs and the blood, of S180 mice. Conclusion: BCESA should be a nano-scaled intercalator capable of targeting tumor tissue to release anti-tumoral ß-carboline-3-carboxylic acid and its 1-methyl derivative, while Ser-Ala-OBzl is a simple and desirable carrier.

Dimethyl 2,2'-[2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]-diacetate: a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect.

BACKGROUND: Due to the discovery that deep venous thrombosis (DVT) inhibitor is of chemotherapeutic importance, the nano-property of dimethyl 2,2'-[2,2'-(ethane-1,1-diyl) bis(1H-indole-3,2-diyl)]-diacetate (DEBIC), a recently reported antitumor agent, is worthy of characterization. MATERIALS AND METHODS: One-pot reaction was used to prepare DEBIC. Electrospray Ionization (+/-)-Fourier Transform-Ion Cyclotron Resonance-Mass Spectrometer (ESI(+/-)-FT-ICR-MS), quadrupole Collision Induced Dissociation (qCID) and nuclear overhauser effect spectroscopy spectra were used to present the assembly of DEBIC. Transmission electron microscopy, scanning electron microscopy, atomic force microscopy and Faraday-Tyndall effect were used to visualize the nano-property of DEBIC. Rat models were used to evaluate DVT inhibition and the bleeding reaction of DEBIC. RESULTS: One-pot reaction can provide DEBIC in acceptable yield and high purity. In water, rat plasma and lyophilized powders of DEBIC existed as particles of small nano-size. In vivo DEBIC inhibited DVT in a dose-dependent manner. The minimal effective dose of DEBIC was 1.7 µmol/kg. Even the dose of 36 µmol/kg/day DEBIC did not induce bleeding side effect in DVT rats like in warfarin (0.82 µmol/kg/day). CONCLUSION: DEBIC is a small molecule capable of nano-scale assembly, inhibiting venous thrombosis and inducing no bleeding side effect.

Discovery of DEBIC to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis.

Arterial thrombosis is one of the major complications of cancer and can seriously worsen the prognosis of the patients. These clinical findings encouraged this paper to correlate P-selectin inhibition and DNA intercalation in cancer therapy and complicated thrombosis. By designing and docking 12 derivatives of bisindole- 2-carboxylic acids into the active sites of P-selectin and d(CGATCG)2 9 derivatives were assigned to receive in vivo anti-tumor assay, and finally provided dimethyl 2,2'-[(2,2'-(ethane-1,1-diyl)bis(1H-indole-3,2-diyl)]diacetate (DEBIC) to receive assays. DEBIC intercalated DNA and inhibited proliferation of tumor cells but not non-tumor cells. It slowed tumor growth of S180 mice at a dose of 0.36 µmol/kg, and slowed tumor growth of A549 bearing BABL/C mice at a dose of 8.9 µmol/kg. DEBIC was also found to inhibit arterial thrombosis by down regulating P-selectin effectively at a dose of 0.36 µmol/kg.

Heptapeptide-based modification leading to enhancing the action of MTCA on activated platelets, P-selectin, GPIIb/IIIa.

AIM: The modification of platelet inhibitor to enhance its targeting capacity toward platelets is of clinical importance. Thus, (1R, 3S)-1-methyl-1, 2, 3, 4-tetrahydro-ß-carboline-3-carboxylic acid (MTCA), a platelet inhibitor, was modified with Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (KKV), platelet targeting peptide, to form MTCA-KKV. MATERIALS & METHODS: MTCA and MTCA-KKV were synthesized to identify the effect of KKV modification on MTCA and platelets. RESULTS: Atomic force microscopy imaged MTCA-KKV effectively accumulated on activated platelets. UV spectra showed that MTCA-KKV concentration dependently changed P-selectin and GPIIb/IIIa conformations. For platelet aggregation, the IC50 of MTCA-KKV was approximately 1/10 folds of MTCA. CONCLUSION: KKV modification led to forming MTCA-KKV that is superior to MTCA in terms of accumulating on activated platelets, targeting P-selectin and GPIIb/IIIa and inhibiting platelet aggregation. MTCA-KKV could be a promising lead for further investigation.

Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors.

BACKGROUND: The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth. METHODS: For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)-ß-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors. RESULTS: The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 µmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver. CONCLUSION: Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.

Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA.

BACKGROUND: Arterial thrombosis has been associated with a series of pathological conditions, and the discovery of arterial thrombosis inhibitor is of clinical importance. METHODS: By analyzing the pharmacophores of anti-platelet agents, thrombus targeting peptide and anti-thrombotic nano-systems 3S-1,2,3,4-tetrahydroisoquino-line-3-carbonyl-Thr-Ala-Arg-Gly-Asp(Val)-Val (IQCA-TAVV) was designed and prepared as a nano-scaled arterial thrombosis inhibitor. RESULTS: In vitro the nanoparticles of IQCA-TAVV were able to adhere onto the surface of activated platelets, attenuate activated platelets to extend pseudopodia and inhibit activated platelets to form aggregators. In vivo IQCA-TAVV targeted arterial thrombus, dose dependently inhibited arterial thrombosis with a 1 nmol/kg of minimal effective dose, and the activity was1670 folds of that of aspirin. CONCLUSION: IQCA-TAVV represented the design, preparation and application of nanomedicine capable of adhering on the surface of activated platelets, attenuating platelet activation, targeting arterial thrombus and inhibiting arterial thrombosis.