Biomedical subjects

Hong Zhang

Publications and source records attributed to Hong Zhang.

At least 19 recordsLinked to original sources

PubMed2026

MACS3: A Peak-calling Platform for Bulk and Single-cell Regulatory Genomics.

Since the original publication of Model-based Analysis for ChIP-Seq (MACS), the software has been widely used to identify enriched genomic regions in ChIP-seq, ATAC-seq, CUT&RUN, DNase-seq, and related regulatory genomics assays. Over the years, MACS has evolved substantially, with MACS version 3 (MACS3) now serving as the actively maintained implementation. MACS3 preserves the core MACS framework for fragment pileup, dynamic local background noise, statistical enrichment testing, and peak refinement, while adding functionality needed for contemporary bulk and single-cell workflows. It supports conventional bulk peak calling, paired-end and fragment-based file formats, modular signal processing, direct analysis of single-cell ATAC-seq fragment files, barcode-restricted pseudobulk and cluster-level peak calling, specialized ATAC-seq and variant-calling modules, as well as command-line and programmatic interfaces. MACS3 is distributed through standard software channels and supported by continuous testing across operating systems, Python versions, and CPU architectures. Here we describe the architecture, current capabilities, and recommended use of MACS3, providing an updated reference for applying the MACS framework in contemporary bulk and single-cell regulatory genomics workflows. MACS3 is open-source software available at https://github.com/macs3-project/MACS.

Bioinformatics software↗

PubMed2026

Insights into the mechanism of enhanced tetramethylpyrazine production in dehulled adlay fermented by Bacillus subtilis BJ3-2.

Tetramethylpyrazine (TTMP) is a vital bioactive alkaloid and characteristic flavor compound in fermented foods. Our previous study found that fermentation of adlay by Bacillus subtilis BJ3-2 efficiently accumulates TTMP, whereas the underlying high-yield mechanism remains unclear. This study investigated the fermentation characteristics, gene transcription and protein expression of B. subtilis BJ3-2 in dehulled adlay (BDA) and soybean (BSB), respectively, and elucidated the mechanism responsible for high-yield TTMP production. The results showed that glutamate, leucine and phenylalanine were major free amino acids in BDA. The TTMP yield in BDA at 48 h (6.11 mg/g dry weight) was 360-fold higher than that in BSB. Transcriptomic and proteomic analysis demonstrated that compared with the soybean substrate, dehulled adlay substrate significantly up-regulated the expression of alsSD and ilvBH genes and their encoding proteins in B. subtilis BJ3-2, which were involved in C5-branched dibasic acid metabolism, 2-oxocarboxylic acid metabolism, and valine, leucine and isoleucine biosynthesis. Meanwhile, acetoin degradation was inhibited by down-regulating acetoin dehydrogenase complex (acoABCL) in citrate cycle, glycolysis/gluconeogenesis and carbon metabolism. Additionally, nitrogen metabolism pathway was transcriptionally enhanced to guarantee sufficient ammonium supply. Notably, protein-protein interaction and molecular docking analyses revealed that acetohydroxyacid synthase (ilvBH) interacted tightly with α-acetolactate decarboxylase (alsD), potentially forming a metabolic channel for acetoin synthesis. In conclusion, the efficient synthesis of TTMP in BDA was primarily attributed to the high synthesis and low degradation of acetoin, and the moderate synthesis of ammonium/ammonia. This study provided a theoretical basis for the targeted and efficient biosynthesis of TTMP.

Bacillus subtilis↗

PubMed2026

Novel bacterial hosts and mobile genetic structure of tet(X) variants in tetracycline-contaminated aquatic environment uncovered by culture and long-read metagenomics.

Clinically important tigecycline (3rd-generation tetracycline) resistance tet(X) variants were inferred to have evolutionarily originated from environmental bacteria, and have been recognized among environment, human and animals. However, genetic basis for environmental proliferation and dissemination of tet(X) variants remains ambiguous. This study profiled tet(X) variants at gene, contig, isolate, and community levels in environmental community subjected to long-term stepwise increasing oxytetracycline (1st-generation tetracycline) or tigecycline pressure using long-term microcosm experiments, quantitative PCR, bacterial isolation, whole-genome sequencing, and Nanopore-based long-read metagenomics. We confirmed that both oxytetracycline and tigecycline enriched the abundance of tetracycline resistance genes especially oxytetracycline-enriched tet(X3). Unexpectedly diverse bacterial hosts and genetic structure of tet(X)-positive mobile elements in the environment microbiome were identified using bacterial isolation and long-read Nanopore metagenomics. Pseudomonas defluvii was first reported to carry tet(X3) in the chromosome, forming IS26-tet(X3)-res-ISCR2 circular intermediate to transfer between different DNA molecules. Database mining revealed similar mobile segments have prevailed among animal-derived Acinetobacter species. Unlike the widely reported ISCR2-mediated transfer of tet(X6), we identified a novel mobile multidrug transposon TnAs3 where tet(X6) and class 1 integron co-transferred as its passenger region. Mobile tet(X2)-ere(D)-aadS-erm(F)-blaOXA-347 segment was annotated in Runella, and co-occurrences of tet(X2) and ere(D), aadS, blaOXA-347 were also found in Flavobacterium, Arsenicibacter, Chryseobacterium and Pedobacter. Overall, tetracycline-contaminated aquatic microbiome harboured diverse mobile tet(X)-positive segments which have not yet been acquired by clinical pathogens, and thus served as the genetic pool of tet(X) variants together with indigenous bacterial hosts, especially the newly reported Pseudomonas defluvii. Reducing pollution of older-generation tetracyclines would be a proactive way to mitigate environmental evolution and possible clinical effects of tet(X) variants.

Metagenomics↗

PubMed2026

Plasma proteomics reveal SERPINA1 and CD59 as candidate biomarkers for COVID-19 severity stratification and prognosis prediction.

BACKGROUND: COVID-19 has been closely associated with coagulation abnormalities. However, existing biomarkers, including D-dimer and fibrin degradation products (FDP), exhibit limited accuracy in stratifying disease severity and predicting long-term clinical outcomes. OBJECTIVES: This study aimed to use proteomic analysis to identify plasma biomarkers associated with COVID-19 severity and prognosis, and validate their predictive utility for mortality and thromboembolic complications. METHODS: Plasma proteomic profiles were analyzed across three COVID-19 severity classes. Differential expression analysis and functional analysis were performed. Clustering analysis was used to identify proteins correlated with disease severity. Candidate biomarkers were validated in an independent cohort. Predictive performance of the biomarkers for mortality, sepsis and venous thromboembolism was evaluated using bootstrap-corrected ROC analyses and multivariable regression analyses. RESULTS: Proteomic analysis revealed progressive involvement of the coagulation and complement pathway with increasing disease severity. SERPINA1 and CD59 were identified as candidate biomarkers and exhibited significantly higher plasma levels in severe cases. Bootstrap-corrected ROC analyses demonstrated strong predictive performance: SERPINA1 achieved AUCs of 0.775 and 0.924 for 30-day and 12-month mortality, and CD59 achieved AUCs of 0.720 for sepsis; the combined model further improved prediction of 12-month mortality (AUC 0.946) and sepsis (AUC 0.904), outperforming D-dimer and FDP. Multivariable regression confirmed their independent prognostic value. CONCLUSION: This exploratory study identifies SERPINA1 and CD59 as candidate prognostic biomarkers in COVID-19, highlighting the role of coagulation and complement-related pathways in disease severity and warranting further prospective validation.

Humans↗

PubMed2026

Thermal analysis techniques for microplastic mass quantification: Methodological challenges and standardization needs.

Microplastics (MPs, 1 μm-5 mm) and nanoplastics (NPs, <1 μm) are ubiquitous contaminants requiring standardized quantification methods. This systematic review evaluates thermal analysis techniques for mass-based MP detection, including pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), thermogravimetry-MS (TGA-MS), thermal extraction desorption-GC-MS (TED-GC-MS), and differential scanning calorimetry (DSC). Database searches (Web of Science, from inception to December 1, 2025) following PRISMA guidelines identified studies across seven environmental matrices (water, soil/sediment, atmosphere, biota, human tissues). We identify critical standardization gaps: inconsistent marker ion selection, unvalidated conversion factors for tire and road wear particles (TRWPs), and the absence of certified reference materials for complex matrices. Py-GC-MS demonstrates versatility but suffers from lipid interference in biological samples; TED-GC-MS offers superior sensitivity (sample capacity ∼200× Py-GC-MS) but lacks real-time chromatographic monitoring. To advance data comparability, we propose: (i) harmonized ion selection hierarchies based on specificity-sensitivity balance, (ii) matrix-specific TRWP quantification protocols, and (iii) inter-laboratory validation using environmental reference materials. This review provides a methodological roadmap for standardizing thermal analysis in MP research.

Humans↗

PubMed2025

MicroRNA-122 overexpression suppresses the colon cancer cell proliferation by downregulating the astrocyte elevated gene-1/metadherin oncoprotein.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate essential cellular functions, such as cell adhesion, proliferation, migration, invasion, and programmed cell death, and therefore, alterations in miRNAs can contribute to carcinogenesis. Previous studies have shown that miRNA-122 is abundant in the liver and regulates cell proliferation, migration, and apoptosis. However, the expression pattern and mechanism of actions of miR-122 remain primarily unknown in colon cancer. METHODS: In this study, we analyzed The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database to assess the clinical significance of astrocyte elevated gene-1 (AEG-1)/metadherin (MTDH) and miR-122 in colon cancer. MiR-122 overexpression studies were performed in HCT116, SW480, and SW620 cell lines. Dual-luciferase assay was carried out to confirm the interaction between AEG-1 and miR-122. In vivo-JetPEI-transfection reagent was used for in-vivo transient transfection of miR-122 in the AOM/DSS-induced colon tumor mouse model. RESULTS: Our results demonstrate that miR-122 was downregulated in colon cancer cells, and it influences the expressions of apoptotic factors and inflammatory cytokines. MiR-122 overexpression in HCT116, SW480, and SW620 cells showed upregulation of Caspase 3, Caspase 9, and BAX and decreased expression of BCL2, which are pro-apoptotic and anti-apoptotic members that maintain a ratio between cellular survival and cell death. In vivo transient transfection of miR-122 mimic in AOM/DSS induced colon tumor mouse model showed less inflammation and disease activity. The TCGA-COAD data indicated that AEG-1 expression was higher in patients with low expression of miR-122 and lower AEG-1 expression in patients with higher expression miR-122. CONCLUSION: Our findings highlight the key role of miR-122 in the high grade of colonic inflammation, and possibly in colon cancer, and the use of miR-122 mimic might be a therapeutic option.

MicroRNAs↗

PubMed2025

Phase separation of hnRNPA1 and TERRA regulates telomeric stability.

Telomeres are the complexes composed of repetitive DNA sequences and associated proteins located at the end of chromatin. As a result of the DNA replication ending issue, telomeric DNA shortens during each cell cycle. The shelterin protein complex caps telomeric ends and forms a high-order protein-DNA structure to protect telomeric DNA. The stability of telomeres is critical for cellular function and related to the progression of many human diseases. Telomeric repeat-containing RNA (TERRA) is a noncoding RNA transcribed from telomeric DNA regions. TERRA plays an essential role in regulating and maintaining the stability of telomeres. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins associated with complex and diverse biological processes. hnRNPA1 can recognize both TERRA and telomeric DNA. Previous research reported that hnRNPA1, TERRA, and POT1, a component of the shelterin complex, work coordinately and displace replication protein A from telomeric single-stranded DNA after DNA replication, promoting telomere capping to preserve genomic integrity. However, the detailed molecular mechanism has remained unclear for >20 years. Here, our study revealed the molecular structure through which the hnRNPA1 UP1 domain interacts with TERRA and identified critical residues on the interacting surface between UP1 and TERRA. Furthermore, we proved that nucleic acids significantly increase the phase-separating ability of hnRNPA1, while disrupting the UP1-TERRA interaction extraordinarily affects hnRNPA1 droplet formation both in vitro and in vivo. Taken together, these data reveal the molecular mechanism of the phase separation of hnRNPA1 and TERRA and the potential contribution of the droplets to maintaining genomic stability.

Heterogeneous Nuclear Ribonucleoprotein A1↗

PubMed2007

Dimeric ansamycins--a new class of antitumor Hsp90 modulators with prolonged inhibitory activity.

The geldanamycin derivative 17-allyamino-17-demethoxygeldanamycin (17-AAG) is a clinical stage ATP-competitive HSP90 inhibitor that induces degradation of HSP90 client proteins. 17-AAG contains 1 ansamycin moiety and is highly potent in conventional cell killing assays. Since active Hsp90 exists as a dimer, we hypothesized that dimeric compounds containing 2 ansamycin pharmacophores might inhibit Hsp90 function more efficiently than 17-AAG. Here, we show that monomeric and dimeric ansamycins exert their activity in distinct ways. Under conditions of continuous exposure, 17-AAG induced client degradation and cell growth inhibition more readily than the dimeric drugs CF237 and CF483. By contrast, 24 hr treatment of various tumor cells with 17-AAG followed by drug washout caused temporary client degradation and cell cycle arrest but minimal cell death, whereas both dimers induced massive apoptosis. CF237 remained bound to Hsp90 for days after drug withdrawal and, while both monomeric and dimeric compounds caused accumulation of the inactive intermediate Hsp90 complex, this effect disappeared following washout of 17-AAG but not CF237. The dimer was also retained for longer in tumor xenografts and displayed superior antitumor activity in vivo. These results indicate that monomeric and dimeric Hsp90 inhibitors have distinct biological profiles and work differentially toward target inhibition.

Animals↗

PubMed2007

A Honglian CMS line of rice displays aberrant F0 of F0F1-ATPase.

Honglian (HL) is one of the three major types of cytoplasmic male sterility (CMS) of rice (Oryza sativa L) that has been commercially used in hybrid production. In previous studies, the CMS in HL is shown to be associated with a chimeric gene orfH79 that is cotranscribed with an extra atp6 in mitochondria. This study demonstrated that the intact F0F1-ATPase in HL CMS line was specifically reduced in both of its protein quantity and enzyme activity, whereas its F1 sector was not affected. It implies that the F0 sector presents a labile linkage with F1. In the presence of fertility restorer gene, F0F1-ATPase can be recovered. Furthermore, orfH79 transcripts were preferentially polyadenylated, and consequently degraded rapidly in florets of the restored hybrid plants, indicating that the atp6-orfH79 is involved in the sterile phenotype. With inhibition of cytochrome pathway of electron transfer chain, the biomass of the sterile plants grown in dark was significantly lower than that of the fertile lines. However, the respiration measurements showed an increase in the electron transferring capacity in the sterile plants, suggesting that the reduction of biomass in sterile line was caused by the disruption of F0F1-ATPase.

Gene Expression Regulation, Plant↗

PubMed2007

Histomorphometric assessment of thoracoscopically assisted anterior release in a porcine model: safety and completeness of disc discectomy with surgeon learning curve.

STUDY DESIGN: A retrospective study using histomorphometric analysis to quantify the percentage of discectomy following thoracoscopic anterior release and fusion in a porcine model. OBJECTIVE: To investigate the safety and completeness of disc and endplate removal with respect to the learning curve of the surgeon in a porcine thoracoscopic anterior fusion model. SUMMARY OF BACKGROUND DATA: The thoracoscopic approach has been used to perform an anterior release and fusion before an open posterior instrumentation, however, there is concern that the technique may not provide sufficient visualization or exposure to perform safely and completely. METHODS: A total of 32 pigs (160 discs) were assigned to 2 groups (early experience, n = 16; late experience, n = 16), and underwent 5 level thoracoscopic anterior release followed by anterior instrumentation and fusion from T5 to T10. At 4 months after surgery, the spines were harvested, and each discectomy disc was histomorphometrically analyzed to determine the percentage of disc excision and amount of endplate removal. RESULTS: There were no significant differences in the percent disc excision between the early (67% +/- 11%) and late groups (69% +/- 10%). Greater than 50% of the disc was excised in 151 of 160 discectomies (94%). Both superior and inferior endplates were resected in 92 of 160 disc levels (57%). The amount of endplate removal had improved over time in both early and late groups (P < 0.0001). The histologic examination revealed no evidence for posterior longitudinal ligament disruption or spinal canal encroachment in any disc. CONCLUSIONS: Video-assisted thoracoscopic discectomy is safe and allows for a significant amount of disc material excision. This study did not demonstrate a learning curve with respect to the amount of disc material excised, but a learning curve was seen for endplate excision.

Animals↗

PubMed2007

Polycomb-like genes are necessary for specification of dopaminergic and serotonergic neurons in Caenorhabditis elegans.

The molecular mechanisms underlying the formation of neurons with defined neurotransmitters are not well understood. In this study, we demonstrate that the PcG-like genes in Caenorhabditis elegans, sop-2 and sor-3, regulate the formation of dopaminergic and serotonergic neurons and several other neuronal properties. sor-3 encodes a novel protein containing an MBT repeat, a domain that contains histone-binding activity and is present in PcG proteins SCM and Sfmbt in other organisms. We further show that mutations in sor-3 lead to ectopic expression of Hox genes and cause homeotic transformations. Specification of certain neuronal identities by these PcG-like genes appears to involve regulation of non-Hox gene targets. Our studies revealed that the PcG-like genes are crucial for coordinately regulating the expression of discrete aspects of neuronal identities in C. elegans.

Amino Acid Motifs↗

PubMed2007

Repeated measurement sampling in genetic association analysis with genotyping errors.

Genotype misclassification occurs frequently in human genetic association studies. When cases and controls are subject to the same misclassification model, Pearson's chi-square test has the correct type I error but may lose power. Most current methods adjusting for genotyping errors assume that the misclassification model is known a priori or can be assessed by a gold standard instrument. But in practical applications, the misclassification probabilities may not be completely known or the gold standard method can be too costly to be available. The repeated measurement design provides an alternative approach for identifying misclassification probabilities. With this design, a proportion of the subjects are measured repeatedly (five or more repeats) for the genotypes when the error model is completely unknown. We investigate the applications of the repeated measurement method in genetic association analysis. Cost-effectiveness study shows that if the phenotyping-to-genotyping cost ratio or the misclassification rates are relatively large, the repeat sampling can gain power over the regular case-control design. We also show that the power gain is not sensitive to the genetic model, genetic relative risk and the population high-risk allele frequency, all of which are typically important ingredients in association studies. An important implication of this result is that whatever the genetic factors are, the repeated measurement method can be applied if the genotyping errors must be accounted for or the phenotyping cost is high.

Case-Control Studies↗

PubMed2007

Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging.

In response to progressive telomere shortening in successive cell divisions, normal somatic cells enter senescence, during which they cease to proliferate irreversibly and undergo dramatic changes in gene expression. Senescence can also be activated by various types of stressful stimuli, including aberrant oncogenic signaling, oxidative stress, and DNA damage. Because of the limited proliferative capacity imposed by senescence, as well as the ability of senescent cells to influence neighboring non-senescent cells, senescence has been proposed to play an important role in tumorigenesis and to contribute to aging. Considerable effort has been put into elucidating the molecular mechanisms of senescence, including the signals that trigger senescence, the molecular pathways by which cells enter senescence, and evidence that supports its role in tumorigenesis and aging.

Aging↗

PubMed2007

Ginsenoside Re promotes human sperm capacitation through nitric oxide-dependent pathway.

The regulation of sperm capacitation is important for successful fertilization. Ginsenosides, the biologically effective components of ginseng, have been found to enhance intracellular nitric oxide (NO) production and the latter has recently been indicated to play a significant role in modulation of sperm functions. We investigated the effect of Ginsenoside Re on human sperm capacitation in vitro and the mechanism by which the Ginsenosides play their roles. Spermatozoa were separated by Percoll and incubated with 0, 1, 10, or 100 microM of Ginsenoside Re. The percentages of spontaneous and lysophosphatidylcholine (LPC)-induced acrosome reaction (AR), as a measure of sperm capacitation, were assayed with fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FITC-PSA). The intracellular cGMP level was measured by [(3)H] cGMP radioimmunoassay system. The results showed that the percentages of both spontaneous and LPC-induced AR and intracellular cGMP level were significantly enhanced by Ginsenoside Re with a concentration-dependent manner. Sodium nitroprusside (SNP, 100 nM), a NO donor, mimicked the effects of Ginsenoside Re. And pretreatment with a NOS inhibitor N(omega)-nitro-l-arginine methyl ester (L-NAME, 100 microM) or a NO scavenger N-acetyl-l-cysteine (LNAC, 1 mM) completely blocked the effects of Ginsenoside Re. Furthermore, the AR-inducing effect of Ginsenoside Re was significantly reduced in the presence of the soluble guanylate cyclase inhibitor LY83583 or cGMP-dependent protein kinase (PCK) inhibitor KT5823, whereas addition of the cGMP analogue 8-Br-cGMP significantly increased the AR of human spermatozoa. Data suggested that Ginsenoside Re is beneficial to sperm capacitation and AR, and that the effect is accomplished through NO/cGMP/PKG pathway.

Acrosome Reaction↗

PubMed2006

Management strategy for congenital choledochal cyst with co-existing intrahepatic dilation and aberrant bile duct as well as other complicated biliary anomalies.

The purpose of this study was to investigate and discuss imaging methods and management strategies for congenital choledochal cyst with co-existing intrahepatic dilation and aberrant bile duct as well as other complicated biliary anomalies. In this study we reviewed and analyzed 72 patients with congenital choledochal cyst, ranging in age from 15 days to 12 years old and who were seen at our hospital during the past 12 years, from January 1993 to October 2005. The image manifestation and clinical significance of patients with co- existing intrahepatic biliary dilation and aberrant bile duct were carefully examined during operation via MRCP, cholangiography and choledochoscope. Twenty-two cases (30.1%) presented with intrahepatic bile duct dilation and 12 of these were of the cystic type. That is, the orifice of the dilated intrahepatic tract that converged into the common hepatic duct showed membrane or septum-like stenosis. In 10 cases the dilation tapered off from the porta hepatis to the initiating terminals of the intra-hepatic bile ducts and was not accompanied by stenosis. An aberrant bile duct was observed in 2 of the cases. In 3 cases, the right and left hepatic ducts converged at the choledochal cyst. In conclusion, the imaging methods for intrahepatic bile duct dilation possess important clinical significance. Further, for hepatojejunostomy with radical excision of a choledochal cyst, additional operative procedures for intrahepatic stenosis, possible bile duct malformation and pancreaticobiliary common duct calculi can potentially reduce postoperative complications.

Bile Ducts↗

PubMed2006

Structure of a conserved hypothetical protein SA1388 from S. aureus reveals a capped hexameric toroid with two PII domain lids and a dinuclear metal center.

BACKGROUND: The protein encoded by the SA1388 gene from Staphylococcus aureus was chosen for structure determination to elucidate its domain organization and confirm our earlier remote homology based prediction that it housed a nitrogen regulatory PII protein-like domain. SA1388 was predicted to contain a central PII-like domain and two flanking regions, which together belong to the NIF3-like protein family. Proteins like SA1388 remain a poorly studied group and their structural characterization could guide future investigations aimed at understanding their function. RESULTS: The structure of SA1388 has been solved to 2.0A resolution by single wavelength anomalous dispersion phasing method using selenium anomalous signals. It reveals a canonical NIF3-like fold containing two domains with a PII-like domain inserted in the middle of the polypeptide. The N and C terminal halves of the NIF3-like domains are involved in dimerization, while the PII domain forms trimeric contacts with symmetry related monomers. Overall, the NIF3-like domains of SA1388 are organized as a hexameric toroid similar to its homologs, E. coli ybgI and the hypothetical protein SP1609 from Streptococcus pneumoniae. The openings on either side of the toroid are partially covered by trimeric "lids" formed by the PII domains. The junction of the two NIF3 domains has two zinc ions bound at what appears to be a histidine rich active site. A well-defined electron density corresponding to an endogenously bound ligand of unknown identity is observed in close proximity to the metal site. CONCLUSION: SA1388 is the third member of the NIF3-like family of proteins to be structurally characterized, the other two also being hypothetical proteins of unknown function. The structure of SA1388 confirms our earlier prediction that the inserted domain that separates the two NIF3 domains adopts a PII-like fold and reveals an overall capped toroidal arrangement for the protein hexamer. The six PII-like domains form two trimeric "lids" that cap the central cavity of the toroid on either side and provide only small openings to allow regulated entry of small molecules into the occluded chamber. The presence of the electron density of the bound ligand may provide important clues on the likely function of NIF3-like proteins.

Bacterial Proteins↗

PubMed2006

A highly polar xanthophyll of 9'-cis-neoxanthin induces apoptosis in HCT116 human colon cancer cells through mitochondrial dysfunction.

Highly polar xanthophylls of 9'-cis-neoxanthin (neoxanthin) and fucoxanthin, which have the characteristic structure of an epoxy group and an allenic bond, were previously found to induce apoptosis in human prostate cancer cells. In the present study, we found apoptosis induction by neoxanthin in HCT116 human colon cancer cells and examined the induction mechanism. The cells exposed to 20 microM neoxanthin clearly showed chromatin condensation, DNA fragmentation, and an increase in hypodiploid cells. Neoxanthin treatment increased the activities of caspase-3, -8 and -9, and the protein levels of their active subunits, except in the case of caspase-8. The treatment also caused the loss of mitochondrial transmembrane potential at an early stage and subsequently the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to cytosol. The exposure of neoxanthin directly to mitochondria isolated from the cells enhanced the release of cytochrome c and AIF in a dose-dependent manner. Approximately 50% of the neoxanthin taken up into the HCT116 cells accumulated in the mitochondrial fraction. These results suggest that the accumulation of neoxanthin in mitochondria causes the loss of mitochondrial transmembrane potential and thereafter releases cytochrome c and AIF, leading to the execution of apoptosis.

Apoptosis↗

PubMed2006

Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia.

Here we show that alpha-synuclein, a major constituent of Lewy bodies, induces inflammation in human microglial and human THP-1 cells. Secretions from such stimulated THP-1 cells contain increased levels of IL-1beta and TNF-alpha. When stimulated by alpha-synuclein in combination with IFN-gamma, secretions from the cells also become toxic towards SH-SY5Y neuroblastoma cells. The A30P, E46K and A53T alpha-synuclein mutations, which induce Parkinson's disease, are more potent than normal alpha-synuclein in the induction of such cytotoxicity. To investigate the signaling mechanisms evoked, protein phosphorylation profiling was applied. At least 81 target phospho-sites were identified. Large increases were induced in the three major mitogen-activated protein (MAP) kinase pathways: p38 MAP kinase, extracellular regulated protein-serine kinase (ERK)1/2 and c-Jun-N-terminal kinase (JNK). Upregulation occurred within minutes following exposure to alpha-synuclein, which is consistent with a receptor-mediated effect. These findings demonstrate that alpha-synuclein acts as a potent inflammatory stimulator of microglial cells, and that inhibitors of such stimulation might be beneficial in the treatment of Parkinson's disease and other synucleinopathies.

Cell Line↗