Lirispirolides A−L(1−12),twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons,were isolated from the branches and leaves of Chinese tulip tree[Liriodendron chinense(L.chinense)],a...Lirispirolides A−L(1−12),twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons,were isolated from the branches and leaves of Chinese tulip tree[Liriodendron chinense(L.chinense)],a rare medicinal and ornamental plant endemic to China.The structural elucidation was accomplished through comprehensive spectroscopic analyses,quantum-chemical calculations,and X-ray crystallography.These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif,biosynthetically formed through intermolecular[4+2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene.The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide(LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators,specifically tumor necrosis factor-α(TNF-α)and nitric oxide(NO).Further investigation revealed that the lirispirolides’inhibition of NO release correlated with decreased messenger ribonucleic acid(mRNA)expression of inducible NO synthase(iNOS).展开更多
Heterodimerization in RTKs is of vital importance in the RTK signaling and cell functions.Heterodimerization between RTKs can result in diversity of downstream signals,increasing the ability of cells to respond to ext...Heterodimerization in RTKs is of vital importance in the RTK signaling and cell functions.Heterodimerization between RTKs can result in diversity of downstream signals,increasing the ability of cells to respond to external experiments.Traditional RTKs heterodimerization always occur in the same families and is lack of agonists to activate the heterodimeric RTKs signaling pathway.Herein,we developed the DNA agonist based on bivalent aptamers for the heterodimerized RTKs of different families,AF/AM-1,which could simultaneously activate FGFR1 and c-Met signaling.It is the first agonist that realizing the heterodimerization and activation of FGFR1 and c-Met,two different RTK families.The activation of FGFR1/c-Met heterodimer result in the down-stream signals transduction,such as the phosphorylation of Akt and Erk,inducing the cell migration and proliferation.The DNA agonist for RTK heterodimer of different families would have potential applications in the fields of biomedicine.展开更多
Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-nam...Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.展开更多
Marine natural products offer a promising source in the development of new antibiotic drugs.Two previously undescribed compounds,including one sulfur-bearing alkaloid named quinosumycin(1)along with one chromone deriv...Marine natural products offer a promising source in the development of new antibiotic drugs.Two previously undescribed compounds,including one sulfur-bearing alkaloid named quinosumycin(1)along with one chromone derivative namely chromycone(2),were discovered from an ethyl acetate(EtOAc)extract of marine Streptomyces diastaticus NBU2966 through a bioactivity-guided isolation prioritized for antimicrobial potential.The analysis of nuclear magnetic resonance(NMR)spectroscopy,high resolution electrospray ionization mass spectroscopy(HRESIMS)data,and electronic circular dichroism(ECD)calculations enabled the elucidation of their structures and the determination of their absolute configurations.Quinosumycin(1)is the first heterodimer scaffold incorporating quinolinone and quinazolinone motifs coupled by a thioether bond.Interestingly,Compound 1 exhibited a relatively selective growth inhibition against methicillin-resistant Staphylococcus aureus(MRSA)with the minimal inhibitory concentration(MIC)value of 8μg/mL.展开更多
Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk strati...Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk stratification and person-alized patient care in clinical oncology.A paradigm shift is emerging with the promise of multi-receptor-targeting compounds.While existing detection and staging methods have demonstrated some success,the traditional approach of monotherapy is being reevaluated to enhance therapeutic effectiveness.Het-erodimeric site-specific agents are a versatile solution by targeting two distinct biomarkers with a single theranostic agent.This review describes the inno-vation of dual-targeting compounds,examining their design strategies,thera-peutic implications,and the promising path they present for addressing complex diseases.展开更多
AIM： TO determine the DNA binding activity and protein levels of the Ku70/80 heterodimer, the functional mediator of the NHEJ activity, in human colorectal carcinogenesis. METHODS： The Ku70/80 DNA-binding activity w...AIM： TO determine the DNA binding activity and protein levels of the Ku70/80 heterodimer, the functional mediator of the NHEJ activity, in human colorectal carcinogenesis. METHODS： The Ku70/80 DNA-binding activity was determined by electrophoretic mobility shift assays in 20 colon adenoma and 15 colorectal cancer samples as well as matched normal colonic tissues. Nuclear and cytoplasmic protein expression was determined by immunohistochemistry and Western blot analysis. RESULTS： A statistical found in both adenomas y significant difference was and carcinomas as compared to matched normal colonic mucosa （P〈0.00）. However, changes in binding activity were not homogenous with approximately 50% of the tumors showing a clear increase in the binding activity, 30% displaying a modest increase and 15% showing a decrease of the activity.Tumors, with increased DNA-binding activity, also showed a statistically significant increase in Ku70 and Ku86 nuclear expression, as determined by Western blot and immunohistochemical analyses （P〈0.001）. Cytoplasmic protein expression was found in pathological samples, but not in normal tissues either from tumor patients or from healthy subjects. CONCLUSION： Overall, our DNA-binding activity and protein level are consistent with a substantial activation of the NHEJ pathway in colorectal tumors. Since the NHEJ is an error prone mechanism, its abnormal activation can result in chromosomal instability and ultimately lead to tumorigenesis.展开更多
The infrared multiphoton dissociation(IRMPD)spectrum of the protonated heterodimer of Pro Phe H+,in the range of 2700-3700 cm^-1,has been obtained with a Fourier-transform ion cyclotron mass spectrometer combined with...The infrared multiphoton dissociation(IRMPD)spectrum of the protonated heterodimer of Pro Phe H+,in the range of 2700-3700 cm^-1,has been obtained with a Fourier-transform ion cyclotron mass spectrometer combined with an IR OPO laser.The experimental spectrum shows one peak at 3565 cm^-1 corresponding to the free carboxyl O-H stretching vibration,and two broad peaks centered at 2935 and 3195 cm^-1.Theoretical calculations were performed on the level of M062 X/6-311++G(d,p).Results show that the most stable isomer is characterized by a charge-solvated structure in which the proton is bound to the unit of proline.Its predicted spectrum is in good agreement with the experimental one,although the coexistence of salt-bridged structures cannot be entirely excluded.展开更多
Heterogeneous nuclear ribonucleoprotein （hnRNP） C plays a key role in RNA processing but also exerts a dominant negative effect on responses to 1,25-dihydroxyvitamin D （1,25（OH）2D） by functioning as a vitamin D ...Heterogeneous nuclear ribonucleoprotein （hnRNP） C plays a key role in RNA processing but also exerts a dominant negative effect on responses to 1,25-dihydroxyvitamin D （1,25（OH）2D） by functioning as a vitamin D response element-binding protein （VDRE-BP）. hnRNPC acts a tetramer of hnRNPC1 （huC1） and hnRNPC2 （huC2）, and organization of these subunits is critical to in vivo nucleic acid-binding. Overexpression of either huC1 or huC2 in human osteoblasts is sufficient to confer VDRE-BP suppression of 1,25（OH）2D-mediated transcription. However, huC1 or huC2 alone did not suppress 1,25（OH）2D-induced transcription in mouse osteoblastic cells. By contrast, overexpression of huC1 and huC2 in combination or transfection with a bone-specific polycistronic vector using a ＂self-cleaving＂ 2A peptide to co-express huC1/C2 suppressed 1,25D-mediated induction of osteoblast target gene expression. Structural diversity of hnRNPC between human/NWPs and mouse/rat/rabbit/dog was investigated by analysis of sequence variations within the hnRNP CLZ domain. The predicted loss of distal helical function in hnRNPC from lower species provides an explanation for the altered interaction between huC1/C2 and their mouse counterparts. These data provide new evidence of a role for hnRNPC1/C2 in 1,25（OH）2D-driven gene expression, and further suggest that species-specific tetramerization is a crucial determinant of its actions as a regulator of VDR-directed transactivation.展开更多
Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (...Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (SCSR-010 Fecal Cell Isolation Kit, NonInvasive Technologies, Elkridge, MD), preserved at room temperature for up to one week, with viability of >85% and low levels of apoptosis (8% - 10%) exhibit two distinct cell size subpopulations, in the 2.5 μM - 5.0 μM and 5.0 μM - 8.0 μM range. In addition to IgA, about 60% of the cells expressed a novel heterodimeric IgA/IgG immunoglobulin that conferred a broad-spectrum cell mediated cytotoxicity against tumor cells. In a cohort of 58 subjects the exclusive absence of this immunoglobulin in two African-Americans was suggestive of a germline deletion. Serial cultures in stem cell medium retained the expression of this heterodimer. Since a majority of the cystic cells expressed the stem cell markers Lgr5 and Musashi-1 we termed these cells as gastrointestinal progenitor stem cells (GIP-C**). CXCR-4, the cytokine co-receptor for HIV was markedly expressed. These cells also expressed CD20, IgA, IgG, CD45, and COX-2. We assume that they originated from mature columnar epithelium by dedifferentiation. Our observations indicate that we have a robust noninvasive method to study mucosal pathophysiology and a direct method to create a database for applications in regenerative medicine.展开更多
Monodisperse Au-Fe3O4 heterodimeric nanoparticles （NPs） were prepared by injecting precursors into a hot reaction solution. The size of Au and Fe3O4 particles can be controlled by changing the injection temperature....Monodisperse Au-Fe3O4 heterodimeric nanoparticles （NPs） were prepared by injecting precursors into a hot reaction solution. The size of Au and Fe3O4 particles can be controlled by changing the injection temperature. UVis spectra show that the surface plasma resonance band of Au-Fe3O4 heterodimeric NPs was evidently red-shifted compared with the resonance band of Au NPs of similar size. The as-prepared heterodimeric Au-Fe3O4 NPs exhibited superparamagnetic properties at room temperature. The Ag-Fe3O4 heterodimeric NPs were also prepared by this synthetic method simply using AgNO3 as precursor instead of HAuCl4. It is indicated that the reported method can be readily extended to the synthesis of other noble metal conjugated heterodimeric NPs.展开更多
Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their functio...Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their function, particularly in case of G-protein coupled receptors. The opioid receptor heteromers having changed pharmacological properties than the constituent protomers provides preferences for novel drug targets that could lead to potential analgesicactivity devoid of tolerance and physical dependence. Heterodimerization of opioid receptors appears to generate novel binding properties with improved specificity and lack of side effects. Further the molecules which can interact simultaneously to both the protomers of the heteromer, or to both the binding sites(orthosteric and allosteric) of a receptor protein could be potential therapeutic molecules. This review highlights the recent advancements in exploring the plausible role of heteromerization of opioid receptors in induction of tolerance free antinociception.展开更多
Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-b...Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.展开更多
Phosphoinositide 3-kinase(PI3K)catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate(PIP_(2))to phosphatidylinositol 3,4,5-trisphosphate(PIP_(3)),a key second messenger that orchestrates downstream signali...Phosphoinositide 3-kinase(PI3K)catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate(PIP_(2))to phosphatidylinositol 3,4,5-trisphosphate(PIP_(3)),a key second messenger that orchestrates downstream signaling by recruiting and activating effector proteins,such as protein kinase B(AKT).PI3Ks are categorized into four classes(IA,IB,II,and III)based on structural characteristics and substrate preferences1.Class IA PI3K enzymes are heterodimeric complexes composed of a catalytic subunit(p110α,p110β,or p110δ)and a regulatory subunit(p85α,p55α,p50α,p85β,or p55γ)2.Although the catalytic isoforms p110αand p110β,are ubiquitously expressed across tissues,p110δis predominantly found in leukocytes3.Notably,p85αfunctions as the primary regulatory subunit.展开更多
In our recent studies, we found that LMP1 encoded by Epstein-Barr virus could accelerate the formation of active c-Jun/Jun B heterodimer. We studied the regulation of cyclinD1 by c-Jun/Jun B heterodimers by laser scan...In our recent studies, we found that LMP1 encoded by Epstein-Barr virus could accelerate the formation of active c-Jun/Jun B heterodimer. We studied the regulation of cyclinD1 by c-Jun/Jun B heterodimers by laser scanning confocal influorescence microscopy, Western blot, luciferase activity assay, super-EMSA and flow cytometry in the Tet-on-LMP1 HNE2 cell line, in which LMP1 expression was regulated by Tet-on system. c-Jun/Jun B heterodimers induced by LMP1 could up regulate cyclin D1 promoter activity and expression. Overexpression of cy-clinD1 accelerated the progression of cell cycle.展开更多
Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effect...Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases(SFKs),such as Fyn or Lyn,to form heterodimers.Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC development.By contrast,Src could not form heterodimers with Fyn or Lyn in NEECs.We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related pathways.Results of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules.Furthermore,results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC prognosis.This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.展开更多
Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) may trigger the transcription factor AP-1 including c-Jun and c-fos. In this report, using a Tet-on LMP1 HNE2 cell line which is a dual-stable LMP1 int...Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) may trigger the transcription factor AP-1 including c-Jun and c-fos. In this report, using a Tet-on LMP1 HNE2 cell line which is a dual-stable LMP1 integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 in which could be regulated by the Tet-on system, we show that Jun B can efficiently form a new heterodimeric complex with the c-Jun protein under the regulation of LMP1, phosphorylation of c-Jun (ser 63, ser 73) and Jun B is involved in the process of the new heterodimeric formation. We also find that this heterodimeric form can bind to the AP-1 consensus sequence. Transfection studies suggest that JNK interaction protein (JIP) could inhibit the heterodimer formation of c-Jun and Jun B through blocking the AP-1 signaling pathway triggered by LMP1. The interaction and function between c-Jun protein and Jun B protein increase the repertoire of possible regulatory complexes by LMP1 that could play an important role in the regulation of transcription of specific cellular genes in the process of genesis of nasopharyngeal carcinoma.展开更多
There is a significant need for magnetite-silver nanocomposites that exhibit durable and recyclable antimicrobial activity.In this study,magnetic iron oxide nanoparticles(Fe3O4 NPs)coated with ethylenediamine-modified...There is a significant need for magnetite-silver nanocomposites that exhibit durable and recyclable antimicrobial activity.In this study,magnetic iron oxide nanoparticles(Fe3O4 NPs)coated with ethylenediamine-modified chitosan/polyacrylic acid copolymeric layer(Fe3O4@ECS/PAA)were fabricated.Subsequently,directly deposited silver(Ag)NPs procedure was carried out to form the antibacterial heterodimers of Fe3O4@ECS/PAA-Ag NPs.The composition and morphology of the resultant nanostructures were confirmed by FT-IR,XRD,TEM and TGA.The overall length of the heterodimers was approximately 45 nm,in which the mean diameter of Fe3O4@ECS/PAA NPs reached up to 35 nm,and that of Ag NPs was around 15 nm.The mass fraction of silver NPs in the nanocomposites was about 63.1%.The obtained Fe3O4@ECS/PAA NPs exhibited good colloidal stability,and excellent response to additional magnetic field,making the NPs easy to recover after antibacterial tests.In particular,the Fe3O4@ECS/PAAAg NPs retained nearly 100%biocidal efficiency(106e107 CFU/mg nanoparticles)for both Gram-negative bacteria E.coli and Gram-positive bacteria S.aureus throughout ten cycles without washing with any solvents or water,exhibiting potent and durable antibacterial activity.展开更多
A novel sextuple hydrogen-bonding （HB） self-assembly molecular heterodimer bearing an iridium complex as the indicator dye and two carbazoles as the reference dye, namely 6HB-Irbt-Cz, was synthesized, and its molecu...A novel sextuple hydrogen-bonding （HB） self-assembly molecular heterodimer bearing an iridium complex as the indicator dye and two carbazoles as the reference dye, namely 6HB-Irbt-Cz, was synthesized, and its molecular structure was confirmed by ^1H NMR, ^13CNMR, TOF-MS and 2D NMR. Because of the inefficient energy transfer process between the carbazole and iridium complex units, 6HB-Irbt-Cz exhibits distinct fluorescence/ phosphorescence dual emission in neat film state. More importantly, the neat film sample of 6HB-Irbt-Cz could display linear ratiometric optical response toward oxygen in the full oxygen concentration range from 0 to 100 vol%, together with good stability, reversibility and rapid response-recovery times. Note that this represents the first discovery of neat-film-based oxygen sensor capable of showing strictly linear ratiometric Stem-Volmer behavior in the oxygen concentration of 0- 100 vol%.展开更多
Five novel heterodimers of cytochalasan and ergosterol,ergochaeglobosins A—E,were isolated from an endophytic fungus Chaetomium globosum P2-2-2.Ergochaeglobosin A(1) possesses an unprecedented 5/6/13/6/5/6/6/6 fused ...Five novel heterodimers of cytochalasan and ergosterol,ergochaeglobosins A—E,were isolated from an endophytic fungus Chaetomium globosum P2-2-2.Ergochaeglobosin A(1) possesses an unprecedented 5/6/13/6/5/6/6/6 fused octacyclic ring system,and ergochaeglobosins B(2) and C(3) form a unique 5/6/13/6/6/6/6/5 fused octacyclic ring system,whereas ergochaeglobosins D(4) and F(5) are the first cytochalasan heterodimers formed via a N-1′/C-3′′single bond.Their structures with absolute configurations were established by extensive spectroscopic analyses,single-crystal X-ray diffraction,and ECD calculations.The plausible biogenetic pathway of 1—5 was postulated.Compound 1 exhibited inhibitory effects against ConA-induced T cells and LPS-induced B cells proliferation with IC50 values of 19.2 and 14.1μmol/L,respectively.Co-treatment of 3(20μmol/L)with TRAIL(150 ng/mL)could significantly decrease the cell viability of A549 by 24.9%comparing with monotherapy of 3(20μmol/L).展开更多
A new series of hydrogen bonding-driven heterodimers have been self-assembled in chloroform from hydrazide-based monomers. Additional intermolecular donor-acceptor interaction between the electron-rich bis（p-phenylen...A new series of hydrogen bonding-driven heterodimers have been self-assembled in chloroform from hydrazide-based monomers. Additional intermolecular donor-acceptor interaction between the electron-rich bis（p-phenylene）-34-crown-10 unit and the electron-deficient naphthalene diimide unit has been utilized to increase the stability of the dimmers, and pronounced cooperativity of the two discrete non-covalent forces to stabilize the dimer has been revealed by the quantitative ^1H （2D） NMR and UV-Vis experiments.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82373752 and 21937002)the Science and Technology Commission of Shanghai Municipality(No.22ZR1414400).
文摘Lirispirolides A−L(1−12),twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons,were isolated from the branches and leaves of Chinese tulip tree[Liriodendron chinense(L.chinense)],a rare medicinal and ornamental plant endemic to China.The structural elucidation was accomplished through comprehensive spectroscopic analyses,quantum-chemical calculations,and X-ray crystallography.These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif,biosynthetically formed through intermolecular[4+2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene.The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide(LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators,specifically tumor necrosis factor-α(TNF-α)and nitric oxide(NO).Further investigation revealed that the lirispirolides’inhibition of NO release correlated with decreased messenger ribonucleic acid(mRNA)expression of inducible NO synthase(iNOS).
基金the National Natural Science Foundation of China(Nos.22104158,82174104,U1903211)the Natural Science Foundation of Hunan Province(No.2021JJ40041)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2023A1515011346)Shenzhen Science and Technology Program(No.SZBH202130)。
文摘Heterodimerization in RTKs is of vital importance in the RTK signaling and cell functions.Heterodimerization between RTKs can result in diversity of downstream signals,increasing the ability of cells to respond to external experiments.Traditional RTKs heterodimerization always occur in the same families and is lack of agonists to activate the heterodimeric RTKs signaling pathway.Herein,we developed the DNA agonist based on bivalent aptamers for the heterodimerized RTKs of different families,AF/AM-1,which could simultaneously activate FGFR1 and c-Met signaling.It is the first agonist that realizing the heterodimerization and activation of FGFR1 and c-Met,two different RTK families.The activation of FGFR1/c-Met heterodimer result in the down-stream signals transduction,such as the phosphorylation of Akt and Erk,inducing the cell migration and proliferation.The DNA agonist for RTK heterodimer of different families would have potential applications in the fields of biomedicine.
基金support from the National Natural Science Foundation of China(22237007 and 22177122)the Biological Resources Program of Chinese Academy of Sciences(CAS)(KFJ-BRP-008-001)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022282)is gratefully acknowledged.We thank Prof.Shi-Man Huang,Department of Biology,Hainan University,China,for the identification of the plant material.
文摘Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.
基金Supported by the National Natural Science Foundation of China(No.42176101)the Ningbo Youth Science and Technology Innovation Leading Project(No.2024QL063)+2 种基金the National 111 Project of China(No.D16013)the Scientific Research Fund of Zhejiang Provincial Education Department(No.Y202250186)the Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Development Fund。
文摘Marine natural products offer a promising source in the development of new antibiotic drugs.Two previously undescribed compounds,including one sulfur-bearing alkaloid named quinosumycin(1)along with one chromone derivative namely chromycone(2),were discovered from an ethyl acetate(EtOAc)extract of marine Streptomyces diastaticus NBU2966 through a bioactivity-guided isolation prioritized for antimicrobial potential.The analysis of nuclear magnetic resonance(NMR)spectroscopy,high resolution electrospray ionization mass spectroscopy(HRESIMS)data,and electronic circular dichroism(ECD)calculations enabled the elucidation of their structures and the determination of their absolute configurations.Quinosumycin(1)is the first heterodimer scaffold incorporating quinolinone and quinazolinone motifs coupled by a thioether bond.Interestingly,Compound 1 exhibited a relatively selective growth inhibition against methicillin-resistant Staphylococcus aureus(MRSA)with the minimal inhibitory concentration(MIC)value of 8μg/mL.
基金NIH Research Evaluation and Commercilization Hub,Grant/Award Number:1U01HL152410USVA Medical Research Service,Grant/Award Number:I01 BX00096409National Institutes of Health,Grant/Award Numbers:R01CA269221,R01CA225837。
文摘Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk stratification and person-alized patient care in clinical oncology.A paradigm shift is emerging with the promise of multi-receptor-targeting compounds.While existing detection and staging methods have demonstrated some success,the traditional approach of monotherapy is being reevaluated to enhance therapeutic effectiveness.Het-erodimeric site-specific agents are a versatile solution by targeting two distinct biomarkers with a single theranostic agent.This review describes the inno-vation of dual-targeting compounds,examining their design strategies,thera-peutic implications,and the promising path they present for addressing complex diseases.
基金Supported by Italian Ministero della Salute, IRCCS, RC0302TG13 by Ministero dell'Istruzíone, Università e Ricerca scientifica e tecnologica (MIUR), COFIN2002, to the Universita Campus Bio-Medico
文摘AIM： TO determine the DNA binding activity and protein levels of the Ku70/80 heterodimer, the functional mediator of the NHEJ activity, in human colorectal carcinogenesis. METHODS： The Ku70/80 DNA-binding activity was determined by electrophoretic mobility shift assays in 20 colon adenoma and 15 colorectal cancer samples as well as matched normal colonic tissues. Nuclear and cytoplasmic protein expression was determined by immunohistochemistry and Western blot analysis. RESULTS： A statistical found in both adenomas y significant difference was and carcinomas as compared to matched normal colonic mucosa （P〈0.00）. However, changes in binding activity were not homogenous with approximately 50% of the tumors showing a clear increase in the binding activity, 30% displaying a modest increase and 15% showing a decrease of the activity.Tumors, with increased DNA-binding activity, also showed a statistically significant increase in Ku70 and Ku86 nuclear expression, as determined by Western blot and immunohistochemical analyses （P〈0.001）. Cytoplasmic protein expression was found in pathological samples, but not in normal tissues either from tumor patients or from healthy subjects. CONCLUSION： Overall, our DNA-binding activity and protein level are consistent with a substantial activation of the NHEJ pathway in colorectal tumors. Since the NHEJ is an error prone mechanism, its abnormal activation can result in chromosomal instability and ultimately lead to tumorigenesis.
基金supported by the National Natural Science Foundation of China(No.21627810)the Fundamental Research Funds for the Central Universities,Nankai University(No.63191523)。
文摘The infrared multiphoton dissociation(IRMPD)spectrum of the protonated heterodimer of Pro Phe H+,in the range of 2700-3700 cm^-1,has been obtained with a Fourier-transform ion cyclotron mass spectrometer combined with an IR OPO laser.The experimental spectrum shows one peak at 3565 cm^-1 corresponding to the free carboxyl O-H stretching vibration,and two broad peaks centered at 2935 and 3195 cm^-1.Theoretical calculations were performed on the level of M062 X/6-311++G(d,p).Results show that the most stable isomer is characterized by a charge-solvated structure in which the proton is bound to the unit of proline.Its predicted spectrum is in good agreement with the experimental one,although the coexistence of salt-bridged structures cannot be entirely excluded.
基金supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number 5R01AR037399the UCLA Vector Core (Emmanuelle Faure and Kip Hermann) for vector and viral preparations supported by JCCC/P30 CA016042 and CURE/P30 DK41301
文摘Heterogeneous nuclear ribonucleoprotein （hnRNP） C plays a key role in RNA processing but also exerts a dominant negative effect on responses to 1,25-dihydroxyvitamin D （1,25（OH）2D） by functioning as a vitamin D response element-binding protein （VDRE-BP）. hnRNPC acts a tetramer of hnRNPC1 （huC1） and hnRNPC2 （huC2）, and organization of these subunits is critical to in vivo nucleic acid-binding. Overexpression of either huC1 or huC2 in human osteoblasts is sufficient to confer VDRE-BP suppression of 1,25（OH）2D-mediated transcription. However, huC1 or huC2 alone did not suppress 1,25（OH）2D-induced transcription in mouse osteoblastic cells. By contrast, overexpression of huC1 and huC2 in combination or transfection with a bone-specific polycistronic vector using a ＂self-cleaving＂ 2A peptide to co-express huC1/C2 suppressed 1,25D-mediated induction of osteoblast target gene expression. Structural diversity of hnRNPC between human/NWPs and mouse/rat/rabbit/dog was investigated by analysis of sequence variations within the hnRNP CLZ domain. The predicted loss of distal helical function in hnRNPC from lower species provides an explanation for the altered interaction between huC1/C2 and their mouse counterparts. These data provide new evidence of a role for hnRNPC1/C2 in 1,25（OH）2D-driven gene expression, and further suggest that species-specific tetramerization is a crucial determinant of its actions as a regulator of VDR-directed transactivation.
文摘Understanding the nature of cell surface markers on exfoliated colonic cells is a crucial step in establishing criteria for a normally functioning mucosa. We have found that colonic cells isolated from stool samples (SCSR-010 Fecal Cell Isolation Kit, NonInvasive Technologies, Elkridge, MD), preserved at room temperature for up to one week, with viability of >85% and low levels of apoptosis (8% - 10%) exhibit two distinct cell size subpopulations, in the 2.5 μM - 5.0 μM and 5.0 μM - 8.0 μM range. In addition to IgA, about 60% of the cells expressed a novel heterodimeric IgA/IgG immunoglobulin that conferred a broad-spectrum cell mediated cytotoxicity against tumor cells. In a cohort of 58 subjects the exclusive absence of this immunoglobulin in two African-Americans was suggestive of a germline deletion. Serial cultures in stem cell medium retained the expression of this heterodimer. Since a majority of the cystic cells expressed the stem cell markers Lgr5 and Musashi-1 we termed these cells as gastrointestinal progenitor stem cells (GIP-C**). CXCR-4, the cytokine co-receptor for HIV was markedly expressed. These cells also expressed CD20, IgA, IgG, CD45, and COX-2. We assume that they originated from mature columnar epithelium by dedifferentiation. Our observations indicate that we have a robust noninvasive method to study mucosal pathophysiology and a direct method to create a database for applications in regenerative medicine.
基金Project supported by the National Natural Science Foundation of China (Grant Nos.60571045 and 50872147)the National High-Tech.Research and Development Program of China (Grant No.2007AA03Z035)
文摘Monodisperse Au-Fe3O4 heterodimeric nanoparticles （NPs） were prepared by injecting precursors into a hot reaction solution. The size of Au and Fe3O4 particles can be controlled by changing the injection temperature. UVis spectra show that the surface plasma resonance band of Au-Fe3O4 heterodimeric NPs was evidently red-shifted compared with the resonance band of Au NPs of similar size. The as-prepared heterodimeric Au-Fe3O4 NPs exhibited superparamagnetic properties at room temperature. The Ag-Fe3O4 heterodimeric NPs were also prepared by this synthetic method simply using AgNO3 as precursor instead of HAuCl4. It is indicated that the reported method can be readily extended to the synthesis of other noble metal conjugated heterodimeric NPs.
基金Supported by Council of Scientific and Industrial Research
文摘Protein to protein interactions leading to homo/heteromerization of receptor is well documented in literature. These interactions leading to dimeric/oligomers formation of receptors are known to modulate their function, particularly in case of G-protein coupled receptors. The opioid receptor heteromers having changed pharmacological properties than the constituent protomers provides preferences for novel drug targets that could lead to potential analgesicactivity devoid of tolerance and physical dependence. Heterodimerization of opioid receptors appears to generate novel binding properties with improved specificity and lack of side effects. Further the molecules which can interact simultaneously to both the protomers of the heteromer, or to both the binding sites(orthosteric and allosteric) of a receptor protein could be potential therapeutic molecules. This review highlights the recent advancements in exploring the plausible role of heteromerization of opioid receptors in induction of tolerance free antinociception.
文摘Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.
基金supported by grants from the Ministry of Science and Technology of China(Grant No.2020YFA0803301)the Natural Science Foundation of Shandong Province(Grant No.ZR2024QH181)The Postdoctoral Fellowship Program(Grade C)of the China Postdoctoral Science Foundation(Grant No.GZC20240770).
文摘Phosphoinositide 3-kinase(PI3K)catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate(PIP_(2))to phosphatidylinositol 3,4,5-trisphosphate(PIP_(3)),a key second messenger that orchestrates downstream signaling by recruiting and activating effector proteins,such as protein kinase B(AKT).PI3Ks are categorized into four classes(IA,IB,II,and III)based on structural characteristics and substrate preferences1.Class IA PI3K enzymes are heterodimeric complexes composed of a catalytic subunit(p110α,p110β,or p110δ)and a regulatory subunit(p85α,p55α,p50α,p85β,or p55γ)2.Although the catalytic isoforms p110αand p110β,are ubiquitously expressed across tissues,p110δis predominantly found in leukocytes3.Notably,p85αfunctions as the primary regulatory subunit.
基金This work was supported by the StateKey Basic Research Program,Foundational Investigation on Human Carcinogenes is of China(Grant No.G1998051201)National Natural Science Foundat ion for Distinguished Young Scholars of China(Grant No.39525022)National Natural Science Foundation of China(Grant Nos.30300403,30100005&30000087).
文摘In our recent studies, we found that LMP1 encoded by Epstein-Barr virus could accelerate the formation of active c-Jun/Jun B heterodimer. We studied the regulation of cyclinD1 by c-Jun/Jun B heterodimers by laser scanning confocal influorescence microscopy, Western blot, luciferase activity assay, super-EMSA and flow cytometry in the Tet-on-LMP1 HNE2 cell line, in which LMP1 expression was regulated by Tet-on system. c-Jun/Jun B heterodimers induced by LMP1 could up regulate cyclin D1 promoter activity and expression. Overexpression of cy-clinD1 accelerated the progression of cell cycle.
基金supported by the National Natural Science Foundation of China (81988101,81830086 and 81972243)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-081)+2 种基金Major Program of Shenzhen Bay Laboratory (S201101004)Guangdong Basic and Applied Basic Research Foundation (2019B030302012)the Fund of“San-ming”Project of Medicine in Shenzhen (SZSM201812088)。
文摘Although Src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined further.In this study,we demonstrated that the inhibition of Src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that Src interacted with the members of Src-family kinases(SFKs),such as Fyn or Lyn,to form heterodimers.Src interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC development.By contrast,Src could not form heterodimers with Fyn or Lyn in NEECs.We used RNA sequencing to comprehensively demonstrate that the inhibition of Src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related pathways.Results of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the Src-mediated expression of tumor growth or metastasis-related molecules.Furthermore,results of the clinical ESCC samples showed that the hyperactivation of pSrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC prognosis.This study illustrates that Src/Fyn and Src/Lyn heterodimers serve as targets for the treatment of ESCC.
文摘Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) may trigger the transcription factor AP-1 including c-Jun and c-fos. In this report, using a Tet-on LMP1 HNE2 cell line which is a dual-stable LMP1 integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 in which could be regulated by the Tet-on system, we show that Jun B can efficiently form a new heterodimeric complex with the c-Jun protein under the regulation of LMP1, phosphorylation of c-Jun (ser 63, ser 73) and Jun B is involved in the process of the new heterodimeric formation. We also find that this heterodimeric form can bind to the AP-1 consensus sequence. Transfection studies suggest that JNK interaction protein (JIP) could inhibit the heterodimer formation of c-Jun and Jun B through blocking the AP-1 signaling pathway triggered by LMP1. The interaction and function between c-Jun protein and Jun B protein increase the repertoire of possible regulatory complexes by LMP1 that could play an important role in the regulation of transcription of specific cellular genes in the process of genesis of nasopharyngeal carcinoma.
基金This research was supported by the funding from the National Natural Science Foundation of China(No.81460107).
文摘There is a significant need for magnetite-silver nanocomposites that exhibit durable and recyclable antimicrobial activity.In this study,magnetic iron oxide nanoparticles(Fe3O4 NPs)coated with ethylenediamine-modified chitosan/polyacrylic acid copolymeric layer(Fe3O4@ECS/PAA)were fabricated.Subsequently,directly deposited silver(Ag)NPs procedure was carried out to form the antibacterial heterodimers of Fe3O4@ECS/PAA-Ag NPs.The composition and morphology of the resultant nanostructures were confirmed by FT-IR,XRD,TEM and TGA.The overall length of the heterodimers was approximately 45 nm,in which the mean diameter of Fe3O4@ECS/PAA NPs reached up to 35 nm,and that of Ag NPs was around 15 nm.The mass fraction of silver NPs in the nanocomposites was about 63.1%.The obtained Fe3O4@ECS/PAA NPs exhibited good colloidal stability,and excellent response to additional magnetic field,making the NPs easy to recover after antibacterial tests.In particular,the Fe3O4@ECS/PAAAg NPs retained nearly 100%biocidal efficiency(106e107 CFU/mg nanoparticles)for both Gram-negative bacteria E.coli and Gram-positive bacteria S.aureus throughout ten cycles without washing with any solvents or water,exhibiting potent and durable antibacterial activity.
基金We acknowledge the financial support for this work by the National Natural Science Foundation of China （No. 21372168）.
文摘A novel sextuple hydrogen-bonding （HB） self-assembly molecular heterodimer bearing an iridium complex as the indicator dye and two carbazoles as the reference dye, namely 6HB-Irbt-Cz, was synthesized, and its molecular structure was confirmed by ^1H NMR, ^13CNMR, TOF-MS and 2D NMR. Because of the inefficient energy transfer process between the carbazole and iridium complex units, 6HB-Irbt-Cz exhibits distinct fluorescence/ phosphorescence dual emission in neat film state. More importantly, the neat film sample of 6HB-Irbt-Cz could display linear ratiometric optical response toward oxygen in the full oxygen concentration range from 0 to 100 vol%, together with good stability, reversibility and rapid response-recovery times. Note that this represents the first discovery of neat-film-based oxygen sensor capable of showing strictly linear ratiometric Stem-Volmer behavior in the oxygen concentration of 0- 100 vol%.
基金financially supported by the National Natural Science Foundation of China(Nos.22077041 and 31770380)。
文摘Five novel heterodimers of cytochalasan and ergosterol,ergochaeglobosins A—E,were isolated from an endophytic fungus Chaetomium globosum P2-2-2.Ergochaeglobosin A(1) possesses an unprecedented 5/6/13/6/5/6/6/6 fused octacyclic ring system,and ergochaeglobosins B(2) and C(3) form a unique 5/6/13/6/6/6/6/5 fused octacyclic ring system,whereas ergochaeglobosins D(4) and F(5) are the first cytochalasan heterodimers formed via a N-1′/C-3′′single bond.Their structures with absolute configurations were established by extensive spectroscopic analyses,single-crystal X-ray diffraction,and ECD calculations.The plausible biogenetic pathway of 1—5 was postulated.Compound 1 exhibited inhibitory effects against ConA-induced T cells and LPS-induced B cells proliferation with IC50 values of 19.2 and 14.1μmol/L,respectively.Co-treatment of 3(20μmol/L)with TRAIL(150 ng/mL)could significantly decrease the cell viability of A549 by 24.9%comparing with monotherapy of 3(20μmol/L).
基金Project supportecl by the National Natural Science Foundation of China （Nos. 20321202. 20332040. 20425208）. Dedicated to Professor Xikui Jiang on the occasion of his 80th birthday.
文摘A new series of hydrogen bonding-driven heterodimers have been self-assembled in chloroform from hydrazide-based monomers. Additional intermolecular donor-acceptor interaction between the electron-rich bis（p-phenylene）-34-crown-10 unit and the electron-deficient naphthalene diimide unit has been utilized to increase the stability of the dimmers, and pronounced cooperativity of the two discrete non-covalent forces to stabilize the dimer has been revealed by the quantitative ^1H （2D） NMR and UV-Vis experiments.
