Hyperglycemia in COVID-19 infection without diabetes mellitus: Association with inflammatory markers

BACKGROUND New onset hyperglycemia is common in patients with severe coronavirus disease 2019(COVID-19) infection. Cytokine storm due to COVID-19 infection is an essential etiology for new-onset hyperglycemia, but factors like direct severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced pancreatic β-cell failure have also been postulated to play a role.AIM We plan to investigate further the mechanisms underlying SARS-CoV-2 infectioninduced hyperglycemia, particularly the rationale ...     

Calcified meconium balls in a newborn: an unusual case with imperforate anus,rectourinary fistula,colpocephaly, and agenesis of corpus callosum

Calcified intraluminal meconium is a rare finding in newborn infants. It is often associated with communication between the urinary and gastrointestinal tracts. Intra-abdominal calcifications are unusual radiographic findings in the newborn and can easily be misinterpreted as meconium peritonitis. We report on a newborn infant with anorectal malformation, meconium balls, intraluminal calcifications, colpocephaly, and agenesis of the corpus callosum, a rare association.     

Evaluation of naphthalmustine, a nitrogen mustard derivative of naphthalimide as a rationally-designed anticancer agent

Naphthalmustine, 2-[2-[bis-(2-chloroethyl)amino]ethyl]-1H-benz[de]isoquinoline-1,3-dione (Compound 1) has been synthesized as a rationally designed new anticancer agent from N-(2-bromoethyl)naphthalimide. Its chemical alkylating activity exceeded that of nor-HN2 used as standard compound for comparison. Its antitumour efficacy was assessed in vivo in two murine ascites tumours namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. The clinical drug cyclophosphamide and the experimental compound mitonafide were used as positive controls for comparison. Compound 1 has displayed substantial and reproducible antitumoural activity in these tumours since very high remission times of treated animals were observed. Significant increase in the life span of mice bearing highly advanced tumour for 10 days before the drug challenge was also noted after its treatment. Its LD50 value was 200 mg/Kg by single i.p. injection. Its toxicity was also assessed in vivo in normal and in S-180 bearing mice by measuring drug-induced changes in hematological parameters, femoral bone marrow and splenic cellularity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 12 mg/kg from day 1 to 7. The results indicated that the compound did not adversely affect hematopoiesis. Drug-induced hepatotoxicity and nephrotoxicity were also evaluated on those days but no such toxicities were detected. Naphthalmustine inhibits the synthesis of DNA and RNA in S-180 tumour cells. It was further screened in vitro in 4 different human tumour cell lines but no significant activity was observed in those lines.     

In vitro cytotoxic elemanolides from Vernonia lasiopus

Two new elemanolides, epivernodalol and lasiopulide, were isolated after chromatographic separation of the alcoholic extract of the dried aerial parts of the Vernonia lasiopus. These elemanolides are new C-10 epimers of the sesquiterpene lactones vernodalol and demethylacroylated vernodalol isolated from other species of Vernonia. Both elemanolides showed in vitro cytotoxicity against human cancer cell lines in culture. This is the first report of isolation and cytotoxic activity of the two elemanolides from V. lasiopus.     

Chemically standardized isolates from Cedrus deodara stem wood having anticancer activity

An isolate "CD lignan mixture" comprising lignans from stem wood of Cedrus deodara consisted of (-)-wikstromal (75 - 79%), (-)-matairesinol (9 - 13%) and benzylbutyrolactol (7 - 11%) and was studied for its in vitro cytotoxicity against human cancer cell lines. The in vivo anticancer activity of CD lignan mixture was studied using Ehrlich ascites carcinoma and colon carcinoma (CA-51) models in mice. Its effect was also studied on annexin V binding, intracellular caspases and DNA fragmentation to gain insight into the mode of action. In vitro cytotoxicity studies showed significant dose-dependent effects against several cancer cell lines from different tissues such as breast, cervix, neuroblastoma, colon, liver, and prostate at 10, 30 and 100 microg/mL. The IC (50) values varied from 16.4 ng/mL to 116.03 microg/mL depending on the cell line. Comparative data of IC (50) values of CD lignan mixture showed a synergistic effect in comparison to the individual molecules, i. e., (-)-matairesinol, (-)-wikstromol present in CD lignan mixture . CD lignan mixture had the most pronounced effect on CNS cell lines followed by colon. The tumor regression observed with Ehrlich ascites carcinoma and CA-51 was 53% and approximately 54%, respectively, when CD lignan mixture was given at 300 mg/kg, I. P. for nine days in the Ehrlich ascites carcinoma model and 400 mg/kg, I. P. for the same period in the CA-51 model. It was comparable with 5-fluorouracil at 22 mg/kg and 20 mg/kg, respectively. CD lignan mixture at 10, 30 and 100 microg/mL increased the percentage of annexin V positive HL-60 cells to 1.9 - 17.18% as compared to control (1.04%). In K562 cells CD lignan mixture at 10, 30 or 100 microg/mL and staurosporine (1 microM) showed 9.13%, 11.38%, 17.22% and 28.07% intracellular caspases activation, respectively. A distinct DNA laddering pattern was observed for treatment with the CD lignan mixture in HL-60, K562 (30 microg/mL and 100 microg/mL) and MOLT-4 cells (30 microg/mL) after 24 h incubation. DNA cell cycle analysis indicated that CD lignan mixture at 10, 30 and 100 microg/mL increased the content of hypodiploid (sub G(1) phase) cells when compared to control (2.55, 5.4 and 6.25% vs. 0.27%). The present study indicates that CD lignan mixture has cytotoxic potential against human cancer cell lines. It has the ability to induce tumor regression in vivo. It induces apoptosis as indicated by annexin V positive cells, induction of intracellular caspases, DNA fragmentation and DNA cell cycle analysis.     

Synthesis and evaluation of ethylnitrosoureas of substituted naphthalimides as anticancer compounds

Four new ethylnitrosourea derivatives of substituted naphthalimides 3a-d have been synthesized from the respective N-(2-ethylamino) naphthalimides. Their chemical alkylating activity compared with the clinical drug CCNU and an experimental compound Mitonafide indicated that they possess lower alkylating activity than CCNU and comparable activity with the latter. Their anti-tumor efficacies were assessed in vivo in two murine ascites tumors namely Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times (MST) of drug treated (T) over untreated control (C) mice. CCNU and Mitonafide were used as positive controls for comparison. The representative compound 3a has displayed marginal anti-tumoral activity in these tumors. Three compounds were further screened in vitro in 4 different human tumor cell lines but no significant activity was observed in those lines. These compounds moderately inhibit the synthesis of DNA and RNA in S-180 tumor cells.     

Induction of apoptosis by a synergistic lignan composition from Cedrus deodara in human cancer cells

AP9‐cd, a synergistic lignan mixture from Cedrus deodara (Pinaceae) consisting of (?)‐wikstromal, (?)‐matairesinol and dibenzyl butyrolactol, depicted cytotoxic effects against numerous human cancer cell lines reported previously. The aim of this study was to investigate the mechanism of cell death in human cancer cells. The viability, morphological and ultrastructural changes in Molt‐4 cells were investigated. Using the trypan blue exclusion assay, we demonstrated that AP9‐cd significantly reduced the viability of Molt‐4 cells in a time‐ and dose‐dependent manner. Apoptotic assays using light microscopy revealed that this agent induced Molt‐4 cell apoptosis at varied concentrations. The treatment causes a loss in cell viability by activating the apoptotic process as identified by light and electron microscopy. The morphological changes of intracellular organelles in Molt‐4 cells treated with 30 µg/ml of AP9‐cd revealed the disruption of mitochondrial cristae. Other features included the vacuolization, chromatin condensation and formation of micronuclei. Surface ultrastructural studies of four different tumor cell lines (Molt‐4, HL‐60, PC‐3 and A‐549) treated with AP9‐cd depicted loss of surface projections, condensation and formation of apoptotic bodies. AP9‐cd treatment to transgenic fruit fly, Drosophila, carrying human adenomatous polpyposis coli (hAPC) gene enhanced eye phenotypes and therefore may inhibit Wnt/Wg pathway which is important in the aetiology of a number of human cancers. Copyright © 2008 John Wiley & Sons, Ltd.     

6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione,a potent antitumor agent,induces cell cycle arrest and apoptosis

Background

Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents.

Methods

Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. ³H-Thymidine and ³H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied.

Results

6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC₅₀ value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G₁ fraction and concomitant accumulation of cells in S and G₂/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron microscopic studies corroborated its apoptosis inducing efficacy at a concentration of 10 μM in MOLT-4 cells. Its apoptosis induction was also observed in HL-60 cells to an extent much greater than well known apoptosis inducing agents as camptothecin and cis-platin at 10 μM concentration each. It significantly inhibited DNA and RNA synthesis in S-180.

Conclusions

In essence, compound 1i showed potential as an antitumor agent.

     

Dry Sliding Wear Studies on Sillimanite and B4C Reinforced Aluminium Hybrid Composites Fabricated by Vacuum Assisted Stir Casting Process

This paper presents the results of studies to understand the influence of hybridisation on mechanical and tribological behaviour as well as dry sliding wear of aluminium metal matrix composites. Sillimanite and boron carbide (B₄C) were used as primary and secondary reinforcements and pure aluminium was used as the matrix material. The composite was fabricated by using a vacuum assisted stir casting process. Different research instruments were used, including a scanning electron microscope with EDX spectrometer, a surface measurement device, a thermal image analyser, as well as a tribotester. The results show that tensile, impact strength and hardness of the hybridised composites are superior (a step ahead) than unreinforced and primary composites. The wear behaviour of the fabricated specimens was tested for the dry sliding wear behaviour under the load range of 10–50 N with the steps of 20 N for the sliding velocities 0.75, 1.5 and 2.25 m/s over a distance of 1000 m. The wear rate increased with load and decreased as the wt.% of reinforcement increased. The wear rate of the composite with 10 wt.% Al₂SiO₅ was approximately 44% lower than that of the composite with 5 wt.% Al₂SiO₅. The same dependence was noted for hybrid composite (5 wt.% Al₂SiO₅ + 5 wt.% B₄C)—the wear rate was approximately 50.8% lower than that of the composite with 5 wt.% Al₂SiO₅ under the same test condition. The friction coefficient decreased as the weight percentage of the reinforcement (Al₂SiO₅ and B₄C) increased due to the uniform distribution of the reinforcement on the surface of the composites. The main wear mechanism of the studied materials was abrasion wear. The wear mechanism of the composite had tribochemical type. It involved the oxidation and transfer of the material, which formed protective tribolayers ensuring an additional sliding process. The mechanism that played the main role in the wear process of the composites was a combination of abrasive, adhesive and oxidative wear.     

Influence of ferulic acid on nicotine-induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N-acetylcysteine

We examined the effect of ferulic acid (FA), a naturally occurring phenolic compound on lipid peroxidation and endogenous antioxidant status, DNA damage and inflammation in nicotine-administered Wistar rats. The effect of FA against nicotine toxicity was compared with N-acetylcysteine (NAC), a well-known antioxidant. Lung toxicity was induced by subcutaneous injection of nicotine at a dose of 2.5mg/kg body weight (5 days a week, for 22 weeks) and FA and NAC were given simultaneously by intragastric intubation for 22 weeks. Seventy two Wistar rats were divided into six groups: (i) control, (ii) nicotine, (iii) nicotine+FA (iv), nicotine+NAC, (v) FA and (vi) NAC. At the end of the experimental period, cellular damage was assessed by measuring the activities of lactate dehydrogenase and alkaline phosphatase in plasma, which were significantly elevated in nicotine-administered rats when compared with control group. Enhanced lipid peroxidation (evaluated by measuring the thiobarbituric acid reactive substances and hydroperoxides) was accompanied by a significant decrease in the endogenous antioxidant status viz., superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione in circulation, lung and liver of nicotine-treated rats when compared with control group. DNA single strand breaks (evaluated by comet assay) and frequency of micronuclei were significantly increased in peripheral blood of nicotine-treated rats when compared with control. Our Western blot analysis showed a significant increase in the expression of cyclooxygenase-2 and NF-kappaB in lung and liver of nicotine-treated rats. FA and NAC co-treated rats showed a significant decrease in the activities of circulatory lactate dehydrogenase and alkaline phosphatase, the levels of lipid peroxidative markers (in circulation, lung and liver), DNA single stranded breaks (comet parameters), micronuclei frequency (in the whole blood) and expression of cyclooxygenase-2 and Nf-kappaB (in lung and liver tissues), and significant increase in antioxidant status (in circulation, lung and liver). The protection of FA against nicotine-induced toxicity was merely equal to the effect of NAC. FA and NAC treatment alone did not produce any damage to control rats. Thus, we propose that FA exerts protective effect against nicotine toxicity by modulating the lipid peroxidation, inflammation, DNA damage and endogenous antioxidant status.