查看更多>>摘要：The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer development. Up to date, there are only a few EZH2 covalent inhibitors. In this study, a new series of 3-acrylamido-2-methyl-N-((2-oxo-1,2-dihydropyridin-3-yl) methyl) benzamide derivatives were designed, synthesized, and demonstrated to act as EZH2 covalent inhibitors, among which SKLB-03176 was the most potent compound. SAM competition experiments, mass spectrometry, and washing-out assays proved that SKLB-03176 could covalently bind to the SAM pocket of EZH2. Remarkably, SKLB-03176 exhibited weak activity against other targets, such as 5 histone methyltransferases and more than 30 kinases. Besides, it could inhibit the activity of a variety of EZH2 mutants and significantly inhibit the expression of H3K27Me3 in cells. Furthermore, SKLB-03176 showed no cytotoxicity to normal cells. Our data suggested that SKLB-03176 could be used as a promising lead compound for the development of new EZH2 covalent inhibitors and a valuable chemical tool to study the biological functions of EZH2 or PRC2.
查看更多>>摘要：Aspirin (ASA) is widely used as an antiplatelet therapeutic drug in secondary prevention. Last years brought many reports on ASA resistance or high on-treatment platelet reactivity (HTPR) to aspirin.This study is a post-hoc prospective analysis with 30 patients evaluated during follow up on average of 6.3 years after hospitalization from myocardial infarction. The examined population was divided into two subgroups according to the response to ASA. In order to estimate the function of blood platelets and their responsiveness to acetylsalicylic acid therapy, ASPI-test was used. The measurements were performed by the method of whole blood impedance aggregometry. During long-term follow up significantly higher percentage of high platelet reactivity was observed, compared with previous visits (p = 0.00001). Considering clinical endpoints of the research that were connected with coronary disease, no differences were obtained.The frequency of HTPR to aspirin in this study was higher than data reported in literature among subjects with CV diseases. In long-term observation the highest percentage of ASA non-responders was reported (58.6%). HTPR to aspirin did not affect the presence of the clinical endpoints for the study.
查看更多>>摘要：To prevent cisplatin (CDDP)-induced nephrotoxicity, co-treatment with massive hydration is essential for its clinical use. However, some patients are ineligible for this treatment. For such patients, a split dose of CDDP has been suggested as an alternative strategy. This study aimed to evaluate the nephrotoxicity of a split dose of CDDP by direct comparison with the conventional single dose of CDDP in rats. Rats were allocated to single- or split-dose groups. In the single-dose group, rats received the total dose of CDDP (from 0 to 7.5 mg/kg) with a single injection, whereas the same total dose of CDDP was split equally across five doses in the corresponding split-dose group. Blood samples were taken until day 21 after the first CDDP injection to monitor the plasma creatinine (Cr) concentration as an index of nephrotoxicity. CDDP-induced nephrotoxicities from day 1-10 and from day 15-21 were defined as acute kidney injury (AKI) and subchronic kidney injury (sCKI), respectively. The toxicity of CDDP-induced AKI in the split-dose group was found to be significantly lower than that in the single-dose group at any given total dose level. At a total dose of 7.5 mg/kg, a decrease of approximately 90% in AKI was found in the split-dose group, while the extent of attenuation of CDDP-induced sCKI in this group was approximately 30%. Our results provide evidence that a split-dose regimen could be an alternative strategy for CDDP-ineligible patients; however, the optimal regimen needs to be determined in future studies.
查看更多>>摘要：Lycium barbarum polysaccharide (LBP), is a major active ingredient Lycium barbarum (LB), which exhibits several beneficial effects through NF-κB, PI3K-Akt-mTOR, p38-MAPK, Wnt-β-catenin, PI3K-Akt-GSK-3β, and MyD88 signal pathway, including anti-oxidation, and anti-aging, hypolipidemic and hypoglycemic, radiation, anti-tumor, and neuroprotection. Today, many researching papers are published on the LBP in physiology and pathology; however, the review of the LBP taking part in the signal transduction pathway in physiology and pathology is rear searched. Therefore, this research topic is a collection of reviews and original research articles that focus on the methods of the LBP extraction and its effects on the signal transduction pathway. The aim of this study is to provide theoretical evidence for in-depth analysis of the mechanisms of LBP in clinical clinical research studies.
Ruth W. MwangiJohn M. MachariaIsabel N. WagaraRaposa L. Bence...
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查看更多>>摘要：Mushroom consumption has grown extraordinarily owing to their high nutritional value, desirable taste, and aroma. Mushrooms continue generating lots of interest chiefly in their consumption as food, as a cure for different ailments, as well as important goods for commerce throughout the globe owing to their dietary, antioxidant, and therapeutic values. Higher Ascomycetes and Basidiomycetes mushrooms have different properties with anticancer and immunological potential. They as well provide vital health benefits and display a wide-ranging continuum of pharmacological effects. The antioxidant activity of different mushrooms was reviewed for different radicals including DPPH, ABTS, OH, Nitrite, metals, and lipid peroxidation. The present review presents pharmacological activities of different species of edible and medicinal mushrooms. This review provides tangible evidence that these mushrooms are an excellent source of natural constituents and antioxidants with potential application in pharmaceuticals and in treating and managing different diseases.
查看更多>>摘要：Nucleic acid-mediated interferon signaling plays a pivotal role in defense against microorganisms, especially during viral infection. Receptors sensing exogenous nucleic acid molecules are localized in the cytosol and endsomes. Cytosolic sensors, including cGAS, RIG-I, and MDA5, and endosome-anchored receptors are toll-like receptors (TLR3, TLR7, TLR8, and TLR9). These TLRs share the same domain architecture and have similar structures, facing the interior of endosomes so their binding to nucleic acids of invading pathogens via endo-cytosis is possible. The correct function of these receptors is crucial for cell homeostasis and effective response against pathogen invasion. A variety of endogenous mechanisms modulates their activities. Nevertheless, naturally occurring mutations lead to aberrant TLR-mediated interferon (IFN) signaling. Furthermore, certain pathogens require a more robust defense against control. Thus, manipulating these TLR activities has a profound impact. High-throughput virtual screening followed by experimental validation led to the discovery of numerous chemicals that can change these TLR-mediated IFN signaling activities. Many of them are unique in selectivity, while others regulate more than one TLR due to commonalities in these receptors. We summarized these nucleic acid-sensing TLR-mediated IFN signaling pathways and the corresponding chemicals activating or deactivating their signaling.
查看更多>>摘要：Background: A better understanding of the evolution of cirrhosis after hepatitis C virus (HCV) clearance is essential since the reversal of liver injury may not happen. We aimed to assess the evolution of plasma metabolites after direct-acting antivirals (DAAs) therapy and their association with liver disease scores in HIV/HCV-coinfected patients with advanced HCV-related cirrhosis. Methods: We performed a prospective study in 49 cirrhotic patients who started DAAs therapy. Data and samples were collected at baseline and 36 weeks after SVR. Metabolomics analysis was carried out using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Inflammation-related bio-markers were analyzed using ProcartaPlex Immunoassays. Results: At 36 weeks after SVR, patients experienced significant decrease in taurocholic acid, 2,3-butanediol, and LPC(18:0); while several phosphatidylcholines (LPC(16:1), LPC(18:1), LPC(20:4), and PC(16:0/9:0(CHO))/PC (16:0/9:0(COH)), 2-keto-n-caproic acid/2-keto-isocaproic acid and N-methyl alanine increased, compared to baseline. The plasma decrease in taurocholic acid was associated with a reduction in Child-Turcotte-Pugh (CTP) (AMR=3.39; q-value=0.006) and liver stiffness measurement (LSM) (AMR=1.06; q-value<0.001), the plasma increase in LPC(20:4) was related to a reduction in LSM (AMR=0.98; q-value=0.027), and the rise of plasma 2-keto-n-caproic acid/2-keto-isocaproic acid was associated with a reduction in CTP (AMR=0.35; q-value=0.004). Finally, plasma changes in taurocholic acid were directly associated with inflammation-related biomarkers, while changes in LPC(20:4) were inversely associated. Conclusions: Plasma metabolomic profile changed after HCV clearance with all oral-DAAs in HIV/HCV-coinfected with advanced HCV-related cirrhosis. Changes in plasma levels of LPC (20: 4), 2-keto-n-caproic acid/2-keto-isocaproic acid, and taurocholic acid were related to improvements in cirrhosis scores and inflammatory status of patients.
Eslam E. Abd El-FattahSameh SaberAhmed A.E. MouradEman El-Ahwany...
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查看更多>>摘要：Acute lung injury (ALI) is one the most common causes of morbidity and mortality in critically ill patients. In this study, we examined for first time the role of dapagliflozin (DPGZ) in lipopolysaccharide (LPS)-induced ALI in rats and determined the underlying molecular mechanisms by evaluating the effects of DPGZ on adenosine mono-phosphate kinase (AMPK), nuclear transcription factor kappa B, nucleotide-binding and oligomerization domain-like receptor 3 inflammasome activation. Treatment of acute lung injured rats with either low dose (5 mg/kg) or high dose (10 mg/kg) DPGZ significantly decreased oxidative stress by decreasing malondialdehyde and nitric oxide tissue levels with a significant increase in spectrophotometric measurements of superoxide dismutase, catalase, and reduced glutathione levels. DPGZ treatment resulted in a significant anti-inflammatory effect as indicated by suppression in myeloperoxidase activity, MCP-1, IL-1β, IL-18, and TNF-α levels. DPGZ treatment also increased p-AMPK/t-AMPK with a significant reduction in NF-kB P65 binding activity and NF?B p65 (pSer536) levels. These effects of DPGZ were accompanied by a significant reduction in NLRP3 levels and NLRP3 gene expression and a significant decrease in caspase-1 activity, which were also confirmed by histopathological examinations. We conclude that DPGZ antioxidant and anti-inflammatory activity may occur through regulation of AMPK/NF?B pathway and inhibition of NLRP3 activation. These results suggest that DPGZ represents a promising intervention for the treatment of ALI, particularly in patients with type 2 diabetes.
查看更多>>摘要：Parkinson's disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and aggregation of α-synuclein (α-syn). Current PD therapies merely provide symptomatic relief, lacking the disease-modifying therapeutic strategies against that could reverse the ongoing neurodegeneration. In the quest of exploring novel disease modifying therapeutic strategies, compounds from natural sources have gained much attention in recent days. YIAEDAER (Tyr-Ile-Ala-Glu-Asp-Ala-Glu-Arg) peptide is a multi-functional peptide isolated and purified from the visceral mass extract of Neptunea arthritica cumingii (NAC) with plethora of pharmacological activities, however its neuroprotective effect against MPTP induced PD model is not yet reported. We found YIAEDAER peptide co-treatment could suppressed the MPTP-induced locomotor impairment in zebrafish, ameliorates the MPTP induced degeneration of DA neurons, inhibited the loss of vasculature and loss of cerebral vessels, suppressed α-syn levels. Moreover, YIAEDAER peptide modulates several genes related to autophagy (α-syn, pink1, parkin, atg5, atg7, beclin1, ulk1b, ulk2, and ambra1a), and oxidative stress (sod1, sod2, gss, gpx4a, gsto2, and cat). Hence, our finding suggests that YIAEDAER peptide might be a potential therapeutic candidate against MPTP-induced PD like condition.
查看更多>>摘要：Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ ABCC11/DPYD to improve systemic chemotherapy in CRC.
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