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A thorough understanding of the pathological process underlying hypertension‐induced cardiac remodelling may help in prevention and treatment of heart failure. Angiotensin II (AngII) results in cardiac fibrosis and hypertrophy partly through activation of inflammation, which increases the fibroblasts and promotes extracellular matrix production. Sulfasalazine (SASP) has evident anti‐inflammatory effects and pharmacological functions on autoimmune disease. The roles of SASP in the cardiac remodelling remain unknown. In this study, we established AngII‐induced cardiac remodelling mice model and then treated with SASP. Blood pressure, cardiac pump function and pathological changes of cardiac remodelling were analysed in these mice. To explore the mechanism, phosphorylated Akt was detected in vivo and vitro. In this study, we found that SASP aggravated cardiac dysfunction, hypertrophy and fibrosis after AngII infusion. In addition, SASP activated Akt in AngII‐remodelled mouse hearts and cardiac cells. Our findings indicate that independent of anti‐inflammatory property, SASP exacerbates AngII‐induced cardiac remodelling by activation of Akt signalling pathway. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a chronic noninfectious disease that is mainly featured by pancreatic β-cell (β-cell) dysfunction and impaired glucose homeostasis. Currently, the pathogenesis of dysfunction of the β-cells in DM remains unclear, and therapeutic approaches to it are limited. Emodin (EMD), a natural anthraquinone derivative, has been preliminarily proven to show antidiabetic effects. However, the underlying mechanism of EMD on β-cells still needs to be elucidated. In this study, we investigated the protective effects of EMD on the high glucose (50 mM)-induced INS-1 cell line and the underlying mechanism. INS-1 cells were treated with EMD (5, 10, and 20 μM) when exposed to high glucose. The effects of EMD were examined by using the inverted phase-contrast microscope, qRT-PCR, ELISA, and western blot. The results showed that EMD could alleviate cellular morphological changes, suppress IL-1β and LDH release, and promote insulin secretion in high-glucose-induced INS-1 cells. Furthermore, EMD inhibits NOD-like receptor protein 3 (NLRP3) activation and gasdermin D (GSDMD) cleavage to alleviate pyroptosis induced by high glucose. Overexpression of NLRP3 reversed the above changes caused by EMD. Collectively, our findings suggest that EMD attenuates high-glucose-induced β-cell pyroptosis by inhibiting NLRP3/GSDMD signaling. [ABSTRACT FROM AUTHOR]

Rad50 is a component of MRN (Mre11‐Rad50‐Nbs1), which participates in DNA double‐strand break repair and DNA‐damage checkpoint activation. Here, we sought to investigate the clinical and functional significance of Rad50 in high‐grade serous ovarian cancer (HGSOC). We found that Rad50 was frequently upregulated in HGSOCs and enhanced Rad50 expression inversely correlated with patient survival. In addition, ectopic expression of Rad50 promoted proliferation/invasion and induced EMT of ovarian cancer cells, whereas knockdown of Rad50 led to decreased aggressive behaviors. Mechanistic investigations revealed that Rad50 induced aggressiveness in HGSOC via activation of NF‐κB signaling pathway. Moreover, we identified CARD9 as an interacting protein of Rad50 in ovarian cancer cells and the activation of NF‐κB pathway by Rad50 is CARD9 dependent. Our findings provide evidence that Rad50 exhibits oncogenic property via NF‐κB activation in HGSOC. [ABSTRACT FROM AUTHOR]

Hypertensive cardiac remodelling is a common cause of heart failure. However, the molecular mechanisms regulating cardiac remodelling remain unclear. Pyruvate kinase isozyme type M2 (PKM2) is a key regulator of the processes of glycolysis and oxidative phosphorylation, but the roles in cardiac remodelling remain unknown. In the present study, we found that PKM2 was enhanced in angiotensin II (Ang II)‐treated cardiac fibroblasts and hypertensive mouse hearts. Suppression of PKM2 by shikonin alleviated cardiomyocyte hypertrophy and fibrosis in Ang‐II‐induced cardiac remodelling in vivo. Furthermore, inhibition of PKM2 markedly attenuated the function of cardiac fibroblasts including proliferation, migration and collagen synthesis in vitro. Mechanistically, suppression of PKM2 inhibited cardiac remodelling by suppressing TGF‐β/Smad2/3, Jak2/Stat3 signalling pathways and oxidative stress. Together, this study suggests that PKM2 is an aggravator in Ang‐II‐mediated cardiac remodelling. The negative modulation of PKM2 may provide a promising therapeutic approach for hypertensive cardiac remodelling. [ABSTRACT FROM AUTHOR]

Exosomal miRNAs are verified critical biomarkers, which participate in several biological processes. The growth and development of the hair follicle (HF) are typically controlled by the exosomal miRNAs via cell-to-cell communication. This study identified a high expression of miR-181a-5p in the low-passage DPC-Exos (exosomes derived from dermal papilla cell), revealing the transportation patterns of the DPC-Exos-derived miR-181a-5p entering the HFSC (hair follicle stem cell). The exosomal miR-181a-5p activates the Wnt/β-catenin signaling pathway by targeting the Wnt inhibitor WIF1 and thereby regulates the proteins and genes related to HF growth and development. Moreover, the exosomal miR-181a-5p was found to suppress the HFSC apoptosis but promoted the HFSC proliferation. The in vitro culture of the HF organ revealed that the exosomal miR-181a-5p possesses a positive role in hair growth. Collectively, the exosomal miR-181a-5p affects the HF growth and development through the Wnt/β-catenin signaling pathway. The exosomal miR-181a-5p might, therefore, act as the novel biomarker and therapeutic target for treating hair-related diseases and wool production in mammals. [ABSTRACT FROM AUTHOR]

• The potential effect of Plk-1 in SIMD is investigated. • Plk-1 promotes SIMD by enhancing inflammation and cardiac injury by inflammatory responses. • Plk-1 promotes cardiac dysfunction in sepsis by activating NF-κB signal pathway. Sepsis-induced myocardial dysfunction (SIMD) is the main cause of mortality in sepsis. In this study, we identified Polo-like kinase 1 (Plk-1) is a promoter of SIMD. Plk-1 expression was increased in lipopolysaccharide (LPS)-treated mouse hearts and neonatal rat cardiomyocytes (NRCMs). Inhibition of Plk-1 either by heterozygous deletion of Plk-1 or Plk-1 inhibitor BI 6727 alleviated LPS-induced myocardial injury, inflammation, cardiac dysfunction, and thereby improved the survival of LPS-treated mice. Plk-1 was identified as a kinase of inhibitor of kappa B kinase alpha (IKKα). Plk-1 inhibition impeded NF-κB signal pathway activation in LPS-treated mouse hearts and NRCMs. Augmented Plk-1 is thus essential for the development of SIMD and is a druggable target for SIMD. [ABSTRACT FROM AUTHOR]

Abstract: Resveratrol has been shown to possess many health-benefiting effects, including the promotion of bone formation. In this report we investigated the mechanism by which resveratrol promotes osteoblastic differentiation from pluripotent mesenchymal cells. Since Wnt signaling is well documented to induce osteoblastogenesis and bone formation, we characterized the factors involved in Wnt signaling in response to resveratrol treatment. Resveratrol treatment of mesenchymal cells led to an increase in stabilization and nuclear accumulation of β-catenin dose-dependently and time-dependently. As a consequence of the increased nuclear accumulation of β-catenin, the ability to activate transcription of β-catenin-TCF/LEF target genes that are required for osteoblastic differentiation was upregulated. However, resveratrol did not affect the initial step of the Wnt signaling pathway, as resveratrol was as effective in upregulating the activity of β-catenin in cells in which Lrp5 was knocked down as in control cells. In addition, while conditioned medium enriched in Wnt signaling antagonist Dkk1 was able to inhibit Wnt3a-induced β-catenin upregulation, this inhibitory effect can be abolished in resveratrol-treated cells. Furthermore, we showed that the level of glycogen synthase kinase 3β (GSK-3β), which phosphorylates and destabilizes β-catenin, was reduced in response to resveratrol treatment. The phosphorylation of GSK-3β requires extracellular signal-regulated kinase (ERK)1/2. Together, our data indicate that resveratrol promotes osteoblastogenesis and bone formation by augmenting Wnt signaling. [Copyright &y& Elsevier]