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Ophthalmology. Retina Aug 2021To determine histologic correlates for stages of drusen-associated atrophy observed with fundus autofluorescence (FAF) and color fundus photography (CFP), of eyes with...
PURPOSE
To determine histologic correlates for stages of drusen-associated atrophy observed with fundus autofluorescence (FAF) and color fundus photography (CFP), of eyes with advanced age-related macular degeneration (AMD).
DESIGN
Case study and clinicopathologic correlation.
PARTICIPANT
A white woman with AMD findings of inactive subretinal fibrosis (right eye) and untreated nonexudative type 1 macular neovascularization (left eye) was followed for 9 years before death at 90 years of age.
METHODS
Eyes preserved 6.25 hours after death were postfixed in osmium tannic acid paraphenylenediamine and were prepared for submicrometer epoxy resin sections (115 and 90 from the right and left eye, respectively), with 19 aligned to clinical B-scans. Drusen visible by CFP at the last visit were assigned to 4 stages of FAF: stage 1, isoautofluorescence; stage 2, mildly uniform hyperautofluorescence; stage 3, a ring of hyperautofluorescence around a center of the hypoautofluorescence; and stage 4, uniform hypoautofluorescence.
MAIN OUTCOME MEASURES
Light microscopic morphologic features at known FAF stages, including druse size, druse contents, and changes in overlying retinal pigment epithelium (RPE), photoreceptors, and external limiting membrane (ELM).
RESULTS
Histologic examination of 166 drusen demonstrated that stage 1 isoautofluorescent drusen were visible on CFP. Hyperautofluorescence in stage 2 corresponded to short photoreceptors and complete coverage by RPE. Hypoautofluorescence in stages 3 and 4 corresponded to different extents of RPE atrophy (RPE gap and no RPE, respectively). Of stage 4 drusen, 67% showed no outer nuclear layer (ONL) and an undetectable ELM. Stage 4 included a high proportion of refractile drusen (82%) with many calcific nodules, visible on CFP.
CONCLUSIONS
We present the first direct clinicopathologic correlation for FAF imaging of drusen-associated atrophy. Our data support 4 FAF stages of drusen-associated atrophy. Stage 2 is the earliest detected stage in which loss of screening by photoreceptor photopigment contributes to uniform hyperautofluorescence. Stages 3 and 4 comport with incomplete RPE and outer retinal atrophy as defined by the Classification of Atrophy Meetings group. Loss of RPE, ONL, and ELM in stage 4 indicates that atrophy can begin over individual drusen. Findings will help the identification of new therapeutic approaches and clinical study end points.
Topics: Aged, 80 and over; Atrophy; Disease Progression; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Humans; Macular Degeneration; Male; Reproducibility of Results; Retinal Drusen; Retinal Pigment Epithelium; Retrospective Studies; Time Factors; Tomography, Optical Coherence
PubMed: 33217617
DOI: 10.1016/j.oret.2020.11.006 -
Science Advances Jun 2022Basalts and mantle peridotites of mid-ocean ridges are thought to sample Earth's upper mantle. Osmium isotopes of abyssal peridotites uniquely preserve melt extraction...
Basalts and mantle peridotites of mid-ocean ridges are thought to sample Earth's upper mantle. Osmium isotopes of abyssal peridotites uniquely preserve melt extraction events throughout Earth history, but existing records only indicate ages up to ~2 billion years (Ga) ago. Thus, the memory of the suspected large volumes of mantle lithosphere that existed in Archean time (>2.5 Ga) has apparently been lost somehow. We report abyssal peridotites with melt-depletion ages up to 2.8 Ga, documented by extremely unradiogenic Os/Os ratios (to as low as 0.1095) and refractory major elements that compositionally resemble the deep keels of Archean cratons. These oceanic rocks were thus derived from the once-extensive Archean continental keels that have been dislodged and recycled back into the mantle, the feasibility of which we confirm with numerical modeling. This unexpected connection between young oceanic and ancient continental lithosphere indicates an underappreciated degree of compositional recycling over time.
PubMed: 35648865
DOI: 10.1126/sciadv.abn6749 -
Inorganic Chemistry Apr 2023We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)]OTf (N^N = 2,2'-bipyridine and...
We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-:2',3'-]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin. The promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.
Topics: Humans; Structure-Activity Relationship; Osmium; Calcium; Cell Line, Tumor; Benzimidazoles; Homeostasis; Antineoplastic Agents; Coordination Complexes; Neoplasms
PubMed: 37040203
DOI: 10.1021/acs.inorgchem.3c00501 -
Coordination Chemistry Reviews Jun 2023The catalytic addition of water to unsaturated C-C or C-N π bonds represent one of the most important and environmentally sustainable methods to form C-O bonds for the...
The catalytic addition of water to unsaturated C-C or C-N π bonds represent one of the most important and environmentally sustainable methods to form C-O bonds for the production of synthetic intermediates, medicinal agents and natural products. The traditional acid-catalyzed hydration of unsaturated compounds typically requires strong acids or toxic mercury salts, which limits practical applications and presents safety and environmental concerns. Today, transition-metal-catalyzed hydration supported by NHC (NHC = N-heterocyclic carbene) ligands has attracted major attention. By rational design of ligands, choice of metals and counterions as well as mechanistic studies and the development of heterogeneous systems, major progress has been achieved for a broad range of hydration processes. In particular, the combination of NHC ligands with gold shows excellent reactivity compared with other catalytic systems; however, other systems based on silver, ruthenium, osmium, platinum, rhodium and nickel have also been discovered. Ancillary NHC ligands provide stabilization of transition metals and ensure high catalytic activity in hydration owing to their unique electronic and steric properties. NHC-Au(I) complexes are particularly favored for hydration of unsaturated hydrocarbons due to soft and carbophilic properties of gold. In this review, we present a comprehensive overview of hydration reactions catalyzed by transition metal-NHC complexes and their applications in catalytic hydration of different classes of π-substrates with a focus on the role of NHC ligands, types of metals and counterions.
PubMed: 37064328
DOI: 10.1016/j.ccr.2023.215110 -
Biomedicine & Pharmacotherapy =... Feb 2024Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of... (Review)
Review
Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.
Topics: Humans; Coordination Complexes; Neoplasms; Antineoplastic Agents; Cisplatin; Platinum
PubMed: 38290253
DOI: 10.1016/j.biopha.2024.116211 -
International Journal of Molecular... Jan 2023Humans exploit heavy metals for various industrial and economic reasons. Although some heavy metals are essential for normal physiology, others such as Tellurium (Te),...
Humans exploit heavy metals for various industrial and economic reasons. Although some heavy metals are essential for normal physiology, others such as Tellurium (Te), Thallium (TI), antimony (Sb), and Osmium (Os) are highly toxic and can lead to Polycystic Ovarian Syndrome (PCOS), a common female factor of infertility. The current study was undertaken to determine levels of the heavy metals TI, Te, Sb and Os in serum of PCOS females ( = 50) compared to healthy non-PCOS controls ( = 56), and to relate such levels with Total Antioxidant Capacity (TAC), activity of key antioxidant enzymes, oxidative stress marker levels and redox status. PCOS serum samples demonstrated significantly higher levels of TI, Te, Sb and Os and diminished TAC compared to control ( < 0.001). Furthermore, there was significant inhibition of SOD, CAT and several glutathione-related enzyme activities in sera of PCOS patients with concurrent elevations in superoxide anions, hydrogen and lipid peroxides, and protein carbonyls, along with disrupted glutathione homeostasis compared to those of controls ( < 0.001 for all parameters). Additionally, a significant negative correlation was found between the elevated levels of heavy metals and TAC, indicative of the role of metal-induced oxidative stress as a prominent phenomenon associated with the pathophysiology of the underlying PCOS. Data obtained in the study suggest toxic metals as risk factors causing PCOS, and thus protective measures should be considered to minimize exposure to prevent such reproductive anomalies.
Topics: Humans; Female; Antioxidants; Polycystic Ovary Syndrome; Antimony; Tellurium; Thallium; Osmium; Oxidative Stress; Metals, Heavy; Oxidation-Reduction; Glutathione
PubMed: 36768916
DOI: 10.3390/ijms24032596 -
Inorganic Chemistry Sep 2022The synthesis and photophysical characterization of two osmium(II) polypyridyl complexes, [Os(TAP)dppz] () and [Os(TAP)dppp2] () containing dppz...
The synthesis and photophysical characterization of two osmium(II) polypyridyl complexes, [Os(TAP)dppz] () and [Os(TAP)dppp2] () containing dppz (dipyrido[3,2-:2',3'-]phenazine) and dppp2 (pyrido[2',3':5,6]pyrazino[2,3-][1,10]phenanthroline) intercalating ligands and TAP (1,4,5,8-tetraazaphenanthrene) ancillary ligands, are reported. The complexes exhibit complex electrochemistry with five distinct reductive redox couples, the first of which is assigned to a TAP-based process. The complexes emit in the near-IR ( at 761 nm and at 740 nm) with lifetimes of >35 ns with a low quantum yield of luminescence in aqueous solution (∼0.25%). The Δ and Λ enantiomers of and are found to bind to natural DNA and with AT and GC oligodeoxynucleotides with high affinities. In the presence of natural DNA, the visible absorption spectra are found to display significant hypochromic shifts, which is strongly evident for the ligand-centered π-π* dppp2 transition at 355 nm, which undergoes 46% hypochromism. The emission of both complexes increases upon DNA binding, which is observed to be sensitive to the Δ or Λ enantiomer and the DNA composition. A striking result is the sensitivity of Λ- to the presence of AT DNA, where a 6-fold enhancement of luminescence is observed and reflects the nature of the binding for the enantiomer and the protection from solution. Thermal denaturation studies show that both complexes are found to stabilize natural DNA. Finally, cellular studies show that the complexes are internalized by cultured mammalian cells and localize in the nucleus.
Topics: Animals; DNA; Intercalating Agents; Ligands; Mammals; Oligodeoxyribonucleotides; Osmium; Phenanthrolines; Phenazines; Ruthenium
PubMed: 36094851
DOI: 10.1021/acs.inorgchem.2c01231 -
Chemical Science Dec 2022By combining the energy input from two red photons, chemical reactions that would normally require blue or ultraviolet irradiation become accessible. Key advantages of...
By combining the energy input from two red photons, chemical reactions that would normally require blue or ultraviolet irradiation become accessible. Key advantages of this biphotonic excitation strategy are that red light usually penetrates deeper into complex reaction mixtures and causes less photo-damage than direct illumination in the blue or ultraviolet. Here, we demonstrate that the primary light-absorber of a dual photocatalytic system comprised of a transition metal-based photosensitizer and an organic co-catalyst can completely alter the reaction outcome. Photochemical reductions are achieved with a copper(i) complex in the presence of a sacrificial electron donor, whereas oxidative substrate activation occurs with an osmium(ii) photosensitizer. Based on time-resolved laser spectroscopy, this changeover in photochemical reactivity is due to different underlying biphotonic mechanisms. Following triplet energy transfer from the osmium(ii) photosensitizer to 9,10-dicyanoanthracene (DCA) and subsequent triplet-triplet annihilation upconversion, the fluorescent singlet excited state of DCA triggers oxidative substrate activation, which initiates the to isomerization of an olefin, a [2 + 2] cycloaddition, an aryl ether to ester rearrangement, and a Newman-Kwart rearrangement. This oxidative substrate activation stands in contrast to the reactivity with a copper(i) photosensitizer, where photoinduced electron transfer generates the DCA radical anion, which upon further excitation triggers reductive dehalogenations and detosylations. Our study provides the proof-of-concept for controlling the outcome of a red-light driven biphotonic reaction by altering the photosensitizer, and this seems relevant in the greater context of tailoring photochemical reactivities.
PubMed: 36605743
DOI: 10.1039/d2sc05229f -
Inorganic Chemistry Frontiers Jun 2022We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial...
We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(-cymene)(1,10-phenanthroline)Cl]PF motif (where M is either Ru or Os) with an appended C fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C Os nanomedicines as highly successful . Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism.
PubMed: 36311556
DOI: 10.1039/d2qi00423b -
Molecules (Basel, Switzerland) Sep 2021Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960's. Facing the resistance mechanisms against... (Review)
Review
Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.
Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960's. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes-as well complexes with other metals (osmium, iron, platinum)-can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Neoplasm; Endoplasmic Reticulum Stress; Humans; Organometallic Compounds; Osmium; Ruthenium
PubMed: 34500819
DOI: 10.3390/molecules26175386