Amelioration of hydrolyzed guar gum on high-fat diet-induced obesity: Integrated hepatic transcriptome and metabolome.

Hydrolyzed guar gum has gained attention as an anti-obesity agent; however, few studies have focused on its role in amelioration of hepatic-associated metabolic processes. Here, the anti-obesity effect of low molecular weight hydrolyzed guar gum (GMLP, 1-10 kDa) on high-fat diet (HFD)-fed C57BL/6 J mice was investigated via transcriptome and metabolome in liver. GMLP reduced body weight gain and hepatic lipid accumulation dose-dependently, regulated blood lipid levels, and improved liver damage in HFD-fed mice. Integrated transcriptome and metabolome indicated that GMLP mainly altered lipid metabolism pathways (glycerophospholipid metabolism, glycerolipid metabolism, and fatty acid degradation), reduced disease biomarkers of ethyl glucuronide and neopterin, and increased levels of choline, flavin adenine dinucleotide, and pantetheine metabolites. Real-time quantitative PCR showed that GMLP downregulated key genes involved in de novo lipogenesis and triacylglycerol synthesis, while promoting fatty acid oxidation and choline synthesis. This study provides a theoretical basis for GMLP treatment in future clinical applications.

Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid.

The incidence of neurodegenerative diseases has increased greatly worldwide due to the rise in life expectancy. In spite of notable development in the understanding of these disorders, there has been limited success in the development of neuroprotective agents that can slow the progression of the disease and prevent neuronal death. Some natural products and molecules are very promising neuroprotective agents because of their structural diversity and wide variety of biological activities. In addition to their neuroprotective effect, they are known for their antioxidant, anti-inflammatory and antiapoptotic effects and often serve as a starting point for drug discovery. In this review, the following natural molecules are discussed: firstly, kynurenic acid, the main neuroprotective agent formed via the kynurenine pathway of tryptophan metabolism, as it is known mainly for its role in glutamate excitotoxicity, secondly, the dietary supplement pantethine, that is many sided, well tolerated and safe, and the third molecule, α-lipoic acid is a universal antioxidant. As a conclusion, because of their beneficial properties, these molecules are potential candidates for neuroprotective therapies suitable in managing neurodegenerative diseases.

Pilot trial on the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration: a single-arm, open-label study.

OBJECTIVE: This study aimed to explore the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration (PKAN). METHODS: A single-arm, open-label study was conducted. All subjects received pantethine during the 24-week period of treatment. The primary endpoints were change of the Unified Parkinson's Disease Rating Scale (UPDRS) I-III and Fahn-Marsden (FM) score from baseline to week 24 after treatment. RESULTS: Fifteen children with PKAN were enrolled, and all patients completed the study. After 24 weeks of treatment with pantethine at 60 mg/kg per day, there was no difference in either UPDRS I-III (t = 0.516, P = 0.614) or FM score (t = 0.353, P = 0.729) between the baseline and W24. Whereas the rates of increase in UPDRS I-III (Z = 2.614, p = 0.009) and FM scores (Z = 2.643, p = 0.008) were slowed. Four patients (26.7%) were evaluated as "slightly improved" by doctors through blinded video assessment. Patients with lower baseline UPDRS I-III or FM scores were more likely to be improved. The quality of life of family members improved after pantethine treatment, evaluated by PedsQL TM 2.0 FIM scores, whereas the quality of life of the patients was unchanged at W24, evaluated by PedsQL TM 4.0 and PedsQL TM 3.0 NMM. Serum level of CoA was comparable between baseline and W24. There was no drug related adverse event during the study. CONCLUSIONS: Pantethine could not significantly improve motor function in children with PKAN after 24 weeks treatment, but it may delay the progression of motor dysfunction in our study. Pantethine was well-tolerated at 60 mg/kg per day. TRIAL REGISTRATION: Clinical trial registration number at www.chictr.org.cn :ChiCTR1900021076, Registered 27 January2019, the first participant was enrolled 30 September 2018, and other 14 participants were enrolled after the trial was registered.

Galactooligosaccharides protects against DSS-induced murine colitis through regulating intestinal flora and inhibiting NF-κB pathway.

BACKGROUND/AIMS: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism. MAIN METHODS: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot. KEY FINDINGS: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways. SIGNIFICANCE: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.

4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN.

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4'-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4'-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4'-phosphopantetheine as a candidate therapeutic for PKAN.

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine.

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1ß). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-ß (Aß) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aß peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Efficacy and tolerability of coenzyme A vs pantethine for the treatment of patients with hyperlipidemia: A randomized, double-blind, multicenter study.

BACKGROUND: New, safer, and more effective agents to treat hyperlipidemia and thereby prevent cardiovascular events are under research. OBJECTIVE: To evaluate the lipid-lowering effects and safety of a natural hypolipidemic compound, coenzyme A (CoA) capsule, in Chinese patients with moderate dyslipidemia, compared with pantethine. METHODS: Overall, 216 subjects (124 males and 92 females; age, 18-75 years) with moderate dyslipidemia (triglyceride [TG], 2.3-6.5 mmol/L) were randomly divided into 2 groups administered CoA 400 U/d (n = 111) or pantethine 600 U/d (n = 105). Blood lipoproteins, liver and renal function, blood glucose, and complete blood count were measured at baseline and after 4- and 8-week treatment. RESULTS: TG reduction was 26.0% with CoA and 17.4% with pantethine after 4 weeks and 33.3% and 16.5% after 8 weeks; compared with baseline, the reduction was significant (P < .01) in both groups. The difference between the 2 groups was significant at both 4 weeks (P = .0413) and 8 weeks (P < .001). Compared with baseline, total cholesterol and non-high-density lipoprotein cholesterol (non-HDL-C) were reduced, whereas HDL-C was increased with CoA after 8 weeks (all P < .05). Compared with pantethine, total cholesterol (P = .026) and non-HDL-C (P = .005) were significantly reduced after 8 weeks of CoA treatment. There was no statistical difference in low-density lipoprotein cholesterol or HDL-C between the 2 groups (P > .05) and no difference in blood glucose, hepatic or renal function, myopathy, or gastrointestinal tract symptoms. CONCLUSIONS: CoA can improve TG and other lipoprotein parameters to a greater extent than pantethine in moderate dyslipidemia, with no obvious adverse effects.

Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding.

OBJECTIVE: Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc. METHODS: First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage. RESULTS: In vitro, pantethine inhibited MP shedding from tumor necrosis factor-stimulated ECs and abrogated MP-induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1. CONCLUSION: Pantethine is a well-tolerated molecule that represents a potential treatment of human SSc.

Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.

High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to 16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines.

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.

Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.

Pantethine, a derivative of vitamin B(5) used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderate-cardiovascular risk North American subjects: a triple-blinded placebo and diet-controlled investigation.

Safety and efficacy of a biologically active derivative of vitamin B(5) (pantethine) on total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) metabolism was studied in North American subjects at conventional low to moderate cardiovascular disease (CVD) risk. A total of 120 subjects initiated a therapeutic lifestyle change (TLC) diet 4 weeks before randomization (baseline) and maintained the diet throughout a 16-week study period; at baseline, subjects were randomized in a triple-blinded manner to either pantethine (600 mg/d, baseline to week 8, and 900 mg/d, weeks 9-16) or identically labeled, nonbiologically active placebo (n = 60 per group). We hypothesized that pantethine would lower TC and low-density lipoprotein in low-CVD-risk North American subjects in a similar manner as reported in high-CVD-risk subjects studied mainly in Italy and Japan. While sustaining a TLC diet and in comparison with placebo, pantethine demonstrated significant (P < .005) and sustained reductions (from baseline to week 16) in TC (6 mg/dL, 0.16 mmol/L, 3%), LDL-C (4 mg/dL, 0.10 mmol/L, 4%), and apolipoprotein B (4 mg/dL, 0.04 g/L, 5%). Our data suggest that pantethine supplementation for 16 weeks (600 mg/d for weeks 1-8 then 900 mg/d for weeks 9-16) is safe and significantly lowers TC and LDL-C over and above the effect of TLC diet alone. Although the absolute magnitude of these effects was small in these low- to moderate-risk North Americans (4-6 mg/dL), the results are noteworthy as prior studies have shown that, for each 1 mg/dL (0.026 mmol/L) reduction in LDL-C, there is a concomitant 1% reduction in overall future CVD risk.

Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.

BACKGROUND: The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. RESULTS: We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals. CONCLUSIONS: These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.

Current medical aspects of pantethine.

Pantethine, the stable disulfide form of pantetheine, is the major precursor of coenzyme A, which plays a central role in the metabolism of lipids and carbohydrates. Coenzyme A is a cofactor in over 70 enzymatic pathways, including fatty acid oxidation, carbohydrate metabolism, pyruvate degradation, amino acid catabolism, haem synthesis, acetylcholine synthesis, phase II detoxification, acetylation, etc. Pantethine has beneficial effects in vascular disease, it able to decrease the hyperlipidaemia, moderate the platelet function and prevent the lipid-peroxidation. Moreover its neuro-endocrinological regulating role, its good influence on cataract and cystinosis are also proved. This molecule is a well-tolerated therapeutic agent; the frequency of its side-effect is very low and mild. Based on these preclinical and clinical data, it could be recommended using this compound as adjuvant therapy.

Dietary and nutraceutical options for managing the hypertriglyceridemic patient.

Scientific evidence continues to accumulate regarding fasting serum triglycerides as an independent risk factor for coronary heart disease. In response, the National Cholesterol Education Program has revised the acceptable level of fasting triglycerides from <200 mg/dL to <150 mg/dL. A significant percentage of Americans suffer from hypertriglyceridemia, and considering the expanding numbers of individuals who are physically inactive, overweight, and suffering from the metabolic syndrome, it is expected that these numbers will continue to rise over the next decade. Fortunately, nutraceutical and lifestyle options have been shown to substantially and consistently reduce this risk factor. This review will focus on management options for the hypertriglyceridemic patient with an emphasis on nicotinic acid, pantethine, fish oils (eicosapentaenoic and docosahexaenoic acids), and modified carbohydrate diets.

Can drugs or micronutrients prevent cataract?

Cataract is the major cause of blindness and of visual impairment worldwide, so its prevention is of the greatest importance. At present no drug therapy is licensed for use in the UK or the US, so the only treatment for cataract is by surgery, which is expensive and has adverse effects. This article reviews research on prevention of cataract by a variety of agents, including micronutrients as well as drugs. Benefits have been claimed for many compounds or mixtures and this review concentrates on those most extensively studied. Information on possible benefits of putative anticataract agents comes from a variety of approaches, from laboratory experiments, both in vitro and in vivo, to epidemiological studies in patients. Sorbitol-lowering drugs were the first to be examined systematically and progressed to clinical trials which were disappointing, and now the entire rationale for their use in prevention of cataract is questionable. Micronutrients showed little promise in animals but came to clinical trial in patients with cataract without the publication of any major benefit. Pantethine showed more promise in animal studies but the only clinical trial was abandoned early. A variety of laboratory and epidemiological evidence supports the benefits of aspirin-like drugs but there has been no trial specifically in patients with cataract. Add-on studies to trials of aspirin for other indications have not been encouraging. Research into other compounds is interesting but less advanced.

The effects of pantethine on fatty liver and fat distribution.

Although the prognosis of fatty liver depends on its causes, we feel from our clinical experience that fatty liver with hypertriglyceridemia has a good prognosis and responds well to treatment. In this study, 600 mg/day of pantethine was administered to 16 outpatients with fatty liver and hypertriglyceridemia for six months or longer to examine whether the drug improved fatty liver using abdominal plain computed tomography (CT). Nine of the 16-pantethine patients were no longer diagnosed as having fatty liver after the study period. An chi2 test indicated the significant disappearance of fatty liver. At the same time, the visceral fat calculated from the CT image passing the umbilical region was also significantly reduced. On the contrary, the subcutaneous fat area tended to increase, so the ratio of the visceral-to-subcutaneous fat area was reduced significantly. This indicates triglycerides may be pooled in the body as hepato-visceral fat and subcutaneous fat, and that pantethine may transfer fat from the liver and viscera to the subcutaneous tissue. This suggests that visceral fat deposition and fatty liver occurring with hypertriglyceridemia may have a common basis, probably excessive matrixes, and that pantethine may simultaneously improve the two conditions.

Effects of antihyperlipidemic drugs and diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia.

We compared the efficacy of two antihyperlipidemic drugs and the efficacy of diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia. The study included 48 patients with moderate hypercholesterolemia (serum total cholesterol [TC], 250 to 320 mg/dL). Patients were divided into three groups: group A--patients administered 10 mg/d of pravastatin; group B--patients administered 500 mg/d of probucol and 600 mg/d of pantethine; and group C--patients administered diet plus exercise therapy. The serum TC and serum high-density lipoprotein cholesterol (HDL-C) values were determined via enzymatic methods before initiation of each therapy and after 4 and 8 weeks of therapy. An atherogenic index (AI) was also calculated. The results indicated that TC showed a statistically significant decrease in all three groups at 4 and 8 weeks (P < 0.001 and P < 0.05, respectively); the HDL-C value did not change significantly in groups A and C, but it had a statistically significant decrease in group B at 4 and 8 weeks. The AI showed a statistically significant decrease in group A at 4 and 8 weeks of treatment and group C at 8 weeks; there were no significant changes in AI in group B. It may be concluded that as an antihyperlipidemic agent, pravastatin is more useful than probucol and that appropriate exercise and strict dietary management for 8 weeks achieve an efficacy close to that achieved by drug therapy.

Effect of selected anti-cataract agents on opacification in the selenite cataract model.

A systematic study of the anti-cataract activity of 14 reagents was conducted using the selenite model. The reagents or their derivatives were identified from literature reports of their potential effectiveness against cataract formation. The effects of each reagent were measured on the phase separation temperature, Tc, of lens homogenate in vitro. Tc is a direct measure of molecular interactions leading to protein aggregation. The protective effect of a single subcutaneous injection of each reagent [at a dose of 1.5 mmol (kg body weight)-1] on lens opacification was evaluated in vivo using rats administered selenite [at a dose of 19 mumol (kg body weight)-1] to initiate cataract formation. The strongest effects on lens opacification in vivo were observed with reagents having the strongest effect on Tc, in vitro. The weakest effects in vivo were observed with the reagents having the weakest effect on Tc, in vitro. The results were suggestive of a relationship between the effect of a reagent on Tc and protection against cataract formation in vivo.