查看更多>>摘要：Cancer patients treated with doxorubicin are at risk of congestive heart failure due to doxorubicin-mediated cardiotoxicity via topoisomerase II? poisoning. Acute cardiac muscle damage occurs in response to the very first dose of doxorubicin, however, cardioprotection has been reported after co-treatment of doxorubicin with acyloxyalkyl ester prodrugs. The aim of this study was to examine the role played by various forms of acute cardiac damage mediated by doxorubicin and determine a mechanism for the cardioprotective effect of formaldehyde-releasing prodrug AN-9 (pivaloyloxymethyl butyrate).
查看更多>>摘要：Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-?B, I?B? and PPAR? levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNF? levels were determined in plasma and prefrontal cortex using ELISA and qPCR techniques, respectively. The precursor tryptophan (TRP), and its metabolites kynurenine (KYN) and serotonin (5-HT) were measured in hippocampus and cortex by HPLC. The ratios KYN/TRP and KYN/5-HT were used to estimate indoleamine 2,3-dioxygenase (IDO) activity and the balance of both metabolic pathways, respectively. CBD reduced the immobility time in the tail suspension test and increased sucrose preference in the LPS model, without affecting locomotion and central activity in the openfield test. CBD diminished cortical NF-?B activation, IL-6 levels in plasma and brain, and the increased KYN/TRP and KYN/5-HT ratios in hippocampus and cortex in the LPS model. Our results demonstrate that CBD produced antidepressant-like effects in the LPS neuroinflammatory model, associated to a reduction in the kynurenine pathway activation, IL-6 levels and NF-?B activation. As CBD stands out as a promising antidepressant drug, more research is needed to completely understand its mechanisms of action in depression linked to inflammation.
查看更多>>摘要：Metastatic melanoma has a very high mortality rate despite the availability of chemotherapy, radiotherapy, and immunotherapy; therefore, more effective therapeutics are needed. The Hippo pathway plays an inhibitory role in melanoma progression, but the tumor suppressors Salvador homolog-1 (SAV1) and large tumor suppressor 1 (LATS1) in this pathway are down-regulated in melanoma. As a result, the downstream oncogenic Yes-associated protein (YAP) is active, resulting in uncontrolled melanoma growth and metastasis. Therapeutics for remedying SAV1 and LATS1 deficiency in melanoma have not yet been reported in the literature. Here, we show that the small molecule triptonide (MW 358 Da) robustly suppressed melanoma cell tumorigenicity, migration, and invasion. Furthermore, triptonide markedly reduced tumor growth and melanoma lung metastasis in tumorbearing mice with low toxicity. Molecular mechanistic studies revealed that triptonide promoted SAV1 and LATS1 expression, strongly activated the tumor-suppressive Hippo pathway, degraded oncogenic YAP via the lysosomal pathway, and reduced levels of tumorigenic microphthalmia-associated transcription factor (MITF) in melanoma cells. Triptonide also strongly inhibited activation of AKT, a SAV1-binding signaling protein. Collectively, our results conceptually demonstrate that induction of SAV1 and LATS1 expression and activation of the tumor-suppressive Hippo pathway by triptonide potently inhibits aggressive melanoma cell growth and metastasis. These findings suggest a new strategy for developing therapeutics to treat metastatic melanoma and highlight a novel drug candidate against aggressive melanoma.
查看更多>>摘要：Dexamethasone is a common synthetic glucocorticoid drug that can promote foetal lung maturity. An increasing number of studies have shown that prenatal dexamethasone exposure (PDE) can cause a variety of short-term and long-term hazards to offspring, including bone development toxicity. H-type vessels are a newly discovered subtype of blood vessels associated with promoted bone formation and maintenance of bone mass. In this study, we aimed to explore whether H-type blood vessels are involved in PDE-induced long bone development toxicity in offspring and its mechanism. In vivo, we injected dexamethasone (0.2 mg/kg.d) subcutaneously at gestational days 9?20 and observed the H-type vessel abundance and bone mass at different time points in the offspring rats. In vitro, we investigated the effect of dexamethasone (0, 20, 100, and 500 nM) on the tube formation function of rat bone marrow-derived endothelial progenitor cells (EPCs) and explored its mechanism. Our results showed that the adult PDE female offspring rats were susceptible to osteoporosis. In addition, PDE inhibited bone mass, H-type vessel formation and the expression of bone platelet-derived growth factor receptor ? (PDGFR?)/focal adhesion kinase (FAK) pathway-related genes in antenatal and postnatal female offspring. Moreover, PDE promoted the expression of bone glucocorticoid receptor (GR), CCAAT and enhancer binding protein ? (C/EBP?) and miR-34c in female foetuses. Dexamethasone suppressed the tube formation of rat bone marrow-derived EPCs and the activity of the PDGFR?/FAK pathway, which was mediated by GR/C/EBP?/miR34c signalling activation. In summary, PDE can cause H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring, and its mechanism is related to the low-activity programming of the PDGFR?/FAK pathway induced by GR/C/EBP?/miR-34c signalling activation. This study enhances the understanding of the molecular mechanism of dexamethasone-induced bone development toxicity and provides new insights for exploring the early intervention and therapeutic targets of foetal-derived osteoporosis.
查看更多>>摘要：Aryl hydrocarbon receptor (AHR) was initially discovered as a cellular protein involved in mediating the detoxification of xenobiotic compounds. Extensive research in the past two decades has identified several families of physiological ligands and uncovered important functions of AHR in normal development and homeostasis. Deficiency in AHR expression disrupts major signaling systems and transcriptional programs, which appear to be responsible for the development of numerous developmental abnormalities including cardiac hypertrophy and epidermal hyperplasia. This mini review primarily summarizes recent advances in our understanding of AHR functions in normal physiology with an emphasis on the cardiovascular, gastrointestinal, integumentary, nervous, and immunomodulatory systems.
查看更多>>摘要：Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS by targeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1 beta and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.
查看更多>>摘要：Epidemiological studies have shown that nonalcoholic fatty liver disease (NAFLD) has an intrauterine developmental origin. We aimed to demonstrate that NAFLD is caused by prenatal dexamethasone exposure (PDE) in adult male rat offspring and to investigate the intrauterine programming mechanism. Liver samples were obtained on gestational day (GD) 21 and postnatal week (PW) 28. The effects and epigenetic mechanism of dexamethasone were studied with bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and other cell models. In the PDE group, lipid accumulation increased, triglyceride synthesis-related gene expression increased, and oxidation-related gene expression decreased in livers of adult male rat offspring. In utero, hepatic triglyceride synthesis increased and oxidative function decreased in PDE fetal male rats. Moreover, low hepatic miR-122 expression, high Yin Yang-1 (YY1) expression and angiotensin-converting enzyme 2 (ACE2)-Mas receptor (MAS1) signaling pathway inhibition were observed before and after birth. At the cellular level, dexamethasone (100?2500 nM) elevated the intracellular triglyceride content, increased triglyceride synthesis-related gene expression and decreased oxidation-related gene expression. Dexamethasone treatment also decreased miR-122 expression, increased YY1 expression and inhibited the ACE2-MAS1 signaling pathway. Interference or overexpression of glucocorticoid receptor (GR), miR-122, YY1 and ACE2 could reverse the changes in downstream gene expression. In summary, PDE could induce NAFLD in adult male rat offspring. The programming mechanism included inhibition of miR-122 expression after GR activation, and dexamethasone increased hepatocyte YY1 expression; these effects resulted in ACE2-MAS1 signaling pathway inhibition, which led to increased hepatic triglyceride synthesis and decreased oxidative function. The increased triglyceride synthesis and decreased oxidative function of hepatocytes caused by low miR-122 expression due to dexamethasone could continue postnatally, eventually leading to NAFLD in adult rat offspring.
查看更多>>摘要：Ca(v)1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on Ca(v)1.2 and K(C)(a)1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective Ca(v)1.2 channel blockers, positioning in the alpha(1C) subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated K(C)a1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the K(C)a1.1 channel 56 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension.
查看更多>>摘要：The tumor suppressor protein p53 participates in the control of key biological functions such as cell death, metabolic homeostasis and immune function, which are closely related to various diseases such as tumors, metabolic disorders, infection and neurodegeneration. The p53 gene is also mutated in approximately 50% of human cancer cells. Mutant p53 proteins escape from the ubiquitination-dependent degradation, gain oncogenic function and promote the carcinogenesis, malignant progression, metastasis and chemoresistance. Therefore, the stability of both wild type and mutant p53 needs to be precisely regulated to maintain normal functions and targeting the p53 stability is one of the therapeutic strategies against cancer. Here, we focus on compoundinduced degradation of p53 by both the ubiquitination-dependent proteasome and autophagy-lysosome degradation pathways. We also review other posttranslational modifications which control the stability of p53 and the biological functions involved in these processes. This review provides the current theoretical basis for the regulation of p53 abundance and its possible applications in different diseases.
NSTL
Elsevier