Expanding the phenotype and metabolic basis of ATP6AP2-congenital disorder of glycosylation in a Chinese patient with a novel variant c.185G>A (p.Gly62Glu).

Background: A rare X-linked hereditary condition known as ATP6AP2-congenital disorder of glycosylation (ATP6AP2-CDG) is caused by pathogenic variants in ATP6AP2, resulting in autophagic misregulation with reduced siganling of mammalian target of rapamycin (mTOR) that clinically presents with aberrant protein glycosylation, hepatosteatosis, immunodeficiency, cutis laxa, and psychomotor dysfunction. To date, only two missense mutations have been reported in three patients from two unrelated families. Methods: In order to extend the profiles of phenotype and genotype associated with ATP6AP2-CDG, we assessed the clinical history, whole exome sequencing (WES), and liver histology as well as immunohistochemistry in a Chinese patient, and performed quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and untargeted metabolomics in genetic exogenously constructed cells. Results: The 11-month-old Chinese boy presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. A novel mutation, c.185G>A (p.Gly62Glu), was identified in exon 3 of ATP6AP2. The expression of ATP6AP2 was observed to remain unchanged in the liver sample of the patient as well as in HEK293T cells harboring the p.Gly62Glu. This missense mutation was found to dysregulate autophagy and mTOR signaling. Moreover, metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. Conclusion: This study may enable a more detailed exploration of its precise pathogenesis and potential therapeutic interventions.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

Synchronous Hepatoblastoma and Neuroblastoma in Two Chinese Infants.

Background: Commonly, pediatric solid tumors occur independently. Only two patients with synchronous hepatoblastoma (HBL) and neuroblastoma (NBL) have been reported. Case reports: Two Chinese infants presented with abdominal mass at 10 and 8 months. Computed tomography (CT) scans in both revealed hepatic masses with additional mediastinal or adrenal masses. Pathology confirmed synchronous HBLs in the liver and NBLs in the mediastinum and adrenal. Next generation sequencing (NGS) found no remarkable germline mutations. Both patients received gross total resections with chemotherapy before or after surgery. They were followed up for 36 and 8 months, and recovered well. Conclusion: These two cases of synchronous HBL and NBL tumors lacked significant genetic alterations.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Neonatal sclerosing cholangitis with novel mutations in DCDC2 (doublecortin domain-containing protein 2) in Chinese children.

Background: Neonatal sclerosing cholangitis (NSC) is a rare and severe autosomal recessive inherited liver disease with mutations in DCDC2, commonly requiring liver transplantation (LT) for decompensated biliary cirrhosis in childhood. Methods: The information of four Chinese patients with NSC caused by mutations in DCDC2 from Children's Hospital of Fudan University were gathered. The four patients' clinicopathological and molecular features were summarized by clinical data, liver biopsy, immunohistochemical, and molecular genetic analysis. Results: All patients presented with jaundice, hepatosplenomegaly, hyperbilirubinemia and bile embolism, and high serum γ-glutamyl transferase activity (GGT). Liver biopsies revealed varying degrees of bile duct hyperplasia, portal-tract inflammation, and/or fibrosis. Whole-exome sequencing (WES) found novel heterozygous variants of c.1024-1G > T /p.? and c.544G > A /p. Gly182Arg in the DCDC2. Conclusion: This study expands the genetic spectrum of DCDC2 in NSC.

Infant-Type Hemispheric Glioma in a Chinese Girl: A Newly Defined Entity.

BACKGROUND: Infant-type hemispheric glioma is a newly defined entity in the updated 2021 WHO classification of tumors of the central nervous system. This lesion occurs in the cerebral hemispheres of newborns and infants and harbors molecular alterations in the NTRK family, ALK, ROS, or MET. Case report: A four-month-old female infant presented with a large space occupying lesion of the left cerebral hemisphere, whose histological manifestation was high-grade hemispheric infantile glioma. Tumor expressed panTRK, indicative of rearranged NTRK1, which was validated by next generation sequencing (NGS) as TPM3-NTRK1 fusion. There was homozygous deletion of CDKN2A/B, and there were ROS1, TLX3, FAT1, ABL1, MSH2, and PALB2 mutations. Conclusion: The additional genetic alterations in this case may expand the genotypic spectrum of this distinct cohort.

A Case Series of Pediatric Intestinal Ganglioneuromatosis With Novel Phenotypic and Genotypic Profile.

Introduction: Intestinal ganglioneuromatosis (IGN) is a rare condition with enteric involvement. Herein, we report a case series of pediatric IGN with a novel phenotypic and genotypic profile. Methods: The clinical presentation, histopathology, immunochemistry, molecular features, treatment, and prognosis of 3 cases of IGN were assessed. Results: The cases involved 3 boys with an age range of 1 year and 4 months to 8 years, mimicking juvenile polyps or pseudomembranous enteritis. One patient carried a novel germline mutation in RTEL1 (c.296C > T/p.Pro99Leu) along with variants in F11 (c.1489C > T/p.Arg497Xaa), NBAS (c.1514delC/p.Pro505Hisfs*15), and FECH (c.315-48T > C/splicing), who died due to intractable inflammation. The other two patients underwent recurrence without significant signs of systemic syndrome or malignant progression. Conclusion: This case series added to the phenotypic and genotypic spectrum of pediatric IGN, which requires the accumulation of more cases and research for in-depth understanding.

TMEM199-Congenital Disorder of Glycosylation With Novel Phenotype and Genotype in a Chinese Boy.

Background: TMEM199-congenital disorder of glycosylation (TMEM199-CDG) is a rare autosomal recessive inherited disease characterized by chronically elevated serum transaminase, decreased serum ceruloplasmin, steatosis and/or fibrosis, TMEM199 mutation, reduced level of TMEM199 protein, and abnormal protein glycosylation. Methods: The information of a Chinese patient with TMEM199-CDG in the Children's Hospital of Fudan University was reviewed. The patient's clinical, pathological, and molecular features were obtained by clinical data study, liver biopsy, immunohistochemistry, and molecular genetic analysis. Results: A 4-year-old Chinese boy presented with hypertransaminasemia, hypercholesterolemia, elevated alkaline phosphatase, decreased serum ceruloplasmin and serum copper level, and coagulopathy since birth. To the best of our knowledge, novel findings included strabismus, cirrhosis by liver biopsy, reduced expression of TMEM199 by immunohistochemistry, and a frameshift variant of c.128delA/p.Lys43Argfs*25 in the TMEM199 gene. Conclusion: This case added to the phenotypic and genotypic spectrum of TMEM199-CDG.

Molecular Evolution of Attachment Glycoprotein (G) and Fusion Protein (F) Genes of Respiratory Syncytial Virus ON1 and BA9 Strains in Xiamen, China.

Monitoring viral transmission and analyzing the genetic diversity of a virus are imperative to better understand its evolutionary history and the mechanism driving its evolution and spread. Especially, effective monitoring of key antigenic mutations and immune escape variants caused by these mutations has great scientific importance. Thus, to further understand the molecular evolutionary dynamics of respiratory syncytial virus (RSV) circulating in China, we analyzed nasopharyngeal swab specimens derived from hospitalized children ≤5 years old with acute respiratory tract infections (ARIs) in Xiamen during 2016 to 2019. We found that infants under 6 months of age (52.0%) were the main population with RSV infection. The prevalent pattern "BBAA" of RSV was observed during the epidemic seasons. RSV ON1 and BA9 genotypes were the dominant circulating strains in Xiamen. Interestingly, we observed four Xiamen-specific amino acid substitution combinations in the G protein and several amino acid mutations primarily occurring at antigenic sites Ø and V in the F protein. Our analyses suggest that introduction of new viruses and local evolution are shaping the diversification of RSV strains in Xiamen. This study provides new insights on the evolution and spread of the ON1 and BA9 genotypes at local and global scales. IMPORTANCE Monitoring the amino acid diversity of the RSV G and F genes helps us to find the novel genotypes, key antigenic mutations affecting antigenicity, or neutralizing antibody-resistant variants produced by natural evolution. In this study, we analyzed the molecular evolution of G and F genes from RSV strains circulating in Xiamen, China. These data provide new insights on local and global transmission and could inform the development of control measures for RSV infections.

Role of Hydrogen Sulfide in Oral Disease.

Oral diseases are among the most common human diseases yet less studied. These diseases affect both the physical, mental, and social health of the patients resulting in poor quality of life. They affect all ages, although severe stages are mostly observed in older individuals. Poor oral hygiene, genetics, and environmental factors contribute enormously to the development and progression of these diseases. Although there are available treatment options for these diseases, the recurrence of the diseases hinders their efficiency. Oral volatile sulfur compounds (VSCs) are highly produced in oral cavity as a result of bacteria activities. Together with bacteria components such as lipopolysaccharides, VSCs participate in the progression of oral diseases by regulating cellular activities and interfering with the immune response. Hydrogen sulfide (H2S) is a gaseous neurotransmitter primarily produced endogenously and is involved in the regulation of cellular activities. The gas is also among the VSCs produced by oral bacteria. In numerous diseases, H2S have been reported to have dual effects depending on the cell, concentration, and donor used. In oral diseases, high production and subsequent utilization of this gas have been reported. Also, this high production is associated with the progression of oral diseases. In this review, we will discuss the production of H2S in oral cavity, its interaction with cellular activities, and most importantly its role in oral diseases.

The Role of Hydrogen Sulfide in Respiratory Diseases.

Respiratory diseases are leading causes of death and disability around the globe, with a diverse range of health problems. Treatment of respiratory diseases and infections has been verified to be thought-provoking because of the increasing incidence and mortality rate. Hydrogen sulfide (H2S) is one of the recognized gaseous transmitters involved in an extensive range of cellular functions, and physiological and pathological processes in a variety of diseases, including respiratory diseases. Recently, the therapeutic potential of H2S for respiratory diseases has been widely investigated. H2S plays a vital therapeutic role in obstructive respiratory disease, pulmonary fibrosis, emphysema, pancreatic inflammatory/respiratory lung injury, pulmonary inflammation, bronchial asthma and bronchiectasis. Although the therapeutic role of H2S has been extensively studied in various respiratory diseases, a concrete literature review will have an extraordinary impact on future therapeutics. This review provides a comprehensive overview of the effective role of H2S in respiratory diseases. Besides, we also summarized H2S production in the lung and its metabolism processes in respiratory diseases.

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases.

Hydrogen sulfide (H2S) has long been considered as a toxic gas, but as research progressed, the idea has been updated and it has now been shown to have potent protective effects at reasonable concentrations. H2S is an endogenous gas signaling molecule in mammals and is produced by specific enzymes in different cell types. An increasing number of studies indicate that H2S plays an important role in cardiovascular homeostasis, and in most cases, H2S has been reported to be downregulated in cardiovascular diseases (CVDs). Similarly, in preclinical studies, H2S has been shown to prevent CVDs and improve heart function after heart failure. Recently, many H2S donors have been synthesized and tested in cellular and animal models. Moreover, numerous molecular mechanisms have been proposed to demonstrate the effects of these donors. In this review, we will provide an update on the role of H2S in cardiovascular activities and its involvement in pathological states, with a special focus on the roles of exogenous H2S in cardiac protection.

The Application of Nanotechnology for the Diagnosis and Treatment of Brain Diseases and Disorders.

Brain is by far the most complex organ in the body. It is involved in the regulation of cognitive, behavioral, and emotional activities. The organ is also a target for many diseases and disorders ranging from injuries to cancers and neurodegenerative diseases. Brain diseases are the main causes of disability and one of the leading causes of deaths. Several drugs that have shown potential in improving brain structure and functioning in animal models face many challenges including the delivery, specificity, and toxicity. For many years, researchers have been facing challenge of developing drugs that can cross the physical (blood-brain barrier), electrical, and chemical barriers of the brain and target the desired region with few adverse events. In recent years, nanotechnology emerged as an important technique for modifying and manipulating different objects at the molecular level to obtain desired features. The technique has proven to be useful in diagnosis as well as treatments of brain diseases and disorders by facilitating the delivery of drugs and improving their efficacy. As the subject is still hot, and new research findings are emerging, it is clear that nanotechnology could upgrade health care systems by providing easy and highly efficient diagnostic and treatment methods. In this review, we will focus on the application of nanotechnology in the diagnosis and treatment of brain diseases and disorders by illuminating the potential of nanoparticles.

Screening Traditional Chinese Medicine Combination for Cotreatment of Alzheimer's Disease and Type 2 Diabetes Mellitus by Network Pharmacology.

BACKGROUND: In recent years, the efficacy of type 2 diabetes mellitus (T2DM) drugs in the treatment of Alzheimer's disease (AD) has attracted extensive interest owing to the close associations between the two diseases. OBJECTIVE: Here, we screened traditional Chinese medicine (TCM) and multi-target ingredients that may have potential therapeutic effects on both T2DM and AD from T2DM prescriptions. METHODS: Network pharmacology and molecular docking were used. RESULTS: Firstly, the top 10 frequently used herbs and corresponding 275 active ingredients were identified from 263 T2DM-related TCM prescriptions. Secondly, through the comparative analysis of 208 potential targets of ingredients, 1,740 T2DM-related targets, and 2,060 AD-related targets, 61 common targets were identified to be shared. Thirdly, by constructing pharmacological network, 26 key targets and 154 representative ingredients were identified. Further enrichment analysis showed that common targets were involved in regulating multiple pathways related to T2DM and AD, while network analysis also found that the combination of Danshen (Radix Salviae)-Gancao (Licorice)-Shanyao (Rhizoma Dioscoreae) contained the vast majority of the representative ingredients and might be potential for the cotreatment of the two diseases. Fourthly, MAPK1, PPARG, GSK3B, BACE1, and NR3C1 were selected as potential targets for virtual screening of multi-target ingredients. Further docking studies showed that multiple natural compounds, including salvianolic acid J, gancaonin H, gadelaidic acid, icos-5-enoic acid, and sigmoidin-B, exhibited high binding affinities with the five targets. CONCLUSION: To summarize, the present study provides a potential TCM combination that might possess the potential advantage of cotreatment of AD and T2DM.

Impact of the factors shaping gut microbiota on obesity.

Obesity is considered as a risk factor for chronic health diseases such as heart diseases, cancer and diabetes 2. Reduced physical activities, lifestyle, poor nutritional diet and genetics are among the risk factors associated with the development of obesity. In recent years, several studies have explored the link between the gut microbiome and the progression of diseases including obesity, with the shift in microbiome abundance and composition being the main focus. The alteration of gut microbiome composition affects both nutrients metabolism and specific gene expressions, thereby disturbing body physiology. Specifically, the abundance of fibre-metabolizing microbes is associated with weight loss and that of protein and fat-metabolizing bacteria with weight gain. Various internal and external factors such as genetics, maternal obesity, mode of delivery, breastfeeding, nutrition, antibiotic use and the chemical compounds present in the environment are known to interfere with the richness of the gut microbiota (GM), thus influencing weight gain/loss and ultimately the development of obesity. However, the effectiveness of each factor in potentiating the shift in microbes' abundance to result in significant changes that can lead to obesity is not yet clear. In this review, we will highlight the factors involved in shaping GM, their influence on obesity and possible interventions. Understanding the influence of these factors on the diversity of the GM and how to improve their effectiveness on disease conditions could be keys in the treatment of metabolic diseases.

Pyruvate-Enriched Oral Rehydration Solution Improves Glucometabolic Disorders in the Kidneys of Diabetic db/db Mice.

Diabetes is prevalent worldwide, but ideally intensive therapeutic strategy in clinical diabetes and diabetic nephropathy (DN) is still lack. Pyruvate is protective from glucometabolic disturbances and kidney dysfunction in various pathogenic insults. Present studies focused on oral pyruvate effects on diabetes status and DN with 0.35% pyruvate in pyruvate-enriched oral rehydration solution (Pyr-ORS) and 1% pyruvate as drinking water for 8 weeks, using the model of diabetic db/db mice. Both Pyr-ORS and 1% pyruvate showed comparable therapeutic effectiveness with controls of body weight and blood sugar, increases of blood insulin levels, and improvement of renal function and pathological changes. Aberrant key enzyme activities in glucometabolic pathways, AR, PK, and PDK/PDH, were also restored; indexes of oxidative stress and inflammation, NAD+/NADH ratio, and AGEs in the kidneys were mostly significantly preserved after pyruvate treatments. We concluded that oral pyruvate delayed DN progression in db/db mice and the modified Pyr-ORS formula might be an ideal novel therapeutic drink in clinical prevention and treatment of type 2 diabetes and DN.

Pyruvate alleviates high glucose-induced endoplasmic reticulum stress and apoptosis in HK-2 cells.

Endoplasmic reticulum (ER) stress plays a critical role in the development of diabetic nephropathy (DN). We previously demonstrated that pyruvate (Pyr)-enriched oral rehydration solution improved glucometabolic disorders and ameliorated DN outcome in db/db mice. Here, we investigated the effects of Pyr on high glucose-induced ER stress and apoptosis in HK-2 cells. Our results suggest that high glucose can induce reactive oxygen species production, apoptosis and ER stress in HK-2 cells, and that Pyr treatment can ameliorate these effects and restore the expression of key proteins involved in ER stress. Thus, Pyr may have potential for the development of novel strategies for the prevention and treatment of clinical DN.

Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing-Induced Cardiomyopathy.

Background The molecular mechanisms through which high-demand pacing induce myocardial dysfunction remain unclear. Methods and Results We created atrioventricular block in pigs using dependent right ventricular septal pacing for 6 months. Echocardiography was performed to evaluate dyssynchrony between pacing (n=6) and sham control (n=6) groups. Microarray and enrichment analyses were used to identify differentially expressed genes ( DEG s) in the left ventricular ( LV ) myocardium between pacing and sham control groups. Histopathological and protein changes were also analyzed and an A cell pacing model was also performed. Pacing significantly increased mechanical dyssynchrony. Enrichment analysis using Ingenuity Pathway Analysis and the activation z-score analysis method demonstrated that there were 5 DEG s ( ABCA 1, APOD , CLU , LY 96, and SERPINF 1) in the LV septum (z-score=-0.447) and 5 DEG s ( APOD , CLU , LY 96, MSR 1, and SERPINF 1) in the LV free wall (z-score=-1.000) inhibited the liver X receptor/retinoid X receptor ( LXR / RXR ) pathway, and 4 DEG s ( ACTA 2, MYL 1, PPP 2R3A, and SNAI 2) activated the integrin-linked kinase ( ILK ) pathway in the LV septum (z-score=1.000). The pacing group had a larger cell size, higher degree of myolysis and fibrosis, and increased expression of intracellular lipid, inflammatory cytokines, and apoptotic markers than the sham control group. The causal relationships between pacing and DEG s related to LXR / RXR and ILK pathways, apoptosis, fibrosis, and lipid expression after pacing were confirmed in the cell pacing model. Luciferase reporter assay in the cell pacing model also supported inhibition of the LXR pathway by pacing. Conclusions Right ventricular septal-dependent pacing was associated with persistent LV dyssynchrony-induced cardiomyopathy through inhibition of the LXR / RXR pathway.

Effect of Heat Treatment on the Antitumor Activity of Lactoferrin in Human Colon Tumor (HT29) Model.

To investigate the effect of heat treatment on the antitumor activity of lactoferrin in colon cancer cells and colon tumors, the HT-29 (human intestinal epithelial tumor cell) cell line was exposed to lactoferrin and various heat treatments. The impacts on cell proliferation, invasion, and migration were observed in vitro, and nude mice bearing HT29 tumors were administered lactoferrin and underwent various heat treatments in vivo. In the HT29 cell proliferation test using transwell and scratch analyses, lactoferrin (20 mg/mL) without or with heat treatment (50 and 70 °C) significantly inhibited cell proliferation, migration, and invasion (compared with the control, p < 0.05), while lactoferrin with heat treatment (100 °C) did not affect these parameters. In vivo, HT29 tumor weight was significantly reduced in the lactoferrin (without heat treatment and with 50 and 70 °C treatment) groups (1.59 ± 0.20, 1.67 ± 0.25, and 2.41 ± 0.42 g, compared with the control, p < 0.05), and there was no significant difference between the control (3.73 ± 0.33 g) and the 100 °C treatment group (3.58 ± 0.29 g). Moreover, 100 °C heat treatment reduced inhibition of the VEGFR2/VEGFA/PI3K/Akt/Erk1/2 angiogenesis pathway by lactoferrin. In summary, HT29 tumors were effectively suppressed by lactoferrin via inhibition of VEGFR2/VEGFA/PI3K/Akt/Erk1/2 pathway, and heat treatment affected the antitumor activity of lactoferrin in a temperature-dependent manner.

Idi1 and Hmgcs2 Are Affected by Stretch in HL-1 Atrial Myocytes.

BACKGROUND: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. METHODS: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). RESULTS: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the "superpathway of cholesterol biosynthesis" were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). CONCLUSIONS: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement.