Biomedical subjects

Zhe Lu

Publications and source records attributed to Zhe Lu.

At least 19 recordsLinked to original sources

PubMed2026

Distinct contributions of schizophrenia and neurotransmitter pathway genetic liability to neurocognition and antipsychotic efficacy in drug-naïve first-episode schizophrenia.

The genetic mechanisms underlying heterogeneity in symptom presentation and antipsychotic response in schizophrenia remain unclear, limiting the development of personalized treatment. We integrated genome-wide schizophrenia polygenic risk scores (SZ-PRS) and pathway-specific PRSs (pPRSs) for four major neurotransmitter systems to examine their associations with clinical phenotypes across the course of illness. Primary analyses were conducted in 394 drug-naïve, first-episode patients from the Chinese First-Episode Schizophrenia Trial (CNFEST) to investigate associations with baseline symptom severity, neurocognitive impairment, and longitudinal treatment response. The CNFEST cohort included 52-week longitudinal assessments of symptoms and neurocognition using the Positive and Negative Syndrome Scale and a modified version of the MATRICS Consensus Cognitive Battery. An independent case-control cohort evaluated associations with schizophrenia diagnosis, while a cohort of 514 healthy adults assessed whether PRS-cognition associations are specific to schizophrenia. Higher SZ-PRS predicted schizophrenia diagnosis (OR = 2.28, Pfdr = 0.003) and poorer baseline executive function (β = -0.44, Pfdr = 0.006) and working memory (β = -0.49, Pfdr = 0.018), but these associations were absent in healthy adults. In contrast, pPRSs showed weaker associations with diagnosis and baseline cognition but were more informative for treatment outcomes: higher serotonin-pPRS predicted greater improvement in depressive symptoms (Pfdr = 0.023-0.032), and higher GABA-pPRS predicted greater improvement in overall symptoms (Pfdr = 0.038-0.043) during weeks 4-24. Exploratory drug-specific analyses further suggested that treatment response varied across antipsychotics and was differentially associated with pPRSs. These findings demonstrate that genome-wide and pathway-specific PRSs contribute distinctly to schizophrenia phenotypes, supporting their integration for personalized stratification and treatment.

Humans↗

PubMed2026

B cell pathways implicate shared genetic architecture between schizophrenia and immune-mediated diseases.

BACKGROUND: Schizophrenia and immune-mediated diseases are globally prevalent and highly heritable conditions that frequently co-occur, posing major public health burdens. However, their shared genetic architecture remains poorly understood. METHODS: We applied the bivariate causal mixture model (MiXeR) to investigate the polygenic overlap between schizophrenia and eight common immune-mediated diseases, using genome-wide association study summary statistics comprising 2,489 to 67,323 cases and 9,066 to 497,622 controls. Shared loci were identified through conditional/conjunctional false discovery rate (cond/conjFDR), local genetic correlation (LAVA), and colocalization analyses. Subsequently, gene mapping, functional annotation, expression-trait association, and drug-gene interaction analyses were performed to explore shared genes and enriched pathways, and genetic risk scores (GRS) from the UK Biobank were used to validate the findings. RESULTS: MiXeR estimated substantial polygenic overlap between schizophrenia and immune-mediated diseases, and conjFDR identified 133 shared loci, with eight prioritized through local genetic correlation and colocalization signals. These eight loci were mapped to 85 protein-coding genes enriched in pathways essential for B cell function. Among them, S-PrediXcan analyses identified 14 genes whose expression in brain tissues or blood was associated with both diseases. These genes also interact with immunomodulatory or antihypertensive drugs. Additionally, 11 of the 14 genes were linked to innate immunity and/or cognitive traits. Using UK Biobank data, we further confirmed that overall, shared gene, and B cell activation and receptor signaling pathway–specific genetic risk for schizophrenia is associated with immune-mediated disease susceptibility. CONCLUSIONS: These findings underscore the shared genetic architecture of schizophrenia and immune-mediated diseases, advancing insights at the interface of psychiatric genetics and immunology.

Schizophrenia↗

PubMed2006

Preparation and evaluation of lectin-conjugated PLGA nanoparticles for oral delivery of thymopentin.

The purpose of this study was to design and evaluate lectin-conjugated PLGA nanoparticles for oral delivery of thymopentin. Thymopentin loaded PLGA nanoparticles (TP5-NPs) were prepared by a double emulsion-solvent evaporation technique. Novel WGA-PLGA conjugates were synthesized by coupling the amino groups of wheat germ agglutinin (WGA) to the carbodiimide-activated carboxylic groups of PLGA, and were incorporated into nanoparticles preparation to take mucoadhesive properties. Important characteristics such as particle size, zeta potential, entrapment efficiency, storage stability, as well as in vitro drug release behavior were investigated. The retention of biorecognitive activity of WGA after covalent coupling was confirmed by haemagglutination test. In vitro experiments with pig mucin (PM) demonstrated that the conjugation of WGA enhanced the interaction about 1.8-4.2 fold compared with that of the non-conjugated nanoparticles, and still exhibited sugar specificity. The pharmacodynamical studies on oral administration of WGA-TP5-NPs were performed in FACScan flow cytometry. The values of CD4(+)/CD8(+) ratios were significantly increased compared with that of TP5-NPs (p<0.01). The enhanced uptake was related to the increasing of WGA content on nanoparticles. These results confirmed that the conjugation of WGA onto PLGA nanoparticles effectively improved the intestinal absorption of TP5 due to specific bioadhesion on GI cell membrane.

Adjuvants, Immunologic↗

PubMed2006

Enzymatic activation of voltage-gated potassium channels.

Voltage-gated ion channels in excitable nerve, muscle, and endocrine cells generate electric signals in the form of action potentials. However, they are also present in non-excitable eukaryotic cells and prokaryotes, which raises the question of whether voltage-gated channels might be activated by means other than changing the voltage difference between the solutions separated by the plasma membrane. The search for so-called voltage-gated channel activators is motivated in part by the growing importance of such agents in clinical pharmacology. Here we report the apparent activation of voltage-gated K+ (Kv) channels by a sphingomyelinase.

Animals↗

PubMed2006

Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.

Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.

Alendronate↗

PubMed2006

[Clinical application and processing of separate movable partial denture].

OBJECTIVE: This report is to introduce the processing method of the separate movable partial denture and get an initial clinical evaluation. METHODS: The separate movable partial denture was developed as a kind of special design in utilizing double base plate to separately get support for bearing stress and get the stability of retention. RESULTS: The clinical application indicated that the separate movable partial denture has effective function of common movable partial denture as well as has a good function of natural human teeth protection, especially for those patients with I -II tooth loose. CONCLUSION: The separate movable partial denture is the ideal choice of treatment for those patients who are suffering I - II teeth loose. This type of movable partial denture was considered effectively protect natural human teeth and extend the lifetime of natural tooth long-term and further observation in clinical care on this type of denture is needed.

Dental Abutments↗

PubMed2005

Mechanism of the voltage sensitivity of IRK1 inward-rectifier K+ channel block by the polyamine spermine.

IRK1 (Kir2.1) inward-rectifier K+ channels exhibit exceedingly steep rectification, which reflects strong voltage dependence of channel block by intracellular cations such as the polyamine spermine. On the basis of studies of IRK1 block by various amine blockers, it was proposed that the observed voltage dependence (valence approximately 5) of IRK1 block by spermine results primarily from K+ ions, not spermine itself, traversing the transmembrane electrical field that drops mostly across the narrow ion selectivity filter, as spermine and K+ ions displace one another during channel block and unblock. If indeed spermine itself only rarely penetrates deep into the ion selectivity filter, then a long blocker with head groups much wider than the selectivity filter should exhibit comparably strong voltage dependence. We confirm here that channel block by two molecules of comparable length, decane-bis-trimethylammonium (bis-QA(C10)) and spermine, exhibit practically identical overall voltage dependence even though the head groups of the former are much wider ( approximately 6 A) than the ion selectivity filter ( approximately 3 A). For both blockers, the overall equilibrium dissociation constant differs from the ratio of apparent rate constants of channel unblock and block. Also, although steady-state IRK1 block by both cations is strongly voltage dependent, their apparent channel-blocking rate constant exhibits minimal voltage dependence, which suggests that the pore becomes blocked as soon as the blocker encounters the innermost K+ ion. These findings strongly suggest the existence of at least two (potentially identifiable) sequentially related blocked states with increasing numbers of K+ ions displaced. Consequently, the steady-state voltage dependence of IRK1 block by spermine or bis-QA(C10) should increase with membrane depolarization, a prediction indeed observed. Further kinetic analysis identifies two blocked states, and shows that most of the observed steady-state voltage dependence is associated with the transition between blocked states, consistent with the view that the mutual displacement of blocker and K+ ions must occur mainly as the blocker travels along the long inner pore.

Animals↗

PubMed2005

Visible study of mercuric ion and its conjugate in living cells of mammals and plants.

The investigation of mercuric ion and mercuric conjugate inside live specimens has drawn intense attention because of their cytotoxicity. The translocation, transportation, and distribution of Hg2+ inside either mammals or plants, however, are still invisible due to the lack of favorable fluorescent molecular sensors for Hg2+. Here, two sensors, 2,6-bis(4'-peperazino-N'-hydroxylethoxylethylene-1',8'-naphthalimide)dimethylpyridine and 2,6-bis(4'-peperazino-N'-butyl-1',8'-naphthalimide)dimethylpyridine, which were composed of nitrogen atoms of 2,6-bis(aminomethyl)pyridine as the ion receptor and the donor of photoinduced electron transfer, were applied to the cultured mammalian cells and plant cells. Their membrane permeability, low toxicity, slow bleaching/fading, and high selectivity and sensitivity to Hg2+ in a live cell rendered them attractive to become real-time and real-space sensors. For the first time, the transportation of Hg2+ cation and Hg2+ conjugate of cysteine was observed with the help of a fluorescence microscope. The chloroplast location of Hg2+ in transgenic tobacco was also visible.

Animals↗

PubMed2005

Evidence for sequential ion-binding loci along the inner pore of the IRK1 inward-rectifier K+ channel.

Steep rectification in IRK1 (Kir2.1) inward-rectifier K(+) channels reflects strong voltage dependence (valence of approximately 5) of channel block by intracellular cationic blockers such as the polyamine spermine. The observed voltage dependence primarily results from displacement, by spermine, of up to five K(+) ions across the narrow K(+) selectivity filter, along which the transmembrane voltage drops steeply. Spermine first binds, with modest voltage dependence, at a shallow site where it encounters the innermost K(+) ion and impedes conduction. From there, spermine can proceed to a deeper site, displacing several more K(+) ions and thereby producing most of the observed voltage dependence. Since in the deeper blocked state the leading amine group of spermine reaches into the cavity region (internal to the selectivity filter) and interacts with residue D172, its trailing end is expected to be near M183. Here, we found that mutation M183A indeed affected the deeper blocked state, which supports the idea that spermine is located in the region lined by the M2 and not deep in the narrow K(+) selectivity filter. As to the shallower site whose location has been unknown, we note that in the crystal structure of homologous GIRK1 (Kir3.1), four aromatic side chains of F255, one from each of the four subunits, constrict the intracellular end of the pore to approximately 10 A. For technical simplicity, we used tetraethylammonium (TEA) as an initial probe to test whether the corresponding residue in IRK1, F254, forms the shallower site. We found that replacing the aromatic side chain with an aliphatic one not only lowered TEA affinity of the shallower site approximately 100-fold but also eliminated the associated voltage dependence and, furthermore, confirmed that similar effects occurred also for spermine. These results establish the evidence for physically separate, sequential ion-binding loci along the long inner pore of IRK1, and strongly suggest that the aromatic side chains of F254 underlie the likely innermost binding locus for both blocker and K(+) ions in the cytoplasmic pore.

Amino Acid Sequence↗

PubMed2004

Characterization of inward-rectifier K+ channel inhibition by antiarrhythmic piperazine.

Strong inward-rectifier K(+) (Kir) channels play a significant role in shaping the cardiac action potential: they help produce its long plateau and accelerate its rate of repolarization. Consequently, genetic deletion of the gene encoding the strongly rectifying K(+) channel IRK1 (Kir2.1) prolongs the cardiac action potential in mice. In principle, broadening the action potential lengthens the refractory period, which may in turn be antiarrhythmogenic. Interestingly, previous studies showed that piperazine, an inexpensive and safe anthelmintic, both inhibits IRK1 channels and is antiarrhythmic in some animal preparations. This potential pharmacological benefit motivated us to further characterize the energetic, kinetic, and molecular properties of IRK1 inhibition by piperazine. We show how its blocking characteristics, in particular, its shallow voltage dependence, allow piperazine to be effective even in the presence of high-affinity polyamine blockers. We also examine the channel selectivity of piperazine and its molecular determinants.

Animals↗

PubMed2004

Short variable sequence acquired in evolution enables selective inhibition of various inward-rectifier K+ channels.

Tertiapin (TPN), a small protein toxin originally isolated from honey bee venom, inhibits only certain eukaryotic inward-rectifier K(+) (Kir) channels with high affinity. We found that a short ( approximately 10 residues) sequence in Kir channels, located in the N-terminal part of the linker between the two transmembrane segments, is essential for high-affinity inhibition by TPN and that variability in the region underlies the great variation of TPN affinities among eukaryotic Kir channels. This short variable region is however not present in a bacterial Kir channel (KirBac1.1) or in many other types of prokaryotic and eukaryotic K(+) channels. Thus, the acquisition in evolution of the variable region in eukaryotic Kir channels has created the opportunity to selectively target the numerous types of Kir channel that play important physiological roles. We also show that TPN sensitivity can be readily conferred onto some Kir channels that currently have no known inhibitors by replacing their variable region with that from a TPN-sensitive channel. In heterologous expression systems, such acquired toxin sensitivity will allow currents carried by mutant channels to be readily isolated from interfering background currents. Finally we show that, in the heteromeric GIRK1/4 channels, the GIRK4 and not GIRK1 subunit confers the high affinity for TPN.

Amino Acid Sequence↗

PubMed2004

Fluorescent imaging of acute mercuric chloride exposure on cultured human kidney tubular epithelial cells.

BACKGROUND: Imaging of intracellular mercuric ion is necessary for mechanism of renal toxicity of exposure to HgCl2. The distribution of Hg2+ inside a living cell, however, is still invisible due to the lack of high selective and sensitive fluorescent molecular probe for Hg2+. METHODS: A new fluorescent probe, EPNP, was applied to the cultured cells of human kidney proximal tubular epithelial cell line (HKC) in the presence of HgCl2 and some other bivalent ions. The relative fluorescence intensity of EPNP was measured and fluorescence images were taken by laser scanning confocal microscope. RESULTS: Results showed it led to an Hg2+ concentration- and time-dependent increase in fluorescence intensity, and responded weakly for some other heavy and transition metal ions. It could be seen during acute exposure on HKC cells, Hg2+ locate perinuclear, and on nuclear membrane, which was beyond what one knew before. CONCLUSION: EPNP is a real-time and on-line probe for imaging Hg2+ in a living cell due to its high selectivity and sensitivity for Hg2+ and slow bleaching/fading. Both the probe and the new results about the distribution of intracellular Hg2+ may be helpful for relevant biologic research.

Cells, Cultured↗

PubMed2004

Mechanism of rectification in inward-rectifier K+ channels.

Inward rectifiers are a class of K+ channels that can conduct much larger inward currents at membrane voltages negative to the K+ equilibrium potential than outward currents at voltages positive to it, even when K+ concentrations on both sides of the membrane are made equal. This conduction property, called inward rectification, enables inward rectifiers to perform many important physiological tasks. Rectification is not an inherent property of the channel protein itself, but reflects strong voltage dependence of channel block by intracellular cations such as Mg2+ and polyamines. This voltage dependence results primarily from the movement of K+ ions across the transmembrane electric field along the pore, which is energetically coupled to the blocker binding and unbinding. This mutual displacement mechanism between several K+ ions and a blocker explains the signature feature of inward rectifier K+ channels, namely, that at a given concentration of intracellular K+, their macroscopic conductance depends on the difference between membrane voltage and the K+ equilibrium potential rather than on membrane voltage itself.

Animals↗

PubMed2004

[Effect of combination of Ginkgo leaf extract and deferoxamine in preventing and treating ototoxicity of cisplatin].

OBJECTIVE: To observe the effect of combined use of jinnaduo (an injection made by extract of Ginkgo leaf, EGb) and Deferoxamine (DFO, a chelating agent) in antagonizing the ototoxicity of cisplatin (CDDP). METHODS: Guinea pigs were randomly divided into the CDDP group, the EGb group, the DFO group, the combined treated group (EGb + DFO) and the control group. Changes of auditory brain-stem response (ABR), serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) content, as well as light and scanning electronic microscopic (SEM) figures were observed before and after treatment. RESULTS: The threshold of ABR was significantly higher in the CDDP group than that in the other groups (P<0.01), but was insignificantly different among the latter groups (P>0.05). Serum SOD activity was lower and MDA content was higher in the CDDP group than those in the control group (P<0.01), but in comparison of the two parameters between control and other groups, the difference was insignificant (P>0.05). SEM examination on cochlea showed that the damage of hair cells was milder in the DFO group and the combined treated group than that in the CDDP group, which was slightly milder in the EGb group than that in the CDDP group. CONCLUSION: Combined use of EGb and DFO could effectively reduce the ototoxicity of CDDP, its effect is better than using EGb singly, and similar to that of using DFO alone. The combination could also prevent the side-effect of CDDP in bone marrow inhibition. The Fe ion participated free radical response could be one of the mechanisms of CDDP in damaging hearing.

Animals↗

PubMed2004

[Short-term follow-up study of Cercon all-ceramic crowns and bridges].

OBJECTIVE: Cercon all-ceramic system was applied clinically for the first time to make all-ceramic crowns and bridges for the patients. The objective of this study was to evaluate the short-term follow-up results of this new system from both technical and clinical aspects. METHODS: 15 units of Cercon all-ceramic crowns and bridges were fabricated and applied to 5 patients, all the cases were followed at 1, 3, 6 and 12 months' periods after cementation of the restorations. RESULTS: Cercon all-ceramic system demonstrate natural and esthetical appearance. No fracture, broken and color change were found. CONCLUSION: The reliability of all-ceramic crowns and bridges made from Cercon system was greatly improved due to the strengthening effects of the zirconia copings and substructures, and the indication of this system can be extended to long span posterior bridges. In addition, the better esthetics compared to PFM technique makes it a comparatively ideal all-ceramic system for crowns and bridges.

Crowns↗

PubMed2003

Mechanism of rectification in inward-rectifier K+ channels.

Rectification in inward-rectifier K+ channels is caused by the binding of intracellular cations to their inner pore. The extreme sharpness of this rectification reflects strong voltage dependence (apparent valence is approximately 5) of channel block by long polyamines. To understand the mechanism by which polyamines cause rectification, we examined IRK1 (Kir2.1) block by a series of bis-alkyl-amines (bis-amines) and mono-alkyl-amines (mono-amines) of varying length. The apparent affinity of channel block by both types of alkylamines increases with chain length. Mutation D172N in the second transmembrane segment reduces the channel's affinity significantly for long bis-amines, but only slightly for short ones (or for mono-amines of any length), whereas a double COOH-terminal mutation (E224G and E299S) moderately reduces the affinity for all bis-amines. The apparent valence of channel block increases from approximately 2 for short amines to saturate at approximately 5 for long bis-amines or at approximately 4 for long mono-amines. On the basis of these and other observations, we propose that to block the channel pore one amine group in all alkylamines tested binds near the same internal locus formed by the COOH terminus, while the other amine group of bis-amines, or the alkyl tail of mono-amines, "crawls" toward residue D172 and "pushes" up to 4 or 5 K+ ions outwardly across the narrow K+ selectivity filter. The strong voltage dependence of channel block therefore reflects the movement of charges carried across the transmembrane electrical field primarily by K+ ions, not by the amine molecule itself, as K+ ions and the amine blocker displace each other during block and unblock of the pore. This simple displacement model readily accounts for the classical observation that, at a given concentration of intracellular K+, rectification is apparently related to the difference between the membrane potential and the equilibrium potential for K+ ions rather than to the membrane potential itself.

Animals↗

PubMed2003

Interaction mechanisms between polyamines and IRK1 inward rectifier K+ channels.

Rectification of macroscopic current through inward-rectifier K+ (Kir) channels reflects strong voltage dependence of channel block by intracellular cations such as polyamines. The voltage dependence results primarily from the movement of K+ ions across the transmembrane electric field, which accompanies the binding-unbinding of a blocker. Residues D172, E224, and E299 in IRK1 are critical for high-affinity binding of blockers. D172 appears to be located somewhat internal to the narrow K+ selectivity filter, whereas E224 and E299 form a ring at a more intracellular site. Using a series of alkyl-bis-amines of varying length as calibration, we investigated how the acidic residues in IRK1 interact with amine groups in the natural polyamines (putrescine, spermidine, and spermine) that cause rectification in cells. To block the pore, the leading amine of bis-amines of increasing length penetrates ever deeper into the pore toward D172, while the trailing amine in every bis-amine binds near a more intracellular site and interacts with E224 and E299. The leading amine in nonamethylene-bis-amine (bis-C9) makes the closest approach to D172, displacing the maximal number of K+ ions and exhibiting the strongest voltage dependence. Cells do not synthesize bis-amines longer than putrescine (bis-C4) but generate the polyamines spermidine and spermine by attaching an amino-propyl group to one or both ends of putrescine. Voltage dependence of channel block by the tetra-amine spermine is comparable to that of block by the bis-amines bis-C9 (shorter) or bis-C12 (equally long), but spermine binds to IRK1 with much higher affinity than either bis-amine does. Thus, counterintuitively, the multiple amines in spermine primarily confer the high affinity but not the strong voltage dependence of channel block. Tetravalent spermine achieves a stronger interaction with the pore by effectively behaving like a pair of tethered divalent cations, two amine groups in its leading half interacting primarily with D172, whereas the other two in the trailing half interact primarily with E224 and E299. Thus, nature has optimized not only the blocker but also, in a complementary manner, the channel for producing rapid, high-affinity, and strongly voltage-dependent channel block, giving rise to exceedingly sharp rectification.

Animals↗

PubMed2002

IRK1 inward rectifier K(+) channels exhibit no intrinsic rectification.

In intact cells the depolarization-induced outward IRK1 currents undergo profound relaxation so that the steady-state macroscopic I-V curve exhibits strong inward rectification. A modest degree of rectification persists after the membrane patches were perfused with artificial solutions devoid of Mg(2+) and polyamines, which has been interpreted as a reflection of intrinsic channel gating and led to the view that inward rectification results from enhancement of the intrinsic gating by intracellular cations rather than simple pore block. Furthermore, IRK1 exhibits significant extracellular K(+)-sensitive relaxation of its inward current, a feature that has been likened to the C-type inactivation observed in the voltage-activated Shaker K(+) channels. We found that both these current relaxations can be accounted for by impurities in some common constituents of recording solutions, such as residual hydroxyethylpiperazine in HEPES and ethylenediamine in EDTA. Therefore, inherently, IRK1 channels are essentially ohmic at the macroscopic level, and the voltage jump-induced current relaxations do not reflect IRK1 gating but the unusually high affinity of its pore for cations. Furthermore, our study helps define the optimal experimental conditions for studying IRK1.

Animals↗