Artemether regulates liver glycogen and lipid utilization through mitochondrial pyruvate oxidation in db/db mice.

OBJECTIVES: Diabetes is an important global health problem. The occurrence and development of type 2 diabetes (T2D) involves multiple organs, among which the liver is an important organ. Artemether is a methyl ether derivative of artemisinin and has displayed significant antidiabetic effects. However, its regulation of glucose metabolism is not clearly elucidated. This study explored the effect of artemether on liver mitochondrial pyruvate metabolism. METHODS: T2D db/db mice were used and grouped into db/db and db/db+Art groups. Lean wild type mice served as control. After artemether intervention for 12 weeks, the respiratory exchange ratio (RER), redox state, relevant serum lipid content, liver glycogen and lipid content, liver insulin and insulin-like growth factor 1 (IGF-1) signal transduction, mitochondrial pyruvate oxidation pathway, fatty acid and glycogen metabolic pathways were evaluated. RESULTS: This experiment demonstrated that artemether raised RER and enhanced liver mitochondrial pyruvate metabolism in db/db mice. Artemether also reduced serum and urinary lipid peroxidation products and regulated the redox status in liver. The accumulation of liver glycogen in diabetic mice was attenuated, the proportion of lipid content in serum and liver was changed by artemether. The signal pathway associated with liver glycogen metabolism was also regulated by artemether. In addition, artemether increased serum insulin and regulated insulin/IGF-1 signal pathway in liver. CONCLUSIONS: The present study confirmed that artemether can regulate liver glycogen and lipid utilization in T2D mice, its biological mechanisms were associated with mitochondrial pyruvate oxidation in the liver.

Artemether ameliorates adriamycin induced cardiac atrophy in mice.

Adriamycin is a widely used and effective antitumor drug; however, its application is limited by various side effects, including irreversible cardiotoxicity. The central role of cardiac atrophy in Adriamycin­induced cardiotoxicity has been revealed; however, the underlying mechanism of this process remains unclear. Artemether is a well­known Chinese herbal medicine, and its pharmacological action is related to the regulation of mitochondrial function and redox status. The present study determined the effects of artemether on Adriamycin­induced cardiotoxicity and investigated the underlying mechanisms. After mouse model establishment and artemether intervention, experimental methods including pathological staining, immunohistochemistry, immunofluorescence, immunoblotting, ELISA and reverse transcription­quantitative PCR were used to evaluate the therapeutic effect. The results demonstrated that artemether prevented Adriamycin­induced cardiac atrophy and recovered the intercombination of connexin 43 and N­cadherin at the intercalated discs. Artemether also regulated the autophagy pathway and restored the unbalanced ratio of Bax and Bcl­2 in myocardial cells. In addition, the increased serum H2O2 levels after Adriamycin exposure were significantly decreased by artemether, and the mitochondrial alterations and redox imbalance in myocardial cells were also improved to varying degrees. In summary, the findings of the present study provide reliable evidence that artemether could ameliorate cardiac atrophy induced by Adriamycin. This therapeutic approach may be translated to the clinic for preventing drug­induced heart diseases.

Artemether attenuates renal tubular injury by regulating iron metabolism in mice with streptozotocin-induced diabetes.

OBJECTIVES: Renal tubular injury plays an important role in the progression of diabetic kidney disease. Previous studies demonstrated that artemether, an antimalarial agent, exerts renal tubular protection in diabetes. However, the detailed mechanisms remain unclear. Several studies have indicated that disorders of iron metabolism have a great impact on renal tubular injury. Therefore, this study was performed to explore whether the therapeutic effects of artemether on diabetic renal tubular injury are related to iron metabolism. METHODS: Male C57BL/6 J mice were randomly divided into three groups. Mice in the type 1 diabetic (T1D) control and streptozotocin (STZ) groups were fed a regular diet; mice in the STZ plus artemether (STZ+Art) group were treated with artemether. RESULTS: Artemether significantly reduced the urinary albumin:creatinine ratio and tubular injury in mice with T1D. Artemether also restored the energy imbalance and restored the changes of mitochondrial cristae in mice with T1D. Increased protein and mRNA levels of ferritin heavy chain (FTH) and ferritin light chain (FTL) were observed in renal tubules of diabetic mice. In response to iron overload, levels of iron transport-related proteins and the antioxidant system related to iron metabolism were abnormal in diabetic mice. Artemether significantly restored the protein and mRNA expression levels of both FTH and FTL. Both the iron transport and antioxidant systems were also restored by artemether to varying degrees. CONCLUSIONS: Artemether attenuates renal tubular injury in diabetic mice; this effect might be related to its regulation of iron metabolism.

Artemether Alleviates Diabetic Kidney Disease by Modulating Amino Acid Metabolism.

Diabetes is a worldwide metabolic disease with rapid growing incidence, characterized by hyperglycemia. Diabetic kidney disease (DKD), the leading cause of chronic kidney disease (CKD), has a high morbidity according to the constantly increasing diabetic patients and always develops irreversible deterioration of renal function. Though different in pathogenesis, clinical manifestations, and therapies, both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can evolve into DKD. Since amino acids are both biomarkers and causal agents, rarely report has been made about its metabolism which lies in T1DM- and T2DM-related kidney disease. This study was designed to investigate artemether in adjusting renal amino acid metabolism in T1DM and T2DM mice. Artemether was applied as treatment in streptozotocin (STZ) induced T1DM mice and db/db T2DM mice, respectively. Artemether-treated mice showed lower FBG and HbA1c and reduced urinary albumin excretion, as well as urinary NAG. Both types of diabetic mice showed enlarged kidneys, as confirmed by increased kidney weight and the ratio of kidney weight to body weight. Artemether normalized kidney size and thus attenuated renal hypertrophy. Kidney tissue UPLC-MS analysis showed that branched-chain amino acids (BCAAs) and citrulline were upregulated in diabetic mice without treatment and downregulated after being treated with artemether. Expressions of glutamine, glutamic acid, aspartic acid, ornithine, glycine, histidine, phenylalanine and threonine were decreased in both types of diabetic mice whereas they increased after artemether treatment. The study demonstrates the initial evidence that artemether exerted renal protection in DKD by modulating amino acid metabolism.

Artemether attenuates renal tubular injury by targeting mitochondria in adriamycin nephropathy mice.

Chronic kidney disease (CKD) is complex and current treatment remains limited. As we know, glomerular injury plays a dominant role in kidney disease progression. However, accumulating evidence demonstrated that renal tubules, rather than being victims or bystanders, are major initiators in renal fibrosis progression. Renal tubules are rich in mitochondria and mitochondrial dysfunction may participate in renal tubular phenotypic changes and ultimately promote renal fibrosis. Previous studies have proved that artemether displayed renal protective effects, but the mechanisms remain unclear. In this experiment, we showed that artemether reduced urinary protein/creatinine ratio and attenuated renal tubular injury. Both in vivo and in vitro results indicated that artemether could restore renal tubular phenotypic alterations. Meanwhile, the unbalanced expressions of Bax and Bcl-xL in renal tubules were restored by artemether. In addition, artemether also regulated mitochondrial pyruvate metabolism, increased mitochondrial biogenesis, and improved mitochondrial function. Taken together, this study suggested that artemether could attenuate renal tubular injury by regulating mitochondrial biogenesis and function. It has great potential to be translated to the clinic as a therapeutic agent for treating kidney diseases, especially those associated with renal tubular injury.

Combination therapy with artemether and enalapril improves type 1 diabetic nephropathy through enhancing antioxidant defense.

Previous studies have demonstrated that both artemether and enalapril are effective in treating diabetic nephropathy (DN). However, the effects and underlying mechanisms of their combination in treating DN remain unknown. The experimental DN model was induced by injecting streptozotocin (STZ) into male C57BL/6J mice. Mice were randomly allocated to the Type 1 diabetes control (T1D-ctrl), STZ, STZ + artemether (STZ + Art), STZ + enalapril (STZ + ACEi), or STZ + artemether + enalapril (STZ + Art + ACEi) group. The interventions lasted for 8 weeks. At the end of the experiment, related urine and serum biochemical values, such as urinary albumin excretion (UAE) and fasting blood glucose (FBG), were measured. In addition, blood pressure (BP) and kidney morphologic changes were also evaluated. The expression of oxidative stress related molecules, such as catalase, acetylated SOD2 (k68) and acetylated SOD2 (k122) in the kidney were measured. Results: combination therapy showed more pronounced effects in reducing UAE, FBG, and BP than any single drug. Typical diabetic kidney injuries, such as heavier kidney weight, and glomerular and tubular hypertrophy, were also further alleviated by combination therapy. Combination therapy also up-regulated the expression of catalase and down-regulated the expression of acetylated SOD2 (k68) and acetylated SOD2 (k122). Combination therapy with artemether and enalapril exhibited renoprotective effects in STZ-induced T1D mice superior to a single drug. The mechanism might be associated with their synergistic effects in enhancing antioxidant defense.

Combined treatment with niclosamide ethanolamine and artemether combination improves type 1 diabetes via the targeting of liver mitochondria.

Type 1 diabetes (T1D) is characterized by dysregulated blood glucose and liver metabolism. In previous studies, niclosamide ethanolamine salt (NEN) and artemether (Art) displayed significant hypoglycemic effects. However, their combined therapeutic effects on the liver in T1D have remained elusive. In the present study, T1D mice were established and randomly allocated into groups. Following treatment, the physiological and metabolic parameters, including liver function, glycogen content, glucose-6-phosphatase (G6Pase) protein expression levels, mitochondrial biogenesis and mitochondrial metabolism were analyzed. Compared with the NEN or Art treatments alone, their combination improved glycometabolism and the symptoms of diabetes. Combined treatment with NEN and Art also significantly ameliorated liver injury and increased liver glycogen storage. Furthermore, combinatorial treatment significantly downregulated hepatic G6Pase protein expression levels and regulated mitochondrial biogenesis. NEN and Art increased the respiratory exchange rate and reduced mitochondrial phosphoenolpyruvate carboxykinase and branched-chain α-keto acid dehydrogenase complex protein expression levels, whereby the effects were obviously enhanced by their application as a combined treatment. In conclusion, the present study confirmed that combined treatment with NEN and Art improved glycometabolism and liver function in T1D mice and the therapeutic effects may be partially associated with the regulation of liver mitochondria.

Niclosamide ethanolamine ameliorates diabetes-related muscle wasting by inhibiting autophagy.

BACKGROUND: Diabetes-related muscle wasting is one of the devastating complications of diabetes, which is associated with muscle autophagy due to insulin-mediated glucose starvation. However, treatment for diabetes-related muscle wasting is limited. Our previous study already found that niclosamide ethanolamine salt has the therapeutic effects on insulin deficiency of type 1 diabetes mice and muscle wasting induced by doxorubicin. Therefore, we aim to investigate the therapeutic effects of niclosamide ethanolamine salt on diabetes-induced muscle wasting and to explore whether the mechanism is associated with muscle autophagy. METHODS: Type 1 diabetes mice were induced by intraperitoneal injection of streptozotocin, then were fed with regular diet supplemented with 10 g/kg niclosamide ethanolamine salt. The whole experiment lasted for 8 weeks. At the end of the study, grip strength, weights of tibialis anterior, gastrocnemius, soleus, and extensor digitorum longus muscle were measured. Tibialis anterior muscles stained with PAS were used for evaluating the fiber cross sectional area. Immunofluorescence analysis of myosin heavy chain expression in extensor digitorum longus and soleus muscle was used for determining the composition of the muscle fiber type. Electronic microscopy was applied to observe the autophagy in the atrophied muscle. Serum insulin levels and fasting blood glucose were also measured. Tissues of gastrocnemius muscle were used for detecting the expression of the proteins related to autophagy. RESULTS: In this study, we found that niclosamide ethanolamine salt could ameliorate muscle atrophy in the type 1 diabetes mice as well, such as enhancing the declined grip strength, improving limb weight and increasing the numbers of glycolytic muscle fiber. Electron microscopy also confirmed that there did exist abundant autophagic vacuoles in the atrophied muscle of the type 1 diabetes mice. Specifically, niclosamide ethanolamine salt could reduce the over expression of autophagy-related proteins, including p-AMPK (Thr172), FoxO3a, p-ULK1 (Ser555), LC3B II, and p-p38 in gastrocnemius muscle of the type 1 diabetes mice. CONCLUSION: Niclosamide ethanolamine salt could ameliorate muscle wasting. The mechanisms underlying might be associated with inhibition of muscle autophagy.

Artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice.

The kidney is a high-energy demand organ rich in mitochondria especially renal tubular cells. Emerging evidence suggests that mitochondrial dysfunction, redox imbalance and kidney injury are interconnected. Artemether has biological effects by targeting mitochondria and exhibits potential therapeutic value for kidney disease. However, the underlying molecular mechanisms have not been fully elucidated. This study was performed to determine the effects of artemether on Adriamycin-induced nephropathy and the potential mechanisms were also investigated. In vivo, an Adriamycin nephropathy mouse model was established, and mice were treated with or without artemether for 2 weeks. In vitro, NRK-52E cells were stimulated with TGF-ß1 and treated with or without artemether for 24 h. Then renal damage and cell changes were evaluated. The results demonstrated that artemether reduced urinary protein excretion, recovered podocyte alterations, attenuated pathological changes and alleviated renal tubular injury. Artemether also downregulated TGF-ß1 mRNA expression levels, inhibited tubular proliferation, restored tubular cell phenotypes and suppressed proliferation-related signalling pathways. In addition, artemether restored renal redox imbalance, increased mtDNA copy number and improved mitochondrial function. In summary, we provided initial evidence that artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice. Artemether may be a promising agent for the treatment kidney disease.

Niclosamide ethanolamine attenuates systemic lupus erythematosus and lupus nephritis in MRL/lpr mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement. Lupus nephritis (LN) is a severe manifestation of the disease and the most common cause of mortality in SLE patients. The etiology of LN is multifactorial and accumulating evidence suggests that mitochondrial dysfunction contributes to LN initiation and progression. Mild mitochondrial uncoupler niclosamide ethanolamine salt (NEN) has recently been shown to be efficacious in the treatment of both diabetic kidney disease and non-diabetic adriamycin nephropathy. However, its role in autoimmune kidney disease has not been explored. Here, we report for the first time that NEN attenuated SLE and lupus nephritis in MRL/lpr mice. NEN treatment reduced urinary protein excretion and attenuated glomerular lesions in this model. NEN treatment also decreased urinary excretion of tubular injury biomarkers NGAL and Kim-1, restored renal tubule phenotypic alterations, inhibited tubular proliferation, and suppressed renal interstitial inflammation and fibrosis. In addition, NEN diet supplementation restored redox imbalance, promoted mitochondrial biogenesis, and improved energy dysregulation in the kidney. Importantly, NEN prevented the enlargement of lymph nodes and the spleen, and decreased serum anti-dsDNA antibody levels in the MRL/lpr mice. Therefore, our data suggest that this mild mitochondrial uncoupling agent has great potential for translational application as a novel therapy for autoimmune disease.

Combination of astragaloside IV and ACEi ameliorates renal injuries in db/db mice.

Evidences demonstrated that the effect on anti-proteinuria and renal protection of Chinese herbs combination with ACEi or ARB seemed to be better than ACEi or ARB alone. Astragaloside IV could decrease the urinary albumin excretion rate and could protect against renal injuries linking to its anti-oxidation ability. We aimed to investigate the effect of astragaloside IV combined with ACEi on diabetic nephropathy and to explore whether its underlying mechanism is dependent on anti-oxidation. 8-week-old male experiment mice were randomly assigned to five groups: lean wild type (wt) group, db/db group, db/db + astragaloside IV group, db/db + enalapril group, db/db + combination therapy with astragaloside IV and enalapril group. During the experiment, 24 hours urinary albumin, fasting glucose, body weight, and metabolic parameters were monitored in regular intervals. At the end of the study, tail blood pressure, serum H2O2, lipid, and liver function were measured and kidney histological injuries were evaluated. Results of the study indicated that combination therapy with astragaloside IV and ACEi further reduced 24 hours urinary albumin excretion rate, blood pressure, and body weight. Combination therapy reduced the foot process width, glomerular base membrane thickness, glomerular tuft cell proliferation, tubular cell atrophy, tubular base membrane thickness, and improved tubular cell proliferation. It modulated the body H2O2 metabolism and up-regulated the expression of the catalase in renal cortex. Astragaloside IV combined with ACEi exerted renal protective effects in db/db mice more significantly than their individual used. The mechanism possibly involved their synergistic effects on anti-oxidation.

Artemether improves type 1 diabetic kidney disease by regulating mitochondrial function.

Many patients with type 1 diabetes mellitus suffer from progressive diabetic kidney disease (DKD). The progression of DKD is largely attributed to mitochondrial dysfunction, with key contributions from mitochondrial reactive oxygen species. Recent studies have revealed that the antimalarial drug artemether has antidiabetic effects. To identify potential effects on type 1 DKD in the present study, mice with streptozotocin-induced diabetes were treated with artemether. Treatment reduced urinary excretion of albumin and tubular injury biomarkers, increased serum albumin and total protein levels, and attenuated renal hypertrophy. In addition, artemether treatment prevented hyperglycemia, raised serum insulin levels, and restored glucagon/insulin and somatostatin/insulin ratios in islets. We found that artemether improved mitochondrial function and regulated redox balance in kidney. These results demonstrate that artemether provides renal protection in type 1 diabetes mellitus, which may be due to improved mitochondrial function.

Artemether ameliorates type 2 diabetic kidney disease by increasing mitochondrial pyruvate carrier content in db/db mice.

Diabetic kidney disease (DKD), the leading cause of kidney failure, is characterized by albuminuria and renal hypertrophy. Metabolic alterations and mitochondrial dysfunction play critical roles in DKD initiation and progression. Artemether, a methyl ether derivative of artemisinin used for the treatment of malaria, has been identified as a putative candidate for treating diabetes, but its effect on DKD has not been studied. The goal of this study was to examine the effect of artemether on type 2 diabetic db/db mice. Our results show that artemether reduced urinary albumin excretion, prevented diabetic kidney hypertrophy, attenuated glomerular basement membrane and tubular basement membrane thickening, and ameliorated foot process effacement in type 2 diabetic db/db mice. Artemether also protected against hyperglycemia and improved diabetic symptoms. In addition, it increased serum insulin level and restored the normal ratio of insulin, glucagon, and somatostatin levels in islets. Specifically, artemether increased the respiratory exchange ratio and regulated mitochondrial function and the redox state in the kidney. In conclusion, this experiment confirmed the renal protection ability of artemether in DKD. The mechanisms of this effect might be associated with the ability of artemether to increase mitochondrial pyruvate carrier content.

Niclosamide ethanolamine protects kidney in adriamycin nephropathy by regulating mitochondrial redox balance.

Chronic kidney disease (CKD) is commonly characterized by proteinuria and leads to progressive glomerulosclerosis and tubulointerstitial fibrosis. Accumulating evidence implicates mitochondrial dysfunction including reactive oxygen species (ROS) overproduction in the pathogenesis of CKD. Mitochondrial function and ROS production are regulated by mitochondrial uncoupling. Niclosamide ethanolamine salt (NEN) is a mild mitochondrial uncoupler, which reduces urinary albumin excretion in mice with diabetic kidney disease. However, its role in nondiabetic kidney disease has not been investigated. Here we show that NEN exerts renoprotective effects in adriamycin induced nondiabetic kidney disease. It reduces urinary protein excretion, restores podocyte function, ameliorates renal pathological injury, and decreases the excretion of the urinary tubular injury biomarkers NGAL and Kim-1. Specifically, NEN uncouples isolated kidney mitochondria, and dose-dependently decreases the renal production and urinary excretion of H2O2. Moreover, NEN increases catalase and PGC-1α expression, which might accelerate H2O2 scavenging. The results of this study provide the first evidence that NEN protects kidney in nondiabetic kidney disease by regulating redox balance.

A novel mutation in a Chinese family with autosomal recessive Alport syndrome: a case report.

Alport syndrome (AS) is a familial hereditary nephropathy which is characterized by molecular abnormalities in Collagen IV a345. As more gene mutations are discovered, it has been reported that autosomal recessive disease accounts for a smaller proportion (about 4%) of AS patients than previously recognized. We report here a novel mutation in COL4A4 in a Chinese family with autosomal recessive AS. Patient 1 was a 24-year-old Chinese man. He and his brother (patient 2) had a history of proteinuria and hematuria with renal dysfunction and sensorineural deafness. Pathologic findings were consistent with Alport syndrome, and genetic analysis revealed that both patients had two heterozygous mutations, c.1423 G>T (p.Gly475Cys) in EX21/CDS20 and c.735 G>A (p.Pro245Pro) in EX12/CDS11, and that each mutation originated from their mother or father who were carriers for one of these two mutations. Both patients showed similar results by laboratory examination and histopathologic assessment. Patient 1 received ACEI treatment and ran a stable clinical course, whereas patient 2 refused ACEI treatment and had progressive deterioration of renal function. This is the first report of a novel mutation in the collagen domain of COL4A4 gene. The results add to the spectrum of mutations in COL4A4 of Alport syndrome.

Niclosamide ethanolamine improves kidney injury in db/db mice.

AIMS: Early diabetic kidney disease (DKD) is characterized by renal hypertrophy and albuminuria. The mTOR signal pathway is closely related to DKD. This study was performed to determine the renal protection of niclosamide ethanolamine salt (NEN) which was identified as mTOR inhibitor. METHODS: Type 2 diabetes (T2D) db/db mice were used and divided into db/db and db/db + NEN groups. Lean wild type mice served as T2D-control. NEN treatment lasted for 12 weeks. The kidney morphological changes, urine indices, blood glucose and metabolic symptoms were evaluated. In addition, the effects of NEN on kidney mitochondria and mTOR/4E-BP pathway were also measured. RESULTS: NEN could prevent diabetic kidney hypertrophy and alleviate glomerular mesangial expansion, attenuate GBM and TBM thickening in db/db mice. It also restored podocyte dysfunction, reduced urinary albumin, NAG, NGAL, and TGF-ß1 excretion. Specifically, it could uncouple kidney mitochondria and significantly inhibit renal cortical activation of mTOR/4E-BP1 pathway. CONCLUSIONS: This study demonstrated that NEN could improve kidney injury in db/db mice and has the potential to translate to future clinical studies.

Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2-ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice.

Objective The aim of this study was to investigate the renoprotective effects and molecular mechanisms of astragaloside IV (AS-IV) in streptozotocin (STZ)-induced diabetic mice. Methods Male C57BL/6 mice were injected intraperitoneally with STZ at 200 mg/kg body weight. AS-IV was administered for 8 consecutive weeks, beginning 1 week after STZ injection. Body weight, 24-hour urinary albumin excretion, and fasting blood glucose were measured. Kidney tissues were examined by histopathological analyses. Total levels and phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal S6 kinase 2 (RSK2) were determined by Western blotting analysis. Results AS-IV treatment significantly reduced albuminuria and serum creatinine levels, ameliorated mesangial matrix expansion and greater foot process width, and decreased the levels of urinary N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and transforming growth factor-beta 1 in STZ-induced diabetic mice. AS-IV also inhibited renal cortical phosphorylation of MEK1/2, ERK1/2 and RSK2. Conclusion Our results suggest that AS-IV attenuates renal injury in STZ-induced diabetic mice. This effect might be partially associated with inhibition of the activation of the MEK1/2-ERK1/2-RSK2 signaling pathway.

Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

Diabetes and its renal complications are major medical challenges worldwide. There are no effective drugs currently available for treating diabetes and diabetic kidney disease (DKD), especially in type 1 diabetes (T1D). Evidence has suggested that niclosamide ethanolamine salt (NEN) could improve diabetic symptoms in mice of type 2 diabetes (T2D). However, its role in T1D and DKD has not been studied to date. Here we report that NEN could protect against diabetes in streptozotocin (STZ) induced T1D mice. It increased serum insulin levels, corrected the unbalanced ratio of α-cells to ß-cells, and induced islet morphologic changes under diabetic conditions. In addition, NEN could impede the progression of DKD in T1D. Specifically, it reduced urinary albumin levels, NAG, NGAL and TGF-ß1 excretion, ameliorated renal hypertrophy, alleviated podocyte dysfunction, and suppressed the renal cortical activation of mTOR/4E-BP1 signaling pathway. Moreover, it is hepatoprotective and does not exhibit heart toxicity. Therefore, these findings open up a completely novel therapy for diabetes and DKD.

Resveratrol Improves Muscle Atrophy by Modulating Mitochondrial Quality Control in STZ-Induced Diabetic Mice.

SCOPE: In this study, we aim to determine the effects of resveratrol (RSV) on muscle atrophy in streptozocin-induced diabetic mice and to explore mitochondrial quality control (MQC) as a possible mechanism. METHODS AND RESULTS: The experimental mice were fed either a control diet or an identical diet containing 0.04% RSV for 8 weeks. Examinations were subsequently carried out, including the effects of RSV on muscle atrophy and muscle function, as well as on the signaling pathways related to protein degradation and MQC processes. The results show that RSV supplementation improves muscle atrophy and muscle function, attenuates the increase in ubiquitin and muscle RING-finger protein-1 (MuRF-1), and simultaneously attenuates LC3-II and cleaved caspase-3 in the skeletal muscle of diabetic mice. Moreover, RSV treatment of diabetic mice results in an increase in mitochondrial biogenesis and inhibition of the activation of mitophagy in skeletal muscle. RSV also protects skeletal muscle against excess mitochondrial fusion and fission in the diabetic mice. CONCLUSION: The results suggest that RSV ameliorates diabetes-induced skeletal muscle atrophy by modulating MQC.

Renalase overexpression in ER-positive breast cancer.

OBJECTIVES: To explore the expression and pathologic significance of renalase in tumor tissues of different molecular subtypes of breast cancer. DESIGN: Immunofluorescence methods and laser confocal scanning microscope observations were used to detect expression of renalase, estrogen receptor (ER), phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (p-STAT3) in 58 cases of breast cancer tissue, 11 normal tissues, and 14 benign fibroadenomas. Statistical analysis of its expression in different molecular subtypes of breast cancer was employed. RESULTS: Compared with control tissue (benign lesions and normal breast tissue), renalase was highly expressed in invasive breast cancer and the difference was significant (P<0.0001). Renalase was also expressed significantly higher in ER-positive breast cancer, compared with control tissue (P<0.0001). There was a positive correlation between renalase and ER expression in breast cancer tissues (R=0.7246, P<0.0001) and a positive correlation between renalase and p-ERK 1/2 expression (R=0.6599, P<0.0001). Renalase had no significant correlation with p-STAT3 protein expression. CONCLUSION: Renalase is a new molecular marker for ER-positive breast cancer and may become a potential therapeutic target for the ER-positive/HER2-negative subtype breast cancer. Renalase may promote high ER expression and breast cancer cell proliferation and growth through the p-ERK1/2 pathway.