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Background: Valproic acid [VA] is an antiepileptic drug that is extensively prescribed for many neurological disorders. Its use is associated with serious pancreatic complications. Marjoram oil [MO] is a health protective agent with proved anti-oxidant activity.Aim: Study of the effect of valproic acid on pancreas of adult male albino rats exploring novel mechanisms of VA-induced pancreatic damage and to evaluate the potential protective role of marjoram oil. Materials and Methods: Fifty adult male albino rats were used as a control group, a valproic acid group and a valproic acid-marjoram group. Both VA [200mg/kg] and MO [0.5ml/kg] were given once a day orally for eight weeks. Specimens of the pancreas were processed for light and electron microscopic studies. Immunohistochemical study was performed using anti-P53 antibodies. Results: Specimens of the valproic acid group showed an obvious distortion in the pancreatic acini as well as the islets of Langerhans. The acinar and islets cells showed cytoplasmic vacuoles and pyknotic nuclei. Large autophagic vacuoles containing an acidophilic material appeared in many cells. Dilated ducts and blood vessels were seen. There was a significant increase in the P53-immunoreaction of the acinar and islets cells and a significant decrease in the number of the zymogen granules of the acinar cells. Ultrastructurally, there were shrunken nuclei with irregularity, dilated rough endoplasmic reticulum and swollen mitochondria in the acinar cells and beta cells. In contrast, minimal changes occurred in the valproic acid-marjoram group that received MO before VA. Conclusion: Valproic acid administration to albino rats resulted in significant structural alterations in the pancreas. Marjoram oil attenuated VA effect and preserved the pancreas structure.

The ubiquitin-proteasome pathway (UPP) and autophagy play integral roles in cellular homeostasis. As part of their normal life cycle, most proteins undergo ubiquitination for some form of redistribution, localization and/or functional modulation. However, ubiquitination is also important to the UPP and several autophagic processes. The UPP is initiated after specific lysine residues of short-lived, damaged or misfolded proteins are conjugated to ubiquitin, which targets these proteins to proteasomes. Autophagy is the endosomal/lysosomal-dependent degradation of organelles, invading microbes, zymogen granules and macromolecules such as protein, carbohydrates and lipids. Autophagy can be broadly separated into three distinct subtypes termed microautophagy, chaperone-mediated autophagy and macroautophagy. Although autophagy was once thought of as non-selective bulk degradation, advancements in the field have led to the discovery of several selective forms of autophagy. Here, we focus on the mechanisms of primary and selective mammalian autophagy pathways and highlight the current knowledge gaps in these molecular pathways.

Primary cilia protrude from the apical surface of many cell types and act as a sensory organelle that regulates diverse biological processes ranging from chemo- and mechanosensation to signaling. Ciliary dysfunction is associated with a wide array of genetic disorders, known as ciliopathies. Polycystic lesions are commonly found in the kidney, liver, and pancreas of ciliopathy patients and mouse models. However, the pathogenesis of the pancreatic phenotype remains poorly understood. Chibby1 (Cby1), a small conserved coiled-coil protein, localizes to the ciliary base and plays a crucial role in ciliogenesis. Here, we report that Cby1-knockout (KO) mice develop severe exocrine pancreatic atrophy with dilated ducts during early postnatal development. A significant reduction in the number and length of cilia was observed in Cby1-KO pancreta. In the adult Cby1-KO pancreas, inflammatory cell infiltration and fibrosis were noticeable. Intriguingly, Cby1-KO acinar cells showed an accumulation of zymogen granules (ZGs) with altered polarity. Moreover, isolated acini from Cby1-KO pancreas exhibited defective ZG secretion in vitro. Collectively, our results suggest that, upon loss of Cby1, concomitant with ciliary defects, acinar cells accumulate ZGs due to defective exocytosis, leading to cell death and progressive exocrine pancreatic degeneration after birth.

The ability of the new coronavirus SARS‐CoV‐2 to spread and contaminate is one of the determinants of the COVID‐19 pandemic status. SARS‐CoV‐2 has been detected in saliva consistently, with similar sensitivity to that observed in nasopharyngeal swabs. We conducted ultrasound‐guided postmortem biopsies in COVID‐19 fatal cases. Samples of salivary glands (SGs; parotid, submandibular, and minor) were obtained. We analyzed samples using RT‐qPCR, immunohistochemistry, electron microscopy, and histopathological analysis to identify SARS‐CoV‐2 and elucidate qualitative and quantitative viral profiles in salivary glands. The study included 13 female and 11 male patients, with a mean age of 53.12 years (range 8–83 years). RT‐qPCR for SARS‐CoV‐2 was positive in 30 SG samples from 18 patients (60% of total SG samples and 75% of all cases). Ultrastructural analyses showed spherical 70–100 nm viral particles, consistent in size and shape with the Coronaviridae family, in the ductal lining cell cytoplasm, acinar cells, and ductal lumen of SGs. There was also degeneration of organelles in infected cells and the presence of a cluster of nucleocapsids, which suggests viral replication in SG cells. Qualitative histopathological analysis showed morphologic alterations in the duct lining epithelium characterized by cytoplasmic and nuclear vacuolization, as well as nuclear pleomorphism. Acinar cells showed degenerative changes of the zymogen granules and enlarged nuclei. Ductal epithelium and serous acinar cells showed intense expression of ACE2 and TMPRSS receptors. An anti‐SARS‐CoV‐2 antibody was positive in 8 (53%) of the 15 tested cases in duct lining epithelial cells and acinar cells of major SGs. Only two minor salivary glands were positive for SARS‐CoV‐2 by immunohistochemistry. Salivary glands are a reservoir for SARS‐CoV‐2 and provide a pathophysiological background for studies that indicate the use of saliva as a diagnostic method for COVID‐19 and highlight this biological fluid's role in spreading the disease. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Secretory carcinoma (SC) is a rare salivary gland tumor that was first specified in the 2017 classification of head and neck cancers by the World Health Organization. Most SCs arise in the parotid gland and rarely in the minor salivary glands. We report a clinical case of SC under the buccal mucosa that was initially considered to be a benign tumor. The patient had noticed the mass under the buccal mucosa 2 months earlier. It was clinically diagnosed as a benign tumor and excised under local anesthesia. Histopathological examination revealed that tumor cells had eosinophilic cytoplasm without zymogen granules and proliferated in the form of micropapillary or cribriform. Immunohistochemical study revealed that tumor cells were positive for S-100, mammaglobin, and vimentin. Fluorescence in situ hybridization (FISH) revealed split of the ETV6 gene in tumor cells. These results confirmed that the tumor was a SC. No additional treatment was performed because the tumor was small and no residual tumor was observed. No recurrence or metastasis was observed during the 1.5 years of postoperative follow-up duration.

Zymogen granule protein 16B (ZG16B) has been identified in various cancers, while so far the association between ZG16B and breast cancer hasn’t been explored. Our aim is to confirm whether it can serve as a prognostic biomarker in breast cancer. In this study, Oncomine, Cancer Cell Line Encyclopedia (CCLE), Ualcan, and STRING database analyses were conducted to detect the expression level of ZG16B in breast cancer with different types. Kaplan–Meier plotter was used to analyze the prognosis of patients with high or low expression of ZG16B. We found that ZG16B was significantly upregulated in breast cancer. Moreover, ZG16B was closely associated with foregone biomarkers and crucial factors in breast cancer. In the survival analysis, high expression of ZG16B represents a favorable prognosis in patients. Our work demonstrates the latent capacity of ZG16B to be a biomarker for prognosis of breast cancer.

Background: Chronic pancreatitis is a progressive inflammatory disease that causes damage and fibrosis of the parenchyma of pancreas, thus leads to endocrine and exocrine dysfunction. Objective: The goals of this review were to analyze morphological alterations in pancreatic tissue during chronic pancreatitis and this analysis addresses the effect of pancreatic stellate cells (PSCs), on chronic pancreatitis, and collagen fiber deposition. Results: This review also discussed the different immunohistochemical markers for PSCs. Alpha smooth muscle actin (α-SMA) is an excellent marker for activated PSCs. Transforming growth factor beta (TGFβ) is an important profibrogenic cytokine that appears to act by stimulating collagen production by PSCs. Conclusion: It was concluded that chronic pancreatitis caused a significant and progressive serious effects on the acinar cells, duct system, and islets of Langerhans in the form of intracellular vacuolations, decreased zymogen granules, pyknotic nuclei and thickening of the duct wall, and extensive fibrosis. It is hypothesised that during pancreatic injury, PSCs are activated and proliferated exhibiting positive staining for the cytoskeletal protein α- SMA, and synthesising amounts of extracellular matrix proteins, particularly collagen.

Purpose Since the original description of “dacryadenoma” by Jakobiec and associates, the data on this unusual epibulbar lacrimal gland lesion remain sparse. The aim of this study was to characterize clinically, morphologically, and immunohistochemically this isolated epibulbar lacrimal gland lesion. Design Retrospective observational case series. Methods Institutional pathology records between 2000 and 2019 were searched for all cases of isolated epibulbar lacrimal gland lesions. Tissue from 3 normal lacrimal glands and 1 complex choristoma were included for comparative analysis. Clinical, histopathologic, and immunohistochemical findings were recorded. Results Four patients with isolated epibulbar lacrimal gland lesions, 2 male and 2 female, with a median age of 18 years (range, 12-57) were identified. All patients presented with recent onset of unilateral pink-to-orange, well-circumscribed subepithelial juxtaforniceal (3/4, 75%), or nasal (1/4, 25%) bulbar conjunctival nodules, which were asymptomatic (3/4, 75%) or associated with foreign body sensation (1/4, 25%). When compared with the normal lacrimal gland and complex choristoma, all isolated epibulbar lacrimal gland lesions were composed predominantly of variably dilated, branching tubular structures with pseudo-apocrine snouts, and either totally absent (2/2, 50%) or rare (2/2, 50%) ducts and rare acinar zymogen granules (3/4, 75%). Conclusion Our study confirms that a subset of isolated epibulbar lacrimal gland lesions differs morphologically and immunohistochemically from normal lacrimal gland tissue and the lacrimal gland in a complex choristoma. These differences range from subtle to overt, suggesting that isolated epibulbar lacrimal gland lesions may have originated from precursor cellular elements indigenous to the conjunctiva (hamartia) and grew into disorganized lacrimal gland tissue.

Aim: The current study evaluates the important role of Nigella Sativa against cadmium (Cd) induced toxic changes in pancreasof rats.Materials and Methods: Eighteen adult Wistar albino rats were divided into three equal groups. Control group, cadmiumtreated group that received 5 mg CdCl2/kg BW/day dissolved in water orally for three months, and cadmium with Nigellasativa (NS) group received a mixture of 1g/kg/day of aqueous suspension of Nigella sativa seeds powder and 5 mgCdCl2/kg BW/day dissolved in water for three consecutive months. Hormonal assay of insulin was done. Pancreatic tissueswere prepared for both Hematoxylin and Eosin and toluidine blue. Electron microscopic study of pancreatic tissues was alsodone.Results: The present study showed that the administration of CdCl2 induced evident decrease in insulin serum level. Thebiochemical results were confirmed by histological investigations where degenerative changes of pancreatic acini with lossof normal lobular architecture, distorted pancreatic acini, degenerated and widely separated cells in the islets of Langerhans,blood vessels congestion and aggregation of perivascular cellular infiltrates were detected in pancreatic tissues stained withH&E. Toluidine blue-stained sections showed few deeply stained apical zymogen granules in some acini, whereas other acinishowed absence of these granules.Administration of NS with CdCl2 showed a significant improvement in the measured serum insulin level and histologicalpictures.Conclusion: CdCl2 induced several toxic changes in the exocrine and endocrine parts of pancreas of rats. NS could protect thepancreas against these alterations.

The aim of this research work was to study the histological structure of the pancreatic acini by transmission electron microscope in two avian species, duck and pigeon. The specimens were collected and processed for electron microscopic study. The results showed that the acini of the two avian species were two types; the first one was an electron dense and the second one an electron lucent. The light acinar cells were larger in size than the dark cells. These cells contained centrally located ovoid nuclei with prominent nucleoli and abundant euchromatin. The cytoplasm was electron lucent, with many rough endoplasmic reticulum, polymorphic mitochondria. Numerous zymogen granules were distributed in the basal part and around the nucleus, so these cells considered active cells. The dark acinar cells were characterized by an electron dense cytoplasm. The most prominent cell organelle in these cells were the zymogen granules that appeared in different sizes while other organelles as mitochondria, and rough endoplasmic reticulum were inconspicuous or few, so these cells were considered as inactive cells. The nucleus with indented nuclear membrane located centrally with prominent nucleoli and abundant heterochromatin. Prominent intercellular spaces between the individual acinar cells, as well as well-developed basement membrane separating the electron dense cells and the lumen contained the secretion between acinar cells. It could be concluded that the acinar cells in ducks and pigeons were divided into two types, that is, light and dark acinar cells which mainly attributed to the activity of these cells.

Background & Aims Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis. Methods Using a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice. Results We found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues. Conclusions our results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcohol-induced pancreatitis.

The current study was designed to perform a transmission electron microscopic investigation focusing on the dark and light pancreatic acinar β-cells of young domesticated pig (Sus Suidae).This study depended on the fresh pancreatic specimens from 5 healthy young (2-month-old) pigs that were collected immediately after they were slaughtered at the abattoir of Abdelkader Alexandria, Egypt.In our findings, the acinar pancreas was formed of pyramidal pancreatic acinar cells with large spherical nuclei of condensed heterochromatin at the periphery and prominent eccentric nucleoli. Zymogen granules were observed at the apical region of the acinar cells, and they appear as electron dense bodies. Numerous mitochondria and Golgi complexes observed in the acinar cell cytoplasm. The electron dense acinar cells were joined by junctional complexes. The rough endoplasmic reticulum was more prominent in the electron-dense acinar cells than did electron-lucent acinar cells. There was no connective tissue capsule separate the acinar portion of pancreas from the pancreatic islets. The pancreatic islets mainly formed of β-cells. The irregular α-cells possess numerous small granules. The cytoplasmic β-cells granules were surrounded by hallow area and enclosed by a limiting membrane. Delta cells were generally polygonal in shape and found in clumps throughout the islet and they were also identified in between β-cells. Their granules were of moderate electron density and were generally smaller than β-cells' granules. The limiting membrane was tightly enclosed the delta cells granules and the hallow area around the granule were found similar to the granules of β-cells.

Funder: AstraZeneca; Id: http://dx.doi.org/10.13039/100004325, Funder: David James Studentship, Department of Pharmacology, University of Cambridge, Syncollin is a 16‐kDa protein found predominantly in the zymogen granules of pancreatic acinar cells, with expression at lower levels in intestinal epithelial cells and neutrophils. Here, we used Strep‐tagged syncollin isolated from the supernatant of transiently transfected mammalian cells to test the hypothesis that syncollin has antibacterial properties, which might enable it to play a role in host defence in the gut and possibly elsewhere. We show that syncollin is an exceptionally thermostable protein with a circular dichroism spectrum consistent with a predominantly beta‐sheet structure. Syncollin binds to bacterial peptidoglycan and restricts the growth of representative Gram‐positive (Lactococcus lactis) and Gram‐negative (Escherichia coli) bacteria. Syncollin induces propidium iodide uptake into E. coli (but not L. lactis), indicating permeabilisation of the bacterial membrane. It also causes surface structural damage in both L. lactis and E. coli, as visualised by scanning electron microscopy. We propose that syncollin is a previously unidentified member of a large group of antimicrobial polypeptides that control the gut microbiome. Take Aways: Syncollin is a 16‐kDa protein found in pancreatic zymogen granules. Syncollin is highly thermostable and has a predominantly beta‐sheet structure. Syncollin binds peptidoglycan and restricts the growth of L. lactis and E. coli. Syncollin causes propidium iodide uptake into E. coli (but not L. lactis). Syncollin causes surface structural damage in both L. lactis and E. coli.

We herein describe a rare case of low-grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha-1-antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen-type granules (600-800 nm in diameter) in the acinic cell component, whereas neuroendocrine-type granules (200-300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen-type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.