International journal of molecular sciences
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Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. ⋯ Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway.
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MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. ⋯ Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR⁻target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases.
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Atherosclerosis is the pathological process in arteries due to the plaque formation that is responsible for several diseases like heart disease, stroke and peripheral arterial disease. In this study, we performed in vitro and in vivo assays to evaluate the potential anti-atherosclerosis activity of peach kernel oil. For the in vitro assay, we incubated human umbilical vein endothelial cells (HUVEC) with tumor necrosis factor-α (TNF-α) to induce tissue factors (TF, an essential mediator of hemostasis and trigger of thrombosis) elevation. ⋯ Results show that peach kernel oil could reduce total cholesterol, triglyceride, low-density lipoprotein cholesterol levels, elevate the high-density lipoprotein cholesterol level in serum, and reduce the area of the aortic atherosclerotic lesions in high-fat diet fed ApoE knockout mice. Moreover, peach kernel oil treatment can significantly down regulate the expression of TF protein to inhibit the formation of atherosclerotic plaque. In conclusion, peach kernel oil may be a potential health food to prevent atherosclerosis in cardiovascular diseases.
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The effects of remote ischemic preconditioning (RIPC) in cardiac surgery have been inconsistent. We investigated whether anesthesia or beta-blockers interfere with RIPC cardioprotection. Fifty patients undergoing cardiac surgery were randomized to receive limb RIPC (four cycles of 5-min of upper arm cuff inflation/deflation) in the awake state (no-anesthesia; n = 17), or under sevoflurane (n = 17) or propofol (n = 16) anesthesia. ⋯ However, post-RIPC MI size was reduced in the no-anesthesia group (27.5 ± 8.0%; p < 0.001), but not in the anesthesia groups (35.7 ± 6.9% sevoflurane and 35.8 ± 5.8% propofol). In the healthy volunteer study, there was a reduction in MI size with RIPC in the no-carvedilol group (41.7 ± 4.3% to 30.6 ± 8.5%; p < 0.0001), but not in the carvedilol group (41.0 ± 4.0% to 39.6 ± 5.6%; p = 0.452). We found that the cardioprotective effects of limb RIPC were abolished under propofol or sevoflurane anesthesia and in the presence of carvedilol therapy.
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Apelin is an inotropic and cardioprotective peptide that exhibits beneficial effects through activation of the APJ receptor in the pathology of cardiovascular diseases. Apelin induces the expression of angiotensin-converting enzyme 2 (ACE2) in failing hearts, thereby improving heart function in an angiotensin 1⁻7-dependent manner. Whether apelin antagonizes the over-activation of the renin⁻angiotensin system in the heart remains elusive. ⋯ Consistently, treatment with the ACE-inhibitor Captopril decreased cardiac contractility in apelin knockout mice. In vitro, apelin ameliorated Ang II-induced TGF-β expression in primary cardiomyocytes, accompanied with reduced hypertrophy. These results provide direct evidence that endogenous apelin plays a crucial role in suppressing Ang II-induced cardiac dysfunction and pathological remodeling.