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Scientific Reports May 2024Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group...
Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-25% of sporadic Parkinson's patients present with genetic abnormalities that could represent a risk factor, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinson's disease, which highlights the critical need for biomarkers. In the present study, we prospectively collected and analyzed plasma samples from 194 Parkinson's disease patients and 197 age-matched non-diseased controls. N-acetyl putrescine (NAP) in combination with sense of smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements demonstrated combined diagnostic utility. NAP was increased by 28% in Parkinsons disease patients and exhibited an AUC of 0.72 as well as an OR of 4.79. The clinical and NAP panel demonstrated an area under the curve, AUC = 0.9 and an OR of 20.4. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinson's disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.
Topics: Humans; Parkinson Disease; Male; Biomarkers; Female; Aged; Middle Aged; Putrescine; Prospective Studies; Case-Control Studies
PubMed: 38693432
DOI: 10.1038/s41598-024-60872-3 -
Experimental & Molecular Medicine May 2024Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma...
Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.
Topics: Eukaryotic Translation Initiation Factor 5A; Peptide Initiation Factors; Hypoxia-Inducible Factor 1, alpha Subunit; Humans; RNA-Binding Proteins; Carcinoma, Hepatocellular; Tumor-Associated Macrophages; Liver Neoplasms; Glutamine; Aspartic Acid; Protein Biosynthesis; Animals; Cell Line, Tumor; Mice; Glycolysis; Lysine
PubMed: 38689086
DOI: 10.1038/s12276-024-01214-1 -
Journal of Pharmacological Sciences Jun 2024Subretinal hemorrhages result in poor vision and visual field defects. During hemorrhage, several potentially toxic substances are released from iron-based hemoglobin...
Subretinal hemorrhages result in poor vision and visual field defects. During hemorrhage, several potentially toxic substances are released from iron-based hemoglobin and hemin, inducing cellular damage, the detailed mechanisms of which remain unknown. We examined the effects of excess intracellular iron on retinal pigment epithelial (RPE) cells. A Fe probe, SiRhoNox-1 was used to investigate Fe accumulation after treatment with hemoglobin or hemin in the human RPE cell line ARPE-19. We also evaluated the production of reactive oxygen species (ROS) and lipid peroxidation. Furthermore, the protective effect of-an iron chelator, 2,2'-bipyridyl (BP), and ferrostatin-1 (Fer-1) on the cell damage, was evaluated. Fe accumulation increased in the hemoglobin- or hemin-treated groups, as well as intracellular ROS production and lipid peroxidation. In contrast, BP treatment suppressed RPE cell death, ROS production, and lipid peroxidation. Pretreatment with Fer-1 ameliorated cell death in a concentration-dependent manner and suppressed ROS production and lipid peroxidation. Taken together, these findings indicate that hemoglobin and hemin, as well as subretinal hemorrhage, may induce RPE cell damage and visual dysfunction via intracellular iron accumulation.
Topics: Humans; Cell Death; Cell Line; Cyclohexylamines; Hemin; Hemoglobins; Iron; Iron Chelating Agents; Lipid Peroxidation; Phenylenediamines; Reactive Oxygen Species; Retinal Pigment Epithelium
PubMed: 38677785
DOI: 10.1016/j.jphs.2024.04.001 -
Environment International May 2024N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is commonly used in rubber compounds as antioxidants to protect against degradation from heat, oxygen, and... (Review)
Review
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is commonly used in rubber compounds as antioxidants to protect against degradation from heat, oxygen, and ozone exposure. This practice extends the lifespan of rubber products, including tires, by preventing cracking, aging, and deterioration. However, the environmental consequences of waste generated during rubber product use, particularly the formation of 6PPD-quinone (6PPD-Q) through the reaction of 6PPD with ozone, have raised significant concerns due to their detrimental effects on ecosystems. Extensive research has revealed the widespread occurrence of 6PPD and its derivate 6PPD-Q in various environmental compartments, including air, water, and soil. The emerging substance of 6PPD-Q has been shown to pose acute mortality and long-term hazards to aquatic and terrestrial organisms at concentrations below environmentally relevant levels. Studies have demonstrated toxic effects of 6PPD-Q on a range of organisms, including zebrafish, nematodes, and mammals. These effects include neurobehavioral changes, reproductive dysfunction, and digestive damage through various exposure pathways. Mechanistic insights suggest that mitochondrial stress, DNA adduct formation, and disruption of lipid metabolism contribute to the toxicity induced by 6PPD-Q. Recent findings of 6PPD-Q in human samples, such as blood, urine, and cerebrospinal fluid, underscore the importance of further research on the public health and toxicological implications of these compounds. The distribution, fate, biological effects, and underlying mechanisms of 6PPD-Q in the environment highlight the urgent need for additional research to understand and address the environmental and health impacts of these compounds.
Topics: Rubber; Animals; Phenylenediamines; Environmental Pollutants; Humans; Environmental Monitoring
PubMed: 38677083
DOI: 10.1016/j.envint.2024.108677 -
Microorganisms Apr 2024Representatives of the genus are widely used as probiotics to modulate the gut microbiome and alleviate various health conditions. The action mechanisms of probiotics...
Representatives of the genus are widely used as probiotics to modulate the gut microbiome and alleviate various health conditions. The action mechanisms of probiotics rely on their direct effect on the gut microbiota and the local and systemic effect of its metabolites. The main purpose of this animal experiment was to assess the biosafety of the strain BIOCC1719. Additional aims were to characterise the influence of the strain on the intestinal microbiota and the effect on several health parameters of the host during 15- and 30-day oral administration of the strain to mice. The strain altered the gut microbial community, thereby altering luminal short-chain fatty acid metabolism, resulting in a shift in the proportions of acetic, butyric, and propionic acids in the faeces and serum of the test group mice. Targeted metabolic profiling of serum revealed the possible ability of the strain to positively affect the hosts' amino acids and bile acids metabolism, as the cholic acid, deoxycholic acid, aspartate, and glutamate concentration were significantly higher in the test group. The tendency to increase anti-inflammatory polyamines (spermidine, putrescine) and neuroprotective 3-indolepropionic acid metabolism and to lower uremic toxins (P-cresol-SO, indoxyl-SO) was registered. Thus, BIOCC1719 may exert health-promoting effects on the host through modulation of the gut microbiome and the host metabolome via inducing the production of health-promoting bioactive compounds. The health effects of the strain need to be confirmed in clinical trials with human volunteers.
PubMed: 38674784
DOI: 10.3390/microorganisms12040840 -
Plants (Basel, Switzerland) Apr 2024Low-temperature stress significantly limits the growth, development, and geographical distribution of apple cultivation. Spermidine (Spd), a known plant growth...
Low-temperature stress significantly limits the growth, development, and geographical distribution of apple cultivation. Spermidine (Spd), a known plant growth regulator, plays a vital role in the plant's response to abiotic stress. Yet, the mechanisms by which exogenous Spd enhances cold resistance in apples remain poorly understood. Therefore, the present study analyzed the effects of exogenous Spd on antioxidant enzyme activity, polyamine metabolism, and related gene expression levels of 1-year-old apple branches under low-temperature stress. Treatment with exogenous Spd was found to stabilize branch tissue biofilms and significantly reduce the levels of reactive oxygen species by elevating proline content and boosting the activity of antioxidants such as superoxide dismutase. It also upregulated the activities of arginine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase and the expression levels of , , and under low-temperature stress and led to the accumulation of large amounts of Spd and spermine. Moreover, compared with the 2 mmol·L Spd treatment, the 1 mmol·L Spd treatment increased the expression levels of cold-responsive genes , , and , significantly. The findings suggest that exogenous Spd can enhance cold resistance in apple branches significantly. This enhancement is achieved by modulating polyamine metabolism and improving antioxidant defense mechanisms, which could be exploited to improve apple cultivation under cold stress conditions.
PubMed: 38674509
DOI: 10.3390/plants13081100 -
International Journal of Molecular... Apr 2024Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy... (Review)
Review
Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative-nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [CaMn(DPDP); PledOx], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying CaMn(DPDP) in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with CaMn(DPDP), a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with CaMn(DPDP). The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving CaMn(DPDP) may be explained by redox interactions between Pt and Mn and subtle oxidative-nitrosative chain reactions. In peripheral sensory nerves, Pt presumably leads to oxidation of the Mn from CaMn(DPDP) as well as from Mn in MnSOD and other endogenous sources. Thereafter, Mn may be oxidized by peroxynitrite (ONOO) into Mn, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart CaMn(DPDP) mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt outcompetes Mn and endogenous Zn in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt by DPDP, which in turn suggests that Mn is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.
Topics: Humans; Antineoplastic Agents; Edetic Acid; Manganese; Nitrosative Stress; Oxaliplatin; Oxidative Stress; Peripheral Nervous System Diseases; Platinum; Pyridoxal Phosphate; Superoxide Dismutase; Clinical Trials, Phase III as Topic
PubMed: 38673932
DOI: 10.3390/ijms25084347 -
International Journal of Molecular... Apr 2024This study investigated the effect of polycationic and uncharged polymers (and oligomers) on the catalytic parameters and thermostability of L-asparaginase from (TsA)....
This study investigated the effect of polycationic and uncharged polymers (and oligomers) on the catalytic parameters and thermostability of L-asparaginase from (TsA). This enzyme has potential applications in the food industry to decrease the formation of carcinogenic acrylamide during the processing of carbohydrate-containing products. Conjugation with the polyamines polyethylenimine and spermine (PEI and Spm) or polyethylene glycol (PEG) did not significantly affect the secondary structure of the enzyme. PEG contributes to the stabilization of the dimeric form of TsA, as shown by HPLC. Furthermore, neither polyamines nor PEG significantly affected the binding of the L-Asn substrate to TsA. The conjugates showed greater maximum activity at pH 7.5 and 85 °C, 10-50% more than for native TsA. The pH optima for both TsA-PEI and TsA-Spm conjugates were shifted to lower pH ranges from pH 10 (for the native enzyme) to pH 8.0. Additionally, the TsA-Spm conjugate exhibited the highest activity at pH 6.5-9.0 among all the samples. Furthermore, the temperature optimum for activity at pH 7.5 shifted from 90-95 °C to 80-85 °C for the conjugates. The thermal inactivation mechanism of TsA-PEG appeared to change, and no aggregation was observed in contrast to that of the native enzyme. This was visually confirmed and supported by the analysis of the CD spectra, which remained almost unchanged after heating the conjugate solution. These results suggest that TsA-PEG may be a more stable form of TsA, making it a potentially more suitable option for industrial use.
Topics: Asparaginase; Thermococcus; Hydrogen-Ion Concentration; Enzyme Stability; Biocatalysis; Polyethylene Glycols; Temperature; Archaeal Proteins
PubMed: 38673759
DOI: 10.3390/ijms25084174 -
Biomolecules Apr 2024Polyamines are polycations derived from amino acids that play an important role in proliferation and growth in almost all living cells. In (the pneumococcus),...
Polyamines are polycations derived from amino acids that play an important role in proliferation and growth in almost all living cells. In (the pneumococcus), modulation of polyamine metabolism not only plays an important regulatory role in central metabolism, but also impacts virulence factors such as the capsule and stress responses that affect survival in the host. However, functional annotation of enzymes from the polyamine biosynthesis pathways in the pneumococcus is based predominantly on computational prediction. In this study, we cloned SP_0166, predicted to be a pyridoxal-dependent decarboxylase, from the Orn/Lys/Arg family pathway in TIGR4 and expressed and purified the recombinant protein. We performed biochemical characterization of the recombinant SP_0166 and confirmed the substrate specificity. For polyamine analysis, we developed a simultaneous quantitative method using hydrophilic interaction liquid chromatography (HILIC)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization. SP_0166 has apparent , , and / values of 11.3 mM, 715,053 min, and 63,218 min mM, respectively, with arginine as a substrate at pH 7.5. We carried out inhibition studies of SP_0166 enzymatic activity with arginine as a substrate using chemical inhibitors DFMO and DFMA. DFMO is an irreversible inhibitor of ornithine decarboxylase activity, while DFMA inhibits arginine decarboxylase activity. Our findings confirm that SP_0166 is inhibited by DFMA and DFMO, impacting agmatine production. The use of arginine as a substrate revealed that the synthesis of putrescine by agmatinase and -carbamoylputrescine by agmatine deiminase were both affected and inhibited by DFMA. This study provides experimental validation that SP_0166 is an arginine decarboxylase in pneumococci.
Topics: Carboxy-Lyases; Tandem Mass Spectrometry; Streptococcus pneumoniae; Chromatography, High Pressure Liquid; Substrate Specificity; Bacterial Proteins; Recombinant Proteins; Polyamines; Kinetics
PubMed: 38672479
DOI: 10.3390/biom14040463 -
Animals : An Open Access Journal From... Apr 2024The gastrointestinal tract plays crucial roles in the digestion and absorption of nutrients, as well as in maintenance of a functional barrier. The development and... (Review)
Review
The gastrointestinal tract plays crucial roles in the digestion and absorption of nutrients, as well as in maintenance of a functional barrier. The development and maturation of the intestine is important for piglets to maintain optimal growth and health. Polyamines are necessary for the proliferation and growth of enterocytes, which play a key role in differentiation, migration, remodeling and integrity of the intestinal mucosa after injury. This review elaborates the development of the structure and function of the intestine of piglets during embryonic, suckling and weaning periods, the utilization and metabolism of polyamines in the intestine, as well as the role of polyamines in intestinal development and mucosal repair. The nutritional intervention to improve intestinal development and functions by modulating polyamine metabolism in piglets is also put forward. These results may help to promote the adaption to weaning in pigs and provide useful information for the development and health of piglets.
PubMed: 38672376
DOI: 10.3390/ani14081228