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1. Inhibition of Bruton's tyrosine kinase regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation

Author

Purvis, GSD, Collino, M, Aranda-Tavio, H, Chiazza, F, O'Riordan, CE, Zeboudj, L, Mohammad, S, Collotta, D, Verta, R, Guisot, NES, Bunyard, P, Yaqoob, MM, Greaves, DR, and Thiemermann, C

Abstract

Background and Purpose Currently there are limited medicines available for the treatment of metabolic inflammation in diseases such as obesity and type 2 diabetes (T2D). Although initially associated with B‐ells, Bruton's tyrosine kinase (BTK) is present in a wide variety of cells including monocytes and macrophages, and has been implicated in the regulation of the NF‐κB and NLRP3 inflammasome activity. Experimental Approach Using in vivo models of chronic inflammation [high‐fat‐diet (HFD) feeding] and in vitro assays in primary murine and human macrophages we investigated if ibrutinib, an FDA approved medicine that targets BTK, may represent a novel anti‐inflammatory drug for the use in treating metabolic inflammation. Key results HFD feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue and kidney. Treatment of mice fed HFD with ibrutinib inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue and kidney. Reduced inflammatory gene expression associated with decreased activation of NF‐κB and the NLRP3 inflammasome in vivo. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS‐1/Akt/GSK‐3β pathway; protecting mice against the development of hepatosteatosis and proteinuria. We show that inhibition of BTK reduces activation of NF‐κB and the NLRP3 inflammasome specifically in primary murine and human macrophages; which are the primary target of ibrutinib in vivo in the setting of metabolic inflammation. Conclusions and Implications In the present study we provide ‘proof of concept' evidence that BTK is a novel therapeutic target for the treatment of diet ‐metabolic inflammation. Ibrutinib may be a candidate for drug repurposing as an anti‐inflammatory for the treatment of metabolic inflammation in T2D and microvascular disease.

Published
2020

8. Histologic type of lung cancer and asbestos exposure

Author

Verta R. Parks, Vincent A. Galdi, Lou Jouberti, Oscar Auerbach, Lawrence Garfinkel, and Alfred S. Conston

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Lung, business.industry, Cancer, Autopsy, medicine.disease, medicine.disease_cause, Small-cell carcinoma, Asbestos, medicine.anatomical_structure, Oncology, Histologic type, Medicine, Basal cell, business, Lung cancer
Abstract

The histologic types of lung cancer in 855 patients (747 men and 107 women) from three hospitals and one international study of insulation workers were evaluated. Of these, 196 cases had asbestos exposure. About one half of the cases were diagnosed from surgical slides and one half from autopsy slides. Squamous cell carcinoma constituted the largest percentage of tumor types and was found with the same frequency in exposed and nonexposed groups. Small cell carcinoma was found in 25% of the exposed and in 15% of the nonexposed patients. Upper lung sites were involved in about two thirds of the cases with asbestos exposure and lower lobes in the other one third. There was little difference in histologic type in cases regardless of whether upper or lower lobes were involved. Cigarette smokers who smoked until their cancer diagnosis showed no difference in histologic type by amount smoked, and slight but not statistically significant differences from ex-cigarette smokers.

Published
1984

9. Scar cancer of the lung.Increase over a 21 year period

Author

Verta R. Parks, Oscar Auerbach, and Lawrence Garfinkel

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Tuberculosis, Lung, business.industry, Large cell, Period (gene), Scars, Cancer, medicine.disease, medicine.anatomical_structure, Oncology, Oat cell, medicine, medicine.symptom, business, Lung cancer
Abstract

In a review of 1,186 cases of lung cancer found amoung 7,629 autopsied cases over a 21 year period a total of 82 peripheral cancers related to scars were found, constituting 1% of the autopsied cases and 7% of the lung tumors. 15% of all lung tumors were peripheral (vs. bronchogenic) and the percentage rose from less than 7 in the time period of 1955 to 1960 to a little more than 23 in the 1970 to 1976 time period. 45% of all peripheral lung cancers originated in a scar. Less than 2% of all lung cancers were found associated with scars in the 1955 through 1959 time period. This increased to nearly 16% in the 1970 through 1975 time period. 72% of the scar cancers were adenocarcinomas and 18% were of squamous cell type. The rest were large cell undifferentiated carcinomas and none was oat cell or small cell type. Over three-quarters of these scar cancers were found in the upper lobes and more than half were related to infarcts. Less than a quarter were related to tuberculosis scars. No relationship was found between smoking habits and scar cancer.

Published
1979

10. A comparison of world health organization (WHO) classification of lung tumors by light and electron microscopy

Author

Verta R. Parks, Julio M. Frasca, Oscar Auerbach, and Harry W. Carter

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Lung, Poorly differentiated, Biology, World health, Well differentiated, law.invention, medicine.anatomical_structure, Oncology, law, medicine, Ultrastructure, Lung tumor, Electron microscope, Who classification
Abstract

Forty-nine cases of lung tumor were initially classified according to the World Health Organization (WHO) system by light microscopy. Additional study by electron microscopy using only a minimum of ultrastructural features as criteria for each type made more precise classification of some of the poorly differentiated or undifferentiated tumors possible. Most significant was the finding of evidence of a second tumor type in nine of the 35 tumors previously classified as moderately to well differentiated thus reclassifying them as mixed tumors. Sixteen of the 49 tumors were reclassified and a more precise classification was made in five others. Only two cases of undifferentiated small cell tumors were available and no unequivocal neurosecretory granules could be found in either. Correlation of the more precise typing of lung tumors by electron microscopy with the clinical data and modes of therapy will provide necessary information for determining the usefulness of the WHO classification.

Published
1982

11. Presence of Asbestos Bodies in Organs Other than the Lung

Author

Verta R. Parks, Hammond Ec, A S Conston, Lawrence Garfinkel, Oscar Auerbach, and H D Kaslow

Subjects
Male, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Asbestosis, Autopsy, Kidney, Critical Care and Intensive Care Medicine, medicine.disease_cause, Asbestos, Humans, Medicine, Tissue Distribution, Mesothelioma, Occupations, Lung cancer, Lung, Pancreas, Aged, Histocytochemistry, business.industry, Myocardium, Kidney metabolism, Environmental Exposure, Environmental exposure, Middle Aged, respiratory system, medicine.disease, respiratory tract diseases, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, business, Spleen
Abstract

This study was designed to test the hypothesis that subjects with many asbestos bodies in their lungs at autopsy would also have asbestos bodies in various other organs. The subjects included 19 cases with diagnosis of asbestosis at death (two of these had mesothelioma, five had lung cancer) and 18 with pleural plaques but not asbestosis. Occupational histories were obtained from relatives. In subjects occupationally exposed to asbestos, large numbers of asbestos bodies were found in the lungs, and in most of these, asbestos bodies were found in many of the other organs examined. In the 18 cases with only pleural plaques found at autopsy, considerably fewer asbestos bodies were found in the lungs. The number of other organs with one or more asbestos bodies ranged from 32 percent to 62 percent of the sites examined. The findings seem to confirm the hypothesis of the study.

Published
1980

12. Electron microscopic observations of the bronchial epithelium of dogs

Author

James D. Jamieson, Oscar Auerbach, Verta R. Parks, and Julio M. Frasca

Subjects
Cuboidal Cell, Basement membrane, Cell type, Pathology, medicine.medical_specialty, Clinical Biochemistry, Cell, Biology, Epithelium, Pathology and Forensic Medicine, medicine.anatomical_structure, Cytoplasm, Organelle, medicine, Respiratory epithelium, Molecular Biology
Abstract

Changes are noted in the bronchial epithelium of dogs subjected to 44 and more than 420 days of experimental cigarette smoke inhalation. At the early time point goblet cells are more numerous and the surface lining cells possess fewer cilia. By 420 days the apparent number of cell layers in the epithelium is double that of the controls. The luminal surface is devoid of ciliated columnar cells and goblet cells, these being replaced by columnar and cuboidal cells whose free surface is covered by stubby projections. Basal cells are frequently columnar-shaped and mitotic figures are common. Most cells contain a profusion of cytoplasmic filaments which often appear to displace cell organelles. A “special type cell” with cell-specific granules, first described in the control, is found in great abundance in the intermediate region between the basal cells and the surface lining cells. In both osmium- and acrolein-fixed tissue the two special migratory cell types, which are so common in the controls, are rarely seen. The basement membrane is frequently interrupted by gaps through which cytoplasmic processes of basal cells protrude; a thickened zone underlying the basement membrane contains an increase in fibrillar components and multiple layers of basement membrane material.

Published
1968

13. Electron microscope observations of nuclear evaginations in bronchial epithelium

Author

Oscar Auerbach, Walther Stoeckenius, Verta R. Parks, and Julio M. Frasca

Subjects
Cell Nucleus, Microscopy, Clinical Biochemistry, Bronchi, Electrons, Vacuole, Anatomy, Biology, Epithelium, Pathology and Forensic Medicine, law.invention, Microscopy, Electron, Cell nucleus, medicine.anatomical_structure, Membrane, Evagination, Geriatrics, law, Cytoplasm, medicine, Biophysics, Electron microscope, Molecular Biology, Nucleus
Abstract

Evaginations or blebs involving both layers of the nuclear envelope were observed in ciliated columnar cells of the bronchial epithelium obtained from four patients during lobectomies. These are visible with the light microscope as supranuclear vacuoles. In adjacent sections electron micrographs showed the “vacules” to be bounded by “double membranes” identical in appearance to, and in some instances continuous, with the nuclear envelope. Nuclear components extend from the nucleus into the evagination. In some cells multiple evaginations extend in a row. These may be interconnected, or only the most proximal one may be continuous with the nucleus. In some evaginations, appearing at a distance from the nucleus and with no apparent attachment to it, breakdown of the enclosing envelope suggests the possible dissolution of the entire structure into the cytoplasm thus providing a means of transfer of nuclear material.

Published
1965

15. Electron microscopic observations of bronchial epithelium

Author

Verta R. Parks, Oscar Auerbach, Julio M. Frasca, and Walther Stoeckenius

Subjects
Annulate lamella, Cilium, Endoplasmic reticulum, Cell, Clinical Biochemistry, Abnormal cell, Anatomy, Biology, Epithelium, Cell biology, Apex (geometry), Pathology and Forensic Medicine, medicine.anatomical_structure, Ciliated columnar, Cytoplasm, Ciliogenesis, Organelle, medicine, Nucleus, Molecular Biology, Electron microscopic, Bronchial epithelium
Abstract

Moderately electron-dense bodies without a limiting membrane and having a diameter of approximately 700A were observed in the cytoplasm of ciliated columnar cells in the bronchial epithelium of man. They seem to consist of aggregates of coiled filaments about 25A thick and have been termed “filosomes.” Filosomes, singly, in small groups, or in larger clusters, were found randomly distributed throughout the cytoplasm between the nucleus and the cell apex and were sometimes associated with structures resembling components of cilia. By site, the filosomes were associated with many cell organelles, especially the nucleus, and their consistont occurrence with annulate lamellae was specifically noted. The similarity of the material of the filosomes to that of structures which have been shown by others to be involved in ciliogenesis suggests a similar role for filosomes.

Published
1967

16. Electron microscopic observations on pulmonary fibrosis and emphysema in smoking dogs

Author

Julio M. Frasca, Oscar Auerbach, Verta R. Parks, and James D. Jamieson

Subjects
Pathology, medicine.medical_specialty, Pulmonary Fibrosis, Alveolar Epithelium, Clinical Biochemistry, Cytoplasmic Granules, Pathology and Forensic Medicine, Dogs, Stroma, Fibrosis, Pulmonary fibrosis, Parenchyma, medicine, Animals, Lung, Molecular Biology, Basement membrane, Inhalation, Chemistry, Macrophages, Smoking, Anatomy, respiratory system, medicine.disease, respiratory tract diseases, Pulmonary Alveoli, Microscopy, Electron, medicine.anatomical_structure, Pulmonary Emphysema, Cytoplasm
Abstract

Electron microscopic observations in areas of fibrosis and emphysema of the lungs of dogs subjected to experimental cigarette smoking show that alterations occur both in the pleura and the lung parenchyma. In the pleura the major alteration is the increased thickness of the stroma due to large amounts of collagen present. In the lung parenchyma two major alterations appear in the interstitium of the alveolar septa where there is a complete loss or a great reduction in the number of capillaries and a marked thickening of the septa due to the increased amounts of collagen. Changes in the alveolar epithelium are slight; changes in capillary endothelium, such as rarefication of cytoplasm and blebbing of the plasmalemma, are found. More frequently noted are the changes involving the basement membrane of the alveolar epithelium which in some places appear to be greatly thickened and in others to be exceptionally thin or missing entirely. Another of the most striking alterations noted in both the pleura and parenchyma is the presence of large numbers of macrophages occurring singly, in clumps, and in granulomas. Although macrophages are found in the lungs of nonsmoking dogs they are not found in such numbers nor with the unique content observed in the lungs of smoking dogs. Crystalline-like structures are found in membrane-bound inclusions and ferritin-like particles occur both in large membrane-bound aggre-gates and lying free in the cytoplasm. Conclusive identification of these structures and their relationship to inhalation of cigarette smoke requires further study.

Published
1971

17. Presence of Asbestos Bodies in Organs Other than the Lung

Author

Auerbach, Oscar, Conston, Alfred S., Garfinkel, Lawrence, Parks, Verta R., Kaslow, Haven D., and Hammond, E. Cuyler

Abstract

This study was designed to test the hypothesis that subjects with many asbestos bodies in their lungs at autopsy would also have asbestos bodies in various other organs. The subjects included 19 cases with diagnosis of asbestosis at death (two of these had mesothelioma, five had lung cancer) and 18 with pleural plaques but not asbestosis. Occupational histories were obtained from relatives. In subjects occupationally exposed to asbestos, large numbers of asbestos bodies were found in the lungs, and in most of these, asbestos bodies were found in many of the other organs examined. In the 18 cases with only pleural plaques found at autopsy, considerably fewer asbestos bodies were found in the lungs. The number of other organs with one or more asbestos bodies ranged from 32 percent to 62 percent of the sites examined. The findings seem to confirm the hypothesis of the study.

Published
1980
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18. Histologic Type of Lung Cancer in Relation to Smoking Habits, Year of Diagnosis and Sites of Metastases

Author

Auerbach, Oscar, Garfinkel, Lawrence, and Parks, Verta R.

Abstract

A study was made of histologic type of lung cancer in relation to smoking habit, year of diagnosis, age and sites of metastasis. It comprised 662 autopsies of men during the period from 1955 to 1972. As classified by the WHO system, 35.2 percent were epidermoid carcinoma, 24.6 percent were small cell carcinoma, 25.2 percent were adenocarcinoma and 14.2 percent were large cell undifferentiated carcinoma. The six non-smokers of the series were all found to be in class 3, adenocarcinoma. No clearcut and consistent relationships were observed. Although there was a steady decrease in the incidence of small cell carcinoma during this time period, this observation did not prove to be statistically significant. Small cell carcinomas increased with amount of smoking but not for all age groups. Adenocarcinomas decreased with advancing age but not in all smoking groups. Metastases were found in 96.3 percent of the cases and the sites most frequently involved were regional lymph nodes, liver, brain, distant lymph nodes, adrenals and bone. Small cell carcinomas showed the greatest percentage of involvement for those major sites and for the same sites, epidermoid carcinoma showed the lowest percentage.

Published
1975
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20. Alveolar cell hyperplasia in the lungs of smoking dogs

Author

James D. Jamieson, Oscar Auerbach, Verta R. Parks, and Julio M. Frasca

Subjects
Pathology, medicine.medical_specialty, Cytoplasm, Alveolar Epithelium, Clinical Biochemistry, Connective tissue, Bronchi, Biology, Epithelium, Pathology and Forensic Medicine, Alveolar cells, Dogs, Parenchyma, medicine, Animals, Molecular Biology, Hyperplasia, Smoking, Epithelial Cells, respiratory system, medicine.disease, Pulmonary Alveoli, medicine.anatomical_structure, Basal lamina, Stem cell
Abstract

Hyperplasia of bronchiolar epithelium was observed in the lung parenchyma of 14 smoking dogs. Besides the increased number of cell layers in the bronchiolar epithelium, there was a virtual absence of glycogen in the cell cytoplasm. Sheetlike arrangements of squamous cells containing an abundance of tonofilament bundles were found lining alveoli. Type II cells were found adjacent to, and sometimes extending over the squamous cells. In all cases, a proliferation of type II cells was found in the alveolar epithelium, almost completely lining some alveoli. Acinarlike structures also lined by many type II cells were sometimes found near the pleura. Microinvasions of cytoplasmic processes into the underlying connective tissue often occurred through defects in the basal lamina. In some type II cells an unusual content of RER was observed. It possessed electron dense banding ≈ 180 A wide with a repeat at intervals of ≈ 540 A and was found in narrow cisternae and in bulbous dilatations of the cisternae of the RER. Fibrogranular material of the same appearance and periodicity was also found in the perinuclear space in some cells. Type II cells are further implicated as a reserve cell or stem cell in metaplastic alterations.

Published
1974

21. Histologic type of lung cancer in relation to smoking habits, year of diagnosis and sites of metastases

Author

Oscar Auerbach, Verta R. Parks, and Lawrence Garfinkel

Subjects
Pulmonary and Respiratory Medicine, Male, Pathology, medicine.medical_specialty, Lung Neoplasms, Adrenal Gland Neoplasms, Bone Neoplasms, Adenocarcinoma, Critical Care and Intensive Care Medicine, Small-cell carcinoma, Metastasis, medicine, Carcinoma, Humans, Neoplasm Metastasis, Lung cancer, Aged, business.industry, Brain Neoplasms, Incidence (epidemiology), Large cell, Splenic Neoplasms, Liver Neoplasms, Smoking, Age Factors, Middle Aged, medicine.disease, Pancreatic Neoplasms, Epidermoid carcinoma, Lymphatic Metastasis, Carcinoma, Squamous Cell, Autopsy, Cardiology and Cardiovascular Medicine, business
Abstract

A study was made of histologic type of lung cancer in relation to smoking habit, year of diagnosis, age and sites of metastasis. It comprised 662 autopsies of men during the period from 1955 to 1972. As classified by the WHO system, 35.2 percent were epidermoid carcinoma, 24.6 percent were small cell carcinoma, 25.2 percent were adenocarcinoma and 14.2 percent were large cell undifferentiated carcinoma. The six non-smokers of the series were all found to be in class 3, adenocarcinoma. No clearcut and consistent relationships were observed. Although there was a steady decrease in the incidence of small cell carcinoma during this time period, this observation did not prove to be statistically significant. Small cell carcinomas increased with amount of smoking but not for all age groups. Adenocarcinomas decreased with advancing age but not in all smoking groups. Metastases were found in 96.3 percent of the cases and the sites most frequently involved were regional lymph nodes, liver, brain, distant lymph nodes, adrenals and bone. Small cell carcinomas showed the greatest percentage of involvement for those major sites and for the same sites, epidermoid carcinoma showed the lowest percentage.

Published
1975

26. Phenotypic and functional characterization of aqueous humor derived extracellular vesicles.

Author

Verta R, Saccu G, Tanzi A, Grange C, Buono L, Fagoonee S, Deregibus MC, Camussi G, Scalabrin S, Nuzzi R, and Bussolati B

Subjects
Humans, Aqueous Humor, Microscopy, Electron, Tetraspanins, Extracellular Vesicles metabolism, Mesenchymal Stem Cells
Abstract

Extracellular vesicles (EVs) are double membrane vesicles, abundant in all biological fluids. However, the characterization of EVs in aqueous humor (AH) is still limited. The aim of the present work was to characterize EVs isolated from AH (AH-EVs) in terms of surface markers of cellular origin and functional properties. We obtained AHs from patients with cataract undergoing surgical phacoemulsification and insertion of intraocular lenses (n = 10). Nanoparticle tracking analysis, electron microscopy, super resolution microscopy and bead-based cytofluorimetry were used to characterize EVs from AH. Subsequently, we investigated the effects of AH-EVs on viability, proliferation and wound healing of human immortalized keratinocyte (HaCaT) cells in vitro in comparison with the effect of mesenchymal stromal cell-EVs (MSC-EVs). AH-EVs had a mean size of around 100 nm and expressed the classical tetraspanins (CD9, CD63 and CD81). Super resolution microscopy revealed co-expression of CD9, CD63 and CD81. Moreover, cytofluorimetric analysis highlighted the expression of mesenchymal, stem, epithelial and endothelial markers. In the in vitro wound healing assay on HaCaT cells, AH-EVs induced a significantly faster wound repair, comparable to the effects of MSC-EVs, and promoted HaCaT cell viability and proliferation. We provide evidence, herein, of the possible AH-EV origin from stromal cells, limbal epithelial/stem cells, ciliary epithelium and corneal endothelium. In addition, we showed their in vitro proliferative and regenerative capacities., Competing Interests: Declaration of competing interest All authors declared that there are no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Published
2023
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27. Generation of Spike-Extracellular Vesicles (S-EVs) as a Tool to Mimic SARS-CoV-2 Interaction with Host Cells.

Author

Verta R, Grange C, Skovronova R, Tanzi A, Peruzzi L, Deregibus MC, Camussi G, and Bussolati B

Subjects
Angiotensin-Converting Enzyme 2 immunology, Antibodies, Blocking pharmacology, COVID-19 virology, Cell Line, Cells, Cultured, Colchicine pharmacology, Flow Cytometry methods, HEK293 Cells, Host Microbial Interactions drug effects, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells virology, Humans, Microscopy, Fluorescence methods, Protein Binding drug effects, SARS-CoV-2 physiology, COVID-19 metabolism, Extracellular Vesicles metabolism, SARS-CoV-2 metabolism, Spike Glycoprotein, Coronavirus metabolism
Abstract

Extracellular vesicles (EVs) and viruses share common features: size, structure, biogenesis and uptake. In order to generate EVs expressing the SARS-CoV-2 spike protein on their surface (S-EVs), we collected EVs from SARS-CoV-2 spike expressing human embryonic kidney (HEK-293T) cells by stable transfection with a vector coding for the S1 and S2 subunits. S-EVs were characterized using nanoparticle tracking analysis, ExoView and super-resolution microscopy. We obtained a population of EVs of 50 to 200 nm in size. Spike expressing EVs represented around 40% of the total EV population and co-expressed spike protein with tetraspanins on the surfaces of EVs. We subsequently used ACE2-positive endothelial and bronchial epithelial cells for assessing the internalization of labeled S-EVs using a cytofluorimetric analysis. Internalization of S-EVs was higher than that of control EVs from non-transfected cells. Moreover, S-EV uptake was significantly decreased by anti-ACE2 antibody pre-treatment. Furthermore, colchicine, a drug currently used in clinical trials, significantly reduced S-EV entry into the cells. S-EVs represent a simple, safe, and scalable model to study host-virus interactions and the mechanisms of novel therapeutic drugs.

Published
2022
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28. The Interplay between Histamine H 4 Receptor and the Kidney Function: The Lesson from H 4 Receptor Knockout Mice.

Author

Verta R, Gurrieri M, Borga S, Benetti E, Pollicino P, Cavalli R, Thurmond RL, Chazot PL, Pini A, Rosa AC, and Grange C

Subjects
Animals, Aquaporin 1 genetics, Aquaporin 2 genetics, Aquaporins genetics, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental pathology, Disease Models, Animal, Gene Expression Regulation genetics, Histamine genetics, Hyperglycemia pathology, Kidney physiology, Mice, Mice, Inbred NOD, Mice, Knockout, Sodium-Hydrogen Exchanger 3 genetics, Diabetes Mellitus, Experimental genetics, Hyperglycemia genetics, Kidney metabolism, Receptors, Histamine H4 genetics
Abstract

Previous studies implicated the histamine H 4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H 4 receptor knockout mice (H 4 R -/- ). Healthy and diabetic H 4 R -/- mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H 4 R -/- and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H 4 R -/- mice displayed a higher basal glycemia. H 4 R -/- mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H 4 R -/- mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H 4 R -/- mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H 4 R -/- mice. The AQP1 and AQP7 patterns were also different between H 4 R -/- and wild-type diabetic mice. The collected results highlight the role of the histamine H 4 receptor in the control of renal reabsorption processes, particularly albumin uptake.

Published
2021
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29. Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death.

Author

Di Pasqua LG, Berardo C, Cagna M, Verta R, Collotta D, Nicoletti F, Ferrigno A, Collino M, and Vairetti M

Subjects
Animals, Liver Transplantation, Male, Rats, Rats, Wistar, Reperfusion Injury etiology, Reperfusion Injury pathology, Tissue Donors, Cold Ischemia adverse effects, Death, Liver metabolism, Organ Preservation methods, Receptors, Metabotropic Glutamate antagonists & inhibitors, Reperfusion Injury prevention & control, Warm Ischemia adverse effects
Abstract

We previously demonstrated that the blockade of mGluR5 by 2-methyl-6(phenylethynyl)pyridine (MPEP) reduces both cold and warm ischemia/reperfusion injury. Here we evaluated whether MPEP reduces the hepatic preservation injury in rat livers from cardiac-death-donors (DCDs). Livers from DCD rats were isolated after an in situ warm ischemia (30 min) and preserved for 22 h at 4 °C with UW solution. Next, 10 mg/Kg MPEP or vehicle were administered 30 min before the portal clamping and added to the UW solution (3 µM). LDH released during washout was quantified. Liver samples were collected for iNOS, eNOS, NO, TNF-α, ICAM-1, caspase-3 and caspase-9 protein expression and nuclear factor-erythroid-2-related factor-2 (Nrf2) gene analysis. Lower LDH levels were detected in control grafts versus DCD groups. An increase in eNOS and NO content occurred after MPEP treatment; iNOS and TNF-α content was unchanged. ICAM-1 expression was reduced in the MPEP-treated livers as well as the levels of caspase-3 and caspase-9. Nrf2, oxidative stress-sensitive gene, was recovered to control value by MPEP. These results suggest that MPEP can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage. MPEP protects against apoptosis and increased eNOS, whose overexpression has been previously demonstrated to be protective in hepatic ischemia/reperfusion damage.

Published
2021
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30. Inhibition of Bruton's TK regulates macrophage NF-κB and NLRP3 inflammasome activation in metabolic inflammation.

Author

Purvis GSD, Collino M, Aranda-Tavio H, Chiazza F, O'Riordan CE, Zeboudj L, Mohammad S, Collotta D, Verta R, Guisot NES, Bunyard P, Yaqoob MM, Greaves DR, and Thiemermann C

Subjects
Animals, Glycogen Synthase Kinase 3 beta, Inflammation drug therapy, Macrophages, Male, Mice, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein, Inflammasomes, NF-kappa B
Abstract

Background and Purpose: There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF-κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet-induced obesity., Experimental Approach: Using an in vivo model of chronic inflammation, high-fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti-inflammatory medication to treat metabolic inflammation., Key Results: HFD-feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD-fed mice decreased the activation of NF-κB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS-1/Akt/GSK-3β pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF-κB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib., Conclusion and Implications: We provide "proof of concept" evidence that BTK is a novel therapeutic target for the treatment of diet-induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti-inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease., (© 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Published
2020
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31. Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.

Author

Collotta D, Hull W, Mastrocola R, Chiazza F, Cento AS, Murphy C, Verta R, Alves GF, Gaudioso G, Fava F, Yaqoob M, Aragno M, Tuohy K, Thiemermann C, and Collino M

Subjects
Animals, Anti-Inflammatory Agents pharmacology, Biomarkers, Disease Models, Animal, Energy Metabolism drug effects, Gastrointestinal Microbiome drug effects, Glucose metabolism, Immunohistochemistry, Inflammation drug therapy, Inflammation etiology, Inflammation metabolism, Insulin metabolism, Janus Kinase 2 metabolism, Male, Metabolic Diseases diagnosis, Metabolic Diseases drug therapy, Mice, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal drug effects, Muscle, Skeletal metabolism, STAT Transcription Factors metabolism, Signal Transduction drug effects, Azetidines pharmacology, Diet, High-Fat adverse effects, Janus Kinase Inhibitors pharmacology, Metabolic Diseases etiology, Metabolic Diseases metabolism, Purines pharmacology, Pyrazoles pharmacology, Sulfonamides pharmacology
Abstract

Objective: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as "metaflammation," which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model., Methods: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar)., Results: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood., Conclusions: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Published
2020
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32. Effects of Exogenous Dietary Advanced Glycation End Products on the Cross-Talk Mechanisms Linking Microbiota to Metabolic Inflammation.

Author

Mastrocola R, Collotta D, Gaudioso G, Le Berre M, Cento AS, Ferreira Alves G, Chiazza F, Verta R, Bertocchi I, Manig F, Hellwig M, Fava F, Cifani C, Aragno M, Henle T, Joshi L, Tuohy K, and Collino M

Subjects
Animals, Cytokines metabolism, Ghrelin metabolism, Glucagon-Like Peptide 1 metabolism, Glucose metabolism, Glycosylation, Inflammation Mediators metabolism, Insulin metabolism, Mice, Inbred C57BL, Muscle, Skeletal metabolism, Signal Transduction, Diet, Gastrointestinal Microbiome, Glycation End Products, Advanced adverse effects, Glycation End Products, Advanced metabolism, Inflammation etiology, Inflammation metabolism, Metabolic Diseases etiology, Metabolic Diseases metabolism
Abstract

Heat-processed diets contain high amounts of advanced glycation end products (AGEs). Here we explore the impact of an AGE-enriched diet on markers of metabolic and inflammatory disorders as well as on gut microbiota composition and plasma proteins glycosylation pattern. C57BL/6 mice were allocated into control diet (CD, n = 15) and AGE-enriched diet (AGE-D, n = 15) for 22 weeks. AGE-D was prepared replacing casein by methylglyoxal hydroimidazolone-modified casein. AGE-D evoked increased insulin and a significant reduction of GIP/GLP-1 incretins and ghrelin plasma levels, altered glucose tolerance, and impaired insulin signaling transduction in the skeletal muscle. Moreover, AGE-D modified the systemic glycosylation profile, as analyzed by lectin microarray, and increased Nε-carboxymethyllysine immunoreactivity and AGEs receptor levels in ileum and submandibular glands. These effects were associated to increased systemic levels of cytokines and impaired gut microbial composition and homeostasis. Significant correlations were recorded between changes in bacterial population and in incretins and inflammatory markers levels. Overall, our data indicates that chronic exposure to dietary AGEs lead to a significant unbalance in incretins axis, markers of metabolic inflammation, and a reshape of both the intestinal microbiota and plasma protein glycosylation profile, suggesting intriguing pathological mechanisms underlying AGEs-induced metabolic derangements.

Published
2020
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33. Transient Expression of Reck Under Hepatic Ischemia/Reperfusion Conditions Is Associated with Mapk Signaling Pathways.

Author

Ferrigno A, Di Pasqua LG, Palladini G, Berardo C, Verta R, Richelmi P, Perlini S, Collotta D, Collino M, and Vairetti M

Subjects
Animals, GPI-Linked Proteins metabolism, Male, Matrix Metalloproteinases metabolism, Nitric Oxide Synthase Type II metabolism, Nitric Oxide Synthase Type III metabolism, Rats, Wistar, Reperfusion Injury blood, Reperfusion Injury enzymology, Tissue Inhibitor of Metalloproteinases metabolism, Liver blood supply, Liver pathology, MAP Kinase Signaling System, Reperfusion Injury pathology, Tumor Suppressor Proteins metabolism
Abstract

In this study, we demonstrated the involvement of matrix metalloproteinases (MMPs) in hepatic ischemia/reperfusion (I/R) injury. Our aim is to evaluate the impact of reperfusion on I/R-related changes in RECK, an MMP modulator, and mitogen-activated protein kinase (MAPKs) pathways (ERK, p38, and JNK). Male Wistar rats were either subjected to 60 min partial-hepatic ischemia or sham-operated. After a 60 min or 120 min reperfusion, liver samples were collected for analysis of MMP-2 and MMP-9 by zymography and RECK, TIMP-1, and TIMP-2 content, MAPKs activation (ERK1/2, JNK1/2, and p38), as well as iNOS and eNOS by Western blot. Serum enzymes AST, ALT, and alkaline-phosphatase were quantified. A transitory decrease in hepatic RECK and TIMPs was associated with a transitory increase in both MMP-2 and MMP-9 activity and a robust activation of ERK1/2, JNK1/2, and p38 were detected at 60 min reperfusion. Hepatic expression of iNOS was maximally upregulated at 120 min reperfusion. An increase in eNOS was detected at 120 min reperfusion. I/R evoked significant hepatic injury in a time-dependent manner. These findings provide new insights into the underlying molecular mechanisms of reperfusion in inducing hepatic injury: a transitory decrease in RECK and TIMPs and increases in both MAPK and MMP activity suggest their role as triggering factors of the organ dysfunction., Competing Interests: The authors declare no conflict of interest.

Published
2020
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34. Histamine in the kidneys: what is its role in renal pathophysiology?

Author

Grange C, Gurrieri M, Verta R, Fantozzi R, Pini A, and Rosa AC

Subjects
Animals, Hemodynamics, Humans, Kidney, Histamine, Receptors, Histamine
Abstract

Starting with a role for histamine role in renal haemodynamics, evidence has accumulated, over time, suggesting a wider range of actions on renal function and this has renewed interest in the pathophysiological role of histamine in the kidney. Here we provide an up-to-date review of this topic. As the kidney expresses enzymes that synthesize and metabolise histamine, along with its receptors, all the components for histaminergic transmission are present in this tissue. The distribution of histamine receptors matches a wide range of effects. We address the questions of the redundancy of H 1 and H 2 receptors in renal haemodynamics, the complementary role of H 1 and H 4 receptors in renal filtration and reabsorption, and the dichotomy between local and neuronal H 1 and H 3 receptors. Experimental models of renal disease raise the possibility of new therapeutic approaches based on histamine. The effects of histamine on renal function are not yet fully understood and their elucidation is still ongoing. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc., (© 2019 The British Pharmacological Society.)

Published
2020
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35. Effect of Bilastine on Diabetic Nephropathy in DBA2/J Mice.

Author

Verta R, Grange C, Gurrieri M, Borga S, Nardini P, Argenziano M, Ghè C, Cavalli R, Benetti E, Miglio G, Bussolati B, Pini A, and Rosa AC

Subjects
Animals, Benzimidazoles pharmacology, Histamine H1 Antagonists pharmacology, Kidney drug effects, Kidney physiopathology, Kidney ultrastructure, Male, Mice, Mice, Inbred DBA, Piperidines pharmacology, Benzimidazoles therapeutic use, Diabetic Nephropathies drug therapy, Histamine H1 Antagonists therapeutic use, Piperidines therapeutic use
Abstract

Diabetic nephropathy is an unmet therapeutic need, and the search for new therapeutic strategies is warranted. Previous data point to histamine H 1 receptor as a possible target for glomerular dysfunction associated with long term hyperglycaemia. Therefore, this study investigated the effects of the H 1 receptor antagonist bilastine on renal morphology and function in a murine model of streptozotocin-induced diabetes. Diabetes was induced in DBA2/J male mice and, from diabetes onset (glycaemia ≥200 mg/dL), mice received bilastine (1-30 mg/kg/day) by oral gavage for 14 consecutive weeks. At the end of the experimental protocol, diabetic mice showed polyuria (+195.5%), increase in Albumin-to-Creatine Ratio (ACR, +284.7%), and a significant drop in creatinine clearance ( p < 0.05). Bilastine prevented ACR increase and restored creatinine clearance in a dose-dependent manner, suggesting a positive effect on glomerular filtration. The ultrastructural analysis showed a preserved junctional integrity. Preservation of the basal nephrin, P-cadherin, and synaptopodin expression could explain this effect. In conclusion, the H 1 receptor could contribute to the glomerular damage occurring in diabetic nephropathy. Bilastine preserved the glomerular junctional integrity, leading to the hypothesis of anti-H 1 antihistamines as a possible add-on therapy for diabetic nephropathy.

Published
2019
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36. Histamine and diabetic nephropathy: an up-to-date overview.

Author

Pini A, Verta R, Grange C, Gurrieri M, and Rosa AC

Subjects
Animals, Blood Vessels physiopathology, Diabetic Angiopathies physiopathology, Diabetic Nephropathies pathology, Diabetic Nephropathies physiopathology, Fibrosis, Humans, Kidney pathology, Kidney physiopathology, Renal Reabsorption, Signal Transduction, Blood Vessels metabolism, Diabetic Angiopathies metabolism, Diabetic Nephropathies metabolism, Glomerular Filtration Rate, Hemodynamics, Histamine metabolism, Kidney metabolism
Abstract

The classification of diabetic nephropathy (DN) as a vascular complication of diabetes makes the possible involvement of histamine, an endogenous amine that is well known for its vasoactive properties, an interesting topic for study. The aim of the present review is to provide an extensive overview of the possible involvement of histamine in the onset and progression of DN. The evidence collected on the role of histamine in kidney function together with its well-known pleiotropic action suggest that this amine may act simultaneously on glomerular hyperfiltration, tubular inflammation, fibrosis development and tubular hypertrophy., (© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Published
2019
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