A morphometric study of human submandibular gland in type 2 diabetic status

Diabetes Mellitus Type 2 represents one of the principal diseases that afflict the world population. It is well documented that diabetes affects both morphology and function of several organs. In diabetic rats significant structural changes have been demonstrated in salivary glands, such as accumulation of secretory material and lipid droplets within secretory cells, parenchymal degeneration and its replacement with fibrous connective tissue (1). With regard to human salivary glands, the data are scanty and conflicting. Our work, carried out by light and electron microscopy, is based on the evaluation of the morphological changes which occur in human submandibular glands of diabetic with respect to non diabetic patients. Surgical fragments of glandular tissue were fixed, dehydrated, and processed for light and electron microscopy. Randomly chosen images were analyzed with Image Pro Plus software to record the dimension of acini, serous cells, secretory granules and other variables. Data were analyzed by Student’s t-test and Mann Whitney test. In diabetic glands statistically significant morphological changes were observed, such as enlargement of serous acini and increase of secretory granules area. These results suggest that the secretory activity of human submandibular gland is severely affected by the diabetic status. Obviously these data need to be confirmed with further measurements in order to explain better how diabetes affects human salivary glands

Ultrastructural evidence of a secretory role for melatonin in the human parotid gland

In vivo animal studies show that pentagastrin, cholecystokinin and melatonin cause the secretion and synthesis of salivary proteins. Melatonin occurs in large amounts in the gut and is released into the blood on food intake. In vitro experiments suggest that pentagastrin exerts secretory activity in human salivary glands, as judged by ultrastructural changes, reflecting secretion, and an actual protein output. Currently, it is hypothesised that melatonin induces secretory exocytotic events in the human parotid gland. Human parotid tissues were exposed to a high single concentration of melatonin in vitro, processed for high resolution scanning electron microscopy and then assessed morphometrically with the emphasis on the membrane of the intercellular canaliculi, a site of protein secretion. Compared with controls and in terms of density, the melatonin-exposed parotid tissues displayed increases in protrusions (signalling anchored granules) and microbuds (signalling membrane recycling and/or vesicle secretion) and decreases in microvilli (signalling cytoskeletal re-arrangement related to exocytosis), phenomena abolished or very largely reduced by the melatonin receptor blocker, luzindole. In conclusion, acinar serous cells of parotid tissue displayed in vitro exocytotic activity to melatonin, signalling protein secretion. Whether, under physiological conditions, melatonin influences the secretion of human parotid glands remains to be explored, however

A morphometric study of human submandibular gland in type 2 diabetic status

Diabetes Mellitus Type 2 represents one of the principal diseases that afflict the world population. It is well documented that diabetes affects both morphology and function of several organs. In diabetic rats significant structural changes have been demonstrated in salivary glands, such as accumulation of secretory material and lipid droplets within secretory cells, parenchymal degeneration and its replacement with fibrous connective tissue (1). With regard to human salivary glands, the data are scanty and conflicting. Our work, carried out by light and electron microscopy, is based on the evaluation of the morphological changes which occur in human submandibular glands of diabetic with respect to non diabetic patients. Surgical fragments of glandular tissue were fixed, dehydrated, and processed for light and electron microscopy. Randomly chosen images were analyzed with Image Pro Plus software to record the dimension of acini, serous cells, secretory granules and other variables. Data were analyzed by Student’s t-test and Mann Whitney test. In diabetic glands statistically significant morphological changes were observed, such as enlargement of serous acini and increase of secretory granules area. These results suggest that the secretory activity of human submandibular gland is severely affected by the diabetic status. Obviously these data need to be confirmed with further measurements in order to explain better how diabetes affects human salivary glands. Maria Alberta Lilliu gratefully acknowledges Sardinia Regional Government for the financial support of her PhD scholarship (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007-2013 - Axis IV Human Resources, Objective l.3, Line of Activity l.3.1.). Michela Isola gratefully acknowledges Sardinia Regional Government for the financial support (P.O.R. Sardegna F.S.E. Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007-2013 - Axis IV Human Resources, Objective l.3, Line of Activity l.3.1 “Avviso di chiamata per il finanziamento di Assegni di Ricerca”)

Emerging Therapeutic Agents for Colorectal Cancer

There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs

Morphological alteration induced by Cytochalasin D on serous cells of human submandibular gland in basal and stimulated conditions

Cytochalasin D (CD) is a fungal toxin which binds to the faster growing end of actin microfilament and inhibits actin polymerization. By an in vitro incubation system of slices of human submandibular glands obtained at surgery, we investigated by light microscope (LM), transmission electron microscope (TEM), and high resolution scanning electron microscope (HRSEM) the morphological changes caused by CD on serous cells. We studied the effects of the drug on secretory events induced by isoproterenol (I) and carbachol (C). With LM, following CD incubation, canaliculi were enlarged and prominent vacuoles were seen throughout the cytoplasm. By TEM, the vacuoles, which in many cases were in continuity with the lumen, represented the distinctive feature of secretory cells. With HRSEM, intercellular canaliculi, seen from their cytoplasmic side, exhibited many small spherical bulges, corresponding to the coated pits seen with TEM and indicating that the retrieval of plasma membrane was arrested at an early phase by the disruption of the actin cytoskeleton. In specimens treated with secretagogues and CD, a consequence reported here for the first time was the presence of dense granules within the vacuoles. The protrusions seen by HRSEM on the cytoplasmic side of intercellular canaliculi, following secretagogues stimulations, appeared peculiar to each stimulants, even if combined with CD, suggesting that besides actin filaments, other components, unaffected by CD, also are involved in the process of exocytosis and related phenomena

Serous and mucous cells of human submandibular salivary gland stimulated in vitro by isoproterenol, carbachol and clozapine. An LM, TEM and HRSEM study

We have investigated by LM, TEM, and HRSEM the effects of D,L-isoproterenol (beta-adrenergic agent), carbachol (muscarinic agent) and clozapine on biopsy specimens of human submandibular gland stimulated in vitro in an inorganic oxygenated medium. Clozapine is a dibenzodiazepine derivative used in psychotic patients that provokes hypersalivation, a displeasing side effect that often causes discontinuance of therapy. Our findings demonstrate that clozapine acts on salivary mucous and seromucous (serous) cells of the gland as a muscarinic agonist. However, the induced secretory response seems to differ qualitatively and quantitatively from that resulting from carbachol. Thus, in agreement with published data resulting from therapeutic treatments and from experimental studies on rats, the mechanism of clozapine induced hypersialorrhea remains open to further investigation

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

Triple-negative breast cancer (TNBC) is one of the most heterogeneous and aggressive breast cancer subtypes with a high risk of death on recurrence. To date, TNBC is very difficult to treat due to the lack of an effective targeted therapy. However, recent advances in the molecular characterization of TNBC are encouraging the development of novel drugs and therapeutic combinations for its therapeutic management. In the present review, we will provide an overview of the currently available standard therapies and new emerging therapeutic strategies against TNBC, highlighting the promises that newly developed small molecules, repositioned drugs, and combination therapies have of improving treatment efficacy against these tumors

First in class pdz1 targeting NHERF1 inhibitors as anticancer agents

NHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains. PDZ1 and PDZ2 bind to specific carboxyl-terminal motifs on target proteins, such as beta-catenin and PTEN, that may have a pivotal role in tumorigenesis. A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1. We herein report the design and synthesis of new NHERF1 inhibitors. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174Tshbeta-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of beta2-AR. When used in combination with antagonists of beta-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/beta-catenin-targeted agents

A Novel Validated UHPLC Method for the Estimation of Rosuvastatin and Its Complete Impurity Profile in Tablet Formulations

A key step in the development of medicinal products is the research and validation of selective and sensitive analytical methods for the control of impurities from synthesis and degradation. As most impurities are similar in structure to the drug substance, the achievement of chemo-selective conditions is usually challenging. Herein, a direct and highly selective ultra-high-performance liquid chromatographic method for determining the assay and related substances content in medicinal products containing rosuvastatin calcium salt (RSV) is presented. RSV is used to treat high cholesterol levels and prevent heart attacks and strokes. The most engaging feature of this method was the baseline separation of all organic related substances listed in the European Pharmacopoeia (EP) monograph for the RSV tablets, achieved for the first time in less than 15 min using the Acquity BEH C18 (100 mm × 2.1 mm, 1.7 μm) column under reversed-phase isocratic conditions. The mobile phase adopted for the chemo-selective analysis does not contain buffers but instead contains trifluoroacetic as an acid additive. The chromatographic method was validated according to the guidelines of the International Conference on Harmonization (ICH) and proved to be linear, precise and accurate for determining the content of RSV and related chiral substances in tablet formulations