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Clinical and biochemical findings in Leber's hereditary optic atrophy.

Clinical findings in Leber's hereditary optic atrophy (LHOA) are reviewed and the results given of treatment with a regimen based on the hypothesis that the disease is a manifestation of cyanide toxicity. Recent biochemical investigations confirm disturbed cyanide metabolism and suggest that zinc deficiency may be implicated.

Potassium citrate for stone prevention - Quantifying benefit through the number needed to treat: A narrative review.

To define how reliable the benefits of potassium citrate (KCit) for stone prevention are framing this in terms of the number needed to treat … um oxalate disease; data for calcium phosphate and brushite stones remain limited. In uric acid and cystine stones, alkalinization is first-line therapy, although precise NNT estimates are unavailable. KCit is one of the most effective preventive pharmacotherapies in nephrolithiasis. In recurrent calcium stone formers, treating two to three patients for a …

Selenium-Thioredoxin Axis Contributes to Ferroptosis Resistance in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) shows substantial heterogeneity in cysteine dependence and ferroptosis sensitivity. We identify two PDAC subtypes distinguished by EMT status: mesenchymal-like cells are highly cysteine-dependent and rapidly undergo ferroptosis upon cystine deprivation or system xc- inhibition, whereas epithelial-type cells are ferroptosis-resistant. Selenium supplementation protects cells from erastin-induced ferroptosis, and this protection persists even when intracellular glutathione (GSH) is depleted, supporting an additional GPX4-independent protective mechanism. Se…

Reactive oxygen species-responsive Pluronic F127 hyaluronic hydrogel for targeted doxorubicin delivery in glioblastoma and enhanced survival with radiotherapy.

Hydrogel systems have been developed for the localized delivery of drugs targeting tumors; however, they undergo rapid degradation and lack precise manipulation of drug release, limiting their effectiveness. Therefore, we designed a material capable of localized drug delivery to the tumor microenvironment (TME). We synthesized a novel thermosensitive hydrogel (CF127) by modifying Pluronic F127 with l-cystine to promote disulfide bond formation, enabling a reactive oxygen species (ROS)-sensitive drug release mechanism triggered by the internal TME and external radiation. Incorporating hyaluroni…

Resolving conformational polymorphism in disulfide-rich peptide drugs.

Disulfide-rich peptide therapeutics often exhibit compact cystine knot-like architectures that endow them with high conformational rigidity, proteolytic stability, and target specificity. Yet their intrinsic polymorphism and structural heterogeneity are difficult to resolve with conventional analytical methods, which lack sufficient power to distinguish subtle structural variants within highly constrained peptide frameworks. Here, cyclic ion mobility-mass spectrometry (cIM-MS), combined with accelerated thermal stress testing, was applied to a manufacturing batch of ziconotide and linaclotide …

The alterations of blood immune subpopulations, cytokines, and metabolites in anti-acetylcholine receptor antibody-positive myasthenia gravis: a real-world, observational, high-throughput study.

Comprehensive profiling of peripheral blood may reveal candidate markers and therapeutic targets for anti-AChR antibody positive myasthenia … RANTES (CCL5), and cystatin-A. Metabolomics indicated lower dehydroepiandrosterone sulfate (DHEAS), cystine, and arginine, with higher lactate, sarcosine, and ornithine. Notably, glucocorticoid pretreatment reduced myeloid dendritic cells, Th2-like cells, dendritic cells, classical monocytes, and total monocytes. Integrated multi-omics analysis identified …

Advances in ferroptosis mechanisms and therapeutic potential in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a biologically aggressive malignancy characterized by late diagnosis, frequent recurrence, … Recent studies elucidate multiple ferroptosis-related pathways in HNSCC, including SLC7A11-mediated cystine/glutamate transport, GPX4 and glutathione metabolism, Nrf2-ARE antioxidant signaling, iron and sulfur metabolism, HDAC and EMT modulation, and TP53 mutations. Pharmacologic inducers such as erastin, RSL3, sulfasalazine, dihydroartemisinin, and HDAC …

Ferroptosis in AML: nanoparticles, biomarkers, and immune rewiring for therapeutic breakthroughs.

Acute myeloid leukemia (AML) remains a formidable clinical challenge due to high relapse rates and therapeutic resistance. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, glutathione depletion, and Glutathione peroxidase 4 (GPX4) inactivation, has emerged as a promising strategy to overcome apoptosis evasion in AML. This review synthesizes recent advances in ferroptosis biology within AML, highlighting the unique metabolic vulnerabilities of leukemic cells, including dysregulated iron homeostasis, elevated reactive oxygen species (ROS), and cystine/glu…

OTUB1-SLC7A11 Axis Mediates 4-Octyl Itaconate Protection Against Acetaminophen-Induced Ferroptotic Liver Injury.

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, plays a crucial role in acetaminophen (APAP)-induced hepatotoxicity. While 4-octyl itaconate (4-OI) demonstrates protective effects against APAP toxicity, its molecular mechanisms remain to be fully elucidated. Through an innovative integration of untargeted metabolomics and pathway analysis, we unveil a novel dual mechanism by which 4-OI prevents APAP-induced ferroptosis. We discovered that 4-OI stabilizes SLC7A11 through OTUB1-mediated deubiquitination, thereby restoring cystine import and glutat…

Self-Accelerated Nanoregulators for Positive Feedback Ferroptosis-Immunotherapy.

Activating specific immunity through intelligent delivery of chemotherapeutic drugs shows great potential for effective tumor therapy. Howev … rsion. Meanwhile, it also enhances ferroptosis by inhibiting reactive oxygen species scavenging and cystine/glutamate antiporter expression, achieving the positive feedback ferroptosis-immunotherapy. This work provides a self-accelerated drug delivery strategy and a potential cooperation mode for tumor synergistic immunotherapy based on ferroptosis-apopto …

MicroRNA-142-3p Затворка в внеклеточной везиклой обозначает регуляционную дисфункцию клеток Т при множественном склерозе.

CD4+CD25hiFoxP3+ Регулирующие T клетки (Treg celects) являются ключевыми регуляторами иммунной самодостаточности, и их подавляющая функция нарушается у людей с повторно излучающимся множественным склерозом (pwRR-MS). Поскольку механизмы, лежащие в основе этого состояния, до сих пор не определены, мы изучили роль внеклеточных везиклов (Treg-EVs) в дисфункции клеток Трега, наблюдаемой в pwRR-MS. Мы обнаружили, что Treg-EV от здоровых людей ингибируют CD4+ обычные T (Tvd) клетки, закрывая miR-142-3p из клетки Treg в камеру Tvv. Там MiR-142-3p, регулируемые понижающими значениями mRNA, необходимые

Совпадение в аннотации оригинала
CD4+CD25hiFoxP3+ regulatory T cells (Treg cells) are key controllers of immune self-tolerance, and their suppressive function is impaired in … egulated mRNAs necessary for Tconv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11. However, Treg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, Treg-EV miR-142-3p inversely correlated with the disability score and gadolinium-enhanc …

mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis.

Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that Xc- cystine/glutamate antiporter (xCT) was elevated in Tsc2-/- or Pten-/- cells, Tsc1 knockout mouse tissues and TSC2-deficient human kidney tumor. xCT was transcriptionally boosted by mTOR-mediated Oct1 signaling cascade. Augmented xCT led to reduction of eumelanin and elevation of pheomelanin in Tsc…

Cystinosis distal myopathy, novel clinical, pathological and genetic features.

Nephropathic cystinosis is an autosomal recessive lysosomal disease in which cystine cannot exit the lysosome to complete its degradation in the cytoplasm, thus accumulating in tissues. Some patients develop a distal myopathy involving mainly hand muscles. Myopathology descriptions from only 5 patients are available in the literature. We present a comprehensive clinical, pathological and genetic description of 3 patients from 2 families with nephropathic cystinosis. Intrafamiliar variability was detected in one family in which one sibling developed a severe distal myopathy while the other sibl…

Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation.

Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pr … ant thioredoxin showed an almost 10-fold higher reactivity towards cysteine persulfide than towards cystine and readily cleaved protein persulfides as well. This reaction resulted in H2S release suggesting that thioredoxin could be an important regulator of H2S levels from persulfide pools. Inhibition of the thioredoxin system caused an increase in intrac …

Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor.

Huwentoxin-IV (HWTX-IV, also named Mu-theraphotoxin-Hh2a) is a typical inhibitor cystine knot peptide isolated from the venom of Chinese tarantula Ornithoctonus huwena and is found to inhibit tetrodotoxin-sensitive (TTX-S) sodium channels from mammalian sensory neurons. This peptide binds to neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II in neuronal sodium channels. However, the molecular surface of HWTX-IV interaction with sodium channels remains unknown. In this study, we synthesized HWTX-IV and three mutants (T28D, R29A and Q34D) and characterized their fu…

In vitro proteoglycan sulfation derived from sulfhydryl compounds in sulfate transporter chondrodysplasias.

Mutations in a sulfate-chloride antiporter gene, the diastrophic dysplasia sulfate transporter (DTDST), have been associated with a family o … ysplasia patients. Incubation of ACG1B fibroblasts in medium containing different concentrations of cystine indicated partial recovery of PG sulfation as measured by HPLC disaccharide analysis of chondroitin sulfate PGs; similar results were observed after incubation with N-acetylcysteine. When both compounds were tested in primary chondrocytes from a DTD …

Oxidative stress-inducible proteins in macrophages.

Macrophages produce reactive oxygen species such as O2-, H2O2 and *OH that contribute to the pathogenesis of diseases such as inflammation a … iquitin- and PKC xi-binding protein. In addition to these two proteins, heme oxygenase-1 (HO-1) and cystine transport activity are also induced in the cells under oxidative stress conditions. Using nrf2-deficient macrophages, we found that transcription factor Nrf2, which is known to interact with antioxidant responsive elements (AREs) in the regulatory s …

Proton nuclear magnetic resonance studies on huwentoxin-I from the venom of the spider Selenocosmia huwena: 2. Three-dimensional structure in solution.

The three-dimensional structure in aqueous solution of native huwentoxin-I, a neurotoxin from the venom of the spider Selenocosmia huwena, h … e. The three disulfide bridges are buried within the molecule. The structure contains an "inhibitor cystine knot motif" which is adopted by several other small proteins, such as omega-conotoxin, agatoxin IVA, and gurmarin.

Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis.

Primary hypothyroidism is a known complication of nephropathic cystinosis, a lysosomal storage disorder characterized by renal failure as well as deterioration of other organs. The drug cysteamine depletes lysosomes of cystine and helps preserve renal function and enhance growth in cystinosis patients. To determine whether cysteamine also prevents hypothyroidism, we retrospectively divided 101 patients into group A (n = 28; well treated), group B (n = 26; partially treated), and group C (n = 47; poorly treated). Lifetable analysis indicated a significantly higher probability of remaining free …

Extracellular: intracellular and subcellular concentration gradients of thiols.

Chinese hamster V79 cells in Eagle's minimum essential medium in vitro at room temperature were incubated with the aminothiol, WR-1065, or g … cellular cysteine was elevated 10-fold. These results are ascribed to thiol/disulfide exchange with cystine in the medium. WR-1065 slowly concentrated intracellularly to approximately 160% of the extracellular concentration. Chemical conjugation of GSH in cells decreased the reducing environment near DNA, but BSO treatment altered the uptake of AO. The el …