90 research outputs found
Antioxidative Activity of Ferrocenes Bearing 2,6-Di-Tert-Butylphenol Moieties
The antioxidative activity of ferrocenes bearing either 2,6-di-tert-butylphenol or phenyl groups has been compared using DPPH (1,1-diphenyl-2-picrylhydrazyl) test and in the study of the in vitro impact on lipid peroxidation in rat brain homogenate and on some characteristics of rat liver mitochondria. The results of DPPH test at 20Ā°C show that the activity depends strongly upon the presence of phenolic group but is improved by the influence of ferrocenyl fragment. The activity of N-(3,5-di-tert-butyl-4-hydroxyphenyl)iminomethylferrocene (1), for instance, was 88.4%, which was higher than the activity of a known antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) (48.5%), whereas the activity of N-phenyl-iminomethylferrocene 2 was almost negligible ā2.9%. The data obtained demonstrate that the compounds with 2,6-di-tert-butylphenol moiety are significantly more active than the corresponding phenyl analogues in the in vitro study of lipid peroxidation in rat brain homogenate. Ferrocene 1 performs a promising behavior as an antioxidant and inhibits the calcium-dependent swelling of mitochondria. These results allow us to propose the potential cytoprotective (neuroprotective) effect of ditopic compounds containing antioxidant 2,6-di-tert-butylphenol group and redox active ferrocene fragment
Assessment of senile asthenia syndrome using the Frailty and Edmonton frail scales in elderly and senile patients who underwent emergency abdominal surgery
The aim of the work was to compare the effectiveness of the assessment of senile asthenia syndrome using the Frailty and Edmonton Frail scales in elderly and senile patients undergoing emergency abdominal surgery.
Materials and methods. The study included 80 patients aged 60 to 89 years with a diagnosis of acute calculous cholecystitis. A correlation was determined between asthenia and the severity of the patientās condition according to the P-POSSUM scale, the peak value of the increase in the risk of postoperative complications and mortality occurs in patients with a sum of points >32, p = 0.012. The syndrome of senile asthenia using the Edmonton Frail scale was detected in 30 (37.5 %) patients, according to the Frailty scale ā 32 (40.0 %), U = 3120.0, p = 0.7862.
Results. The main advantage of the Edmonton Frail scale is the examination time of 22 Ā± 3 min, while with the Frailty scale 360 Ā± 22 min (U = 24.5, p < 0.0001). Based on the assessment of the severity of the condition using the P-POSSUM scale, we determined a direct correlation of average strength between the presence of asthenia and the number of points: Edmonton Frail subgroup A ā rs = 0.81, p = 0.000001. The same results, respectively, on the Frailty scale ā rs = 0.78, p = 0.000004. The frequency of complications increases significantly in the category of patients with asthenia, which is confirmed by both the Edmonton Frail scale ā 23.3 % (U = 605.0, p = 0.0087), and the Frailty scale ā 21.9 % (U = 632.0, p = 0.0150).
Conclusions. The frequency of detection of senile asthenia syndrome using the Edmonton Frail and Frailty scale in patients was equivalent (U = 3120.0, p = 0.7862). The Edmonton Frail scale is more convenient to use in urgent situations, and the mean time to diagnose asthenia using it was 22 Ā± 3 min, while the complete diagnosis using the Frailty scale took 360 Ā± 22 min (U = 24.5, p < 0.0001).
A significant increase in the frequency of postoperative complications was determined in the category of patients with asthenia, confirmed both by the Edmonton Frail scale ā 23.3 % (U = 605.0, p = 0.0087), and by the Frailty scale ā 21.9 % (U = 632.0, p = 0.0150)
Salmonella-induced changes of the rat intestinal microbiota
The gut microbiome profoundly affects the body functioning: it participates in host protection against pathogenic microorganisms, metabolic events, inhibition of inflammatory responses, formation of innate and adaptive immune response in the intestinal mucosa. One of the causes altering microbiota community is due to antibiotics. Therefore, the processes of antibiotics interaction together with Salmonella enteritidis and Salmonella typhimurium with representatives of normal intestinal microflora are of particular interest. Materials and methods. The quantitative and qualitative analysis of the wall microbiota composition in rats was evaluated by bacteriological method, the statistical data analysis was performed using the software StatSoft Statistica v.12. Results and discussion. Inoculation of vancomycin and S. enteritidis, S. typhimurium in groups II, III, IV resulted in quantitatively decreased E. coli level by 10-, 7- and 110-fold, respectively (p ā¤ 0.05). The count of P. aeruginosa decreased markedly only in the group III (p ā¤ 0.05). The count of Bacteroides spp. members was profoundly decreased by several thousand times (group II) as well as 70- and 87-fold (groups III and IV), respectively (p ā¤ 0.05). The count of E. faecalis and E. faecium decreased by 861-, 6- and several thousand times (groups II, III, IV), respectively (p ā¤ 0.05). The count of Proteus spp. markedly decreased in group II by 27-fold and rapidly increased in group IV (p ā¤ 0.05). Group III revealed a sharp decline in level of Enterobacter spp. and Klebsiella spp. by 847- and 150-fold, whereas in group II they were increased by 7- and 46-fold, respectively (p ā¤ 0.05). The count of Staphylococcus spp. decreased by 10-fold only in group II. The level of Clostridium spp. decreased by several thousand times (group II) and by 5,500 times (group IV) (p ā¤ 0.05). The count of Lactobacillus spp. decreased by several thousand times (group II). The count of Bifidobacterium spp. members significantly decreased by 10.9-fold and by several thousand times (groups III, IV). The level of Peptostreptococcus anaerobius profoundly decreased in all three study groups (p ā¤ 0.05). The level of Salmonella spp. increased in group II by 49 times, but markedly increased in groups III and IV (p ā¤ 0.05). Inoculation of Salmonella after vancomycin pretreatment caused dramatic change in the microbiota composition in groups V and VI, namely: increased count of E. coli by 65- and 105-fold, markedly increased level of P. aeruginosa in group V and VI ā by 3-fold. In addition, these groups also showed decreased level of Bacteroides spp. by 9- and 10-fold (p ā¤ 0.05). The count of E. faecalis and E. faecium decreased dramatically only in group V (p ā¤ 0.05). The count of Proteus spp. decreased by 17 times in group V as well as in group VI (p ā¤ 0.05). A sharp increase in level of Enterobacter spp. and Klebsiella spp. members was observed in groups V and VI (p ā¤ 0.05). However, representatives of Peptostreptococcus anaerobius in groups V and VI decreased by 20 and 9 times, respectively (p ā¤ 0.05). The count of Salmonella spp. decreased only in group V by 7 times (p ā¤ 0,05). Inoculating experimental animals with B. fragilis conditioned with S. enteritidis, S. typhimurium and pretreated with vancomycin resulted in markedly decreased level of E. coli in group VII and VIII by 538 times (p ā¤ 0.05). The count of P. aeruginosa in groups VII and VIII decreased profoundly, whereas level of Bacteroides spp. members was reciprocally increased (p ā¤ 0.05). The level of Lactobacillus spp. decreased by 10.3 times only in group VI. The count of E. faecalis and E. faecium increased by 10 and 19 times in groups VII and VIII, respectively, whereas level of Proteus spp. decreased only in group VII by 322 times (p ā¤ 0.05). In addition, a sharp decrease in level of Enterobacter spp. and Klebsiella spp. members (p ā¤ 0.05) was found in groups VII and VIII. The count of Peptostreptococcus anaerobius and Lactobacillus spp. members was markedly increased by 7-, 12-, several thousand-fold and 40 times (groups VII and VIII, respectively) (p ā¤ 0.05). The count of S. enteritidis and S. typhimurium in groups VII and VIII decreased rapidly (p ā¤ 0.05). Conclusion. Inoculation of B. fragilis can be used in treatment of inflammatory bowel diseases or disorders with impaired gut barrier function
Dimebon Does Not Ameliorate Pathological Changes Caused by Expression of Truncated (1ā120) Human Alpha-Synuclein in Dopaminergic Neurons of Transgenic Mice
Background: Recent clinical studies have demonstrated that dimebon, a drug originally designed and used as a non-selective antihistamine, ameliorates symptoms and delays progress of mild to moderate forms of Alzheimerās and Huntingtonās diseases. Although the mechanism of dimebon action on pathological processes in degenerating brain is elusive, results of studies carried out in cell cultures and animal models suggested that this drug might affect the process of pathological accumulation and aggregation of various proteins involved in the pathogenesis of proteinopathies. However, the effect of this drug on the pathology caused by overexpression and aggregation of alpha-synuclein, including Parkinsonās disease (PD), has not been assessed. Objective: To test if dimebon affected alpha-synuclein-induced pathology using a transgenic animal model. Methods: We studied the effects of chronic dimebon treatment on transgenic mice expressing the C-terminally truncated (1ā120) form of human alpha-synuclein in dopaminergic neurons, a mouse model that recapitulates several biochemical, histopathological and behavioral characteristics of the early stage of PD. Results: Dimebon did not improve balance and coordination of aging transgenic animals or increase the level of striatal dopamine, nor did it prevent accumulation of alpha-synuclein in cell bodies of dopaminergic neurons. Conclusion: Our observations suggest that in the studied model of alpha-synucleinopathy dimebon has very limited effect on certain pathological alterations typical of PD and related diseases
Low level of expression of C-terminally truncated human FUS causes extensive changes in the spinal cord transcriptome of asymptomatic transgenic mice
A number of mutations in a gene encoding RNA-binding protein FUS have been linked to the development of a familial form of amyotrophic lateral sclerosis known as FUS-ALS. C-terminal truncations of FUS by either nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients bearing these highly pathogenic mutations the function of motor neurons is not noticeably compromised for at least a couple of decades, suggesting that until cytoplasmic levels of FUS lacking its C-terminal nuclear localisation signal reaches a critical threshold, motor neurons are able to tolerate its permanent production.In order to identify how the nervous system responds to low levels of pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low neuronal expression level of a highly aggregation-prone and pathogenic form of C-terminally truncated FUS. In contrast to mice that express substantially higher level of the same FUS variant and develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any clinical or histopathological signs of motor neuron deficiency even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice compared to their wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating for the potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective targets for therapy of FUS-ALS and possibly, other forms of ALS
Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit Ī²-amyloid self-aggregation: potential therapeutic agents for Alzheimerās disease
We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of Ī²-amyloid (AĪ²42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 Ā± 0.23 ĀµM and 3.22 Ā± 0.25 ĀµM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 Ā± 0.55 Ī¼M), consistent with docking results. Dihydroacridines inhibited AĪ²42 self-aggregation; 1d and 1e were the most active (58.9% Ā± 4.7% and 46.9% Ā± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTSā¢+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good bloodābrain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and AĪ²42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations. Copyright Ā© 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.122041400110-4; FFSN-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, Š Š¤Š¤Š: 19-29-08037; Russian Science Foundation, RSFThis research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RRās contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan
C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population
Cohorts of amyotrophic lateral sclerosis (ALS) patients and control individuals of Caucasian origin from the Central European Russia (Moscow city and region) were analyzed for the presence of hexanucleotide repeat GGGGCC expansion within the first intron of the C9ORF72 gene. The presence of a large (>40) repeat expansion was found in 15% of familial ALS cases (3 of 20 unrelated familial cases) and 2.5% of sporadic ALS cases (6 of 238) but in none of control cases. These results suggest that the frequency of C9ORF72 hexanucleotide repeats expansions in the Central Europea
Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit Ī²-amyloid self-aggregation: potential therapeutic agents for Alzheimerās disease
We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of Ī²-amyloid (AĪ²42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 Ā± 0.23Ā ĀµM and 3.22 Ā± 0.25Ā ĀµM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 Ā± 0.55Ā Ī¼M), consistent with docking results. Dihydroacridines inhibited AĪ²42 self-aggregation; 1d and 1e were the most active (58.9% Ā± 4.7% and 46.9% Ā± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTSā¢+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good bloodābrain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and AĪ²42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations
Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice
Peculiarities of the formation of multicomponent AlN-TiB2-TiSi2 composite ceramics coatings during heat treatment
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