Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.

The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies.

Effect of Thermal Stimulus on Kinetic Rehydration of Thermoresponsive Poly(diethylene glycol monomethyl ether methacrylate)-block-poly(poly(ethylene glycol) methyl ether methacrylate) Thin Films Probed by In Situ Neutron Reflectivity.

The kinetic rehydration of thin di-block copolymer poly(diethylene glycol monomethyl ether methacrylate)-block-poly(poly(ethylene glycol) methyl ether methacrylate) (PO2-b-PO300) films containing two thermoresponsive components is probed by in situ neutron reflectivity (NR) with different thermal stimuli in the D2O vapor atmosphere. The transition temperatures (TTs) of PO2 and PO300 blocks are 25 and 60 °C, respectively. After the one-step stimulus (rapid decrease in temperature from 60 to 20 °C), the film directly switches from a collapsed to a fully swollen state. The rehydration process is divided into four steps: (a) D2O condensation, (b) D2O absorption, (c) D2O evaporation, and (d) film reswelling. However, the film presents a different rehydration behavior when the thermal stimulus is separated into two smaller steps (first decrease from 60 to 40 °C and then to 20 °C). The film first switches from a collapsed to a semiswollen state caused by the rehydrated PO300 blocks after the first step of thermal stimulus (60 to 40 °C) and then to a swollen state induced by the rehydrated PO2 blocks after the second step (40 to 20 °C). Thus, the kinetic responses are distinct from that after the one-step thermal stimulus. Both the time and extent of condensation as well as evaporation processes are significantly reduced in these two smaller steps. However, the final states of the rehydrated PO2-b-PO300 films are basically identical irrespective of the applied thermal stimulus. Thus, the final state of thermoresponsive di-block copolymer films is not affected by the external thermal stimuli, which is beneficial for the design and preparation of sensors or switches based on thermoresponsive polymer films.

Two Transition Metal Coordination Polymers: Luminescent Sensing Properties and Treatment Effect on Chronic Periodontitis by Reducing IL-6 and TNF-α Content.

Two novel sulfonic functionalized coordination polymers (CPs) {[Cd1.5(dimb)(5-sip)(H2O)3]·3H2O}n (1, dimb = 1,4-di(1H-imidazol-1-yl)butane) and [Co2(iptz)(Hiptz)(5-sip)(H2O)]·4H2O (2, Hiptz = 1-(4-(1H-imidazole-5-yl)phenyl)-1H-1,2,4-triazole) were acquired via different metal(II) salts reacting with the mixed ligands containing 1-(4-(1H-imidazole-5-yl)phenyl)-1H-1,2,4-triazole, 1,4-di(1H-imidazol-1-yl)butane and sodium 5-sulfoisophthalate (NaH2sip), respectively. Furthermore, the complex 1 based on Cd(II) could be utilized as the luminescent senor for picric acid (PA) detection in water. In bio-research, compounds 1 and 2 treatment effect on chronic periodontitis was assessed and the specific mechanism was discussed. First of all, the RT-PCR was performed to measure the HmuY and fimA genes relative expression level in P.gingivalis after treated by compounds 1 and 2. Then, the TNF-α and IL-6 content in the fluid of gingival crevicular after compounds treatment was determined with ELISA detection kit.

Thermoresponsive Diblock Copolymer Films with a Linear Shrinkage Behavior and Its Potential Application in Temperature Sensors.

The linear shrinkage behavior in thermoresponsive diblock copolymer films and its potential application in temperature sensors are investigated. The copolymer is composed of two thermoresponsive blocks with different transition temperatures (TTs): di(ethylene glycol) methyl ether methacrylate (MEO2MA; TT1 = 25 °C) and poly(ethylene glycol) methyl ether methacrylate (OEGMA300; TT2 = 60 °C) with a molar ratio of 1:1. Aqueous solutions of PMEO2MA-b-POEGMA300 show a three-stage transition upon heating as seen with optical transmittance and small-angle X-ray scattering: dissolution (T < TT1), self-assembled micelles with core-shell structure (TT1 < T < TT2), and aggregation of collapsed micelles (T > TT2). Due to the restrictions in the polymer chain arrangement introduced by the solid Si substrate, spin-coated PMEO2MA-b-POEGMA300 films exhibit an entirely different internal structure and transition behavior. Neutron reflectivity shows the absence of an ordered structure normal to the Si substrate in as-prepared PMEO2MA-b-POEGMA300 films. After exposure to D2O vapor for 3 h and then increasing the temperature above its TT1 and TT2, the ordered structure is still not observed. Only a D2O enrichment layer is formed close to the hydrophilic Si substrate. Such PMEO2MA-b-POEGMA300 films show a linear shrinkage between TT1 and TT2 in a D2O vapor atmosphere. This special behavior can be attributed to the synergistic effect between the restrained collapse of the PMEO2MA blocks by the still swollen POEGMA300 blocks and the impedance of chain arrangement by the Si substrate. Based on this unique behavior, spin-coated PMEO2MA-b-POEGMA300 films are further prepared into a temperature sensor by implementing Ag electrodes. Its resistance decreases linearly with temperature between TT1 and TT2.

Impact of Thermal History on the Kinetic Response of Thermoresponsive Poly(diethylene glycol monomethyl ether methacrylate)-block-poly(poly(ethylene glycol)methyl ether methacrylate) Thin Films Investigated by In Situ Neutron Reflectivity.

The impact of thermal history on the kinetic response of thin thermoresponsive diblock copolymer poly(diethylene glycol monomethyl ether methacrylate)-block-poly(poly(ethylene glycol) methyl ether methacrylate), abbreviated as PMEO2MA-b-POEGMA300, films is investigated by in situ neutron reflectivity. The PMEO2MA and POEGMA300 blocks are both thermoresponsive polymers with a lower critical solution temperature. Their transition temperatures (TTs) are around 25 °C (TT1, PMEO2MA) and 60 °C (TT2, POEGMA300). Thus, by applying different temperature protocols (20 to 60 or 20 to 40 to 60 °C), the PMEO2MA-b-POEGMA300 thin films experience different thermal histories: the first protocol directly switches from a swollen to a collapsed state, whereas the second one switches first from a swollen to a semicollapsed and finally to a collapsed state. Although the applied thermal histories differ, the response and final state of the collapsed films are very close to each other. After the thermal stimulus, both films present a complicated response composed of an initial shrinkage, followed by a rearrangement. Interestingly, a subsequent reswelling of the collapsed film is only observed in the case of having applied a thermal stimulus of 20 to 40 °C. The normalized film thickness and the D2O amount of each layer in the PMEO2MA-b-POEGMA300 films are consistent at the end of the two different thermal stimuli. Hence, it can be concluded that the thermal history does not influence the final state of the PMEO2MA-b-POEGMA300 films upon heating. Based on this property, these thin films are especially suitable for the temperature switches on the nanoscale, which may experience different thermal histories.

Effect of chain architecture on the swelling and thermal response of star-shaped thermo-responsive (poly(methoxy diethylene glycol acrylate)-block-polystyrene)3 block copolymer films.

The effect of chain architecture on the swelling and thermal response of thin films obtained from an amphiphilic three-arm star-shaped thermo-responsive block copolymer poly(methoxy diethylene glycol acrylate)-block-polystyrene ((PMDEGA-b-PS)3) is investigated by in situ neutron reflectivity (NR) measurements. The PMDEGA and PS blocks are micro-phase separated with randomly distributed PS nanodomains. The (PMDEGA-b-PS)3 films show a transition temperature (TT) at 33 °C in white light interferometry. The swelling capability of the (PMDEGA-b-PS)3 films in a D2O vapor atmosphere is better than that of films from linear PS-b-PMDEGA-b-PS triblock copolymers, which can be attributed to the hydrophilic end groups and limited size of the PS blocks in (PMDEGA-b-PS)3. However, the swelling kinetics of the as-prepared (PMDEGA-b-PS)3 films and the response of the swollen film to a temperature change above the TT are significantly slower than that in the PS-b-PMDEGA-b-PS films, which may be related to the conformation restriction by the star-shape. Unlike in the PS-b-PMDEGA-b-PS films, the amount of residual D2O in the collapsed (PMDEGA-b-PS)3 films depends on the final temperature. It decreases from (9.7 ± 0.3)% to (7.0 ± 0.3)% or (6.0 ± 0.3)% when the final temperatures are set to 35 °C, 45 °C and 50 °C, respectively. This temperature-dependent reduction of embedded D2O originates from the hindrance of chain conformation from the star-shaped chain architecture.

Assembly and Maintenance of Myofibrils in Striated Muscle.

In this chapter, we present the current knowledge on de novo assembly, growth, and dynamics of striated myofibrils, the functional architectural elements developed in skeletal and cardiac muscle. The data were obtained in studies of myofibrils formed in cultures of mouse skeletal and quail myotubes, in the somites of living zebrafish embryos, and in mouse neonatal and quail embryonic cardiac cells. The comparative view obtained revealed that the assembly of striated myofibrils is a three-step process progressing from premyofibrils to nascent myofibrils to mature myofibrils. This process is specified by the addition of new structural proteins, the arrangement of myofibrillar components like actin and myosin filaments with their companions into so-called sarcomeres, and in their precise alignment. Accompanying the formation of mature myofibrils is a decrease in the dynamic behavior of the assembling proteins. Proteins are most dynamic in the premyofibrils during the early phase and least dynamic in mature myofibrils in the final stage of myofibrillogenesis. This is probably due to increased interactions between proteins during the maturation process. The dynamic properties of myofibrillar proteins provide a mechanism for the exchange of older proteins or a change in isoforms to take place without disassembling the structural integrity needed for myofibril function. An important aspect of myofibril assembly is the role of actin-nucleating proteins in the formation, maintenance, and sarcomeric arrangement of the myofibrillar actin filaments. This is a very active field of research. We also report on several actin mutations that result in human muscle diseases.

CPXM1 correlates to poor prognosis and immune cell infiltration in gastric cancer.

Background: Gastric cancer (GC) is the fourth most common cause of cancer-related death and the fifth most frequent malignant cancer, especially advanced GC. Carboxypeptidase X member 1 (CPXM1) is an epigenetic factor involved in many physiological processes, including osteoclast differentiation and adipogenesis. Several studies have shown the association of CPXM1 with multiple tumors; however, the mechanism of CPXM1 involvement in the progression of GC is yet to be characterized. Method: CPXM1 expression data were obtained from the Tumor Immune Estimation Resource. The Cancer Genome Atlas and the Gene Expression Omnibus databases were used to obtain patient-matched clinicopathological information, and the Kaplan-Meier plot database was utilized for the prognosis analysis of GC patients. The Catalog of Somatic Mutations in Cancer and cBioportal databases were adopted to study CPXM1 mutations in tumors. Next, we utilized the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis for mechanism research. Furthermore, we performed tumor microenvironment and immune infiltration analysis based on CPXM1. Finally, we predicted sensitivity to several targeted drugs in GC patients based on CPXM1.CPXM1 is upregulated in GC and is correlated with poor prognosis, gender, and tumor stage in GC patients. Gene enrichment analysis suggested that CPXM1 may regulate the occurrence and progression of GC via the PI3K-AKT and TGF-ß pathway. Moreover, CPXM1 expression results in an increase in the proportion of immune and stromal cells. Additionally, the proportion of plasma cells was inversely related to the expression of CPXM1, whereas macrophage M2 expression was proportionate to CPXM1 expression. Finally, six small-molecule drugs that showed notable variations in IC50 between two groups were screened. Conclusion: These results suggested that CPXM1 regulates the progression of GC and may represent a novel target for the detection and treatment of GC.

Acute neck tendonitis with dyspnea: A case report.

BACKGROUND: Longus colli tendinitis (LCT) with dyspnea is a relatively less-reported condition in the literature, and physicians should be aware of its existence. Misdiagnosis of this condition may cause unnecessary treatment for dyspnea. CASE SUMMARY: Herein, we report the case of a 40-year-old man with acute neck tendonitis. The patient presented to the pneumology department clinic with a complaint of acute neck tendonitis with dyspnea. An emergency cervical magnetic resonance examination was performed, and the preliminary diagnosis was "acute longus cervicalis tendinitis." After aggressive medical treatment, the symptoms obviously improved. CONCLUSION: LCT is a self-limiting disease that usually improves after three to seven days of conservative treatment following a definite diagnosis. However, owing to its insidious onset and complex clinical manifestations, most relevant personnel are not fully understood. The definite diagnosis of LCT is based on a comprehensive understanding of the triad, rare symptoms, and the clear identification of cervical 1 and 2 levels calcification and prevertebral edema by medical imaging examination, especially magnetic resonance imaging and computed tomography.

Finite element analysis comparison of Type 42A2 fracture fixed with external titanium alloy locking plate and traditional external fixation frame.

BACKGROUND: At present, not all Type AO/OTA 42A2 open fractures can be treated by external fixation brackets, not to mention the inconvenience of this technique in clinical practice. External titanium alloy locking plates, which are lightweight and easy-to-operate, can be used as an alternative treatment option for such patients. However, there are few reports of finite element biomechanical analysis on the titanium alloy locking plates and fixation brackets being placed on the medial side of the tibial fracture. In this study, the biomechanical properties of titanium alloy locking plates and fixation brackets for treating Type AO/OTA 42A2 fractures were compared by applying the finite element method, and the results provided data support for the clinical application of the external titanium alloy locking plate technique. METHODS: Type AO/OTA 42A2 fracture models were constructed using CT data of a male volunteer for two external fixation techniques, namely the external titanium alloy locking plate technique and the external fixation bracket technique, according to commonly-used clinical protocols. Then, the four-point bending, axial compression, clockwise rotation and counterclockwise rotation tests under the maximum load were simulated in finite element analysis software. The stress distribution, peak stress and overall tibial displacement data for the two different external fixation techniques were obtained and compared. RESULTS: In the four different test conditions (i.e., four-point bending, axial compression, clockwise torsion, counterclockwise torsion) under the maximum load, the two external fixation techniques showed obvious von Mises stress concentration at the contacts between the screw and tibia, between the screw and titanium alloy locking plate, between the self-tapping self-drilling needle and tibia, between the self-tapping self-drilling needle and the external fixation device, as well as around the fracture end and around the cortical bone at the upper and lower ends of the tibia. The peak stress was ranged 26.67-558.77 MPa, all below the yield stress strength of titanium alloy. The peak tibial displacement of the external titanium alloy locking plate model was smaller than that of the fixation bracket model. In terms of structural stability, the external titanium alloy locking plate technique was superior to the external fixation bracket technique. CONCLUSIONS: When fixing Type AO/OTA 42A2 fractures, external titanium alloy locking plates are not only lightweight and easy-to-operate, but also have better performance in terms of axial compression, bending and torsion resistance. According to the finite element biomechanical analysis, external titanium alloy locking plates are superior to traditional external fixation brackets in treating Type AO/OTA 42A2 fractures and can better meet the needs of clinical application.

Bacterial translocation contributes to cachexia from locally advanced gastric cancer.

BACKGROUND/AIMS: Studies have indicated that cancer cachexia patients have high cytokines levels and worse prognosis and bacterial translocation can increase cytokines production. So we aimed to investigate the association of BT with cachexia and prognosis of cachectic patients. METHODOLOGY: The locally advanced gastric cancer patients enrolled in this study were divided into cachectic and non-cachectic. Polymerase chain reaction was performed to detect bacterial DNA Cytokines levels were tested by enzyme-linked immunosorbent assay. Flow cytometry was used to detect immunological indicators. RESULTS: BT ratio was significantly higher in cachectic patients than in non-cachectic patients and healthy volunteers (p=0.019, p=0.000). BT positive cachectic patients had significantly higher levels of IL-1a, IL-6, TNF-α and IFN-γ and worse survival than BT negative cachectic patients. The levels of CD3⁺T, CD4⁺T, NK cell and CD4⁺T /CD8⁺T in gastric cancer patients were lower as compared to healthy volunteers. The level of CD8⁺T-cell was significantly higher in gastric cancer patients than that in healthy volunteers. CONCLUSIONS: This study for the first time suggested that bacterial translocation may contribute to cancer cachexia and impact prognosis of cachectic patients with locally advanced gastric cancer.

Metformin protects against abdominal aortic aneurysm by Atg7-induced autophagy.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta. It is often asymptomatic, yet it has a high susceptibility to rupture. Our previous study showed that metformin protected against the pathophysiology of AAA by reducing the activation of the PI3K/AKT/mTOR pathway. OBJECTIVES: To investigate the potential involvement of the autophagy-related pathways in AAA and the ability of metformin to modulate these effects. MATERIAL AND METHODS: The expression of autophagy-related proteins was detected with western blot in patients with AAA. Angiotensin II (Ang-II) was also used to construct an AAA model in mice and in vascular smooth muscle cells (VSMCs). The expression of Atg7 and Atg4 was determined using western blot assay. The Atg7 expression was regulated by overexpressed plasmid, siRNA (small interfering RNA), or metformin, and cell proliferation, migration, apoptosis and autophagy caused by Ang-II were examined. RESULTS: Autophagy-related proteins were increased in patients with AAA. The Ang-II also induced the expression of Atg7, and metformin reversed this effect both in vivo and in vitro. The suppression of Atg7 inhibited cell proliferation and cell migration, and reduced cell apoptosis and autophagy, while the overexpression of Atg7 enhanced cell proliferation and migration, and induced cell apoptosis and autophagy. Furthermore, Atg7 regulated the expression of the autophagy-related protein in Ang-II treated VSMCs. The Atg7-mediated autophagy was also attenuated by metformin. CONCLUSIONS: Metformin reduced autophagy in AAA and this effect was mediated by Atg7, suggesting that Atg7 is a potential downstream effector of metformin in protecting against the pathophysiology of AAA.

Circ-CCS enhances autophagy during imatinib resistance of gastrointestinal stromal tumor by regulating miR-197-3p/ATG10 signaling.

Context: Drug resistance in gastrointestinal stromal tumors (GISTs) is connected with autophagy activation. Accumulating data demonstrates the critical role of circular RNAs (circRNAs) dysregulation in this development. Aim: To explore the possible function of hsa_circ_0092306 (circ-CCS) in GIST imatinib resistance. Materials and Methods: Quantitative real-time reverse transcription PCR (RT-qPCR) was used to determine the expression levels of circ-CCS and miR-197-3p. The vitality and apoptosis of cells were determined using the Cell Counting Kit-8 and TUNEL assays, respectively. Western blot analysis was used to evaluate the relative protein expression. A dual-luciferase reporter assay was used to validate the link between circ-CCS, miR-197-3p, and ATG10. Statistical Analysis Used: Comparisons of two groups were analyzed using Student's t tests, and analysis of variance (ANOVA) with Tukey's post hoc test was used to compare three or more groups. Results: Circulating-CCS expression was considerably increased in the serum of imatinib-resistant GIST patients (P < 0.001). Circulating-CCS deficiency decreased cell proliferation and autophagy in GIST-882 and GIST-T1 cells, but promoted apoptosis (P < 0.05). Additionally, circ-CCS was predominantly found in the cytoplasm. Mechanically, circ-CCS targeted miR-197-3p, which may influence autophagy by downregulating ATG10, in order to modulate GIST cells' malignant tendencies. Moreover, silencing miR-197-3p reversed the effect of circ-CCS knockdown on apoptosis and autophagy in GIST cells. Conclusions: By modulating the miR-197-3p/ATG10 axis, circ-CCS increased imatinib resistance in GIST cells, establishing a potential target for reversing medication resistance in such patients.

Remote ischemic post­conditioning alleviates ischemia/reperfusion­induced intestinal injury via the ERK signaling pathway­mediated RAGE/HMGB axis.

Intestinal ischemia reperfusion (I/R) injury is a tissue and organ injury that frequently occurs during surgery and significantly contributes to the pathological processes of severe infection, injury, shock, cardiopulmonary insufficiency and other diseases. However, the mechanism of intestinal I/R injury remains to be elucidated. A mouse model of intestinal I/R injury was successfully established and the model mice were treated with remote ischemic post­conditioning (RIPOC) and/or an ERK inhibitor (CC­90003), respectively. Histopathological changes of the intestinal mucosa were determined by hematoxylin and eosin staining. In addition, the levels of high­mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) expression were confirmed by reverse transcription­quantitative polymerase chain reaction, western blotting and immunohistochemistry assays. The levels of antioxidants, oxidative stress markers (8­OHdG) and interleukin 1 family members were evaluated by ELISA assays and the levels of NF­κB pathway proteins were analyzed by western blotting. The data demonstrated that RIPOC could attenuate the histopathological features of intestinal mucosa in the intestinal I/R­injury mouse models via the ERK pathway. It was also revealed that HMGB1 and RAGE expression in the mouse models could be markedly reduced by RIPOC (P<0.05) and that these reductions were associated with inhibition of the ERK pathway. Furthermore, it was demonstrated that RIPOC produced significant antioxidant and anti­inflammatory effects following an intestinal I/R injury and that these effects were mediated via the ERK pathway (P<0.05). In addition, RIPOC was demonstrated to suppress the NF­κB (p65)/NLR family pyrin domain containing 3 (NLRP3) inflammatory pathways in the intestinal I/R injury mouse models via the ERK pathway. The findings of the present study demonstrated that RIPOC helped to protect mice with an intestinal I/R injury by downregulating the ERK pathway.

IFI16 contributes to the pathogenesis of abdominal aortic aneurysm by regulating the caspase-1/IL-1ß/MCPIP1 pathway.

AIMS: Abdominal aortic aneurysm (AAA) is a multi-factorial progressive vascular disease characterized by chronic inflammatory cell infiltration. We investigated the roles played by IFI16 and ASC inflammasomes in AAA development and progression. MATERIALS AND METHODS: Western blot and qRT-PCR studies were performed to analyze the expression of relative genes in AAA specimens and mouse vascular smooth muscle cells (VSMCs). The apoptosis rates and ROS levels of VSMCs were assessed by flow cytometry. Transwell assays were performed to analyze the migration ability of VSMCs. The levels of MCP-1, IL-1ß, and IL-6 in the supernatants of cultured VSMCs were analyzed by ELISA. KEY FINDINGS: Increased levels of IFI16 expression were found in AAA specimens and Ang-II-treated VSMCs. IFI16 and ASC silencing suppressed the apoptosis and migration ability of VSMCs undergoing Ang-II treatment, reduced elasticity damage to the aortic wall, and decreased the levels of MMP expression. The effect of IFI16 knockdown in Ang-II-induced VSMCs was reversed by MCPIP1 overexpression. SIGNIFICANCE: Our data suggest that an up-regulation of IFI16 and ASC expression might promote the apoptosis of VSMCs, enhance the inflammatory response, and impairs vascular wall elasticity via a MCPIP1-related mechanism. The inflammasome components IFI16 and ASC might be involved in AAA progression and serve as target molecules for diagnosing and treating AAA.

What's Next for Key and Core Tech?

The Universe is a complicated network that evolved out of the Big Bang to the human-dominated world we see today. Technology is a collection of natural or scientific phenomena that have been discovered and used by human beings. The combination and evolution of technology is forming a complex, self-organizing, and evolving scale-free network. Originating from a technological system, key and core technology is the cornerstone to boosting economic and social progress. To develop a more sustainably focused planet, key and core technologies will play an increasingly vital role.

In vivo elongation of thin filaments results in heart failure.

A novel cardiac-specific transgenic mouse model was generated to identify the physiological consequences of elongated thin filaments during post-natal development in the heart. Remarkably, increasing the expression levels in vivo of just one sarcomeric protein, Lmod2, results in ~10% longer thin filaments (up to 26% longer in some individual sarcomeres) that produce up to 50% less contractile force. Increasing the levels of Lmod2 in vivo (Lmod2-TG) also allows us to probe the contribution of Lmod2 in the progression of cardiac myopathy because Lmod2-TG mice present with a unique cardiomyopathy involving enlarged atrial and ventricular lumens, increased heart mass, disorganized myofibrils and eventually, heart failure. Turning off of Lmod2 transgene expression at postnatal day 3 successfully prevents thin filament elongation, as well as gross morphological and functional disease progression. We show here that Lmod2 has an essential role in regulating cardiac contractile force and function.

Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production.

Abdominal aortic aneurysm (AAA) is often clinically silent before rupture characterized by extensive vascular inflammation and degenerative elasticity of aortic wall. Monocyte chemotactic protein-induced protein-1 (MCPIP1) exhibits anti-infllammatory and pro-apoptotic effects involved in atherogenesis. However, little is known about the expression and the contribution of MCPIP1 in AAA. In the present study, we collected clinical AAA specimens and constructed AAA mice model through Ang-II infusion, and found apparently increased MCPIP1 expression and severe inflammatory infiltration in AAA aortic membrane as evidenced by elevated levels of monocyte chemotactic protein 1 (MCP-1), interleukin 1 ß (IL-1ß) and NF-κB, as well as HE staining. The elasticity of aortic tunica media was impaired along with multiple apoptosis of vascular smooth muscle cells (VSMCs) in Ang-II-induced aneurysmal mouse. In vitro Ang-II administration of VSMCs induced MCPIP1 expression, accompanied by up-regulation of matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, as well as enhancement of VSMCs proliferation and apoptosis, which may cause damage of intima-media elasticity. Silencing MCPIP1 reversed above effects to further restore the balance of proliferation and apoptosis in VSMCs. Overall, our data indicated that up-regulation of MCPIP1 may become a promising candidate for the diagnosis of AAA, and specific knockdown of MCPIP1 in VSMCs could inhibit VSMCs apoptosis and down-regulate MMPs to maintain vascular wall elasticity. Therefore, knockdown of MCPIP1 may serve as a potential target for gene therapy of AAA.

Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE-/- mice.

BACKGROUND: The protective effect of metformin (MET) on abdominal aortic aneurysm (AAA) has been reported. However, the related mechanism is still poor understood. In this study, we deeply investigated the role of metformin in AAA pathophysiology. METHODS: Angiotensin II (Ang-II) was used to construct the AAA model in ApoE -/- mice. The related mechanism was explored using Western blot and quantitative real time PCR (qRT-PCR). We also observed the morphological changes in the abdominal aorta and the influence of metformin on biological behaviors of rat abdominal aortic VSMCs. RESULTS: The PI3K/AKT/mTOR pathway was activated in aneurysmal wall tissues of AAA patients and rat model. Treatment with metformin inhibited the breakage and preserved the elastin structure of the aorta, the loss of collagen, and the apoptosis of aortic cells. In addition, metformin significantly suppressed the activation of the PI3K/AKT/mToR pathway and decreased the mRNA and protein levels of LC3B and Beclin1, which were induced by Ang-II. Moreover, PI3K inhibitors enhanced the effect of metformin while PI3K agonists largely reversed this effect. Interestingly, the cell proliferation, apoptosis, migration and autophagy of vascular smooth muscle cells (VSMCs) induced by Ang-II were also decreased following metformin treatment. PI3K inhibitors and agonists strengthened and weakened the effects of metformin in VSMCs, respectively. CONCLUSIONS: Metformin represses the pathophysiology of AAA by inhibiting the activation of PI3K/AKT/mTOR/autophagy pathway. This repression may be useful as a new therapeutic strategy for AAA.