Objective:This study aimed to evaluate the prognostic impact of citicoline sodium capsules on patients with traumatic brain injury(TBI)and its safety.Methods:This study is a multicenter,single-arm,prospective,observat...Objective:This study aimed to evaluate the prognostic impact of citicoline sodium capsules on patients with traumatic brain injury(TBI)and its safety.Methods:This study is a multicenter,single-arm,prospective,observational study of brain trauma patients who met the inclusion criteria between March 2023 and June 2024 and who could be treated with citicoline sodium capsules after being evaluated by the investigator.The Glasgow Coma Scale(GCS)and Mini-Mental State Examination(MMSE),the incidence of adverse drug reactions/adverse events during treatment,and the abnormalities of safety tests with clinical evaluation significance were observed at 1 month and 2 months after treatment.Results:A total of 2806 patients,63.1%of whom were male,with an average age of 58.85 years old.The GCS and MMSE scores of the patients at 1 month and 2 months after treatment were significantly improved and were statistically significant,indicating that citicoline sodium had a significant effect on improving the state of consciousness and cognitive function of patients with TBI.Only 8 adverse reactions were reported in the study,all of which were mild gastrointestinal reactions and anaphylaxis,and did not lead to treatment interruption or serious consequences.Conclusion:Citicoline sodium has a significant therapeutic effect on patients with TBI and has good safety.展开更多
AIM: To evaluate the short-term effects of oral citicoline therapy on the retinal nerve fiber layer(RNFL) and the macular ganglion cell-inner plexiform layer(m GCIPL) in patients with primary open angle glaucoma(POAG)...AIM: To evaluate the short-term effects of oral citicoline therapy on the retinal nerve fiber layer(RNFL) and the macular ganglion cell-inner plexiform layer(m GCIPL) in patients with primary open angle glaucoma(POAG).METHODS: Fifty-four eyes of 54 patients with POAG glaucoma included in the study.In addition to a topical hypotensive, 250-mg oral citicoline was administered to 27 patients, while 27 patients were assigned as the control group.RNFL and m GCIPL values were measured using optical coherence tomography(OCT) at 1 d before treatment and 3 mo after the initiation of treatment.At the third month visit, citicoline treatment was discontinued and drug-free control(wash-out) measurements were obtained at the fourth month in citicoline group.RESULTS: The average RNFL thickness was significantly higher at month 3 than the baseline(P=0.038) in citicoline group.However, this improvement partially regressed after a 1-month wash-out period.No statistically significant changes in RNFL were observed in the superior, nasal, temporal and inferior quadrants at months 3 and 4(P>0.05).The change in the average and inferior quadrant RNFL thickness in the citicoline group at 3 mo was significantly greater than the control group(P=0.006 and P=0.014, respectively).There were no significant differences between the groups according to the change in m GCIPL thickness and the superior, nasal and temporal quadrant RNFL thickness(P>0.05).CONCLUSION: With oral citicoline treatment, the loss in the average RNFL is prevented in POAG patients in the short-term.Study data show that citicoline may have a significant impact on slowing glaucoma progression, which could have a potential neuroprotective effect.展开更多
Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be ...Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be associated with improved attention compared to placebo. Methods: The investigation was a double-blind, randomized, placebo-controlled three-arm study. Sixty healthy adult women ages 40 - 60 completed a clinical screening visit, including a medical exam. After study enrollment each subject was randomly assigned to one of three groups: a daily oral dose of 250 mg citicoline, 500 mg citicoline, or placebo for 28 days. Participants were evaluated with the Continuous Performance Test II (CPT-II), a measure sensitive to attentional function, during a baseline visit and 28 days after baseline. Results: All 60 participants were included in the analyses, which included an ANOVA with Tukey’s post-hoc tests and t-tests. After 28 days of supplementation, individuals in the 250 mg group made fewer omission (p = 0.04) and commission (p = 0.03) errors compared to those in the placebo group. Individuals in the 500 mg group made significantly fewer commission errors compared to those in the placebo group (p = 0.03) and trended toward making fewer omission errors (p = 0.07). Conclusion: After 28 days of daily citicoline supplementation, participants who were administered either the 250 mg or the 500 mg citicoline doses showed significantly better ability to produce correct responses on the CPT-II, likely due to improved cognitive inhibition. Our findings suggest that citicoline may improve attentional performance in middle-aged women and may ameliorate attentional deficits associated with central nervous system disorders.展开更多
Background: Citicoline and homotaurine are compounds with a potent neuroprotective activity and they have been administered for many years in the treatment of numerous neurodegenerative and ophthalmological diseases, ...Background: Citicoline and homotaurine are compounds with a potent neuroprotective activity and they have been administered for many years in the treatment of numerous neurodegenerative and ophthalmological diseases, including glaucoma. Initially available only as liquid form, through parenteral route, nowadays citicoline can be administered also as tablet but no data on bioavailability of these different forms are available. In the present study, pharmacokinetics of citicoline in tablet versus vials, each at the therapeutic dose of 500 mg, in addition to 50 mg of homotaurine was investigated. Materials and methods: Ten mixed breed dogs received a single dose of 50 mg oral homotaurine and 500 mg citicoline in tablet and vials with the same dose were administered after a seven days wash-out period. Parameters assessed for citicoline metabolites (cytidine, uridine and choline) were AUC0−t, Cmax and Tmax. Results: Citicoline bioavailability appeared to be slightly higher for the tablet compared to the vial formulation. Cytidine is equivalent in absorption dynamics both for tablet and liquid form;uridine for tablet reaches its maximum and is reabsorbed more quickly while choline for the liquid form reaches the maximum first and is reabsorbed more quickly. Conclusions: Citicoline in tablet and liquid formulation have pharmacokinetic properties leading to a very similar bioavailability.展开更多
Objective: to explore whether citicoline combined with memantine therapy can help patients return to normal life as soon as possible for the majority of patients with vascular dementia. Methods: selected 150 patients ...Objective: to explore whether citicoline combined with memantine therapy can help patients return to normal life as soon as possible for the majority of patients with vascular dementia. Methods: selected 150 patients with vascular dementia admitted to our hospital from January 2020 to January 2022 , according to the difference between the two sets of treatment plans established by the organizing committee, all the selected patients were randomly and equally divided into groups, the number of patients in each group was 75 cases, and the patients treated with memantine were included in the control group, and the remaining 75 patients were included in the control group. On the basis of the control group, patients were treated with citicoline combined with citicoline. After the treatment, the researchers of the organizing committee were responsible for the quality of life score, dementia degree score, various stress indicators and adverse reactions of the two groups of patients before and after treatment. Occurrence, hospitalization, clinical efficacy and other data results. Results: the social function score of the control group before treatment was (56.21 ± 5.79), the physical function score was (59.67 ± 5.76), the sleep function score was (60.48 ± 5.52), and the psychological state score was (61.38 ± 6.85). The functional score was (66.85 ± 3.15), the physical function score was (67.51 ± 5.49), the sleep function score was (65.18 ± 5.82), and the mental state score was (64.78 ± 3.22);The social function score of the experimental group before treatment was (55.48 ± 5.52), physical function score (60.45 ± 5.84), sleep function score (59.67 ± 3.38), mental state score (60.84 ± 5.27), social function score after treatment (86.59 ± 3.41), physical function score (86.59 ± 3.41) was (88.55 ± 3.27), the sleep function score was (89.63 ± 6.64), and the psychological state score was (90.37 ± 5.53). There was no significant difference in the quality of life scores between the two groups before treatment (P > 0.05). After the treatment, the quality of life scores of the two groups gradually widened, and the experimental group was significantly higher than the control group (P < 0.05). The dementia degree score of the control group before treatment was (32.68 ± 3.69), and the dementia degree score after treatment was (56.96 ± 4.04). (76.93 ± 3.84), there was no significant difference in the scores of dementia degree before treatment between the two groups of patients (P > 0.05). After implementing different treatment plans, the scores of dementia degree of the two groups of patients gradually widened the gap, and the experimental group was significantly better. in the control group (P < 0.05). The serum calcitonin peptide level in the control group before treatment was (36.95 ± 6.84), the serum homocysteine level was (16.96 ± 6.29), and the serum calcitonin peptide level after treatment was (56.93 ± 5.41), the serum homocysteine level was (56.93 ± 5.41), the cysteine level was (13.21 ± 3.99);The serum calcitonin peptide level before treatment in the experimental group was (38.46 ± 5.48), the serum homocysteine level was (17.05 ± 3.84), and the serum calcitonin level after treatment was (17.05 ± 3.84). The level of prime peptide was (79.32 ± 5.16), and the level of serum homocysteine was (19.68 ± 5.13). There was no significant difference in the two stress indicators between the two groups before treatment (P > 0.05). The comparison of the two stress indicators gradually widened the gap, and the experimental group was significantly better than the control group (P < 0.05). Among the 40 patients in the control group, 4 patients felt significant headache, accounting for 10% of all patients, and 3 patients felt obvious abdominal distension, accounting for 7.5% of all patients. The incidence of adverse reactions in this group of patients was 17.5%;Among the 40 patients in the experimental group, only 2 patients felt obvious abdominal distension, accounting for 5% of all patients. Control group (P < 0.05). Conclusion: in the clinical treatment of patients with vascular dementia, in order to strengthen the cognitive function of the patients and improve the daily living ability of the patients, it is necessary to give citicoline combined with memantine therapy. It is the first choice for the majority of patients with vascular dementia and is worthy of vigorous promotion and application in clinical practice.展开更多
The present study aimed to investigate the rationale and efficacy of testing endogenous substances widely used as dietary supplement such as citicoline,coenzyme Q10(CoQ10)and a fixed combination of them in countering ...The present study aimed to investigate the rationale and efficacy of testing endogenous substances widely used as dietary supplement such as citicoline,coenzyme Q10(CoQ10)and a fixed combination of them in countering the oxidative stress and neurotoxicity occurring in neurological diseases.Rat CTX-TNA2 astrocytes,which have considerable antioxidant potential and could represent a key target for neurotherapies were selected as in vitro model to conduct the experiments.The efficacy of citicoline and coenzyme Q10(1 nM-10μM),with their fixed combination,were assayed in rat astrocytes either in basal condition or after challenging the cells with hydrogen peroxide in order to evaluate the biocompatibility of treatments.The gene expression of B-Cell Lymphoma protein 2(BCL-2),BCL-2 Associated X(BAX),Superoxide dismutase 2(SOD2),Cardiolipin Synthase 1(CRLS1),interleukin-6(IL-6),tumor necrosis factorα(TNFα),and nuclear factor kappa-light-chain-enhancer of activated B cells(NFkB)involved in neurodegenerative diseases and neuroinflammation were investigated in CTX-TNA2 cells.Furthermore,in the same condition,Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)was carried out to assess apoptosis in astrocytes.Neither citicoline,nor coenzyme Q10 significantly altered astrocytes cell viability;thus,suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study.Moreover,each compound tested alone or in combination were effective in inhibiting the hydrogen peroxide-induced gene expression of BAX,and SOD2,in inducing the gene expression of BCL-2 and CRLS1 and in reducing apoptosis.The blunting effects induced by the above-mentioned treatments on hydrogen-peroxide induced apoptosis was also confirmed by TUNEL assay that demonstrated the capability of citicoline,CoQ10,and their combination to reduce the ratio TUNEL positive nuclei/total nuclei,a reliable marker of apoptosis.Additionally,citicoline,CoQ10,and their association were effective in inhibiting the hydrogen peroxide-induced NFkB,TNFα,and IL-6 gene.In parallel,there was an in-hibition of both TNFαand IL-6 gene expression in basal condition.The co-administration of citicoline/coenzyme Q10 was overall more effective than individual ingredients.The present findings support the beneficial and synergistic effects of citicoline and coenzyme Q10 in fixed combination in reducing oxidation,and in stimulating neuroprotection in rat CTX-TNA2 astrocytes.展开更多
Phosphocholine cytidylyltransferase(CCT)is an important biocatalyst for citicoline(CDP-choline)production.However,it suffers from relatively low catalytic activity and halotolerance when it was applied in the one-pot ...Phosphocholine cytidylyltransferase(CCT)is an important biocatalyst for citicoline(CDP-choline)production.However,it suffers from relatively low catalytic activity and halotolerance when it was applied in the one-pot catalytic system coupling with the acetylphosphate based ATP regeneration system.A machine learning guided directed evolution approach was applied to simultaneously improve activity and halotolerance of Saccharomyces cerevisiae CCT(ScCCT),through random mutation on“hot-spot”regions predicted by selected models trained on different combinatory datasets generated by site-directed mutagenesis and random mutagenesis.The most desirable variant M3(P347S/P365L/K340T)exhibited an approximately 1.4 folds improvement in final titer of CDP-choline(182 mM)comparing with WT.This research proves that machine learning can improve effectiveness of random mutagenesis,and provides a possible solution to engineering membrane protein with complicated evolutionary fitness landscapes,which can be difficult for classic enzyme engineering approaches.展开更多
Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver...Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver is now viewed as a mitochondrial-centric metabolic-inflammatory disorder;ethanol and excess linoleic acid(LA)can magnify bioenergetic stress when choline is insufficient to sustain phosphatidylcholine/phosphatidylethanolamine.This narrative review examines whether optimized choline delivery,alongside reduced exposure to mitochondrial toxicants,offers a rational therapeutic approach.Low choline intake associates with higher liver fat and aminotransferases.In rodents,choline deficiency combined with ethanol or LA lowers mitochondrial membrane potential,limitsβ-oxidation,and promotes steatosis and inflammation.Advanced formulations-especially citicoline-demonstrate favorable absorption and tissue choline delivery and may lessen trimethylamine-N-oxide formation versus free choline salts.Early,small human studies suggest that choline repletion,together with curtailed ethanol or dietary LA,can reduce intrahepatic triglyceride content and improve insulin sensitivity,though large randomized trials are lacking.Framing fatty liver as nutrition-modifiable mitochondrial toxicosis highlights correctable choline insufficiency when the liver is burdened by ethanol or excess LA.A dual strategy-using higher-bioavailability,gutmicrobial trimethylamineNoxide-sparing choline forms and mitigating mitochondrial toxicants-targets core bioenergetic defects,may reverse early steatosis,and warrants testing in adequately powered clinical trials.展开更多
Delivering pharmacologic agents directly into the brain has been proposed as a means of bypassing the blood brain barrier.However,despite 16 years of research on a number of central nervous system disorders,an effecti...Delivering pharmacologic agents directly into the brain has been proposed as a means of bypassing the blood brain barrier.However,despite 16 years of research on a number of central nervous system disorders,an effective treatment using this strategy has only been observed in the brain tumor glioblastoma multiforme.Within this study we propose a novel system for delivering drugs into the brain named the simple diffusion (SDD) system.To validate this technique,rats were subjected to a single intracranial (at the caudate nucleus),or intraperitoneal injection,of the compound citicoline,followed two hours later by a permanent middle cerebral artery occlusion (pMCAO).Results showed that 12 h after pMCAO,with 0.0025 g kg-1 citicoline,an infarct volume 1/6 the size of the intraperitoneal group was achieved with a dose 1/800 of that required for the intraperitoneal group.These results suggest that given the appropriate injection point,through SDD a pharmacologically effective concentration of citicoline can be administered.展开更多
文摘Objective:This study aimed to evaluate the prognostic impact of citicoline sodium capsules on patients with traumatic brain injury(TBI)and its safety.Methods:This study is a multicenter,single-arm,prospective,observational study of brain trauma patients who met the inclusion criteria between March 2023 and June 2024 and who could be treated with citicoline sodium capsules after being evaluated by the investigator.The Glasgow Coma Scale(GCS)and Mini-Mental State Examination(MMSE),the incidence of adverse drug reactions/adverse events during treatment,and the abnormalities of safety tests with clinical evaluation significance were observed at 1 month and 2 months after treatment.Results:A total of 2806 patients,63.1%of whom were male,with an average age of 58.85 years old.The GCS and MMSE scores of the patients at 1 month and 2 months after treatment were significantly improved and were statistically significant,indicating that citicoline sodium had a significant effect on improving the state of consciousness and cognitive function of patients with TBI.Only 8 adverse reactions were reported in the study,all of which were mild gastrointestinal reactions and anaphylaxis,and did not lead to treatment interruption or serious consequences.Conclusion:Citicoline sodium has a significant therapeutic effect on patients with TBI and has good safety.
文摘AIM: To evaluate the short-term effects of oral citicoline therapy on the retinal nerve fiber layer(RNFL) and the macular ganglion cell-inner plexiform layer(m GCIPL) in patients with primary open angle glaucoma(POAG).METHODS: Fifty-four eyes of 54 patients with POAG glaucoma included in the study.In addition to a topical hypotensive, 250-mg oral citicoline was administered to 27 patients, while 27 patients were assigned as the control group.RNFL and m GCIPL values were measured using optical coherence tomography(OCT) at 1 d before treatment and 3 mo after the initiation of treatment.At the third month visit, citicoline treatment was discontinued and drug-free control(wash-out) measurements were obtained at the fourth month in citicoline group.RESULTS: The average RNFL thickness was significantly higher at month 3 than the baseline(P=0.038) in citicoline group.However, this improvement partially regressed after a 1-month wash-out period.No statistically significant changes in RNFL were observed in the superior, nasal, temporal and inferior quadrants at months 3 and 4(P>0.05).The change in the average and inferior quadrant RNFL thickness in the citicoline group at 3 mo was significantly greater than the control group(P=0.006 and P=0.014, respectively).There were no significant differences between the groups according to the change in m GCIPL thickness and the superior, nasal and temporal quadrant RNFL thickness(P>0.05).CONCLUSION: With oral citicoline treatment, the loss in the average RNFL is prevented in POAG patients in the short-term.Study data show that citicoline may have a significant impact on slowing glaucoma progression, which could have a potential neuroprotective effect.
文摘Objectives: The present study assessed the potential cognitive-enhancing effects of citicoline, a dietary supplement, in healthy adult women. Specifically, it was hypothesized that citicoline supplementation would be associated with improved attention compared to placebo. Methods: The investigation was a double-blind, randomized, placebo-controlled three-arm study. Sixty healthy adult women ages 40 - 60 completed a clinical screening visit, including a medical exam. After study enrollment each subject was randomly assigned to one of three groups: a daily oral dose of 250 mg citicoline, 500 mg citicoline, or placebo for 28 days. Participants were evaluated with the Continuous Performance Test II (CPT-II), a measure sensitive to attentional function, during a baseline visit and 28 days after baseline. Results: All 60 participants were included in the analyses, which included an ANOVA with Tukey’s post-hoc tests and t-tests. After 28 days of supplementation, individuals in the 250 mg group made fewer omission (p = 0.04) and commission (p = 0.03) errors compared to those in the placebo group. Individuals in the 500 mg group made significantly fewer commission errors compared to those in the placebo group (p = 0.03) and trended toward making fewer omission errors (p = 0.07). Conclusion: After 28 days of daily citicoline supplementation, participants who were administered either the 250 mg or the 500 mg citicoline doses showed significantly better ability to produce correct responses on the CPT-II, likely due to improved cognitive inhibition. Our findings suggest that citicoline may improve attentional performance in middle-aged women and may ameliorate attentional deficits associated with central nervous system disorders.
文摘Background: Citicoline and homotaurine are compounds with a potent neuroprotective activity and they have been administered for many years in the treatment of numerous neurodegenerative and ophthalmological diseases, including glaucoma. Initially available only as liquid form, through parenteral route, nowadays citicoline can be administered also as tablet but no data on bioavailability of these different forms are available. In the present study, pharmacokinetics of citicoline in tablet versus vials, each at the therapeutic dose of 500 mg, in addition to 50 mg of homotaurine was investigated. Materials and methods: Ten mixed breed dogs received a single dose of 50 mg oral homotaurine and 500 mg citicoline in tablet and vials with the same dose were administered after a seven days wash-out period. Parameters assessed for citicoline metabolites (cytidine, uridine and choline) were AUC0−t, Cmax and Tmax. Results: Citicoline bioavailability appeared to be slightly higher for the tablet compared to the vial formulation. Cytidine is equivalent in absorption dynamics both for tablet and liquid form;uridine for tablet reaches its maximum and is reabsorbed more quickly while choline for the liquid form reaches the maximum first and is reabsorbed more quickly. Conclusions: Citicoline in tablet and liquid formulation have pharmacokinetic properties leading to a very similar bioavailability.
文摘Objective: to explore whether citicoline combined with memantine therapy can help patients return to normal life as soon as possible for the majority of patients with vascular dementia. Methods: selected 150 patients with vascular dementia admitted to our hospital from January 2020 to January 2022 , according to the difference between the two sets of treatment plans established by the organizing committee, all the selected patients were randomly and equally divided into groups, the number of patients in each group was 75 cases, and the patients treated with memantine were included in the control group, and the remaining 75 patients were included in the control group. On the basis of the control group, patients were treated with citicoline combined with citicoline. After the treatment, the researchers of the organizing committee were responsible for the quality of life score, dementia degree score, various stress indicators and adverse reactions of the two groups of patients before and after treatment. Occurrence, hospitalization, clinical efficacy and other data results. Results: the social function score of the control group before treatment was (56.21 ± 5.79), the physical function score was (59.67 ± 5.76), the sleep function score was (60.48 ± 5.52), and the psychological state score was (61.38 ± 6.85). The functional score was (66.85 ± 3.15), the physical function score was (67.51 ± 5.49), the sleep function score was (65.18 ± 5.82), and the mental state score was (64.78 ± 3.22);The social function score of the experimental group before treatment was (55.48 ± 5.52), physical function score (60.45 ± 5.84), sleep function score (59.67 ± 3.38), mental state score (60.84 ± 5.27), social function score after treatment (86.59 ± 3.41), physical function score (86.59 ± 3.41) was (88.55 ± 3.27), the sleep function score was (89.63 ± 6.64), and the psychological state score was (90.37 ± 5.53). There was no significant difference in the quality of life scores between the two groups before treatment (P > 0.05). After the treatment, the quality of life scores of the two groups gradually widened, and the experimental group was significantly higher than the control group (P < 0.05). The dementia degree score of the control group before treatment was (32.68 ± 3.69), and the dementia degree score after treatment was (56.96 ± 4.04). (76.93 ± 3.84), there was no significant difference in the scores of dementia degree before treatment between the two groups of patients (P > 0.05). After implementing different treatment plans, the scores of dementia degree of the two groups of patients gradually widened the gap, and the experimental group was significantly better. in the control group (P < 0.05). The serum calcitonin peptide level in the control group before treatment was (36.95 ± 6.84), the serum homocysteine level was (16.96 ± 6.29), and the serum calcitonin peptide level after treatment was (56.93 ± 5.41), the serum homocysteine level was (56.93 ± 5.41), the cysteine level was (13.21 ± 3.99);The serum calcitonin peptide level before treatment in the experimental group was (38.46 ± 5.48), the serum homocysteine level was (17.05 ± 3.84), and the serum calcitonin level after treatment was (17.05 ± 3.84). The level of prime peptide was (79.32 ± 5.16), and the level of serum homocysteine was (19.68 ± 5.13). There was no significant difference in the two stress indicators between the two groups before treatment (P > 0.05). The comparison of the two stress indicators gradually widened the gap, and the experimental group was significantly better than the control group (P < 0.05). Among the 40 patients in the control group, 4 patients felt significant headache, accounting for 10% of all patients, and 3 patients felt obvious abdominal distension, accounting for 7.5% of all patients. The incidence of adverse reactions in this group of patients was 17.5%;Among the 40 patients in the experimental group, only 2 patients felt obvious abdominal distension, accounting for 5% of all patients. Control group (P < 0.05). Conclusion: in the clinical treatment of patients with vascular dementia, in order to strengthen the cognitive function of the patients and improve the daily living ability of the patients, it is necessary to give citicoline combined with memantine therapy. It is the first choice for the majority of patients with vascular dementia and is worthy of vigorous promotion and application in clinical practice.
文摘The present study aimed to investigate the rationale and efficacy of testing endogenous substances widely used as dietary supplement such as citicoline,coenzyme Q10(CoQ10)and a fixed combination of them in countering the oxidative stress and neurotoxicity occurring in neurological diseases.Rat CTX-TNA2 astrocytes,which have considerable antioxidant potential and could represent a key target for neurotherapies were selected as in vitro model to conduct the experiments.The efficacy of citicoline and coenzyme Q10(1 nM-10μM),with their fixed combination,were assayed in rat astrocytes either in basal condition or after challenging the cells with hydrogen peroxide in order to evaluate the biocompatibility of treatments.The gene expression of B-Cell Lymphoma protein 2(BCL-2),BCL-2 Associated X(BAX),Superoxide dismutase 2(SOD2),Cardiolipin Synthase 1(CRLS1),interleukin-6(IL-6),tumor necrosis factorα(TNFα),and nuclear factor kappa-light-chain-enhancer of activated B cells(NFkB)involved in neurodegenerative diseases and neuroinflammation were investigated in CTX-TNA2 cells.Furthermore,in the same condition,Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)was carried out to assess apoptosis in astrocytes.Neither citicoline,nor coenzyme Q10 significantly altered astrocytes cell viability;thus,suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study.Moreover,each compound tested alone or in combination were effective in inhibiting the hydrogen peroxide-induced gene expression of BAX,and SOD2,in inducing the gene expression of BCL-2 and CRLS1 and in reducing apoptosis.The blunting effects induced by the above-mentioned treatments on hydrogen-peroxide induced apoptosis was also confirmed by TUNEL assay that demonstrated the capability of citicoline,CoQ10,and their combination to reduce the ratio TUNEL positive nuclei/total nuclei,a reliable marker of apoptosis.Additionally,citicoline,CoQ10,and their association were effective in inhibiting the hydrogen peroxide-induced NFkB,TNFα,and IL-6 gene.In parallel,there was an in-hibition of both TNFαand IL-6 gene expression in basal condition.The co-administration of citicoline/coenzyme Q10 was overall more effective than individual ingredients.The present findings support the beneficial and synergistic effects of citicoline and coenzyme Q10 in fixed combination in reducing oxidation,and in stimulating neuroprotection in rat CTX-TNA2 astrocytes.
基金funded by the Jiangsu Province Outstanding Postdoctoral Program under grant number 379365.
文摘Phosphocholine cytidylyltransferase(CCT)is an important biocatalyst for citicoline(CDP-choline)production.However,it suffers from relatively low catalytic activity and halotolerance when it was applied in the one-pot catalytic system coupling with the acetylphosphate based ATP regeneration system.A machine learning guided directed evolution approach was applied to simultaneously improve activity and halotolerance of Saccharomyces cerevisiae CCT(ScCCT),through random mutation on“hot-spot”regions predicted by selected models trained on different combinatory datasets generated by site-directed mutagenesis and random mutagenesis.The most desirable variant M3(P347S/P365L/K340T)exhibited an approximately 1.4 folds improvement in final titer of CDP-choline(182 mM)comparing with WT.This research proves that machine learning can improve effectiveness of random mutagenesis,and provides a possible solution to engineering membrane protein with complicated evolutionary fitness landscapes,which can be difficult for classic enzyme engineering approaches.
文摘Choline supports phospholipid synthesis,membrane integrity,neurotransmission,verylowdensity lipoprotein export,and one-carbon/epigenetic pathways,yet most United States adults fall short of adequate intake.Fatty liver is now viewed as a mitochondrial-centric metabolic-inflammatory disorder;ethanol and excess linoleic acid(LA)can magnify bioenergetic stress when choline is insufficient to sustain phosphatidylcholine/phosphatidylethanolamine.This narrative review examines whether optimized choline delivery,alongside reduced exposure to mitochondrial toxicants,offers a rational therapeutic approach.Low choline intake associates with higher liver fat and aminotransferases.In rodents,choline deficiency combined with ethanol or LA lowers mitochondrial membrane potential,limitsβ-oxidation,and promotes steatosis and inflammation.Advanced formulations-especially citicoline-demonstrate favorable absorption and tissue choline delivery and may lessen trimethylamine-N-oxide formation versus free choline salts.Early,small human studies suggest that choline repletion,together with curtailed ethanol or dietary LA,can reduce intrahepatic triglyceride content and improve insulin sensitivity,though large randomized trials are lacking.Framing fatty liver as nutrition-modifiable mitochondrial toxicosis highlights correctable choline insufficiency when the liver is burdened by ethanol or excess LA.A dual strategy-using higher-bioavailability,gutmicrobial trimethylamineNoxide-sparing choline forms and mitigating mitochondrial toxicants-targets core bioenergetic defects,may reverse early steatosis,and warrants testing in adequately powered clinical trials.
基金supported by the National Natural Science Foundation of China(Grant Nos. 30972811 and 81071148)Natural Science Foundation of Beijing(Grant No. 7093137)
文摘Delivering pharmacologic agents directly into the brain has been proposed as a means of bypassing the blood brain barrier.However,despite 16 years of research on a number of central nervous system disorders,an effective treatment using this strategy has only been observed in the brain tumor glioblastoma multiforme.Within this study we propose a novel system for delivering drugs into the brain named the simple diffusion (SDD) system.To validate this technique,rats were subjected to a single intracranial (at the caudate nucleus),or intraperitoneal injection,of the compound citicoline,followed two hours later by a permanent middle cerebral artery occlusion (pMCAO).Results showed that 12 h after pMCAO,with 0.0025 g kg-1 citicoline,an infarct volume 1/6 the size of the intraperitoneal group was achieved with a dose 1/800 of that required for the intraperitoneal group.These results suggest that given the appropriate injection point,through SDD a pharmacologically effective concentration of citicoline can be administered.
