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Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID‐19), caused by SARS‐CoV‐2 virus. As ADP‐ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID‐19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell‐based experiments using multiple variants of SARS‐CoV‐2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti‐inflammatory properties of rucaparib were demonstrated in cell‐based models upon challenging with recombinant spike protein or SARS‐CoV‐2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID‐19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS‐CoV‐2 infection rate through binding to the conserved 493–498 amino acid region located in the spike‐ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA‐induced overexpression of cytokines was down‐regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID‐19. [ABSTRACT FROM AUTHOR]

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol‐induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol‐induced AP. Intact guinea‐pig pancreatic ducts were pre‐treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX‐809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi‐treated guinea‐pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose‐dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol‐induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol‐induced pancreatitis. This is the first in vivo pre‐clinical evidence of Orkambi efficacy in the treatment of alcohol‐induced AP. Key points: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role.The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3– secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development.CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol‐induced pancreatitis.CFTR modulators present a novel option in the pharmacotherapy of alcohol‐induced pancreatitis by enhancing pancreatic functions or preventing recurrence. [ABSTRACT FROM AUTHOR]

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Background and aims: Smoking is recognised as an independent risk factor in the development of chronic pancreatitis (CP). Cystic fibrosis transmembrane conductance regulator (CFTR) function and ductal fluid and bicarbonate secretion are also known to be impaired in CP, so it is crucial to understand the relationships between smoking, pancreatic ductal function and the development of CP. Methods: We measured sweat chloride (Cl–) concentrations in patients with and without CP, both smokers and non‐smokers, to assess CFTR activity. Serum heavy metal levels and tissue cadmium concentrations were determined by mass spectrometry in smoking and non‐smoking patients. Guinea pigs were exposed to cigarette smoke, and cigarette smoke extract (CSE) was prepared to characterise its effects on pancreatic HCO3– and fluid secretion and CFTR function. We administered cerulein to both the smoking and non‐smoking groups of mice to induce pancreatitis. Results: Sweat samples from smokers, both with and without CP, exhibited elevated Cl– concentrations compared to those from non‐smokers, indicating a decrease in CFTR activity due to smoking. Pancreatic tissues from smokers, regardless of CP status, displayed lower CFTR expression than those from non‐smokers. Serum levels of cadmium and mercury, as well as pancreatic tissue cadmium, were increased in smokers. Smoking, CSE, cadmium, mercury and nicotine all hindered fluid and HCO3– secretion and CFTR activity in pancreatic ductal cells. These effects were mediated by sustained increases in intracellular calcium ([Ca2+]i), depletion of intracellular ATP (ATPi) and mitochondrial membrane depolarisation. Conclusion: Smoking impairs pancreatic ductal function and contributes to the development of CP. Heavy metals, notably cadmium, play a significant role in the harmful effects of smoking. Key points: Smoking and cigarette smoke extract diminish pancreatic ductal fluid and HCO3– secretion as well as the expression and function of CFTRCd and Hg concentrations are significantly higher in the serum samples of smokersCd accumulates in the pancreatic tissue of smokers [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild‐type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO3− secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real‐time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme‐linked immunosorbent assay. Ductal fluid and HCO3− secretion, CFTR activity, and the expression of CFTR, Na+/H+ exchanger‐1, anoctamine‐1 and aquaporin‐1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO3− secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO3− secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO3− secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. Key points: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditionsThe most common disease affecting the endocrine part is type‐1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiencyCompared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO3− produced by ductal cells is essential for maintaining normal pancreatic functionsDuctal fluid and HCO3− secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role.We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue. [ABSTRACT FROM AUTHOR]

In this work, the effects of femtosecond laser irradiation and doping with plasmonic gold nanorods on the degree of conversion (DC) of a urethane dimethacrylate (UDMA)–triethylene glycol dimethacrylate (TEGDMA) nanocomposite were investigated. The UDMA-TEGDMA photopolymer was prepared in a 3:1 weight ratio and doped with dodecanethiol- (DDT) capped gold nanorods of 25 × 75 or 25 × 85 nm nominal diameter and length. It was found that the presence of the gold nanorods alone (without direct plasmonic excitation) can increase the DC of the photopolymer by 6–15%. This increase was found to be similar to what could be achieved with a control heat treatment of 30 min at 180 °C. It was also shown that femtosecond laser impulses (795 nm, 5 mJ pulse energy, 50 fs pulse length, 2.83 Jcm−2 fluence), applied after the photopolymerization under a standard dental curing lamp, can cause a 2–7% increase in the DC of undoped samples, even after thermal pre-treatment. The best DC values (12–15% increase) were obtained with combined nanorod doping and subsequent laser irradiation close to the plasmon resonance peak of the nanorods (760–800 nm), which proves that the excited plasmon field can directly facilitate double bond breakage (without thermoplasmonic effects due to the short pulse length) and increase the crosslink density independently from the initial photopolymerization process. [ABSTRACT FROM AUTHOR]