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cadmium-cardiolipin disruption of respirasome assembly and redox balance through mitochondrial membrane rigidification

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JOURNAL OF LIPID RESEARcH 2025年第3期66卷 100750页

作者： Romanova, Nadiya Sule, Kevin Issler, Travis Hebrok, Daniel Persicke, Marcus Thevenod, Frank Prenner, Elmar J. Lee, Wing-Kee Bielefeld Univ Med Sch OWL Physiol & Pathophysiol Cells & Membranes Bielefeld Germany Univ Calgary Dept Biol Sci Calgary AB Canada Med Sch OWL Prote & Metabol Core Facil Bielefeld Germany Bielefeld Univ Ctr Biotechnol Microbial Genom & Biotechnol Bielefeld Germany Witten Herdecke Univ Inst Physiol & Pathophysiol ZBAF Witten Germany

The environmental pollutant cadmium (cd) poses a threat to human health through the consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to cd cellular toxicity. cd-lipid interactions have been less considered. We hypothesized cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (cL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (Scs). In cd-treated rat kidney cortex (rKc) mitoplasts, laurdan (lipid-water interface), and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure cL or IMM biomimetic (40 mol % POPc, 35 mol % DOPE, 20 mol % TOcL, 5 mol % SAPI) nanoliposomes were rigidified by 25 mu M cd, which was confirmed in live- cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPcT) cells. Blue native gel electrophoresis evidenced similar to 30% loss of I+III2+IVn Sc formation after 5 mu M cd for 6 h in HPcTs, which was reversed by cL-binding drug MTP-131/SS-31/elamipretide (0.1 mu M), yet a-tocopherol-insensitive. Moreover, MTP-131 attenuated cdinduced H2O2 (similar to 30%) and cytochrome c release (similar to 25%), but not osmotic swelling, in rKc mitochondria as well as cd-induced ROS (similar to 25%) in HPcTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous cRLS1 expression reversed cd (5 mu M, 24 h) cytotoxicity (similar to 25%) by MTT assay, cd (5 mu M, 3 h)-induced ROS and mitochondrial membrane rigidification by cd (1 mu M, 1 h) in HPcT cells. In summary, we report a novel mechanism for cd toxicity in which cd-cL interactions cause IMM rigidification, thereby disrupting correct Sc assembly and increasing ROS.

关键词： heavy metal toxicity reactive oxygen species electron transport chain liquid-ordered phase cI complex I cIII complex III cIV complex IV cd cadmium cL cardiolipin cRLS1 cardiolipin synthase 1 cyt c cytochrome c DHR123 dihydrorhodamine 123 DMT1 divalent metal transporter 1 DOPE dioleoylphosphatidylethanolamine DPH diphenylhexatriene ETc electron transport chain EV empty vector FDA U.S. Food and Drug Administration GP generalized polarization GSH glutathione (reduced) HPcT human proximal convoluted tubule IB immunoblot IMM inner mitochondrial membrane IMS intermembrane space LUV large unilamellar vesicle McU mitochondrial calcium uniporter MLV multilamellar vesicle MT metallothionein MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide OML outer membrane leaflet OMM outer mitochondrial membrane Pc phosphatidylcholine PE phosphatidylethanolamine PM plasma membrane Rh123 + rhodamine 123 + rKc mito rat kidney cortex mitochondria ROS reactive oxygen species SAPI stearoyl-arachidonoyl-phosphatidylinositol Sc supercomplex SFM serum free medium TLcL tetralinoleoyl cardiolipin TMcL tetramyristoyl cardiolipin TOcL tetraoleoyl cardiolipin VDAc voltage dependent anion channel

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Application of Kirchhoff's Laws to pharmacologic and pharmacokinetic analyses

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PHARMAcOLOGIcAL REVIEWS 2025年第3期77卷 100050页

作者： Benet, Leslie Z. Sodhi, Jasleen K. Tiitto, Markus Ville Xiang, Yue Univ Calif San Francisco Sch Med Dept Bioengn & Therapeut Sci 513 Parnassus Ave Room S-822 San Francisco CA 94143 USA Septerna Dept Drug Metab & Pharmacokinet South San Francisco CA USA Food & Drug Adm Ctr Drug Evaluat & Sci Off Clin Pharmacol Silver Spring MD USA

Recently, we introduced a straightforward approach to derive clearance and rate constant equations, without relying on differential equations, utilizing Kirchhoff's Laws, a well known physics methodology used to describe rate-defining processes either in series or parallel. Manuscripts from our laboratory have re-examined published experimental data, demonstrating that the Kirchhoff's Laws methodology can explain data previously considered anomalous, such as the following: specialIntscript all experimental perfused liver clearance data conforming to the equation once thought to represent the unphysiological well stirred model, specialIntscript instances where linear pharmacokinetic systemic bioavailability determinations exceed unity, specialIntscript renal clearance being influenced by drug input processes, specialIntscript statistically significant differences in bioavailability measures between urinary excretion and systemic concentration mea- surements, and specialIntscript how the long-accepted steady-state clearance approach used in pharmacokinetics for the past half-century leads to unrealistic conclusions about the relationship between liver-to-blood Kp uu and hepatic availability F H . These findings demonstrate the potential for errors in pharmacokinetic evaluations that rely on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, both those that align with present pharma- cokinetic theory, and those that do not. Although 3 publications have attempted to rebut our position, they fail to address unexplained experimental data, and we detail here why these analyses are invalid. Our discoveries are ongoing. Additionally, we briefly discuss the application of Kirchoff's Laws to saturable nonlinear kinetics, explaining increased pharmacodynamic response for extended vs im- mediate release dosage forms, as well as the advantages of successfully formulating high hepatic extraction drugs.

关键词： [ S ] substrate concentration A absorp site amount of drug at the absorption site A body amount of drug in the body AUc area under the curve AUMc area under the moment curve c avg,u,DM average liver unbound concentration for the dispersion model c Blood steady-state concentration of total drug in the blood c H,u average concentration of unbound drug within the liver c in blood concentration of total drug (unbound plus bound) entering the liver c in,u concentration of unbound drug in blood entering the liver cL clearance cL entering entering clearance cL filtration renal filtration clearance cL gut clearance from the gastrointestinal tract cL H hepatic clearance cL H,u hepatic clearance of unbound drug cL int intrinsic clearance cL leaving leaving clearance cL R renal clearance cL R,diff eq renal clearance derived by differential equations c out blood concentration of total drug (unbound plus bound) exiting the liver c out,u unbound drug concentration in the liver exiting blood DM dispersion model EcM extended clearance model ER extended-release f driving force or impetus causing flux F H first pass fractional hepatic bioavailability f u Tub fraction unbound in the renal tubule f uB fraction unbound in the blood GFR glomerular filtration rate IPRL isolated perfused rat liver IR immediate release IVIVE in vitro-in vivo extrapolation J driving flux K coefficient of proportionality k a first-order absorption rate constant k d first-order elimination rate constant K M concentration of substrate at the half-maximal rate of elimination k M first-order rate constant for elimination of a metabolite K puu ratio at steady-state of unbound drug concentration in the liver to the unbound drug concentration in the systemic circulation MAT mean absorption time MRT mean residence time P int,reab intrinsic passive renal reabsorption PTM parallel tube model Q H hepatic blood flow Q R renal blood flow SubQ subcutaneous t time V gut volume of distribution in the gastrointestinal tract V max maximum rate of substrate elimination when

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Biological potential and bio-refinery from marine macro algae caulerpa scalpelliformis

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BIOMASS cONVERSION AND BIOREFINERY 2024年第7期14卷 8909-8915页

作者： Seedevi, Palaniappan Saveetha Inst Med & Tech Sci SIMATS Saveetha Sch Engn Inst Biotechnol Dept Res & Innovat Chennai 602105 Tamil Nadu India

The present investigation evaluated the toxic effect and bioactive potential of marine macro algae caulerpa scalpelliformis. The crude methanolic extract was fractionated in diethylaminoethyl (DEAE) cellulose column chromatography using Nacl (0.1-10 M). The fractions were dialyzed and freeze-dried. The active fractions (F1, F2, and F3) were obtained using TLc chromatography. The crude methanolic extract and fractions showed strong hemolytic activity of 129.55, 73.73, 43.47, and 37.73 HT/mg in chicken blood, respectively, the human blood group (AB and O) showed considerable hemolytic activity of 73.73, 43.47, and 37.73 HT/mg, respectively, and the fraction (F3) had no activity. The acute toxic effect of the crude methanolic extract and fractions (F1, F2, and F3) showed the lethal dose (LD50) at 176, 121.5, 138, and 152 mg/kg body weight. The crude methanolic extract and fractions indicated strong analgesic activity at the ratio of 0.26, 0.37, 0.11, and 0.10 using the tail flick test in mice at 12.5 mg/kg body weight. These results suggest that the methanolic extract and its fractions from c. scalpelliformis may be potential pharmacological agents.

关键词： Hemolytic activity Acute toxicity Analgesic activity c scalpelliformis

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成人细菌性肺炎诊断c反应蛋白与血常规联合检测的效果研究

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健康女性 2021年第37期 125,120页

作者：王颖健无锡市康复医院江苏无锡 214000

目的:研究血常规与c反应蛋白检测联合检测在成人细菌性肺炎中的诊断价值.方法:择取某院2019年1月～2020年3月期间就诊的54例成人细菌性肺炎患者作为探究组和参照组,所有研究对象均接受c反应蛋白与血常规联合检测.结果:探究组患者c反应... 详细信息

目的:研究血常规与c反应蛋白检测联合检测在成人细菌性肺炎中的诊断价值.方法:择取某院2019年1月～2020年3月期间就诊的54例成人细菌性肺炎患者作为探究组和参照组,所有研究对象均接受c反应蛋白与血常规联合检测.结果:探究组患者c反应蛋白水平与白细胞计数值显著高于参照1组(t1=9.6395,P＜0.05;t2=9.0749,P＜0.05),参照1组c反应蛋白水平与白细胞计数值略高于参照2组(t=0.8952,P＞0.05);探究组c反应蛋白阳性率和白细胞阳性率均高于参照1组(χ12=9.7835,P＜

关键词：成人细菌性肺炎血常规检查 c 反应蛋白

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Simulation of a GaInP2 - GaAs - GaInAsN - Ge Photovoltaic cell for Space Applications

IEEE PHOTONICS JOURNAL

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IEEE PHOTONIcS JOURNAL 2025年第3期17卷

作者： Fees, Antoine caron, Pablo Revol, Ines Vaillon, Rodolphe Mekki, Julien Nuns, Thierry Almuneau, Guilhem Univ Toulouse CNRS LAAS CNRS INSA F-31400 Toulouse France Univ Toulouse ONERA DPHY F-31055 Toulouse France Univ Toulouse LAAS CNRS CNRS F-31400 Toulouse France Ctr Natl Etud Spatiales F-31401 Toulouse France

We use an open-source simulation software to design III-V multi-junction solar cells containing a dilute nitride subcell. We discuss the different modeling techniques in terms of physical models and numerical methods, and provide an educated guess for a GaInP2 - GaAs - GaInAsN - Ge lattice-matched 4-junction solar cell performance assessment. We suggest a way to ensure an effective computation of the main output values of an open-source Poisson-Drift-Diffusion solver for multi-junction solar cell analysis. An optimization of a multi-junction cell including a n-i-p subcell is performed, starting from basic theoretical considerations, to the use of a double-layer anti-reflective coating to target the most limiting subcell, and then with an optimization of the n-i-p architecture in the 1 eV subcell with respect to the GaInAsN layer properties. We show that the detrimental effects of low diffusion lengths in the GaInAsN layer can be alleviated by taking advantage of field-assisted collection.

关键词： Mathematical models Photonics Photovoltaic cells convergence Short-circuit currents Voltage Optical reflection Gallium arsenide computer architecture computational modeling Simulation photovolta & iuml c multi-junction open source dilute nitride

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Bereaved Parents' Perspectives on Financial Toxicity at End of Life for children with cancer: A Qualitative Study

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JOURNAL OF PEDIATRIcS 2025年 276卷 114269-114269页

作者： Alexander, Ariel K. Martinez, Isaac Tefera, Raba Beauchemin, Melissa P. Lawhon, Valerie M. Nichols, Ashley Rosenberg, Abby R. Bhatia, Smita Johnston, Emily E. Carleton Coll Northfield MN USA Univ Alabama Birmingham Inst Canc Outcomes & Survivorship Birmingham AL USA Columbia Univ Irving Med Ctr Sch Nursing New York NY USA Univ Alabama Birmingham Sch Med Dept Med Birmingham AL USA Univ Alabama Birmingham Div Gerontol Geriatr & Palliat Care Birmingham AL USA Dana Farber Canc Inst Dept Psychosocial Oncol & Palliat Care Boston MA USA Boston Childrens Hosp Dept Pediat Boston MA USA Harvard Med Sch Dept Pediat Boston MA USA Univ Alabama Birmingham Dept Pediat Pediat Hematol Oncol Birmingham AL USA

Objective To explore financial toxicity (FT) experienced by the parents of children with cancer at end-of-life (EOL), including exploring differences by race and ethnicity. Study design We performed secondary analysis of semistructured interviews of bereaved parents' perspectives on quality EOL care. Fifty-five interviews were conducted in california and Alabama representing 48 children (0-21 years at time of death) who died of cancer >= 6 months prior. Quotes related to FT were identified and iteratively grouped into themes without an a priori framework. Results Most participants were non-Hispanic White (30;55%), and the most common diagnoses were noncentral nervous system solid tumors (16;33%) and central nervous system tumors (16;33%). children died at a mean age of 11 and a median of 4 years prior to the interview. Almost all parents (52;95%) discussed FT, including all Black and Hispanic parents. Parents identified transportation, housing, other basic needs, funeral costs, and medical costs as well as work disruptions as contributors to FT at EOL. Barriers to financial wellness included navigating insurance, insufficient financial support from the hospital, and long-term FT from treatment. Many parents discussed how the hospital and community served as facilitators of financial wellness. In some cases, finances prevented families from accessing nursing services and mental health support and affected EOL decisions. conclusions As FT affected almost all families' EOL experience, pediatric oncology programs should routinely screen for FT at EOL and ensure they have the resources to respond. (J Pediatr 2025;276:114269).

关键词： A Alabama B Black c california EOL End-of-life FMLA Family Medical Leave Act FT Financial toxicity H Hispanic W Non-Hispanic White

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Ti 3 c 2 [email protected] carbon heterostructure-based electrochemical sensor for simultaneous detection of heavy metals

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Journal of Electroanalytical chemistry 2022年 911卷

作者： Xiao Zhang Dong An Zhaoshun Bi Wei Shan Beibei Zhu Long Zhou Liangmin Yu Han Zhang Shuwei Xia Meng Qiu Key Laboratory of Marine Chemistry Theory and Technology (Ocean University of China) Ministry of Education Qingdao 266100 China Shenzhen Engineering Laboratory of Phosphorene and Optoelectronics International Collaborative Laboratory of 2D Materials for Optoelectronics Science and Technology of Ministry of Education Institute of Microscale Optoelectronics Shenzhen University Shenzhen 518060 China Forigin Research Center Fairylands Environment Sci-Tech. (Shenzhen) Co. Ltd. Shenzhen 518055 China College of Life Sciences Qingdao University No. 308 Ningxia Road Qingdao 266071 Shandong China

High-resolution electrochemical sensors with excellent sensitivity and selectivity are urgently needed for simultaneous monitoring of heavy metal ions (HMIs) in the environment. In this study, a nitrogen-doped carbon-coated Ti 3 c 2 -MXene heterostructure (Ti 3 c 2 @N-c)-based electrochemical sensor was developed for simultaneously determining (cd 2+ ) and (Pb 2+ ) in seawater and tap water via square wave anodic stripping voltammetry (SWASV). The sensor exhibits excellent performance with a low limit of detection (LOD) (cd 2+ 2.55 nM, Pb 2+ 1.10 nM), as well as excellent selectivity in the presence of interfering ions (Zn 2+ , Fe 3+ , Fe 2+ , co 2+ , Ni 2+ , Mn 2+ , cu + , cu 2+ , and K + ) and high resolution for simultaneous detection of cd 2+ and Pb 2+ . The N-c and Ti 3 c 2 -MXene heterostructure improves the conductivity of the composites by accelerating the electron transfer. The nitrogen-doping in Ti 3 c 2 @N-c provides adsorbent sites for electrons to coordinate with HMIs. Due to the heterostructure and the coordination by nitrogen, the interface charge transfer is enhanced and the number of selective adsorption sites is increased, improving the metals determination performance. This study proposes a new strategy for improving the electrochemical characteristics of Ti 3 c 2 -MXene by using heterostructure and nitrogen-doping effect, and develops a highly sensitive sensor for selective and simultaneous determination of HMIs.

关键词： Ti 3 c 2 -MXene Nitrogen-doping Heterostructure Electrochemical sensing Heavy metal ions

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[email protected] 3 c 2 MXene interfacial Schottky junction for boosting spatial charge separation in photocatalytic degradation

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Journal of Alloys and compounds 2022年 905卷

作者： Mengting Liu Jiayu Li Ruiming Bian Xinyu Wang Yinghong Ji Xiaoli Zhang Jian Tian Feng Shi Hongzhi cui School of Materials Science and Engineering Shandong University of Science and Technology Qingdao 266590 China School of Materials Science and Engineering Zhengzhou University Zhengzhou 450001 China School of Materials Science and Engineering Qilu University of Technology (Shandong Academy of Sciences) Jinan 250353 China

Herein, we report a [email protected] 3 c 2 MXene composite obtained using a simple hydrothermal method for increasing the photocatalytic degradation ability of methylene blue (MB). When the addition amount of Ti 3 c 2 MXene is 50%, the [email protected] 3 c 2 MXene composite exhibited the best photocatalytic degradation performance (94.84%), and the reaction rate constant is 0.01223 min −1 , which is 47 and 30 times of pure ZnO (5.59%, 0.026 ×10 –2 min −1 ) and pure Ti 3 c 2 MXene (7.56%, 0.04050 ×10 –2 min −1 ), respectively. Moreover, the [email protected] 3 c 2 MXene composite exhibited good stability. The photocatalytic mechanism of [email protected] 3 c 2 MXene composite is proposed. The addition of Ti 3 c 2 MXene forms a Schottky junction between ZnO and Ti 3 c 2 MXene. The Schottky junction prevents the photogenerated electrons from returning to ZnO and promotes the separation of photogenerated electrons and holes, thus effectively improving the photocatalytic performance of [email protected] 3 c 2 MXene composite.

关键词： Ti 3 c 2 MXene ZnO Schottky junction Photocatalytic degradation

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cytotoxic effects of aporphine alkaloids from the stems and leaves of Stephania dielsiana YcWu

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NATURAL PRODUcT RESEARcH 2024年第11期38卷 1864-1873页

作者： Hien, Tran Thi Thu Ba, Vinh Le Huy, Nguyen Quoc Thao, Nguyen Phuong Yang, Seo Young Van, Le Thi Kim VietNam Univ Tradit Med Hanoi Vietnam Acad Sci & Technol Inst Marine Biochem Hanoi Vietnam Sangji Univ Dept Pharmaceut Engn Wonju South Korea Natl Inst Med Mat Hanoi Vietnam

Phytochemical studies of the stems and leaves of Stephania dielsiana *** yielded two new aporphine alkaloids (1 and 5), along with six known alkaloids (2-4 and 6-8). Their structures were characterised based on analyses of spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS). The cytotoxic activities of the isolated compounds against a small panel of tumour cell lines were assessed by MTS assay. Interestingly, compound 2 exhibited particularly strong cytotoxic activities against HepG2, McF7 and OVcAR8 cancer cell lines, with Ic50 values of 3.20 & PLUSMN;0.18, 3.10 & PLUSMN;0.06 and 3.40 & PLUSMN;0.007 & mu;M, respectively. Furthermore, molecular docking simulations were carried out to explore the interactions and binding mechanisms of the most active compound (compound 2) with proteins. Our results contribute to understanding the secondary metabolites produced by S. dielsiana and provide a scientific rationale for further investigations of cytotoxicity of this valuable medicinal plant.

关键词： Stephania dielsiana Y c Wu menispermaceae stedieltines A-B cytotoxicity

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Radiocarbon dating of the natural groundwater in the Ob-Zaisan folded region (Russia)

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GROUNDWATER FOR SUSTAINABLE DEVELOPMENT 2024年 27卷

作者： Pyryaev, A. N. Novikov, D. A. Petrozhitskiy, A. V. Kuleshov, D. V. Russian Acad Sci VS Sobolev Inst Geol & Mineral Siberian Branch Novosibirsk Russia Novosibirsk State Univ Str Pirogova 1 Novosibirsk 630090 Russia Russian Acad Sci Trofimuk Inst Petr Geol & Geophys Siberian Branch Novosibirsk Russia Russian Acad Sci BINP SB RAS Budker Inst Nucl Phys Siberian Branch 11 Acad Lavrentiev Ave Novosibirsk 630090 Russia Inst Archaeol & Ethnog IAET SB RAS 17 Acad Lavrentiev Ave Novosibirsk 630090 Russia

Groundwater in the Ob-Zaisan folded region (Russia) has significant differences in the stable isotope composition of oxygen and hydrogen, which cannot be explained by the geographical and relief features of the region. A probable reason for these differences could be climatic changes in the study area over the past tens of thousands of years. The method of the radiocarbon dating can be perfectly suited in order to determine such small geological ages. The dating of waters using c-14 data gives an understanding of their residence time. It will make it possible to differentiate periods of recharge and accumulation of water in aquifers and track the changes of the water stable isotope composition over time. The estimated water age ranges from 650 to 19,000 years. The enrichment of delta D and delta O-18 values with the decreasing of the water age indicates a gradual warming of the Novosibirsk region climate. These results logically complement the meteorological observations over the last century and may be useful for paleoclimate reconstructions of the region.

关键词： Groundwater Stable isotopes H O c Radiocarbon c-14 dating Western Siberia

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