Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies: incidence using different testing criteria, and case series.

OBJECTIVES: To estimate the incidence of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies utilising different testing criteria, and review the clinical details of a series of patients with associated autoimmune myopathy. METHODS: The incidence of anti-HMGCR antibodies in 2019 from 3 groups, South West London, Berkshire/Surrey and Southampton, were compared in the adult population. Anti-HMGCR antibodies were measured by commercial chemiluminescent and immunodot assays. The case notes of patients with anti-HMGCR antibodies were reviewed for the case series. RESULTS: The estimated incidence of anti-HMGCR antibodies in the first 2 groups was 1.94 per million adults per year, and in the third group 10.3 per million adults per year. In the first 2 groups the test criteria restricted analysis to specific clinician request for anti-HMGCR. In the third group test criteria included cases with less specific clinical features or a cytoplasmic indirect immunofluorescence anti-nuclear antibody pattern. The latter strategy had a positive predictive value of 66.1% for anti-HMGCR associated myopathy. A case series of 27 patients with anti-HMGCR antibodies revealed 19 with myopathy, oesophageal involvement in 26% and median peak CK 8000 IU/L. Response to treatment, including intravenous immunoglobulin, was good with CK normalising after median 5.5 months. In 8 cases there was no evidence of autoimmune muscle disease, 7 not statin exposed. CONCLUSIONS: Varying criteria result in a 5-fold difference in estimated incidence of anti-HMGCR antibodies, revealing positive cases without evidence of myopathy. Patients with anti-HMGCR myopathy respond well to immune suppression, supporting wider testing for these antibodies amongst patients with myopathy.

A Child with Refractory and Relapsing Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Myopathy: Case-Based Review.

BACKGROUND/OBJECTIVE: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy is rare in children. Here, we present a boy with relapsing refractory anti-HMGCR myopathy along with a systematic literature review. CASE REPORT: 17-year-old boy with five years of muscle weakness, rash, high creatinine kinase (CK) levels, and muscle biopsy compatible with inflammatory myopathy was diagnosed with juvenile dermatomyositis. He was treated with corticosteroids, intravenous immunoglobulin (IVIG), and methotrexate. His muscle weakness improved with this treatment although never completely resolved. CK levels decreased from ∼15000 U/L to ∼3000 U/L. At the age of 15, muscle weakness relapsed after an upper respiratory tract infection; pulse corticosteroid treatment was administered. The re-evaluated muscle biopsy showed a necrotizing pattern and the HMGCR antibody was positive confirming anti-HMGCR myopathy when he was 16. The diagnostic delay was 50 months. Disease activity was monitored by Medical Research Council score, MRI and functional tests. Despite corticosteroids, methotrexate, IVIG, cyclosporine A, and rituximab therapies, muscle weakness improved only slightly during the first three months and remained stable afterwards.Results of the Literature Search:We identified 16 articles describing 50 children (76% female) with anti-HMGCR myopathy by reviewing the English literature up to March 1st, 2022. Proximal muscle weakness was the most common clinical symptom (70.8%). Corticosteroids (84.8%), IVIG (58.7%), and methotrexate (56.5%) were preferred in most cases. Complete remission was achieved in nine patients (28.1%). CONCLUSION: Diagnosis and management of children with anti-HMGCR myopathy are challenging. Complete remission is achieved in only one third of these patients. Imaging biomarkers may aid treatment.

Network pharmacology combined with metabolomics reveals the mechanism of Fuzi decoction against chronic heart failure in rats.

Chronic heart failure (CHF) is the end stage of many severe heart diseases. Fuzi decoction (FZD) originates from Zhang Zhongjing's Treatise on Febrile Diseases and is widely used in the treatment of CHF in the clinic, but the potential mechanism of FZD in CHF is unclear. In this study, an integrated approach combining network pharmacology and metabolomics was adopted to explore the mechanism of FZD in CHF. Network pharmacological studies indicated that the most significant signaling pathway was the HIF-1 signaling pathway. Untargeted metabolomics indicated abnormalities in serum metabolism in CHF rats, and FZD treatment significantly improved the metabolic abnormalities and altered the levels of 30 metabolites. A pathway enrichment analysis showed that FZD was mainly involved in glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, ß-alanine metabolism, pantothenate and CoA biosynthesis, glyoxylate and dicarboxylate metabolism and other metabolic pathways. A correlation analysis showed that pyruvate and lactate were strongly correlated with the heart failure index, and a targeted metabolomics study showed that FZD restored the balance of the pyruvate-lactate axis that was disrupted due to CHF. Therefore, the mechanism of FZD against CHF may be related to regulate HIF-1 signaling pathway, pyruvate-lactate axis and glycine, serine and threonine metabolism.

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling.

The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.

Dihydromyricetin Attenuates Cerebral Ischemia Reperfusion Injury by Inhibiting SPHK1/mTOR Signaling and Targeting Ferroptosis.

Background: Dihydromyricetin (DHM) exerts protective effects in various brain diseases. The aim of this research was to investigate the biological role of DHM in cerebral ischemia reperfusion (I/R) injury. Methods: We generated a rat model of cerebral I/R injury by performing middle cerebral artery occlusion/reperfusion (MCAO/R). The neurological score and brain water content of the experimental rats was then evaluated. The infarct volume and extent of apoptosis in brain tissues was then assessed by 2,3,5-triphenyltetrazolium (TTC) and TdT-mediated dUTP nick end labeling (TUNEL) staining. Hippocampal neuronal cells (HT22) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) and cell counting kit-8 (CCK-8) assays and flow cytometry were performed to detect cell viability and apoptosis. The levels of lipid reactive oxygen species (ROS) and iron were detected and the expression levels of key proteins were assessed by Western blotting. Results: DHM obviously reduced neurological deficits, brain water content, infarct volume and cell apoptosis in the brain tissues of MCAO/R rats. DHM repressed ferroptosis and inhibited the sphingosine kinase 1 (SPHK1)/mammalian target of rapamycin (mTOR) pathway in MCAO/R rats. In addition, DHM promoted cell viability and repressed apoptosis in OGD/R-treated HT22 cells. DHM also suppressed the levels of lipid ROS and intracellular iron in OGD/R-treated HT22 cells. The expression levels of glutathione peroxidase 4 (GPX4) was enhanced while the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) and phosphatidylethanolamine binding protein 1 (PEBP1) were reduced in OGD/R-treated HT22 cells in the presence of DHM. Moreover, the influence conferred by DHM was abrogated by the overexpression of SPHK1 or treatment with MHY1485 (an activator of mTOR). Conclusion: This research demonstrated that DHM repressed ferroptosis by inhibiting the SPHK1/mTOR signaling pathway, thereby alleviating cerebral I/R injury. Our findings suggest that DHM may be a candidate drug for cerebral I/R injury treatment.

Selenium and vitamin B6 cosupplementation improves dyslipidemia and fatty liver syndrome by SIRT1/SREBP-1c pathway in hyperlipidemic Sprague-Dawley rats induced by high-fat diet.

Previously, our group found that the dietary trace mineral element selenium and vitamin B6 (VitB6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1, increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element-binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation.

Influenza infection elicits an expansion of gut population of endogenous Bifidobacterium animalis which protects mice against infection.

BACKGROUND: Influenza is a severe respiratory illness that continually threatens global health. It has been widely known that gut microbiota modulates the host response to protect against influenza infection, but mechanistic details remain largely unknown. Here, we took advantage of the phenomenon of lethal dose 50 (LD50) and metagenomic sequencing analysis to identify specific anti-influenza gut microbes and analyze the underlying mechanism. RESULTS: Transferring fecal microbes from mice that survive virulent influenza H7N9 infection into antibiotic-treated mice confers resistance to infection. Some gut microbes exhibit differential features to lethal influenza infection depending on the infection outcome. Bifidobacterium pseudolongum and Bifidobacterium animalis levels are significantly elevated in surviving mice when compared to dead or mock-infected mice. Oral administration of B. animalis alone or the combination of both significantly reduces the severity of H7N9 infection in both antibiotic-treated and germ-free mice. Functional metagenomic analysis suggests that B. animalis mediates the anti-influenza effect via several specific metabolic molecules. In vivo tests confirm valine and coenzyme A produce an anti-influenza effect. CONCLUSIONS: These findings show that the severity of influenza infection is closely related to the heterogeneous responses of the gut microbiota. We demonstrate the anti-influenza effect of B. animalis, and also find that the gut population of endogenous B. animalis can expand to enhance host influenza resistance when lethal influenza infection occurs, representing a novel interaction between host and gut microbiota. Further, our data suggest the potential utility of Bifidobacterium in the prevention and as a prognostic predictor of influenza.

Efficacy and safety of coenzyme A versus fenofibrate in patients with hyperlipidemia: a multicenter, double-blind, double-mimic, randomized clinical trial.

Background: We investigated the lipid-lowering efficacy and safety of coenzyme A (CoA) versus fenofibrate in Chinese patients with moderate dyslipidemia.Methods: A total of 417 subjects (aged 18-75 years) diagnosed with moderate dyslipidemia (triglyceride 2.3-6.5 mmol/L) from 13 large cardiovascular centers in China were recruited and randomly divided into a fenofibrate group (n = 207), which received 200 mg of fenofibrate orally once daily, and a CoA group (n = 210), which received 400 mg of CoA orally once a day. Blood lipoproteins, liver and renal function, creatine kinase, and blood glucose were measured at baseline, and after 4 and 8 weeks of treatment.Results: The baseline triglyceride (TG) level in the fenofibrate group and the CoA group was 3.39 ± 0.99 mmol/L and 3.60 ± 1.11 mmol/L, respectively. After treatment for 4 and 8 weeks with fenofibrate, TG was reduced by 31.62% and 33.13%. In the CoA group, TG was reduced by 17.29% and 23.80%. Compared with baseline, total cholesterol (TC) was significantly decreased in both groups after either 4 or 8 weeks of treatment (p < .05). CoA increased high-density lipoprotein cholesterol (HDL-C) after 4 weeks of treatment, whereas it had no significant effect on HDL-C after 8 weeks of treatment. Low-density lipoprotein cholesterol (LDL-C) was not modified in either group. The incidence of side effects was significantly lower in the CoA group compared with the fenofibrate group (p < .05).Conclusions: Compared with fenofibrate, CoA has less effect on reducing plasma TG levels in subjects with moderate dyslipidemia. However, it has fewer adverse effects.

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.

[Clinical trial of coenzyme A in hepatopathies]. / Spermintazione clinica del coenzima A in corso di epatopatie

Coenzyme A (900 L.U. i.v.) was administered for 20 days in 18 cases of viral hepatitis, 2 of chronic ethylic hepatosis, and 5 of ascitic portal cirrhosis. Blood lactic acid, pyruvic acid, serum transaminase and beta/alpha lipoprotein ratio were determined. BSF and colloidal serolability tests were also carried out. The benefits of coenzyme A treatment were particularly indicated by the significant changes noted in lactic and pyruvic acid values.

Coenzyme A and hyperlipoproteinaemias.

Coenzyme A (CoA) exerts a favourable effect in lowering plasma lipids in patients with primary hyperlipoproteinaemias of phenotype IV (hypertriglyceridaemia) and of phenotype IIb (combined hyperlipidaemia). The mechanism by which CoA influences plasma lipids may be associated with the well-known role of this coenzyme in the catalysis of acylation reactions and in the control of lipid metabolism. The administration of CoA in animals fed on hyperlipidaemic diets reduces plasma lipid levels and causes a reduction of the hepatic concentrations of triglycerides and/or lipids. Mitochondria and peroxisomes isolated from liver of rats fed on a hyperlipidaemic diet and treated with CoA present an increased oxidation of palmitate. These results suggest that the primary effect of CoA is to increase fatty-acid oxidation in the liver that results in a decrease in endogenous synthesis of triglycerides as well as a reduced formation of VLDL and probably of cholesterol. The stimulation of fatty-acid oxidation in extrahepatic tissues may be also responsible for an increased catabolism of VLDL.

[Modification of the level of adenosine triphosphate in digital pulp capillary blood in patients with microcirculatory disorders following i.v. injection of coenzyme A (CoA 1000)]. / Modification du taux d'adénosine tri-phosphate (ATP) dans le sang capillaire prélevé au niveau de la pulpe digitale, dans les troubles de la microcirculation, après injection i.v. de coenzyme A (CoA 1000).

Capillary blood ATP assay was performed in 2 groups of patients (diabetic and non-diabetic) with disorders of microcirculation, before and several minutes after 2 mg I.V. of Coenzyme A (CoA 1000). Values obtained showed a significant increase in both groups. The hypothesis advanced, based on previous experimental data indicating an action of CoA on intracellular calcium movement, is that CoA 1000 acts by elevation of the membrane ATP/Ca+ ratio of red corpuscles, and possible activation of their deformability and flow rate in the microcirculation.

[An experimental study on the treatment of fetal rabbits with intrauterine growth retardation].

OBJECTIVE: To investigate the effect of histocyte activators and vasodilators on the amino acids concentration in fetal rabbits with intrauterine growth retardation (IUGR). METHODS: The rabbits with IUGR were caused by passive smoking and treated with histocyte activators (adenosine triphosphatase, coenzyme A, cytochrome C, and vasodilators (injectio salviac molfiorrhizae composita, anisodamine). The effects of different remedies on the fetal plasma amino acids' concentration and the fetal development (i.e. birth weight, the weights of fetal liver and fetal brain) were studied. RESULTS: Both histocyte activators and vasodilators had favorable effects on the improvement of fetal development and the increase of fetal plasma amino acids' concentration. But the action of histocyte activators was stronger than vasodilators. CONCLUSIONS: The results suggested that vasodilators could improve the uterine-placental flow, and histocyte activators could enhance placental transfer of amino acids. But histocyte activators seem to be better than vasodilators.

[Clinical study on Shuanghuanglian powder in treating children viral myocarditis].

OBJECTIVE: To study immune function of children viral myocarditis and to evaluate the clinical effect of Shuanghuanglian Powder (SHLP). METHODS: The authors determined serum COXB-IgM and the numbers of lymphocyte subsets CD3+, CD4+, CD8+, CD4+/CD8+ with viral myocarditis patients by ELISA and indirect immunofluorescent assay. Sixty-two cases were divided randomly into two groups. Thirty-two cases treated by conventional therapy with SHLP and the other 30 cases treated with conventional therapy alone were taken as control group. RESULTS: COXB-IgM was positive in 39 of 62 patients, which were significantly different with those of normal controls (P < 0.001). In addition, the level of CD4+ cells and the ratio of CD4+/CD8+ were decreased while CD8+ increased. After treatment with SHLP, the recovery of symptoms, signs and immune function in patients were better than that of controls. These changes were significantly different (P < 0.01). CONCLUSIONS: There were disturbance of immune regulatory function with children viral myocarditis patients and SHLP is an effective drug in treating children viral myocarditis.

[Morphological and functional correlations of the protective action of coenzyme A in cisplatin ototoxicity (II)]. / Correlaciones morfofuncionales de la acción protectora del coenzima A en la ototoxia por cisplatino (II).

Earlier studies have shown that coenzyme A (CoA) protects against cisplatin (CP) induced deafness in guinea pigs. We studied the correlation between the latency of the N1 wave in electrocochleography and total loss of cilia in hair cells by scanning electron microscopy.

[The pharmacological properties of coenzyme A disulfide]. / Farmakologicheskie svoistva kofermenta A-disulfida.

Coenzyme A disulfide (CoA disulfide) was pharmacologically studied. It has been found to normalize lipid and carbohydrate metabolism when given in a dose of 2 mg/kg, i.m., in diverse liver dysfunctions. It possesses an antihypoxic action under hemic and histotoxic hypoxia. When given in small doses (80-160 micrograms/kg, i.v.), CoA disulfide depresses the function of cellular hemostasis.

The effects of coenzyme A on serum lipids in patients with hyperlipidemia: results of a multicenter clinical trial.

OBJECTIVES: The aim of the study was to evaluate the lipid-lowering effects and clinical safety of a natural hypolipidemic compound, coenzyme A (CoA) capsule, in Chinese patients with moderate dyslipidemia. METHODS: A total of 244 subjects (170 males and 74 females; aged 18-75 y) having moderate dyslipidemia (triglyceride [TG], 2.3-6.5 mmol · L(-1)) were randomly divided into 3 groups, to which placebo (group A, n = 81), CoA 200 U/d (group B, n = 79), and CoA 400 U/d (group C, n = 84) were administered, respectively. Blood lipoproteins, liver and renal functions, blood glucose, and complete blood count were measured at the baseline and after 4 or 8 weeks of treatment. RESULTS: After treatment for 4 weeks, TG was reduced by 5.1, 15.7, and 14.4% in groups A, B, and C, respectively. After treatment for 8 weeks, TG decreased .9, 21.7, and 36.1%, respectively. Compared with group A, the primary efficacy outcome TG in groups B and C significantly decreased (P < .01), and the difference between groups B and C was also significant (P < .01). Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were not significantly different. Furthermore, there was no difference in blood glucose, hepatic and renal function test parameters, incidence of myopathy, or gastrointestinal tract symptoms among the 3 groups. CONCLUSION: CoA can effectively reduce plasma TG levels in subjects with moderate dyslipidemia and has no obvious adverse effect.