NF-kappab facilitates oridonin-induced apoptosis and autophagy in HT1080 cells through a p53-mediated pathway.

In this study, we investigated the molecular mechanisms involving in oridonin-induced apoptosis and autophagy. We found that apoptosis and autophagy were simultaneously induced by oridonin time-dependently in HT1080 cells, and inhibition of autophagy by 3MA decreased oridonin-induced apoptosis, indicating that they act in synergy to mediate cell death. In addition, treatment with oridonin caused an increase in NF-kappaB and p53 activities in a time-dependent manner.

Transcriptome analysis of the venom gland of the scorpion Scorpiops jendeki: implication for the evolution of the scorpion venom arsenal.

Background: The family Euscorpiidae, which covers Europe, Asia, Africa, and America, is one of the most widely distributed scorpion groups. However, no studies have been conducted on the venom of a Euscorpiidae species yet. In this work, we performed a transcriptomic approach for characterizing the venom components from a Euscorpiidae scorpion, Scorpiops jendeki.

Intersubunit coupling in the pore of BK channels.

The structural basis underlying the gating of large conductance Ca(2+)-activated K(+) (BK) channels remains elusive. We found that substitution of Leu-312 in the S6 transmembrane segment of mSlo1 BK channels with hydrophilic amino acids of smaller side-chain volume favored the open state. The sensitivities of channels to calcium and voltage were modified by some mutations and completely abolished by others.

Molecular Information of charybdotoxin blockade in the large conductance calcium-activated potassium channel.

The scorpion toxin, charybdotoxin (ChTX), is the first identified peptide inhibitor for the large-conductance Ca2+ and voltage-dependent K+ (BK) channel, and the chemical information of the interaction between ChTX and BK channel remains unclear today. Using combined computational methods, we obtained a ChTX-BK complex structure model, which correlated well with the mutagenesis data. In this complex, ChTX mainly used its beta-sheet domains to associate the BK channel with a conserved pore-blocking Lys27.

Imcroporin, a new cationic antimicrobial peptide from the venom of the scorpion Isometrus maculates.

The pace of resistance against antibiotics almost exceeds that of the development of new drugs. As many bacteria have become resistant to conventional antibiotics, new drugs or drug resources are badly needed to combat antibiotic-resistant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA). Antimicrobial peptides, rich sources existing in nature, are able to effectively kill multidrug-resistant pathogens.

Chronic organophosphate (OP)-induced neuropsychiatric disorder is a withdrawal syndrome.

Chronic organophosphate-induced neuropsychiatric disorder is a less well-characterized syndrome, which is usually delay-occurred, persists long and is similar to the symptom of cholinergic deficit, its mechanism is unclear. The characteristics of chronic organophosphate-induced neuropsychiatric disorder are somewhat opposite to the direct action of OP pesticide, since withdrawal effect is usually opposite to the original effect of a drug, hypothesis that chronic organophosphate-induced neuropsychiatric disorder is a kind of withdrawal syndrome is suggested.

Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia with or without clozapine.

This study investigated the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice with or without clozapine. MK-801 (0.6 mg/kg) acute administration produced a significant increase in the expression of c-Fos protein in the layers III-IV of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports.

Molecular cloning and functional identification of a new K(+) channel blocker, LmKTx10, from the scorpion Lychas mucronatus.

Scorpions have a venom gland which is an important determinant in contributing to their successful survival for more than 400 million years. Their venoms contain a diversity of neurotoxins, which represent a tremendous hitherto partially unexplored resource not only for understanding ion channels but also for use in drug design and development. In this investigation, LmKTx10, a new toxin gene was identified from the venom of the scorpion Lychas mucronatus by constructing cDNA library method, and its product was expressed and characterized physiologically.

[Apoptosis induced by NNAMB, a novel polyamine conjugate, in human erythroleukemia K562 cells and its mechanism].

Objective: To investigate the apoptosis-inducing effects of NNAMB, a novel polyamine conjugate, in erythroleukemia K562 cells and its molecular mechanism.

Methods: Cell viability was assessed by MTT assay and trypan blue dye exclusion method. The cell morphology was observed by fluorescence microscopy.

Characterization of LmTxLP11 and LmVP1.1 transcripts and genomic organizations: alternative splicing contributing to the diversity of scorpion venom peptides.

Scorpion venoms are rich resources of bioactive peptides with extreme variability. Multiple molecular mechanisms are involved in the diversity of scorpion venom peptides. However, alternative splicing, which plays a major role in the generation of proteomic and functional diversity in metazoan organisms, hasn't been reported in genes coding for scorpion venom peptides.

Involvement of PKC signal pathways in oridonin-induced autophagy in HeLa cells: a protective mechanism against apoptosis.

Our previous studies showed that oridonin could induce both apoptosis and autophagy in HeLa cells, and this autophagy might be a protective mechanism against apoptosis. In this study, the roles of PKC signal pathways in oridonin-induced HeLa cell autophagy and apoptosis were further investigated. We found that inhibition of PKC significantly reduced oridonin-induced autophagy whereas markedly increased apoptosis, while pretreatment with PKC activator caused opposite results.

Fas-mediated autophagy requires JNK activation in HeLa cells.

Fas has been reported to play an important role in apoptosis; however, Fas-mediated autophagy and its mechanism are still unclear. Here, we found that Fas agonistic antibody CH11-induced autophagy in HeLa cells, and inhibition of autophagy by 3-MA increased CH11-induced apoptosis. A Fas antagonistic antibody (UB2) suppressed both CH11-induced autophagy and apoptosis.

Different residues in channel turret determining the selectivity of ADWX-1 inhibitor peptide between Kv1.1 and Kv1.3 channels.

The low selectivity of Kv1 peptide inhibitors for specific isoforms makes them poor candidates for the development of theraputics. Using combined approaches, we showed that the Kv1 turret is the critical determinant for ADWX-1 peptide inhibitor selectivity of Kv1.3 over Kv1.

Mucroporin, the first cationic host defense peptide from the venom of Lychas mucronatus.

The misuse of antibiotics has led our age to a dangerous edge, as antibiotic-resistant pathogens appear to evolve more quickly than antibiotics are invented. Thus, new agents to treat bacterial infection are badly needed. Cationic host defense peptides are on the first line of a host defense system and are thought to be good candidates for treating bacterial infection.

Characterization of a new Kv1.3 channel-specific blocker, J123, from the scorpion Buthus martensii Karsch.

The potassium channel Kv1.3 is an attractive pharmacological target for T-cell-mediated autoimmune diseases, and specific and selective peptidic blockers of Kv1.3 channels have served as valuable therapeutic leads for treating these diseases.

Structural basis for toxin resistance of beta4-associated calcium-activated potassium (BK) channels.

The functional diversity of large conductance Ca(2+)- and voltage-dependent K(+) (BK) channels arises mainly from co-assembly of the pore-forming mSlo alpha subunits with four tissue-enriched auxiliary beta subunits. The structural basis of the interaction between alpha subunits with beta subunits is not well understood. Using computational and experimental methods, we demonstrated that four mSlo turrets decentralized distally from the channel pore to provide a wide open conformation and that the mSlo and hbeta4 subunits together formed a "helmet" containing three basic residues (Lys-120, Arg-121, and Lys-125), which impeded the entry of charybdotoxin (ChTX) by both the electrostatic interaction and limited space.

[Process of HIV-1 reverse transcription and its detection by using PCR].

Human immunodeficiency virus (HIV) is a retrovirus, belongs to Lentiviridae family. As long as viral genetic material entering into host cytoplasm, double-strand DNAs synthesis occurs which is catalyzed by reverse transcriptase (RT) with viral plus-strand RNA as template. This reverse transcription is a key link of HIV-1 life cycle and an important target for anti-HIV drug development.

Structural basis of a potent peptide inhibitor designed for Kv1.3 channel, a therapeutic target of autoimmune disease.

The potassium channel Kv1.3 is an attractive pharmacological target for immunomodulation of T cell-mediated autoimmune diseases. Potent and selective blockers of Kv1.

Lysine-rich extracellular rings formed by hbeta2 subunits confer the outward rectification of BK channels.

The auxiliary beta subunits of large-conductance Ca(2+)-activated K(+) (BK) channels greatly contribute to the diversity of BK (mSlo1 alpha) channels, which is fundamental to the adequate function in many tissues. Here we describe a functional element of the extracellular segment of hbeta2 auxiliary subunits that acts as the positively charged rings to modify the BK channel conductance. Four consecutive lysines of the hbeta2 extracellular loop, which reside sufficiently close to the extracellular entryway of the pore, constitute three positively charged rings.

Comparison of enantiomers of SPFF, a novel beta2-Adrenoceptor agonist, in bronchodilating effect in guinea pigs.

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel beta2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta2-adrenoceptor selectivity. On the basis of this study, we compared the pharmacological properties of SPFF and its enantiomers ((-)-SPFF and (+)-SPFF) in guinea pigs taking isoprenaline or salbutamol (SAB) as referenced drugs. For the relaxation of both normal and precontracted trachea strips in vitro, (-)-SPFF was found more potent than (+/-)-SPFF or (+)-SPFF.

A residue at the cytoplasmic entrance of BK-type channels regulating single-channel opening by its hydrophobicity.

Single large-conductance calcium-activated K(+) (BK) channels encoded by the mSlo gene usually have synchronous gating, but a Drosophila dSlo (A2/C2/E2/G5/10) splice variant (dSlo1A) exhibits very flickery openings. To probe this difference in gating, we constructed a mutant I323T. This channel exhibits four subconductance levels similar to those of dSlo1A.

[Correlation between the refractory periods and threshold potentials and the spike programming in cortical neurons].

Aim: To investigate the intrinsic mechanisms underlying spike programming at pyramidal neurons and interneurons in layer II/III of sensorimotor cortex.

Methods: Electrical signals at the cortical neurons were recorded in current clamp model with multi-clamp700B Amplifiers. Signals were inputted into pClamp and Origin for data acquisition and analyses.

Synergistic antitumor effects of anthracenylmethyl homospermidine and alpha-difluoromethylornithine on promyelocytic leukemia HL60 cells.

The present study was designed to assess the synergistic antitumor effects of anthracenylmethyl homospermidine (ANTMHspd), a novel polyamine conjugate, with alpha-difluoromethylornithine (DFMO) and to elucidate the mechanism of these effects on human leukemia HL60 cells. Cell proliferation was assessed by the MTT assay. Cell cycle, apoptosis and mitochondria membrane potential (MMP) were evaluated by flow cytometry.

A novel homospermidine conjugate inhibits growth and induces apoptosis in human hepatoma cells.

Aim: To elucidate the mechanism responsible for the antiproliferative effects of a novel homospermidine conjugate, anthracenylmethyl homospermidine (ANTMHspd), in the human hepatoma BEL-7402 cell line.

Methods: The viability of the cells was assessed by MTT assay and the trypan blue dye exclusion method. Morphological changes were observed by fluorescence microscopy with Hoechst 33258 staining.

Clonidine, moxonidine, folic acid, and mecobalamin improve baroreflex function in stroke-prone, spontaneously hypertensive rats.

Aim: To investigate the effect of clonidine, moxonidine, folic acid, and mecobalamin on arterial baroreflex (ABR) function in stroke-prone spontaneously hypertensive rats (SHR-SP) and the possible mechanisms involved.

Methods: Eighty-one SHR-SP were divided into 7 groups. Four groups were designated for the intragastric (ig) administration of clonidine (1.