An Electron Microscopic Study of the Intestinal Villus: II. The Pathway of Fat Absorption
TL;DR: The intestinal pathway for absorbed fat was traced in thin sections of intestinal villi from rats fed corn oil by stomach tube after a fast of 24 to 40 hours, and it is impossible to evaluate from the electron microscopic evidence thus far available the quantitative importance of particulate fat absorption by the mechanism described.
Abstract: The intestinal pathway for absorbed fat was traced in thin sections of intestinal villi from rats fed corn oil by stomach tube after a fast of 24 to 40 hours. For electron microscopy the tissues were fixed in chilled buffered osmium tetroxide and embedded in methacrylate. For light microscopy, other specimens from the same animals were fixed in formal-calcium, mordanted in K2Cr2O7, and embedded in gelatin. Frozen sections were stained with Sudan black B or Sudan IV. About 20 minutes after feeding, small fat droplets (65 mµ maximal diameter) appear in the striated border between microvilli. At the same time fat particles are seen within pinocytotic vesicles in the immediately subjacent terminal web. In later specimens the fat droplets are generally larger (50 to 240 mµ) and lie deeper in the apical cytoplasm. All intracellular fat droplets are loosely enveloped in a thin membrane, the outer surface of which is sometimes studded with the fine particulate component of the cytoplasm. This envelope, apparently derived from the cell surface by pinocytosis, has at this stage evidently become a part of the endoplasmic reticulum. Just above the nucleus numerous fat droplets lie clustered within the dilated cisternae of the Golgi complex. As absorption progresses fat droplets appear in the intercellular spaces of the epithelium, in the interstitial connective tissue spaces of the lamina propria, and in the lumen of the lacteals. All of these extracellular fat droplets are devoid of a membranous envelope. The picture of fat absorption as reconstructed from these studies involves a stream of fat droplets filtering through the striated border, entering the epithelial cell by pinocytosis at the bases of the intermicrovillous spaces, and coursing through the endoplasmic reticulum to be discharged at the sides of the epithelial cell into extracellular spaces. From the epithelial spaces, the droplets move into the lamina propria and thence into the lymph. If the lumen of the endoplasmic reticulum is considered as continuous with the extracellular phase, then the entire pathway of fat absorption may be regarded as extracellular. However, it is impossible to evaluate from the electron microscopic evidence thus far available the quantitative importance of particulate fat absorption by the mechanism described.
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1,417 citations
TL;DR: The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology where required.
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
1,201 citations
Cites background from "An Electron Microscopic Study of th..."
..., 1971) or via transcellular transport within vesicles (Palay and Karlin, 1959; Papp et al., 1962; Dobbins and Rollins, 1970; Dobbins, 1971; Dixon et al., 2009)....
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...…open intercellular gaps (Palay and Karlin, 1959; Casley-Smith, 1962; Papp et al., 1962; Ladman et al., 1963; Rubin, 1966; Tytgat et al., 1971) or via transcellular transport within vesicles (Palay and Karlin, 1959; Papp et al., 1962; Dobbins and Rollins, 1970; Dobbins, 1971; Dixon et al., 2009)....
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...Nonetheless, numerous studies have shown chylomicron entry into lacteals either via paracellular transport through open intercellular gaps (Palay and Karlin, 1959; Casley-Smith, 1962; Papp et al., 1962; Ladman et al., 1963; Rubin, 1966; Tytgat et al., 1971) or via transcellular transport within…...
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...Nonetheless, numerous studies have shown chylomicron entry into lacteals either via paracellular transport through open intercellular gaps (Palay and Karlin, 1959; Casley-Smith, 1962; Papp et al., 1962; Ladman et al., 1963; Rubin, 1966; Tytgat et al., 1971) or via transcellular transport within vesicles (Palay and Karlin, 1959; Papp et al....
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01 Jan 1966
437 citations
TL;DR: In this article, it was shown that the hairlike projections are actually the superimposed visual images of the regular hexagons and pentagons of the network composing the basketwork.
Abstract: Five points are discussed regarding the vesicular structure isolated by fractionation techniques from the brain and liver of the guinea pig. 1. One type of vesicle, fixed by OsO4 and shown in thin sections, is identified with the coated vesicle that has been observed in many varieties of tissues. 2. The vesicle contained in a spherical polygonal "basketwork" shown by the negative-staining techniques is identical with the coated vesicle shown in sections. 3. Despite minute observation of this basketwork we could not confirm the existence of "hairlike projections" extending from the convex cytoplasmic surface of the vesicle. We are inclined to believe, therefore, that the hairlike projections are actually the superimposed visual images of the regular hexagons and pentagons of the network composing the basketwork. 4. We repeat the hypothesis originally advanced by Roth and Porter (1) that the "coating" of the coated vesicle plays a role in the mechanism of the infolding and fission of the membrane; we suggest that these events are caused by the transformation of the regular hexagons (of the coating) into regular pentagons. 5. Finally, we make a suggestion as to the nature of those vesicles which have on their surface subparticles which look like "elementary particles (2)."
422 citations
References
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01 Jan 1962
TL;DR: The cell Epithelium Glands and secretion Blood Connective tissue proper Adipose tissue Cartilage Bone Bone marrow and blood cell formation Muscular tissue The nervous tissue, Jay B. Angevine
Abstract: The cell Epithelium Glands and secretion Blood Connective tissue proper Adipose tissue Cartilage Bone Bone marrow and blood cell formation Muscular tissue The nervous tissue, Jay B. Angevine Blood and lymph vascular systems The immune system, Elio Raviola Thymus, Elio Raviola Lymph nodes, Elio Raviola Spleen, Elio Raviola Hypophysis The thyroid gland Parathyroid glands Adrenal glands and paraganglia Pineal gland Skin Oral cavity and associated glands The teeth The oesophagus and stomach Intestines The liver and gall-bladder Pancreas Respiratory system The urinary system Male reproductive system Female reproductive system Mammary gland The eye The ear.
2,397 citations
TL;DR: In the Discussion an attempt is made to integrate the observations presented in this paper with the already available cytological, histochemical, and cytochemical information.
Abstract: A particulate component of small dimensions (100 to 150 A) and high density is described in the ground substance of the cytoplasm of mammalian and avian cells. In many cell types that seem to have in common a high degree of differentiation, the new component is preferentially associated with the membrane of the endoplasmic reticulum; whereas in other cell types, characterized by rapid proliferation, it occurs more or less freely distributed in the ground substance of the cytoplasm. In the Discussion an attempt is made to integrate the observations presented in this paper with the already available cytological, histochemical, and cytochemical information.
840 citations
TL;DR: Porter's studies established a number of other important features for the new cytoplasmic component, namely the usual continuity of the system throughout the endoplasm of normal cells, the remarkable polymorphism of its component elements, and the breaking down of the entire system in cytolysis into a collection of isolated vesicles.
Abstract: and (b) the vesicular character of its component elements, were already clearly noted in its first description. In subsequent papers, Porter and his collaborators described the preferential concentration of the vesicular elements of the reticulum in the endoplasm, and their scarcity or absence in the supposedly exoplasmic periphery of the cytoplasm (2, 3), a finding which eventually led to the selection of "endoplasmic reticulum" as a name for the system. The term was first cautiously tried in a caption in 1948 (3) and finally used in an article published by Porter and Kallman in 1952 (4). It appears that, at that time, our group was not yet engaged in large scale production of new cytological terms with a heavy Latin flavor, and was still proceeding with cautious restraint in matters of nomenclature. Besides the reticular disposition and the endoplasmic location implied in the name, Porter's studies established a number of other important features for the new cytoplasmic component, namely the usual continuity of the system throughout the endoplasm of normal cells, the remarkable polymorphism of its component elements, and the breaking down of the entire system in cytolysis into a collection of isolated vesicles.
695 citations
TL;DR: Cells of onion and garlic root tips were examined under the electron and phase contrast microscopes after fixation in KMnO4 to focus on the distribution and behavior of the endoplasmic reticulum (ER) during the several phases of mitosis.
Abstract: A survey of a large number of different cell types has indicated the presence of a network of membrane-bound cavities (the endoplasmic reticulum) in the cytoplasm of all cell types examined, with the exception of the mature erythrocyte. In its simplest form, encountered in seminal epithelia and in leucocytes, the reticulum consists mainly of interconnected strings of vesicles and appears to be randomly disposed in three dimensions. Local differentiations occur within the endoplasmic reticulum of all the cell types studied. The membrane limiting the cavities of the endoplasmic reticulum appears to be continuous with the cell membrane and the nuclear membranes.
473 citations
TL;DR: The hypothesis that membrane flow may be an important part of a type of active transport mechanism carrying particles, including ions, along, within, into, and out of cells is introduced.
Abstract: Dr. Palade has shown that in many cells the cell membrane is infolded extensively and that such folds may carry the cell membrane to positions deep in the cell. Moreover, he has shown that such deep folds often appear to lie close to isolated vesicles in the cytoplasm. Dr. Palade has pointed out that such vesicles are often arranged so as to suggest that they might have formed from the pinching off of a recessed tip of such a fold, or that they might represent vesicles destined to coalesce with such a recessed fold. Dr. Palade referred to the classical paper on pinocytosis by Lewis (8). Lewis showed cells in which the cell surface and adjacent cytoplasm were in a state of vigorous activity, with an orderly flow of granules and vesicles from one portion of a cell to another. Similar activity and orderly movements within cells have been demonstrated by Gey, Shapras, and Borysko (6), by Frederic and Ch~vremont (5), and by Blandau, De Marsh, and Ralph (1). Dr. Palade's pictures suggest that in such cells as macrophages, in which pinocytosis and orderly flow of cytoplasmic particles are evident, the cytoplasmic membranes of the endoplasmic reticulum, particularly those components representing membranes folded inwards from the outer cell border, might participate in or even mediate these activities. I would like to introduce the hypothesis that membrane flow may be an important part of a type of active transport mechanism carrying particles, including ions, along, within, into, and out of cells. If membrane is being formed or synthesized in one region, and is being broken down or enzymatically destroyed at another, it would be expected to flow from the membrane source to the membrane sink or site of breakdown. If the source is at the exposed cell surface, as at A and A' in Fig. 1, and the sink is deep in the cell as at B (Fig. 1), the membrane would flow from the surface to a position deep in the recess as indicated by the arrows. A membrane flow in the reverse direction would result from a source at the tip of the recess at B and a sink on the surface at A or A'. Membranes entirely within the cell or entirely on the exposed cell surface or extending through the cell as tunnels or slits could be envisioned as similarly motivated to flow from sources to appropriately placed sinks. The energy required for such kinesis would be provided by oxidative mechanisms in the cell. 99
429 citations