gebhart/patrepeval huggingface dataset:
High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships (2010)

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Antimalarials. "Distal" hydrazine derivatives of 7-chloroquinoline (1971)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAntimalarials. "Distal" hydrazine derivatives of 7-chloroquinolineTara Singh, John F. Hoops, John H. Biel, Wallace K. Hoya, Robert George Stein, and Deanna R. CruzCite this: J. Med. Chem. 1971, 14, 6, 532–535Publication Date (Print):June 1, 1971Publication History Published online1 May 2002Published inissue 1 June 1971https://pubs.acs.org/doi/10.1021/jm00288a018https://doi.org/10.1021/jm00288a018research-articleACS PublicationsRequest reuse permissionsArticle Views109Altmetric-Citations8LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Changes in Mitochondrial Function Resulting from Synaptic Activity in the Rat Hippocampal Slice (1998)

Digital imaging microfluorimetry was used to visualize changes in mitochondrial potential and intracellular Ca2+ concentration, [Ca2+]i, in thick slices of rat hippocampus. Electrical activity, especially stimulus train-induced bursting (STIB) activity, produced slow, prolonged changes in mitochondrial potential within hippocampal slices as revealed by fluorescence measurements with rhodamine dyes. Changes in mitochondrial potential showed both temporal and spatial correlations with the intensity of the electrical activity. Patterned changes in mitochondrial potential were observed to last from tens of seconds to minutes as the consequence of epileptiform discharges. STIB-associated elevations in [Ca2+]i were also prolonged and exhibited a spatial pattern similar to that of the mitochondrial depolarization. The mitochondrial depolarization was sensitive to TTX and glutamate receptor blockers ([Mg2+]o and CNQX or DNQX plus D-AP-5) and to the inhibition of glutamate release by activation of presynaptic NPY receptors. The monitoring of mitochondrial potential in slice preparations provides a new tool for mapping synaptic activity in the brain and for determining the roles of mitochondria in regulation of brain synaptic activity.
Identification of Tumor Suppressor Genes via Cell Fusion and Chromosomal Transfer (2012)

Loss of DNA or chromosomal deletion was frequently reported in different sporadic tumors, suggesting that those lost regions may contain putative tumor suppressor genes (TSGs). To map and isolate candidate genes from vast randomly lost areas, functional and complementary evidence is usually needed to define these areas to critical regions (CR). This is particularly important when one is dealing with sporadic cancers where clearly defined familial predisposition is present but high cancer risk families are not available for position cloning. A numerous studies have revealed extensive DNA deletions in nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). To identify candidate genes from these cancers, we used cell fusion and microcell-mediated chromosome transfer (MMCT) to introduce the whole chromosome or a chromosome fragment, into NPC and ESCC cell lines. Combined with other molecular approaches, we have successfully identified a number of novel TSGs on various human chromosomes. The nasopharynx is located behind the nasal cavity in the upper part of the pharynx (Fig. 1). NPC is a type of malignancy which arises from the epithelial cells in the nasopharynx. NPC is an unique cancer, which is commonly found in, Southeast Asia, North Africa, Middle East, and Arctic regions, but rare in most parts of the world (Jeyakumar et al 2006, Wei et al 2005). The esophagus is a tube, which is about 25 cm long, for the food passage from mouth to stomach (Fig. 2). Esophageal cancer (EC) is classified into two major histologic subtypes: squamous cell carcinoma and adenocarcinoma (Daly et al 2000). Esophageal adenocarcinoma (EAC) arises from the cells of glands responsible for producing mucous in the esophageal wall. The majority of the cases (>80%) are ESCC in Hong Kong, while EAC shows a climbing incidence in Western countries. EC varies greatly in geographical distribution; high-risk areas include north-central China in Henan and Shanxi (Holmes et al 2007, Qi et al 2005, Wu et al 2006).
Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. (1994)

Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and flt-1, are overexpressed by papillary dermal microvascular endothelial cells. Transforming growth factor alpha (TGF-alpha), a cytokine that is also overexpressed in psoriatic epidermis, induced VPF gene expression by cultured epidermal keratinocytes. VPF secreted by TGF-alpha-stimulated keratinocytes was bioactive, as demonstrated by its mitogenic effect on dermal microvascular endothelial cells in vitro. Together, these findings suggest that TGF-alpha regulates VPF expression in psoriasis by an autocrine mechanism, leading to vascular hyperpermeability and angiogenesis. Similar mechanisms may operate in tumors and in healing skin wounds which also commonly express both VPF and TGF-alpha.
Pharmacological inhibition of hematopoietic progenitor kinase 1 positively regulates T-cell function (2020)

Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-specific Ste20-related serine/threonine kinase, is a negative regulator of signal transduction in immune cells, including T cells, B cells, and dendritic cells (DCs). In mice, HPK1 deficiency subverts inhibition of the anti-tumor immune response and is associated with functional augmentation of anti-tumor T cells. We have used a potent, small molecule HPK1 inhibitor, Compound 1, to investigate the effects of pharmacological intervention of HPK1 kinase activity in immune cells. Compound 1 enhanced Th1 cytokine production in T cells and fully reverted immune suppression imposed by the prostaglandin E2 (PGE2) and adenosine pathways in human T cells. Moreover, the combination of Compound 1 with pembrolizumab, a humanized monoclonal antibody against the programmed cell death protein 1 (PD-1), demonstrated a synergistic effect, resulting in enhanced interferon (IFN)-γ production. Collectively, our results suggest that blocking HPK1 kinase activity with small molecule inhibitors alone or in combination with checkpoint blockade may be an attractive approach for the immunotherapy of cancer.
THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger Gases (1997)

The heme oxygenase (HO) system consists of two forms identified to date: the oxidative stress-inducible protein HO-1 (HSP32) and the constitutive isozyme HO-2. These proteins, which are different gene products, have little in common in primary structure, regulation, or tissue distribution. Both, however, catalyze oxidation of heme to biologically active molecules: iron, a gene regulator; biliverdin, an antioxidant; and carbon monoxide, a heme ligand. Finding the impressive heme-degrading activity of brain led to the suggestion that "HO in brain has functions aside from heme degradation" and to subsequent exploration of carbon monoxide as a promising and potentially significant messenger molecule. There is much parallelism between the biological actions and functions of the CO- and NO-generating systems; and their regulation is intimately linked. This review highlights the current information on molecular and biochemical properties of HO-1 and HO-2 and addresses the possible mechanisms for mutual regulatory interactions between the CO- and NO-generating systems.
Circulating Tumor Cells: Not All Detected Cells Are Bad and Not All Bad Cells Are Detected (2011)

More than 90% of cancer deaths result from the development of hematogenously disseminated metastasis. The presence of circulating tumor cells (CTCs) in patients with cancer was first reported in 1869. 1 More recently, methods have been developed to detect, isolate, and characterize CTCs in multiple different malignancies that arise in solid organs. 2 The most widely used method, designated CellSearch (Veridex, Raritan, NJ), relies on immunomagnetic capture of CTCs using antibodies against the epithelial cell adhesion molecule (EpCam), which is expressed on the cell surface of many epithelial malignancies, followed by additional characterization with 4,6-diamidino-2-phenylindole staining (to
Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF). (1982)

Abstract Delayed-type hypersensitivity reactions are characterized by mononuclear cell infiltration consisting of macrophages and lymphocytes, the majority of which are not specifically sensitized for the antigen eliciting the reaction. Although chemotactic and migration inhibitory factors for macrophages have been extensively characterized, little is known about similar human chemoattractants generated by lymphocytes for lymphocytes. A companion paper describes some of the biologic characteristics of a human mitogen-induced lymphokine that is specifically chemokinetic for nonadherent lymphocytes over other cell types. Further chemical characterization of lymphotactic activity derived from crude Con A-stimulated peripheral blood lymphocyte supernatants by Sephadex G-100 gel filtration chromatography revealed a peak that eluted in a region corresponding to a m.w. of 56,200. This activity was cationic, eluting from a QAE Sephadex anion-exchange column at 4 to 6 mS. Subsequent isoelectric focusing in sucrose revealed an isoelectric point of 9.0–9.1. Activity after sequential Sephadex G-100 and QAE chromatography and isoelectric focusing was subjected to electrophoresis in sodium dodecyl sulfate Polyacrylamide gels (SDS-PAGE). A single band of stainable protein was evident in both nonreduced and reduced gels, which corresponded to a m.w. of 14,000, and to a region from which lymphotactic activity could be detected in eluates from slices of unstained gels run in parallel. Subsequent Sephadex G-50 gel filtration chromatography demonstrated a m.w. of 14,400 of the lymphotactic activity after interaction with SDS. It is postulated that in vitro stimulation of peripheral blood lymphocytes by Con A results in the secretion of a cationic lymphocyte chemokinetic activity that is present in aggregated tetrametric form. Interaction with SDS is sufficient to reduce the factor to a monomeric form of 14,000 without significant loss of activity. The simultaneous generation of lymphocyte migration inhibitory activity (approximately 25,000 daltons) in size could provide a mechanism for immobilization of nonsensitized lymphocytes once attracted to sites of delayed-type hypersensitivity reactions.
Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, blocks lysosomal cholesterol trafficking in macrophages. (1993)

Certain steroids having an oxo group at the C-17 or C-20 position such as pregnenolone and dehydroisoandrosterone inhibit the cholesterol transport from lysosomes to other cellular sites. Taking advantage of the fact that the inhibition is reversed upon removal of the steroids, we studied the factors that control the cholesterol transport from lysosomes to other cellular sites in macrophages. Macrophages that accumulated unesterified cholesterol in their lysosomes were prepared by incubating cells with liposomes containing cholesterol and phosphatidylserine in the presence of a steroid inhibitor. These cells were chased by means of steroid washout, and then the effects of various pharmacological agents on the subsequent metabolism of cholesterol were examined. When the cells were chased in the absence of the agents, some of the cholesterol was converted to cholesteryl esters in the cells, and others were desorbed into the medium as unesterified forms, suggesting recovery of lysosomal cholesterol trafficking. Among the agents tested, bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, completely blocked both cholesterol esterification and cholesterol desorption at 10 nM. Moreover, agents that neutralize the lysosomal proton gradient, such as ammonium chloride and chloroquine, also reduced both of the processes. Fluorescent microscopic examination of bafilomycin A1-treated cells revealed extensive filipin-cholesterol staining of perinuclear lysosomes. From these data, we conclude that acidic pH is required for the efflux of cholesterol from lysosomes to other cellular sites.
Redox modulation of oxidative stress by Mn porphyrin-based therapeutics: The effect of charge distribution (2008)

We evaluate herein the impact of positive charge distribution on the in vitro and in vivo properties of Mn porphyrins as redox modulators possessing the same overall 5+ charge and of minimal stericity demand: Mn(III) meso-tetrakis(trimethylanilinium-4-yl)porphyrin (MnTTriMAP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylpyrazolium-4-yl)porphyrin (MnTDM-4-PzP(5+)), Mn(III) meso-tetrakis(N,N'-dimethylimidazolium-2-yl)porphyrin (MnTDM-2-ImP(5+)), and the ortho and para methylpyridinium complexes Mn(III) meso-tetrakis(N-methylpyridinium-4-yl)porphyrin (MnTM-4-PyP(5+)) and Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP(5+)). Both Mn(III)/Mn(II) reduction potential and SOD activity within the series follow the order: MnTTriMAP(5+)<MnTDM-4-PzP(5+)<MnTM-4-PyP(5+)<MnTM-2-PyP(5+)<MnTDM-2-ImP(5+). The kinetic salt effect (KSE) on the catalytic rate constant for superoxide dismutation (k(cat)) indicates that the electrostatic contribution to the O(2)*(-) dismutation is the greatest with MnTM-2-PyP(5+) and follows the order: MnTM-4-PyP(5+)<MnTDM-4-PzP(5+) approximately MnTDM-2-ImP(5+)<MnTM-2-PyP(5+). The KSE observed on k(cat) suggests that the charges are relatively confined within specific regions of the aryl rings. Whereas the charges in imidazolium, pyrazolium, and MnTM-4-PyP(5+) compounds are distributed in-plane with the porphyrin ring, the charges of MnTM-2-PyP(5+) are either above or below the plane, which channels the negatively-charged superoxide toward the axial positions of the Mn porphyrin more efficiently, and leads to the highest KSE. This mimics the tunneling effect observed in the SOD enzymes themselves. The modulation of the reactivity of the Mn center by the electronic perturbations caused by the meso-aryl substituent could be explained by DFT calculation, whereby a correlation between the Mn(III)/Mn(II) reduction potential (and/or SOD activity) and meso-aryl fragment softness descriptors for nucleophilic (s(f)(+)) and radical (s(f)(o)) attacks was observed. MnTDM-4-PzP(5+) and MnTM-4-PyP(5+) did not protect SOD-deficient E. coli grown aerobically, which is in agreement with their low k(cat). MnTM-2-PyP(5+) and MnTDM-2-ImP(5+) have similar high k(cat), but MnTDM-2-ImP(5+) was significantly less protective to E. coli, probably due to its bulkier size, decreased cellular uptake, and/or observed toxicity. The placement of charges closer to the metal center and spatial charge localization increases both the in vitro and the in vivo SOD activity of the compound.
β-Amyloid1–42 Gene Transfer Model Exhibits Intraneuronal Amyloid, Gliosis, Tau Phosphorylation, and Neuronal Loss (2010)

Alzheimer disease is characterized by extracellular beta-amyloid (Abeta) plaques and intracellular inclusions containing neurofibrillary tangles of phospho-Tau and intraneuronal Abeta associated with neuronal cell death. We generated a novel gene transfer animal model using lentiviral Abeta(1-42) that resulted in intracellular but not extracellular Abeta accumulations in the targeted rat primary motor cortex. Expression of intracellular Abeta(1-42) led to pathological changes seen in human Alzheimer disease brains, including cell death, inflammatory signs, activation of two Tau kinases, and Tau hyperphosphorylation. Promoting clearance of lentiviral Abeta(1-42) reversed these effects, demonstrating that intraneuronal Abeta(1-42) is a toxic peptide that lies upstream of Tau modification. These studies reveal the role of intracellular Abeta(1-42) in a novel gene transfer animal model, which is a useful tool to study intraneuronal Abeta(1-42)-induced pathology in the absence of extracellular plaques. Targeted delivery of Abeta will allow speedy delineation of pathological mechanisms associated with specific neurodegenerative lesions.
The α- and β-subunits of the Human UDP-N-acetylglucosamine:Lysosomal Enzyme Phosphotransferase Are Encoded by a Single cDNA (2005)

Lysosomal enzymes are targeted to the lysosome through binding to mannose 6-phosphate receptors because their glycans are modified with mannose 6-phosphate. This modification is catalyzed by UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase). Bovine GlcNAc-phosphotransferase was isolated using monoclonal antibody affinity chromatography, and an alpha2beta2gamma2-subunit structure was proposed. Although cDNA encoding the gamma-subunit has been described, cDNAs for the alpha- and beta-subunits have not. Using partial amino acid sequences from the bovine alpha- and beta-subunits, we have isolated a human cDNA that encodes both the alpha- and beta-subunits. Both subunits contain a single predicted membrane-spanning domain. The alpha- and beta-subunits appear to be generated by a proteolytic cleavage at the Lys928-Asp929 bond. Transfection of 293T cells with the alpha/beta-subunits-precursor cDNA with or without the gamma-subunit cDNA results in a 3.6- or 17-fold increase in GlcNAc-phosphotransferase activity in cell lysates, suggesting that the precursor cDNA contains the catalytic domain. The sequence lacks significant similarity with any described vertebrate enzyme except for two Notch-like repeats in the alpha-subunit. However, a 112-amino acid sequence is highly similar to a group of bacterial capsular polymerases (46% identity). A BAC clone containing the gene that spanned 85.3 kb and was composed of 21 exons was sequenced and localized to chromosome 12q23. We now report the cloning of both the cDNA and genomic DNA of the precursor of Glc-NAc-phosphotransferase. The completion of cloning all three subunits of GlcNAc-phosphotransferase allows expression of recombinant enzyme and dissection of lysosomal targeting disorders.
Millimeter-scale self-assembly and its applications (2003)

Abstract Self-assembly is a concept familiar to chemists. In the molecular and nanoscale regimes, it is often used as a strategy in fabricating regular 3D structures—that is, crystals. Self-assembly of components with sizes in the µm-to-mm range is less familiar to chemists; this type of self-assembly may, however, become technologically important in the future. In this size range, self-assembly offers methods to form regular 3D structures from components too small or too numerous to be manipulated by other means, and methods to incorporate function into these structures; it also offers simplicity and economy. This paper focuses on the use of self-assembly to build functional systems of components with sizes in the range from microns to millimeters. It compares the principles of selfassembly at the molecular and millimeter scales, reviews the possible applications of mesoscale, self-assembled systems, and outlines some of the most important issues in the use of self-assembly to build functional systems.
Approaches to the release of a master cell bank of PER.C6 cells; a novel cell substrate for the manufacture of human vaccines. (2006)

At Merck and Co. we have developed a recombinant E1 deficient adenovirus type 5 vaccine vector for HIV-1 and have adopted the PER.C6 cell line as a cell substrate for the manufacture of this vector for Phase I and II clinical trials. The PER.C6 cell line was developed at Crucell by the transfection of human primary embryonic retinoblasts with a transgene of E1 constructed with a minimum of E1 coding sequences to preclude homologous recombination generating replication-competent adenovirus, between E1 sequences in PER.C6 and adenovirus vectors with E1 deletions of the same molecular coordinates. We have developed a Master Cell Bank (MCB) of PER.C6 cells under serum-free conditions of suspension culture from a vial of PER.C6 cells obtained from Crucell. This MCB has been released according to an extensive panel of testing for the detection of adventitious viral agents, including assays for sterility and mycoplasma, in vivo and in vitro assays for the detection of viruses of human, bovine and porcine origin, replication competent adenoviruses, sensitive PERT assays for the detection of RT in supernatants of co-cultivations, electron microscopy and a panel of PCR-based assays for specific human and animal viruses. This MCB has been used for the manufacture of vaccine vector supporting a number of IND submissions for Phase I clinical trials over a three-year period during which the panel of PCR testing applied to the MCB has been judiciously expanded. Advances in QPCR technology, liquid handling systems, and more recently mass spectrometry offer the possibility that very broad panels of primers and probes capable of the detection of all known human viruses can be applied routinely to support the release of biologicals for human clinical trials. The impact of this breadth of testing on the continued reliance of classical in vivo and in vitro assays for adventitious viruses is clearly an emerging issue worthy of serious debate.
Porphyrin–phospholipid liposomes permeabilized by near-infrared light (2014)

The delivery of therapeutic compounds to target tissues is a central challenge in treating disease. Externally controlled drug release systems hold potential to selectively enhance localized delivery. Here we describe liposomes doped with porphyrin-phospholipid that are permeabilized directly by near-infrared light. Molecular dynamics simulations identified a novel light-absorbing monomer esterified from clinically approved components predicted and experimentally demonstrated to give rise to a more stable porphyrin bilayer. Light-induced membrane permeabilization is enabled with liposomal inclusion of 10 molar % porphyrin-phospholipid and occurs in the absence of bulk or nanoscale heating. Liposomes reseal following laser exposure and permeability is modulated by varying porphyrin-phospholipid doping, irradiation intensity or irradiation duration. Porphyrin-phospholipid liposomes demonstrate spatial control of release of entrapped gentamicin and temporal control of release of entrapped fluorophores following intratumoral injection. Following systemic administration, laser irradiation enhances deposition of actively loaded doxorubicin in mouse xenografts, enabling an effective single-treatment antitumour therapy.