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54 pages, 2627 KiB  
Review
Calcium Signaling Dynamics in Vascular Cells and Their Dysregulation in Vascular Disease
by Chang Dai and Raouf A. Khalil
Biomolecules 2025, 15(6), 892; https://doi.org/10.3390/biom15060892 - 18 Jun 2025
Viewed by 1247
Abstract
Calcium (Ca2+) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca2+ concentration [...] Read more.
Calcium (Ca2+) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca2+ concentration is tightly regulated by a balance between Ca2+ mobilization mechanisms, including Ca2+ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca2+ entry via voltage-dependent, transient-receptor potential, and store-operated Ca2+ channels, and Ca2+ elimination pathways including Ca2+ extrusion by the plasma membrane Ca2+-ATPase and Na+/Ca2+ exchanger and Ca2+ re-uptake by the sarco(endo)plasmic reticulum Ca2+-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca2+ mobilization and Ca2+ removal pathways. Also, the individual Ca2+ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca2+ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca2+ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca2+-dependent phosphorylation of the myosin light chain and Ca2+ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca2+ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca2+-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca2+ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca2+-dependent mechanisms, including Ca2+ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca2+ homeostasis and mitigating vascular disease progression. Full article
(This article belongs to the Special Issue Calcium Signaling in Cell Function and Dysfunction)
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23 pages, 3535 KiB  
Article
Cardio–Renal and Systemic Effects of SGLT2i Dapagliflozin on Short-Term Anthracycline and HER-2-Blocking Agent Therapy-Induced Cardiotoxicity
by Vincenzo Quagliariello, Annabella Di Mauro, Gerardo Ferrara, Francesca Bruzzese, Giuseppe Palma, Antonio Luciano, Maria Laura Canale, Irma Bisceglia, Martina Iovine, Christian Cadeddu Dessalvi, Carlo Maurea, Matteo Barbato, Alessandro Inno, Massimiliano Berretta, Andrea Paccone, Alfredo Mauriello, Celeste Fonderico, Anna Chiara Maratea and Nicola Maurea
Antioxidants 2025, 14(5), 612; https://doi.org/10.3390/antiox14050612 - 20 May 2025
Cited by 1 | Viewed by 796
Abstract
Anthracyclines and human epidermal growth factor receptor 2 (HER-2) inhibitors are cornerstone therapies for breast cancer but are associated with significant cardiotoxicity. While sodium–glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin have demonstrated cardio–renal protective effects during anthracycline treatment, their efficacy in preventing [...] Read more.
Anthracyclines and human epidermal growth factor receptor 2 (HER-2) inhibitors are cornerstone therapies for breast cancer but are associated with significant cardiotoxicity. While sodium–glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin have demonstrated cardio–renal protective effects during anthracycline treatment, their efficacy in preventing cardiotoxicity from sequential anthracycline and HER-2 blockade remains poorly understood. This study investigates the cardioprotective role of dapagliflozin in a preclinical model of chemotherapy-induced cardiotoxicity. Female C57Bl/6 mice were divided into four groups and treated for 10 days as follows: (1) a normal control group receiving saline (sham); (2) a model control group receiving doxorubicin (2.17 mg/kg/day for 5 days) followed by HER-2-blocking monoclonal antibody (2.25 mg/kg/day for 5 days); (3) a dapagliflozin-only group (10 mg/kg/day via oral gavage); and (4) a treatment group receiving the combination of doxorubicin, HER-2 inhibitor, and dapagliflozin. Cardiac function was assessed using echocardiography (VEVO 2100). Biomarkers of myocardial injury and inflammation (NLRP3, MyD88, CXCR4, H-FABP, troponin-T, and cytokines) were quantified via ELISA and immunohistochemistry. Circulating markers such as mitofusin-2, cardiac myosin light chain, malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE) were also measured. Dapagliflozin significantly preserved the ejection fraction and reduced both radial and longitudinal strain impairment in mice treated with the doxorubicin–HER-2 inhibitor combination (p < 0.001). Levels of myocardial NLRP3, MyD88, CXCR4, H-FABP, interleukin-1β, and troponin-T were significantly lower in the dapagliflozin-treated group compared to the chemotherapy-only group. Serum markers of oxidative stress and cardiac injury, including mitofusin-2, MDA, 4-HNE, BNP, and high-sensitivity C-reactive protein (hs-CRP), were also reduced by dapagliflozin treatment. Our findings demonstrate that dapagliflozin effectively mitigates early cardiac dysfunction and injury in a preclinical model of sequential doxorubicin and HER-2 inhibitor therapy. Full article
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12 pages, 1743 KiB  
Article
Cell-Penetrating Peptide Based on Myosin Phosphatase Target Subunit Sequence Mediates Myosin Phosphatase Activity
by Andrea Kiss, Mohamad Mahfood, Zsófia Bodogán, Zoltán Kónya, Bálint Bécsi and Ferenc Erdődi
Biomolecules 2025, 15(5), 705; https://doi.org/10.3390/biom15050705 - 12 May 2025
Cited by 1 | Viewed by 492
Abstract
Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The [...] Read more.
Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The association of MYPT1 with PP1c increases the phosphatase activity toward myosin; therefore, disrupting/dissociating this interaction may result in inhibition of the dephosphorylation of myosin. In this study, we probed how MYPT132–58 peptide including major PP1c interactive regions coupled with biotin and cell-penetrating TAT sequence (biotin-TAT-MYPT1) may influence MP activity. Biotin-TAT-MYPT1 inhibited the activity of MP holoenzyme and affinity chromatography as well as surface plasmon resonance (SPR) binding studies established its stable association with PP1c. Biotin-TAT-MYPT1 competed for binding to PP1c with immobilized GST-MYPT1 in SPR assays and it partially relieved PP1c inhibition by thiophosphorylated (on Thr696 and Thr853) MYPT1. Moreover, biotin-TAT-MYPT1 dissociated PP1c from immunoprecipitated PP1c-MYPT1 complex implying its holoenzyme disrupting ability. Biotin-TAT-MYPT1 penetrated into A7r5 smooth muscle cells localized in the cytoplasm and nucleus and exerted inhibition on MP with a parallel increase in MLC20 phosphorylation. Our results imply that the biotin-TAT-MYPT1 peptide may serve as a specific MP regulatory cell-penetrating peptide as well as possibly being applicable to further development for pharmacological interventions. Full article
(This article belongs to the Section Enzymology)
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16 pages, 2571 KiB  
Article
Chloroquine Inhibits Contraction Elicited by the Alpha-1 Adrenoceptor Agonist Phenylephrine in the Isolated Rat Aortas
by Soo Hee Lee, Kyeong-Eon Park, Seong-Chun Kwon, Seong-Ho Ok, Seung Hyun Ahn, Gyujin Sim and Ju-Tae Sohn
Int. J. Mol. Sci. 2025, 26(10), 4556; https://doi.org/10.3390/ijms26104556 - 9 May 2025
Viewed by 423
Abstract
Although chloroquine appears to inhibit the alpha-1 adrenoceptor, whether the chloroquine-mediated inhibition of phenylephrine-induced contraction is associated with the blockade of alpha-1 adrenoceptors remains unknown. This study examined the effect of chloroquine on contractions elicited by the alpha-1 adrenoceptor agonist phenylephrine in isolated [...] Read more.
Although chloroquine appears to inhibit the alpha-1 adrenoceptor, whether the chloroquine-mediated inhibition of phenylephrine-induced contraction is associated with the blockade of alpha-1 adrenoceptors remains unknown. This study examined the effect of chloroquine on contractions elicited by the alpha-1 adrenoceptor agonist phenylephrine in isolated rat aortas and determined the underlying mechanism. The effects of chloroquine and the alpha-1 adrenoceptor inhibitor prazosin on phenylephrine-elicited contractions were examined. The effects of the irreversible alpha-adrenoceptor inhibitor phenoxybenzamine followed by washout with fresh Krebs solution, as well as combined treatment with chloroquine and phenoxybenzamine followed by washout with fresh Krebs solution, on phenylephrine-induced contraction were investigated. Chloroquine and prazosin inhibited phenylephrine-induced contractions. However, pretreatment with prazosin eliminated the chloroquine-induced inhibition of contractions elicited by phenylephrine. Additionally, pretreatment with chloroquine and phenoxybenzamine followed by washout produced a higher contraction elicited by phenylephrine than pretreatment with phenoxybenzamine alone followed by washout. Although chloroquine did not affect the contraction induced by KCl in the endothelium-denuded aorta, it inhibited phenylephrine-induced protein kinase C (PKC) and myosin light-chain (MLC20) phosphorylation and Rho-kinase membrane translocation. These results suggest that chloroquine inhibits vasoconstriction elicited by phenylephrine via alpha-1 adrenoceptor inhibition, which is mediated by decreased MLC20 phosphorylation, the attenuation of PKC phosphorylation, and Rho-kinase membrane translocation. Full article
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17 pages, 2384 KiB  
Article
The Contractile Function of Ventricular Cardiomyocytes Is More Sensitive to Acute 17β-Estradiol Treatment Compared to Atrial Cardiomyocytes
by Tatiana A. Myachina, Xenia A. Butova, Raisa A. Simonova, Denis A. Volzhaninov, Anastasia M. Kochurova, Galina V. Kopylova, Daniil V. Shchepkin and Anastasia D. Khokhlova
Cells 2025, 14(8), 561; https://doi.org/10.3390/cells14080561 - 8 Apr 2025
Viewed by 622
Abstract
17β-estradiol (E2) is the most active metabolite of estrogen with a wide range of physiological action on cardiac muscle. Previous studies have reported E2 effects predominantly for the ventricles, while the E2 impact on the atria has been less examined. In this study, [...] Read more.
17β-estradiol (E2) is the most active metabolite of estrogen with a wide range of physiological action on cardiac muscle. Previous studies have reported E2 effects predominantly for the ventricles, while the E2 impact on the atria has been less examined. In this study, we focused on the direct E2 effects on atrial and ventricular contractility at the cellular and molecular levels. Single atrial and ventricular cardiomyocytes (CM) from adult (24 weeks-old) female Wistar rats were incubated with 10 nM E2 for 15 min. Sarcomere length and cytosolic [Ca2+]i transients were measured in mechanically non-loaded CM, and the tension–length relationship was studied in CM mechanically loaded by carbon fibers. The actin–myosin interaction and sarcomeric protein phosphorylation were analyzed using an in vitro motility assay and gel electrophoresis with Pro-Q Diamond phosphoprotein stain. E2 had chamber-specific effects on the contractile function of CM with a pronounced influence on ventricular CM. The characteristics of [Ca2+]i transients did not change in both atrial and ventricular CM. However, in ventricular CM, E2 reduced the amplitude and maximum velocity of sarcomere shortening and decreased the slope of the passive tension–length relationship that was associated with increased TnI and cMyBP-C phosphorylation. E2 treatment accelerated the cross-bridge cycle of both atrial and ventricular myosin that was associated with increased phosphorylation of the myosin essential light chain. This study shows that E2 impairs the mechanical function of the ventricular myocardium while atrial contractility remains mostly preserved. Hormonal replacement therapy (HRT) with estrogen is by far the most effective therapy for treating climacteric symptoms experienced during menopause. Here we found a chamber specificity of myocardial contractile function to E2 that should be taken into account for the potential side effects of HRT. Full article
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22 pages, 14596 KiB  
Article
The Minute Virus of Canines (MVC) Activates the RhoA/ROCK1/MLC2 Signal Transduction Pathway Resulting in the Dissociation of Tight Junctions and Facilitating Occludin-Mediated Viral Infection
by Xiang Ren, Zhiping Hei, Kai Ji, Yan Yan, Chuchu Tian, Yin Wei and Yuning Sun
Microorganisms 2025, 13(3), 695; https://doi.org/10.3390/microorganisms13030695 - 20 Mar 2025
Viewed by 514
Abstract
The Minute Virus of Canines (MVC), belonging to the genus Bocaparvovirus within the family Parvoviridae, is associated with enteritis and embryonic infection in neonatal canines. Viral attachment to host cells is a critical step in infection, and viral protein 2 (VP2) as [...] Read more.
The Minute Virus of Canines (MVC), belonging to the genus Bocaparvovirus within the family Parvoviridae, is associated with enteritis and embryonic infection in neonatal canines. Viral attachment to host cells is a critical step in infection, and viral protein 2 (VP2) as an important structural protein of MVC influences host selection and infection severity. Nevertheless, little is known about the interaction between VP2 protein and host cells. In this study, we identified that VP2 directly interacts with the kinase domain of RhoA-associated protein kinase 1 (ROCK1) by using mass spectrometry and immunoprecipitation approach and demonstrated that the RhoA/ROCK1/myosin light chain 2 (MLC2) signaling pathway was activated during the early stage of MVC infection in Walter Reed canine cell/3873D (WRD) cells. Further studies indicated that RhoA/ROCK1-mediated phosphorylation of MLC2 triggers the contraction of the actomyosin ring, disrupts tight junctions, and exposes the tight junction protein Occludin, which facilitates the interaction between VP2 and Occludin. Specific inhibitors of RhoA and ROCK1 restored the MVC-induced intracellular translocation of Occludin and the increase in cell membrane permeability. Moreover, the two inhibitors significantly reduced viral protein expression and genomic copy number. Collectively, our study provides the first evidence that there is a direct interaction between the structural protein VP2 of MVC and ROCK1, and that the tight junction protein Occludin can serve as a potential co-receptor for MVC infection, which may offer new targets for anti-MVC strategies. Full article
(This article belongs to the Section Molecular Microbiology and Immunology)
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19 pages, 8939 KiB  
Article
Gastrodin Mitigates Ketamine-Induced Inhibition of F-Actin Remodeling and Cell Migration by Regulating the Rho Signaling Pathway
by Ping-Cheng Shih, I-Shiang Tzeng, Yi-Chyan Chen and Mao-Liang Chen
Biomedicines 2025, 13(3), 649; https://doi.org/10.3390/biomedicines13030649 - 6 Mar 2025
Cited by 1 | Viewed by 843
Abstract
Background/Objects: Rho signaling plays a role in calcium-regulated cytoskeletal reorganization and cell movement, processes linked to neuronal function and cancer metastasis. Gastrodia elata, a traditional herbal medicine, can regulate glutamate-induced calcium influx in PC12 cells and influence cell function by modulating [...] Read more.
Background/Objects: Rho signaling plays a role in calcium-regulated cytoskeletal reorganization and cell movement, processes linked to neuronal function and cancer metastasis. Gastrodia elata, a traditional herbal medicine, can regulate glutamate-induced calcium influx in PC12 cells and influence cell function by modulating neuronal cytoskeleton remodeling via the monoaminergic system and Rho signaling. This study investigates the effects of gastrodin, a key component of Gastrodia elata, on Rho signaling, cytoskeleton remodeling, and cell migration in B35 and C6 cells. It also explores gastrodin’s impact on Rho signaling in the prefrontal cortex of Sprague Dawley rats. Methods: B35 cells, C6 cells, and Sprague Dawley rats were treated with ketamine, gastrodin, or both. The expression of examined proteins from B35 cells, C6 cells, and the prefrontal cortex of Sprague Dawley rats were analyzed using immunoblotting. Immunofluorescent staining was applied to detect the phosphorylation of RhoGDI1. F-actin was stained using phalloidin-488 staining. Cell migration was analyzed using the Transwell and wound-healing assays. Results: Gastrodin reversed the ketamine-induced regulation of cell mobility inhibition, F-actin condensation, and Rho signaling modulation including Rho GDP dissociation inhibitor 1 (RhoGDI1); the Rho family protein (Ras homolog family member A (RhoA); cell division control protein 42 homolog (CDC42); Ras-related C3 botulinum toxin substrate 1(Rac1)); rho-associated, coiled-coil-containing protein kinase 1 (ROCK1); neural Wiskott–Aldrich syndrome protein (NWASP); myosin light chain 2 (MLC2); profilin1 (PFN1); and cofilin-1 (CFL1) in B35 and C6 cells. Similar modulations on Rho signaling were also observed in the prefrontal cortex of rats. Conclusions: Our findings show that gastrodin counteracts ketamine-induced disruptions in Rho signaling, cytoskeletal dynamics, and cell migration by regulating key components like RhoGDI1, ROCK1, MLC2, PFN1, and CFL1. This suggests the potential of gastrodin as a comprehensive regulator of cellular signaling. Full article
(This article belongs to the Section Cell Biology and Pathology)
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24 pages, 577 KiB  
Review
Research Progress on Shrimp Allergens and Allergenicity Reduction Methods
by Bingjie Chen, Hui He, Xiao Wang, Songheng Wu, Qiankun Wang, Jinglin Zhang, Yongjin Qiao and Hongru Liu
Foods 2025, 14(5), 895; https://doi.org/10.3390/foods14050895 - 6 Mar 2025
Cited by 2 | Viewed by 1895
Abstract
Shrimp are highly favored by consumers for their delicious taste and rich nutritional value. However, reports of allergic reactions caused by shrimp and its derivatives have been increasing, significantly impacting consumer health and posing a growing global food safety concern. This article introduces [...] Read more.
Shrimp are highly favored by consumers for their delicious taste and rich nutritional value. However, reports of allergic reactions caused by shrimp and its derivatives have been increasing, significantly impacting consumer health and posing a growing global food safety concern. This article introduces the structure and biochemical characteristics of major allergenic proteins in shrimp, including tropomyosin (TM), arginine kinase, sarcoplasmic calcium-binding protein, myosin light chain, troponin C, and hemocyanin. Currently, there is no effective treatment for shrimp allergies, and prevention is mainly achieved by avoiding consumption. The study of shrimp allergen sensitization reduction technology is of great significance to the development of hypoallergenic or desensitized products. The article provides a detailed overview of the effects of common processing techniques, including physical, chemical, biological, and combined methods, on the allergenicity of shrimp allergens; for instance, the binding rate to immunoglobulin E (IgE) was reduced by 73.59% after treating TM with high pressure (500 MPa) at 55 °C for 10 min and the recognition rate of TM to IgE decreased by 89.4% on average after treating TM with pepsin (30 μg/mL, pH 2) for 2 h. These techniques provide references for the development of hypoallergenic aquatic products or desensitized foods. Full article
(This article belongs to the Special Issue Marine Food: Development, Quality and Functionality)
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15 pages, 2950 KiB  
Article
Involvement of RhoA/ROCK Signaling Pathway in Methamphetamine-Induced Blood-Brain Barrier Disruption
by Jong Su Hwang, Tam Thuy Lu Vo, Mikyung Kim, Eun Hye Cha, Kyo Cheol Mun, Eunyoung Ha and Ji Hae Seo
Biomolecules 2025, 15(3), 340; https://doi.org/10.3390/biom15030340 - 27 Feb 2025
Cited by 1 | Viewed by 1134
Abstract
Methamphetamine (METH) is a powerful addictive psychostimulant that gives rise to severe abusers worldwide. While many studies have reported on the neurotoxicity of METH, blood–brain barrier (BBB) dysfunction has recently attracted attention as an essential target in METH-induced pathological changes in the brain. [...] Read more.
Methamphetamine (METH) is a powerful addictive psychostimulant that gives rise to severe abusers worldwide. While many studies have reported on the neurotoxicity of METH, blood–brain barrier (BBB) dysfunction has recently attracted attention as an essential target in METH-induced pathological changes in the brain. However, its mechanism has not been fully understood. We found that METH increased paracellular permeability and decreased vascular integrity through FITC–dextran and trans-endothelial electrical resistance (TEER) assay in primary human brain endothelial cells (HBMECs). Also, redistribution of tight junction proteins (zonula occluden-1 and claudin-5) and reorganization of F-actin cytoskeleton were observed in METH-exposed HBMECs. To determine the mechanism of METH-induced BBB disruption, the RhoA/ROCK signaling pathway was examined in METH-treated HBMECs. METH-activated RhoA, followed by an increase in the phosphorylation of downstream effectors, myosin light chain (MLC) and cofilin, occurs in HBMECs. Pretreatment with ROCK inhibitors Y-27632 and fasudil reduced the METH-induced increase in phosphorylation of MLC and cofilin, preventing METH-induced redistribution of junction proteins and F-actin cytoskeletal reorganization. Moreover, METH-induced BBB leakage was alleviated by ROCK inhibitors in vitro and in vivo. Taken together, these results suggest that METH induces BBB dysfunction by activating the RhoA/ROCK signaling pathway, which results in the redistribution of junction proteins via F-actin cytoskeletal reorganization. Full article
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16 pages, 5500 KiB  
Article
Helicobacter hepaticus CdtB Triggers Colonic Mucosal Barrier Disruption in Mice via Epithelial Tight Junction Impairment Mediated by MLCK/pMLC2 Signaling Pathway
by Tao Wang, Xiao Meng, Miao Qian, Shanhao Jin, Ruoyu Bao, Liqi Zhu and Quan Zhang
Vet. Sci. 2025, 12(2), 174; https://doi.org/10.3390/vetsci12020174 - 14 Feb 2025
Cited by 3 | Viewed by 948
Abstract
Background: Helicobacter hepaticus (H. hepaticus) has been demonstrated to have clinical relevance to the development of colitis in rodents. H. hepaticus produces cytolethal distending toxins (CDTs), which are identified as the most important virulence factors to the pathogenicity of CDT-producing [...] Read more.
Background: Helicobacter hepaticus (H. hepaticus) has been demonstrated to have clinical relevance to the development of colitis in rodents. H. hepaticus produces cytolethal distending toxins (CDTs), which are identified as the most important virulence factors to the pathogenicity of CDT-producing bacteria in animals. However, the precise relationship between CDTs of H. hepaticus and intestinal barrier dysfunction remains unclear. The objective of the present study was to ascertain the impact of CdtB, the active subunit of CDTs, on the colonic mucosal barrier during H. hepaticus infection. Materials and Methods: We investigated the infection of male BALB/c mice, intestinal organoids, and IEC-6 cell monolayers by H. hepaticus or CdtB-deficient H. hepaticus (ΔCdtB). A comprehensive histopathological examination was conducted, encompassing the assessment of H. hepaticus colonization, the levels of mRNA expression for inflammatory cytokines, the expression levels of tight junction proteins, and the related signaling pathways. Results: The results demonstrate that the presence of ΔCdtB led to a mitigation of the symptoms associated with H. hepaticus-induced colitis, as evidenced by colon length shortening and the colon histological inflammation score. In addition, the levels of pro-inflammatory cytokines were reduced in the ΔCdtB group. Moreover, a downward trend was observed in the phosphorylation levels of STAT3 and nuclear factor-κB (p65). In vitro, the presence of H. hepaticus resulted in a reduction in the expression of tight junction (TJ) markers (ZO-1 and occludin) and an impairment of the F-actin structure in either the intestinal epithelium or intestinal organoids. However, these effects were reversed by CdtB deletion. Concurrently, both ROS levels and apoptosis levels were found to be significantly reduced in cells treated with the ΔCdtB strain. Mechanistically, myosin light chain kinase (MLCK) activation was observed in the H. hepaticus-infected group in vivo, whereas the MLCK inhibitor ML-7 was found to reverse the CdtB-induced alterations in TJ proteins in IEC6 cells. Conclusions: The collective findings demonstrate that CdtB plays a pivotal role in the H. hepaticus-induced colonic mucosal barrier. This is achieved through the regulation of TJs via the MLCK/pMLC2 signaling pathway, which is linked to elevations in oxidative stress and inflammation within intestinal epithelial cells. Full article
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17 pages, 4074 KiB  
Article
A Platform Integrating Biophysical and Biochemical Stimuli to Enhance Differentiation and Maturation of Cardiomyocyte Subtypes Derived from Human Induced Pluripotent Stem Cells
by Zhonggang Feng, Kota Sawada, Iori Ando, Riku Yoshinari, Daisuke Sato and Tadashi Kosawada
J. Cardiovasc. Dev. Dis. 2025, 12(2), 56; https://doi.org/10.3390/jcdd12020056 - 4 Feb 2025
Viewed by 1022
Abstract
To enhance the differentiation and maturation of cardiomyocytes derived from human induced pluripotent stem cells, we developed a bioreactor system that simultaneously imposes biophysical and biochemical stimuli on these committed cardiomyocytes. The cells were cultured within biohydrogels composed of the extracellular matrix extracted [...] Read more.
To enhance the differentiation and maturation of cardiomyocytes derived from human induced pluripotent stem cells, we developed a bioreactor system that simultaneously imposes biophysical and biochemical stimuli on these committed cardiomyocytes. The cells were cultured within biohydrogels composed of the extracellular matrix extracted from goat ventricles and purchased rat-origin collagen, which were housed in the elastic PDMS culture chambers of the bioreactor. Elastic and flexible electrodes composed of PEDOT/PSS, latex, and graphene flakes were embedded in the hydrogels and chamber walls, allowing cyclic stretch and electrical pulses to be simultaneously and coordinately applied to the cultured cells. Furthermore, a dynamic analysis method employing the transverse forced oscillation theory of a cantilever was used to analyze and discriminate the subtype-specific beating behavior of the cardiomyocytes. It was found that myosin light chain 2v (MLC2v), a ventricular cell marker, was primarily upregulated in cells aggregated on the (+) electrode side, while cardiomyocytes with faint MLC2v but strong cardiac troponin T (cTNT) expression aggregated at the ground electrode (GND) side. mRNA analysis using rtPCR and the gel beating dynamics further suggested a subtype deviation on the different electrode sides. This study demonstrated the potential of our bioreactor system in enhancing cardiac differentiation and maturation, and it showed an intriguing phenomenon of cardiomyocyte subtype aggregation on different electrodes, which may be developed into a new method to enhance the maturation and separation of cardiomyocyte subtypes. Full article
(This article belongs to the Section Cardiac Development and Regeneration)
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20 pages, 4651 KiB  
Article
Reduced Glutathione Promoted Growth Performance by Improving the Jejunal Barrier, Antioxidant Function, and Altering Proteomics of Weaned Piglets
by Zhimei Tian, Yiyan Cui, Miao Yu, Dun Deng, Zhenming Li, Xianyong Ma and Mingren Qu
Antioxidants 2025, 14(1), 107; https://doi.org/10.3390/antiox14010107 - 17 Jan 2025
Cited by 1 | Viewed by 1070
Abstract
Reduced glutathione (GSH) is a main nonenzymatic antioxidant, but its effects and underlying mechanisms on growth and intestinal health in weaned piglets still require further assessment. A total of 180 weaned piglets were randomly allotted to 5 groups: a basal diet (CON), and [...] Read more.
Reduced glutathione (GSH) is a main nonenzymatic antioxidant, but its effects and underlying mechanisms on growth and intestinal health in weaned piglets still require further assessment. A total of 180 weaned piglets were randomly allotted to 5 groups: a basal diet (CON), and a basal diet supplemented with antibiotic chlortetracycline (ABX), 50 (GSH1), 65 (GSH2), or 100 mg/kg GSH (GSH3). Results revealed that dietary GSH1, GSH2, and ABX improved body weight and the average daily gain of weaned piglets, and ABX decreased albumin content but increased aspartate aminotransferase (AST) activity and the ratio of AST to alanine transaminase levels in plasma. GSH2 significantly decreased glucose content but increased the content of triglyceride and cholesterol in the plasma. Both GSH1 and GSH2 improved the jejunal mucosa architecture (villus height, crypt depth, and the ratio of villus height to crypt depth), tight junction protein (ZO-1 and Occludin), and antioxidant capacity (CAT and MDA), and the effects were superior to ABX. Dietary GSH improved the jejunal barrier by probably inhibiting the myosin light chain kinas pathway to up-regulate the transcript expression of tight junction protein (ZO-1 and Occludin) and Mucins. Through the proteomics analysis of the jejunal mucosa using 4D-DIA, the KEGG pathway enrichment analysis showed that differentiated proteins were significantly enriched in redox homeostasis-related pathways such as glutathione metabolism, cytochrome P450, the reactive oxygen species metabolic pathway, the oxidative phosphorylation pathway, and the phosphatidylinositol 3-kinase-serine/threonine kinase pathway in GSH2 vs. CON and in GSH2 vs. ABX. The results of proteomics and qRT-PCR showed that GSH supplementation might dose-dependently promote growth performance and that it alleviated the weaning stress-induced oxidative injury of the jejunal mucosa in piglets by activating SIRTI and Akt pathways to regulate GPX4, HSP70, FoxO1. Therefore, diets supplemented with 50–65 mg/kg GSH can promote the growth of and relieve intestinal oxidative injury in weaned piglets. Full article
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25 pages, 15907 KiB  
Article
Antiedemic Effect of the Myosin Light Chain Kinase Inhibitor PIK7 in the Rat Model of Myocardial Ischemia Reperfusion Injury
by Dmitry L. Sonin, Mikhail S. Medved, Asker Y. Khapchaev, Maria V. Sidorova, Marina E. Palkeeva, Olga A. Kazakova, Garry V. Papayan, Daniil A. Mochalov, Sarkis M. Minasyan, Ilya E. Anufriev, Daria V. Mukhametdinova, Natalia M. Paramonova, Ksenia M. Balabanova, Anastasia S. Lopatina, Ilia V. Aleksandrov, Natalya Yu. Semenova, Anna A. Kordyukova, Kirill V. Zaichenko, Vladimir P. Shirinsky and Michael M. Galagudza
Curr. Issues Mol. Biol. 2025, 47(1), 33; https://doi.org/10.3390/cimb47010033 - 6 Jan 2025
Viewed by 1117
Abstract
Myocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species and inflammatory mediators during reperfusion causes myosin light chain kinase [...] Read more.
Myocardial ischemia-reperfusion injury increases myocardial microvascular permeability, leading to enhanced microvascular filtration and interstitial fluid accumulation that is associated with greater microvascular obstruction and inadequate myocardial perfusion. A burst of reactive oxygen species and inflammatory mediators during reperfusion causes myosin light chain kinase (MLCK)-dependent endothelial hyperpermeability, which is considered a preventable cause of reperfusion injury. In the present study, a single intravenous injection of MLCK peptide inhibitor PIK7 (2.5 mg/kg or 40 mg/kg) was found to suppress the vascular hyperpermeability caused by ischemia/reperfusion injury in an in vivo rat model. The antiedemic effect of PIK7 is transient and ceases within 90 min of reperfusion. The early no-reflow detected for the first time after 30 min ischemia in this model of myocardial infarction reduces the area accessible for PIK7. Electron microscopy has shown membrane-bound blebs of endotheliocytes, which partially or completely obturate the capillary lumen, and few capillaries with signs of intercellular gap formation in samples obtained from the center of the early no-reflow zone in control and PIK7-injected rats. Co-injection of PIK7 with NO donor sodium nitroprusside (SNP) increases blood flow in the zone of early no-reflow, while reducing the increased vascular permeability caused by SNP. Full article
(This article belongs to the Section Molecular Medicine)
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14 pages, 711 KiB  
Article
Effects of Dietary Gallic Acid on Growth Performance, Meat Quality, Antioxidant Capacity, and Muscle Fiber Type-Related Gene Expression in Broiler Chickens Challenged with Lipopolysaccharide
by Taidi Xiong, Zhilong Chen, Mubashar Hassan, Cui Zhu, Junyan Wang, Shujun Tan, Fayuan Ding, Zhonggang Cheng, Jinling Ye, Qiuli Fan, Danlei Xu, Shouqun Jiang and Dong Ruan
Animals 2024, 14(24), 3670; https://doi.org/10.3390/ani14243670 - 19 Dec 2024
Cited by 1 | Viewed by 1395
Abstract
In this study, broilers were selected as the research object to investigate the effects and mechanisms of dietary gallic acid (GA) supplementation on growth performance, meat quality, antioxidant capacity, and muscle fiber-related gene expression. A total of 750 one-day-old healthy 817 male crossbred [...] Read more.
In this study, broilers were selected as the research object to investigate the effects and mechanisms of dietary gallic acid (GA) supplementation on growth performance, meat quality, antioxidant capacity, and muscle fiber-related gene expression. A total of 750 one-day-old healthy 817 male crossbred broiler chickens were divided into five treatment groups, with six replicates per group. Birds in the control (CON) group and LPS-challenged treatment (LPS) group were fed a basal diet, and birds in the other three treatment groups received the basal diet with 150, 300, or 450 mg/kg added GA (GA150, GA300, GA450). On days 14, 17, and 20, chickens in the LPS, GA150, GA300, and GA450 groups received intramuscular injections of LPS, while chickens in the CON group received saline. The results showed that the addition of GA to the diet could effectively increase the average daily gain (ADG) of broilers from 1 to 50 days of age, and had a trend (p = 0.078) of increasing the average daily feed intake (ADFI). Adding 450 mg/kg GA to the diet significantly reduced (p < 0.05) the drip loss and pH value of pectoral muscles 45 min after slaughter, and significantly increased (p < 0.05) the lightness value of pectoral muscles 45 min post-slaughter. With an increase in GA level, the content of total volatile basic nitrogen (TVB-N) in pectoral muscles decreased linearly (p < 0.05), and the concentration of C22:6n-3 increased linearly (p < 0.05). GA effectively improved (p < 0.05) the antioxidant capacity of muscles and significantly increased (p < 0.05) the activity of total superoxide dismutase (T-SOD) in pectoral muscles after LPS stimulation, exhibiting linear and quadratic changes (p < 0.05). It also significantly increased (p < 0.05) the activity of hydrogen peroxide and decreased the activity of glutathione peroxidase (GSH-Px), while it linearly decreased (p < 0.05) the content of malondialdehyde (MDA). In addition, the dietary supplementation of GA significantly increased (p < 0.05) the expression levels of myosin heavy chain (MyHC) I and MyHC IIa in pectoral muscles and significantly decreased (p < 0.05) the expression level of MyHC IIx. In summary, the dietary addition of GA can alleviate the effect of the stress response on the growth performance of broiler chickens and improve antioxidant capacity and meat quality. The appropriate amount of dietary GA at each stage was 300 mg/kg. Full article
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12 pages, 1307 KiB  
Review
Myosin Light Chains in the Progression of Cancer
by Savannah L. Kozole and Karen A. Beningo
Cells 2024, 13(24), 2081; https://doi.org/10.3390/cells13242081 - 17 Dec 2024
Cited by 1 | Viewed by 1745
Abstract
The myosin light chains (MLCs) of non-muscle myosin II are known to regulate cellular architecture and generate cellular forces; they also have an increasingly emerging role in the progression of cancer. The phosphorylation state of the myosin light chains controls the activity of [...] Read more.
The myosin light chains (MLCs) of non-muscle myosin II are known to regulate cellular architecture and generate cellular forces; they also have an increasingly emerging role in the progression of cancer. The phosphorylation state of the myosin light chains controls the activity of myosins that are implicated in invasion and proliferation. In cancers, when proliferation is greatly increased, cytokinesis relies on phosphorylated light chains to activate the contractile forces used to separate the cells. Likewise, during metastasis, kinase pathways culminate in aligning MLC structures for enhanced cell motility through stress fiber contraction and the accumulation of myosin filaments at the leading edge. This review summarizes the myosin light chain family members known to promote cancer progression and evidence of how their altered activities change the behavior of cells involving the mechanical-based processes of proliferation and cell movements during metastasis. In addition, myosin light chains impact the immune response to cancers and currently serve as biomarkers in staging this disease; a brief summary of these topics is provided at the end of the review. Full article
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