OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways.

BACKGROUND AND AIMS: NAFLD is considered as the hepatic manifestation of the metabolic syndrome, which includes insulin resistance, obesity and hyperlipidemia. NASH is a progressive stage of NAFLD with severe hepatic steatosis, hepatocyte death, inflammation, and fibrosis. Currently, no pharmacological interventions specifically tailored for NASH are approved. Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), the founding member of deubiquitinases, regulates many metabolism-associated signaling pathways. However, the role of OTUB1 in NASH is unclarified. METHODS AND RESULTS: We demonstrated that mice with Otub1 deficiency exhibited aggravated high-fat diet-induced and high-fat high-cholesterol (HFHC) diet-induced hyperinsulinemia and liver steatosis. Notably, hepatocyte-specific overexpression of Otub1 markedly alleviated HFHC diet-induced hepatic steatosis, inflammatory responses, and liver fibrosis. Mechanistically, we identified apoptosis signal-regulating kinase 1 (ASK1) as a key candidate target of OTUB1 through RNA-sequencing analysis and immunoblot analysis. Through immunoprecipitation-mass spectrometry analysis, we further found that OTUB1 directly bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppressed its lysine 63-linked polyubiquitination, thus inhibiting the activation of ASK1 and its downstream pathway. CONCLUSIONS: OTUB1 is a key suppressor of NASH that inhibits polyubiquitinations of TRAF6 and attenuated TRAF6-mediated ASK1 activation. Targeting the OTUB1-TRAF6-ASK1 axis may be a promising therapeutic strategy for NASH.

Feasibility of Using a Portable MyotonPRO Device to Quantify the Elastic Properties of Skeletal Muscle.

BACKGROUND The aims of this study were to (1) calculate the correlation between different tensile force levels and corresponding muscle stiffness both in vitro and in vivo; (2) determine whether muscle stiffness assessed using a MyotonPRO myotonometer can be used to accurately estimate muscle activity level; and (3) evaluate the inter-operator reliability of MyotonPRO-based measurement in assessing biceps brachii muscle (BBM) stiffness. MATERIAL AND METHODS In Experiment I, muscle stiffness, as measured using the MyotonPRO, was obtained at 0 N, 2 N, 4 N, 6 N, 8 N, and 10 N of applied force on 6 fresh medial gastrocnemius muscle specimens. In Experiment II, 11 healthy subjects were recruited. BBM stiffness, assessed by the same device, was obtained at different tensile force levels, from 0 to 50% of maximal voluntary contraction (MVC). For the reliability test, the score for each subject was quantified by 2 operators (I and II), thrice, at 30-minute intervals on the same day. RESULTS A strong correlation was found between the different tensile force levels, which corresponded to muscle stiffness in vitro (r=0.71-0.95, all P<0.05). In vivo, muscle stiffness increased linearly with an increase of the tensile force levels from 0 to 50% of MVC (r=0.99, P=0.00) and there was a significant difference in BBM stiffness among the incremental isometric tasks (F [1.76, 17.60]=91.52, P=0.00). The inter-operator reliability for the measurement of BBM stiffness was good (ICC=0.86). CONCLUSIONS Our findings indicate that muscle stiffness measured using the MyotonPRO is strongly related to muscle activity level and that the MyotonPRO is a feasible tool for quantifying BBM stiffness as well as for quantifying changes in MVC levels.

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD-induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogen-activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.

Finding a resveratrol analogue as potential anticancer agent with apoptosis and cycle arrest.

Resveratrol has been extensively studied as the anti-cancer agent. A variety of resveratrol analogues have been developed with structural modification to improve its bioactivity. In this work, resveratrol analogues, compound 1-4, were designed and synthesized with the Stille-Heck reaction. These results showed compound 1-4 had better anticancer effect than that of parent resveratrol. Especially compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3-methylphenol)) displayed the excellent cytotoxicity and high selectivity. The mechanism research indicated compound 1 inhibited cell proliferation by binary paths of cell cycle arrest in S phase regulated by cyclin A1/A2 and apoptosis induction mediated by Bax/Bcl2 in a prooxidant manner.

Quantifying the Stiffness of Achilles Tendon: Intra- and Inter-Operator Reliability and the Effect of Ankle Joint Motion.

BACKGROUND The objectives of the present study were to examine the intra- and inter-operator reliability of the MyotonPRO device in quantifying the stiffness of the Achilles tendon and the device's ability to examine the modulation in stiffness of the Achilles tendon during ankle joint flexion. MATERIAL AND METHODS Twenty asymptomatic participants (10 males and 10 females; mean age: 25.0±3.1 years) were recruited for this study. The stiffness of the Achilles tendon was quantified using the MyotonPRO device. RESULTS The results revealed excellent intra- and inter-operator reliability for quantifying Achilles tendon stiffness with the ankle joint in a neutral position and detected a 13.9% increase in stiffness of the Achilles tendon between 0° and 30° of ankle joint flexion. The minimal detectable change (MDC) in tendon stiffness was 45 Newton/meter (N/m). CONCLUSIONS Our findings indicated that the MyotonPRO device is a feasible method to quantify the stiffness of the Achilles tendon and monitor its changes. Thus, it is an essential tool to use to examine the modulation in the stiffness of the Achilles tendon due to pathology or interventions for future studies.

Attacker-defender game from a network science perspective.

Dealing with the protection of critical infrastructures, many game-theoretic methods have been developed to study the strategic interactions between defenders and attackers. However, most game models ignore the interrelationship between different components within a certain system. In this paper, we propose a simultaneous-move attacker-defender game model, which is a two-player zero-sum static game with complete information. The strategies and payoffs of this game are defined on the basis of the topology structure of the infrastructure system, which is represented by a complex network. Due to the complexity of strategies, the attack and defense strategies are confined by two typical strategies, namely, targeted strategy and random strategy. The simulation results indicate that in a scale-free network, the attacker virtually always attacks randomly in the Nash equilibrium. With a small cost-sensitive parameter, representing the degree to which costs increase with the importance of a target, the defender protects the hub targets with large degrees preferentially. When the cost-sensitive parameter exceeds a threshold, the defender switches to protecting nodes randomly. Our work provides a new theoretical framework to analyze the confrontations between the attacker and the defender on critical infrastructures and deserves further study.

The impact of Zearalenone on the meiotic progression and primordial follicle assembly during early oogenesis.

Zearalenone (ZEA) is a mycotoxin produced by fusarium graminearum. It can cause abnormal reproductive function by acting as an environmental estrogen. Research has traditionally focused on acute and chronic injury on mammalian reproductive capacity after ZEA treatment. Little research has been done studying the effects of ZEA exposure on early oogenesis. In this study, we investigate the effects of ZEA exposure on meiotic entry, DNA double-strand breaks (DSBs), and primordial follicle assembly during murine early oogenesis. The results show that ZEA exposure significantly decreased the percentage of diplotene stage germ cells, and made more germ cells remain at zygotene or pachytene stages. Moreover, the mRNA expression level of meiosis-related genes was significantly reduced after ZEA treatment. ZEA exposure significantly increased DNA-DSBs at the diplotene stage. Meanwhile, DNA damage repair genes such as RAD51 and BRCA1 were activated. Furthermore, maternal exposure to ZEA significantly decreased the number of primordial follicles in newborn mouse ovaries. In conclusion, ZEA exposure impairs mouse female germ cell meiotic progression, DNA-DSBs, and primordial follicle assembly.

Zearalenone exposure impairs ovarian primordial follicle formation via down-regulation of Lhx8 expression in vitro.

Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on primordial follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and primordial follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30µM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and γH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2. Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 (Lhx8), newborn ovary homeobox (Nobox), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and factor in the germline alpha (Figlα) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3'-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse primordial follicle formation in vitro.

HAp/Ti2Ni coatings of high bonding strength on Ti-6Al-4V prepared by the eutectic melting bonding method.

Eutectic melting bonding (EMB) method is a useful technique for fabricating bioactive coatings with relatively high crystallinity and bonding strength with substrate on titanium substrates. Using the EMB method, hydroxyapatite/Ti2Ni coatings were prepared on the surface of Ti-6Al-4V at a relatively low temperature (1,050 °C) in a vacuum furnace. The coatings were then characterized in terms of phase components, microstructure, bonding strength and cytotoxicity. The results showed that the coatings were mainly composed of HAp and Ti2Ni, and the thickness of the coatings was approximately 300 µm. X-ray diffraction analysis showed that the coatings exhibited relatively high crystallinity. The tensile bonding strength between the coatings and the substrates was 69.68±5.15 MPa. The coatings had a porous and rough surface which is suitable for cell attachment and filopodia growth. The cell culture study showed that the number of MG-63 cells increased, and the cell morphology changed with the incubation time. This study showed that the EMB method can be utilized as a potentially powerful method to obtain high quality hydroxyapatite coatings with desired mechanical and biocompatibility properties on Ti-alloy substrates.

Melanoma differentiation-associated protein 5 prevents cardiac hypertrophy via apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 signaling.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target.

[Epidemic features of dyslipidemia among Uygur, Kazakh, and Han adults in Xinjiang, China in 2010].

OBJECTIVE: To investigate the prevalence of dyslipidemia among the Uyghur, Kazakh, and Han adults in Xinjiang Region and to analyze the features of distribution. METHODS: 3625 Uygur residents, 1773 males and 1852 females, aged (42.89 ± 15.95) years old, 4148 Kazakh residents, 1649 males and 2499 females, aged (44.14 ± 13.27) years old, and 3733 Han residents, 1563 males and 2170 females, aged (49.66 ± 12.24) years old, were selected by stratified cluster random sampling method in year 2010, 11 506 adults in total. Questionnaire and physical examination were conducted, including fasting venous blood samples to test the levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C). RESULTS: The levels of TG, TC, HDL-C and LDL-C were separately (1.31 ± 1.03), (4.44 ± 1.20), (1.41 ± 0.62), and (2.44 ± 0.81) mmol/L in the Uygur adults; separately (1.24 ± 0.99), (4.55 ± 1.31), (1.41 ± 0.62), and (2.40 ± 0.87) mmol/L in the Kazakh adults; and (1.62 ± 1.34), (4.60 ± 1.10), (1.16 ± 0.68), and (2.23 ± 0.93) mmol/L in the Han adults, respectively. The general prevalence of dyslipidemia in the Uygur, Kazakh, and Han adults were 42.4% (1537/3625), 31.6% (1311/4148), and 30.2% (1127/3733) respectively; while the age-standardized prevalence were separately 42.4%, 31.8%, and 28.2%. The prevalence of dyslipidemia in the Uygur adults was significantly higher than it of the Kazakh and Han adults, with statistical significance (χ(2) = 179.87, P < 0.01). The standardized prevalence of dyslipidemia in the Uygur males was 52.6%, significantly higher than it of the Kazakh and Han males (35.4% and 33.2%), with statistical significance (χ(2) = 159.19, P < 0.01). The prevalence of hypertriglyceridemia among the Han adults was 17.3%, which was significantly higher than it among the Uyghur and Kazakh adults (χ(2) = 172.55, P < 0.01). The prevalence of hypercholesterolemia in Kazakh (6.9%) was higher than it in Uygur (5.2%), with statistical significance (χ(2) = 10.20, P < 0.01). The prevalence of low HDL-C hyperlipidemia in the above 3 ethnic were 33.6%, 20.8% and 11.1%, respectively; while Uygur was the highest (χ(2) = 552.82, P < 0.01), followed by Kazakh, which was higher than Han (χ(2) = 138.01, P < 0.01). There was no significant difference in the prevalence of high LDL-C hyperlipidemia among the adults of the 3 ethnics. CONCLUSION: The prevalence of dyslipidemia among the Uygur, Kazakh, and Han adults in Xinjiang were all higher than the national average prevalence, the distribution of dyslipidemia varied with ethnicity, age and sex.

The Positional Relationship between Lacunae and White Matter Hyperintensity in Patients with Cerebral Small Vessel Disease.

BACKGROUND: Lacunae and white matter hyperintensity (WMH) are two crucial imaging biomarkers of cerebral small vessel disease (CSVD). Multiple studies have revealed a close relationship between WMH and lacunae and found that a double penumbra existed at the edge of WMH that affects lacunae formation. The study aimed to explore the spatial distribution characteristics and possible influencing factors of lacuna in relation to white matter hyperintensity in patients with CSVD. METHODS: A total of 480 CSVD patients with WMH and with or without lacunae were included. Data about blood biochemical indicators, cerebrovascular CT angiography, 24-hour ambulatory blood pressure and ambulatory electrocardiogram, brain magnetic resonance imaging, and transcranial Doppler ultrasound were gathered from all subjects. They were categorised into four groups based on the spatial interaction between lacunae and WMH. Univariate analyses and multiple logistic regression analyses were used to compare the differences in traditional vascular risk factors, heart rate and blood pressure indicators, arterial pulsatility index (PI) values, and arterial stenosis among different groups. RESULTS: The average age of 480 patients was (58.63 ± 11.91) years, with 347 males (72.3%). Univariate analysis indicated that age, fasting blood glucose, triglycerides, total cholesterol, highdensity lipoprotein, 24-hour and daytime and night systolic and diastolic blood pressure, nocturnal heart rate, heart rate variability, PI values of ipsilateral and contralateral MCA (middle cerebral artery) and ICA (Internal carotid artery) of the lacunae, Fazekas score of PWMH (periventricular white matter hyperintensities), the proportion of MCA or ICA with stenosis rate over 50% on the ipsilateral side of the lacunae were significantly different between different groups (p < 0.05). High fasting blood glucose (OR=1.632, 95% CI= (1.128, 2.361), p =0.009), (OR=1.789, 95%CI= (1.270, 2.520), p = 0.001), (OR=1.806, 95% CI= (1.292, 2.524), p =0.001) was identified as a risk factor for lacunae formation by logistic regression analysis. CONCLUSION: High fasting blood glucose can be considered a risk factor for lacunae formation in patients with WMH. The more severe the PWMH and the higher the nocturnal heart rate, the more likely the lacunae, as well as PWMH, overlap completely. Ipsilateral arteriosclerosis and stenosis are independent risk factors for no contact between lacunae and PWMH.

[The study on the UV and fluorescence properties of PAMAM dendrimers].

From 0.5 to 5.0 generation PAMAM dendrimers were synthesized with ethylenediamine core by Michael addition reaction and aminolysis reaction two repeated steps. The structure of dendrimers were confirmed by FTIR 1H NMR 13C NMR MS and all of these measurements showed that they were successfully synthesized. Furthermore, The authors studied the UV and fluorescence properties of different generation dendrimers. Because of diffenent terminal groups, it was found that the whole generation and half generation show different ultraviolet absorption peaks and the intensity of ultraviolet absorption is closely related to the molecular skeleton. There is no traditional fluorescence emission groups, but PAMAM dendrimers show the peculiar phenomenon. In this paper we detailedly studied the factors which affect PAMAM dendrimers fluorescence properties.

Modulation in the Stiffness of Specific Muscles of the Quadriceps in Patients With Knee Osteoarthritis and Their Relationship With Functional Ability.

Deficits in the flexibility of the quadriceps are one of the risk factors for developing knee joint disorders. No studies have investigated the changes in the stiffness of the quadriceps muscle among patients with knee osteoarthritis (OA). Therefore, the purpose of this study was to investigate changes in the stiffness of specific-muscle of the quadriceps in patients with knee OA and their relationship with functional ability. Twenty-five patients with knee OA and 25 healthy, asymptomatic subjects were recruited in this study. The stiffness of the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) in all participants was evaluated using MyotonPRO at 60° and 90° flexion of the knee joint. The results of this study showed a greater VL stiffness in patients with knee OA than in healthy subjects at both 60° and 90° of knee flexion (p < 0.05). Significant differences in VL, VM and RF stiffness were obtained at different knee joint angles in individuals with and without knee OA (p < 0.05). In addition, there was a positive correlation between VL stiffness and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in patients with Knee OA (60° of knee flexion: r = 0.508, p = 0.010; 90° of knee flexion: r = 0.456, p = 0.022). These results indicate that there is an increase in VL stiffness in patients with knee OA compared with healthy, asymptomatic subjects, and the quadriceps stiffness was increased with knee flexion in both healthy subjects and patients with knee OA. VL stiffness is associated with WOMAC scores in patients with knee OA.

Paraffin therapy induces a decrease in the passive stiffness of gastrocnemius muscle belly and Achilles tendon: A randomized controlled trial.

BACKGROUND: The purposes of this study were to examine the feasibility of using the MyotonPRO digital palpation device in measuring the passive stiffness of gastrocnemius muscle belly and Achilles tendon; to determine between-days test-retest reliability of MyotonPRO; and to evaluate the acute effect of paraffin therapy on stiffness measurements in healthy participants. METHODS: It is a randomized controlled trial. Twenty healthy participants (male, n = 10; female, n = 10; total, n = 20) were recruited to evaluate the passive stiffness of gastrocnemius muscle belly and Achilles tendon. Dominant and nondominant legs were randomly divided into an experimental side (20 cases) and a control side (20 cases). The experimental side received 20 minutes of paraffin therapy. RESULTS: The stiffness of muscle and tendon in the experimental side decreased significantly after paraffin therapy (P < .01), whereas no significant differences in stiffness measurements were found in the control side (P > .05). The passive stiffness of muscle and tendon was positively correlated with the ankle from 30° plantar flexion to10° dorsiflexion for dominant legs. Between-days test-retest reliability in stiffness measurements was high or very high (ICCs were above 0.737). CONCLUSION: Paraffin therapy induces a decrease in the passive stiffness of gastrocnemius muscle belly and Achilles tendon. Furthermore, the MyotonPRO can reliably determine stiffness measurements.

Application of a mechanically responsive, inflammatory macrophage-targeted dual-sensitive hydrogel drug carrier for atherosclerosis.

Atherosclerotic lesions create obvious vascular stenosis due to the presence of plaque, and a large number of inflammatory macrophages are enriched in the thrombus. In this study, we develop a composite hydrogel drug delivery system that is capable of both mechanically-sensitive drug release and of targeting inflammatory macrophages at the thrombus. The hydrogel is a high molecular weight hyaluronic acid (HA) modified with glycidyl methacrylate as a hydrogel precursor; a cross-linkable block copolymer (CBC) is used as the drug coating material and a microscopic cross-linking agent. The difference in drug release rate of the composite hydrogel (HACBC) in simulated blood vessels with 0 % and 75 % occlusion was as high as 49.3 %. Under long-term cycling conditions in stenotic vessels, dynamic shear rheometry revealed that the HACBC still maintained the hydrogel properties. However, the micelles were deformed and recombined to produce smaller sized micelles. An in vitro cell culture demonstrated precise targeting of the HACBC to inflammatory macrophages, and our rabbit experiments with simvastatin-coated HACBC confirmed the effective release of simvastatin in the plaque of the drug carrier. Moreover, we demonstrated the precise targeting of HACBC in vivo in apoE-/- mice by using HACBC coated with cy7. The mechanical stress-sensitive and CD44 receptor-targeted dual-response drug delivery system prepared by micellar composite hydrogel is the first application in the field of atherosclerosis, which provides a new method for diagnosing and treating atherosclerosis.

Deubiquitinase Ubiquitin-Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy.

Background Cardiac hypertrophy (CH) is a physiological response that compensates for blood pressure overload. Under pathological conditions, hypertrophy can progress to heart failure as a consequence of the disorganized growth of cardiomyocytes and cardiac tissue. USP10 (ubiquitin-specific protease 10) is a member of the ubiquitin-specific protease family of cysteine proteases, which are involved in viral infection, oxidative stress, lipid drop formation, and heat shock. However, the role of USP10 in CH remains largely unclear. Here, we investigated the roles of USP10 in CH. Methods and Results Cardiac-specific USP10 knockout (USP10-CKO) mice and USP10-transgenic (USP10-TG) mice were used to examined the role of USP10 in CH following aortic banding. The specific functions of USP10 were further examined in isolated cardiomyocytes. USP10 expression was increased in murine hypertrophic hearts following aortic banding and in isolated cardiomyocytes in response to hypertrophic agonist. Mice deficient in USP10 in the heart exhibited exaggerated cardiac hypertrophy and fibrosis following pressure overload stress, which resulted in worsening of cardiac contractile function. In contrast, cardiac overexpression of USP10 protected against pressure overload-induced maladaptive CH. Mechanistically, we demonstrated that USP10 activation and interaction with Sirt6 in response to angiotensin II led to a marked increase in the ubiquitination of Sirt6 and resulted in Akt signaling downregulation and attenuation of cardiomyocyte hypertrophy. Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6-induced downstream signaling in cardiomyocytes. Conclusions USP10 functions as a Sirt6 deubiquitinase that induces cardiac myocyte hypertrophy and triggers maladaptive CH.

Finding an efficient tetramethylated hydroxydiethylene of resveratrol analogue for potential anticancer agent.

With the improvement and advance in cancer diagnosis and treatment, the cancer is still a major cause of morbidity and mortality throughout the world. Obviously, new breakthroughs in therapies remain be urgent needed. In this work, we designed and synthesized the compound 1-4, namely resveratrol analogues with methylation of hydroxy distyrene, to further explore its new anti-cancer potential. Encouragingly, compound 1 ((E)-4,4'-(ethene-1,2-diyl)bis(3,5-dimethylphenol)) exhibited cytotoxicity superior to resveratrol in MCF 7 cells. More importantly, the compound 1 showed greater toxicity to tumor cells than that to normal cells, which proved that it could selectively kill tumor cells. The favorable results encouraged us to explore the inhibitory mechanism of compound 1 on MCF 7 cells. The research finding indicated the compound 1 inhibited tumor cell proliferation by both arresting cell cycle in S phase and apoptosis via a prooxidant manner. In addition, the results further verified compound 1 caused cell cycle arrest in S phase and apoptosis by down-regulation of the cycling A1/cycling A2 expression and the rise of Bax/Bcl-2 ratio in a p21-dependant pathway in MCF 7 cells. Therefore, these results are helpful for the effective design of anticancer reagents and the better understanding of their mechanism of action.

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt.

Cardiac hypertrophy (CH) is an independent risk factor for many cardiovascular diseases, and is one of the primary causes of morbidity and mortality in elderly people. Pathological CH involves excessive protein synthesis, increased cardiomyocyte size, and ultimately the development of heart failure. Myotubularin-related protein 14 (MTMR14) is a member of the myotubularin (MTM)-related protein family, which is involved in apoptosis, aging, inflammation, and autophagy. However, its exact function in CH is still unclear. Herein, we investigated the roles of MTMR14 in CH. We show that MTMR14 expression was increased in hypertrophic mouse hearts. Mice deficient in heart MTMR14 exhibited an aggravated aortic-banding (AB)-induced CH phenotype. In contrast, MTMR14 overexpression prevented pressure overload-induced hypertrophy. At the molecular level, prevention of CH in the absence of MTMR14 involved elevations in Akt pathway components, which are key elements that regulate apoptosis and cell proliferation. These results demonstrate that MTMR14 is a new molecular target for the treatment of CH.

Molecular regulation of miR-378 on the development of mouse follicle and the maturation of oocyte in vivo.

MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs which can bind to completely or partially complementary sequences in the 3'UTR of target mRNAs, therefore degrading the mRNA or repressing translation. We previously reported that miR-378 played a role in estradiol production via suppression of aromatase translation in porcine granulosa cells and could affect oocyte maturation in vitro by inhibiting cumulus cell expansion. However, the role of miR-378 on ovary development in vivo is unknown. The current study aimed to uncover the molecular mechanism of miR-378 in regulating mouse follicular development via micro-injection of CMV-miR-378 lentivirus into the bursa of mouse ovary. The results showed that CMV-miR-378 lentivirus transduction in the mouse ovaries resulted in reduced ovary size, extended oestrous cycle (6-7 d in miR-378 overexpression group and 4-5 dyas in GFP control group) due to continuous oestrum, decreased percentage of oocytes in vitro maturation rate (IVM 60.8% vs. 89.4% in GFP control), increased apoptosis rate (Bax/Bcl2 in mRNA and protein level), decreased expression of genes associated with gap junction, such as connexin 43 (Cx-43) and connexin (Cx-37) and decreased expression of genes associated with follicular development, such as BMP15 and GDF9. Moreover, the number of pups/litter was consistently lower in the miR-378 group in each batch of the paired breeding. Our data suggest that miR-378 alters gene expression in cumulus cells and indirectly influences oocyte maturation competency, possibly via inhibition of oocyte-cumulus interaction or induction of apoptosis.