Mosquito larvicidal, pupicidal, adulticidal, and repellent activity of Artemisia nilagirica (Family: Compositae) against Anopheles stephensi and Aedes aegypti

Mosquito-borne diseases have an economic impact, including loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates; however, no part of the world is free from vector-borne diseases. The aim of the present study, to evaluate the larvicidal, pupicidal, repellent, and adulticidal activities of methanol crude extract of Artemisia nilagirica were assayed for their toxicity against two important vector mosquitoes, viz., Anopheles stephensi and Aedes aegypti (Diptera: Culicidae). The fresh leaves of A. nilagirica were washed thoroughly in tap water and shade dried at room temperature (28?±?2?°C) for 5?C8?days. The air-dried materials were powdered separately using commercial electrical blender. From the plants, 500?g powdered was macerated with 1.5?L organic solvents of methanol sequentially for a period of 72?h each and filtered. The larval and pupal mortality was observed after 24?h of exposure; no mortality was observed in the control group. The first- to fourth-instar larvae and pupae of A. stephensi had values of LC₅₀?=?272.50, 311.40, 361.51, 442.51, and 477.23?ppm, and the LC₉₀?=?590.07, 688.81, 789.34, 901.59, and 959.30?ppm; the A. aegypti had values of LC₅₀?=?300.84, 338.79, 394.69, 470.74, and 542.11?ppm, and the LC₉₀?=?646.67, 726.07, 805.49, 892.01, and 991.29?ppm, respectively. The results of the repellent activity of plant extract of A. nilagirica plants at five different concentrations of 50, 150, 250, 350, and 450?ppm were applied on skin of fore arm in man and exposed against adult female mosquitoes. In this observation, the plant crude extract gave protection against mosquito bites without any allergic reaction to the test person, and also, the repellent activity is dependent on the strength of the plant extracts. The adult mortality was found in methanol extract of A. nilagirica, with the LC₅₀ and LC₉₀ values of 205.78 and 459.51?ppm for A. stephensi, and 242.52 and 523.73?ppm for A. aegypti, respectively. This result suggests that the leaf extract have the potential to be used as an ideal eco-friendly approach for the control of vector mosquito as target species.     

A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells

Overexpression of Notch receptors and ligands has been associated with various cancers and developmental disorders, making Notch a potential therapeutic target. Here, we report characterization of Notch1 monoclonal antibodies (mAb) with therapeutic potential. The mAbs generated against epidermal growth factor (EGF) repeats 11 to 15 inhibited binding of Jagged1 and Delta-like4 and consequently, signaling in a dose-dependent manner, the antibodies against EGF repeats 11 to 12 being more effective than those against repeats 13 to 15. These data emphasize the role of EGF repeats 11 to 12 in ligand binding. One of the mAbs, 602.101, which specifically recognizes Notch1, inhibited ligand-dependent expression of downstream target genes of Notch such as HES-1, HES-5, and HEY-L in the breast cancer cell line MDA-MB-231. The mAb also decreased cell proliferation and induced apoptotic cell death. Furthermore, exposure to this antibody reduced CD44(Hi)/CD24(Low) subpopulation in MDA-MB-231 cells, suggesting a decrease in the cancer stem-like cell subpopulation. This was confirmed by showing that exposure to the antibody decreased the primary, secondary, and tertiary mammosphere formation efficiency of the cells. Interestingly, effect of the antibody on the putative stem-like cells appeared to be irreversible, because the mammosphere-forming efficiency could not be salvaged even after antibody removal during the secondary sphere formation. The antibody also modulated expression of genes associated with stemness and epithelial-mesenchymal transition. Thus, targeting individual Notch receptors by specific mAbs is a potential therapeutic strategy to reduce the potential breast cancer stem-like cell subpopulation.     

Dietary chlorophyllin inhibits the canonical NF-κB signaling pathway and induces intrinsic apoptosis in a hamster model of oral oncogenesis

Chlorophyllin, a water-soluble, semi-synthetic derivative of the ubiquitous green pigment chlorophyll is shown to exert potent anticarcinogenic effects. In the present study, we investigated the chemopreventive effects of chlorophyllin on 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis by analyzing the expression of NF-κB family members and markers of intrinsic apoptosis. Dietary administration of chlorophyllin (4 mg/kg bw) suppressed the development of HBP carcinomas by inhibiting the canonical NF-κB signaling pathway by downregulating IKKβ, preventing the phosphorylation of IκB-α, and reducing the expression of nuclear NF-κB. Inactivation of NF-κB signaling by chlorophyllin was associated with the induction of intrinsic apoptosis as evidenced by modulation of Bcl-2 family proteins, enforced nuclear localization of survivin, upregulation of apoptogenic molecules, activation of caspases, and cleavage of PARP. The results of the present study demonstrate that chlorophyllin inhibits the development of DMBA-induced HBP carcinogenesis by targeting NF-κB and the intrinsic apoptotic pathway. Thus, dietary agents such as chlorophyllin that simultaneously target divergent pathways of cell survival and cell death are novel candidates for cancer chemoprevention.     

Uncommon GNAQ, MMP8, AKT3, EGFR, and PIK3R1 mutations in thyroid cancers

Frequent mutations in the GNAQ, MMP8, Akt3, EGFR, and PIK3R1 genes have been reported in human cancers but mostly have not been well examined in thyroid cancer. Selected exons of GNAQ, MMP8, AKT3, EGFR, and PIK3R1 genes were sequenced in various thyroid cancers. We found a G2203A EGFR mutation, resulting in a G735S amino acid change, in one of 21 (5%) papillary thyroid cancer samples. We did not find any mutation in the MMP8 gene, but observed a frequent SNP A259G (K87E) genotype switch in various types of thyroid cancer samples. We did not find any mutation in the GNAQ, AKT3, and PIK3R1genes in various types of thyroid cancer. No mutation in these genes was found in 12 cell lines derived from various types of thyroid cancer. Therefore, unlike in other cancers, mutations in these genes are uncommon in thyroid cancer.     

Identification and Characterization of Potential Impurities in Raloxifene Hydrochloride

During the synthesis of the bulk drug Raloxifene hydrochloride, eight impurities were observed, four of which were found to be new. All of the impurities were detected using the gradient high performance liquid chromatographic (HPLC) method, whose area percentages ranged from 0.05 to 0.1%. LCMS was performed to identify the mass number of these impurities, and a systematic study was carried out to characterize them. These impurities were synthesized and characterized by spectral data, subjected to co-injection in HPLC, and were found to be matching with the impurities present in the sample. Based on their spectral data (IR, NMR, and Mass), these impurities were characterized as Raloxifene-N-Oxide [Impurity: 1]; EP impurity A [Impurity: 2]; EP impurity B [Impurity: 3]; Raloxifene Dimer [Impurity: 4]; HABT (6-Acetoxy-2-[4-hydroxyphenyl]-1-benzothiophene or 6-Hydroxy-2-[4-acetoxyphenyl]-1-benzothiophene) [Impurity: 5]; PEBE (Methyl[4-[2-(piperidin-1-yl)ethoxy]]benzoate) [Impurity: 6]; HHBA (1-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]ethanone) [Impurity: 7]; 7-MARLF (7-Acetyl-[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][4-[2-(piperidin-1-yl)ethoxy]phenyl methanone) [Impurity: 8]; of which impurities 5–8 are reported for the first time.     

Therapy of intracranial hypertension in patients with fulminant hepatic failure

Severe intracranial hypertension (IH) in the setting of fulminant hepatic failure (FHF) carries a high mortality and is a challenging disease for the critical care provider. Despite considerable improvements in the understanding of the pathophysiology of cerebral edema during liver failure, therapeutic maneuvers that are currently available to treat this disease are limited. Orthotopic liver transplantation is currently the only definitive therapeutic strategy that improves outcomes in patients with FHF. However, many patients die prior to the availability of donor organs, often because of cerebral heniation. Currently, two important theories prevail in the understanding of the pathophysiology of IH during FHF. Ammonia and glutamine causes cytotoxic cerebral injury while cerebral vasodilation caused by loss of autoregulation increases intracranial pressure (ICP) and predisposes to herniation. Although ammonia-reducing strategies are limited in humans, modulation of cerebral blood flow seems promising, at least during the early stages of hepatic encephalopathy. ICP monitoring, transcranial Doppler, and jugular venous oximetry offer valuable information regarding intracranial dynamics. Induced hypothermia, hypertonic saline, propofol sedation, and indomethacin are some of the newer therapies that have been shown to improve survival in patients with severe IH. In this article, we review the pathophysiology of IH in patients with FHF and outline various therapeutic strategies currently available in managing these patients in the critical care setting.     

A simplified, non-invasive fecal-based DNA integrity assay and iFOBT for colorectal cancer detection

Purpose

Neoplasia cells exfoliated from colorectal epithelium have dysfunctional apoptotic mechanisms, thus it is possible to identify high-molecular weight DNA fragments in feces. This prospective single-center study was performed to evaluate the sensitivity and specificity of fecal-based DNA integrity versus immunological fecal occult blood test (iFOBT) and calprotectin for colorectal cancer (CRC) and adenoma detection.

Methods

Feces were collected from 204 subjects and DNA integrity was quantified by quantitative-denaturing high performance liquid chromatography (QdHPLC). Calprotectin and iFOBT were assessed using commercial kits. The diagnostic performance was calculated by receiver operating characteristic (ROC) curves analysis.

Results

A total of 192 fecal specimens were analyzed and 12 samples were excluded due to DNA degradation. We found long DNA (L-DNA) occurrence in feces with a sensitivity of 86% (n?=?24/28) and a specificity of 81% for CRC detection. To minimize false-positive cases of the developed test, area under the curve of ROC was evaluated such that the specificity was increased to 92% with decreased sensitivity to 79%, p?=?0.0001 for CRC detection. iFOBT was positive in 51% (n?=?14/27) while calprotectin was positive in 75% (n?=?18/27). The combination of iFOBT and L-DNA identified a greater number of CRC cases with a sensitivity of 89% and a specificity of 95%, p?p?=?0.0015) as opposed to a single evaluation assay (17?C21%).

Conclusions

This study illustrates the usefulness of fecal DNA integrity assay by QdHPLC as a non-invasive, easy-to-perform, and reproducible method with a high level of sensitivity in detecting individuals with colorectal neoplasia. Combination of iFOBT and L-DNA improves the sensitivity for CRC and adenoma detection.     

Gender and ethnic differences in prevalence of self-reported insomnia among patients with obstructive sleep apnea

Background  

Insomnia and obstructive sleep apnea (OSA) are the two most common sleep disorders. Studies have shown that complaints of insomnia are prevalent among sleep clinic patients evaluated for OSA. Less is known about the gender and ethnic variations in this association.