Up-frameshift protein 1 (UPF1) is an evolutionarily conserved protein with RNA/DNA-dependent ATPase and RNA helicase activity. The protein is well known for its central role in nonsense-mediated mRNA decay (NMD), which eliminates aberrant mRNAs harboring premature termination codon (PTC), preventing the accumulation of nonfunctional or potentially harmful truncated proteins. NMD is also involved in the regulation of the state-levels of many normal physiological mRNAs. Moreover UPF1 is not only a key player in NMD but is also involved in non-NMD RNA degradation, such as staufen1 (STAU1)-mediated mRNA decay (SMD) and replication-dependent histone mRNA decay. Thus, UPF1 is an important factor for the RNA quality control system and the regulation of physiological gene expression. Further, recent studies have clarified that UPF1 contributes to DNA replication, DNA repair, telomere metabolism, and stabilization of HIV-1 genomic RNA. In the review, we summarize numerous functions of UPF1.
N-Acylsulfonamide derivatives have important applications in organic synthesis and drug discovery. It was found that many problems occurred preparing amino acid derived N-acylsulfonamides with the commonly used coupling approach in our previous studies. In this paper, we report an efficient approach to synthesize various amino acids derived N-acylsulfonamides in high yields without any racemization.
Histamine H1 receptor antagonists play a vital role in the first line treatment of a broad range of allergic diseases. Frequent dosing of the antagonist results in side effects like sedation and cardiovascular toxicity. The present study highlights the important structural requirement and mechanistic interpretation of novel indolylpiperidinyl derivatives as H1 receptor antagonists so as to facilitate the design of newer antihistaminics with increased duration of action and comparatively reduced side effects. The significance of the developed quantitative structure-activity relationship (QSAR) models were evaluated on the basis of statistical values of square of correlation coefficient (r2); (multiple linear regression (MLR), 0.86; and partial least squares (PLS), 0.85). The predictive ability of the resulting QSAR models was evaluated with cross-validated correlation coefficient (r2cv) values (MLR, 0.82; PLS, 0.82) generated for the training set and r2 values (MLR, 0.763; PLS, 0.855) derived for test set. The final models comprised of multidimensional steric (verloop length, verloop B3), electronic (total dipole moment) and steric (KAlpha1 index) descriptors. The study indicates that antihistaminic activity is largely explained by steric and electronic parameters. In line with parameters entered in the model some indolylpiperidines derivatives were designed with good antihistaminic properties and pharmacokinetic profiles.
A new series of N'-((1-(substituted amino)methyl)-2-oxoindolin-3-ylidene)-4-(2-(methyl/ phenyl)-4-oxoquinazolin-3(4H)-yl)benzohydrazide derivatives 4a-4l were designed and synthesized from anthranilic acid. All the synthesized compounds were characterized by spectroscopic means and elemental analyses. The tail-flick technique and the carrageenan-induced foot paw edema test were performed for screening analgesic and anti-inflammatory activity, respectively. All of the compounds were also examined for their ulcerogenicity. Some of the compounds showed significant activity. Among the test compounds, 4b exhibited 53% and 69% analgesic activity at a dose of 10 and 20 mg/kg, respectively. It also displayed 47% (10 mg/kg) and 65% (20 mg/kg) anti-inflammatory activity with one-fourth of ulcer index of the reference drugs diclofenac and aspirin.
In silkworm larvae, the mature form of paralytic peptide (PP), an insect cytokine, is produced from pro-PP in association with activation of innate immune responses, resulting in slow muscle contraction. We utilized this reaction, muscle contraction in silkworms coupled with innate immunity stimulation, to quantitatively measure the innate immune stimulating activity of various natural polysaccharides. β-Glucan of Gyrophora esculenta (GE-3), fucoidan from sporophyll of Undaria pinnatifida, and curldan induced silkworm muscle contraction. We further demonstrated that GE-3 had therapeutic effects on silkworms infected by baculovirus. Based on these findings, we propose that the silkworm muscle contraction assay is useful for screening substances that stimulate innate immunity before evaluating therapeutic effectiveness in mammals.
Janus-activated kinase-2 (JAK2) plays an important role in the activation of signal transducer and activation of transcription 3 (STAT3), which is over expressed in majority of ovarian tumors. We have reported previously that diindolylmethane (DIM) induces apoptosis in ovarian cancer cells by inhibiting STAT3. However, the role of JAK2 in our model was not yet understood and hence evaluated in this report. SKOV-3 human ovarian cancer cells were used to evaluate concentration and time dependent effects of DIM. Interleukin 3 (IL-3) and epidermal growth factor (EGF) were used to activate JAK2. Tumor xenograft studies were used to determine modulation of JAK2 in vivo. DIM treatment blocked the phosphorylation of JAK2 at Tyr-1007 in a concentration-dependent manner. In a time-dependent study, inhibition of JAK2 by DIM was as early as 1 h, which was followed by the inhibition of STAT3 and survivin. IL-3-induced phosphorylation of JAK2 and STAT3 was significantly blocked by DIM. IL-3 treatment blocked DIM-induced apoptosis. EGF treatment resulted in the activation of JAK2 and STAT3 but suppressed by DIM. These results indicate the involvement of cytokines and growth factors in the activation of JAK2/STAT3 and that DIM suppress their activation. Furthermore, DIM in combination with cisplatin drastically reduced the phosphorylation of JAK2 when compared to cisplatin alone. Western blot analysis of tumors from DIM treated mice showed significant inhibition of JAK2 activation as compared with controls. These findings provide a rationale for further clinical investigation of DIM for its potential use alone or in combination with chemotherapy of ovarian cancer.
The trend of biomarker use in drug interventional clinical studies was analyzed using ClinicalTrials.gov to provide an overview of how biomarkers are used to streamline clinical studies and to examine regional differences. A total of 3,383 clinical study data was analyzed according to phase, region, sponsor, and therapeutic class. The number of clinical studies using biomarkers has been increasing constantly and is dependent on the number of Phase I and II studies. The majority of studies (58.5%) were sponsored by the United States, with the studies being conducted mainly in the sponsor's home region (80.3%). The use of biomarkers was prominent in the oncology area (37.1%). Although current data indicates some bias in the clinical use of biomarkers, it is expected that their use will increase in later phase studies or other therapeutic areas as biomarker development proceeds. In addition, limited regional use of biomarkers may lead to differences in biomarker use in drug development and in combination with political support may result in differences in competitiveness of drug development. Biomarkers would be a powerful tool against deteriorating research and development productivity when used more in appropriate clinical study conditions.
Japan-China Joint Medical Workshop (2012) on standardization of perioperative management on hepato-biliary-pancreatic surgery was held by the Center for Medical Standards Research, IRCA-BSSA Group in Japan on April 15-16, 2012. Experts in the fields of surgery, anesthesia, pharmacy, and public health from 21 health institutions from Japan and China presented their research achievements and shared their medical experience of perioperative management on hepato-biliary-pancreatic surgery, which should facilitate building of guidelines for hepatocellular carcinoma and be expected to promote standardized management of liver cancer in Asia.