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Intrinsic mineralocorticoid agonist activity of some nonsteroidal anti-inflammatory drugs. A postulated mechanism for sodium retention.

Because some nonsteroidal anti-inflammatory drugs (NSAID) induce salt and water retention and exhibit other steroid-like actions, studies were performed to ascertain whether these drugs possess intrinsic mineralocorticoid agonist activity. In vitro competitive binding assays utilizing tissue from adrenalectomized rats demonstrated that some NSAID can displace [3H]-aldosterone from renal cytoplasmic mineralocorticoid receptors. Displacement potency for these sites was in the sequence: aldosterone greater than spironolactone greater than phenylbutazone (PBZ) greater than aspirin (ASA) greater th

Theophylline metabolism by the rat liver microsomal system.

The metabolism of 8-14C-theophylline (14C-Theo) was investigated in vivo and in vitro in the rat. In vivo, 14C-Theo at an initial blood conc … in the liver was localized in the subcellular fraction of microsomes and not in the mitochondria or cytosol. 14C-Theo metabolism by liver slices or liver microsomes was inhibited by typical liver microsomal inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525-A) and 3-methyl-4-methylaminoazobenzene. 14C-Theo metabolism in liver slices was …

Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.

Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has r…

Dietary modulation of CMA: implications for cancer prevention and therapy.

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that links nutrient availability to intracellular proteostasis through the targeted turnover of selective cytosolic proteins. Through this selective control of protein quality, CMA participates in the regulation of metabolic adaptation, cellular homeostasis, and stress responses. CMA is highly responsive to nutritional cues, including caloric restriction (CR), fasting, and changes in macronutrient composition, positioning this pathway as a key mediator of cellular adaptation to metabolic stress. In cancer, CMA disp…

ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often … protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating …

Halogenation effects on the structure, spectral properties, and cytotoxicity of BOIMPYs.

This article presents the targeted synthesis and comprehensive investigation of novel dihalogenated Cl2-BOIMPY and Br2-BOIMPY dyes. DFT/TDDF … 2), outperforming the chlorinated analogue (16%). In vitro confocal imaging demonstrates successful cytosolic internalization and robust intracellular ROS generation in HeLa cells. With a photocytotoxicity IC50 of 2.5 μM, Br2-BOIMPY shows superior PDT efficiency compared to previously reported brominated BOIMPYs. These findings expand the library of avail …

How hypoxia-induced diabetes develops and is maintained in children born preterm.

A puzzling metabolic question is the emergence of rapid-onset diabetes in the postnatal period of pre-term infants without the usual preceding prodromal characteristics. The etio-pathophysiology is unclear, but continues to be a concern, since the prevalence remains a significant health issue. We hypothesize that this new diabetes type is hypoxemia-driven from compromised ventilation via periodic breathing or apnea of infancy during the immediate postnatal period. The resulting intermittent hypoxia leads to elevated cytosolic chloride levels in pancreatic beta-cells affecting insulin secretion…

Mechanisms and balanced regulation of plant immunity.

Plants have evolved sophisticated immune systems to defend against a wide array of pathogens. These defence mechanisms are primarily mediated by cell surface pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat receptors (NLRs). Recent studies indicate that immune signalling involving PRRs and NLRs converges on cytosolic calcium (Ca2+) and other signals, which act synergistically to mount robust plant defences. However, uncontrolled activation of these defence mechanisms often negatively affects plant growth. In this Review, we discuss recent findings o…

Supplementation with bovine thymus extract improves survival, motility and stress resistance in C. elegans.

Nutritional support for healthy aging is an active field of research. Bovine organ extracts, and glandular therapy in general, became popular in the 1900s, but their effect on healthy aging is unexplored, and their mechanisms of action are unclear. Here, we evaluated three bovine thymus materials with regards to their effect on healthy aging in C. elegans: two thymus extracts, a nuclear fraction (TNF) and a cytosolic fraction, and desiccated bovine thymus. All three materials extended C. elegans mid-life survival and improved mid-life motility. RNA sequencing revealed that TNF treatment elicit…

Host prenylation promotes membrane association of the Salmonella effector GtgE during infection.

The Rab32 antimicrobial pathway restricts Salmonella Typhi replication in murine macrophages. The broad-host pathogen Salmonella Typhimurium has evolved a solution to disrupt this pathway via effector proteins, including GtgE. The presence of a C-terminal CaaX motif in GtgE prompted the hypothesis that the effector was prenylated by the host. Here, we show that the CaaX motif enhances GtgE membrane association and intracellular targeting. Substitution of the C-terminal cysteine (C225S) caused diffused cytosolic distribution and loss of membrane enrichment. Inhibition of host isoprenoid biosynt…

DHX34 deficiency triggers tumor-intrinsic immunity via a dsRNA-mediated type I interferon pathway activation in HCC.

Tumors often evade immune surveillance by crippling their immunogenicity in the microenvironment. DHX34, an RNA helicase involved in nonsens … survival in mice. Mechanistically, DHX34 depletion triggered dsRNA accumulation which may activate cytosolic RNA-sensing pathway effectors such as MAVS, p-IKK, p-IRF3, and the subsequent type-I interferon response, evoking tumor-intrinsic immunity and leading to CD8 T activation. Collectively, DHX34 is implicated as a regulator that orchestrates a barrie …

Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in … rate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance i …

Functional inactivation of oligosaccharyltransferase a isoform suppresses tumor metastasis.

Oligosaccharyltransferase (OST), which is a multi-membrane protein complex that catalyzes asparagine-linked glycosylation (N-glycosylation) … r co-expression was required for efficient experimental lung metastasis. We further showed that the cytosolic N-terminal region of Stt3a, which is the catalytic subunit of OST-A, was critical for the N-glycosylation reaction and lung metastasis. This study opens a novel avenue for selective manipulation of OST-A activity, which might offer potential thera …

Unraveling the Potential of Amino‑, Acylamino‑, and Ureido-Substituted 3H‑1,2-Benzoxaphosphepine 2‑Oxides toward Nanomolar Inhibitors of Tumor-Associated Carbonic Anhydrases IX and XII.

3H-1,2-Benzoxaphosphepine 2-oxides were recently identified as a novel class of carbonic anhydrase (CA) inhibitors. In this study, which aims to broaden the chemical space around this scaffold and improve inhibition potency against cancer-related isoforms (CA IX and CA XII), we report the synthesis and biochemical evaluation of amino-, acylamino-, and ureido-substituted benzoxaphosphepine oxides 2-4. All members of these series showed no off-target inhibition of cytosolic CA I and CA II activity, while the inhibition of the target isoforms was strongly dependent on the substitution pattern. To…

Atg23 Interacts With Both the N- and C-termini of Atg9 Via a Hydrophobic Binding Pocket.

Macroautophagy is a cellular process where cytosolic material is captured in double membrane vesicles, termed autophagosomes, which fuse with the vacuole or lysosomes leading to the degradation of the captured contents. In yeast, the biogenesis of autophagosomes is initiated by the fusion of a few small vesicles which contain the integral membrane protein Atg9. Atg9 vesicle trafficking is in part regulated by the peripheral membrane protein Atg23. However, the structure of Atg23 and the mechanism by which Atg23 interacts with Atg9 are currently unknown. Therefore, we determined the crystal str…

Comment on "Organelles Ca²⁺ redistribution contributes to cadmium-induced EMT of renal cancer cells through p-cPLA2-mediated arachidonic acid release".

This commentary proposes enhancements to improve a study on cadmium-induced EMT in renal cancer cells. Key recommendations encompass the fol … /AM fluorescent probes; Experimental verification of PMCA inhibition synergism with cadmium-induced cytosolic Ca²⁺ overload. These recommendations would enhance the robustness of the original study's conclusions.

In Vitro Cleavage Assay to Characterize DENV NS2B3 Antagonism of cGAS.

cGAS is a key cytosolic dsDNA receptor that senses viral infection and elicits interferon production through the cGAS-cGAMP-STING axis. cGAS is activated by dsDNA from viral and bacterial origins as well as dsDNA leaked from damaged mitochondria and nucleus. Eventually, cGAS activation launches the cell into an antiviral state to restrict the replication of both DNA and RNA viruses. Throughout the long co-evolution, viruses devise many strategies to evade cGAS detection or suppress cGAS activation. We recently reported that the Dengue virus protease NS2B3 proteolytically cleaves human cGAS in …

Недостаток сигнала приводит к обезвоживанию и проникновению иммунной информации в координационные лизы EAE.

Стимулирование интерфероновых генов (STING) — цитосолический сенсор ДНК, который активирует интерферон типа I (IFN) сигнализацию, играющую ключевую роль в нейроинфламмации. Хотя роль СТИНГ в экспериментальном аутоиммунном энцефаломиелите (EAE), являющемся моделью множественного склероза (MS), по-прежнему обсуждается, еще предстоит изучить вопрос о его участии в развитии ОВЧ-повреждений, особенно в рамках локальной патологии, моделируемой здесь на основе целлюлозы корпуса. Используя фокусную модель EAE, мы сравнили инъекцию повреждений в мышах диких типов и мышах, страдающих дефицитом зрения (S

Совпадение в аннотации оригинала
Stimulator of interferon genes (STING) is a cytosolic DNA sensor that activates type I interferon (IFN) signaling, which plays a key role in neuroinflammation. Although the role of STING in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), remains debated, its involvement in the development of CNS lesions, particularly with…

Therapeutic Targets in Innate Immunity to Tackle Alzheimer's Disease.

There is an urgent need for effective disease-modifying therapeutic interventions for Alzheimer's disease (AD)-the most prevalent cause of d … D and discuss potential targets such as microglia, TREM2, the complement system, inflammasomes, and cytosolic DNA sensors. We also present an overview of ongoing studies targeting specific innate immune system components, highlighting the progress in this field of drug research while bringing attention to the delicate nature of innate immune modulations i …

Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide-hydantoin hybrids.

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO2 hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with KIs values in…