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Knowledge of dasatinib-induced nephrotic syndrome is largely based on case reports. The clinical features of dasatinib-induced nephrotic syndrome are unknown. We collected case reports of 25 patients with nephrotic syndrome and analyzed their clinical characteristics. Overall, the onset of nephrotic syndrome ranged from 10 days to 5 years after dasatinib administration. Nine patients (36.0%) had clinical symptoms, mainly periorbital edema and lower-extremity edema. Serum albumin ranged from 1.2 g/dL to 3.7 g/dL in 10 patients (38.5%). The 24-h urine protein values ranged from 3.54 g/day to 118 g/day. Kidney biopsy of 13 patients (52.0%) mainly showed focal foot process effacement, mesangial hyperplasia, endothelial cell damage and focal segmental glomerulosclerosis. Proteinuria resolved or recovered after dasatinib discontinuation or dose reduction or switching to other tyrosine kinase inhibitors (TKIs).

Understanding the relationship between contrast agents and Kounis syndrome (KS) is mainly based on case reports. The purpose of this research is to explore the clinical characteristics of contrast media induced KS.We searched for contrast-induced KS case reports through Chinese and English databases from 1991 to October 31, 2021.A total of 26 patients (19 men and 7 women,) were included, with a median age of 60 years (range 30-83). The contrast agents that cause KS mainly included gadolinium-based contrast agent (7 cases), iodine-containing contrast media (12 cases). KS mainly occurred within 30 min after administration and mainly manifests as chest pain and allergic reactions. Electrocardiogram (ECG) mainly showed ST elevation. Echocardiography mainly revealed normal. Coronary angiography showed normal, coronary vasospasm, stent thrombosis, occlusion and stenosis. After treatment with steroids, antihistamines and anti-ischemic therapy, 24 patients recovered completely and 2 patients died.KS is a rare adverse reaction of contrast media. Radiologists should recognize this rare but serious disease to ensure rapid diagnosis and proper management.

What is known and objective Knowledge regarding the association between clopidogrel exposure and acute arthritis is based mainly on case reports. The purpose of this article was to assess the clinical characteristics of clopidogrel-induced acute arthritis. Methods We collected literature from 1998 to 2020 in Chinese and English on acute arthritis induced by clopidogrel for retrospective analysis. Results and discussion The median age of 21 patients (6 females and 15 males) was 63 years (range 34-77). The median time of symptom onset was 10 days (range 0.21-21) overall. The median onset time of symptoms of clopidogrel-induced arthritis was 14 days (range 3-21) and 3 days (range 0.21-7) in patients with and without a loading dose of clopidogrel, respectively. Arthralgias (100%), joint swelling (61.9%), fever (57.1%), rash (33.3%) and pruritus (28.6%) were the most common accompanying symptoms. Most cases were accompanied by different degrees of acute inflammation markers: the median ESR was 68 mm/h (range 10-120), and the median CRP was 142.4 mg/L (range 2.3-408). X-ray films were unremarkable. Symptoms disappeared completely in all patients at a median time of 4 days (range 0.17-30) after the discontinuation of clopidogrel. Prasugrel, ticagrelor and ticlopidine can be used as safe alternatives to clopidogrel in patients with clopidogrel-induced acute arthritis with no recurrence of arthritis. What is new and conclusion Clopidogrel-induced arthritis is a rare adverse reaction and should be suspected in patients with arthralgia and fever during clopidogrel use.

Histidine phosphorylation (pHis) was first reported in 1962. There are few studies on pHis because of the thermal and acidic instability of pHis and the lack of specific methods to detect it. pHis has two isomers of 1-phosphate histidine (1-pHis) and 3-phosphate histidine (3-pHis). pHis antibodies have been developed recently and have promoted research in this field. In this study, we established a CCl4-induced liver fibrosis model in C57 mice and a TGF-β1-induced HSC activation model in LX-2 cells, to study the role of histidine phosphorylation. The expression of histidine kinases NME1 and NME2 was increased, histidine phosphatase PGAM5 and PHPT1 was unchanged, and 1-pHis and 3-pHis were increased in the in vivo and in vitro models. The expression of LHPP was decreased in the in vivo model but not in the in vitro model. To further study the role of NME1, NME2, and histidine phosphorylation in HSC activation, we silenced NME1 or NME2 and administered TGF-β1 in LX-2 cells. The results showed silencing NME1 or NME2 decreased TGF-β1-induced pHis levels and the expression of α-SMA and COL1A1, indicating the activation of HSC was suppressed. Then, we found the inhibitory effect on HSC activation is due to reduced phosphorylation of Smad2 and Smad3. In summary, our studies indicate that NME1 and NME2 are involved in TGF-β1-induced HSC activation and CCl4-induced liver fibrosis, which may be mediated by histidine phosphorylation.

Numerous case reports of acute pancreatitis (AP) induced by olanzapine have been published. Little is, however, known about the clinical features of olanzapine-induced AP. The aim of the study was to explore the clinical characteristics of olanzapine-induced AP. We collected literature on AP cases induced by olanzapine from 1996 to April 2021 for retrospective analysis in Chinese and English. The median time to onset of olanzapine-induced acute pancreatic symptoms was 12 (range = 0.86–216) weeks in 25 patients. The clinical features of AP range from asymptomatic elevation of blood amylase/lipase levels to digestive system symptoms (abdominal pain, vomiting, and nausea) and even death in a small number of patients. Laboratory tests showed varying degrees of elevated serum amylase and lipase levels, along with high blood sugar and high triglyceride levels in some patients. Computed tomography showed acute edematous pancreatitis, acute hemorrhagic pancreatitis, and acute necrotizing pancreatitis in the patients. The patients’ symptoms were completely relieved and high triglyceride levels gradually returned to normal levels after olanzapine was stopped. Some patients with hyperglycemia still needed hypoglycemic therapy. AP is a rare adverse effect of olanzapine. Clinicians should be aware of such complications and monitor pancreatin.

Background The exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention. Methods The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis. Results A total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60). Conclusions EIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.

What is known and objective Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. Methods We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. Results and discussion The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 μIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). What is new and conclusion ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Acne vulgaris of wind-heat in lung meridian is a common skin disease, and there are many traditional Chinese medicine prescriptions, but the mechanism is still not clear. In this paper, the literature on the treatment of acne due to wind-heat in lung meridian and the prescriptions in the patents were collected and sorted out in the past twenty years. Excel 2019 was used for medication frequency statistics, and IBM SPSS 25.0 was used for clustering analysis to obtain the core formula. Network pharmacology was used to collect the related targets of drugs and diseases, to construct the action network, and to conduct enrichment analysis. A total of 137 prescriptions and 167 drugs were obtained. The core prescriptions were Cortex mori, Folium eriobotryae, Scutellariae radix, Glycyrrhrizae radix, Fructus gardeniae, Radix rehmanniae, and Cortex moutan. The treatment of acne due to wind-heat in lung meridian should begin with clearing heat, purging the lung, cooling blood and detoxicating. The core prescriptions mainly played a role through AKT1, IL6, TP53, TNF, VEGFA, EGF targets and Kaposi's sarcoma-related herpes virus infection, measles, toxoplasmosis, EB virus infection, IL-17, MAPK and other signaling pathways, so as to provide reference for further clinical research.

WHAT IS KNOWN AND OBJECTIVE The number of case reports of insulin autoimmune syndrome (IAS) induced by methimazole (MMI) is increasing. The purpose of this study is to explore the clinical characteristics and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS The literature on IAS cases and case series induced by MMI in Chinese and English was collected for retrospective analysis. RESULTS AND DISCUSSION A total of 106 patients (males 33, females 73) were described in the Chinese and English literature. The median age of patients with IAS induced by MMI was 37 years (range 15-76) occurring during both regular and irregular MMI therapy or after resumption of medication. The onset of symptoms occurred at night or early morning, within days in some and up to 6 months in others; the symptoms were neuropathic in 65.31% and related to the autonomic nervous system in 33.67%. Blood glucose concentration in samples presumably taken during the hypoglycaemic phase was 1.7 mmol/L (median; range 0.03-4.7); insulin concentrations were elevated ≥100 mU/L (ref range) and associated with low C-peptide levels (

What is known and objective The purpose of this study is to explore the clinical characteristics of tigecycline-induced acute pancreatitis. Methods We searched the PubMed/Medline, Web of Knowledge, OVID, Elsevier, Springer Link, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and Chinese VIP databases from 2005 and identified 19 studies of tigecycline-induced acute pancreatitis involving a total of 22 patients for inclusion in a retrospective analysis. Results and discussion The median (range) age of 22 patients with acute pancreatitis was 58 years (range 9-83). Overall, the median (range) time of symptom onset was 6.5 days (range 2-28), or 6 days (range 2-14) and 6 days (range 3-28) in patients with or without a loading dose of tigecycline, respectively. Symptoms included nausea, vomiting and abdominal distension (73%) and abdominal pain (73%); 90% (18/20) of patients developed mild acute pancreatitis (MAP), and 10% (2/20) developed severe acute pancreatitis (SAP). Computed tomography (CT) scans showed oedematous infiltrate in 56% (10/18) of cases and acute pancreatitis in 28% (5/18) of cases. The median (range) level of lipase and amylase was 936U/L (range 382-4089) and 588U/L (range 312-1166), respectively. The median (range) time to recovery of symptoms was 4 days (range 1-10), and the time for recovery of pancreatic enzymes to the normal range was 5 days (range 1-30) after the withdrawal of tigecycline in all patients. What is new and conclusion Clinicians should be particularly mindful of clinical signs and symptoms, the level of serum pancreatic enzymes and abdominal CT images in order to monitor the development of pancreatitis when using tigecycline.

Histidine phosphorylation (pHis) was first reported in 1962. There are few studies on pHis because of the thermal and acidic instability of pHis and the lack of specific methods to detect it. pHis has two isomers of 1-phosphate histidine (1-pHis) and 3-phosphate histidine (3-pHis). pHis antibodies have been developed recently and have promoted research in this field. In this study, we established a CCl

Purpose: SET and MYND domain-containing protein2 (SMYD2), a histone lysine methyltransferases, is a candidate human oncogene in multiple tumors. However, the expression dynamics of SMYD2 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. Methods: The SMYD2 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) in HCC tissues and matched adjacent non-tumorous tissues. SMYD2 was silenced in HCC cell lines to determine its role in tumor proliferation and cell cycle progression, and the possible mechanism. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results: The SMYD2 expression in HCC tissues were significantly up-regulated at both mRNA and protein levels as compared with the matched adjacent non-tumorous tissues. By IHC, positive expression of SMYD2 was examined in 122/163 (74.85%) of HCC and in 10/59 (16.95%) of tumor-adjacent tissues. Positive expression of SMYD2 was correlated with tumor size, vascular invasion, differentiation and TNM stage (P < 0.05). In univariate survival analysis, a significant association between positive expression of SMYD2 and shortened patients' survival was found (P < 0.05). Importantly, SMYD2 expression together with vascular invasion (P < 0.05) provided significant independent prognostic parameters in multivariate analysis. Functionally, SMYD2 silenced markedly inhibited cell proliferation and cell cycle progression in SMMC-7721 cell. Conclusions: Our findings provide evidences that positive expression of SMYD2 in HCC may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with HCC.

Recent evidence shows that resveratrol (RSV) may ameliorate high-glucose-induced cardiac oxidative stress, mitochondrial dysfunction and myocardial fibrosis in diabetes. However, the mechanisms by which RSV regulates mitochondrial function in diabetic cardiomyopathy have not been fully elucidated. Mitochondrial dysfunction contributes to cardiac dysfunction in diabetic patients, which is associated with dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In this study we examined whether resveratrol alleviated cardiac dysfunction in diabetes by improving mitochondrial function via SIRT1-mediated PGC-1α deacetylation. T2DM was induced in rats by a high-fat diet combined with STZ injection. Diabetic rats were orally administered RSV (50 mg·kg–1·d–1) for 16 weeks. RSV administration significantly attenuated diabetes-induced cardiac dysfunction and hypertrophy evidenced by increasing ejection fraction (EF%), fraction shortening (FS%), ratio of early diastolic peak velocity (E velocity) and late diastolic peak velocity (A velocity) of the LV inflow (E/A ratio) and reducing expression levels of pro-hypertrophic markers ANP, BNP and β-MHC. Furthermore, manganese superoxide dismutase (SOD) activity, ATP content, mitochondrial DNA copy number, mitochondrial membrane potential and the expression of nuclear respiration factor (NRF) were all significantly increased in diabetic hearts by RSV administration, whereas the levels of malondialdehvde (MDA) and uncoupling protein 2 (UCP2) were significantly decreased. Moreover, RSV administration significantly activated SIRT1 expression and increased PGC-1α deacetylation. H9c2 cells cultured in a high glucose (HG, 30 mmol/L) condition were used for further analyzing the role of SIRT1/PGC-1α pathway in RSV regulation of mitochondrial function. RSV (20 μmol/L) caused similar beneficial effects in HG-treated H9c2 cells in vitro as in diabetic rats, but these protective effects were abolished by addition of a SIRT1 inhibitor sirtinol (25 μmol/L) or by SIRT1 siRNA transfection. In H9c2 cells, RSV-induced PGC-1α deacetylation was dependent on SIRT1, which was also abolished by a SIRT1 inhibitor and SIRT1 siRNA transfection. Our results demonstrate that resveratrol attenuates cardiac injury in diabetic rats through regulation of mitochondrial function, which is mediated partly through SIRT1 activation and increased PGC-1α deacetylation.

Background Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-β/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-β1/miR-195/Smads signaling or not. Methods First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA’s expressions to prove the correlation between OM and the TGF-β1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. Results Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 μg/mL after 24 h, 100 μg/mL after 48 h and 10 μg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 μg/mL respectively. OM could down-regulate miR-195 and α-SMA (P

Pharmacological inhibition of reactive oxygen species (ROS) is a potential strategy to prevent diabetes-induced cardiac dysfunction. This study was designed to investigate precise effects of antioxidant N‑acetylcysteine (NAC) in alleviating diabetic cardiomyopathy (DCM). Echocardiography and histologic studies were performed 12 weeks after streptozocin injection. Protein levels involved in endoplasmic reticulum stress (ERS) and apoptosis were analyzed by western blotting in diabetic hearts or high-glucose (HG, 30 mM)- and palmitic acid (PA, 300 μM)-cultured neonatal rat cardiomyocytes (NRCMs). ROS generation and structural alterations of mitochondria were also assessed. We report that NAC alleviated diabetes-induced cardiac abnormality, including restored ejection fraction (EF %), fraction shortening (FS %), peak E to peak A ratio (E/A) and reduced cardiac hypertrophy and fibrosis. These effects were concomitant with blocked ERS and apoptosis, as evidenced by inactivation of phosphorylated inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein 1 (XBP1), phosphorylated protein kinase-like kinase (PERK)/phosphorylated eukaryotic initiation factor 2α (eIF2α) and glucose-regulated protein 78 (GRP78)/activating transcription factor 6 (ATF6α)/C/EBP homologous protein (CHOP) pathways, as well as suppressed Bcl-2-associated X protein (BAX)/B-cell lymphoma-2 (Bcl-2) and cleaved caspase 3 expressions. Mechanistically, PA mediated excessive mitochondrial ROS generation and oxidative stress, which were antagonized by NAC and Mito-TEMPO, a mitochondrial ROS inhibitor. No effects were noted by addition of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, and NADPH oxidase 4 (NOX 4) and NOX 2 expressions were not altered, indicating that PA-induced ROS generation is independent of NADPH oxidases. Most intriguingly, HG failed to promote ROS production despite its ability to promote ERS and apoptosis in NRCMs. Collectively, these findings indicate that NAC primarily abrogates PA-mediated mitochondrial ROS through ERS and therefore alleviates myocardial apoptosis but has little effect on HG-induced cardiac injury. This uncovers a potential role for NAC in formulating novel cardioprotective strategies in DCM patients.

In recent years, the rate of disease outbreaks caused by food-borne microorganisms is gradually increasing. The abuse of food preservatives has not only caused environmental problems, but also led to the gradual increase in the resistance of bacteria. As a non-thermal physical sterilization technology, pulsed light sterilization has attracted more and more attention in the field of food sterilization. Traditional heat sterilization will destroy the quality of food and cannot be used for preservation of fruits and vegetables. Chemical reagents will cause environmental problems. The pulsed light sterilization technology has the advantages of low cost, pollution-free, safe and efficient, and will not damage food quality. It can be perfectly applied in the field of food sterilization. Pulsed light can also be used in combination with other sterilization technologies. For example, the combined application of pectin coating and UV sterilization technology to treat food will achieve better results. The research on pulsed light sterilization at home and abroad is mainly based on the application in food sterilization. This article describes the mechanism of pulsed light sterilization, introduces the application examples of pulsed light sterilization in the food field, and discusses the impact on food quality.

A novel full-duplex radio-over-fiber system is proposed and demonstrated, in which an external modulator and an optical interleaver are used to generate dual octupling-frequency optical millimeter waves for two base stations and wavelength reuse for uplink connection. This scheme is simplified and low-cost because no additional laser is utilized for uplink connection at two base stations and one laser at central office works for two base stations simultaneously. The frequency of local oscillator signal is reduced largely due to frequency octupling. The theorem about how to generate optical millimeter waves is analyzed. The simulation results show that the bidirectional 5 Gb/s system has a perfect performance because the power penalty for the downlink and uplink signals of two base stations are less than 0.6 dB after successful transmission over 60 km standard single mode fiber.

To investigate the dynamic changes and effect of primary cilia on adipogenesis during 3T3-L1 cell differentiation into adipocyte.Chloral hydrate was applied to inhibit primary cilia on day 0 and 4 of 3T3-L1 cell differentiation into adipocyte. The expression levels of primary cilia key proteins like kinesin family member 3a (Kif3a), intraflagellar transport protein 88 (IFT88), acetylated α-tubulin (acAT) and adipogenic key protein peroxisome proliferator activated receptor γ (PPARγ) were detected by Western blotting. The number of primary cilia was analyzed by immunofluorescence assay. The promoter activity of PPARγ gene was measured with dual-luciferase reporter assay system. The lipid accumulation was observed by oil red O staining.The levels of primary cilia key proteins, including Kif3a, IFT88, acAT, and the number of the primary cilia were higher on day 0 of cell differentiation, decreased on day 2, and then increased to the beginning levels on day 4, and significantly decreased again on day 8. Incubation with chloral hydrate on day 0 of differentiation significantly reduced the levels of Kif3a, IFT88, acAT proteins and the number of primary cilia, dramatically enhanced the promoter activity of PPARγ gene, level of PPAR γ protein and lipid accumulation. However, although primary cilia was significantly inhibited by the incubation with chloral hydrate on day 4 of differentiation, the promoter activity and protein expression of PPARγ, lipid accumulation had no obvious changes compared with vehicle groups.Primary cilia presented a dynamic change during 3T3-L1 cell differentiation into adipocytes. Few primary cilia in the early differentiation led to significantly enhanced adipogenesis, but once the differentiation was under way, the decrease of primary cilia would not affect adipogenesis.

Objective Increasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes. Methods Immunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress. Results ER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress. Conclusions These results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling.

The NADPH oxidases (Noxes) are a family of ROS (reactive oxygen species)-generating enzymes which play a critical role in the development of cardiac remodeling associated with heart failure. The Noxes of their catalytic isoforms include multiple homologues in cardiovascular cells with wide range tissue distribution. It is still unclear which Noxes represent the major enzymatic source of ROS in the heart and play a predominant role in cardiac hypertrophy. In this study we investigated the differential expression changes of NAD(P)H oxidase P47phox isoform and Nox homologues in left ventricle and the effects of atorvastatin on cardiac remodeling in two-kidney two-clip(2K2C) hypertensive rats. The mRNA and protein expression of Nox2, Nox4 and P47phox showed a sustained increase at 4, 8, 12 weeks after surgery in 2K2C rats. Administration of atorvastatin attenuated cardiac dysfunction, hypertrophy and fibrosis of 2K2C rats. However, atorvastatin treatment had no effects on BP regulation. Further studies revealed that atorvastatin inhibited the increased expression of Nox2, Nox4, P47phox as well as 02"- production in 2K2C hypertensive rats. These findings indicate that Nox2, Nox4 and P47phox play a crucial role in the development of cardiac remodeling in the 2K2C hypertensive rats. Atorvastatin, independent of BP control, exerts anti-remodeling effects partially by inhibition of NAD(P)H oxidase-mediated cardiac oxidative stress.