Inflammation is well known as an important driver of the initiation of colitis-associated cancer (CAC). Some cytokines, such as IL-6 and TNF- can activate expression of the oncogene c-Myc (MYC) and regulate its downstream effects. Cullin-RING E3 Ligases (CRLs) are emerging as master regulators controlling tumorigenesis.Here, we demonstrate that two cullin genes, CUL4A and CUL4B, but not other members, are specifically overexpressed in CAC tumour samples and positively correlate with levels of the proinflammatory cytokines IL-1 and IL-6. In vitro experiments revealed that the transcription factor c-Myc can specifically activate the expression of CUL4A and CUL4B by binding to a conserved site (CACGTG) located in their promoters. Additionally, we found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4 DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). Overexpression of c-Myc in human colon epithelial cells resulted in the accumulation of CUL4A, CUL4B and DCAF4, but degradation of ST7. In contrast, knockdown of c-Myc, CUL4A or CUL4B in the colon adenocarcinoma cell line HT29 caused accumulation of ST7 and inhibition of cell proliferation, colony formation ability and in vivo tumour growth. Collectively, our results provide in vitro and in vivo evidence that c-Myc regulates CRL4 DCAF4 E3 ligase activity to mediate ubiquitination of ST7, whose presence is physiologically essential for CAC tumorigenesis.No conflicts of interest were declared. ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) [16,17]. The human genome encodes two E1s, ∼40 E2s and more than 600 E3s [18,19]. Of these E3 ligases, Cullin-RING

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.

Dx combined with DCQD could decrease the risk of developing ARDS in SAP patients with SIRS and shorten their length of hospitalization.

No abstract

Severity of acute pancreatitis contributes to the modality of cell death. Pervious studies have demonstrated that the herb medicine formula “Dachengqi Decoction” (DCQD) could ameliorate the severity of acute pancreatitis. However, the biological mechanisms governing its action of most remain unclear. The role of apoptosis/necrosis switch within acute pancreatitis has attracted much interest, because the induction of apoptosis within injured cells might suppress inflammation and ameliorate the disease. In this study, we used cerulein (10−8 M)-stimulated AR42J cells as an in vitro model of acute pancreatitis and retrograde perfusion into the biliopancreatic duct of 3.5% sodium taurocholate as an in vivo rat model. After the treatment of DCQD, cell viability, levels of apoptosis and necrosis, reactive oxygen species positive cells, serum amylase, concentration of nitric oxide and inducible nitric oxide syntheses, pancreatic tissue pathological score and inflammatory cell infiltration were tested. Pretreatment with DCQD increased cell viability, induced apoptosis, decreased necrosis and reduced the severity of pancreatitis tissue. Moreover, treatment with DCQD reduced the generation of reactive oxygen species in AR42J cells but increased the concentration of nitric oxide of pancreatitis tissues. Therefore, the regulation of apoptosis/necrosis switch by DCQD might contribute to ameliorating the pancreatic inflammation and pathological damage. Further, the different effect on reactive oxygen species and nitric oxide may play an important role in DCQD-regulated apoptosis/necrosis switch in acute pancreatitis.

PET/CT and PET were found to be superior modalities for the detection of recurrent lung cancer, and PET/CT was superior to PET.

AIM:To investigate the effect of severe acute pancreatitis (SAP) on pharmacokinetics of Da-Cheng-Qi Decoction (DCQD) components in rats. METHODS:Rats were divided into SAP group and sham-operation group as a control group (n = 6). Rhein, chrysophanol, rheochrysidin, magnolol, hesperidin and naringin in DCQD were quantified in rat serum by high performance liquid chromatography tandem mass spectrometry for studying their pharmacokinetics. RESULTS:Early absorption of each DCQD component was tended to degrade in SAP group after treatment with DCQD by gavage. The Cmax (chrysophanol, P = 0.0059; rheochrysidin, P = 0.0288; magnolol, P = 0.0487; hesperidin, P = 0.0277; naringin, P = 0.0023) and AUC (rhein, P = 0.0186; chrysophanol, P = 0.0013; magnolol, P = 0.001; hesperidin, P = 0.0081; naringin, P = 0.0272) of DCQD component were obviously lower in SAP group than in control group. The T1/2α of chrysophanol and rheochrysidin (P = 0.0467 and 0.0005, respectively) and Tmax of chrysophanol and rheochrysidin (P = 0.0101 and 0.0037, respectively) lasted longer in SAP group than in control group. CONCLUSION:

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.