ATP12A Proton Pump as an Emerging Therapeutic Target in Cystic Fibrosis and Other Respiratory Diseases.

ATP12A encodes the catalytic subunit of the non-gastric proton pump, which is expressed in many epithelial tissues and mediates the secretion of protons in exchange for potassium ions. In the airways, ATP12A-dependent proton secretion contributes to complex mechanisms regulating the composition and properties of the fluid and mucus lining the respiratory epithelia, which are essential to maintain the airway host defense and the respiratory health. Increased expression and activity of ATP12A in combination with the loss of other balancing activities, such as the bicarbonate secretion mediated by CFTR, leads to excessive acidification of the airway surface liquid and mucus dysfunction, processes that play relevant roles in the pathogenesis of cystic fibrosis and other chronic inflammatory respiratory disorders. In this review, we summarize the findings dealing with ATP12A expression, function, and modulation in the airways, which led to the consideration of ATP12A as a potential therapeutic target for the treatment of cystic fibrosis and other airway diseases; we also highlight the current advances and gaps regarding the development of therapeutic strategies aimed at ATP12A inhibition.

Lupeol: A Triterpenoid Isolated from the Stem Bark of Hymenocardia Acida (tul.) Exhibits a van der Waal Antagonism on the Alpha Subunit of Gastric H+K+Atpase - A Promising Antiulcer Principle.

BACKGROUND: Hymenocardia acida (HA) is one of the numerous medicinal plants in Nigeria with ethnomedicinal history of usage in the treatment of ulcer. The study aimed at isolating antiulcer principle(s) from the stem bark of HA as well as the mechanism of action determination. METHODS: Antiulcer screenings of the crude extract, aqueous fraction, and bulked VLC fractions were performed using in vivo and in vitro models. Docking was carried out by using PyRx. RESULTS: Crude extract (HA; 1 mg/mL) and the aqueous fraction of H. acida (HAA; 1 mg/mL) showed an acid neutralizing capacity (MEq) of 0.3948 and 0.4035, respectively which is significantly different from 0.431 MEq showed by negative control (distilled water) at p<0.05. BVLC 3 (1 mg/mL) showed a significant value of 0.4049 MEq. However, HA showed a dose-dependent decrease in activity across doses examined, with 100 mg/kg showing an ulcer index of 10.00±2.89 (61.50%) and cimetidine (positive control; 100 mg/kg), also showed the highest ulcer index of 3.67±0.88 (85.9%), which is significantly different from ulcer index of 26.00±6.35 (0.00%) p<0.05 observed in the negative control (5% dimethylsulphoxide). The highest ulcer index of 8.00±1.32 (65.10%) was noted in BVLC 3. Bioactive BVLC 3, resulted in an isolated compound (BF3B2A). The compound was suggested to be lupeol, with a docking score of -7.7. It showed a van der Waal interaction with some key amino acid residues in the vonoprazan binding site. CONCLUSION: The experimental studies justify the ethnomedicinal claim of usage among locals.

The revolution of personalized pharmacotherapies for cystic fibrosis: what does the future hold?

INTRODUCTION: Cystic fibrosis (CF), a potentially fatal genetic disease, is caused by loss-of-function mutations in the gene encoding for the CFTR chloride/bicarbonate channel. Modulator drugs rescuing mutant CFTR traffic and function are now in the clinic, providing unprecedented breakthrough therapies for people with CF (PwCF) carrying specific genotypes. However, several CFTR variants are unresponsive to these therapies. AREA COVERED: We discussed several therapeutic approaches that are under development to tackle the fundamental cause of CF, including strategies targeting defective CFTR mRNA and/or protein expression and function. Alternatively, defective chloride secretion and dehydration in CF epithelia could be restored by exploiting pharmacological modulation of alternative targets, i.e., ion channels/transporters that concur with CFTR to maintain the airway surface liquid homeostasis (e.g., ENaC, TMEM16A, SLC26A4, SLC26A9, and ATP12A). Finally, we assessed progress and challenges in the development of gene-based therapies to replace or correct the mutant CFTR gene. EXPERT OPINION: CFTR modulators are benefiting many PwCF responsive to these drugs, yielding substantial improvements in various clinical outcomes. Meanwhile, the CF therapy development pipeline continues to expand with the development of novel CFTR modulators and alternative therapeutic strategies with the ultimate goal of providing effective therapies for all PwCF in the foreseeable future.

'Free' surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis.

AIM: Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. METHODS: Children aged <14 years were defined as 'coughers' if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough-sensitivity test was carried out in children aged >6 years before the endoscopy. RESULTS: Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 microg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough-sensitivity outcome measures. CONCLUSION: We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors.

Effectiveness of peripheral hepatogastrostomy versus hepatojejunostomy in the treatment of obstructive cholestasis: results of an experimental model.

PURPOSE: Tumors of the liver hilum frequently cause obstructive cholestasis. When a curative resection of the tumor is impossible, palliative bile drainage is indicated. A hepatojejunostomy is performed if conservative treatment fails or if irresectability is proven during an initial laparotomy. In patients with peritoneal carcinosis and mesentery retraction, a hepatogastrostomy may represent a helpful alternative. An experimental study was designed to compare the bile drainage effectiveness of a hepatogastrostomy versus a hepatojejunostomy. METHODS: Two-month-old outbred piglets were used in all experiments. The animals were randomized into three groups (hepatojejunostomy, hepatogastrostomy alone, hepatogastrostomy and proton pump inhibitors). Obstructive cholestasis was induced by common bile duct ligation; hepatojejunostomy and hepatogastrostomy were performed 2 weeks later. The serum bilirubin levels were monitored weekly. All animals were killed 4 weeks after the drainage operation. RESULTS: Following a hepatojejunostomy (n = 5) all animals showed decreasing cholestasis parameters. All animals (n = 3) died within 3-5 days after a hepatogastrostomy due to gastrointestinal bleeding caused by gastric ulcers and ulcers of the liver surface. The administration of pantoprazole prevented these bleeding complications. In animals treated by hepatogastrostomy and proton pump inhibitors (n = 5), bile drainage effectiveness was similar to that following hepatojejunostomy. CONCLUSION: A hepatogastrostomy represents an alternative treatment option for surgical bile drainage with a similar effectiveness to that of a hepatojejunostomy. To prevent postoperative gastrointestinal bleeding, proton pump inhibitors should be used.

Hydrogen-potassium ATPase inhibitors induce relaxation on rabbit prostatic strips in vitro.

BACKGROUND: To determine the relaxant effect of omeprazole and lansaprazole, hydrogen-potassium (H+-K+) ATPase inhibitors, on rabbit prostatic tissue in vitro. METHODS: Male New Zealand white rabbits were sacrificed and their prostatic tissues were removed. The prostatic stromal strips were mounted in organ baths and relaxation responses were obtained in precontracted tissues with phenylephrine, carbachol and potassium chloride (KCl). Relaxation responses were controlled in the presence of various antagonists to explain the mechanism for relaxation exerted by omeprazole and lansaprazole. RESULTS: Omeprazole and lansaprazole caused similar relaxation responses in the prostatic strips precontracted with phenylephrine, carbachol and KCl. The addition of prostaglandin synthase inhibitor indomethacin, nitric oxide synthase inhibitor L-NAME, potassium channel blockers, glibenclamide and tetraethylammonium into the organ baths did not change the relaxations induced by omeprazole and lansaprazole in vitro. CONCLUSION: Omeprazole and lansaprazole cause a relaxation in prostatic stromal tissue precontracted with phenyephrine, carbachol and KC1 in vitro. This relaxant effect is independent of H+-K+ ATPase inhibition. Additionally, cyclooxygenase and nitric oxide pathways do not contribute to this relaxant effect. Further studies are required to determine whether these drugs may have a beneficial effect in the non-operative treatment of benign prostatic hyperplasia.

[A clinical trial of lansoprazole in the treatment of duodenal ulcer].

To evaluate the efficacy of a second generation acid pump inhibitor-lansoprazole (L) a controlled clinical trial in 72 patients of duodenal ulcer was carried out with omeprazole (O) as control. The results showed that the ulcer healing rate after 4-week treatment was 97.4% in lansoprazole group and 91.2% in omeprazole, while the effective rate was 100% and 97.1% respectively (P > 0.05). Ulcer related pain was relieved more quickly in lansoprazole group. The pain relief rate after treatment of 3 days was different significantly between the two group, being 74.3% (L) and 51.6% (O) respectively (P < 0.05). No marked side-effect was observed in lansoprazole group. It is shown that lansoprazole is effective and safe for treatment of duodenal ulcer.