An Enhanced Differential Evolution Algorithm with Bernstein Operator and Refracted Oppositional-Mutual Learning Strategy.

Numerical optimization has been a popular research topic within various engineering applications, where differential evolution (DE) is one of the most extensively applied methods. However, it is difficult to choose appropriate control parameters and to avoid falling into local optimum and poor convergence when handling complex numerical optimization problems. To handle these problems, an improved DE (BROMLDE) with the Bernstein operator and refracted oppositional-mutual learning (ROML) is proposed, which can reduce parameter selection, converge faster, and avoid trapping in local optimum. Firstly, a new ROML strategy integrates mutual learning (ML) and refractive oppositional learning (ROL), achieving stochastic switching between ROL and ML during the population initialization and generation jumping period to balance exploration and exploitation. Meanwhile, a dynamic adjustment factor is constructed to improve the ability of the algorithm to jump out of the local optimum. Secondly, a Bernstein operator, which has no parameters setting and intrinsic parameters tuning phase, is introduced to improve convergence performance. Finally, the performance of BROMLDE is evaluated by 10 bound-constrained benchmark functions from CEC 2019 and CEC 2020, respectively. Two engineering optimization problems are utilized simultaneously. The comparative experimental results show that BROMLDE has higher global optimization capability and convergence speed on most functions and engineering problems.

Correction to: Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

The original version of this article unfortunately contained a mistake.

Exercise-induced circulating extracellular vesicles protect against cardiac ischemia-reperfusion injury.

Extracellular vesicles (EVs) serve an important function as mediators of intercellular communication. Exercise is protective for the heart, although the signaling mechanisms that mediate this cardioprotection have not been fully elucidated. Here using nano-flow cytometry, we found a rapid increase in plasma EVs in human subjects undergoing exercise stress testing. We subsequently identified that serum EVs were increased by ~1.85-fold in mice after 3-week swimming. Intramyocardial injection of equivalent quantities of EVs from exercised mice and non-exercised controls provided similar protective effects against acute ischemia/reperfusion (I/R) injury in mice. However, injection of exercise-induced EVs in a quantity equivalent to the increase seen with exercise (1.85 swim group) significantly enhanced the protective effect. Similarly, treatment with exercise-induced increased EVs provided additional anti-apoptotic effect in H2O2-treated H9C2 cardiomyocytes mediated by the activation of ERK1/2 and HSP27 signaling. Finally, by treating H9C2 cells with insulin-like growth factor-1 to mimic exercise stimulus in vitro, we found an increased release of EVs from cardiomyocytes associated with ALIX and RAB35 activation. Collectively, our results show that exercise-induced increase in circulating EVs enhances the protective effects of endogenous EVs against cardiac I/R injury. Exercise-derived EVs might serve as a potent therapy for myocardial injury in the future.

miR-149 controls non-alcoholic fatty liver by targeting FGF-21.

Non-alcoholic fatty liver disease (NAFLD), a lipid metabolism disorder characterized by the accumulation of intrahepatic fat, has emerged as a global public health problem. However, its underlying molecular mechanism remains unclear. We previously have found that miR-149 was elevated in NAFLD induced by high-fat diet mice model, whereas decreased by a 16-week running programme. Here, we reported that miR-149 was increased in HepG2 cells treated with long-chain fatty acid (FFA). In addition, miR-149 was able to promote lipogenesis in HepG2 cells in the absence of FFA treatment. Moreover, inhibition of miR-149 was capable of inhibiting lipogenesis in HepG2 cells in the presence of FFA treatment. Meanwhile, fibroblast growth factor-21 (FGF-21) was identified as a target gene of miR-149, which was demonstrated by the fact that miR-149 could negatively regulate the protein expression level of FGF-21, and FGF-21 was also responsible for the effect of miR-149 inhibitor in decreasing lipogenesis in HepG2 cells in the presence of FFA treatment. These data implicate that miR-149 might be a novel therapeutic target for NAFLD.

miR-19b controls cardiac fibroblast proliferation and migration.

Cardiac fibrosis is a fundamental constituent of a variety of cardiac dysfunction, making it a leading cause of death worldwide. However, no effective treatment for cardiac fibrosis is available. Therefore, novel therapeutics for cardiac fibrosis are highly needed. Recently, miR-19b has been found to be able to protect hydrogen peroxide (H2 O2 )-induced apoptosis and improve cell survival in H9C2 cardiomyocytes, while down-regulation of miR-19b had opposite effects, indicating that increasing miR-19b may be a new therapeutic strategy for attenuating cellular apoptosis during myocardial ischaemia-reperfusion injury. However, considering the fact that microRNAs might exert a cell-specific role, it is highly interesting to determine the role of miR-19b in cardiac fibroblasts. Here, we found that miR-19b was able to promote cardiac fibroblast proliferation and migration. However, miR-19b mimics and inhibitors did not modulate the expression level of collagen I. Pten was identified as a target gene of miR-19b, which was responsible for the effect of miR-19b in controlling cardiac fibroblast proliferation and migration. Our data suggest that the role of miR-19b is cell specific, and systemic miR-19b targeting in cardiac remodelling might be problematic. Therefore, it is highly needed and also urgent to investigate the role of miR-19b in cardiac remodelling in vivo.

Therapeutic inhibition of phospholipase D1 suppresses hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a leading cause of deaths worldwide. Novel therapeutic targets for HCC are needed. Phospholipase D (PD) is involved in cell proliferation and migration, but its role in HCC remains unclear. In the present study, we show that PLD1, but not PLD2, was overexpressed in HCC cell lines (HepG2, Bel-7402 and Bel-7404) compared with the normal human L-02 hepatocytes. PLD1 was required for the proliferation, migration and invasion of HCC cells without affecting apoptosis and necrosis, and PLD1 overexpression was sufficient to promote those effects. By using HCC xenograft models, we demonstrated that therapeutic inhibition of PLD1 attenuated tumour growth and epithelial-mesenchymal transition (EMT) in HCC mice. Moreover, PLD1 was found to be highly expressed in tumour tissues of HCC patients. Finally, mTOR (mechanistic target of rapamycin) and Akt (protein kinase B) were identified as critical pathways responsible for the role of PLD1 in HCC cells. Taken together, the present study indicates that PLD1 activation contributes to HCC development via regulation of the proliferation, migration and invasion of HCC cells, as well as promoting the EMT process. These observations suggest that inhibition of PLD1 represents an attractive and novel therapeutic modality for HCC.

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4.

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.

miR-19b attenuates H2O2-induced apoptosis in rat H9C2 cardiomyocytes via targeting PTEN.

Myocardial ischemia-reperfusion (I-R) injury lacks effective treatments. The miR-17-92 cluster plays important roles in regulating proliferation, apoptosis, cell cycle and other pivotal processes. However, their roles in myocardial I-R injury are largely unknown. In this study, we found that miR-19b was the only member of the miR-17-92 cluster that was downregulated in infarct area of heart samples from a murine model of I-R injury. Meanwhile, downregulation of miR-19b was also detected in H2O2-treated H9C2 cells in vitro mimicking oxidative stress occurring during myocardial I-R injury. Using flow cytometry and Western blot analysis, we found that overexpression of miR-19b decreased H2O2-induced apoptosis and improved cell survival, while downregulation of that had inverse effects. Furthermore, PTEN was negatively regulated by miR-19b at the protein level while silencing PTEN could completely block the aggravated impact of miR-19b inhibitor on H2O2-induced apoptosis in H9C2 cardiomyocytes, indicating PTEN as a downstream target of miR-19b controlling H2O2-induced apoptosis. These data indicate that miR-19b overexpression might be a novel therapy for myocardial I-R injury.

Cardiac telocytes and fibroblasts in primary culture: different morphologies and immunophenotypes.

Telocytes (TCs) are a peculiar type of interstitial cells with very long prolongations termed telopodes. TCs have previously been identified in different anatomic structures of the heart, and have also been isolated and cultured from heart tissues in vitro. TCs and fibroblasts, both located in the interstitial spaces of the heart, have different morphologies and functionality. However, other than microscopic observation, a reliable means to make differential diagnosis of cardiac TCs from fibroblasts remains unclear. In the present study, we isolated and cultured cardiac TCs and fibroblasts from heart tissues, and observed their different morphological features and immunophenotypes in primary culture. Morphologically, TCs had extremely long and thin telopodes with moniliform aspect, stretched away from cell bodies, while cell processes of fibroblasts were short, thick and cone shaped. Furthermore, cardiac TCs were positive for CD34/c-kit, CD34/vimentin, and CD34/PDGFR-ß, while fibroblasts were only vimentin and PDGFR-ß positive. In addition, TCs were also different from pericytes as TCs were CD34 positive and α-SMA weak positive while pericytes were CD34 negative but α-SMA positive. Besides that, we also showed cardiac TCs were homogenously positive for mesenchymal marker CD29 but negative for hematopoietic marker CD45, indicating that TCs could be a source of cardiac mesenchymal cells. The differences in morphological features and immunophenotypes between TCs and fibroblasts will provide more compelling evidence to differentiate cardiac TCs from fibroblasts.

Targeting microRNAs in Pathological Hypertrophy and Cardiac Failure.

MicroRNAs (miRNAs) are a novel class of endogenous, short, non-coding, posttranscriptional RNAs, which play important roles in regulating lots of important biological functions. Evidences show that altered expression of miRNAs are involved in pathological hypertrophy and cardiac failure, making it possible to target miRNAs as a novel therapy. In this review, we focus on very recent progresses in the regulation of miRNAs in pathological hypertrophy and cardiac failure. In addition, we also discuss the potential of using miRNAs as a new therapy for pathological hypertrophy and cardiac failure.

MicroRNA-221 is required for proliferation of mouse embryonic stem cells via P57 targeting.

Factors responsible for the rapid proliferative properties of embryonic stem (ES) cells are largely unknown. MicroRNA-221/222 (miR-221/222) regulate proliferation in many somatic cells, however, their roles in proliferation of ES cells are unclear. In this study, E14 mouse ES cells proliferation was determined by total cell counting, Cell Counting Kit (CCK-8), size of colonies and cell cycle analysis, while apoptosis and necrosis using Annexin V and propidium iodide staining. miR-221 inhibitor decreased proliferation of ES cells without inducing apoptosis and necrosis. miR-221 mimic, miR-222 mimic and miR-222 inhibitor did not affect ES cells proliferation. The expression level of miR-221 remained unchanged upon embryoid body (EB) formation. ES cells with miR-221 inhibition maintained an undifferentiated state, as indicated by unchanged alkaline phosphatase enzyme activity and Sox2, Nanong, and Oct4 expressions. P57 was post-transcriptionally regulated by miR-221 in ES cells. P57 knockdown completely abolished the inhibition effects of ES cells proliferation observed in miR-221 reduction, further indicating that miR-221 inhibition is likely to mediate its antiproliferative effects via P57 expression. To exclude that the function of miR-221 in ES cells is E14 specific, the effects of miR-221 mimic and inhibitor in size of colonies and cell cycle of R1 mouse ES cells were also determined and similar effects in inhibiting proliferation were achieved with miR-221 inhibition. Therefore, miR-221 is required for mouse ES cells proliferation via P57 targeting. This study indicates that miR-221 is among the regulators that control ES cells proliferation and might be used to influence the fate of ES cells.