International Journal of Molecular Sciences最新文献

High-density lipoprotein (HDL) is associated with decreased incidence of cardiovascular events, and its functionality also influences prognosis. Exercise is an important tool to improve prognosis in the post-infarction (MI) population, but the role of exercise on HDL functionality is poorly understood. Sixty-two patients with acute MI were randomized in a supervised exercise program for 12-14 weeks (exercise group-EG) or a control group (CG). The main objective of the study was to analyze the role of exercise on esterified cholesterol (EC) and unesterified cholesterol (UC) transfer to HDL. For the total population, the baseline mean rate of EC transfer to HDL was 2.53 ± 0.83 and at the end of follow-up, it was 2.74 ± 0.64 (p = 0.03). The figures for UC were, respectively, 4.08 ± 1.2 and 4.4 ± 1.06 (p = 0.02). The difference (follow-up minus baseline) for EC was 0.15 ± 0.84 for the control group and 0.27 ± 0.69 for the exercise group (p = 0.53); for UC, the figures were 0.28 ± 1.14 and 0.35 ± 0.96 (p = 0.80), respectively, for the control and exercise groups. In post-MI patients, 12-14 weeks of supervised exercise did not improve HDL functionality.

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure to GCs continues to affect not only intrauterine fetal development itself, but also the metabolic status and neural activity in adulthood through epigenetic changes such as microRNA change, histone modification, and DNA methylation. We have shown that the IUGR model induced DNA hypomethylation in the paraventricular nucleus (PVN) in the brain, which in turn activates sympathetic activities, the renin-angiotensin system (RAS), contributing to the development of salt-sensitive hypertension. Even in adulthood, strong stress and/or exogenous steroids have been shown to induce epigenetic changes in the brain. Furthermore, DNA hypomethylation in the PVN is also observed in other hypertensive rat models, which suggests that it contributes significantly to the origins of elevated blood pressure. These findings suggest that if we can alter epigenetic changes in the brain, we can treat or prevent hypertension.

Over recent decades, Northern Patagonia in Chile has seen significant growth in agriculture, livestock, forestry, and aquaculture, disrupting lake ecosystems and threatening native species. These environmental changes offer a chance to explore how anthropization impacts zooplankton communities from a molecular-ecological perspective. This study assessed the anthropogenic impact on Daphnia pulex by comparing its proteomes from two lakes: Llanquihue (anthropized) and Icalma (oligotrophic). Results showed substantial differences in protein expression, with 17 proteins upregulated and 181 downregulated in Llanquihue, linked to elevated levels of copper, manganese, dissolved solids, phosphate, and nitrogen. These stressors caused metabolic damage and environmental stress in D. pulex. Our findings highlight the importance of monitoring pollution's effects on Northern Patagonian ecosystems, especially on keystone species like D. pulex, essential for ecosystem stability. This research provides fresh molecular-ecological insights into pollution's impacts, a perspective rarely addressed in this region. Understanding these effects is critical for conserving natural resources and offers pathways to study adaptive mechanisms in keystone species facing pollution. This approach also informs strategies for ecosystem management and restoration, addressing both immediate and long-term challenges in Northern Patagonian aquatic environments.

Autoimmune diseases are complex conditions characterized by immune-mediated tissue damage and chronic inflammation. Protease-activated receptor 2 (Par2) has been implicated in these diseases, exhibiting dual roles that complicate its therapeutic potential. This review examines the perplexing functions of Par2, which promotes inflammation through immune cell activation while facilitating tissue healing in damaged organs. By analyzing findings across diverse autoimmune conditions, including rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease, we highlight how the context and location of Par2 activation determine its effects. Recent studies from our laboratory have resolved some of these contradictions by distinguishing Par2's immune-mediated inflammatory roles from its tissue-reparative functions. These insights pave the way for context-specific therapeutic strategies, such as selective Par2 modulators, that can mitigate inflammation while enhancing tissue repair. However, achieving such precision in modulation remains a significant challenge, necessitating further research into Par2's signaling pathways. This review underscores Par2's complexity and its transformative potential in autoimmune disease management, offering a nuanced perspective on its duality and therapeutic implications.

During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca²⁺ to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca²⁺-dependent signaling pathways by reducing the mRNA expression of the Ca²⁺-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy.

While the pulmonary effects of regular waterpipe smoking (R-WPS) are well-defined, the impact of occasional waterpipe smoking (O-WPS) on the lungs remains less established. This study investigated the pulmonary toxicity and underlying mechanisms of O-WPS versus R-WPS following 6 months of exposure, focusing on histopathology, inflammation in the lung, bronchoalveolar lavage fluid (BALF), and plasma, as well as oxidative stress, genotoxicity, mitochondrial dysfunction, and the expression of mitogen-activated protein kinases (MAPKs) in lung homogenates. Exposure to both O-WPS and R-WPS resulted in significant histological changes, including increased numbers of alveolar macrophages and lymphocytes, as well as interstitial fibrosis. Only R-WPS increased the number of neutrophil polymorphs and plasma cells. R-WPS also significantly increased the chemokines CXCL1, CXCL2, and CCL2 in the lung, BALF, and plasma, while O-WPS increased CXCL1 and CXCL2 in the lung and CXCL1 in the plasma. Both exposure regimens significantly increased lung injury markers, including matrix metalloproteinase-9 and myeloperoxidase. Additionally, R-WPS induced a significant increase in the cytokines IL1β, IL6, and TNFα in the lung, BALF, and plasma, while O-WPS elevated IL1β and IL6 in the lung. Oxidative stress was observed, with increased levels of thiobarbituric acid reactive substances and superoxide dismutase in both the O-WPS and R-WPS groups. Exposure to either O-WPS or R-WPS triggered genotoxicity and altered mitochondrial complex activities. R-WPS exposure also resulted in elevated expression of p-JNK/JNK, p-ERK/ERK, and p-p38/p38, while O-WPS augmented the p-ERK/ERK ratio in the lungs. Taken together, these findings indicate that both O-WPS and R-WPS contribute to lung injury and induce inflammation, oxidative stress, genotoxicity, and mitochondrial dysfunction, with R-WPS having a more pronounced effect. These effects were associated with the activation of MAPKs.

The trans-translation system, mediated by transfer-messenger RNA (tmRNA, encoded by the ssrA gene) and its partner protein SmpB, helps to release ribosomes stalled on defective mRNA and targets incomplete protein products for hydrolysis. Knocking out the ssrA and smpB genes in various pathogens leads to different phenotypic changes, indicating that they have both cooperative and independent functionalities. This study aimed to clarify the functional relationships between tmRNA and SmpB in Aeromonas veronii, a pathogen that poses threats in aquaculture and human health. We characterized the expression dynamics of the ssrA and smpB genes at different growth stages of the pathogen, assessed the responses of deletion strains ΔssrA and ΔsmpB to various environmental stressors and carbon source supplementations, and identified the gene-regulatory networks involving both genes by integrating transcriptomic and phenotypic analyses. Our results showed that the gene ssrA maintained stable expression throughout the bacterial growth period, while smpB exhibited upregulated expression in response to nutrient deficiencies. Compared to the wild type, both the ΔssrA and ΔsmpB strains exhibited attenuated resistance to most stress conditions. However, ΔssrA independently responded to starvation, while ΔsmpB specifically showed reduced resistance to lower concentrations of Fe³⁺ and higher concentrations of Na⁺ ions, as well as increased utilization of the carbon source β-Methyl-D-glucoside. The transcriptomic analysis supported these phenotypic results, demonstrating that tmRNA and SmpB cooperate under nutrient-deficient conditions but operate independently in nutrient-rich environments. Phenotypic experiments confirmed that SsrA and SmpB collaboratively regulate genes involved in siderophore synthesis and iron uptake systems in response to extracellular iron deficiency. The findings of the present study provide crucial insights into the functions of the trans-translation system and highlight new roles for tmRNA and SmpB beyond trans-translation.

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Recently, we demonstrated that the alopecia observed in vitamin D receptor gene-deficient (Vdr-KO) rats is not seen in rats with a mutant VDR(R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since Vdr-KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among Vdr-KO, Vdr-R270L/H301Q, and wild-type (WT) rats. While Vdr-R270L/H301Q rats exhibited normal skin formation similar to WT rats, Vdr-KO rats showed remarkable hyperkeratosis and trans-epidermal water loss in the skin. RNA sequencing and proteomic analysis revealed that the gene and protein expression patterns in Vdr-KO rats significantly differed from those in WT and Vdr-R270L/H301Q rats, with a marked decrease in the expression of factors involved in Shh, Wnt, and Bmp signaling pathways, a dramatic reduction in the expression of hair keratins, and a substantial increase in the expression of epidermal keratins. This study clearly demonstrated that non-liganded VDR is significantly involved in the differentiation, proliferation, and cell death of keratinocytes in hair follicles and the epidermis.

Melanoma is among the most common malignancies and has recently exhibited increased resistance to treatments, resulting in a more aggressive disease course. Mesenchymal stem cells (MSCs) secrete cytokines both in vivo and in vitro, which regulate tumor cell signaling pathways and the tumor microenvironment, thereby influencing tumor progression. This study investigates the anti-melanogenesis effects of sheep umbilical cord mesenchymal stem cells (SUCMSCs) to assess their potential application in melanoma treatment. Our findings indicate that, in vitro, SUCMSCs reduce melanin content and tyrosinase activity, inhibit melanoma cell viability, proliferation, migration, and invasion, and promote melanoma cell apoptosis. Subsequent in vivo experiments confirmed that SUCMSCs effectively suppress tumor growth, and histological analysis via HE staining revealed notable differences. Additionally, transcriptome sequencing analysis indicated that the anti-tumor effects were primarily mediated through autophagy, apoptosis, and the TGF-β and NF-κB signaling pathways. The RT-qPCR validation results aligned with the transcriptome data. In summary, SUCMSCs exert anti-melanogenesis effects through the interaction of multiple signaling pathways and cytokines, demonstrating significant potential for melanoma treatment.