Biomedical subjects

Feng Han

Publications and source records attributed to Feng Han.

At least 19 recordsLinked to original sources

PubMed2026

Integrative multi-omics identifies DOC2A as a novel pharmacological target for bipolar disorder.

BACKGROUND: Current bipolar disorder (BD) therapies suffer from limited efficacy and adverse effects, necessitating mechanistically grounded targets. METHODS: We integrated BD genome-wide association study data (158,036 cases; 2,796,499 controls) with brain proteomics (ROSMAP and Banner dorsolateral prefrontal cortex, n = 376 and 152) to perform proteome-wide association studies (PWAS). Bayesian colocalization and summary-data-based Mendelian randomization (SMR) prioritized causal genes. Cell-type-specific transcriptomics validated dysregulation in iPSC-derived neurons, astrocytes, and postmortem hippocampus/prefrontal cortex. Weighted gene co-expression networks (WGCNAs), functional enrichment, and molecular docking assessed functional pathways and druggability. RESULTS: PWAS identified eight BD-associated genes (false discovery rate < 0.05), with DOC2A emerging as the top candidate. Colocalization (H4 > 0.8) and SMR supported a causal association of DOC2A with BD, with no pleiotropy (heterogeneity in dependent instruments P > 0.01); DOC2A expression decreased in BD across neurons (P = 4.26 × 10-2), astrocytes (P = 2.09 × 10-2), hippocampus (P = 9.80 × 10-3, t = -2.738), and prefrontal cortex (P = 1.44 × 10-2, t = -2.580); WGCNA positioned DOC2A as a key regulator (module membership/gene significance P < 0.05) of co-expression networks enriched for BD-associated processes including neurotransmitter secretion and postsynaptic actin cytoskeleton organization (P < 0.05); molecular docking revealed favorable-affinity binding (ΔG < -4 kcal/mol) between DOC2A and BD-related drugs and neuroprotective compounds. CONCLUSIONS: Our convergent multi-omics framework highlights DOC2A dysregulation as a key contributor to synaptic dysfunction in BD and nominates it as a promising therapeutic target. The demonstrated interaction with existing neuroactive compounds provides immediate translational avenues.

Bipolar Disorder↗

PubMed2007

Augmented chemosensitivity in black-eyed white Mitfmi-bw mice, lacking melanocytes.

Microphthalmia-associated transcription factor (Mitf) is responsible for differentiation of melanocytes, and a recessive Mitf mutant, black-eyed white (bw) mouse, is characterized by the lack of melanocytes in the skin and inner ear. To search for the hitherto unknown roles of melanocytes, we analysed the ventilatory responses of unanaesthetized bw mice by whole body plethysmography. During air breathing, bw mice showed lower breathing frequency and larger tidal volume, compared with age-matched wild-type mice, although there was no difference in the minute ventilation. Importantly, bw mice present normal haematocrit values and red blood cell counts. We next measured the immediate ventilatory responses to acute hypoxia (10% O2) and to hyperoxic hypercapnia (10% CO2). Hypoxic and hypercapnic ventilatory responses represent the functions of the chemoreceptors in the carotid body and the brainstem, respectively. The bw mice retain the peripheral hypoxic and central hypercapnic sensing functions, but exhibited augmented ventilatory responses to both hypoxia and hypercapnia. Unexpectedly, RT-PCR analysis has shown the expression of melanocyte-specific Mitf mRNA in the brain of bw mice, suggesting the presence of leptomeningeal melanocytes. These findings suggest a functional link between skin melanocytes and the central respiratory controller that generates respiratory rhythm and pattern.

Animals↗

PubMed2007

Simple bis-thiocarbono-hydrazones as sensitive, selective, colorimetric, and switch-on fluorescent chemosensors for fluoride anions.

Bis-thiocarbono-hydrazones are found to be a class of sensitive, selective, ratiometric, and colorimetric chemosensors for anions such as fluoride (F(-)) or acetate (Ac(-)). The sensitivities, or the binding constants of the sensors with anions, were found to be strongly dependent on the substituents appended on the pi-conjugation framework, the delocalization bridge CH==N, the aromatic moiety, and the hetero atom in the C==X group (X=O, S) of the sensors. Single-crystal structures and (1)H NMR titration analysis shows that the --CH==N-- moiety is a hydrogen-bond donor, and it is proposed that an additional CHF hydrogen bond is formed for the sensors in the presence F(-). A sensor bearing anthracenyl groups is demonstrated as a switch-on fluorescent chemosensor for F(-) and Ac(-). The recognition of F(-) in acetonitrile (MeCN) by a sensor with nitrophenyl substituents is tolerant to MeOH (MeCN/MeOH=10:1, v/v) and water (MeCN/H(2)O=30:1, v/v); at these solvent ratios the absorption intensity of the sensor-F(-) complex solution at maximal absorption wavelength was attenuated to half of the original value in pure MeCN.

Absorption↗

PubMed2006

Molecular cloning and characterization of a novel beta-agarase, AgaB, from marine Pseudoalteromonas sp. CY24.

Agarases are generally classified into glycoside hydrolase families 16, 50, and 86 and are found to degrade agarose to frequently generate neoagarobiose, neoagarotetraose, or neoagarohexaose as the main products. In this study we have cloned a novel endo-type beta-agarase gene, agaB, from marine Pseudoalteromonas sp. CY24. The novel agarase encoded by agaB gene has no significant sequence similarity with any known proteins including all glycoside hydrolases. It degrades agarose to generate neoagarooctaose and neoagarodecaose as the main end products. Based on the analyses of enzymatic kinetics and degradation patterns of different oligosaccharides, the agarase AgaB appears to have a large substrate binding cleft that accommodates 12 sugar units, with 8 sugar units toward the reducing end spanning subsites +1 to +8 and 4 sugar units toward the non-reducing end spanning subsites -4 to -1, and enzymatic cleavage taking place between subsites -1 and +1. In addition, 1H NMR analysis shows that this enzyme hydrolyzes the glycosidic bond with inversion of anomeric configuration, in contrast to other known agarases that are retaining. Altogether, AgaB is structurally and functionally different from other known agarases and appears to represent a new family of glycoside hydrolase.

Cloning, Molecular↗

PubMed2006

Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model.

Lithium used in bipolar mood disorder therapy protects neurons from brain ischemic cell death. Here, we documented that lithium administration under microsphere-embolism (ME)-induced brain ischemia restored decreased protein kinase B (Akt) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activities 24 h after ischemia in rat brain. Akt activation was associated with increased phosphorylation of its potential targets forkhead transcription factor (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). In parallel with decreased CaMKII autophosphorylation, we also found marked dephosphorylation of tau proteins 24-72 h after ME. Increased protein phosphatase 2A (PP2A) activity was found 24 h after ME. Inhibition of increased PP2A activity by lithium treatment apparently mediated restored tau phosphorylation. Taken together, activation of Akt and CaMKII by lithium was associated with neuroprotective activity in ME-induced neuronal injury.

Animals↗

PubMed2006

Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice.

Olfactory bulbectomized (OBX) mice showed significant impairment of learning and memory-related behaviors 14 days after olfactory bulbectomy, as measured by passive avoidance and Y-maze tasks. We here observed a large impairment of hippocampal long-term potentiation (LTP) in the OBX mice. Concomitant with decreased acetylcholinesterase expression, protein kinase C (PKC)alpha autophosphorylation and NR1(Ser-896) phosphorylation significantly decreased in the hippocampal CA1 region of OBX mice. Both PKCalpha and NR1(Ser-896) phosphorylation significantly increased following LTP in the control mice, whereas increases were not observed in OBX mice. Like PKC activities, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in the hippocampal CA1 region of OBX mice as compared with that of control mice. In addition, increased CaMKII autophosphorylation following LTP was not observed in OBX mice. Finally, the impairment of CaMKII autophosphorylation was closely associated with reduced pGluR1(Ser-831) phosphorylation, without change in synapsin I (site 3) phosphorylation in the hippocampal CA1 region of OBX mice. Taken together, in OBX mice NMDA receptor hypofunction, possibly through decreased PKCalpha activity, underlies decreased CaMKII activity in the post-synaptic regions, thereby impairing LTP induction in the hippocampal CA1 region. Both decreased PKC and CaMKII activities with concomitant LTP impairment account for the learning disability observed in OBX mice.

Acetylcholine↗

PubMed2006

Transitions of organized assemblies in mixed systems of cationic bolaamphiphile and anionic conventional surfactants.

The transition from vesicles to tubelike structures has been studied in mixed systems of cationic bolaamphiphile BPHTAB [biphenyl-4,4'-bis(oxyhexamethylenetrimethylammonium bromide)] and its oppositely charged conventional surfactants with transmission electron microscopy (TEM) and dynamic light scattering (DLS). This transition can be attributed to the fact that tube-like structures are more stable aggregates than vesicles because of the special molecular packing in the aggregates of the mixed systems. The effects of temperature and salt addition on this transition have also been investigated, and the rate of the transition was found to be strongly dependent on temperature. Addition of the appropriate amount of NaBr will accelerate the transition from vesicles to tube-like structures, but the vesicles will transform into micelles at higher salt concentration. Moreover, the micelle-vesicle transition can be realized by addition of n-octanol in the mixed system of BPHTAB/sodium caprate (SC) at higher salt concentrations.

Journal Article↗

PubMed2006

3-[2-[4-(3-Chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydro-chloride 3.5 hydrate (DY-9760e) is neuroprotective in rat microsphere embolism: role of the cross-talk between calpain and caspase-3 through calpastatin.

Microsphere embolism (ME)-induced cerebral ischemia can elicit various pathological events leading to neuronal death. Western blotting and immunohistochemical studies revealed that expression of calpastatin, an endogenous calpain inhibitor, decreased after ME induction. Calpain activation after ME was apparently due to, in part, a decrease in calpastatin in a late phase of neuronal injury. The time course of that decrease also paralleled caspase-3 activation. In vitro studies demonstrated that calpastatin was degraded by caspase-3 in a Ca(2+)/calmodulin (CaM)-dependent manner. Because CaM binds directly to calpastatin, we asked whether a novel CaM antagonist, 3-[2-[4-(3-chloro-2-methylphenylmethyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydro-chloride 3.5 hydrate (DY-9760e), inhibits caspase-3-induced calpastatin degradation during ME-induced neuronal damage. We also tested the effect of DY-9760e on degradation of fodrin, a calpain substrate. Consistent with our hypothesis, DY-9760e (25 or 50 mg/kg i.p.) treatment inhibited degradation of calpastatin and fodrin in a dose-dependent manner. Because DY-9760e showed powerful neuroprotective activity with concomitant inhibition of calpastatin degradation, cross-talk between calpain and caspase-3 through calpastatin possibly accounts for ME-induced neuronal injury. Taken together, both inhibition of caspase-3-induced calpastatin degradation and calpain-induced fodrin breakdown by DY-9760e in part mediate its neuroprotective action.

Animals↗

PubMed2006

Microsphere embolism-induced endothelial nitric oxide synthase expression mediates disruption of the blood-brain barrier in rat brain.

Microsphere embolism (ME)-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was observed 2-48 h after ischemia. eNOS induction preceded disruption of the blood-brain barrier (BBB) observed 6-72 h after ischemia. In vascular endothelial cells, ME-induced eNOS expression was closely associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. Leakage of rabbit IgG from microvessels was also evident around protein tyrosine nitration-immunoreactive microvessels. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates BBB disruption in the ME brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), which inhibits eNOS activity and, in turn, protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY-9760e significantly inhibited BBB disruption as assessed by Evans blue (EB) excretion. DY-9760e also inhibited cleavage of poly (ADP-ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY-9760e inhibited brain edema, ME-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and, in turn, brain edema.

Animals↗

PubMed2006

DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart.

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride-3.5 hydrate) inhibits Ca(2+)/CaM-dependent nitric oxide synthase (NOS), thereby inhibiting nitric oxide (NO) production. In cardiomyocytes from ischemic rat heart NO and superoxide levels are increased causing protein tyrosine nitration. In hearts subjected to ischemia/reperfusion DY-9760e totally abolishes protein tyrosine nitration. Notably, DY-9760e also inhibits calpain and cas-pase-3 activation that occurs prior to apoptosis in cardiomyocytes. In ischemic hearts fodrin is the substrate for calpain. DY-9760e inhibits fodrin breakdown in the peri-infarct area rather than in the infarct core. In the ischemic rat brain DY-9760e inhibits caspase-3-induced proteolysis of calpastatin, an endogenous calpain inhibitor, suggesting that crosstalk between calpain and caspase-3 is mediated by calpastatin breakdown. Thus, DY-9760e rescues neurons and cardiomyocytes from ischemic injury by inhibiting crosstalk between calpain and caspase-3 as well as protein tyrosine nitration.

Animals↗

PubMed2005

Lipocalin-type prostaglandin D synthase as a melanocyte marker regulated by MITF.

Microphthalmia-associated transcription factor (MITF) is responsible for differentiation of melanocytes. A recessive MITF mutant, black-eyed white Mitf(mi-bw) mouse, is characterized by white coat color and deafness, due to the lack of melanocytes in the skin and inner ears. By cDNA microarray analysis, we have identified lipocalin-type prostaglandin D synthase (L-PGDS), whose mRNA is undetectable in the homozygous Mitf(mi-bw) skin. Immunohistochemical analysis of wild-type mice identified the specific expression of L-PGDS in follicular melanocytes. L-PGDS mRNA is expressed in B16 mouse melanoma cells, but undetectable in human melanoma cell lines. RNA interference analysis against MITF suggests that L-PGDS expression is dependent on MITF in B16 melanoma cells. Furthermore, we have provided evidence that MITF is involved in the melanocyte lineage-specific transcription of the mouse L-PGDS gene. Thus, L-PGDS represents a newly identified melanocyte marker. MITF may modulate the production of prostaglandin D(2) by activating the L-PGDS gene in melanocytes.

Animals↗

PubMed2005

Cortical sensitivity to visual features in natural scenes.

A central hypothesis concerning sensory processing is that the neuronal circuits are specifically adapted to represent natural stimuli efficiently. Here we show a novel effect in cortical coding of natural images. Using spike-triggered average or spike-triggered covariance analyses, we first identified the visual features selectively represented by each cortical neuron from its responses to natural images. We then measured the neuronal sensitivity to these features when they were present in either natural images or random stimuli. We found that in the responses of complex cells, but not of simple cells, the sensitivity was markedly higher for natural images than for random stimuli. Such elevated sensitivity leads to increased detectability of the visual features and thus an improved cortical representation of natural scenes. Interestingly, this effect is due not to the spatial power spectra of natural images, but to their phase regularities. These results point to a distinct visual-coding strategy that is mediated by contextual modulation of cortical responses tuned to the spatial-phase structure of natural scenes.

Animals↗

PubMed2005

Dynamic changes in expression of heme oxygenases in mouse heart and liver during hypoxia.

Heme oxygenase cleaves heme to form biliverdin, carbon monoxide (CO), and iron, and consists of two structurally related isozymes, HO-1 and HO-2. HO-2 is also known as a potential oxygen sensor. Here we show that the relative CO content in arterial blood, which reflects the total amount of endogenous heme degradation, dynamically changes in mice during acclimatization to normobaric hypoxia (10% O2), with the two peaks at 1 day and 21 days of hypoxia. The expression levels of HO-1 and HO-2 proteins were decreased by 20% and 40%, respectively, in the mouse liver at 7 days of hypoxia, which returned to the basal levels at 14 days. On the other hand, HO-1 and HO-2 proteins were increased 2-fold and 1.3-fold, respectively, in the heart at 28 days of hypoxia. Thus, hypoxia induces or represses the expression of HO-1 and HO-2 in vivo, depending on cellular microenvironments.

Animals↗

PubMed2005

GABAergic neurons express mu-opioid receptors in the ventrolateral orbital cortex of the rat.

Behavioral studies have indicated that GABAergic modulation is involved in the opioid-induced antinociception in the ventrolateral orbital cortex (VLO). The aim of the current study was to examine whether the GABAergic neurons in the rat VLO expressed mu-opioid receptor subtype 1 (MOR1). This study employed immunofluorescence histochemical double-staining technique and showed that a considerable amount of GABA- and MOR1-like immunoreactive neurons existed in layers II-VI in the VLO. Of these GABA-like immunoreactive neurons, 92.0% of them showed MOR1-like immunoreactivities. Similarly, 80.2% of MOR1-like immuoreactive neurons also exhibited GABA-like immunoreactivities. These results provide morphological evidence that opioid-induced antinociception in the VLO might be due to an inhibitory effect by opioid via MOR1 on GABAergic neurons, resulting in disinhibition of VLO projection neurons and leading to activation of the VLO-PAG brainstem descending pain control system to depress the nociceptive inputs at the spinal cord level.

Animals↗

PubMed2005

[Analysis of the treatment of unexpected gallbladder cancer].

OBJECTIVE: To investigate the secondary operation methods and the effects on the prognosis of unexpected gallbladder cancer (UGC). METHODS: A retrospective analysis on the clinical data was made for 41 patients who underwent extended radical excision from June 1995 to December 2002. Among the patients, 12 were male, 29 were female. The average age was 51 years old. The 41 patients had undergone gallbladder excision because of cholecystitis complicated lithiasis of gallbladder (32 cases), polypi of gallbladder or adenoma (9 cases). Postoperative pathology showed that 32 cases were adenocarcinoma of gallbladder, 6 cases were squamous carcinoma, 3 cases were squamous adenocarcinoma. Six cases were on the stage of Nevin I, 16 on Nevin II, 17 on Nevin III, 2 on Nevin IV. The second operation was performed after 6-30 d of the first operation. The second operation chose the improved method of Glenn excision of carcinoma of gallbladder. RESULTS: On the second operation, 14 cases were with lymphatic metastasis, 14 with gallbladder metastasis, 6 with bile duct metastasis, 2 with pancreas metastasis. Fourteen cases were on the stage of Nevin IV, 9 on Nevin V, none on Nevin I, II and III. After the second operation, 1 year survival rate was 100% (41 cases); The three-year survival rate was 53.8% (22 cases); The five-year survival rate was 17.5% (7 cases). CONCLUSION: Extended radical excision is one of the most important methods for the treatment of UGC.

Adult↗

PubMed2005

Inhibition of nitric oxide production and protein tyrosine nitration contribute to neuroprotection by a novel calmodulin antagonist, DY-9760e, in the rat microsphere embolism.

Microsphere embolism (ME)-induced ischemia model in rat resembles to multiple brain embolism in human with several clinical features. We here tested whether nitric oxide (NO) production contributes to the neuronal injury in the ME model. A novel calmodulin antagonist, DY-9760e, having a potent inhibitory effect on neuronal nitric oxide synthase (nNOS), reduced brain infarct size in the ME-induced brain ischemia. Consistent with our previous observation with gerbil ischemia/reperfusion model, DY-9760e completely inhibited NO production immediately after and 24 or 48 h after ME. Unlike the gerbil ischemia/reperfusion model, protein tyrosine nitration markedly increased 6-48 h after ME. DY-9760e treatment completely inhibited the marked increase in the protein tyrosine nitration at 24 h after ME. These results suggest that the inhibition of NO production and protein tyrosine nitration by DY-9760e contribute to its neuroprotective action in the ME-induced brain damage.

Animals↗

PubMed2004

Inhibition of MUC1 expression by indole-3-carbinol.

MUC1 is a large transmembrane glycoprotein overexpressed by a majority of carcinomas. High expression of MUC1 is associated with aggressive tumors, and MUC1 antigen is used as a marker to monitor disease progression in breast cancer patients. Several lines of evidence strongly suggest that the overexpression of MUC1 contributes to cancer progression and metastasis. In this report, we demonstrate that the naturally occurring cancer preventative, indole-3-carbinol (I3C), inhibits the expression of MUC1 in breast cancer cells. I3C inhibited both MUC1 mRNA and protein levels in a dose- and time-dependent manner. This inhibition was seen in the estrogen responsive MCF-7 cells as well as unresponsive MDA-MB-468 cells, indicating that the inhibitory pathway is independent of estrogen receptor. Gene expression studies using the human MUC1 gene promoter connected to a luciferase reporter demonstrated that I3C inhibits the transcription of the MUC1 gene. Promoter deletion studies indicate that the region containing up to 600 bp upstream (-600) of the initiation site is sufficient for inhibition by I3C. Furthermore, I3C represses the activation of transcription mediated by the region between -600 and -450 bp. A putative xenobiotic response element was located within this region but the binding of AhR/Arnt heterodimer to this site was undetectable by electrophoretic mobility shift assays. Our results may point to the existence of a novel pathway of transcriptional inhibition by I3C in cancer cells as well as a new mechanism of MUC1 gene inhibition. Our findings might have implications in the use of I3C as a preventative as well as a therapeutic agent for breast cancer.

Anticarcinogenic Agents↗

PubMed2004

Range image segmentation by an effective jump-diffusion method.

This paper presents an effective jump-diffusion method for segmenting a range image and its associated reflectance image in the Bayesian framework. The algorithm works on complex real-world scenes (indoor and outdoor), which consist of an unknown number of objects (or surfaces) of various sizes and types, such as planes, conics, smooth surfaces, and cluttered objects (like trees and bushes). Formulated in the Bayesian framework, the posterior probability is distributed over a solution space with a countable number of subspaces of varying dimensions. The algorithm simulates Markov chains with both reversible jumps and stochastic diffusions to traverse the solution space. The reversible jumps realize the moves between subspaces of different dimensions, such as switching surface models and changing the number of objects. The stochastic Langevin equation realizes diffusions within each subspace. To achieve effective computation, the algorithm precomputes some importance proposal probabilities over multiple scales through Hough transforms, edge detection, and data clustering. The latter are used by the Markov chains for fast mixing. The algorithm is tested on 100 1D simulated data sets for performance analysis on both accuracy and speed. Then, the algorithm is applied to three data sets of range images under the same parameter setting. The results are satisfactory in comparison with manual segmentations.

Algorithms↗