[3a,4]-Dihydropyrazolo[1,5a]pyrimidines: Novel,Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors

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Eugenol,a Component of Holy Basil (Tulsi) and Common Spice Clove,Inhibits the Interaction Between SARS-CoV-2 Spike S1 and ACE2 to Induce Therapeutic Responses

Journal of Neuroimmune Pharmacology - Spike S1 of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) on host cells to enter the cell and...     

In vivo confocal microscopic findings of interlamellar stromal keratopathy induced by elevated intraocular pressure

We report the confocal microscopic findings in a case of interlamellar stromal keratopathy induced by elevated intraocular pressure (IOP) after laser in situ keratomileusis (LASIK). In vivo confocal microscopy showed swollen and enlarged cellular structures and the presence of microlacunae separating the stromal collagen lamellae. Inflammatory mononuclear cells and granulocytes typically seen in patients with diffuse lamellar keratitis (DLK) were absent. Stopping the topical steroids with concurrent lowering of the IOP resulted in improvement in the uncorrected and best corrected visual acuities and was associated with resolution of the corneal findings. In vivo confocal microscopy is a useful tool to study interlamellar stromal keratopathy induced by elevated IOP after LASIK in humans and the response to treatment and to differentiate interlamellar stromal keratopathy from DLK.     

Disposition kinetics in dogs of diethyldithiocarbamate,a metabolite of disulfiram

Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min^–1 (t_1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min^–1 (t_1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min^–1 (t_1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man.Glossary A plasma concentration intercept at the cessation of infusion (mass/volume) - A _T simplifying constant (mass/volume/time) - AUC _M area under the plasma concentration-time curve for MeDDC (mass × time/volume) - b time variable; equalst during infusion, equalsT after the cessation of infusion - B plasma concentration intercept at the cessation of infusion (mass/volume) - B _T simplifying constant (mass/volume/time) - C _D plasma concentration of DDC at any timet (mass/volume) - C _M plasma concentration of MeDDC, expressed as DDC, at any timet (mass/volume) - C _T plasma concentration of total DDC, expressed as DDC, at any timet;C _T=C_D+C_M (mass/volume) - C _t plasma concentration of total DDC, expressed as DDC, at any timet (mass/volume) - Cl _D total body clearance of DDC (volume/time) - Cl _M total body clearance of MeDDC (volume/time) - DDC diethyldithiocarbamate - f fraction of DDC that is methylated;f=K _DM/K _D - K _A apparent first-order rate constant (reciprocal time) - K _B apparent first-order rate constant (reciprocal time) - K _D apparent first-order rate constant for the elimination of DDC by all routes (reciprocal time) - K _M apparent first-order rate constant for the elimination of MeDDC by all routes (reciprocal time) - K _DE apparent first-order rate constant for the elimination of DDC by all routes except methylation (reciprocal time) - K _DM apparent first-order rate constant for theS-methylation of DDC (reciprocal time) - MeDDC methyl diethyldithiocarbamate - NaDDC sodium diethyldithiocarbamate (trihydrate) - Q zero-order infusion rate constant (mass/time) - Q ₁ zero-order infusion rate constant for the faster of two consecutive infusions (mass/time) - Q ₂ zero-order infusion rate constant for the slower of two consecutive infusions (mass/time) - t elapsed time since dosing (e.g., infusion) commenced - t elapsed time since the cessation of infusion - T duration of infusion (time) - T ₁ duration of the faster of two consecutive infusions (time) - T ₂ total duration of infusion when two consecutive infusions are administered (time) - V _D apparent volume of distribution of DDC - V _M apparent volume of distribution of MeDDC This work was supported by the Atkinson Charitable Foundation (Toronto, Ontario, Canada) and the Non-Medical Use of Drugs Directorate, Health and Welfare Canada (Grant No. 1212-5-206).     

Characterization of monoclonal antibodies against GRIM-19, a novel IFN-beta and retinoic acid-activated regulator of cell death.

A combination of interferon-beta (IFN-beta) and all-trans retinoic acid (IFN/RA) induces tumor cell apoptosis via some unknown mechanisms. Apoptosis is a gene-directed process that limits the proliferation of undesired cells. Several genes are required to regulate cell death in the higher-order animals. Earlier, we employed a gene expression knockout technique to isolate cell death-related genes. A novel gene, the gene associated with retinoid-interferon-induced mortality-19 (GRIM-19), was found to be essential for tumor cell death induced by IFN/RA. Here, we describe the development and characterization of three monoclonal antibodies (mAbs) against GRIM-19. GRIM-19 is present in the nucleus and cytoplasm. Its expression is induced by the IFN/RA combination. We also show that GRIM-19 inhibits the cell-transforming property of viral oncogenic protein viral IFN regulatory factor-1 (vIRF-1) via a physical interaction. mAbs developed in this study should be useful for studying the other physiologic roles of GRIM-19 and serve as a potent tool for studying tumor responses to IFN/RA therapy.     

Fetal bladder rupture due to anteriorurethral valves

A rupture of the fetal bladder that resulted in urinary ascites has rarely been reported in published studies. We present the first case of a spontaneous rupture of the fetal bladder, due to an anterior urethral valve, in which the diagnosis was suspected prenatally by means of Doppler ultrasonography and was confirmed postnatally.     

Immunolocalization of cell signaling molecules in the granular cell ameloblastoma

BACKGROUND: Bone morphogenic protein (BMP) and Wnt signaling pathway molecules play important roles in cytodifferentiation and cell proliferation. We attempted to localize these signaling molecules in the granular cell ameloblastoma. MATERIALS AND METHODS: Four samples of paraffin-embedded ameloblastoma with granular cells were studied. Immunohistochemistry was performed to detect basement membrane type heparan sulfate (HS) (JM403), cell surface type HS (10E4), heparanase, Wnt-5a, Wnt-2, beta-catenin, and BMP-4. RESULTS: In all four samples, strong expression of beta-catenin and Wnt-5a was detected within the granular cells, while BMP-4 expression was weak and Wnt-2 was negative. Immunoreactivities of basement membrane type HS, cell surface type HS, and heparanase were variable within granular cells in ameloblastoma. CONCLUSION: Granular cells in ameloblastoma exhibit abnormal biological behaviors, particularly synthesis and secretion of protein. Synthesis of signaling molecules is upregulated, but secretion is arrested in some cases, while both are lost in other cases.     

Risk of finding an endometrial cancer when atypical hyperplasia was incidentally diagnosed on hysteroscopic resection products

OBJECTIVE: To evaluate the risk of discovering an endometrial cancer when atypical hyperplasia was diagnosed by histologic examination of hysteroscopic resection products. STUDY DESIGN: A retrospective monocentric study from January 1994 to January 2001. Seventeen patients with atypical hyperplasia were included. Initial endometrial status was provided by operative hysteroscopy resection products. For all patients, there was no hysteroscopical aspect evocative of adenocarcinoma. Histopathological analysis of the hysterectomy pieces precised the final diagnosis. RESULTS: Among the 17 hysterectomy pieces, one adenocarcinoma was diagnosed. Risk for discovering adenocarcinoma when atypical hyperplasia was diagnosed by operative hysteroscopy resection products was 5.9% (1/17). CONCLUSION: Risk of omitting adenocarcinoma when atypical hyperplasia is discovered by hysteroscopy resection pieces is low.     

Flavonoids of Korean Citrus aurantium L. Induce Apoptosis via Intrinsic Pathway in Human Hepatoblastoma HepG2 Cells

Korean Citrus aurantium L. has long been used as a medicinal herb for its anti‐inflammatory, antioxidant, and anticancer properties. The present study investigates the anticancer role of flavonoids extracted from C. aurantium on human hepatoblastoma cell, HepG2. The Citrus flavonoids inhibit the proliferation of HepG2 cells in a dose‐dependent manner. This result was consistent with the in vivo xenograft results. Apoptosis was detected by cell morphology, cell cycle analysis, and immunoblot. Flavonoids decreased the level of pAkt and other downstream targets of phosphoinositide‐3‐kinase/Akt pathway – P‐4EBP1 and P‐p70S6K. The expressions of cleaved caspase 3, Bax, and Bak were increased, while those of Bcl‐2 and Bcl‐xL were decreased with an increase in the expression of Bax/Bcl‐xL ratio in treated cells. Loss of mitochondrial membrane potential was also observed in flavonoid‐treated HepG2 cells. It was also observed that the P‐p38 protein level was increased both dose and time dependently in flavonoid‐treated cells. Collectively, these results suggest that flavonoid extracted from Citrus inhibits HepG2 cell proliferation by inducing apoptosis via an intrinsic pathway. These findings suggest that flavonoids extracted from C. aurantium L. are potential chemotherapeutic agents against liver cancer. Copyright © 2015 John Wiley & Sons, Ltd.