Effects of L-carnitine on treatment outcomes of COVID-19 patients hospitalized in intensive care units:A double-blind randomized clinical trial

Objective:To assess the effects of L-carnitine on the outcomes of patients with moderate to severe coronavirus disease 2019(COVID-19)in intensive care unit(ICU).Methods:This double-blind clinical trial was carried out in 2022-2023.64 Patients with COVID-19 were selected from Amiralmomenin and Khansari hospitals in Arak,Iran.They were randomly assigned to the control and the L-carnitine treatment group via block randomization.Venous blood gases,disease severity,and levels of D-dimer,lactate dehydrogenase,ferritin,and C-reactive protein were daily assessed during the seven days of the intervention,and the length of ICU stay,the need for endotracheal intubation,and mortality rate were documented.Results:There were significant differences in length of ICU stay,the need for endotracheal intubation,and levels of D-dimer,lactate dehydrogenase,ferritin,APACHE栻score,and C-reactive protein between the two groups(P<0.05).However,the groups did not significantly differ in mortality rate and venous blood gas indexes(P>0.05).Conclusions:L-carnitine can improve outcomes of patients with COVID-19.Therefore,it can be used as an adjuvant therapy for these patients.

Improvement of hepatic fibrosis after tenofovir disoproxil fumarate switching to tenofovir alafenamide for three years

BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase(ALT)improvement,but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.AIM To assess the benefits of TDF switching to TAF for 3 years on ALT,aspartate aminotransferase(AST),and hepatic fibrosis improvement in patients with CHB.METHODS A single center retrospective study on 53 patients with CHB who were initially treated with TDF,then switched to TAF to determine dynamic patterns of ALT,AST,AST to platelet ratio index(APRI),fibrosis-4(FIB-4)scores,and shear wave elastography(SWE)reading improvement at switching week 144,and the associated factors.RESULTS The mean age was 55(28-80);45.3%,males;15.1%,clinical cirrhosis;mean baseline ALT,24.8;AST,25.7 U/L;APRI,0.37;and FIB-4,1.66.After 144 weeks TDF switching to TAF,mean ALT and AST were reduced to 19.7 and 21,respectively.From baseline to switching week 144,the rates of ALT and AST<35(male)/25(female)and<30(male)/19(female)were persistently increased;hepatic fibrosis was also improved by APRI<0.5,from 79.2%to 96.2%;FIB-4<1.45,from 52.8%to 58.5%,respectively;mean APRI was reduced to 0.27;FIB-4,to 1.38;and mean SWE reading,from 7.05 to 6.30 kPa after a mean of 109 weeks switching.The renal function was stable and the frequency of patients with glomerular filtration rate>60 mL/min was increased from 86.5%at baseline to 88.2%at switching week 144.CONCLUSION Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement,but also hepatic fibrosis improvement by APRI,FIB-4 scores,as well as SWE reading,the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Metabolic rewiring underlies the effector functions of macrophages1-3,but the mechanisms involved remain incompletely defined.Here,using unbiased metabolomics and stable isotope-assisted tracing,we show that an inflammatory aspartate argininosuccinate shunt is induced following lipopolysaccharide stimulation.The shunt,supported by increased argininosuccinate synthase(ASS1)expression,also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination.Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase(FH)further increases intracellular fumarate levels.

Progress in the Study of Vonoprazan Fumarate vs. Proton Pump Inhibitors in the Treatment of Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disease, and proton pump inhibitors (PPIs) have been recommended as the first-line treatment for GERD. In recent years, studies on vonoprazan fumarate in the treatment of GERD have attracted widespread attention. In this paper, we review the research progress of vonoprazan fumarate and proton pump inhibitors in the treatment of GERD in recent years, and compare and analyze the efficacy, safety, tolerability, and advantages and disadvantages of long-term application of both. By reviewing the relevant literature, we found that vonoprazan fumarate has similar performance with proton pump inhibitors in terms of efficacy and safety, but has potential advantages in terms of tolerability and long-term application. Therefore, we believe that vonoprazan fumarate may become a new option for GERD treatment, helping clinicians to develop more appropriate treatment plans for patients and providing new ideas and directions for research in related fields.

L-Carnitine拮抗培养心肌细胞缺氧/复氧损伤

目的 探讨L Carnitine对心肌细胞缺氧 /复氧损伤的防护作用及其可能的机制。方法 以原代培养新生鼠心肌细胞建立缺氧 /复氧损伤模型 ,观察不同剂量L Carnitine处理后细胞增殖活性、凋亡细胞百分率及DNA断片化率 ,作为反映L Carnitine对心肌细胞缺氧 /复氧损伤防护作用及其机制的指标。结果 在 5～ 5 0 0 0nmol/L范围内 ,L Carnitine预处理对培养心肌细胞缺氧 /复氧损伤均显示保护效应 ;在 5、5 0及 5 0 0nmol/L时均显著降低DNA断片化率 ;L Carnitine在 5 0nmol/L时与单纯缺氧 /复氧组比较可显著降低凋亡细胞百分率。结论 缺氧 /复氧对心肌细胞的影响之一是可诱导心肌细胞凋亡 ;L Carnitine对培养心肌细胞培养缺氧/复氧损伤具有防护作用 ,其机制可能与抑制缺氧 /复氧诱导细胞凋亡有关。

Effects of L-carnitine on Population Growth of Nannochloropsis oculata and Tetrahymena sp.

[Objective] The aim was to study the effects of L-carnitine on population growth of Nannochloropsis oculata and Tetrahymena sp..[Method] When the concentration of L-carnitine was 0,50,100 and 1 000 mg/L,population densities of Nannochloropsis oculata and Tetrahymena were determined respectively.[Result] Adding high-dose L-carnitine had a significant inhibition effect on the population growth of Nannochloropsis oculata （P0.05）.Adding L-carnitine had a significant proliferation promoting effect on the population growth of Tetrahymena （P0.05）.[Conclusion] The research provides theoretical basis for the application of L-carnitine as feed additive in aquaculture.

The Protective Effect of L-carnitine on Ischemia-reperfusion Heart

To investigate the protective effect of L-carnitine on myocardial ischemia-reperfusion injury in rat heart,all harvested isolated hearts were perfused on Langendorff apparatus with oxygenized K-H solution for 20 min. The hearts were then exposed to ischemia for 30 min. Following the ischemia the hearts were re-perfused with K-H solution for 120 min to serve as the control group A. Either 5 or 10 mmol/L of L-carnitine was added into the K-H solution for 20 min at the beginning of reperfusion to generate group B and group C, respectively. The derivatives of the intraventricular pressure curve （DP/DT）, left ventricular developed pressure （LVDP）, and coronary flux were monitored during the entire experiment. The levels of ATP, hepatin, malondialdehyde （MDA）, and superoxide dismutase （SOD） in tissue, and lactic dehydrogenase （LDH）, creatine phosphate kinase （CPK）, malondialdehyde （MDA）, and superoxide dismutase （SOD） concentration in the coronary efflux were all measured. Compared with the control group, the treatment with L-carnitine resulted in better results, i. e. , higher DP/DTmax and LVDP. At the same time, ventricular fibrillation was reduced, and the levels of ATP, hepatin and SOD were all elevated. However, the concentrations of MDA, CPK and LDH were all reduced. In conclusion, L-carnitine has a protective effect on ischemia-reperfusion injury, which is partly due to its prevention of energy loss and its antioxidant activity.

Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury

To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODSRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. RESULTSHistological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. CONCLUSIONDMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-α 2b plus ribavirin

AIM：To evaluate the efficacy of L-carnitine on alleviating anemia,thrombocytopenia and leukopenia,and minimizing dose reductions in patients with chronic hepatitis C virus（HCV）in treatment with Interferonα（IFN-α）plus ribavirin.METHODS：Sixty-nine patients with chronic hepatitis C were enrolled in the study and divided into two groups.group A（n=35）received Peg-IFN-α2b plus ribavirin plus L-carnitine,and group B（n=34）received Peg-IFN-αand ribavirin for 12 mo.All patients underwent laboratory investigations including：red cell count,he-moglobin,white cell count,platelets,bilirubin,alanineaminotransferase（ALT）,aspartate aminotransferase（AST）,and viremia.RESULTS：After 12 mo in group A compared to group B we observed significant differences in AST 108.8 vs 76.8（IU/L;P0.001）,ALT 137.vs 112.3（IU/L;P 0.001）,viremia 4.04 vs 2.36（106 copies/mL;P 0.001）,Hb 1 vs 3.5（g/dL;P0.05）,red blood cells 0.3 vs 1.1（1012/L;P0.001）,white blood cells 1.5 vs 3（10/L;P0.001）and platelets 86 vs 85（×10/L;P0.001）.The end treatment responders were 18 vs 12（60%vs 44%）and the non responders were 12 vs 15（40%vs 50%）[odds ratio（OR）1.65,5%CI =0.65-5.37,P0.05.In group A compared to group B there was a significant improvement of sustained vi-rological response in 15 vs 7 patients（50%vs25%）,while the relapsers were 3 vs 5（10%vs 18%）（OR 3.57,5%CI=0.65-1.3,P0.001）.CONCLUSION：L-carnitine supplementations modulate erythropoiesis,leucopoiesis and thrombocytopoiesis,and may be useful in patients treated for HCV.L-carni-tine treatment offers the possibility of achieving a sus-tained virological response while preventing overtreat-ment.

Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis

AIM: To investigate the beneficial effect of the combination of butyrate, Lactobacillus casei, and L-carnitine in a rat colitis model.

Development and validation of a UPLC–MS/MS assay for the determination of gemcitabine and its L-carnitine ester derivative in rat plasma and its application in oral pharmacokinetics

A simple and rapid UPLC–MS/MS method to simultaneously determine gemcitabine and its L-carnitine ester derivative(2’-deoxy-2’, 2’-difluoro-N-((4-amino-4-oxobutanoyl) oxy)-4-(trimethyl amm-onio) butanoate-cytidine, JDR) in rat plasma was developed and validated.The conventional plasma sample preparation method of nucleoside analogues is solidphase extraction(SPE) which is time-consuming and cost-expensive. In this study, gradient elution with small particles size solid phase was applied to effectively separate gemcitabine and JDR, and protein precipitation pretreatment was adopted to remove plasma protein and extract the analytes with high recovery(>81%). Method validation was performed as per the FDA guidelines, and the standard curves were found to be linear in the range of 5–4000 ng/ml for JDR and 4–4000 ng/ml for gemcitabine, respectively. The lower limit of quantitation(LLOQ)of gemcitabine and JDR was 4 and 5 ng/ml, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limits. Finally, the developed method was successfully applied to investigate the pharmacokinetic studies of JDR and gemcitabine after oral administration to rats.

Enantiomeric Resolution on L-Carnitine Selective Polymers Prepared by Molecular Imprinting

L-carnitine selective polymers were prepared by molecular imprinting using methacrylic acid as the functional monomer. The acid function of the monomer is expected to form hydrogen bond and ionic interactions with the amine function of the target molecule L-carnitine. The imprinted polymers were used as stationary phases in high-performance liquid chromatography (HPLC). It was shown that L-carnitine imprinted polymer exhibited a higher affinity to its template molecule, while the non-imprinted polymer had no affinity to the compounds tested. Racemic carnitine hydrochloride was efficiently resolved on the L-carnitine imprinted polymer, and the separation factor is 1.9.

L-carnitine alleviates sciatic nerve crush injury in rats:functional and electron microscopy assessments

Several studies have demonstrated that L-carnitine exhibits neuroprotective effects on injured sciatic nerve of rats with diabetes mellitus. It is hypothesized that L-carnitine exhibits neuro-protective effects on injured sciatic nerve of rats. Rat sciatic nerve was crush injured by a forceps and exhibited degenerative changes. After intragastric administration of 50 and 100 mg/kg L-carnitine for 30 days, axon area, myelin sheath area, axon diameter, myelin sheath diameter, and numerical density of the myelinated axons of injured sciatic nerve were similar to normal, and the function of injured sciatic nerve also improved signiifcantly. These ifndings suggest that L-carnitine exhibits neuroprotective effects on sciatic nerve crush injury in rats.

The Electrocatalytic Activity of Bare Pyrolytic Graphite and Single Wall Carbon Nanotube Modified Glassy Carbon Sensors Is Same for the Quantification of Bisoprolol Fumarate

A comparison of voltammetric behavior of bisoprolol fumarate (BF) at edge and basal plane pyrolytic graphite electrodes (EPPGE/BPPGE) has been made with single wall carbon nanotube modified glassy carbon. The electrochemical properties are investigated exercising the cyclic voltammetry and square wave voltammetry (SWV). Enhanced peak current associated with bisoprolol fumarate oxidation at EPPGE is due to its better electron transfer property. Quantification of bisoprolol fumarate was carried out at pH 7.2 at both the pyrolytic graphite electrodes. Well-defined peak has been observed at ~ 792 and 954 mV at EPPGE and BPPGE respectively for bisoprolol fumarate oxidation. The detection limit is found to be 2.8 × 10–7 M and 7.3 × 10–7 M for EPPGE and BPPGE respectively. A comparison of common quantification parameters for bisoprolol at carbon nanotube modified glassy carbon electrode and bare BPPGE and EPPGE has been made and it is observed that carbon naotube modified glassy carbon exhibits sensitivity and detection limit close to that observed at bare basal plane pyrolytic graphite electrode. The method developed is applicable for determination of bisoprolol fumarate in pharmaceutical preparations and real samples.

Effect of L-carnitine on Cardiomyocyte Apoptosis and Cardiac Function in Patients Undergoing Heart Valve Replacement Operation

Summary： The effects of L-carnitine, as an ingredient of cardioplegia solution, on cardiac function and cardiomyocyte apoptosis in patients undergoing heart valve replacement operation were investigated. Twenty-three cases undergoing heart valve replacement with cardiopulmonary bypass （CPB） were randomly allocated into two groups： L-carnitine group （n=12, 12 g/L L-carnitine was put in the ST. Thomas cardioplegia） and control group （n=11, identical to the L-carnitine group except that normal saline was administered instead of L-carnitine）. Serum cardial troponin I （cTnI） levels, the left ventricular ejection fraction （LVEF）, and cardiac index （CI） were measured perioperatively. A bit of myocardial tissue obtained from right atria was taken before CPB and by the end of intracardiac procedure to undergo electron microscopy examination and estimate apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling （TUNEL）. From the end of CPB to 3 days after operation, the serum levels of cTnI in the L-carnitine group was significantly lower than that in the control group （P〈0.05）. Heart color ultrasonogram showed that the CI index and LVEF at 7th day postoperatively in the L-carnitine group were significantly higher than in the control group （P〈0.05）. Compared to the control group, L-carnitine significantly alleviated the morphologic changes of cardiac muscle cells （electron microscopy examination） and decreased the amounts of apoptotic cardiac muscle cells （TUNEL）. Furthermore, the dosage of vasoactive drugs used after operation was significantly less in the L-carnitine group （P〈0.01）. It was concluded that L-carnitine cardioplegia solution could improve cardiac function in patients undergoing heart valve replacement operation and alleviate CPB-mediated apoptosis of cardiac muscle cells.

Fumarate hydratase inactivation in renal tumors: HIF1α, NRF2, and "cryptic targets" of transcription factors

Biallelic inactivation of fumarate hydratase (FH) causes type 2 papillary renal cell carcinoma (PRCC2), uterine fibroids, and cutaneous leimyomas, a condition known as hereditary leiomyomatosis and renal cell cancer (HLRCC). The most direct effect of FH inactivation is intracellular fumarate accumulation. A majority of studies on FH inactivation over the past decade have focused on the theory that intracellular fumarate stabilizes hypoxia-inducible factor 1α (HIF1A) through competitive inhibition of HIF prolyl hydroxylases. Recently, a competing theory that intracellular fumarate activates nuclear factor (erythroid-derived 2)-like 2 (NRF2) through post-translational modification of its negative regulator. Kelch-like ECH-associated protein 1 (KEAP1) has emerged from a computational modeling study and mouse model studies. This review dissects the origin of these two governing theories and highlights the presence of chromatin-structure-regulated targets of transcription factors, which we refer to as "cryptic targets" of transcription factors. One such cryptic target is heme oxygenase I (HMOX1), the expression of which is known to be modulated by the gene product of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1).

L-carnitine supplementation in non-alcoholic fatty liver disease: A systematic review and meta-analysis

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)dominates the landscape of modern hepatology.Affecting 25%of the general population,there is critical unmet need to identify broadly available,safe and cost-effective treatments.Cumulative evidence in animal and human models suggests that intrahepatic and skeletal muscle fatty acid oxidation is impaired in NAFLD,such that lipid accretion is not matched by efficient utilisation.L-carnitine is a crucial mediator of fatty acid metabolism in vivo,promoting mitochondrial lipidβ-oxidation and enhancing tissue metabolic flexibility.These physiological properties have generated research interest in L-carnitine as a potentially effective adjunctive therapy in NAFLD.AIM To systematically review randomised trials reporting effects of dietary L-carnitine supplementation on liver biochemistry,liver fat and insulin sensitivity in NAFLD.METHODS Search strategies,eligibility criteria and analytic methods were specified a priori(PROSPERO reference:CRD42018107063).Ovid MEDLINE,Ovid EMBASE,PubMed,Web of Science and the Cochrane Library were searched from their inception until April 2019.Outcome measures included serum concentrations of alanine and aspartate aminotransferase(ALT and AST),liver fat and insulin sensitivity assessed by the homeostasis model of insulin resistance(HOMA-IR).A random effects meta-analysis was performed for,ALT,AST and HOMA-IR measures separately.Between-study heterogeneity was measured using I2 statistics.RESULTS Five eligible randomised trials were included in the qualitative and quantitative synthesis(n=338).All of the 5 included trials assessed the effect of L-carnitine on serum ALT,identified from Italy,South Korea and Iran.Weighted mean difference(WMD)for ALT between L-carnitine and control groups after intervention was-25.34 IU/L[95%CI:-41.74-(-8.94);P=0.002].WMD for AST between L-carnitine and control groups was-13.68 IU/L(95%CI:-28.26-0.89;P=0.066).In three studies(n=204),HOMA-IR was evaluated.WMD for HOMA-IR between L-carnitine and control groups was-0.74 units[95%CI:-1.02-(-0.46);P<0.001].Two studies using validated outcome measures reported a significant reduction in liver fat in L-carnitine vs control groups post-intervention(P<0.001).CONCLUSION Pooled results indicate that L-carnitine supplementation attenuates ALT,liver fat and insulin resistance in NAFLD cohorts,confirming a beneficial effect of Lcarnitine for a highly prevalent condition with a growing economic burden.

Effect of dimethyl fumarate on rats with chronic pancreatitis

Objective:To discuss the effect of dimethyl fumarate(DMF) on rats with L-arginine induced chronic pancreatitis(CP).Methods:Male Wistar rats were given DMF treatment(25 mg/kg) by oral lavage method;then Wistar rats were given the intraperitoneal injection of L-arginine for 5times(250 mg/100 kg,twice per time,each interval of 1 h) for building of CP model.Rats were divided into control group,CP group,DMF group and CP+DMF group.Rats in CP+DMF group were given the oral intragastric administration of DMF(25 mg/kg),while rats in control group and CP group were given the equal volume of normal saline.The weight of rats was evaluated and the intraperitoneal glucose tolerance test was performed(IPGTT,2 g/kg).The islet of rats was isolated and then flow cytometry was employed to evaluate the quality and activity of islets.Meanwhile,the histology of non-endocrine tissues and levels of myeloperoxidase(MPO) and malondialdchyde(MDA) were detected.Results:Compared with control group,the weight of rats in CP group was significantly reduced at week 2,4 and 6;the blood glucose significantly increased,AUC increased,the histopathological scores of pancreatic atrophy,acinar injury,edema and cellular infiltration increased,levels of MDA and MPO increased,the islet equivalent and islet activity decreased at 0.30,60,120 and 180 min.Compared with CP group,the weight of rats in CP+DMF group significantly increased at week 2,4 and 6;the blood glucose significantly decreased.AUC decreased,the histopathological scores of pancreatic atrophy,acinar injury,edema and cellular infiltration decreased,levels of MDA and MPO decreased,the islet equivalent and islet activity increased at 0,30.60,120 and 180 min.Conclusions:DMF treatment can improve CP induced by L-argininc and islet function in rats.

A Pilot Clinical Trial on L-Carnitine Supplementation in Combination with Motivation Training: Effects on Weight Management in Healthy Volunteers

A 4-week low dosage (500 mg/day) L-carnitine supplementation in combination with motivation training was carried out in 24 overweight (BMI 25.8 - 26.6 kg/m2) Japanese males in the course of a double-blind randomized placebo-controlled study. L-carnitine motivated group showed significant body weight loss and a decrement of serum triglyceride level vs. the non-motivated placebo group. Serum adiponectin levels increased in both L-carnitine supplemented groups. The beneficial effects of L-carnitine were amplified by motivation training. For clinical evaluation of supplements, whose efficacy is potentially affected by inter-individual life style variability, supportive motivation training might be advisable for future clinical trials.

国际最近确定的人体特定条件的必需营养物质左旋肉碱(L-Carnitine)简介

早在1905年,俄国二位科学家WL.Gulewitsch与R.Krimberg,首先从肌肉中发现提取了肉碱(Carnitine).1947年美国科学家Frankel研究确定肉碱属维生素B族,命名为 Vitamin BT。