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Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
Medicina 2024Mushrooms containing amatoxins generate the highest number of fatal mycete poisonings on the planet. These toxins are produced not only by Amanita species, such as the...
Mushrooms containing amatoxins generate the highest number of fatal mycete poisonings on the planet. These toxins are produced not only by Amanita species, such as the well-known Amanita phalloides, but also by other genera, including Lepiota. In this work we report the treatment of a 51-year-old male patient weighing 79 kg who was referred to the hospital after 36 h of ingesting mushrooms. The mushrooms were identified as Lepiota brunneoincarnata, found for the first time in Argentina. The patient presented general malaise, nausea and repeated vomiting, abdominal pain, and diarrhea. Thanks to a quick anamnesis and early and accurate identification of the fungus, he was administered a nasogastric tube and serial activated charcoal. Additionally, N-acetylcysteine, phytomenadione and penicillin G EV were administered. The patient was discharged 11 days after admission. This case highlights the importance of obtaining a correct and sufficient anamnesis on fungi, enabling rapid analysis of them, and initiation of timely treatment for intoxication. Once again, the importance of having Toxicological Information and Advice Centers (CIAT) with experience and knowledge of micetisms is demonstrated.
Topics: Male; Middle Aged; Humans; Mushroom Poisoning; Argentina; Treatment Outcome
PubMed: 38907978
DOI: No ID Found -
Stem Cell Research & Therapy Jun 2024Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by...
BACKGROUND
Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length.
METHODS
In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed.
RESULTS
We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation.
CONCLUSIONS
Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.
Topics: Humans; Human Embryonic Stem Cells; Autophagy-Related Proteins; Mitochondria; Proteostasis; Telomere; Telomere Homeostasis; Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Oxidative Stress; DNA Damage
PubMed: 38902824
DOI: 10.1186/s13287-024-03789-y -
Cureus May 2024With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been...
With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.
PubMed: 38899269
DOI: 10.7759/cureus.60649 -
Nutrients May 2024Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate....
-Acetylcysteine Alleviates Impaired Muscular Function Resulting from Sphingosine Phosphate Lyase Functional Deficiency-Induced Sphingoid Base and Ceramide Accumulation in .
Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate. Depletion of SPL precipitates compromised muscle morphology and function; nevertheless, the precise mechanistic underpinnings remain elusive. Here, we elucidate a model of SPL functional deficiency in using RNA interference. Within these SPL-deficient nematodes, we observed diminished motility and perturbed muscle fiber organization, correlated with the accumulation of sphingoid bases, their phosphorylated forms, and ceramides (collectively referred to as the "sphingolipid rheostat"). The disturbance in mitochondrial morphology was also notable, as SPL functional loss resulted in heightened levels of reactive oxygen species. Remarkably, the administration of the antioxidant -acetylcysteine (NAC) ameliorates locomotor impairment and rectifies muscle fiber disarray, underscoring its therapeutic promise for ceramide-accumulation-related muscle disorders. Our findings emphasize the pivotal role of SPL in preserving muscle integrity and advocate for exploring antioxidant interventions, such as NAC supplementation, as prospective therapeutic strategies for addressing muscle function decline associated with sphingolipid/ceramide metabolism disruption.
Topics: Animals; Caenorhabditis elegans; Acetylcysteine; Ceramides; Aldehyde-Lyases; Sphingolipids; Reactive Oxygen Species; Antioxidants; Muscles; RNA Interference; Sphingosine
PubMed: 38892556
DOI: 10.3390/nu16111623 -
International Journal of Molecular... Jun 2024Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the...
Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP 5 mg/kg or NAC 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca, and Mg ATPase using validated methods. TBARS, HO, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.
Topics: Animals; Cisplatin; Acetylcysteine; Rats; Rats, Wistar; Lung; Lipid Peroxidation; Oxidative Stress; Male; Cerebrum; Glutathione; Neuroprotective Agents; Antineoplastic Agents
PubMed: 38892427
DOI: 10.3390/ijms25116239 -
International Journal of Molecular... May 2024N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important... (Review)
Review
N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models ( = 18), animal models ( = 7), and mixed models ( = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.
Topics: Humans; Acetylcysteine; Respiratory Syncytial Virus Infections; Animals; Air Pollution; ErbB Receptors
PubMed: 38892239
DOI: 10.3390/ijms25116051 -
Polymers May 2024We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and -acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide...
We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and -acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide (HO)-treated dentin, and their effects on the characteristics of dentin in comparison to ascorbic acid (AA) and sodium thiosulfate (STS). HO-treated dentin was conditioned with 5% AA, GSH, NAC, or STS applied for 1 or 5 min. The positive control group received HO without antioxidant application, and the first negative control group received distilled water (DW). The specimens received resin bonding immediately after treatment except for the second negative control group (delayed bonding). Microhardness, roughness, and topography were studied. The SBS values of all antioxidants were statistically greater than the positive control group ( < 0.05); however, NAC and AA applied for 1 min demonstrated the highest values, which were comparable to delayed bonding. All treatments removed the smear layer except DW, HO, and STS. The negative effect of HO on resin-dentin bonding was mitigated by the application of the antioxidants; however, their efficiencies were dependent on the antioxidant type and time of application. NAC was more effective in optimizing resin bonding to bleached dentin compared to GSH at 1 min application and STS at both application times but was comparable to AA. Negligible negative effects on the substrate's roughness and microhardness were detected. The antioxidant properties of the agent and its capacity to remove the smear layer are the processes underpinning the ability of a certain antioxidant to reverse the effect of HO on bonding.
PubMed: 38891420
DOI: 10.3390/polym16111473 -
Foods (Basel, Switzerland) May 2024The post-harvest processing of coffee beans leads to a wide range of reactions involving proteins. The formation of crosslinks between proteins and phenolic compounds...
The post-harvest processing of coffee beans leads to a wide range of reactions involving proteins. The formation of crosslinks between proteins and phenolic compounds present in high concentrations of coffee beans represents one of the most challenging and still not fully characterized reactions. The aim of this work was to assess the presence of products from such reactions in coffee samples, focusing on the adducts between cysteine and chlorogenic acids (CQAs). For this purpose, 19 green and 15 roasted coffee samples of the , , and varieties were selected for this study and basically characterized. Then, targeted liquid chromatography mass spectrometry (LC-MS/MS) methods were developed to assess the formation of adducts between CQA and cysteine, glutathione, and N-acetylcysteine as the amino acid and peptide models, and quantified such adducts in coffee samples. The results of the characterization showed a heterogeneous distribution of the protein content (8.7-14.6%), caffeine (0.57-2.62 g/100 g), and antioxidant capacity (2-4.5 g ascorbic acid/100 g) in , , and samples. Glutamic acid, arginine, and proline were found to be the major amino acids, while 5-CQA (38-76%), 3-CQA (4-13%), and 4-CQA (4-13%) were the most abundant CQA derivatives of all coffee varieties. The model experiments for adduct formation demonstrated that cysteine binds to CQA via thiol groups and 5-CQA initially isomerizes to 3- and 4-CQA, depending on the conditions, allowing cysteine to bind to two different sites on 3-, 4- or 5-CQA molecules, thus, forming six different Cys-CQA adducts with / 476. The reaction was more favored at pH 9, and the adducts proved to be stable up to 90 °C for 10 min and up to 28 days at room temperature. The relative quantification of adducts showed peak area values ranging from 1100 to 3000 in green coffee bean samples, while no adducts were detected in roasted coffee beans. Overall, this work was the first attempt to demonstrate the presence of Cys-CQA adducts in coffee beans and paves the way for further investigations of such adduct formation at the protein level.
PubMed: 38890888
DOI: 10.3390/foods13111660 -
European Review For Medical and... Jun 2024Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors...
Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors have found some mistakes. This erratum corrects the following: In Figure 1, "4 withdrawal" has been corrected into "7 withdrawal" and "95 completed study" has been corrected into "97 corrected study" In the "Efficacy" paragraph at page 5123, "1.0 in the placebo group" has been corrected into "-1.0 in the placebo group". The legend of Table V has been corrected as follows: Table V. Published clinical studies of the mucolytic and expectorant efficacy of IV NAC in respiratory diseases. In Table V, the data regarding the Treatment groups (duration) by Grassi et al5 have been corrected as follows: NAC oral 200 mg TID NAC IM 300 mg BID NAC IV 500 mg OD (6 days) In Table V, the data regarding the Treatment groups (duration) by Henneghien et al8 have been corrected as follows: NAC oral 200 mg TID NAC IV 300 mg TID (3-10 days) NAC IV 500 mg BID (12 days) There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32628.
PubMed: 38884516
DOI: 10.26355/eurrev_202406_36388