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Biomedical subjects

Min Dong

Publications and source records attributed to Min Dong.

At least 19 recordsLinked to original sources
PubMed2025

Heme oxygenase 1 (HO-1) is a drug target for reversing cisplatin resistance in non-small cell lung cancer.

INTRODUCTION: Platinum-based drugs, the most widely used chemotherapeutic drugs in clinical oncology, have long faced the problem of drug resistance, which is urgently in need of resolution. Identifying biomarkers of drug resistance may help reduce platinum resistance and improve therapeutic efficacy. OBJECTIVES: This study aims to identify potential biomarkers associated with the development of cisplatin resistance in non-small cell lung cancer (NSCLC) and explore mechanisms to overcome chemoresistance. METHODS: NSCLC cisplatin resistance cell lines were constructed, and transcriptome sequencing was performed. Results were validated using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Molecular docking, proteomics sequencing, and in vitro and in vivo experiments were conducted to evaluate the role of Heme Oxygenase 1 (HO-1) in cisplatin resistance. RESULTS: NSCLC cisplatin resistance cell lines, GEO and TCGA data identified HMOX1, downstream of Nrf2, as a key drug resistance gene induced by cisplatin. Activation of the Nrf2/HO-1 pathway was found to induce ferroptosis resistance, a critical mechanism of cisplatin resistance. Candidate compounds SB 202190 and Nordihydroguaiaretic acid (NDGA) effectively reactivated ferroptosis by inhibiting HO-1, thereby increasing cisplatin sensitivity. CONCLUSION: The Nrf2/HO-1 pathway is a significant contributor to cisplatin resistance in NSCLC. Targeting HO-1 with SB 202190 and NDGA presents a promising strategy to overcome resistance and improve chemotherapy outcomes.

Cisplatin↗
PubMed2007

Sarcoplasmic reticulum calcium overloading in junctin deficiency enhances cardiac contractility but increases ventricular automaticity.

BACKGROUND: Abnormal sarcoplasmic reticulum calcium (Ca) cycling is increasingly recognized as an important mechanism for increased ventricular automaticity that leads to lethal ventricular arrhythmias. Previous studies have linked lethal familial arrhythmogenic disorders to mutations in the ryanodine receptor and calsequestrin genes, which interact with junctin and triadin to form a macromolecular Ca-signaling complex. The essential physiological effects of junctin and its potential regulatory roles in sarcoplasmic reticulum Ca cycling and Ca-dependent cardiac functions, such as myocyte contractility and automaticity, are unknown. METHODS AND RESULTS: The junctin gene was targeted in embryonic stem cells, and a junctin-deficient mouse was generated. Ablation of junctin was associated with enhanced cardiac function in vivo, and junctin-deficient cardiomyocytes exhibited increased contractile and Ca-cycling parameters. Short-term isoproterenol stimulation elicited arrhythmias, including premature ventricular contractions, atrioventricular heart block, and ventricular tachycardia. Long-term isoproterenol infusion also induced premature ventricular contractions and atrioventricular heart block in junctin-null mice. Further examination of the electrical activity revealed a significant increase in the occurrence of delayed afterdepolarizations. Consistently, 25% of the junctin-null mice died by 3 months of age with structurally normal hearts. CONCLUSIONS: Junctin is an essential regulator of sarcoplasmic reticulum Ca release and contractility in normal hearts. Ablation of junctin is associated with aberrant Ca homeostasis, which leads to fatal arrhythmias. Thus, normal intracellular Ca cycling relies on maintenance of junctin levels and an intricate balance among the components in the sarcoplasmic reticulum quaternary Ca-signaling complex.

Animals↗
PubMed2006

N-formylation of lysine in histone proteins as a secondary modification arising from oxidative DNA damage.

The posttranslational modification of histone and other chromatin proteins has a well recognized but poorly defined role in the physiology of gene expression. With implications for interfering with these epigenetic mechanisms, we now report the existence of a relatively abundant secondary modification of chromatin proteins, the N(6)-formylation of lysine that appears to be uniquely associated with histone and other nuclear proteins. Using both radiolabeling and sensitive bioanalytical methods, we demonstrate that the formyl moiety of 3'-formylphosphate residues arising from 5'-oxidation of deoxyribose in DNA, caused by the enediyne neocarzinostatin, for example, acylate the N(6)-amino groups of lysine side chains. A liquid chromatography (LC)-tandem mass spectrometry (MS) method was developed to quantify the resulting N(6)-formyl-lysine residues, which were observed to be present in unperturbed cells and all sources of histone proteins to the extent of 0.04-0.1% of all lysines in acid-soluble chromatin proteins including histones. Cells treated with neocarzinostatin showed a clear dose-response relationship for the formation of N(6)-formyl-lysine, with this nucleosome linker-selective DNA-cleaving agent causing selective N(6)-formylation of the linker histone H1. The N(6)-formyl-lysine residue appears to represent an endogenous histone secondary modification, one that bears chemical similarity to lysine N(6)-acetylation recognized as an important determinant of gene expression in mammalian cells. The N(6)-formyl modification of lysine may interfere with the signaling functions of lysine acetylation and methylation and thus contribute to the pathophysiology of oxidative and nitrosative stress.

Acetylation↗
PubMed2006

Structural basis of cell surface receptor recognition by botulinum neurotoxin B.

Botulinum neurotoxins (BoNTs) are potent bacterial toxins that cause paralysis at femtomolar concentrations by blocking neurotransmitter release. A 'double receptor' model has been proposed in which BoNTs recognize nerve terminals via interactions with both gangliosides and protein receptors that mediate their entry. Of seven BoNTs (subtypes A-G), the putative receptors for BoNT/A, BoNT/B and BoNT/G have been identified, but the molecular details that govern recognition remain undefined. Here we report the crystal structure of full-length BoNT/B in complex with the synaptotagmin II (Syt-II) recognition domain at 2.6 A resolution. The structure of the complex reveals that Syt-II forms a short helix that binds to a hydrophobic groove within the binding domain of BoNT/B. In addition, mutagenesis of amino acid residues within this interface on Syt-II affects binding of BoNT/B. Structural and sequence analysis reveals that this hydrophobic groove is conserved in the BoNT/G and BoNT/B subtypes, but varies in other clostridial neurotoxins. Furthermore, molecular docking studies using the ganglioside G(T1b) indicate that its binding site is more extensive than previously proposed and might form contacts with both BoNT/B and synaptotagmin. The results provide structural insights into how BoNTs recognize protein receptors and reveal a promising target for blocking toxin-receptor recognition.

Animals↗
PubMed2006

Effect of simulated I(to) on guinea pig and canine ventricular action potential morphology.

The transient outward current (I(to)) is a major repolarizing current in the heart. Marked reduction of I(to) density occurs in heart failure and is accompanied by significant action potential duration (APD) prolongation. To understand the species-dependent role of I(to) in regulating the ventricular action potential morphology and duration, we introduced simulated I(to) conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique and perforated patch-clamp recordings. The effects of simulated I(to) in both types of cells were complex and biphasic, separated by a clear density threshold of approximately 40 pA/pF. Below this threshold, simulated I(to) resulted in a distinct phase 1 notch and had little effect on or moderately prolonged the APD. I(to) above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. Qualitatively, these results agreed with our previous studies in canine ventricular cells using whole cell recordings. We conclude that 1) contrary to previous gene transfer studies involving the Kv4.3 current, the response of guinea pig ventricular myocytes to a fully inactivating I(to) is similar to that of canine ventricular cells and 2) in animals such as dogs that have a broad cardiac action potential, I(to) does not play a major role in setting the APD.

Action Potentials↗
PubMed2006

SV2 is the protein receptor for botulinum neurotoxin A.

How the widely used botulinum neurotoxin A (BoNT/A) recognizes and enters neurons is poorly understood. We found that BoNT/A enters neurons by binding to the synaptic vesicle protein SV2 (isoforms A, B, and C). Fragments of SV2 that harbor the toxin interaction domain inhibited BoNT/A from binding to neurons. BoNT/A binding to SV2A and SV2B knockout hippocampal neurons was abolished and was restored by expressing SV2A, SV2B, or SV2C. Reduction of SV2 expression in PC12 and Neuro-2a cells also inhibited entry of BoNT/A, which could be restored by expressing SV2 isoforms. Finally, mice that lacked an SV2 isoform (SV2B) displayed reduced sensitivity to BoNT/A. Thus, SV2 acts as the protein receptor for BoNT/A.

Animals↗
PubMed2006

Relatively small increases in the steady-state levels of nucleobase deamination products in DNA from human TK6 cells exposed to toxic levels of nitric oxide.

Nitric oxide (NO) is a physiologically important molecule that has been implicated in the pathophysiology of diseases associated with chronic inflammation, such as cancer. While the complicated chemistry of NO-mediated genotoxicity has been extensively study in vitro, neither the spectrum of DNA lesions nor their consequences in vivo have been rigorously defined. We have approached this problem by exposing human TK6 lymphoblastoid cells to controlled steady-state concentrations of 1.75 or 0.65 microM NO along with 186 microM O2 in a recently developed reactor that avoids the anomalous gas-phase chemistry of NO and approximates the conditions at sites of inflammation in tissues. The resulting spectrum of nucleobase deamination products was defined using a recently developed liquid chromatography/mass spectrometry (LC/MS) method, and the results were correlated with cytotoxicity and apoptosis. A series of control experiments revealed the necessity of using dC and dA deaminase inhibitors to avoid adventitious formation of 2'-deoxyuridine (dU) and 2'-deoxyinosine (dI), respectively, during DNA isolation and processing. Exposure of TK6 cells to 1.75 microM NO and 186 microM O2 for 12 h (1260 microM x min dose) resulted in 32% loss of cell viability measured immediately after exposure and 87% cytotoxicity after a 24 h recovery period. The same exposure resulted in 3.5-, 3.8-, and 4.1-fold increases in dX, dI, and dU, respectively, to reach the following levels: dX, 7 (+/- 1) per 10(6) nt; dI, 25 (+/- 2.1) per 10(6) nt; and dU, 40 (+/- 3.8) per 10(6) nt. dO was not detected above the limit of detection of 6 lesions per 10(7) nt in 50 microg of DNA. A 12 h exposure to 0.65 microM NO and 190 microM O2 (468 microM x min dose) caused 1.7-, 1.8-, and 2.0-fold increases in dX, dI, and dU, respectively, accompanied by a approximately 15% (+/- 3.6) reduction in cell viability immediately after exposure. Again, dO was not detected. These results reveal modest increases in the steady-state levels of DNA deamination products in cells exposed to relatively cytotoxic levels of NO. This could result from limited nitrosative chemistry in nuclear DNA in cells exposed to NO or high levels of formation balanced by rapid repair of nucleobase deamination lesions in DNA.

Cell Line, Tumor↗
PubMed2006

[Clinical characteristics and genetic analyses of familial recurrent moles].

OBJECTIVE: To probe the clinical characteristics and genetic origin of familial recurrent mole (FRM). METHODS: Two cases of FRM were reported retrospectively. Microsatellite polymorphism was used to determine the genetic origin of the two FRM and other six sporadic moles from other independent families. RESULTS: The two FRM patients came from two independent families. Both of them had more than two times of hydatidiform moles and the same condition had happened to their sisters. The last mole from each of these two patients was identified as biparental complete hydatidiform mole (BiCHM). Among the six sporadic moles, one was partial hydatidiform mole (PHM), which was identified as triploid with one haploid maternal set of chromosomes and two haploid paternal sets of chromosomes. The other five sporadic moles were all androgenetic complete hydatidiform mole (AnCHM), which lacked maternal genetic material. The two women with FRM developed into persistent trophoblastic disease (PTD) and gained complete remission (CR) after medical therapy and/or pulmonary lobectomy. CONCLUSIONS: FRM is exceedingly rare. Most of them are biparental in origin. It ought to be an important step to identify the genetic origin in evaluating the outcomes of the women with recurrent hydatidiform moles.

Abortion, Spontaneous↗
PubMed2006

[Influence of graft-versus-host disease on long-term survival of 26 patients with hematologic malignancies after transplantation].

BACKGROUND & OBJECTIVE: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and also is an important factor affecting the outcome of transplantation. Some researches showed that either acute or chronic GVHD is often accompanied by graft-versus-leukemia (GVL) effect, and this positive effect is associated with the decrease of leukemia relapse and the prolongation of disease-free survival of recipients. This study was to assess the influence of GVHD on the outcome of allo-HSCT. METHODS: Twenty-six patients with hematologic malignancies received allo-HSCT from Mar. 1995 to Oct. 2005. The occurrence of GVHD, relapse of leukemia, and survival of recipients were analyzed retrospectively, and the correlations of GVHD to leukemia relapse and patients' survival were evaluated. RESULTS: With a median follow-up of 20 months (range 2-127 months) after transplantation, 20 (76.9%) patients developed GVHD, 1 of which had tumor relapsed; 3 of the 6 patients without GVHD had tumor relapsed. The relapse rate was significantly lower in the recipients with GVHD than in the recipients without GVHD (P<0.05). After transplantation, 16 patients survived disease-freely, and 10 died. Kaplan-Meier survival curves showed that the 3-year disease-freely survival rate was 60%. The disease-freely survival rate was significantly higher in the recipients with GVHD than in the recipients without GVHD (15/20 vs. 1/6, log-rank=7.30, P<0.05). Cox regression models showed a significantly decreased risk of death in the recipients with GVHD (risk ratio=0.2, P<0.05). Of the 20 recipients with GVHD, 17 achieved complete response (CR), 15 of whom survived disease-freely; no survived in the 3 patients who did not achieve CR. The disease-freely survival rate was significantly higher in the recipients achieved CR than in the recipients did not (P<0.05). CONCLUSIONS: GVHD is an important factor that may influence the outcome of allo-HSCT. Treatment efficacy of GVHD is significantly associated with the disease-free survival of recipients. Early recognition and treatment of acute GVHD is the key factor of successful treatment.

Adolescent↗
PubMed2005

Development of enzymatic probes of oxidative and nitrosative DNA damage caused by reactive nitrogen species.

Chronic inflammation is associated with a variety of human diseases, including cancer, with one possible mechanistic link involving over-production of nitric oxide (NO*) by activated macrophages. Subsequent reaction of NO* with superoxide in the presence of carbon dioxide yields nitrosoperoxycarbonate (ONOOCO2-), a strong oxidant that reacts with guanine in DNA to form a variety of oxidation and nitration products, such 2'-deoxy-8-oxoguanosine. Alternatively, the reaction of NO and O2 leads to the formation of N2O3, a nitrosating agent that causes nucleobase deamination to form 2'-deoxyxanthosine (dX) and 2'-deoxyoxanosine (dO) from dG; 2'-deoxyinosine (dI) from dA; and 2'-deoxyuridine (dU) from dC, in addition to abasic sites and dG-dG cross-links. The presence of both ONOOCO2- and N2O3 at sites of inflammation necessitates definition of the relative roles of oxidative and nitrosative DNA damage in the genetic toxicology of inflammation. To this end, we sought to develop enzymatic probes for oxidative and nitrosative DNA lesions as a means to quantify the two types of DNA damage in in vitro DNA damage assays, such as the comet assay and as a means to differentially map the lesions in genomic DNA by the technique of ligation-mediated PCR. On the basis of fragmentary reports in the literature, we first systematically assessed the recognition of dX and dI by a battery of DNA repair enzymes. Members of the alkylpurine DNA glycosylase family (E. coli AlkA, murine Aag, and human MPG) all showed repair activity with dX (k(cat)/Km 29 x 10(-6), 21 x 10(-6), and 7.8 x 10(-6) nM(-1) min(-1), respectively), though the activity was considerably lower than that of EndoV (8 x 10(-3) nM(-1) min(-1)). Based on these results and other published studies, we focused the development of enzymatic probes on two groups of enzymes, one with activity against oxidative damage (formamidopyrimidine-DNA glycosylase (Fpg); endonuclease III (EndoIII)) and the other with activity against nucleobase deamination products (uracil DNA glycosylase (Udg); AlkA). These combinations were assessed for recognition of DNA damage caused by N2O3 (generated with a NO*/O2 delivery system) or ONOOCO2- using a plasmid nicking assay and by LC-MS analysis. Collectively, the results indicate that a combination of AlkA and Udg react selectively with DNA containing only nitrosative damage, while Fpg and EndoIII react selectively with DNA containing oxidative base lesions caused by ONOOCO2-. The results suggest that these enzyme combinations can be used as probes to define the location and quantity of the oxidative and nitrosative DNA lesions produced by chemical mediators of inflammation in systems, such as the comet assay, ligation-mediated polymerase chain reaction, and other assays of DNA damage and repair.

Animals↗
PubMed2005

Biological role of glutathione in nitric oxide-induced toxicity in cell culture and animal models.

Glutathione (GSH) plays an important role in cellular defense response in many in vitro and in vivo models. Here we investigated its role in NO()-induced toxicity in cell culture and mouse models. Wild-type (TK6) and p53-null (NH32) human lymphoblastoid cells were treated with NO(.) at a steady-state concentration of 0.6 muM, similar to the level estimated to occur in inflamed tissues. In both cell types, GSH was depleted by this exposure in a dose- and time-dependent manner. Contrary to expectations, prior depletion of GSH by treatment with l-buthionine-SR-sulfoximine did not potentiate NO(.)-induced cell killing or DNA deamination in TK6 cells. In activated RAW264.7 murine macrophages producing NO(.), intracellular GSH content did not change, although gamma-glutamate-cysteine ligase was upregulated. NO(.) overproduction in RcsX lymphoma-bearing SJL mice resulted in significantly elevated GSH levels in various organs. Administration of the NO(.) synthase inhibitor N-methylarginine abolished the increase in GSH in these animals. Collectively, these data indicate a multifaceted and complex involvement of GSH in responses of cells and tissues to toxic levels of NO(.). NO(.) treatment effectively depleted GSH levels in human lymphoblastoid cells, but this alteration was not a critical initiating factor for NO(.)-mediated toxicity. Murine macrophages maintained GSH homeostasis when exposed to endogenously produced NO(.). In RcsX lymphoma-bearing mice, upregulation of de novo synthesis of GSH appeared to be a response to the toxic effects of NO(.).

Animals↗
PubMed2005

Delineation of the chemical pathways underlying nitric oxide-induced homologous recombination in mammalian cells.

Inflammation is an important risk factor for cancer. During inflammation, macrophages secrete nitric oxide (NO*), which reacts with superoxide or oxygen to create ONOO- or N2O3, respectively. Although homologous recombination causes DNA sequence rearrangements that promote cancer, little was known about the ability of ONOO- and N2O3 to induce recombination in mammalian cells. Here, we show that ONOO- is a potent inducer of homologous recombination at an integrated direct repeat substrate, whereas N2O3 is relatively weakly recombinogenic. Furthermore, on a per lesion basis, ONOO(-)-induced oxidative base lesions and single-strand breaks are significantly more recombinogenic than N2O3-induced base deamination products, which did not induce detectable recombination between plasmids. Similar results were observed in mammalian cells from two different species. These results suggest that ONOO(-)-induced recombination may be an important mechanism underlying inflammation-induced cancer.

Animals↗
PubMed2005

Effects of peroxynitrite dose and dose rate on DNA damage and mutation in the supF shuttle vector.

Peroxynitrite (ONOO-) induces oxidative and nitrosative DNA damage, and previous studies by our group have shown that it is strongly mutagenic in the supF shuttle vector pSP189 replicated in Escherichia coli MBL50 cells. In those experiments, however, the pSP189 plasmid was exposed under unphysiological conditions to large single bolus doses of ONOO-, which limits extrapolation of the data to in vivo pathological states in which ONOO- may play a role. We have thus sought to define the effects of ONOO- dose and dose rate on the DNA damage and mutations induced in the supF gene by three different dosage mechanisms: (i) by infusion of ONOO- solution into suspensions of pSP189 at rates approximating those estimated to occur in inflamed tissues; (ii) by exposure to 3-morpholinosydnonimine (SIN-1), which generates ONOO- spontaneously during decomposition; and (iii) by bolus doses of ONOO- solution. In all cases, plasmid DNA was exposed in the presence of 25 mM bicarbonate, since the reaction of CO2 with ONOO- (to form nitrosoperoxycarbonate) has a major impact on mutagenic potency of ONOO- in this system. Nucleobase and deoxyribose damage were evaluated by a plasmid nicking assay immediately after ONOO- and SIN-1 exposures. Mutation frequency (MF) and mutational spectra in the supF gene were determined after plasmid pSP189 replicated in host E. coli cells. Bolus ONOO- addition caused the highest amount of DNA damage, including base and deoxyribose lesions, while infusion caused the least. SIN-1 was found to induce almost exclusively deoxyribose oxidation, while bolus addition generated a high percentage of base damage. MF increased in a dose-dependent manner following all treatments, but infused ONOO- and SIN-1 exposures were less mutagenic than bolus ONOO- exposure. MFs induced by infusion and by SIN-1 incubated for 100 min at the highest level (4 mM) were 63 and 43% less, respectively, than that induced by bolus. All mutational hot spots were located at G:C sites except for A121 and A177 induced by SIN-1 exposure. Hot spots at C108 and C168 were common to all exposures; G113, G115, and G116 were common to bolus and infused ONOO- exposures; and G129 was common to infused ONOO- and SIN-1 exposures. Almost all mutations were single base pair substitutions under all exposure conditions. Whereas those induced by infused or bolus ONOO- and SIN-1 consisted predominantly of G:C to T:A transversions (66, 65, and 51%, respectively), G:C to C:G mutations were much less frequent following infusion and SIN-1 (8 and 19%, respectively) than those induced by bolus exposure (29%). A:T to T:A mutations induced were detected only after ONOO- infusion and SIN-1 exposure (9 and 11%, respectively). In conclusion, both dose and dose rate at which a genetic target is exposed to ONOO- substantially influence the damage and mutational response, indicating that these parameters will need to be taken into account in assessing the potential effects of ONOO- in vivo. Furthermore, the results indicate that the chemistry of SIN-1-induced DNA damage differs substantially from native ONOO-, which suggests the need for caution in interpreting the biological relevance of SIN-1 as a surrogate for ONOO-.

Base Sequence↗
PubMed2004

Identification of the DNA binding element of the human ZNF333 protein.

ZNF 333 is a new and sole gene containing two KRAB domains which has been identified currently. It is a member of subfamilies of zinc finger gene complex which had been localized on chromosome 19p13.1. The ZNF333 gene mainly encodes a 75.5 kDa protein which contains 10 zinc finger domains. Using the methods of random oligonucleotide selection assay, electromobility gel shift assay and luciferase activity assay, we found that ZNF333 recognized the specific DNA core binding sequence ATAAT. Moreover, these data indicated that the KRAB domain of ZNF333 really has the ability of transcriptional repression.

Base Sequence↗
PubMed2004

Using fluorescent sensors to detect botulinum neurotoxin activity in vitro and in living cells.

Botulinum neurotoxins (BoNTs) act as zinc-dependent endopeptidases that cleave proteins required for neurotransmitter release. To detect toxin activity, fragments of the toxin substrate proteins, synaptobrevin (Syb) or synaptosome-associated protein of 25 kDa (SNAP-25), were used to link cyan fluorescent protein (CFP) to yellow fluorescent protein (YFP). Cleavage of these fusion proteins by BoNTs abolished fluorescence resonance energy transfer between the CFP and YFP, providing a sensitive means to detect toxin activity in real-time in vitro. Furthermore, using full-length SNAP-25 and Syb as the linkers, we report two fluorescent biosensors that can detect toxin activity within living cells. Cleavage of the SNAP-25 fusion protein abolished fluorescence resonance energy transfer between CFP and YFP, and cleavage of Syb resulted in spatial redistribution of YFP fluorescence in cells. This approach provides a means to carry out cell-based screening of toxin inhibitors and to study toxin activity in situ. By using these biosensors, we found that the subcellular localizations of SNAP-25 and Syb are critical for efficient cleavage by BoNT/A and B, respectively.

Animals↗
PubMed2004

Inhibition of platelet aggregation by polyaspartoyl L-arginine and its mechanism.

AIM: To observe the oral anti-platelet efficacy and the potential action mechanism of polyaspartoyl L-arginine (PDR), a new L-arginine rich compound. METHODS: Platelet aggregation was conducted by Born's method; bleeding time was determined using tail's bleeding time in mice; platelet adhesion was carried out with glass bottle method; nitric oxide (NO) was tested with Griess's method; and cAMP, thromboxane B(2) (TXB(2)) and 6-keto-PGF(1 alpha ) were assessed with commercial kits. RESULTS: The inhibition by PDR (15-60 mg/kg i.g. or 10 mg/kg i.v.) of platelet aggregation induced by adenosine diphosphate (ADP), collagen or thrombin at 1 h after oral administration or at 20 min after i.v. injection for rats (P<0.01), and its (15 mg/kg, i.g.) inhibition of ADP-induced platelet aggregation for rabbits during 6 h after administration were observed. PDR (15-60 mg/kg) prolonged the bleeding time of mice (P<0.05) and (30 mg/kg) increased NO concentration in plasma. On the other hand PDR did not change the contents of cAMP in platelet and TXB2 or 6-keto-PGF(1 alpha) in plasma. CONCLUSION: PDR is a novel, oral effective platelet aggregation inhibitor and its action mechanism possibly related to increasing NO generation.

6-Ketoprostaglandin F1 alpha↗
PubMed2003

Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells.

Botulinum neurotoxins (BoNTs) cause botulism by entering neurons and cleaving proteins that mediate neurotransmitter release; disruption of exocytosis results in paralysis and death. The receptors for BoNTs are thought to be composed of both proteins and gangliosides; however, protein components that mediate toxin entry have not been identified. Using gain-of-function and loss-of-function approaches, we report here that the secretory vesicle proteins, synaptotagmins (syts) I and II, mediate the entry of BoNT/B (but not BoNT/A or E) into PC12 cells. Further, we demonstrate that BoNT/B entry into PC12 cells and rat diaphragm motor nerve terminals was activity dependent and can be blocked using fragments of syt II that contain the BoNT/B-binding domain. Finally, we show that syt II fragments, in conjunction with gangliosides, neutralized BoNT/B in intact mice. These findings establish that syts I and II can function as protein receptors for BoNT/B.

Amino Acid Sequence↗