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Environmental Science & Technology May 2022The bioaccumulation of the neurotoxin methylmercury (MeHg) in rice is a significant concern due to its potential risk to humans. Thiols have been known to affect MeHg...
The bioaccumulation of the neurotoxin methylmercury (MeHg) in rice is a significant concern due to its potential risk to humans. Thiols have been known to affect MeHg bioavailability in microorganisms, but how thiols influence MeHg accumulation in rice plants remains unknown. Here, we investigated effects of common low-molecular-weight thiols, including cysteine (Cys), glutathione (GSH), and penicillamine (PEN), on MeHg uptake and translocation by rice plants. Results show that rice roots can rapidly take up MeHg, and this process is influenced by the types and concentrations of thiols in the system. The presence of Cys facilitated MeHg uptake by roots and translocation to shoots, while GSH could only promote MeHg uptake, but not translocation, by roots. Conversely, PEN significantly inhibited MeHg uptake and translocation to shoots. Using labeled Cys assays, we also found that MeHg uptake was coupled with Cys accumulation in rice roots. Moreover, analyses of comparative transcriptomics revealed that key genes associated with metallothionein and SULTR transporter families may be involved in MeHg uptake. These findings provide new insights into the uptake and translocation of MeHg in rice plants and suggest potential roles of thiol attributes in affecting MeHg bioavailability and bioaccumulation in rice.
Topics: Cysteine; Humans; Mercury; Methylmercury Compounds; Oryza; Soil; Soil Pollutants; Sulfhydryl Compounds
PubMed: 35483101
DOI: 10.1021/acs.est.2c00169 -
Angewandte Chemie (International Ed. in... Jul 2023Chiral inorganic superstructures have received considerable interest due to the chiral communication between inorganic compounds and chiral organic additives. However,...
Chiral inorganic superstructures have received considerable interest due to the chiral communication between inorganic compounds and chiral organic additives. However, the demanding fabrication and complex multilevel structure seriously hinder the understanding of chiral transfer and self-assembly mechanisms. Herein, we use chiral CuO superstructures as a model system to study the formation process of hierarchical chiral structures. Based on a simple and mild synthesis route, the time-resolved morphology and the in situ chirality evolution could be easily followed. The morphology evolution of the chiral superstructure involves hierarchical assembly, including primary nanoparticles, intermediate bundles, and superstructure at different growth stages. Successive redshifts and enhancements of the CD signal support chiral transfer from the surface penicillamine to the inorganic superstructure. Full-field electro-dynamical simulations reproduced the structural chirality and allowed us to predict its modulation. This work opens the door to a large family of chiral inorganic materials where chiral molecule-guided self-assembly can be specifically designed to follow a bottom-up chiral transfer pathway.
PubMed: 37186081
DOI: 10.1002/anie.202305353 -
Veterinary Research Communications Sep 2023In vitro capacitation is essential in assisted reproductive technologies (ART) for embryo production. Recently, arginine has been proven to enhance capacitation in...
INTRODUCTION
In vitro capacitation is essential in assisted reproductive technologies (ART) for embryo production. Recently, arginine has been proven to enhance capacitation in mammalian spermatozoa. However, the detailed mechanism of action of arginine remains elusive.
AIM
This study investigated the effect of arginine-induced capacitation and motility enhancement on the spermatozoal RNA (spRNA) population in goats.
MATERIAL AND METHODS
Goat spermatozoa were treated with arginine for up to six hours and compared with non-treated or PHE (penicillamine, hypotaurine, and epinephrine)-treated spermatozoa at different intervals (0, 1, 2, 4, and 6 hours). Sperm parameters, including viability, individual motility, capacitation, acrosome reaction, and ROS production, were evaluated. The spRNA population was analyzed by short-read RNA sequencing (RNA-seq).
RESULTS
The percentage of capacitated (73.21 ± 4.22%) and acrosome reacted (18.35 ± 0.56%) spermatozoa was highest in arginine treatment, while PHE treatment showed the highest percentage (79.82 ± 4.31%) of motile spermatozoa from 0 to 4 hours of incubation. RNA-seq analysis identified 1,321 differentially expressed genes (DEGs) in arginine-treated spermatozoa compared to the control. The PGK2, RNASE10, ODF1, and ROPN1L genes involved in sperm motility and ACR, DKKL1, KCNJ11, and PRND genes involved in the capacitation process were upregulated in arginine-treated spermatozoa. The DEGs regulate sperm capacitation-related cAMP-PKA, PI3-Akt, calcium, and MAPK signaling pathways.
CONCLUSION
The arginine-induced capacitation and enhanced sperm motility were associated with the upregulation of several genes involved in sperm motility and capacitation pathways. The comparative study also suggests that arginine may be used in lieu of PHE for motility enhancement and in vitro capacitation of goat spermatozoa.
Topics: Male; Animals; Arginine; RNA; Goats; Sperm Motility; Semen; Spermatozoa; Sperm Capacitation
PubMed: 37162640
DOI: 10.1007/s11259-023-10092-3 -
Archives of Biochemistry and Biophysics Jul 2020Hydropersulfides are reported to be good biological reductants, superior to thiols and akin to selenols. As such, they have been previously shown to reduce...
Hydropersulfides are reported to be good biological reductants, superior to thiols and akin to selenols. As such, they have been previously shown to reduce metalloproteins such as ferric myoglobin and ferric cytochrome c to their ferrous forms under conditions where little or no reduction from corresponding thiols is observed. Not surprisingly, the reduction of ferric myoglobin to ferrous myoglobin under aerobic conditions results in the generation of oxymyoglobin (dioxygen bound ferrous myoglobin). Previous studies have demonstrated that oxymyoglobin can also act as an oxidant with highly reducing species such as hydroxylamine and ascorbate. Considering the reducing properties of hydropersulfides, it is possible that they can also react with oxymyoglobin similarly to hydroxylamine or ascorbate. Herein, this reaction is examined and indeed hydropersulfides are found to react with oxymyoglobin similarly to other reducing species leading to a fleeting ferric myoglobin which is rapidly reduced to the ferrous form also by hydropersulfide.
Topics: Animals; Ascorbic Acid; Cattle; Horses; Hydroxylamine; Models, Chemical; Myoglobin; Oxidation-Reduction; Oxygen; Penicillamine; Sulfides
PubMed: 32360749
DOI: 10.1016/j.abb.2020.108391 -
Antioxidant effects of penicillamine against in vitro-induced oxidative stress in human spermatozoa.Andrologia Jun 2020Oxidative stress contributes importantly to the aetiology of male infertility, impairing sperm function. The protective effect of antioxidants on seminal parameters has...
Oxidative stress contributes importantly to the aetiology of male infertility, impairing sperm function. The protective effect of antioxidants on seminal parameters has been established, and the antioxidant penicillamine has shown beneficial effects; however, its protective effect on human spermatozoa exposed to oxidative stress has not been reported. The objective of this work was to evaluate the effect of penicillamine on human spermatozoa exposed in vitro to oxidative stress. First, the effect of penicillamine on spermatozoa from normozoospermic donors was evaluated. Then, the effect of penicillamine on spermatozoa exposed to oxidative stress induced separately by ionomycin and hydrogen peroxide (H O ) was analysed. An untreated control and a control treated only with the oxidative stress inducer were included. Reactive oxygen species (ROS) levels, viability, mitochondrial membrane potential (MMP) and motility were analysed. The results showed that penicillamine, added to the incubation medium, decreased the ROS levels induced by ionomycin and H O , and this effect was associated with better preservation of MMP, motility, and ATP levels. These results highlight the potential advantages of penicillamine supplementation of sperm culture medium, especially for semen samples with high ROS levels and also in circumstances where laboratory handling can cause an increase in ROS production.
Topics: Antioxidants; Culture Media; Humans; Hydrogen Peroxide; Infertility, Male; Ionomycin; Male; Membrane Potential, Mitochondrial; Oxidative Stress; Penicillamine; Reactive Oxygen Species; Reproductive Techniques, Assisted; Semen Preservation; Sperm Motility; Spermatozoa
PubMed: 32196709
DOI: 10.1111/and.13553 -
Clinical Drug Investigation Feb 2022BACKGROUND AND OBJECTIVE: There are limited data on the adverse events of D-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment...
UNLABELLED
BACKGROUND AND OBJECTIVE: There are limited data on the adverse events of D-penicillamine in Wilson's disease (WD) that can result in dose modification or treatment discontinuation. The objective of this study was to observe the adverse events related to D-penicillamine in patients with hepatic WD.
METHODS
A retrospective audit of prospectively registered hepatic WD patients at a tertiary care center between December 2006 and January 2020 was carried out. Demographic variables, laboratory parameters, and details of treatment were noted. Adverse events (AEs) related to D-penicillamine treatment, the timing and management of these AEs were analysed.
RESULTS
The study included 112 patients with hepatic WD on D-penicillamine. D-penicillamine intolerance was seen in 28/112 (25%) over 179 person-years. Of the 28 AEs, severe AEs leading to permanent D-penicillamine discontinuation occurred in 16 (57%) [never reintroduced 12 (43%), discontinued after intolerant to rechallenge, 4 (14%)], temporary cessation followed by reintroduction to initial dose 13 (46%) and continuation with reduced dose in 3 (11%) patients. Overall, most common AEs were hematological [16, 57% (pancytopenia n = 8, bicytopenia n = 5 and hemolytic anemia n = 3)] while renal adverse events (n = 7, 25%) constituted the most common indication for permanent discontinuation. Cytopenias developed beyond 12 months of D-penicillamine initiation whereas hemolytic anemia developed within first 3 months. Following D-penicillamine discontinuation in 25 patients, it was reintroduced to initial dose in 13/25 (52%), switched to trientine due to neurological worsening in 2/25 (8%) and switched to zinc in 10/25 (40%). In patients with reintroduction, gradual dose escalation was tolerated in 9/13 (69%) with a recurrence of AEs leading to permanent discontinuation in 4/13 (31%).
CONCLUSION
D-penicillamine treatment is associated with significant AEs mainly related to blood, kidney, and skin. Temporary cessation of drug with reintroduction at a lower dose is an effective and safe option.
Topics: Chelating Agents; Hepatolenticular Degeneration; Humans; Penicillamine; Retrospective Studies; Trientine; Zinc
PubMed: 35102516
DOI: 10.1007/s40261-022-01117-x -
Biomedicines Dec 2021Bis-choline-tetrathiomolybdate, introduced as WTX101 (now known as ALXN1840), is a first-in-class copper-protein-binding agent for oral therapy of Wilson's disease. In...
Bis-choline-tetrathiomolybdate, introduced as WTX101 (now known as ALXN1840), is a first-in-class copper-protein-binding agent for oral therapy of Wilson's disease. In contrast to other decoppering agents such as trientine or D-penicillamine it acts by forming a tripartite complex with copper and albumin, thereby detoxifying excess liver and blood copper through biliary excretion. Preclinical animal experimentation with this drug was typically done with the alternative ammonium salt of tetrathiomolybdate, which is expected to have identical properties in terms of copper binding. Here, we comparatively analyzed the therapeutic efficacy of ALXN1840, D-penicillamine and trientine in lowering hepatic copper content in mouse. Liver specimens were subjected to laser ablation inductively conductively plasma mass spectrometry and electron microscopic analysis. We found that ALXN1840 caused a massive increase of hepatic copper and molybdenum during early stages of therapy. Prolonged treatment with ALXN1840 reduced hepatic copper to an extent that was similar to that observed after administration of D-penicillamine and trientine. Electron microscopic analysis showed a significant increase of lysosomal electron-dense particles in the liver confirming the proposed excretory pathway of ALXN1840. Ultrastructural analysis of mice treated with dosages comparable to the bis-choline-tetrathiomolybdate dosage used in an ongoing phase III trial in Wilson's disease patients, as well as D-penicillamine and trientine, did not show relevant mitochondrial damage. In contrast, a high dose of ALXN1840 applied for four weeks triggered dramatic structural changes in mitochondria, which were notably characterized by the formation of holes with variable sizes. Although these experimental results may not be applicable to patients with Wilson's disease, the data suggests that ALXN1840 should be administered at low concentrations to prevent mitochondrial dysfunction and overload of hepatic excretory pathways.
PubMed: 34944677
DOI: 10.3390/biomedicines9121861 -
Molecules (Basel, Switzerland) Dec 2022Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial-mesenchymal transition...
Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial-mesenchymal transition (EMT), which is a crucial biological process in embryonic development and cell metastasis, and are highly invasive. Copper reportedly plays a critical role in the progression of a variety of cancers, including brain, breast, and lung cancers. However, excessive copper is toxic to cells. D-penicillamine (DPA) and triethylenetetramine (TETA) are well-known copper chelators and are the mainstay of treatment for copper-associated diseases. Following treatment with copper sulfate and DPA, GBM cells showed inhibition of proliferation and suppression of EMT properties, including reduced expression levels of N-cadherin, E-cadherin, and Zeb, which are cell markers associated with EMT. In contrast, treatment with copper sulfate and TETA yielded the opposite effects in GBM. Genes, including , are associated with an increase in copper levels, implying their role in EMT. To analyze the invasion and spread of GBM, we used zebrafish embryos xenografted with the GBM cell line U87. The invasion of GBM cells into zebrafish embryos was markedly inhibited by copper treatment with DPA. Our findings suggest that treatment with copper and DPA inhibits proliferation and EMT through a mechanism involving TGF-β/Smad signaling in GBM. Therefore, DPA, but not TETA, could be used as adjuvant therapy for GBM with high copper concentrations.
Topics: Animals; Glioblastoma; Copper; Zebrafish; Cell Line, Tumor; Copper Sulfate; Brain Neoplasms; Signal Transduction; Transforming Growth Factor beta; Chelating Agents; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 36557987
DOI: 10.3390/molecules27248851 -
International Journal of Molecular... Aug 2022The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the...
The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC’s differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone.
Topics: Animals; Brain; Cell Movement; Cell Proliferation; Copper; Lateral Ventricles; Mice; Neurogenesis; Olfactory Bulb
PubMed: 36077284
DOI: 10.3390/ijms23179888 -
Bioscience Reports Jan 2021Wilson's disease (WD) is an autosomal recessive disease caused by mutation of the ATPase copper transporting β (ATP7B) gene, resulting in abnormal copper metabolism. We...
Wilson's disease (WD) is an autosomal recessive disease caused by mutation of the ATPase copper transporting β (ATP7B) gene, resulting in abnormal copper metabolism. We aimed to investigate the protective effect of GanDouLing (GDL) on neural stem cell (NSC) function in a mouse model of WD. NSCs were treated with different concentrations of GDL alone or in combination with penicillamine, following which we evaluated cellular growth, apoptosis, and differentiation. Nuclear factor E2-related factor 2 (Nrf2) pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation were analyzed via Western blotting. Treatment with GDL alone or in combination with penicillamine significantly increased proliferation and inhibited apoptosis of NSCs in a dose-dependent manner. In addition, GDL treatment remarkably promoted differentiation of NSCs. Consistently, levels of class III β-tubulin (Tuj1) and microtubule-associated protein 2 (MAP2) were significantly elevated, whereas glial fibrillary acidic protein (GFAP) levels were obviously suppressed in the presence of GDL or penicillamine. In vivo assays confirmed that GDL increased the ratio of Ki67+, Tuj1+, and MAP2+ cells and suppressed apoptosis in the hippocampal region in WD mice. Behavioral assays revealed that both GDL and penicillamine improved memory ability in WD models. Mechanistically, GDL treatment led to activation of Nrf2 signaling and suppression of the NLRP3 inflammasome in WD mice. Notably, inhibition of Nrf2 signaling reversed the protective effects of GDL on hippocampal NSCs. Collectively, these findings demonstrate that GDL exerts a protective effect on NSCs and promotes neurogenesis by targeting Nrf2 signaling and the NLRP3 inflammasome in WD.
Topics: Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Female; Hepatolenticular Degeneration; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neural Stem Cells; Neuroprotective Agents
PubMed: 33300046
DOI: 10.1042/BSR20202717