Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.

α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway.

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.

Nuclear Factor Erythroid 2 Related Factor 2 and Mitochondria Form a Mutually Regulating Circuit in the Prevention and Treatment of Metabolic Syndrome.

Significance: Metabolic syndrome (MetS) has become a major global public health problem and there is an urgent need to elucidate its pathogenesis and find more effective targets and modalities for intervention. Recent Advances: Oxidative stress and inflammation are two of the major causes of MetS-related symptoms such as insulin resistance and obesity. Nuclear factor erythroid 2 related factor 2 (Nrf2) is one of the important systems responding to oxidative stress and inflammation. As cells undergo stress, cysteines within Kelch-like ECH-associated protein 1 (Keap1) are oxidized or electrophilically modified, allowing Nrf2 to escape ubiquitination and be translocated from the cytoplasm to the nucleus, facilitating the initiation of the antioxidant transcriptional program. Meanwhile, a growing body of evidence points out a specific modulation of mitochondrial homeostasis by Nrf2. After nuclear translocation, Nrf2 activates downstream genes involved in various aspects of mitochondrial homeostasis, including mitochondrial biogenesis and dynamics, mitophagy, aerobic respiration, and energy metabolism. In turn, mitochondria reciprocally activate Nrf2 by releasing reactive oxygen species and regulating antioxidant enzymes. Critical Issues: In this review, we first summarize the interactions between Nrf2 and mitochondria in the modulation of oxidative stress and inflammation to ameliorate MetS, then propose that Nrf2 and mitochondria form a mutually regulating circuit critical to maintaining homeostasis during MetS. Future Directions: Targeting the Nrf2-mitochondrial circuit may be a promising strategy to ameliorate MetS, such as obesity, diabetes, and cardiovascular diseases.

Long-term simulated microgravity fosters carotid aging-like changes via Piezo1.

AIMS: Elucidating the impacts of long-term spaceflight on cardiovascular health is urgently needed in face of the rapid development of human space exploration. Recent reports including the NASA Twins Study on vascular deconditioning and aging of astronauts in spaceflight are controversial. The aims of this study were to elucidate whether long-term microgravity promotes vascular aging and the underlying mechanisms. METHODS AND RESULTS: Hindlimb unloading (HU) by tail suspension was used to simulate microgravity in rats and mice. The dynamic changes of carotid stiffness in rats during 8 weeks of HU were determined. Simulated microgravity led to carotid artery aging-like changes as evidenced by increased stiffness, thickness, fibrosis, and elevated senescence biomarkers in the HU rats. Specific deletion of the mechanotransducer Piezo1 in vascular smooth muscles significantly blunted these aging-like changes in mice. Mechanistically, mechanical stretch-induced activation of Piezo1 elevated microRNA-582-5p in vascular smooth muscle cells, with resultant enhanced synthetic cell phenotype and increased collagen deposition via PTEN/PI3K/Akt signalling. Importantly, inhibition of miRNA-582-5p alleviated carotid fibrosis and stiffness not only in HU rats but also in aged rats. CONCLUSIONS: Long-term simulated microgravity induces carotid aging-like changes via the mechanotransducer Piezo1-initiated and miRNA-mediated mechanism.

SOX10 deficiency-mediated LAMB3 upregulation determines the invasiveness of MAPKi-resistant melanoma.

Melanoma that develops adaptive resistance to MAPK inhibitors (MAPKi) through transcriptional reprograming-mediated phenotype switching is associated with enhanced metastatic potential, yet the underlying mechanism of this improved invasiveness has not been fully elucidated. In this study, we show that MAPKi-resistant melanoma cells are more motile and invasive than the parental cells. We further show that LAMB3, a ß subunit of the extracellular matrix protein laminin-332 is upregulated in MAPKi-resistant melanoma cells and that the LAMB3-Integrin α3/α6 signaling mediates the motile and invasive phenotype of resistant cells. In addition, we demonstrate that SOX10 deficiency in MAPKi-resistant melanoma cells drives LAMB3 upregulation through TGF-ß signaling. Transcriptome profiling and functional studies further reveal a FAK/MMPs axis mediates the pro-invasiveness effect of LAMB3. Using a mouse lung metastasis model, we demonstrate LAMB3 depletion inhibits the metastatic potential of MAPKi-resistant cells in vivo. In summary, this study identifies a SOX10low/TGF-ß/LAMB3/FAK/MMPs signaling pathway that determines the migration and invasion properties of MAPKi-resistant melanoma cells and provide rationales for co-targeting LAMB3 to curb the metastasis of melanoma cells in targeted therapy.

Hydrogen: A Rising Star in Gas Medicine as a Mitochondria-Targeting Nutrient via Activating Keap1-Nrf2 Antioxidant System.

The gas molecules O2, NO, H2S, CO, and CH4, have been increasingly used for medical purposes. Other than these gas molecules, H2 is the smallest diatomic molecule in nature and has become a rising star in gas medicine in the past few decades. As a non-toxic and easily accessible gas, H2 has shown preventive and therapeutic effects on various diseases of the respiratory, cardiovascular, central nervous system, and other systems, but the mechanisms are still unclear and even controversial, especially the mechanism of H2 as a selective radical scavenger. Mitochondria are the main organelles regulating energy metabolism in living organisms as well as the main organelle of reactive oxygen species' generation and targeting. We propose that the protective role of H2 may be mainly dependent on its unique ability to penetrate every aspect of cells to regulate mitochondrial homeostasis by activating the Keap1-Nrf2 phase II antioxidant system rather than its direct free radical scavenging activity. In this review, we summarize the protective effects and focus on the mechanism of H2 as a mitochondria-targeting nutrient by activating the Keap1-Nrf2 system in different disease models. In addition, we wish to provide a more rational theoretical support for the medical applications of hydrogen.

Melatonin Restores Autophagic Flux by Activating the Sirt3/TFEB Signaling Pathway to Attenuate Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.

Conjugation of Triterpenic Acids of Ursane and Oleanane Types with Mitochondria-Targeting Cation F16 Synergistically Enhanced Their Cytotoxicity against Tumor Cells.

The present work shows the cytotoxic effects of novel conjugates of ursolic, oleanolic, maslinic, and corosolic acids with the penetrating cation F16 on cancer cells (lung adenocarcinoma A549 and H1299, breast cancer cell lines MCF-7 and BT474) and non-tumor human fibroblasts. It has been established that the conjugates have a significantly enhanced toxicity against tumor-derived cells compared to native acids and also demonstrate selectivity to some cancer cells. The toxic effect of the conjugates is shown to be due to ROS hyperproduction in cells, induced by the effect on mitochondria. The conjugates caused dysfunction of isolated rat liver mitochondria and, in particular, a decrease in the efficiency of oxidative phosphorylation, a decrease in the membrane potential, and also an overproduction of ROS by organelles. The paper discusses how the membranotropic- and mitochondria-targeted effects of the conjugates may be related to their toxic effects.

Hydrogen Protection Boosts the Bioactivity of Chrysanthemum morifolium Extract in Preventing Palmitate-Induced Endothelial Dysfunction by Restoring MFN2 and Alleviating Oxidative Stress in HAEC Cells.

As the most important natural antioxidants in plant extracts, polyphenols demonstrate versatile bioactivities and are susceptible to oxidation. The commonly used ultrasonic extraction often causes oxidation reactions involving the formation of free radicals. To minimize the oxidation effects during the ultrasonic extraction process, we designed a hydrogen (H2)-protected ultrasonic extraction method and used it in Chrysanthemum morifolium extraction. Hydrogen-protected extraction improved the total antioxidant capacity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, and polyphenol content of Chrysanthemum morifolium water extract (CME) compared with air and nitrogen (N2) conditions. We further investigated the protective effects and mechanisms of CME on palmitate (PA)-induced endothelial dysfunction in human aorta endothelial cells (HAECs). We found that hydrogen-protected CME (H2-CME) best-prevented impairment in nitric oxide (NO) production, endothelial NO synthase (eNOS) protein level, oxidative stress, and mitochondrial dysfunction. In addition, H2-CME prevented PA-induced endothelial dysfunction by restoring mitofusin-2 (MFN2) levels and maintaining redox balance.

Thinned young apple polyphenols may prevent neuronal apoptosis by up-regulating 5-hydroxymethylcytosine in the cerebral cortex of high-fat diet-induced diabetic mice.

Apple polyphenols exert neuroprotective effects by improving the mitochondrial tricarboxylic acid (TCA) cycle function, but the details of their mechanisms are still not fully understood. TCA cycle metabolites regulate the level of 5-hydroxymethylcytosine (5hmC) by affecting the ten-eleven translocation (TET) enzyme activity. Therefore, we hypothesized that thinned young apple polyphenols (TYAPs) inhibit neuronal apoptosis by up-regulating the level of 5hmC in the cerebral cortex of high-fat diet-induced diabetic mice. C57BL/6J mice were randomly divided into 5 groups (n = 10 each group): the control (CON) group, the high-fat diet (HFD, negative control) group, the lovastatin (LOV, positive drug control) group, the resveratrol (RES, positive polyphenol control) group and the TYAP group during an eight-week intervention. The presented results verified that in the HFD group, the level of 5hmC and the expression of TET2 in the cerebral cortex were significantly lower, and the ratio of (succinic acid + fumaric acid)/α-ketoglutarate and the neuronal apoptosis rate were significantly higher than those in the CON group. However, TYAP intervention effectively restored the level of 5hmC through up-regulating the expression and activity of TET2, so as to improve diabetes symptoms and prevent diabetes-induced neuronal apoptosis.

Hydroxytyrosol improves strenuous exercise-associated cardiac pathological changes via modulation of mitochondrial homeostasis.

Strenuous exercise is reported to provoke deleterious consequences including cardiac impairments, while the detailed mechanisms and effective interventions remain limited. The current study aims to explore the profitable effects of hydroxytyrosol (HT), one of the most abundant polyphenols derived from olive oil, on strenuous exercise-induced pathological changes in the heart and its underlying mechanisms. Sprague-Dawley male rats at the age of 8-week-old were supplemented with 25 mg kg-1 day-1 of HT 45 min before the beginning of strenuous exercise for a total of 8 weeks. HT treatment obviously improved the heart weight and morphology with lowered serum cardiac hypertrophy markers as well as cardiac oxidative stress. Moreover, the down-regulated mitochondrial biogenesis pathway, impaired mitochondrial complex activity, dysregulated expression of mitochondrial dynamics-related proteins and activated apoptotic pathway induced by Exe were all improved by HT. In vitro, 10 µM HT effectively reduced the reactive oxygen species level, promoted mitochondrial biogenesis, and inhibited apoptosis and cardiomyocyte hypertrophy in an angiotensin II-induced cardiomyocyte hypertrophy model. In addition, knockdown of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha, the key regulator of mitochondrial biogenesis, partially abolished the benefits of HT. Our results demonstrate that the disturbance of mitochondrial homeostasis plays a substantial role in strenuous exercise-induced pathological cardiac hypertrophy, and HT presents as an effective intervention strategy targeting mitochondrial homeostasis for cardiac health.

Daphnetin ameliorates Aß pathogenesis via STAT3/GFAP signaling in an APP/PS1 double-transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has become a major public health problem that affects the elderly population. Therapeutic compounds with curative effects are not available due to the complex pathogenesis of AD. Daphnetin, a natural coumarin derivative and inhibitor of various kinases, has anti-inflammatory and antioxidant activities. In this study, we found that daphnetin improved spatial learning and memory in an amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mouse model of AD. Daphnetin markedly decreased the levels of amyloid-ß peptide 1-40 (Aß40) and 1-42 (Aß42) in the cerebral cortex, downregulated the expressions of enzymes involved in APP processing, e.g., beta-site APP-cleaving enzyme (BACE), nicastrin and presenilin enhancer protein 2 (PEN2). We further found the reduced serum levels of inflammatory factors, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and chemokine (C-C motif) ligand 3 (CCL3), while daphnetin increased total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels in the serum. Interestingly, daphnetin markedly decreased the expression of glial fibrillary acidic protein (GFAP) and the upstream regulatory molecule- phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in APP/PS1 mice, and mainly inhibited the phosphorylation of STAT3 at Ser727 to decrease GFAP expression evidenced in a LPS-activated glial cell model. These results suggest that daphnetin ameliorates cognitive deficits and that Aß deposition in APP/PS1 mice is mainly correlated with astrocyte activation and APP processing.

Choledocholithiasis characteristics with periampullary diverticulum and endoscopic retrograde cholangiopancreatography procedures: Comparison between two centers from Lanzhou and Kyoto.

BACKGROUND: Most of study regarding periampullary diverticulum (PAD) impact on endoscopic retrograde cholangiopancreatography (ERCP) therapy for choledocholithiasis based on data from one endoscopy center and lacked to compare the clinical characteristic of choledocholithiasis with PAD from different geographical patients. AIM: To compare the choledocholithiasis clinical characteristics between two regional endoscopy centers and analyze impacts of clinical characteristics on ERCP methods for choledocholithiasis patients with PAD. METHODS: Patients seen in two endoscopy centers (The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China, and Kyoto Second Red Cross Hospital, Kyoto, Japan) underwent ERCP treatment for the first time between January 2012 and December 2017. The characteristics of choledocholithiasis with PAD were compared between the two centers, and their ERCP procedures and therapeutic outcomes were analyzed. RESULTS: A total of 829 out of 3608 patients in the Lanzhou center and 241 out of 1198 in the Kyoto center had choledocholithiasis with PAD. Lots of clinical characteristics were significantly different between the two centers. The common bile duct (CBD) diameter was wider, choledocholithiasis size was lager and multiple CBD stones were more in the Lanzhou center patients than those in the Kyoto center patients (14.8 ± 5.2 mm vs 11.6 ± 4.2 mm, 12.2 ± 6.5 mm vs 8.2 ± 5.3 mm, 45.3% vs 20.3%, P < 0.001 for all). In addition, concomitant diseases, such as acute cholangitis, gallbladder stones, obstructive jaundice, cholecystectomy, and acute pancreatitis, were significantly different between the two centers (P = 0.03 to < 0.001). In the Lanzhou center, CBD diameter and choledocholithiasis size were lower, and multiple CBD stones and acute cholangitis were less in non-PAD patients than those in PAD patients (13.4 ± 5.1 mm vs 14.8 ± 5.2 mm, 10.3 ± 5.4 mm vs 12.2 ± 6.5, 39% vs 45.3%, 13.9% vs 18.5%, P = 0.002 to < 0.001). But all these characteristics were not significantly different in the Kyoto center. The proportions of endoscopic sphincterotomy (EST), endoscopic balloon dilatation (EPBD), and EST+EPBD were 50.5%, 1.7%, and 42.5% in the Lanzhou center and 90.0%, 0.0%, and 0.4% in the Kyoto center, respectively. However, the overall post-ERCP complication rate was not significantly different between the two centers (8.9% in the Lanzhou and 5.8% in the Kyoto. P = 0.12). In the Lanzhou center, the difficulty rate in removing CBD stones in PAD was higher than in non-PAD group (35.3% vs 26.0%, P < 0.001). But the rate was no significant difference between the two groups in Kyoto center. The residual rates of choledocholithiasis were not significantly different between the two groups in both centers. Post-ERCP complications occurred in 8.9% of the PAD patients and 8.1% of the non-PAD patients in the Lanzhou Center, and it occurred in 5.8% in PAD patients and 10.0% in non-PAD patients in the Kyoto center, all P > 0.05. CONCLUSION: Many clinical characteristics of choledocholithiasis patients with PAD were significantly different between the Lanzhou and Kyoto centers. The patients had larger and multiple stones, wider CBD diameter, and more possibility of acute cholangitis and obstructive jaundice in the Lanzhou center than those in the Kyoto center. The ERCP procedures to manage native duodenal papilla were different depending on the different clinical characteristics while the overall post-ERCP complications were not significantly different between the two centers. The stone residual rate and post-ERCP complications were not significantly different between choledocholithiasis patients with PAD and without PAD in each center.

Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc.

MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.

The Association of Trefoil Factors with Gastric Cancer and Premalignant Lesions: A Cross-Sectional Population-Based Cohort Study.

BACKGROUND: A lack of research on the association of trefoil factors (TFF) with gastric cancer and premalignant lesions (PML) in the general population is an important obstacle to the application of TFFs for gastric cancer screening. We aimed to analyze the association of TFFs with gastric cancer and PMLs in a general population. METHODS: We evaluated 3,986 adults residing in Wuwei, China. We collected baseline characteristics and gastric cancer risk factors, including TFFs, endoscopic diagnosis, and pathologic information. Three logistic regression models were generated to analyze the association between TFFs and gastric cancer, as well as PMLs. Adjusted odds ratio (OR) and 95% confidence intervals (95% CI) were calculated to determine the strength of association. RESULTS: Compared with pepsinogen (PG) and anti-Helicobacter pylori immunoglobulin G antibody (Hp-IgG), TFFs had significant association with gastric cancer and PMLs after adjusting for biomarkers and risk factors (P < 0.05). The ORs (95% CI) for TFF1 (1.67; 1.27-2.20), TFF2 (2.66; 2.01-3.51), and TFF3 (1.32; 1.00-1.74) were larger than the ORs for PGI (0.79; 0.61-1.03), PGI/II (1.00; 0.76-1.31), and Hp-IgG (0.99; 0.73-1.35) in the gastric cancer group. In the intestinal metaplasia (IM) group, not only the TFF3 serum level was the highest, but also the OR (1.92; 1.64-2.25) was the highest. CONCLUSIONS: TFFs were associated with risk of gastric cancer and PMLs. IMPACT: Serum TFFs can improve the screening of high-risk populations for gastric cancer.

A nascent protein labeling strategy disclosed mitochondrial proteomic responses in punicalagin intervened insulin resistance of HepG2 cells.

Insulin resistance (IR), as a common pathophysiological basis, is closely related to a variety of metabolic diseases, such as obesity and diabetes. IR is often accompanied by mitochondrial dysfunction which could be induced by a high fat diet. Punicalagin (PU), a natural compound extracted from pomegranate, could ameliorate palmitate-induced IR. However, the underlying mechanisms are not well known. We propose that understanding the proteomic response of mitochondria may help define the mechanisms of PU in the prevention of IR. Most of the mitochondrial proteins are encoded by nuclear genes and transported from cytoplasm. To distinguish newly incorporated proteins responding to stimuli from pre-existing mitochondrial proteome, nascent proteins in HepG2 cells were pulse labeled by an amino acid analog L-azidohomoalanine. Nascent nuclear encoded mitochondrial proteins were enriched by click reaction followed by mass detection. Our data showed that PU increased nuclear encoded protein incorporation to mitochondria in general though the total protein levels remained immobile. To decipher this phenomenon, we tested the protein and mRNA levels of genes related to mitophagy and mitochondrial biogenesis and found that the mitochondrial turnover was accelerated by PU treatment. By the nascent protein labeling strategy and pathway analysis, we enriched the newly incorporated proteins of mitochondria for responding to PU treatment and found that PU induced nascent protein incorporation into mitochondria and enhanced mitochondrial turnover. These findings demonstrate that PU prevents IR by targeting mitochondria, and thus, is an effective natural nutrient beneficial for mitochondrial turnover.

Post-translational modifications on mitochondrial metabolic enzymes in cancer.

Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment.

Risk factors in the development of gastric adenocarcinoma in the general population: A cross-sectional study of the Wuwei Cohort.

Several risk factors have been identified for the development of gastric adenocarcinoma (GAC), where the control group was usually a healthy population. However, it is unclear at what stage known risk factor exert their influence toward the progression to cancer. Based on the Wuwei Cohort, we enrolled 1,739 patients with chronic non-atrophic gastritis (no-CAG), 3,409 patients with chronic atrophic gastritis (CAG), 1,757 patients with intestinal metaplasia (IM), 2,239 patients with low-grade dysplasia (LGD), and 182 patients with high-grade dysplasia (HGD) or GAC to assess the risk factors between each two consecutive stages from no-CAG to GAC/HGD using adjusted logistic regression. We found that different groups of risk factors were associated with different stages. Age, occupation of farmer, low annual family income, Helicobacter pylori (H. pylori) infection, drinking, eating hot food, histories of gastritis and peptic ulcer were associated with the development of CAG. Age, illiteracy, H. pylori infection, smoking, eating hot food, eating quickly, and histories of gastritis and gallbladder diseases were associated with the progression to IM from CAG. Male, occupation of farmer and history of peptic ulcer were associated with the development of LGD from IM. Age, male and polyp history appeared to be risk factors associated with the development of GAC/HGD from LGD. In conclusion, it seems that most risk factors function more as a set of switches that initiated the GAC carcinogenesis. H. Pylori eradication and control of other risk factors should be conducted before IM to decrease the incidence of GAC.