Defending Antiviral Cationic Amphiphilic Drugs That May Cause Drug-Induced Phospholipidosis.

A recent publication in Science has proposed that cationic amphiphilic drugs repurposed for COVID-19 typically use phosholipidosis as their antiviral mechanism of action in cells but will have no in vivo efficacy. On the contrary, our viewpoint, supported by additional experimental data for similar cationic amphiphilic drugs, indicates that many of these molecules have both in vitro and in vivo efficacy with no reported phospholipidosis, and therefore, this class of compounds should not be avoided but further explored, as we continue the search for broad spectrum antivirals.

Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effects of age and drug were sex dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving balance/coordination on an accelerating rotarod, rotarod endurance, and grip strength test. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth-promoting pathways and increased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids - changes that have previously been associated with aging, cardiac dysfunction, and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride (TAG) accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging antiaging effects in multiple tissues, and it may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.

Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system.

BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver. OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system. ANIMALS: Liver organoids obtained from 6 cats. METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR. RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863. CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.

PPAR δ inhibition protects against palmitic acid-LPS induced lipidosis and injury in cultured hepatocyte L02 cell.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to evaluate the role of PPAR δ in LPS associated NAFLD and to investigate the signal transduction pathways underlying PPAR δ treatment in vitro. Material and Methods: L02 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of PPAR δ inhibition and/or activation. Results: LPS treatment markedly increased lipid deposition, FFA contents, IL-6 and TNF-α levels, and cell apoptosis in PA treatment (NAFLD model). PPAR δ inhibition protects L02 cells against LPS-induced lipidosis and injury. Conversely, the result of PPAR δ activation showed the reverse trend. LPS+PA treatment group significantly decreases the relative expression level of IRS-1, PI3K, AKT, phosphorylation of AKT, TLR-4, MyD88, phosphorylation of IKKα, NF-κB, Bcl-2 and increases the relative expression level of Bax, cleaved caspase 3 and cleaved caspase 8, compared with the cells treated with NAFLD model. PPAR δ inhibition upregulated the related proteins' expression level in insulin resistance and inflammation pathway and downregulated apoptotic relevant proteins. Instead, PPAR δ agonist showed the reverse trend. Conclusion: Our data show that PPAR δ inhibition reduces steatosis, inflammation and apoptosis in LPS-related NAFLD damage, in vitro. PPAR δ may be a potential therapeutic implication for NAFLD.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908.

Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.

Design, synthesis and evaluation of MCH receptor 1 antagonists--Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition.

Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.

[Multiple acyl-CoA dehydrogenase deficiency (MADD): a curable cause of genetic muscular lipidosis]. / Déficit multiple en acyl-CoA déshydrogénases : une cause traitable de lipidose musculaire d'origine génétique.

INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare genetic disease involving fatty acid oxidation. It is due to the deficiency of one of the two electron transporters: electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxydoreductase (ETF-QO). Symptoms begin more often in childhood or in young adulthood with a multisystemic disease with encephalopathy or muscular weakness. CASE REPORTS: We report here two adult cases with ETF-QO deficiency, confirmed by mutation analysis (ETFDH gene), revealed by a muscular weakness associated with muscle lipidosis. One of our patients presented an acute encephalopathy with vomiting ten years before the onset of muscular symptoms. The second patient exhibited a slowly progressive pelvic girdle muscle weakness. Diagnosis was established by characteristic abnormalities of acylcarnitine profile by tandem mass spectrometry. For both patients, a dramatic clinical improvement was observed under treatment with riboflavine and L-carnitine. CONCLUSION: Since it is a treatable disorder, this diagnosis must be considered by performing an acylcarnitine profile in all patients presenting with an unexplained muscular weakness.

Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome.

BACKGROUND AND AIM: We have previously shown that serum plasmalogen levels positively correlate with HDL, and significantly decrease with aging, and may be related to LDL particle size. The objective of the present study was to investigate the effects of increased serum plasmalogens on lipidosis, particularly the appearance of atherogenic small dense LDL (sdLDL), of subjects with hyperlipidemia and metabolic syndrome (MetS). METHODS AND RESULTS: The effects of increased serum plasmalogen levels, induced by 2 wk of myo-inositol treatment, on several clinical and biochemical parameters were examined in 17 hyperlipidemic subjects including some with MetS. After myo-inositol treatment, significant increases in plasmalogen-related parameters, particularly ChoPlas, and significant decreases in atherogenic cholesterols including sdLDL, were observed. Among the hyperlipidemic subjects treated with myo-inositol, compared to subjects without MetS, subjects with MetS had a significant increase in plasmalogens and a tendency towards reduced sdLDL, high sensitivity C-reactive protein (hsCRP), and blood glucose levels. Correlation analyses between the measured parameters showed that plasmalogens, as well as HDL, function as beneficial factors, and that sdLDL is a very important risk factor that shows positive correlations with many other risk factors. CONCLUSION: These results suggest that increased plasmalogen biosynthesis and/or serum levels are especially effective in improving MetS among hyperlipidemic subjects with MetS.

Protective effect of Chinese prescription Kangen-karyu and its crude drug Tanjin against age-related lipidosis in rats.

We have investigated the effect of the Chinese prescription Kangen-karyu and its crude drug Tanjin against age-related lipidosis in-vivo in a rat model. The serum and hepatic triglyceride levels were remarkably elevated in 12-month-old compared with two-month-old rats. However, the administration of Kangen-karyu and Tanjin extracts significantly decreased these levels. This suggested a protective role against related pathological conditions as well as hyperlipidaemia. On the other hand, the reduction of the levels of adiponectin in serum with ageing did not show significant changes in rats given diets supplemented with Kangen-karyu and Tanjin extracts. Furthermore, the expression of transcription factors in nuclear hepatic tissue related to lipid metabolism was investigated. The decline in the expression of nuclear peroxisome proliferator-activated receptor alpha protein in hepatic tissue with age was ameliorated by the administration of Kangen-karyu and Tanjin supplements. On the other hand, the overexpression of sterol regulatory element-binding proteins (SREBP)-1 and SREBP-2 in old rats compared with young rats showed a tendency to decrease with Kangen-karyu and Tanjin administration. The decline of hepatic function with ageing was attenuated by Kangen-karyu and Tanjin, suggesting the beneficial role of Kangen-karyu and Tanjin on lipid metabolism through the improvement of hepatic function. This study has demonstrated that Kangen-karyu and Tanjin inhibited the accumulation of triglyceride with regulation of related protein expressions and they improved hepatic function. Evidence has been provided for the anti-ageing activity of Kangen-karyu and its crude drug Tanjin against age-related lipidosis.

An aminomethylpyrimidine DPP-IV inhibitor with improved properties.

A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic analogues was synthesized in an effort to overcome these issues. One compound from this series was equipotent to 1, did not induce phospholipidosis and showed a reduced CYP3A4 inhibition.

[Experimental observation of antagonism of polyaspartic acid against gentamicin-induced phospholipidosis in cochlea of guinea pig].

OBJECTIVE: To observe the effect of polyaspartic acid (PAA) on gentamicin-induced disturbance of phospholipid metabolism in cochlea of Guinea pig. METHODS: Ninety-four Guinea pigs were divided into 4 groups administered with PAA, PAA + GM, GM, or normal saline respectively. Auditory brain-stem response (ABR) was recorded before and one, five and ten days after the experiment. High performance liquid chromatography (HPLC) was used to determinate the amount of phospholipid in cochlear tissue, and ultrastructural change of lysosomes in the cochlear hair cells was observed by transmission electron microscopy one, five, and ten days after the experiment. RESULTS: No difference in any indicator was found one day after the beginning of experiment in all groups. The amounts of phosphatidylinositol (PI) and phosphatidylinositol-phosphate (PIP) increased significantly five days after administration of GM (19.7 micrograms +/- 6.6 micrograms and 121 micrograms +/- 21 micrograms respectively). The amount of PIP increased significantly 10 days after administration of GM (126 micrograms +/- 8 micrograms). Transmission electron microscopy showed an increase of number and volume of lysosome in cochlear outer hair cells and appearance of Hensen's body five days after administration of GM. Such changes became more significant and some lysosomes broke in the 10th day. The ABR threshold began to increase 5 days after the administration of GM, and continued to increase with time. CONCLUSION: PAA has inhibitory effect on gentamicin-induced lysosomal phospholipidosis in cochlea of Guinea pig, thus inhibiting gentamicin-induce hearing loss.

[Studies of the clinicopathological changes of eight patients with lipid storage myopathy].

OBJECTIVE: The clinicopathological analysis of eight patients with lipid storage myopathy are presented. The pathogeny and therapeutic effect are probed into. METHODS: Eight cases of lipid storage myopathy diagnosed by muscle biopsies with microscopic and electron-microscopic examination are analyzed. Quadriceps or biceps were biopsied. Muscle samples were stained with routine histology and histochemical enzyme and inspected by microscopy. Thin sections were stained with uranyl acetate followed by lead citrate prior to examination in a electron microscopy. Also, the therapeutic drugs of eight patients were evaluated. RESULTS: Vacuole or crack of muscular fibers involved all eight patients. Sudan Black B and Oil Red O stains demonstrated increase of lipid droplets within muscle fibers. Ultrastructural examination revealed numerous lipid droplets dispersed throughout the residual myofilaments. Three cases with pathologic changed muscular fibers occupying less than 1/5 were belong to low-grade, two cases (between 1/5 to 1/3) were moderate, three cases (more than 1/2) were severe. There was one case accompanying glycogen storage disease. One case was concomitant with deficiency of cytochrome C oxidase. After prednisone treatment, seven cases had greatly improved and one case failed to respond to. Treatment using vitamin B(2) together with other vitamins brought about a striking effect. Carnitine was very effective on the patients with system deficiency of carnitine. CONCLUSIONS: The pathogeny of lipid storage myopathy is varied. The confirmed diagnosis is depend on pathological features of muscle biopsy. Treatment with prednisone, carnitine, vitamins and food containing carnitine rich is very effective. It should be select the special treatment method if the pathogeny is clear.

[Lipid storage myopathy. Report of 2 cases].

This paper reports two cases of lipid storage myopathy. Light microscopic studies of muscle biopsy materials showed excessive amounts of neutral fatty droplets under oil red O staining. Electron-microscopic studies showed that the fatty droplets were situated in the myofibrils, under the sarcolemma or even in lines. Symptoms of the patients were improved after treatment with prednisone. The clinical, pathological and electromyographic characteristics of both types (I and II) of lipid storage myopathy are reviewed.

Remarkable response of lipoid proteinosis to oral dimethyl sulphoxide.

We report the successful treatment of lipoid proteinosis in a 41-year-old man using oral dimethyl sulphoxide. The initial dosage was 40 mg/kg/day, which was then increased progressively to 60 mg/kg/day. After 3 years of treatment, the patient's skin lesions, hoarseness of voice and abnormal oesophageal function improved remarkably. No side-effects were noted except for a garlic-like smell on the patient's breath.

[Effect of 17 alpha-ethinyl estradiol on the blood serum lipid indices of rats]. / Vliianie 17 al'fa-étiniléstradiola na lipidnye pokazateli syvorotki krovi krys.

The administration of 17-ethinyl estradiol (0.25 mg/kg) to male Wistar rats caused on the 3rd day a decrease of the levels of free and esterified cholesterol, blood serum triglycerides and also a reduction of the content of esterified cholesterol with respect to total cholesterol while the lecithin-cholesterol-acyltransferase activity appeared to be unchanged. The effect of ethinyl estradiol on blood lipid parameters against the background of lipemia induced by triton WR 1339 was reduced.

Successful carnitine treatment in two siblings having lipid storage myopathy with hypertrophic cardiomyopathy.

Two Japanese siblings had lipid storage myopathy with hypertrophic cardiomyopathy (HCM). They had slowly progressive muscle weakness and ventricular hypertrophy of the heart evidenced by electrocardiography and echocardiography. Their developmental milestones were normal until three years of age when mild weakness in the lower limbs became evident. Laboratory examination showed transient high creatine kinase levels (CK) and hyperammonemia. Histochemical investigation on the muscles revealed abnormal accumulation of sudanophilic lipid droplets predominantly in type 1 fibers, type 2 A fiber atrophy and type 2 B fiber deficiency. In case 1, excessive lipid droplets were also observed in the biopsied cardiac muscle. Carnitine was decreased in the skeletal muscles and the serum. Treatment with DL-carnitine to both cases resulted in marked clinical improvement and decreased lipid droplets in the muscles.